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CitationGPTv2_test

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CitationGPTRetr0

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Behavioral and cognitive effects of tyrosine intake in healthy human adults. Abstract of the paper: The amino acid tyrosine is the precursor to the catecholamine neurotransmitters dopamine and norepinephrine. Increasing tyrosine uptake may positively influence catecholamine-related psychological functioning. We conducted a systematic review to examine the effects of tyrosine on behavior and cognition. Fifteen studies were reviewed. All studies except one involved tyrosine loading during a single test session. In most behavioral studies, there were no significant effects of tyrosine on exercise performance. In contrast, cognitive studies employing neuropsychological measures found that tyrosine loading acutely counteracts decrements in working memory and information processing that are induced by demanding situational conditions such as extreme weather or cognitive load. The buffering effects of tyrosine on cognition may be explained by tyrosine's ability to neutralize depleted brain catecholamine levels. There is evidence that tyrosine may benefit healthy individuals exposed to demanding situational conditions. For future research we recommend moving from studying the acute effects of a single tyrosine load in small samples to studying the behavioral and cognitive effects of tyrosine in larger groups over multiple weeks.

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CitationGPTRetr1

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. Abstract of the paper: Aromatic amino acids in the brain function as precursors for the monoamine neurotransmitters serotonin (substrate tryptophan) and the catecholamines [dopamine, norepinephrine, epinephrine; substrate tyrosine (Tyr)]. Unlike almost all other neurotransmitter biosynthetic pathways, the rates of synthesis of serotonin and catecholamines in the brain are sensitive to local substrate concentrations, particularly in the ranges normally found in vivo. As a consequence, physiologic factors that influence brain pools of these amino acids, notably diet, influence their rates of conversion to neurotransmitter products, with functional consequences. This review focuses on Tyr and phenylalanine (Phe). Elevating brain Tyr concentrations stimulates catecholamine production, an effect exclusive to actively firing neurons. Increasing the amount of protein ingested, acutely (single meal) or chronically (intake over several days), raises brain Tyr concentrations and stimulates catecholamine synthesis. Phe, like Tyr, is a substrate for Tyr hydroxylase, the enzyme catalyzing the rate-limiting step in catecholamine synthesis. Tyr is the preferred substrate; consequently, unless Tyr concentrations are abnormally low, variations in Phe concentration do not affect catecholamine synthesis. Unlike Tyr, Phe does not demonstrate substrate inhibition. Hence, high concentrations of Phe do not inhibit catecholamine synthesis and probably are not responsible for the low production of catecholamines in subjects with phenylketonuria. Whereas neuronal catecholamine release varies directly with Tyr-induced changes in catecholamine synthesis, and brain functions linked pharmacologically to catecholamine neurons are predictably altered, the physiologic functions that utilize the link between Tyr supply and catecholamine synthesis/release are presently unknown. An attractive candidate is the passive monitoring of protein intake to influence protein-seeking behavior.

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CitationGPTRetr2

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: The effects of dietary neurotransmitter precursors on human behavior. Abstract of the paper: The neurotransmitter precursors tryptophan and tyrosine are present in a variety of foods. In order to document possible effects of tryptophan and tyrosine on human behavior, single oral doses of these substances and matched placebos were administered to 20 men in a double-blind, crossover study. Various tests of mood state and performance were then administered. Tryptophan increased subjective fatigue and decreased self-ratings of vigor and alertness, but did not impair performance on any of the tests. Tyrosine produced no effects in our young population compared with placebo, but did decrease reaction time relative to tryptophan. It may be concluded that tryptophan has significant sedative-like properties, but unlike other sedatives may not impair performance.

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CitationGPTRetr3

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Changes in catecholamine excretion after short-term tyrosine ingestion in normally fed human subjects. Abstract of the paper: The effects of ingesting the aromatic amino acid L-tyrosine on excretion of unconjugated catecholamines (dopamine, norepinephrine, and epinephrine) and tyrosine were studied. (Tyrosine is the circulating precursor for the catecholamines, but only a small fraction of the tyrosine in the body is utilized for catecholamine synthesis.) In 10 of 11 normal volunteer subjects, ingestion of 100 mg/kg tyrosine (in three divided doses, preceding each meal, between 8 AM and 5 PM) for 1 day increased the 24-h excretions of total catecholamines by 25%. Only 0.42% of the tyrosine dose was excreted unchanged, but this was sufficient to increase urinary tyrosine by 138%. Both tyrosine and catecholamine excretions varied diurnally; 60% or more of the total output occurred during the day. Since urinary catecholamines reflect molecules synthesized outside the central nervous system, these findings indicate that tyrosine administration can accelerate catecholamine synthesis in the human sympathoadrenal system, probably by enhancing saturation of tyrosine hydroxylase. Therefore, tyrosine may be useful therapeutically in diseases characterized by peripheral catecholamine deficiencies.

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CitationGPTRetr4

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Dietary amino acids and brain function. Abstract of the paper: Two groups of amino acids--the aromatic and the acidic amino acids--are reputed to influence brain function when their ingestion in food changes the levels of these amino acids in the brain. The aromatic amino acids (tryptophan, tyrosine, phenylalanine) are the biosynthetic precursors for the neurotransmitters serotonin, dopamine, and norepinephrine. Single meals, depending on their protein content, can rapidly influence uptake of aromatic amino acid into the brain and, as a result, directly modify their conversion to neurotransmitters. Such alterations in the production of transmitters can directly modify their release from neurons and, thus, influence brain function. The acidic amino acids glutamate and aspartate are themselves brain neurotransmitters. However, they do not have ready access to the brain from the circulation or the diet. As a result, the ingestion of proteins, which are naturally rich in aspartate and glutamate, has no effect on the level of acidic amino acid in the brain (or, thus, on brain function by this mechanism). Nevertheless, the food additives monosodium glutamate and aspartame (which contains aspartate) have been reputed to raise the level of acidic amino acid in the brain (when ingested in enormous amounts), to modify brain function, and even to cause neuronal damage. Despite such claims, a substantial body of published evidence clearly indicates that the brain is not affected by ingestion of aspartame and is affected by glutamate only when the amino acid is administered alone in extremely large doses. Therefore, when consumed in the diet neither compound presents a risk to normal brain function.

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CitationGPTRetr5

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Abstract of the paper: Acutely stressful situations can disrupt behavior and deplete brain norepinephrine and dopamine, catecholaminergic neurotransmitters. In animals, administration of tyrosine, a food constituent and precursor of the catecholamines, reduces these behavioral and neurochemical deficits. Using a double-blind, placebo-controlled crossover design we investigated whether tyrosine (100 mg/kg) would protect humans from some of the adverse consequences of a 4.5 hour exposure to cold and hypoxia. Tyrosine significantly decreased symptoms, adverse moods, and performance impairments in subjects who exhibited average or greater responses to these environmental conditions. These results suggest that tyrosine should be evaluated in a variety of acutely stressful situations.

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CitationGPTRetr6

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Effects of tyrosine and tryptophan ingestion on plasma catecholamine and 3,4-dihydroxyphenylacetic acid concentrations. Abstract of the paper: The effect of oral tyrosine or tryptophan ingestion on plasma concentrations of norepinephrine (NE), dopamine (DA), epinephrine (EPI), and 3,4-dihydroxyphenylacetic acid (DOPAC) was investigated in a double blind, placebo-controlled study in fasted men. Tyrosine ingestion induced within 45 min a significant but short-lasting (approximately 30 min) increase in plasma concentrations of NE, EPI, and DA and a coincident decrease in plasma DOPAC levels. Ingestion of tryptophan or lactose placebo did not after plasma DA, EPI, NE, or DOPAC levels. Since plasma catecholamines derive from peripheral sources, while circulating DOPAC may reflect both brain and peripheral DA turnover, these results suggest that the oral ingestion of tyrosine can exert acute effects on catecholamine systems within and outside the brain.

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CitationGPTRetr7

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Brain catechol synthesis: control by train tyrosine concentration. Abstract of the paper: Brain catechol synthesis was estimated by measuring the rate at which brain dopa levels rose following decarboxylase inhibition. Dopa accumulation was accelerated by tyrosine administration, and decreased by treatments that lowered brain tyrosine concentrations (for example, intraperitoneal tryptophan, leucine, or parachlorophenylalanine). A low dose of phenylalanine elevated brain tyrosine without accelerating dopa synthesis. Our findings raise the possibility that nutritional and endocrine factors might influence brain catecholamine synthesis by controlling the availability of tyrosine.

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CitationGPTRetr8

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Tyrosine depletion attenuates dopamine function in healthy volunteers. Abstract of the paper: RATIONALE Tyrosine depletion has been shown to reduce dopamine over activity in animal and human investigations. However, the effects on basal dopamine function have not been explored. Such information could establish tyrosine depletion as an effective probe of dopamine function in healthy volunteers and would also have relevance for future therapeutic applications of this manipulation. OBJECTIVE The present study investigated the effect of acute tyrosine depletion on dopamine function in healthy volunteers using a combination of neuroendocrine, neuropsychological and subjective measures. METHODS On one occasion, volunteers received an amino acid drink selectively lacking tyrosine and phenylalanine (TYR-free), whilst on the other they received a balanced (BAL) amino acid drink. Plasma prolactin, amino acid levels and subjective state were monitored over 6 h following the two drinks, and volunteers also completed a battery of tests from the CANTAB, including measures of spatial memory previously found to be sensitive to changes in dopamine function. RESULTS Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, indicative of decreased dopamine neurotransmission within the hypothalamus. Following the TYR-free drink, volunteers were impaired at spatial recognition memory and spatial working memory. Volunteers also tended to report that they felt less good following the TYR-free than the BAL mixture. CONCLUSION Tyrosine depletion in healthy volunteers affected baseline dopamine function on the different measures employed in this study. Tyrosine depletion would thereby seem valuable as a probe of dopamine function in human volunteers. Ratings of depression and other aspects of cognitive function were unaffected, suggesting that this manipulation may be free of significant side effects when used as a treatment for conditions characterised by dopamine over activity, such as acute mania and schizophrenia.

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CitationGPTRetr9

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Tyrosine improves cognitive performance and reduces blood pressure in cadets after one week of a combat training course. Abstract of the paper: The effects of the amino acid tyrosine on cognitive task performance were studied on a group of 21 cadets during a demanding military combat training course. In addition, the effects on mood, blood pressure and the norepinephrine metabolite MHPG were determined. Ten subjects received five daily doses of a protein-rich drink containing 2 g tyrosine, and 11 subjects received a carbohydrate rich drink with the same amount of calories (255 kcal). Assessments were made both immediately prior to the combat course and on the 6th day of the course. The group supplied with the tyrosine-rich drink performed better on a memory and a tracking task than the group supplied with the carbohydrate-rich drink. In addition, the supplementation of tyrosine decreased systolic blood pressure. No effects on mood were found. These findings suggest that supplementation with tyrosine may, under operational circumstances characterized by psychosocial and physical stress, reduce the effects of stress and fatigue on cognitive task performance.

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CitationGPTRetr10

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Food for thought: association between dietary tyrosine and cognitive performance in younger and older adults. Abstract of the paper: The fact that tyrosine increases dopamine availability that, in turn, may enhance cognitive performance has led to numerous studies on healthy young participants taking tyrosine as a food supplement. As a result of this dietary intervention, participants show performance increases in working memory and executive functions. However, the potential association between habitual dietary tyrosine intake and cognitive performance has not been investigated to date. The present study aims at clarifying the association of episodic memory (EM), working memory (WM) and fluid intelligence (Gf), and tyrosine intake in younger and older adults. To this end, we acquired habitual tyrosine intake (food frequency questionnaire) from 1724 participants of the Berlin Aging Study II (1383 older adults, 341 younger adults) and modelled its relations to cognitive performance assessed in a broad battery of cognitive tasks using structural equation modeling. We observed a significant association between tyrosine intake and the latent factor capturing WM, Gf, and EM in the younger and the older sample. Due to partial strong factorial invariance between age groups for a confirmatory factor analysis on cognitive performance, we were able to compare the relationship between tyrosine and cognition between age groups and found no difference. Above and beyond previous studies on tyrosine food supplementation the present result extend this to a cross-sectional association between habitual tyrosine intake levels in daily nutrition and cognitive performance (WM, Gf, and EM). This corroborates nutritional recommendations that are thus far derived from single-dose administration studies.

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CitationGPTRetr11

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Effect of tyrosine on cognitive function and blood pressure under stress. Abstract of the paper: The effects of tyrosine on mood, performance, heart rate and blood pressure of 16 healthy young subjects were assessed. Subjects were tested on two separate days, one test session after ingestion of 100 mg/kg tyrosine and the other test session after placebo, in random order. While performing a number of stress sensitive tasks, subjects were exposed to a stressor consisting of 90 dB noise. Tyrosine was found to improve the performance on two cognitive tasks, which were performed 1 h after administration of the medication and which could be characterized as highly sensitive to stress. In addition, tyrosine decreased diastolic blood pressure 15 min after ingestion, while 1 h after ingestion diastolic blood pressure was the same with tyrosine and placebo. No effects on mood, systolic blood pressure and heart rate were found.

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CitationGPTRetr12

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Literature review on the role of dietary protein and amino acids in cognitive functioning and cognitive decline. Abstract of the paper: As the population of elderly people is growing rapidly, the number of individuals with dementia and cognitive impairment is also increasing. One of the preventive measures against cognitive decline is diet and different dietary factors have already been investigated. This review provides an overview of studies on dietary protein and cognitive functioning and cognitive decline. Also studies on the individual amino acids that are related to brain function, tryptophan and tyrosine, are discussed. Overall, the role of dietary protein intake on cognitive functioning as well as cognitive decline has hardly been studied; we found eight observational studies and three intervention studies. More studies investigated the role of tryptophan (14 studies) and tyrosine (nine studies) in relation to cognitive functioning, but all these studies were performed in young adult populations and mostly under special conditions. Research in elderly populations, in particular, is warranted. Also more research is needed to come to definitive conclusions and specific recommendations regarding protein intake or intake of specific amino acids for maintaining optimal cognitive functioning.

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CitationGPTRetr13

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Dietary Neurotransmitters: A Narrative Review on Current Knowledge. Abstract of the paper: Foods are natural sources of substances that may exert crucial effects on the nervous system in humans. Some of these substances are the neurotransmitters (NTs) acetylcholine (ACh), the modified amino acids glutamate and γ-aminobutyric acid (GABA), and the biogenic amines dopamine, serotonin (5-HT), and histamine. In neuropsychiatry, progressive integration of dietary approaches in clinical routine made it necessary to discern the more about some of these dietary NTs. Relevant books and literature from PubMed and Scopus databases were searched for data on food sources of Ach, glutamate, GABA, dopamine, 5-HT, and histamine. Different animal foods, fruits, edible plants, roots, and botanicals were reported to contain NTs. These substances can either be naturally present, as part of essential metabolic processes and ecological interactions, or derive from controlled/uncontrolled food technology processes. Ripening time, methods of preservation and cooking, and microbial activity further contributes to NTs. Moreover, gut microbiota are considerable sources of NTs. However, the significance of dietary NTs intake needs to be further investigated as there are no significant data on their bioavailability, neuronal/non neuronal effects, or clinical implications. Evidence-based interventions studies should be encouraged.

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CitationGPTRetr14

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: The role of prefrontal catecholamines in attention and working memory. Abstract of the paper: While much progress has been made in identifying the brain regions and neurochemical systems involved in the cognitive processes disrupted in mental illnesses, to date, the level of detail at which neurobiologists can describe the chain of events giving rise to cognitive functions is very rudimentary. Much of the intense interest in understanding cognitive functions is motivated by the hope that it might be possible to understand these complex functions at the level of neurons and neural circuits. Here, we review the current state of the literature regarding how modulations in catecholamine levels within the prefrontal cortex (PFC) alter the neuronal and behavioral correlates of cognitive functions, particularly attention and working memory.

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CitationGPTRetr15

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Monoaminergic neurotransmitters, their precursors and metabolites in brains of Alzheimer patients. Abstract of the paper: The catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A), their aminoacid precursors tyrosine (Tyr), L-3,4-dihydroxyphenylalanine (L-DOPA), two of their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy phenyl glycol (MHPG), serotonin (5-HT) and its precursor tryptophan (Trp), were measured by high pressure liquid chromatography (HPLC) with electrochemical detection in seven regions (globus pallidus, putamen, nucleus amygdalae, nucleus caudatus, substantia nigra, gyrus cinguli and raphe) of postmortem brains from eight histologically verified cases with Alzheimer's disease (AD) and six histologically normal controls. Concentrations of L-DOPA, DA, DOPAC, NA and 5-HT were significantly reduced, while Tyr and MHPG concentrations were significantly increased in AD versus control patients. The concentrations of Trp and A in AD patients were not significantly different from controls. Furthermore, for most brain regions examined, significant negative correlations between Tyr and DA as well as between NA and MHPG levels were found. These data confirm and extend findings of monoaminergic systems disturbances in AD, emphasize the significance of dopaminergic deficit for AD and suggest that in pharmacotherapy of AD, attempts to restore deficits of the transmitter systems should be directed to the monoaminergic, in particular the dopaminergic system.

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CitationGPTRetr16

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Serum tyrosine is associated with better cognition in Lewy body dementia. Abstract of the paper: Amino acids' neuroactivity, and roles in excitotoxity and oxidative stress are linked to dementia. We aimed to investigate whether circulating amino acid concentrations were associated with cognitive decline in patients with mild Alzheimer's disease (AD) and Lewy body dementia (LBD). Baseline serum amino acid concentrations were measured in 89 patients with AD and 65 with LBD (13 with Parkinson's disease dementia and 52 with dementia with Lewy bodies). The Mini-Mental State Examination (MMSE) was administered at baseline and annually for five years. Associations between baseline amino acid concentrations and longitudinal MMSE score were assessed using a linear-mixed effects model stratified by diagnosis with adjustment for multiple comparisons. The results of the study indicated that serum tyrosine was positively associated with MMSE performance during the five-year follow-up period in patients with LBD (q-value = 0.012), but not AD. In conclusion, higher baseline serum concentrations of tyrosine, the precursor amino acid in dopamine and norepinephrine synthesis, was associated with better cognitive performance in patients with LBD, but not AD, throughout the 5-year follow-up period.

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CitationGPTRetr17

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Catecholamine and second messenger influences on prefrontal cortical networks of "representational knowledge": a rational bridge between genetics and the symptoms of mental illness. Abstract of the paper: Both dopamine (DA) and norepinephrine (NE) have powerful, inverted U influences on prefrontal cortical (PFC) cognitive function. Optimal NE levels engage alpha2A-adrenoceptors and increase "signals" via inhibition of cAMP-HCN (cAMP-hyperpolarization-activated cyclic nucleotide-gated cation channel) signaling near preferred inputs, whereas optimal levels of DA D1 receptor stimulation decrease "noise" by increasing cAMP signaling near nonpreferred inputs. Excessive levels of catecholamine release during stress impair working memory 1) by very high levels of cAMP-HCN signaling diminishing preferred as well as nonpreferred inputs and 2) by high levels of NE engaging alpha1 stimulation of phosphotidyl inositol (PI) signaling that suppresses cell firing. Common mental illnesses are associated with extracellular changes in these pathways: Attention Deficit Hyperactivity Disorder is linked to genetic changes that reduce catecholamine transmission to suboptimal levels and is treated with agents that increase catecholamine transmission, whereas Post-Traumatic Stress Disorder (PTSD) is associated with amplified noradrenergic transmission that impairs PFC but strengthens amygdala function. PTSD is now treated with agents that block alpha1 or beta adrenoceptors. In contrast, the more severe mental illnesses, schizophrenia and bipolar disorder, are associated with genetic changes in molecules regulating intracellular signaling pathways activated by stress. Specifically, DISC1 inhibits cAMP signaling whereas regulator of G-protein signaling 4 inhibits PI signaling. Loss of function in these genes may render patients vulnerable to profound stress-induced PFC dysfunction including symptoms of thought disorder.

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CitationGPTRetr18

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: Sources and significance of plasma levels of catechols and their metabolites in humans. Abstract of the paper: Human plasma contains several catechols, including the catecholamines norepinephrine, epinephrine, and dopamine, their precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), and their deaminated metabolites, dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, and dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of metabolism of catechols include 3-methoxytyrosine (from L-DOPA), homovanillic acid and dopamine sulfate (from dopamine), normetanephrine, vanillylmandelic acid, and methoxyhydroxyphenylglycol (from norepinephrine), and metanephrine (from epinephrine). Plasma levels of catechols and their metabolites have related but distinct sources and therefore reflect different functions of catecholamine systems. This article provides an update about plasma levels of catechols and their metabolites and the relevance of those levels to some issues in human health and disease.

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CitationGPTRetr19

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: phenylalanine and tyrosine must be ingested from food and serve as precursors of catecholamine 33 therefore their depletion may contribute to impaired catecholamine synthesis low catecholamine levels and behavioural deficits including cognitive and emotional impairments Title of the paper: The neurochemistry of Alzheimer's disease. Abstract of the paper: This paper gives a review of the neurochemical alterations that characterize Alzheimer's disease. The quantitative distribution of each compound or group of compounds over the central nervous system and their concentrations in the cerebrospinal fluid as well as receptor interactions and densities are discussed. Where possible, these neurochemical alterations are correlated with cognitive and noncognitive symptoms. A degeneration of the cholinergic nucleus basalis of Meynert characterizes Alzheimer's disease and results in neocortical cholinergic deficits correlating with cognitive impairment. Catecholaminergic changes include prominent cell loss of the noradrenergic locus coeruleus leading to decreased norepinephrine concentrations in cerebrospinal fluid and several cortical and subcortical areas. Modest, but identical trends are reported for epinephrine and dopamine. The former alterations are correlated with depression and psychosis in Alzheimer's disease. The serotonergic nucleus raphe dorsalis shows evidence of degeneration, causing a decreased serotonin content of the neocortex and the cerebrospinal fluid, which is correlated with both cognitive and noncognitive symptomatology. Several-often less understood-changes of amino acids and neuropeptides will be reviewed. Finally, the neurochemical aspects of cytokine-mediated inflammatory reactions and of oxidative stress in the physiopathology of Alzheimer's disease are reviewed.

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CitationGPTRetr20

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Sex differences in mitochondrial (dys)function: Implications for neuroprotection. Abstract of the paper: Decades of research have revealed numerous differences in brain structure size, connectivity and metabolism between males and females. Sex differences in neurobehavioral and cognitive function after various forms of central nervous system (CNS) injury are observed in clinical practice and animal research studies. Sources of sex differences include early life exposure to gonadal hormones, chromosome compliment and adult hormonal modulation. It is becoming increasingly apparent that mitochondrial metabolism and cell death signaling are also sexually dimorphic. Mitochondrial metabolic dysfunction is a common feature of CNS injury. Evidence suggests males predominantly utilize proteins while females predominantly use lipids as a fuel source within mitochondria and that these differences may significantly affect cellular survival following injury. These fundamental biochemical differences have a profound impact on energy production and many cellular processes in health and disease. This review will focus on the accumulated evidence revealing sex differences in mitochondrial function and cellular signaling pathways in the context of CNS injury mechanisms and the potential implications for neuroprotective therapy development.

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CitationGPTRetr21

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Role of Sex Hormones on Brain Mitochondrial Function, with Special Reference to Aging and Neurodegenerative Diseases. Abstract of the paper: The mitochondria have a fundamental role in both cellular energy supply and oxidative stress regulation and are target of the effects of sex steroids, particularly the neuroprotective ones. Aging is associated with a decline in the levels of different steroid hormones, and this decrease may underline some neural dysfunctions. Besides, modifications in mitochondrial functions associated with aging processes are also well documented. In this review, we will discuss studies that describe the modifications of brain mitochondrial function and of steroid levels associated with physiological aging and with neurodegenerative diseases. A special emphasis will be placed on describing and discussing our recent findings concerning the concomitant study of mitochondrial function (oxidative phosphorylation, oxidative stress) and brain steroid levels in both young (3-month-old) and aged (20-month-old) male and female mice.

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CitationGPTRetr22

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Mitochondrial mechanisms of estrogen neuroprotection. Abstract of the paper: Mitochondria have become a primary focus in our search not only for the mechanism(s) of neuronal death but also for neuroprotective drugs and therapies that can delay or prevent Alzheimer's disease and other chronic neurodegenerative conditions. This is because mitochrondria play a central role in regulating viability and death of neurons, and mitochondrial dysfunction has been shown to contribute to neuronal death seen in neurodegenerative diseases. In this article, we review the evidence for the role of mitochondria in cell death and neurodegeneration and provide evidence that estrogens have multiple effects on mitochondria that enhance or preserve mitochondrial function during pathologic circumstances such as excitotoxicity, oxidative stress, and others. As such, estrogens and novel non-hormonal analogs have come to figure prominently in our efforts to protect neurons against both acute brain injury and chronic neurodegeneration.

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CitationGPTRetr23

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice. Abstract of the paper: Sex steroids regulate brain function in both normal and pathological states. Mitochondria are an essential target of steroids, as demonstrated by the experimental administration of 17β-estradiol or progesterone (PROG) to ovariectomized female rodents, but the influence of endogenous sex steroids remains understudied. To address this issue, mitochondrial oxidative stress, the oxidative phosphorylation system, and brain steroid levels were analyzed under 3 different experimental sets of endocrine conditions. The first set was designed to study steroid-mediated sex differences in young male and female mice, intact and after gonadectomy. The second set concerned young female mice at 3 time points of the estrous cycle in order to analyze the influence of transient variations in steroid levels. The third set involved the evaluation of the effects of a permanent decrease in gonadal steroids in aged male and female mice. Our results show that young adult females have lower oxidative stress and a higher reduced nicotinamide adenine dinucleotide (NADH)-linked respiration rate, which is related to a higher pyruvate dehydrogenase complex activity as compared with young adult males. This sex difference did not depend on phases of the estrous cycle, was suppressed by ovariectomy but not by orchidectomy, and no longer existed in aged mice. Concomitant analysis of brain steroids showed that pregnenolone and PROG brain levels were higher in females during the reproductive period than in males and decreased with aging in females. These findings suggest that the major male/female differences in brain pregnenolone and PROG levels may contribute to the sex differences observed in brain mitochondrial function.

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CitationGPTRetr24

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Alzheimer, mitochondria and gender. Abstract of the paper: Epidemiological studies revealed that two-thirds of Alzheimer's disease (AD) patients are women and the drop of sex steroid hormones after the menopause has been proposed to be one risk factor in AD. Similarly, the decrease of circulating testosterone levels with aging may also increase the risk of AD in men. Studies attest the neuroprotective effects of sex hormones in animal models of AD, but clinical trial data remain controversial. Here, we discuss the implication of mitochondria in gender differences observed in AD patients and animal models of AD. We summarize the role of mitochondria in aging and AD, pointing to the potential correlation between the loss of sex hormones and changes in the brain redox status. We discuss the protective effects of the sex hormones, estradiol, progesterone and testosterone with a specific focus on mitochondrial dysfunction in AD. The understanding of pathological processes linking the loss of sex hormones with mitochondrial dysfunction and mechanisms that initiate the disease onset may open new avenues for the development of gender-specific therapeutic approaches.

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CitationGPTRetr25

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Neuroprotection by estrogen in the brain: the mitochondrial compartment as presumed therapeutic target. Abstract of the paper: Neuroprotection by estrogen in the CNS is well-documented and comprises the intricate regulation of cell-cell communication between neurons and supportive non-neuronal glial cells. It is assumed that these interactions are essential for cell survival under pathological and toxic conditions by regulating the allocation of trophic molecules, e.g., growth factors, controlling relevant intracellular anti-apoptotic and death cascades, and attenuating inflammatory processes. Malfunction and disturbance of mitochondria are doubtlessly associated with brain cell degeneration during neurotoxic and neurodegenerative processes. Estrogen has been documented as protective agent in the brain by stimulating growth factor supply and cell-intrinsic pro-/anti-apoptotic signaling pathways. In recent years, an additional estrogen-dependent safe-guarding strategy comes into the focus of neuronal protection. The mitochondrial compartment appears to be regulated by estrogen at the level of ATP and reactive oxygen species production as well as under a structural-functional viewpoint. In the present article, we would like to highlight recent data which demonstrate that sex steroids can directly and indirectly interfere with mitochondrial properties via non-nuclear, presumably mitochondria-intrinsic and nuclear signaling mechanisms. This enables mitochondria to cope with pathological processes and provide stabile local energy homeostasis and an anti-apoptotic base setting in the brain which, in turn, is a prerequisite for neuronal survival.

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CitationGPTRetr26

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. Abstract of the paper: The ovarian hormones progesterone and estrogen have well-established neurotrophic and neuroprotective effects supporting both reproductive function and cognitive health. More recently, it has been recognized that these steroids also regulate metabolic functions sustaining the energetic demands of this neuronal activation. Underlying this metabolic control is an interpretation of signals from diverse environmental sources integrated by receptor-mediated responses converging upon mitochondrial function. In this study, to determine the effects of progesterone (P4) and 17beta-estradiol (E2) on metabolic control via mitochondrial function, ovariectomized rats were treated with P4, E2, or E2 plus P4, and whole-brain mitochondria were isolated for functional assessment. Brain mitochondria from hormone-treated rats displayed enhanced functional efficiency and increased metabolic rates. The hormone-treated mitochondria exhibited increased respiratory function coupled to increased expression and activity of the electron transport chain complex IV (cytochrome c oxidase). This increased respiratory activity was coupled with a decreased rate of reactive oxygen leak and reduced lipid peroxidation representing a systematic enhancement of brain mitochondrial efficiency. As such, ovarian hormone replacement induces mitochondrial alterations in the central nervous system supporting efficient and balanced bioenergetics reducing oxidative stress and attenuating endogenous oxidative damage.

False

CitationGPTRetr27

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease. Abstract of the paper: Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E(2) mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E(2) promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.

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CitationGPTRetr28

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Mitochondrial mechanisms of estrogen neuroprotection. Abstract of the paper: Oxidative stress, bioenergetic failure and mitochondrial dysfunction are all implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD). The mitochondrial involvement in neurodegenerative diseases reflects the regulatory role mitochondrial failure plays in both necrotic cell death and apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), is neuroprotective in a host of cell and animal models of stroke and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as neuroprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where neuroprotection is independent of hormonal potency. Studies of structure-activity relationships and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The neuroprotective and mitoprotective potencies for a series of estrogen analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD.

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CitationGPTRetr29

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Estrogen: a master regulator of bioenergetic systems in the brain and body. Abstract of the paper: Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer's disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions.

False

CitationGPTRetr30

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimer's disease. Abstract of the paper: Age-related mitochondrial oxidative stress is highly gender dependent. The aim of this study was to determine the role of gender in the mitochondrial contribution to neuronal apoptosis in Alzheimer's disease (AD). We used mitochondria isolated from brains of Wistar rats to study the toxicity of ss-amyloid peptide (Ass), and found that it increases mitochondrial peroxide production, nitration and oxidation of proteins, and release of cytochrome c. The toxic effects occurred in young males and in old females but not in young females, indicating their resistance to Ass. This resistance was abolished with age. These toxic effects of Ass were prevented by heme. Our findings provide a molecular mechanism for the contribution of Abeta to the mitochondrial dysfunction and oxidative stress seen in AD, as well as for the mitochondria-dependent pathway of apoptosis in AD. Gender and age-related differences seen in the development of AD can also be partially explained.

False

CitationGPTRetr31

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Abstract of the paper: We have investigated the differential mitochondrial oxidative stress between males and females to understand the molecular mechanisms enabling females to live longer than males. Mitochondria are a major source of free radicals in cells. Those from female rats generate half the amount of peroxides than those of males. This does not occur in ovariectomized animals. Estrogen replacement therapy prevents the effect of ovariectomy. Mitochondria from females have higher levels of reduced glutathione than those from males. Those from ovariectomized rats have similar levels to males, and estrogen therapy prevents the fall in glutathione levels that occurs in ovariectomized animals. Oxidative damage to mitochondrial DNA in males is 4-fold higher than that in females. This is due to higher expression and activities of Mn-superoxide dismutase and of glutathione peroxidase in females, which behave as double transgenics overexpressing superoxide dismutase and glutathione peroxidase, conferring protection against free-radical-mediated damage in aging. Moreover, 16S rRNA expression, which decreases significantly with aging, is four times higher in mitochondria from females than in those from males of the same chronological age. The facts reported here provide molecular evidence to explain the different life span in males and females.

False

CitationGPTRetr32

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: New evidence of mitochondria dysfunction in the female Alzheimer's disease brain: deficiency of estrogen receptor-β. Abstract of the paper: Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor β (ERβ) in neuronal mitochondrial (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERβ is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lack of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is associated with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ERβ depletion impairs mitochondrial function in mice, and reduction of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women.

False

CitationGPTRetr33

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Estrogens and brain function. Abstract of the paper: Cognitive decline is well recognized during ageing but is often accelerated in women after menopause. Studies have shown that there are significant gender differences in brain ageing with significantly greater changes in brain structure, function and metabolism between females and males. Estrogens exert protective effects on neuronal cells in culture but the exact underlying mechanism for their neuroprotective effect in humans is not completely understood. Estrogens have been shown to affect the nervous system in many different ways: via binding to estrogen receptors (ERs) but also via multiple pathways. The results of small randomized trials and larger observational studies suggest a beneficial effect of estrogen therapy on cognitive function in symptomatic postmenopausal women. However, the results of the Women's Health Initiative Study (WHIMS) do not support this, at least not in women over the age of 65. Alzheimer's disease (AD) is two to three times more common in women than in men. Based on currently available data, routine therapeutic use of estrogens in women with AD is not justified but it may have a role in the prophylaxis of AD. The existing evidence supports the use of HRT only in women with menopausal symptoms for a few years following menopause.

False

CitationGPTRetr34

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Different expression of alpha and beta mitochondrial estrogen receptors in the aging rat brain: interaction with respiratory complex V. Abstract of the paper: Recent evidence suggests that hormonal effects on mitochondria could be mediated by mitochondrial estrogen receptors (mtERs). These receptors are new candidates for the beneficial estrogenic effects on mitochondria in different physiological conditions. The aim of this investigation was to study mtER expression during brain aging. We analyzed mtERalpha and mtERbeta expression in cortical, hippocampal and hypothalamic mitochondria of young adult (3months) and aged (18 months) female Wistar rats by Western blot. In addition, we explored the interaction of mtERbeta with respiratory complex V by using coimmunoprecipitation assays. The results show that mtERalpha and mtERbeta are present in young and aged brain mitochondria. We also demonstrate that mtERs are expressed as variants and have a brain region specific distribution. The predominant mtER variants detected were of 61 and 55KDa for mtERalpha and of 63 and 52KDa for mtERbeta. However, we did not observe differences in the mtERalpha or beta content between the two age groups studied. Additionally, we show that mtERbeta interacts with complex V. The overall results demonstrate that there is a differential expression of mtERalpha and mtERbeta variants in different brain areas, indicating that they may participate in different functions in the brain during aging.

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CitationGPTRetr35

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: NAD+ and nicotinamide: sex differences in cerebral ischemia. Abstract of the paper: BACKGROUND Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes. While caspase-dependent mechanisms predominate in the female brain, caspase-independent cell death induced by the activation of poly(ADP-ribose) polymerase (PARP) predominates in the male brain. PARP-1 gene deletion decreases infarction volume in the male brain, but paradoxically increases damage in PARP-1 knockout females. PURPOSE This study examined stroke-induced changes in NAD+, a key energy molecule involved in PARP-1 activation in both sexes. METHODS Mice were subjected to middle cerebral artery occlusion and NAD+ levels were assessed. Caspase-3 activity and nuclear translocation were assessed 6h after ischemia. In additional cohorts, Nicotinamide (500 mg/kg i.p.) a precursor of NAD+ or vehicle was administered and infarction volume was measured 24h after ischemia. RESULTS Males have higher baseline NAD+ levels than females. Significant stroke-induced NAD+ depletion occurred in males and ovariectomized females but not in intact females. PARP-1 deletion prevented the stroke-induced loss in NAD+ in males, but worsened NAD+ loss in PARP-1 deficient females. Preventing NAD+ loss with nicotinamide reduced infarct in wild-type males and PARP-1 knockout mice of both sexes, with no effect in WT females. Caspase-3 activity was significantly increased in PARP-1 knockout females compared to males and wild-type females, this was reversed with nicotinamide. CONCLUSIONS Sex differences exist in baseline and stroke-induced NAD+ levels. Nicotinamide protected males and PARP knockout mice, but had minimal effects in the wild-type female brain. This may be secondary to differences in energy metabolism between the sexes.

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CitationGPTRetr36

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair. Abstract of the paper: Aging is an inevitable biological process characterized by a progressive decline in physiological function and increased susceptibility to disease. The detrimental effects of aging are observed in all tissues, the brain being the most important one due to its main role in the homeostasis of the organism. As our knowledge about the underlying mechanisms of brain aging increases, potential approaches to preserve brain function rise significantly. Accumulating evidence suggests that loss of genomic maintenance may contribute to aging, especially in the central nervous system (CNS) owing to its low DNA repair capacity. Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer's disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain.

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CitationGPTRetr37

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Estrogen and neurodegeneration. Abstract of the paper: Although estrogen is best known for its effects on the maturation and differentiation of the primary and secondary sex organs, increasing evidence suggests that its influence extends beyond this system, and its activity in the CNS may initiate, or influence our susceptibility to neurodegenerative decline. Estrogen has been proposed to act as a neuroprotectant at several levels, and it is probable that deprivation of estrogen as a result of menopause exposes the aging or diseased brain to several insults. In addition, estrogen deprivation is likely to initiate or enhance degenerative changes caused by oxidative stress, and to reduce the brain's ability to maintain synaptic connectivity and cholinergic integrity leading to the cognitive decline seen in aged and disease-afflicted individuals.

False

CitationGPTRetr38

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease. Abstract of the paper: Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.

False

CitationGPTRetr39

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: why females respond to qr2is so much faster than males will be the subject of future studies and may be related to estrogen metabolism though this does not exclude other possibilities such as those pertaining mitochondrial function and nadh homeostasis Title of the paper: Sex differences in the brain: Implications for behavioral and biomedical research. Abstract of the paper: Biological differences between males and females are found at multiple levels. However, females have too often been under-represented in behavioral neuroscience research, which has stymied the study of potential sex differences in neurobiology and behavior. This review focuses on the study of sex differences in the neurobiology of social behavior, memory, emotions, and recovery from brain injury, with particular emphasis on the role of estrogens in regulating forebrain function. This work, presented by the authors at the 2016 meeting of the International Behavioral Neuroscience Society, emphasizes varying approaches from several mammalian species in which sex differences have not only been documented, but also become the focus of efforts to understand the mechanistic basis underlying them. This information may provide readers with useful experimental tools to successfully address recently introduced regulations by granting agencies that either require (e.g. the National Institutes of Health in the United States and the Canadian Institutes of Health Research in Canada) or recommend (e.g. Horizon 2020 in Europe) the inclusion of both sexes in biomedical research.

False

CitationGPTRetr40

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia activation and anti-inflammatory regulation in Alzheimer's disease. Abstract of the paper: Inflammatory regulators, including endogenous anti-inflammatory systems, can down-regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer's disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti-inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases.

False

CitationGPTRetr41

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglial activation and its implications in the brain diseases. Abstract of the paper: An inflammatory process in the central nervous system (CNS) is believed to play an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, prion diseases, multiple sclerosis and HIV-dementia. The inflammatory response is mediated by the activated microglia, the resident immune cells of the CNS, which normally respond to neuronal damage and remove the damaged cells by phagocytosis. Activation of microglia is a hallmark of brain pathology. However, it remains controversial whether microglial cells have beneficial or detrimental functions in various neuropathological conditions. The chronic activation of microglia may in turn cause neuronal damage through the release of potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. Therefore, suppression of microglia-mediated inflammation has been considered as an important strategy in neurodegenerative disease therapy. Several anti-inflammatory drugs of various chemical ingredients have been shown to repress the microglial activation and to exert neuroprotective effects in the CNS following different types of injuries. However, the molecular mechanisms by which these effects occur remain unclear. In recent years, several research groups including ours have attempted to explain the potential mechanisms and signaling pathways for the repressive effect of various drugs, on activation of microglial cells in CNS injury. We provide here a comprehensive review of recent findings of mechanisms and signaling pathways by which microglial cells are activated in CNS inflammatory diseases. This review article further summarizes the role of microglial cells in neurodegenerative diseases and various forms of potential therapeutic options to inhibit the microglial activation which amplifies the inflammation-related neuronal injury in neurodegenerative diseases.

False

CitationGPTRetr42

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain. Abstract of the paper: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function. There is no therapy that can halt or reverse its progression. Contemporary research suggests that age-dependent neuroinflammatory changes may play a significant role in the decreased neurogenesis and cognitive impairments in AD. The innate immune response is characterized by pro-inflammatory (M1) activation of macrophages and subsequent production of specific cytokines, chemokines, and reactive intermediates, followed by resolution and alternative activation for anti-inflammatory signaling (M2a) and wound healing (M2c). We propose that microglial activation phenotypes are analogous to those of macrophages and that their activation plays a significant role in regulating neurogenesis in the brain. Microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging. This review will assess the neuroimmunological studies that led to characterization of the different microglial activation states in AD mouse models. It will also discuss the roles of microglial activation on neurogenesis in AD and propose anti-inflammatory molecules as exciting therapeutic targets for research. Molecules such as interleukin-4 and CD200 have proven to be important anti-inflammatory mediators in the regulation of neuroinflammation in the brain, which will be discussed in detail for their therapeutic potential.

False

CitationGPTRetr43

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia and Alzheimer's Disease. Abstract of the paper: There is a huge need for novel therapeutic and preventative approaches to Alzheimer's disease (AD) and neuroinflammation seems to be one of the most fascinating solutions. The primary cell type that performs immunosurveillance and helps clear out unwanted chemicals from the brain is the microglia. Microglia work to reestablish efficiency and stop further degeneration in the early stages of AD but mainly fail in the illness's later phases. This may be caused by a number of reasons, e.g., a protracted exposure to cytokines that induce inflammation and an inappropriate accumulation of amyloid beta (Aβ) peptide. Extracellular amyloid and/or intraneuronal phosphorylated tau in AD can both activate microglia. The activation of TLRs and scavenger receptors, inducing the activation of numerous inflammatory pathways, including the NF-kB, JAK-STAT, and NLRP3 inflammasome, facilitates microglial phagocytosis and activation in response to these mediators. Aβ/tau are taken up by microglia, and their removal from the extracellular space can also have protective effects, but if the illness worsens, an environment that is constantly inflamed and overexposed to an oxidative environment might encourage continuous microglial activation, which can lead to neuroinflammation, oxidative stress, iron overload, and neurotoxicity. The complexity and diversity of the roles that microglia play in health and disease necessitate the urgent development of new biomarkers that identify the activity of different microglia. It is imperative to comprehend the intricate mechanisms that result in microglial impairment to develop new immunomodulating therapies that primarily attempt to recover the physiological role of microglia, allowing them to carry out their core function of brain protection.

False

CitationGPTRetr44

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Targeting Microglia in Alzheimer's Disease: From Molecular Mechanisms to Potential Therapeutic Targets for Small Molecules. Abstract of the paper: Alzheimer's disease (AD) is a common, progressive, and devastating neurodegenerative disorder that mainly affects the elderly. Microglial dysregulation, amyloid-beta (Aβ) plaques, and intracellular neurofibrillary tangles play crucial roles in the pathogenesis of AD. In the brain, microglia play roles as immune cells to provide protection against virus injuries and diseases. They have significant contributions in the development of the brain, cognition, homeostasis of the brain, and plasticity. Multiple studies have confirmed that uncontrolled microglial function can result in impaired microglial mitophagy, induced Aβ accumulation and tau pathology, and a chronic neuroinflammatory environment. In the brain, most of the genes that are associated with AD risk are highly expressed by microglia. Although it was initially regarded that microglia reaction is incidental and induced by dystrophic neurites and Aβ plaques. Nonetheless, it has been reported by genome-wide association studies that most of the risk loci for AD are located in genes that are occasionally uniquely and highly expressed in microglia. This finding further suggests that microglia play significant roles in early AD stages and they be targeted for the development of novel therapeutics. In this review, we have summarized the molecular pathogenesis of AD, microglial activities in the adult brain, the role of microglia in the aging brain, and the role of microglia in AD. We have also particularly focused on the significance of targeting microglia for the treatment of AD.

False

CitationGPTRetr45

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia in Alzheimer's disease. Abstract of the paper: Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an "activated state"). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer's disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.

True

CitationGPTRetr46

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia in Alzheimer's disease. Abstract of the paper: Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer's disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.

False

CitationGPTRetr47

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Minocycline selectively inhibits M1 polarization of microglia. Abstract of the paper: Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1(G93A) mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1(G93A) mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

False

CitationGPTRetr48

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease. Abstract of the paper: Compelling evidence from basic molecular biology has demonstrated the dual roles of microglia in the pathogenesis of Alzheimer's disease (AD). On one hand, microglia are involved in AD pathogenesis by releasing inflammatory mediators such as inflammatory cytokines, complement components, chemokines, and free radicals that are all known to contribute to beta-amyloid (Aβ) production and accumulation. On the other hand, microglia are also known to play a beneficial role in generating anti-Aβ antibodies and stimulating clearance of amyloid plaques. Aβ itself, an inducer of microglia activation and neuroinflammation, has been considered as an underlying and unifying factor in the development of AD. A vicious cycle of inflammation has been formed between Aβ accumulation, activated microglia, and microglial inflammatory mediators, which enhance Aβ deposition and neuroinflammation. Thus, inhibiting the vicious cycle seems to be a promising treatment to restrain further development of AD. With increasing research efforts on microglia in AD, intervention of microglia activation and neuroinflammation in AD may provide a potential target for AD therapy in spite of the provisional failure of nonsteroidal antiinflammatory drugs in clinical trials.

False

CitationGPTRetr49

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. Abstract of the paper: Deficits in cognitive function are associated with neuroinflammatory changes, typified by activation of glial cells and an alteration of the pro- and anti-inflammatory cytokine balance in the brain. Although there is evidence to suggest that activation of microglia is regulated by interaction with other cell types in the brain, the mechanism(s) involved is poorly understood. Here, we provide evidence that interaction between CD200 and its receptor plays a role in modulating microglial activation under conditions of chronic and acute inflammation of the brain. We report that interleukin-4 (IL-4) plays a central role in modulating expression of CD200 and identify a mechanism by which IL-4 directly controls microglial cell activation. Our findings provide the first demonstration of a role for IL-4 in modulating CD200 expression and suggest a mechanism for regulation of microglial activation in the intact CNS under inflammatory conditions.

False

CitationGPTRetr50

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies. Abstract of the paper: Chronic activation of microglia is the hallmark of numerous neuropathologies such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The activated microglia perpetuate inflammation by releasing an array of pro-inflammatory and neurotoxic factors, which eventually exacerbate neurotoxicity and neurodegeneration upon chronic activation of these cells. However, under acute conditions, activated microglia elicit pro-inflammatory as well as anti-inflammatory responses that are associated with neuroprotection. Given the role of microglia in neuroinflammation, recent studies have attempted to unravel the mechanisms that aid to establish microglial cell-based therapy. Areas covered: While total suppression of microglial activation may compromise its beneficial role in tissue repair in the aftermath of an insult, the benefits of modulating microglial activation and promoting microglia polarization to a neuroprotective phenotype have been highlighted recently. Expert opinion: So far, the therapeutic strategy focussed on neutralizing microglia-mediated neuroinflammation using drugs that block the release of pro-inflammatory mediators has limitations, such as unwarranted side effects. Recent advances reveal several alternative molecular targets and potential epi-drugs that are capable of modulating microglial function and promoting neuroprotection. This review discusses the recent progress made in understanding the mechanisms of microglia-mediated neuroinflammation in various neuropathologies, and the emerging anti-inflammatory therapeutic strategies in this field.

False

CitationGPTRetr51

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Possible roles of microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models. Abstract of the paper: Microglia has been demonstrated to play critical roles in various neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) as well as neuroinflammatory disorders including AIDS encephalitis, multiple sclerosis. In this manuscript, we review the possible roles of microglial cells in animal models of these clinical disorders and human clinical cases. Activated microglia has been demonstrated in various brain regions, such as the hippocampus, substantia nigra and cortex in PD, AD and HD. The contribution of microglial cells to these neurodegenerative disorders is supported by findings in animal experiments: (1) microglial activation precedes the neurodegenerative changes; (2) activated microglia surround the region that undergo neurodegeneration and phagocytose the degenerating cells; (3) activated microglia release neurotoxic molecules such as interleukin(IL)-1beta, IL-6, TNF-alpha, nitric oxide, reactive oxygen species; (4) inhibition of microglial activation leads to the amelioration of neurodegeneration, (5) microglia derived from aged animal exert more toxicity to neurons in an age-dependent fashion, in the same way neurodegenerative disorders occur. Although roles of activated microglia in those clinical disorders needs to be further investigated, these findings suggest that microglial cells may contribute to the progression of neurodegenerative changes as well as inflammation in the brain. Thus, the treatment to target microglial inhibition may help to develop the pharmaceutical approaches for those clinical disorders.

False

CitationGPTRetr52

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia in the Neuroinflammatory Pathogenesis of Alzheimer's Disease and Related Therapeutic Targets. Abstract of the paper: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.

False

CitationGPTRetr53

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglial activation in Alzheimer's disease. Abstract of the paper: Alzheimer's disease (AD) is a devastating chronic neurodegenerative disease with currently no available disease modifying treatment. In recent years, the peptide amyloid-beta has been proposed as the major pathogenic force in the development and progression of AD. Microglia, the resident immune and phagocytic cells of the brain, are known to constantly scan brain tissue and to respond to various pathological stimuli. Thus, newly formed plaque composed of A beta seem to activate and recruit microglia in AD transgenic mice. However, the role of microglia is only poorly understood in AD. Microglia may act as a double-edged sword being either detrimental or protective depending on the context. In this mini-review, we discuss the importance of microglia and its receptors in neuroinflammation and plaque clearance. A possible disease modifying role of blood-borne monocytes, which are close relatives of bone-marrow derived microglia, will also be addressed.

False

CitationGPTRetr54

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer's disease. Abstract of the paper: BACKGROUND Activated microglia with macrophage-like functions invade and surround β-amyloid (Aβ) plaques in Alzheimer's disease (AD), possibly contributing to the turnover of Aβ, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis. OBJECTIVES/METHODS To determine the role of microglia on neurogenesis in brains with Aβ pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1). RESULTS Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of Aβ and Aβ-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice. CONCLUSIONS These results suggest a role for microglia in Aβ-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of Aβ pathology.

True

CitationGPTRetr55

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia in Alzheimer's Disease: An Unprecedented Opportunity as Prospective Drug Target. Abstract of the paper: Alzheimer's disease (AD) is an ever more common neurodegenerative disease among the elderly, characterized by recurrent neuroinflammation and amyloid beta (Aβ) accumulation in the brain parenchyma. Recent genome-wide association studies (GWAS) have shown a distinct role for the innate immune system in AD, with microglia playing a key role. The function of microglial cells is stringently regulated by the neighboring microenvironment in the brain. Upon interruption in diseases, like AD, it demonstrates neurotoxic and neuroprotective action by M1 (neurotoxic) and M2 (neuroprotective) microglial phenotypes, respectively, in the brain. Microglial cells on activation by complement factors, toll-like receptors, and genetic variants result in Aβ' phagocytosis, synaptic pruning, and reactivation of complement pathway. Recent studies have demonstrated the presence of potential therapeutic targets in microglial cells. Immune receptors revealed on microglia as potential drug targets can be paired immunoglobulin-like type 2 receptor (PILR), CD3358, and triggering receptor expressed on myeloid cells 2 (TREM2), as they can have impact on late-onset AD occurrence and progression. Thus, targeting these receptors can accentuate the beneficial effects of microglial cells required to decelerate the progression of AD. This review emphasizes the microglial phenotypes, its function in AD brain, and potential immunological and therapeutic targets to fight this highly progressive neurodegenerative disorder.

False

CitationGPTRetr56

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglia function in Alzheimer's disease. Abstract of the paper: Contrary to early views, we now know that systemic inflammatory/immune responses transmit to the brain. The microglia, the resident "macrophages" of the brain's innate immune system, are most responsive, and increasing evidence suggests that they enter a hyper-reactive state in neurodegenerative conditions and aging. As sustained over-production of microglial pro-inflammatory mediators is neurotoxic, this raises great concern that systemic inflammation (that also escalates with aging) exacerbates or possibly triggers, neurological diseases (Alzheimer's, prion, motoneuron disease). It is known that inflammation has an essential role in the progression of Alzheimer's disease (AD), since amyloid-β (Aβ) is able to activate microglia, initiating an inflammatory response, which could have different consequences for neuronal survival. On one hand, microglia may delay the progression of AD by contributing to the clearance of Aβ, since they phagocyte Aβ and release enzymes responsible for Aβ degradation. Microglia also secrete growth factors and anti-inflammatory cytokines, which are neuroprotective. In addition, microglia removal of damaged cells is a very important step in the restoration of the normal brain environment, as if left such cells can become potent inflammatory stimuli, resulting in yet further tissue damage. On the other hand, as we age microglia become steadily less efficient at these processes, tending to become over-activated in response to stimulation and instigating too potent a reaction, which may cause neuronal damage in its own right. Therefore, it is critical to understand the state of activation of microglia in different AD stages to be able to determine the effect of potential anti-inflammatory therapies. We discuss here recent evidence supporting both the beneficial or detrimental performance of microglia in AD, and the attempt to find molecules/biomarkers for early diagnosis or therapeutic interventions.

False

CitationGPTRetr57

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Purinergic modulation of microglial cell activation. Abstract of the paper: Microglial cells are resident macrophages in the brain and their activation is an important part of the brain immune response and the pathology of the major CNS diseases. Microglial activation is triggered by pathological signals and is characterized by morphological changes, proliferation, phagocytosis and the secretion of various cytokines and inflammatory mediators, which could be both destructive and protective for the nervous tissue. Purines are one of the most important mediators which regulate different aspects of microglial function. They could be released to the extracellular space from neurons, astrocytes and from the microglia itself, upon physiological neuronal activity and in response to pathological stimuli and cellular damage. Microglial activation is regulated by various subtypes of nucleotide (P2X, P2Y) and adenosine (A₁, A(₂A) and A₃) receptors, which control ionic conductances, membrane potential, gene transcription, the production of inflammatory mediators and cell survival. Among them, the role of P2X₇ receptors is especially well delineated, but P2X₄, various P2Y, A₁, A(₂A) and A₃ receptors also powerfully participate in the microglial response. The pathological role of microglial purine receptors has also been demonstrated in disease models; e.g., in ischemia, sclerosis multiplex and neuropathic pain. Due to their upregulation and selective activation under pathological conditions, they provide new avenues in the treatment of neurodegenerative and neuroinflammatory illnesses.

False

CitationGPTRetr58

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Microglial activation in Alzheimer's disease: The role of flavonoids and microRNAs. Abstract of the paper: Alzheimer's disease (AD) is the most common form of senile dementia and is characterized by progressive cognitive impairment and neuronal degeneration. Microglial activation is an important pathologic hallmark of AD. During disease progression, microglial cells switch from an alternative or anti-inflammatory and neuroprotective profile (M2) to a classic or proinflammatory and neurotoxic profile (M1). Phenotypically, M1 microglia is characterized by the activation of inflammatory signaling pathways that cause increased expression of proinflammatory genes, including those coding for cytokines and chemokines. This microglia-mediated neuroinflammation contributes to neuronal cell death. Recent studies in microglial cells have shown that a group of plant-derived compounds, known as flavonoids, possess anti-inflammatory properties and therefore exert a neuroprotective effect through regulating microglia activation. Here, we discuss how flavonoids can promote the switch from an inflammatory M1 phenotype to an anti-inflammatory M2 phenotype in microglia and how this represents a valuable opportunity for the development of novel therapeutic strategies to blunt neuroinflammation and boost neuronal recovery in AD. We also review how certain flavonoids can inhibit neuroinflammation through their action on the expression of microglia-specific microRNAs (miRNAs), which also constitute a key therapeutic approach in different neuropathologies involving an inflammatory component, including AD. Finally, we propose novel targets of microglia-specific miRNAs that may be considered for AD treatment.

False

CitationGPTRetr59

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: to prevent excessive activation the homologous receptors expressed on microglia combine with a variety of neuronal immunomodulators to inhibit them such as cd200cd200r cx3cl1cx3clr1 cd22cd45 cd172acd47 and so forth it is worth noting that high cholesterol and telomere shortening also play a role in the activation of microglia however in drug research pls inhibits the endocytosis of tlr4 and the activation of downstream caspases thereby inhibiting the activation of microglia in a model expressing mutant human app and mutant human progerin1 ps1 it was found that minocycline also inhibited the activation of microglia Title of the paper: Role of Microglia in Neurological Disorders and Their Potentials as a Therapeutic Target. Abstract of the paper: Microglia are resident macrophage-like immune cells in the central nervous system (CNS) and play a vital role in both physiological and pathological conditions, including restoring the integrity of the CNS and promoting the progression of neurodegenerative disorders. Upon stimulation, microglia typically convert from a surveillant to an activated phenotype. The major function of microglia is to maintain homeostasis and normal function of the CNS, both during development and in response to CNS injury. Microglia regulate multiple aspects of inflammation, such as repair, cytotoxicity, regeneration, and immunosuppression due to their different kind of activation states or phenotypes. Although microglia are involved in almost all neurodegenerative disorders, the mechanisms for microglial activation and their potential contributions to neuronal degeneration remain a matter of intense debate. In inflammatory process of the CNS, polarized M1 microglia can produce proinflammatory cytokines, neurotoxic molecules, which contribute to dysfunction of neural network and promoting inflammation reaction, whereas polarized M2 microglia secrete antiinflammatory mediators and neurotrophic factors that are involved in restoring homeostasis. Modulation of microglial activation for therapeutic purposes might be realized via suppressing the deleterious effects of these cells, while simultaneously retaining their protective functions. Here, we summarize the functions of microglia and discuss dual role of microglia in neurodegenerative diseases as well as multiple sclerosis.

False

CitationGPTRetr60

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Diagnostic and Prognostic Performance of Neurofilaments in ALS. Abstract of the paper: There is a need for biomarkers for amyotrophic lateral sclerosis (ALS), to support the diagnosis of the disease, to predict disease progression and to track disease activity and treatment responses. Over the last decade multiple studies have investigated the potential of neurofilament levels, both in cerebrospinal fluid and blood, as biomarker for ALS. The most widely studied neurofilament subunits are neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH). Neurofilament levels are reflecting neuronal injury and therefore potentially of value in ALS and other neurological disorders. In this mini-review, we summarize and discuss the available evidence about neurofilaments as diagnostic and prognostic biomarker for human ALS.

True

CitationGPTRetr61

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Serial measurements of phosphorylated neurofilament-heavy in the serum of subjects with amyotrophic lateral sclerosis. Abstract of the paper: There is a need for a blood biomarker of disease activity in ALS. This marker needs to measure the loss of motor neurones. Phosphorylated neurofilament heavy chain (pNfH) in the serum is a biomarker of axonal injury. Previous studies have found that levels of pNfH are elevated in ALS. We have performed a serial study of pNfH levels in 98 subjects from our ALS clinic. There was significant elevation of levels of pNfH in subjects with ALS compared to controls, although there was considerable variability. In studies of individuals who had two or more serial samples, we found that the levels of pNfH increased over time in the early stage of disease. Levels were low in subjects with long survival. The rate of rise of pNfH was inversely correlated with survival. We suggest that the initial level of pNfH is a marker of disease severity and that changes in pNfH levels are markers of disease progression.

False

CitationGPTRetr62

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament light chain as a biomarker in neurological disorders. Abstract of the paper: In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.

False

CitationGPTRetr63

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Abstract of the paper: OBJECTIVE To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase. METHODS We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters. RESULTS pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%-92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%-94.8%), a specificity of 88.0% (CI 75.7%-95.5%) and a likelihood ratio of 7.6 (CI 3.6-16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement. CONCLUSIONS In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.

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CitationGPTRetr64

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. Abstract of the paper: OBJECTIVE To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS). METHODS This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology. RESULTS Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time. CONCLUSIONS Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.

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CitationGPTRetr65

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Serum neurofilament light chain is increased in hereditary spastic paraplegias. Abstract of the paper: Blood biomarkers are still largely missing in hereditary spastic paraplegias (HSPs). We here explored Neurofilament light chain (NfL) as a biomarker in HSP. Serum NfL was assessed in 96 HSP (63 genetically confirmed), 96 healthy control, and 33 ALS subjects by single molecule array (Simoa). Compared to controls, NfL was increased in HSP (P < 0.001), correlating with cross-sectional disease progression (ρ = 0.28). Levels were lower than in ALS (P < 0.001), allowing to differentiate HSP from ALS (AUC = 0.91). Serum NfL might serve as a biomarker in HSP indicating neuronal damage and, if confirmed longitudinally, disease progression. It might also support differentiating HSP from ALS.

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CitationGPTRetr66

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Abstract of the paper: OBJECTIVE To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). METHODS Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). CONCLUSION Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. CLASSIFICATION OF EVIDENCE This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls.

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CitationGPTRetr67

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament light: A candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. Abstract of the paper: OBJECTIVE To evaluate neurofilament light (NfL) as a biomarker of the presymptomatic phase of amyotrophic lateral sclerosis (ALS). METHODS The study population includes 84 individuals at risk for developing ALS, 34 controls, 17 ALS patients, and 10 phenoconverters (at-risk individuals observed both before and after the emergence of clinically manifest disease). At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation (in SOD1, C9orf72, TARDBP, FUS, VCP, etc), but who, at the time of enrollment, demonstrated no clinical symptoms or signs (including electromyographic evidence) of manifest disease. NfL in serum and cerebrospinal fluid (CSF) were quantified using an electrochemiluminescence immunoassay. RESULTS Serum and CSF NfL are substantially higher in ALS patients compared to controls and at-risk individuals and remain relatively stable over time. Among phenoconverters, however, NfL levels were elevated (ie, above the range observed in controls) as far back as ∼12 months preceding the emergence of the earliest clinical symptoms or signs of disease. INTERPRETATION Serum (and CSF) NfL are informative biomarkers of presymptomatic ALS, providing a new tool to quantify presymptomatic disease progression and to potentially predict the timing of clinical phenoconversion. As such, quantification of NfL may aid the design and implementation of early therapeutic intervention for affected individuals and/or disease prevention trials for individuals at short-term risk of developing ALS. Ann Neurol 2018 Ann Neurol 2018;83:130-139.

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CitationGPTRetr68

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament Proteins as Prognostic Biomarkers in Neurological Disorders. Abstract of the paper: Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.

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CitationGPTRetr69

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis: Neurofilament Light Chain Levels in Definite Subtypes of Disease. Abstract of the paper: Importance A clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed. Objectives To assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS. Design, Setting, and Participants In this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score-Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months. Cerebrospinal fluid samples were obtained from 176 patients admitted to the Department of Neurosciences of the University of Padua, Padova, Italy, from January 1, 2010, through February 29, 2016. Patients with ALS underwent ambulatory follow-up at the same department. Main Outcomes and Measures Levels of NFL. Results The study included 94 patients with ALS (64 men [36.4%] and 30 women [17.0%]; median age, 62.5 years), 20 patients with frontotemporal dementia (FTD) (8 men [4.5%] and 12 women [6.8%]; median age, 65 years), 18 patients with motor neuropathies (14 men [8.0%] and 4 women [2.3%]; median age, 63 years), and 44 controls (24 men [13.6%] and 20 women [11.4%]; median age, 54 years). Log-transformed NFL (log[NFL]) concentrations were higher in the ALS and FTD groups compared with the motor neuropathies and control groups (hazard ratio [HR], 2.45; 95% CI, 1.66-3.61; P < .001). Patients with typical ALS (HR, 1.0 [reference]), progressive bulbar palsy (HR, 1.48; 95% CI, 0.58-3.75; P = .41), and upper motor neuron dominant ALS (HR, 0.12; 95% CI, 0.02-0.61; P = .01) had higher levels of NFL than did those with flail arm or leg syndrome (HR, 0.28; 95% CI, 0.08-0.10; P = .049) and progressive muscular atrophy (HR, 0.17; 95% CI, 0.22-1.36; P = .10). There was an inverse correlation between log[NFL] concentration and overall survival (HR, 2.45; 95% CI, 1.66-3.61; P < .001). There was no evidence of different log[NFL] concentrations and survival in genetic ALS. Conclusions and Relevance This study confirms the role of NFL as a biomarker in ALS. Elevation in NFL levels in patients with upper motor neuron involvement and FTD might reflect the corticospinal tract degeneration. Low NFL levels in patients with lower motor neuron signs might be a prognostic indicator of milder phenotypes of disease.

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CitationGPTRetr70

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Abstract of the paper: OBJECTIVE To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. METHODS In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. RESULTS For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. CONCLUSIONS Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

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CitationGPTRetr71

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament light chain protein in neurodegenerative dementia: A systematic review and network meta-analysis. Abstract of the paper: The diagnostic value of neurofilament light chain protein in neurodegenerative dementia diseases is still controversial. A systematic literature search was performed to identify relevant case-control studies conducted through October 2018. Traditional and net meta-analyses were performed based on 42 studies that tested the diagnostic performance of neurofilament light chain protein (NfL) concentration in CSF and serum/plasma from patients with neurodegenerative dementia. CSF and serum/plasma NfL levels were significantly increased in patients with neurodegenerative dementia diseases. Network meta-analysis showed a significant reduction in CSF NfL levels during mild cognitive impairment, whereas an increase was observed in vascular dementia compared to Alzheimer's disease. Surface under the cumulative ranking curve and cluster analysis showed that the NfL concentration in CSF (vascular dementia, frontotemporal dementia, and Alzheimer's disease) and serum/plasma (frontotemporal dementia and Alzheimer's disease) ranked first among neurodegenerative dementia diseases. NfL is an important biomarker that can help clinical neurologists make early diagnoses of neurodegenerative diseases, so patients can receive prompt treatment.

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CitationGPTRetr72

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Blood Neurofilament Light Chain: The Neurologist's Troponin? Abstract of the paper: Blood neurofilament light chain (NfL) is a marker of neuro-axonal injury showing promising associations with outcomes of interest in several neurological conditions. Although initially discovered and investigated in the cerebrospinal fluid (CSF), the recent development of ultrasensitive digital immunoassay technologies has enabled reliable detection in serum/plasma, obviating the need for invasive lumbar punctures for longitudinal assessment. The most evidence for utility relates to multiple sclerosis (MS) where it serves as an objective measure of both the inflammatory and degenerative pathologies that characterise this disease. In this review, we summarise the physiology and pathophysiology of neurofilaments before focusing on the technological advancements that have enabled reliable quantification of NfL in blood. As the test case for clinical translation, we then highlight important recent developments linking blood NfL levels to outcomes in MS and the next steps to be overcome before this test is adopted on a routine clinical basis.

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CitationGPTRetr73

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with Amyotrophic Lateral Sclerosis. Abstract of the paper: AIMS Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degeneration disease with a diagnostic delay of about 1 year after symptoms onset. In ALS, blood neurofilament light chain (NfL) levels are elevated, but it is not entirely clear what drives this increase and what the diagnostic performance of serum NfL is in terms of predictive values and likelihood ratios. The aims of this study were to further explore the prognostic and diagnostic performances of serum NfL to discriminate between patients with ALS and ALS mimics, and to investigate the relationship between serum NfL with motor neuron degeneration. METHODS The diagnostic performances of serum NfL were based on a cohort of 149 serum samples of patients with ALS, 19 serum samples of patients with a disease mimicking ALS and 82 serum samples of disease control patients. The serum NfL levels were correlated with the number of regions (thoracic, bulbar, upper limb and lower limb) displaying upper and/or lower motor neuron degeneration. The prognostic performances of serum NfL were investigated based on a Cox regression analysis. RESULTS The associated predictive values and likelihood ratio to discriminate patients with ALS and ALS mimics were established. Serum NfL was associated with motor neuron degeneration driven by upper motor neuron (UMN) degeneration and was independently associated with survival in patients with ALS. CONCLUSIONS Altogether, these findings suggest that elevated serum NfL levels in ALS are driven by UMN degeneration and the disease progression rate and are independently associated with survival at time of diagnosis.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Diagnostic and prognostic significance of neurofilament light chain NF-L, but not progranulin and S100B, in the course of amyotrophic lateral sclerosis: Data from the German MND-net. Abstract of the paper: There is a need for diagnostic, prognostic, and monitoring blood biomarkers for ALS. We aimed to analyse and compare proposed candidate markers for disease progression in the course of ALS. Blood samples were taken from 125 ALS patients, including nine patients with C9orf72 or SOD1 mutation, at regular intervals of six months. ALS patients were characterized by the ALS functional rating scale (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). We quantified neurofilament light chain (NF-L), S100B, and progranulin (PGRN) and analysed it in relation to disease progression. Results showed that, at baseline, serum concentrations of NF-L but not PGRN or S100B discriminated significantly between ALS and controls. Within 24 months follow-up the marker concentrations remained stable. Baseline serum NF-L levels correlated with survival time, which was confirmed in subgroups with fast, intermediate, and slow disease progression and there was a weak association with disease duration. For S100B and PGRN we found an association with ALSFRS-R score changes and a trend for decreased levels in the fast progressor subgroup. In conclusion, serum NF-L in any ALS disease stage is a promising marker to support diagnosis and predict outcome, while serum PGRN and S100B are only of minor prognostic value.

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CitationGPTRetr75

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Tracing Neurological Diseases in the Presymptomatic Phase: Insights From Neurofilament Light Chain. Abstract of the paper: The identification of neurological diseases in their presymptomatic phase will be a fundamental aim in the coming years. This step is necessary both to optimize early diagnostics and to verify the effectiveness of experimental disease modifying drugs in the early stages of diseases. Among the biomarkers that can detect neurological diseases already in their preclinical phase, neurofilament light chain (NfL) has given the most promising results. Recently, its measurement in serum has enabled the identification of neurodegeneration in diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD) up to 6-10 years before the onset of symptoms. Similar results have been obtained in conditions such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), up to 2 years before clinical onset. Study of the longitudinal dynamics of serum NfL has also revealed interesting aspects of the pathophysiology of these diseases in the preclinical phase. This review sought to discuss these very recent findings on serum NfL in the presymptomatic phase of neurological diseases.

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CitationGPTRetr76

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: CSF Neurofilament Light Chain Levels in Primary Progressive MS: Signs of Axonal Neurodegeneration. Abstract of the paper: Objectives: Elevated neurofilament light chain (NFL) levels within the cerebrospinal fluid (CSF) are a biomarker representing axonal neurodegeneration in rapid progressive neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). It is unclear to what extent the levels of NFL increase in the CSF (CSF-NFL) in a chronic neuroinflammatory process with axonal neurodegeneration, as found in primary progressive multiple sclerosis (PPMS). Methods: We used a multicenter approach to statistically compare CSF-NFL levels between PPMS patients (n = 50), ALS patients (n = 50), and healthy controls (n = 50). Clinical findings, including disease duration, expanded disability status scale (EDSS), electrophysiological recordings such as visual evoked potentials or spinal and cerebral MRI, and previously administered treatment were selected as experimental parameters retrospectively. Results: Median [range] CSF-NFL concentrations in PPMS patients were significantly higher than in the controls [1724 (799-4275) pg/ml vs. 1202 (612-2934) pg/ml, p = 0.015], and significantly lower compared to ALS patients [1724 (799-4275) pg/ml vs. 10238 (2610-35138) pg/ml, p < 0.001]. There was no correlation between CSF-NFL and disease duration (p = 0.5), EDSS (p = 0.2) or treatment (p = 0.3). Conclusion: We conclude that CSF-NFL may mirror the proposed slow axonal degeneration in PPMS, but does not reflect the disease severity.

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CitationGPTRetr77

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases. Abstract of the paper: One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).

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CitationGPTRetr78

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Abstract of the paper: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper and lower motor neurons causing relentless paralysis of voluntary muscles, whereas in FTD, progressive atrophy of the frontal and temporal lobes of the brain results in deterioration of cognitive functions, language, personality, and behavior. In contrast to Alzheimer's disease (AD), ALS and FTD still lack a specific neurochemical biomarker reflecting neuropathology ex vivo. However, in the past 10 years, considerable progress has been made in the characterization of neurofilament light chain (NFL) as cerebrospinal fluid (CSF) and blood biomarker for both diseases. NFL is a structural component of the axonal cytoskeleton and is released into the CSF as a consequence of axonal damage or degeneration, thus behaving in general as a relatively non-specific marker of neuroaxonal pathology. However, in ALS, the elevation of its CSF levels exceeds that observed in most other neurological diseases, making it useful for the discrimination from mimic conditions and potentially worthy of consideration for introduction into diagnostic criteria. Moreover, NFL correlates with disease progression rate and is negatively associated with survival, thus providing prognostic information. In FTD patients, CSF NFL is elevated compared with healthy individuals and, to a lesser extent, patients with other forms of dementia, but the latter difference is not sufficient to enable a satisfying diagnostic performance at individual patient level. However, also in FTD, CSF NFL correlates with several measures of disease severity. Due to technological progress, NFL can now be quantified also in peripheral blood, where it is present at much lower concentrations compared with CSF, thus allowing less invasive sampling, scalability, and longitudinal measurements. The latter has promoted innovative studies demonstrating longitudinal kinetics of NFL in presymptomatic individuals harboring gene mutations causing ALS and FTD. Especially in ALS, NFL levels are generally stable over time, which, together with their correlation with progression rate, makes NFL an ideal pharmacodynamic biomarker for therapeutic trials. In this review, we illustrate the significance of NFL as biomarker for ALS and FTD and discuss unsolved issues and potential for future developments.

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CitationGPTRetr79

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the cytoskeletal protein nfl and its phosphorylated form pnfh are increasingly recognized as the most promising diagnostic biomarkers for als 110119120 which are correlated to rapid progression and a worse prognosis of the disease Title of the paper: Neurological symptoms and blood neurofilament light levels. Abstract of the paper: Neurofilament light chain (NfL) is an incredibly specific marker of neuronal injury that is not specific for cause or location of the neuronal damage. NfL is increasingly considered as possible biomarker of disease activity in neurological conditions. Several works reviewed the utility of NfL in the different diseases. Nonetheless, NfL is a universal marker of neuronal damage, which interpretation spaces beyond the single disease. Because of this, the interpretation of NfL may benefit by also considering how neurological symptoms relate to its blood concentration. Here, we review how different neurological symptoms can be associated with blood NfL levels with a practical interpretation of it.

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CitationGPTRetr80

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Modelling disease progression in Alzheimer's disease: a review of modelling methods used for cost-effectiveness analysis. Abstract of the paper: The literature reporting economic evaluations related to the treatment of Alzheimer's disease (AD) has developed over the last decade. Most analyses have used economic models to estimate the cost effectiveness of drugs for the treatment of AD. This review considers the range of methods used in the published cost-effectiveness literature to model AD progression and the effect of interventions on the progression of AD. The review builds on and updates an earlier systematic review of cost-effectiveness studies on drugs for AD. Systematic and rigorous methods were used to search the literature for economic evaluations estimating the cost effectiveness of donepezil, rivastigmine, galantamine or memantine in AD. The literature search covered a wide range of electronic databases (e.g. MEDLINE, EMBASE), and included literature from the inception of databases up to the end of 2005. The search identified 22 published economic evaluations. An outline and brief critical review of the identified studies is provided, and thereafter the methods used to model disease progression were considered in more detail. The review employs recent guidance on good practice in decision-analytic modelling in HTA to critically review the modelling methods used. Using this guidance, the models are assessed against the broad criteria of model structure, data inputs and assessment of uncertainty and inconsistency. Concerns were noted over the model structure employed in all models. The reliance on cognitive scores to model AD, the progression of the disease, and the effect of treatment on costs and consequences is regarded as a serious limitation in almost all of the studies identified. There are also limitations over the data used to populate published models, especially around the failure of studies to document and establish the basis for the modelling of treatment effects. It is also clear that studies modelling AD progression, and subsequently the cost effectiveness of treatment, have not addressed uncertainty or consistency (internal and/or external) in sufficient detail. Further research is required on more appropriate methods for the modelling of AD progression. In the meantime, future economic evaluations of treatment need to be more explicit on the methods used to model AD, and the data used to populate models.

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CitationGPTRetr81

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Challenges in demonstrating the value of disease-modifying therapies for Alzheimer's disease. Abstract of the paper: INTRODUCTION Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting millions of people worldwide and imposing heavy economic burdens to societies. Currently, only symptomatic treatments are available for patients, but there is ongoing research on potential therapies that can modify the course of disease. The main objective of this work is to identify and explore the challenges surrounding decision modeling for economic evaluation of interventions for AD. AREAS COVERED This article discusses the challenges in modeling the natural history of disease, particularly regarding the selection of disease progression and outcome measures, the inclusion of biomarker status in models, and the approach to model mortality. Challenges stemming from the use of long-term assumptions regarding treatment effects and the need for real-world evidence to fill data gaps are discussed. Lastly, the overwhelming economic impact of disease and the challenges in estimating these costs for modeling are addressed. EXPERT OPINION Value assessment frameworks need to be reconsidered in order to demonstrate the full benefit of new disease-modifying therapies spanning beyond the scope of health systems. Data collection efforts that expand the evidence base, upon which economic models are based, will reduce the uncertainties surrounding the long-term outcomes of interventions in AD.

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CitationGPTRetr82

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Model-based economic evaluation in Alzheimer's disease: a review of the methods available to model Alzheimer's disease progression. Abstract of the paper: OBJECTIVE To consider the methods available to model Alzheimer's disease (AD) progression over time to inform on the structure and development of model-based evaluations, and the future direction of modelling methods in AD. METHODS A systematic search of the health care literature was undertaken to identify methods to model disease progression in AD. Modelling methods are presented in a descriptive review. RESULTS The literature search identified 42 studies presenting methods or applications of methods to model AD progression over time. The review identified 10 general modelling frameworks available to empirically model the progression of AD as part of a model-based evaluation. Seven of these general models are statistical models predicting progression of AD using a measure of cognitive function. The main concerns with models are on model structure, around the limited characterization of disease progression, and on the use of a limited number of health states to capture events related to disease progression over time. None of the available models have been able to present a comprehensive model of the natural history of AD. CONCLUSIONS Although helpful, there are serious limitations in the methods available to model progression of AD over time. Advances are needed to better model the progression of AD and the effects of the disease on peoples' lives. Recent evidence supports the need for a multivariable approach to the modelling of AD progression, and indicates that a latent variable analytic approach to characterising AD progression is a promising avenue for advances in the statistical development of modelling methods.

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CitationGPTRetr83

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Systematic Review of Model-Based Economic Evaluations of Treatments for Alzheimer's Disease. Abstract of the paper: BACKGROUND Numerous economic evaluations using decision-analytic models have assessed the cost effectiveness of treatments for Alzheimer's disease (AD) in the last two decades. It is important to understand the methods used in the existing models of AD and how they could impact results, as they could inform new model-based economic evaluations of treatments for AD. OBJECTIVE The aim of this systematic review was to provide a detailed description on the relevant aspects and components of existing decision-analytic models of AD, identifying areas for improvement and future development, and to conduct a quality assessment of the included studies. METHODS We performed a systematic and comprehensive review of cost-effectiveness studies of pharmacological treatments for AD published in the last decade (January 2005 to February 2015) that used decision-analytic models, also including studies considering patients with mild cognitive impairment (MCI). The background information of the included studies and specific information on the decision-analytic models, including their approach and components, assumptions, data sources, analyses, and results, were obtained from each study. A description of how the modeling approaches and assumptions differ across studies, identifying areas for improvement and future development, is provided. At the end, we present our own view of the potential future directions of decision-analytic models of AD and the challenges they might face. RESULTS The included studies present a variety of different approaches, assumptions, and scope of decision-analytic models used in the economic evaluation of pharmacological treatments of AD. The major areas for improvement in future models of AD are to include domains of cognition, function, and behavior, rather than cognition alone; include a detailed description of how data used to model the natural course of disease progression were derived; state and justify the economic model selected and structural assumptions and limitations; provide a detailed (rather than high-level) description of the cost components included in the model; and report on the face-, internal-, and cross-validity of the model to strengthen the credibility and confidence in model results. The quality scores of most studies were rated as fair to good (average 87.5, range 69.5-100, in a scale of 0-100). CONCLUSION Despite the advancements in decision-analytic models of AD, there remain several areas of improvement that are necessary to more appropriately and realistically capture the broad nature of AD and the potential benefits of treatments in future models of AD.

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CitationGPTRetr84

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Taking stock: A multistakeholder perspective on improving the delivery of care and the development of treatments for Alzheimer's disease. Abstract of the paper: Health-care stakeholders increasingly recognize that the scientific and economic challenges associated with Alzheimer's disease (AD) are simply too great for individual stakeholder groups to address solely from within their own silos. In the necessary spirit of collaboration, we present in this perspective a set of multicountry multistakeholder recommendations to improve the organization of existing AD and dementia care and the development of new treatments. In brief, the five recommendations are (1) health-care systems must make choices regarding the patient populations to be diagnosed and treated, (2) health-care systems should use an evidence-based standard of care, (3) increased collaboration between public and private institutions is needed to enhance research, (4) reimbursement end points need to be agreed on and validated, and (5) innovative business models should be used to spur the introduction of new medicines.

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CitationGPTRetr85

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Assessing cost-effectiveness of early intervention in Alzheimer's disease: An open-source modeling framework. Abstract of the paper: INTRODUCTION We develop a framework to model disease progression across Alzheimer's disease (AD) and to assess the cost-effectiveness of future disease-modifying therapies (DMTs) for people with mild cognitive impairment (MCI) due to AD. METHODS Using data from the US National Alzheimer's Coordinating Center, we apply survival analysis to estimate transition from predementia to AD dementia and ordered probit regression to estimate transitions across AD dementia stages. We investigate the cost-effectiveness of a hypothetical treatment scenario for people in MCI due to AD. RESULTS We present an open-access model-based decision-analytic framework. Assuming a modest DMT treatment effect in MCI, we predict extended life expectancy and a reduction in time with AD dementia. DISCUSSION Any future DMT for AD is expected to pose significant economic challenges across all health-care systems, and decision-analytic modeling will be required to assess costs and outcomes. Further developments are needed to inform these health policy considerations.

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CitationGPTRetr86

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Current issues and future research priorities for health economic modelling across the full continuum of Alzheimer's disease. Abstract of the paper: Available data and models for the health-economic evaluation of treatment in Alzheimer's disease (AD) have limitations causing uncertainty to decision makers. Forthcoming treatment strategies in preclinical or early AD warrant an update on the challenges associated with their economic evaluation. The perspectives of the co-authors were complemented with a targeted review of literature discussing methodological issues and data gaps in AD health-economic modelling. The methods and data available to translate treatment efficacy in early disease into long-term outcomes of relevance to policy makers and payers are limited. Current long-term large-scale data accurately representing the continuous, multifaceted, and heterogeneous disease process are missing. The potential effect of disease-modifying treatment on key long-term outcomes such as institutionalization and death is uncertain but may have great effect on cost-effectiveness. Future research should give priority to collaborative efforts to access better data on the natural progression of AD and its association with key long-term outcomes.

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CitationGPTRetr87

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Modelling the value of innovative treatments for Alzheimer's disease in the United States. Abstract of the paper: Alzheimer's disease (AD) is the predominant cause of dementia and a leading cause of death globally. With no cure or treatment to slow disease progression, AD-related healthcare costs are substantial and increase as the severity of the disease progresses. Given the complexity of this disease, including initial pathophysiological damage occurring decades before clinical manifestation, finding new impactful treatments for AD relies on highly innovative research and development. However, such sizable and sustained investments bring into question whether conventional value assessment models are fit for this purpose. In this article, we examine the importance and challenges of assimilating the perspectives of varied stakeholders, including patients, caregivers, health systems, payers, and society at large, into a comprehensive value assessment model that may be well suited for a breakthrough treatment for AD.

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CitationGPTRetr88

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Who funds Alzheimer's disease drug development? Abstract of the paper: INTRODUCTION Despite the increase in Alzheimer's disease (AD) cases in the United States, no new treatments have been approved in the United States since 2003. The costs associated with drug development programs are high and serve as a significant deterrent to AD therapeutic investigations. In this study, we analyze the sponsorship data for AD clinical trials conducted since 2016 to assess the fiscal support for AD clinical trials. METHODS We analyzed the funding sources of all AD trials over the past 5 years as reported on ClinicalTrials.gov. RESULTS There were 136 trials being conducted for treatments in the US AD therapeutic pipeline on the index date of this study. Among non-prevention trials, disease-modifying therapies (DMT) in Phase 3 were almost entirely sponsored by the biopharmaceutical industry; Phase 2 DMT trials were split between the biopharmaceutical industry and funding from the National Institutes of Health (NIH) to academic medical centers (AMCs). The majority of prevention trials received sponsorship from public-private partnerships (PPP). Trials of symptomatic agents are equally likely to have biopharmaceutical or NIH/AMC sponsorship. Most trials with repurposed agents had NIH/AMC funding (89%). Since 2016, there has been consistent growth in the number of trials sponsored both in part and fully by NIH/AMC sources and in PPP, and there has been a reduction in biopharmaceutical company-sponsored trials. DISCUSSION The number of trials supported by the biopharmaceutical industry has decreased over the past 5 years; trials supported from federal sources and PPP have increased. Repurposed compounds are mostly in Phase 2 trials and provide critical mechanistic information.

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CitationGPTRetr89

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Global Trends in Alzheimer Disease Clinical Development: Increasing the Probability of Success. Abstract of the paper: PURPOSE Alzheimer disease (AD) is a growing global health and economic issue as elderly populations increase dramatically across the world. Despite the many clinical trials conducted, currently no approved disease-modifying treatment exists. In this commentary, the present status of AD drug development and the grounds for collaborations between government, academia, and industry to accelerate the development of disease-modifying AD therapies are discussed. METHODS Official government documents, literature, and news releases were surveyed by MEDLINE and website research. FINDINGS Currently approved anti-AD drugs provide only short-lived symptomatic improvements, which have no effect on the underlying pathogenic mechanisms or progression of the disease. The failure to approve a disease-modifying drug for AD may be because the progression of AD in the patient populations enrolled in clinical studies was too advanced for drugs to demonstrate cognitive and functional improvements. The US Food and Drug Administration and the European Medicines Agency recently published draft guidance for industry which discusses approaches for conducting clinical studies with patients in early AD stages. For successful clinical trials in early-stage AD, however, it will be necessary to identify biomarkers highly correlated with the clinical onset and the longitudinal progress of AD. In addition, because of the high cost and length of clinical AD studies, support in the form of global initiatives and collaborations between government, industry, and academia is needed. IMPLICATIONS In response to this situation, national guidance and international collaborations have been established. Global initiatives are focusing on 2025 as a goal to provide new treatment options, and early signs of success in biomarker and drug development are already emerging.

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CitationGPTRetr90

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: model development is based on prior research eg study by green and zhang 22 a strong understanding of the existing methods and literature in this area 13152324 clinical input and consultation across a wide range of stakeholders eg via international conference on pharmacoeconomics of alzheimers disease Title of the paper: Alzheimer's disease drug development pipeline: 2022. Abstract of the paper: Introduction Alzheimer's disease (AD) represents a global health crisis. Treatments are needed to prevent, delay the onset, slow the progression, improve cognition, and reduce behavioral disturbances of AD. We review the current clinical trials and drugs in development for the treatment of AD. Methods We searched the governmental website clinicaltrials.gov where are all clinical trials conducted in the United States must be registered. We used artificial intelligence (AI) and machine learning (ML) approaches to ensure comprehensive detection and characterization of trials and drugs in development. We use the Common Alzheimer's Disease Research Ontology (CADRO) to classify drug targets and mechanisms of action of drugs in the pipeline. Results As of January 25, 2022 (index date for this study) there were 143 agents in 172 clinical trials for AD. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease-modifying therapies represent 83.2% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent 9.8% of agents in trials; and drugs for the treatment of neuropsychiatric symptoms comprise 6.9%. There is a diverse array of drug targets represented by agents in trials including nearly all CADRO categories. Thirty-seven percent of the candidate agents in the pipeline are repurposed drugs approved for other indications. A total of 50,575 participants are needed to fulfill recruitment requirements for all currently active clinical trials. Discussion The AD drug development pipeline has agents representing a substantial array of treatment mechanisms and targets. Advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with AD. Highlights There are 143 drugs in the current Alzheimer's disease (AD) drug development pipeline.Disease-modifying therapies represent 83.2% of the candidate treatments.Current trials require 50,575 participants who will donate 3,878,843 participant-weeks to clinical trials.The biopharmaceutical industry sponsors 50% of all clinical trials including 68% of Phase 3 trials.Sixty-three percent of Phase 3 trials and 46% of Phase 2 trials include non-North American clinical trial site locations indicating the global ecosystem required for AD drug development.

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