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Clinical and biological significance of RNA N6-methyladenosine regulators in Alzheimer disease.

RNA N6-methyladenosine (m6A) regulators are essential for a variety of biological functions, such as early development, viral infections, and cancer. However, their roles in Alzheimer disease (AD) are still not very clear. Here, 16 significant m6A regulators were identified using difference analysis between AD patients and non-demented controls based on the GSE132903 dataset from the Gene Expression Omnibus database. Using these 16 m6A regulators, a nomogram model was established to predict the prevalence of AD. We found that patients could obtain a good clinical benefit based on this model. In addition, we revealed 2 distinct m6A patterns and 2 distinct m6A gene patterns in AD and demonstrated their prognostic and risk assessment significance. This present work comprehensively evaluated the functions of m6A regulators in the diagnosis and subtype classification of AD. These results suggested they have potential prognostic and risk assessment significance in AD.

Computer assisted diagnosis of Alzheimers disease using statistical likelihood-ratio test.

The purpose of this work is to present a computer assisted diagnostic tool for radiologists in their diagnosis of Alzheimers disease. A statistical likelihood-ratio procedure from signal detection theory was implemented in the detection of Alzheimers disease. The probability density functions of the likelihood ratio were constructed by using medial temporal lobe (MTL) volumes of patients with Alzheimers disease (AD) and normal controls (NC). The volumes of MTL as well as other anatomical regions of the brains were calculated by the FreeSurfer software using T1 weighted MRI images. The MRI images of AD and NC were downloaded from the database of Alzheimers disease neuroimaging initiative (ADNI). A separate dataset of minimal interval resonance imaging in Alzheimers disease (MIRIAD) was used for diagnostic testing. A sensitivity of 89.1% and specificity of 87.0% were achieved for the MIRIAD dataset which are better than the 85% sensitivity and specificity achieved by the best radiologists without input of other patient information.

The impact of attending historically Black colleges and universities on cognitive decline in Black adults A longitudinal analysis in the KHANDLE and STAR cohorts.

Black students attending predominantly White institutions (PWIs) versus historically Black colleges and universities (HBCUs) report more harmful discrimination and develop worse mental health outcomes, potentially offsetting the established benefits of college for lowering dementia incidence. Black participants in two cohorts (the Kaiser Healthy Aging and Diverse Life Experiences KHANDLE and the Study of Healthy Aging in African Americans STAR) who had attended college (N 716) self-reported the college name (classified as HBCU vs. PWI) and completed three waves of executive function (EF) and verbal episodic memory (VEM) assessments. HBCU effects on cognitive level and decline were estimated using adjusted linear mixed-effects models. HBCU (vs. PWI) attendees averaged better EF (β 0.05 -0.22, 0.32) and VEM (β 0.21 -0.06, 0.46) at age 70 though neither association was statistically significant. HBCU attendance was associated with slightly faster VEM decline (β -0.03 -0.05, 0.00). Harmonized analyses with larger studies are needed to estimate important effects of HBCU attendance. Higher education is robustly linked to lower dementia risk, yet Black-White inequities persist among college-educated adults. Black students attending predominantly White institutions (PWIs) versus historically Black colleges and universities (HBCUs) report more harmful discrimination and develop worse mental health outcomes, which may offset the established benefits of college for lowering dementia incidence. HBCU (vs. non-HBCU) attendees averaged better executive function and verbal episodic memory (VEM) at average age 70, though confidence intervals were wide and associations were not statistically significant, and averaged slightly faster decline in VEM. Harmonized analyses using larger nationally representative studies are likely needed to avoid underestimating the health effects of HBCU attendance.

Caprylic acid attenuates amyloid-β proteotoxicity by supplying energy via β-oxidation in an Alzheimers disease model of the nematode

Computer-based analysis of motility was used as a measure of amyloid-β (Aβ) proteotoxicity in the transgenic strain GMC101, expressing human Aβ

What happens when people develop dementia whilst working An exploratory multiple case study.

This study is an in-depth exploration of the unfolding experiences of five persons who developed dementia while still in paid workemployment, and of their significant others. Namely, we explore how they experienced the actions and decisions taken with respect to work, and what the consequences meant to them. A qualitative longitudinal case study design with multiple cases was used, including five participants with dementia and significant others of their choice. Interviews were undertaken longitudinally and analysed with the Formal Data-Structure Analysis approach. The joint analysis resulted in two intertwined themes 1) The significance and consequences of a dementia diagnosis a double-edged trigger, and 2) Sensemaking and agency. The prevalent images of what dementia is, who cancannot get it and what it will bring, were revealed as the critical aspects. Having the opportunity to make sense of what has happened and participate in decision-making, contributed decisively to the participants experiences. Findings illustrate how a dementia diagnosis is alien in work-life, but once diagnosed, it may trigger self-fulfiling expectations based upon stereotypical understanding of dementia. A shift is needed from a deficit-focused perspective, to viewing people with dementia as citizens capable of agency.

Using Explainable Artificial Intelligence in the Clock Drawing Test to Reveal the Cognitive Impairment Pattern.

The prevalence of dementia is currently increasing worldwide. This syndrome produces a deterioration in cognitive function that cannot be reverted. However, an early diagnosis can be crucial for slowing its progress. The Clock Drawing Test (CDT) is a widely used paper-and-pencil test for cognitive assessment in which an individual has to manually draw a clock on a paper. There are a lot of scoring systems for this test and most of them depend on the subjective assessment of the expert. This study proposes a computer-aided diagnosis (CAD) system based on artificial intelligence (AI) methods to analyze the CDT and obtain an automatic diagnosis of cognitive impairment (CI). This system employs a preprocessing pipeline in which the clock is detected, centered and binarized to decrease the computational burden. Then, the resulting image is fed into a Convolutional Neural Network (CNN) to identify the informative patterns within the CDT drawings that are relevant for the assessment of the patients cognitive status. Performance is evaluated in a real context where patients with CI and controls have been classified by clinical experts in a balanced sample size of Formula see text drawings. The proposed method provides an accuracy of Formula see text in the binary case-control classification task, with an AUC of Formula see text. These results are indeed relevant considering the use of the classic version of the CDT. The large size of the sample suggests that the method proposed has a high reliability to be used in clinical contexts and demonstrates the suitability of CAD systems in the CDT assessment process. Explainable artificial intelligence (XAI) methods are applied to identify the most relevant regions during classification. Finding these patterns is extremely helpful to understand the brain damage caused by CI. A validation method using resubstitution with upper bound correction in a machine learning approach is also discussed.

Brain deficit patterns of metabolic illnesses overlap with those for major depressive disorder A new metric of brain metabolic disease.

Metabolic illnesses (MET) are detrimental to brain integrity and are common comorbidities in patients with mental illnesses, including major depressive disorder (MDD). We quantified effects of MET on standard regional brain morphometric measures from 3D brain MRI as well as diffusion MRI in a large sample of UK BioBank participants. The pattern of regional effect sizes of MET in non-psychiatric UKBB subjects was significantly correlated with the spatial profile of regional effects reported by the largest meta-analyses in MDD but not in bipolar disorder, schizophrenia or Alzheimers disease. We used a regional vulnerability index (RVI) for MET (RVI-MET) to measure individuals brain similarity to the expected patterns in MET in the UK Biobank sample. Subjects with MET showed a higher effect size for RVI-MET than for any of the individual brain measures. We replicated elevation of RVI-MET in a sample of MDD participants with MET versus non-MET. RVI-MET scores were significantly correlated with the volume of white matter hyperintensities, a neurological consequence of MET and age, in both groups. Higher RVI-MET in both samples was associated with obesity, tobacco smoking and frequent alcohol use but was unrelated to antidepressant use. In summary, MET effects on the brain were regionally specific and individual similarity to the pattern was more strongly associated with MET than any regional brain structural metric. Effects of MET overlapped with the reported brain differences in MDD, likely due to higher incidence of MET, smoking and alcohol use in subjects with MDD.

Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation.

Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor for cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates cognitive impairment via anti-oxidative stress and anti-inflammation properties however, the underlying mechanisms linking riboflavin metabolism and microglial function in cognitive impairment remain unclear. Here, it is demonstrated that riboflavin kinase (RFK), a critical enzyme in riboflavin metabolism, is specifically expressed in microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression via regulation of lysine-specific methyltransferase 2B (KMT2B). FMN supplementation attenuated the pro-inflammatory TNFR1NF-κB signaling pathway, and this effect is abolished by KMT2B overexpression. To improve the limited anti-inflammatory efficiency of free FMN, a biomimetic microglial nanoparticle strategy (designated as MNPsFMN) is established, which penetrated the blood brain barrier with enhanced microglial-targeted delivery efficiency. Notably, MNPsFMN ameliorated cognitive impairment and dysfunctional synaptic plasticity in a lipopolysaccharide-induced inflammatory mouse model and in a 5xFAD mouse model of Alzheimers disease. Taken together, biomimetic microglial delivery of FMN may serve as a potential therapeutic approach for inflammation-dependent cognitive decline.

The β-adrenergic hypothesis of synaptic and microglial impairment in Alzheimers disease.

Alzheimers disease (AD) is a progressive neurodegenerative disease originating partly from amyloid β protein-induced synaptic failure. As damaging of noradrenergic neurons in the locus coeruleus (LC) occurs at the prodromal stage of AD, activation of adrenergic receptors could serve as the first line of defense against the onset of the disease. Activation of β

NLRP3-directed antisense oligonucleotides reduce microglial immunoactivities in vitro.

Alzheimers disease (AD) is associated with the cerebral deposition of Amyloid-β (Aβ) peptide, which leads to NLRP3 inflammasome activation and subsequent release of interleukin-1β (IL-1β) and interleukin-18 (IL-18). NLRP3 reduction has been found to increase microglial clearance, protect from synapse loss, and suppress both the changes to synaptic plasticity and spatial memory dysfunction observed in murine AD models. Here we test whether NLRP3-directed antisense oligonucleotides (ASOs) can be harnessed as immune modulators in primary murine microglia and human THP-1 cells. NLRP3 mRNA degradation was achieved at 72 hours of ASO treatment in primary murine microglia. Consequently, NLRP3-directed ASOs significantly reduced the levels of cleaved-caspase-1 and mature IL-1β when microglia were either activated by LPS and nigericin or LPS and Aβ. In human THP-1 cells NLRP3-targeted ASOs also significantly reduced the LPS plus nigericin or LPS plus Aβ-induced release of mature IL-1β. Together NLRP3-directed ASOs can suppress NLRP3 inflammasome activity and subsequent release of IL-1β in primary murine microglia and THP-1 cells. ASOs may represent a new and alternative approach to modulate NLRP3 inflammasome activation in neurodegenerative diseases, in addition to attempts to inhibit the complex pharmacologically.

Preclinical and translational models for delirium Recommendations for future research from the NIDUS delirium network.

Delirium is a common, morbid, and costly syndrome that is closely linked to Alzheimers disease (AD) and AD-related dementias (ADRD) as a risk factor and outcome. Human studies of delirium have advanced our knowledge of delirium incidence and prevalence, risk factors, biomarkers, outcomes, prevention, and management. However, understanding of delirium neurobiology remains limited. Preclinical and translational models for delirium, while challenging to develop, could advance our knowledge of delirium neurobiology and inform the development of new prevention and treatment approaches. We discuss the use of preclinical and translational animal models in delirium, focusing on (1) a review of current animal models, (2) challenges and strategies for replicating elements of human delirium in animals, and (3) the utility of biofluid, neurophysiology, and neuroimaging translational markers in animals. We conclude with recommendations for the development and validation of preclinical and translational models for delirium, with the goal of advancing awareness in this important field.

Discovery of reversible selective monoamine oxidase B inhibitors with anti-acetylcholinesterase activity derived from 4-oxo-N-4-diphenyl butanamides.

The ScreeLing Detecting Semantic, Phonological, and Syntactic Deficits in the Clinical Subtypes of Frontotemporal and Alzheimers Dementia.

The ScreeLing is a screening instrument developed to assess post-stroke aphasia, via the linguistic levels Syntax, Phonology, and Semantics. It could also be a useful test for the clinical subtypes of frontotemporal dementia (FTD) and Alzheimers dementia (AD), as specific and often selective disorders are expected. Its ability to differentiate between the clinical subtypes of FTD and AD is, however, still unknown. We investigated differences in ScreeLing total and subscores, linguistic-level disorders relationship with disease severity, and classification abilities, in patients with behavioral variant FTD (bvFTD

Autonomic nervous system and cardiac neuro-signaling pathway modulation in cardiovascular disorders and Alzheimers disease.

The heart is a functional syncytium controlled by a delicate and sophisticated balance ensured by the tight coordination of its several cell subpopulations. Accordingly, cardiomyocytes together with the surrounding microenvironment participate in the heart tissue homeostasis. In the right atrium, the sinoatrial nodal cells regulate the cardiac impulse propagation through cardiomyocytes, thus ensuring the maintenance of the electric network in the heart tissue. Notably, the central nervous system (CNS) modulates the cardiac rhythm through the two limbs of the autonomic nervous system (ANS) the parasympathetic and sympathetic compartments. The autonomic nervous system exerts non-voluntary effects on different peripheral organs. The main neuromodulator of the Sympathetic Nervous System (SNS) is norepinephrine, while the principal neurotransmitter of the Parasympathetic Nervous System (PNS) is acetylcholine. Through these two main neurohormones, the ANS can gradually regulate cardiac, vascular, visceral, and glandular functions by turning on one of its two branches (adrenergic andor cholinergic), which exert opposite effects on targeted organs. Besides these neuromodulators, the cardiac nervous system is ruled by specific neuropeptides (neurotrophic factors) that help to preserve innervation homeostasis through the myocardial layers (from epicardium to endocardium). Interestingly, the dysregulation of this neuro-signaling pathway may expose the cardiac tissue to severe disorders of different etiology and nature. Specifically, a maladaptive remodeling of the cardiac nervous system may culminate in a progressive loss of neurotrophins, thus leading to severe myocardial denervation, as observed in different cardiometabolic and neurodegenerative diseases (myocardial infarction, heart failure, Alzheimers disease). This review analyzes the current knowledge on the pathophysiological processes involved in cardiac nervous system impairment from the perspectives of both cardiac disorders and a widely diffused and devastating neurodegenerative disorder, Alzheimers disease, proposing a relationship between neurodegeneration, loss of neurotrophic factors, and cardiac nervous system impairment. This overview is conducive to a more comprehensive understanding of the process of cardiac neuro-signaling dysfunction, while bringing to light potential therapeutic scenarios to correct or delay the adverse cardiovascular remodeling, thus improving the cardiac prognosis and quality of life in patients with heart or neurodegenerative disorders.

pKr-2 induces neurodegeneration

We recently demonstrated that prothrombin kringle-2 (pKr-2) derived from blood-brain barrier (BBB) disruption could induce hippocampal neurodegeneration and object recognition impairment through neurotoxic inflammatory responses in the five familial Alzheimers disease mutation (5XFAD) mice. In the present study, we aimed to determine whether pKr-2 induces microglial activation by stimulating toll-like receptor 4 (TLR4) upregulation and examine whether this response contributes to pKr-2-induced neuroinflammatory damage in the hippocampi of mice models. We observed that inflammatory responses induced by pKr-2 administration in the hippocampi of wild-type mice were significantly abrogated in TLR4-deficient mice (TLR4

Resting-State Functional Connectivity Changes in Older Adults with Sleep Disturbance and the Role of Amyloid Burden.

Sleep and related disorders could lead to changes in various brain networks, but little is known about the role of amyloid β (Aβ) burden-a key Alzheimers disease (AD) biomarker-in the relationship between sleep disturbance and altered resting state functional connectivity (rsFC) in older adults. This cross-sectional study examined the association between sleep disturbance, Aβ burden, and rsFC using a large-scale dataset from the Alzheimers Disease Neuroimaging Initiative (ADNI). Sample included 489 individuals (53.6% cognitively normal, 32.5% mild cognitive impairment, and 13.9% AD) who had completed sleep measures (Neuropsychiatric Inventory), PET Aβ data, and resting-state fMRI scans at baseline. Within and between rsFC of the Salience (SN), the Default Mode (DMN) and the Frontal Parietal network (FPN) were compared between participants with sleep disturbance versus without sleep disturbance. The interaction between Aβ positivity and sleep disturbance was evaluated using linear regressions, controlling for age, diagnosis status, gender, sedatives and hypnotics use, and hypertension. Although no significant main effect of sleep disturbance was found on rsFC, a significant interaction term emerged between sleep disturbance and Aβ burden on rsFC of SN (β0.11, P0.006). Specifically, sleep disturbance was associated with SN hyperconnectivity, only with the presence of Aβ burden. Sleep disturbance may lead to altered connectivity in the SN when Aβ is accumulated in the brain. Individuals with AD pathology may be at increased risk for sleep-related aberrant rsFC therefore, identifying and treating sleep problems in these individuals may help prevent further disease progression.

ApoE Alzheimers Disease Aβ-amyloid plaque morphology varies according to APOE isotype.

Heterogeneity in Preclinical Alzheimers Disease Trial Cohort Identified by Image-based Data-Driven Disease Progression Modelling.

Undetected biological heterogeneity adversely impacts trials in Alzheimers disease because rate of cognitive decline - and perhaps response to treatment - differs in subgroups. Recent results show that data-driven approaches can unravel the heterogeneity of Alzheimers disease progression. The resulting stratification is yet to be leveraged in clinical trials. Investigate whether image-based data-driven disease progression modelling could identify baseline biological heterogeneity in a clinical trial, and whether these subgroups have prognostic or predictive value. Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected between April 2014 and December 2017, and longitudinal data from the Alzheimers Disease Neuroimaging Initiative (ADNI) observational study downloaded in February 2022 were used. The A4 Study is an interventional trial involving 67 sites in the US, Canada, Australia, and Japan. ADNI is a multi-center observational study in North America. Cognitively unimpaired amyloid-positive participants with a 3-Tesla T1-weighted MRI scan. Amyloid positivity was determined using florbetapir PET imaging (in A4) and CSF Aβ(1-42) (in ADNI). Regional volumes estimated from MRI scans were used as input to the Subtype and Stage Inference (SuStaIn) algorithm. Outcomes included cognitive test scores and SUVr values from florbetapir and flortaucipir PET. We included 1,240 Aβ participants (and 407 Aβ- controls) from the A4 Study, and 731 A4-eligible ADNI participants. SuStaIn identified three neurodegeneration subtypes - In a large secondary prevention trial, our image-based model detected neurodegenerative heterogeneity predictive of cognitive heterogeneity. We argue that such a model is a valuable tool to be considered in future trial design to control for previously undetected variance.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimers disease.

Females with Alzheimers disease (AD) present accelerated damage to cholinergic neurons and undergo accelerated cognitive decline compared to males, but the underlying mechanisms are incompletely understood. Here, we report that tRNA fragments (tRFs) carrying complementary sequences to cholinergic transcripts (CholinotRFs) may causally contribute to both these phenomena. We found that the

Contributions of rare and common variation to early-onset and atypical dementia risk.

We collected and analyzed genomic sequencing data from individuals with clinician- diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients reported Caucasian, non-Hispanic ethnicity and six reported as African American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score was calculated for Alzheimers patients in the total cohort and compared to the scores of a late-onset Alzheimers cohort and a control set. Patients with early-onset Alzheimers had higher non-

MS4A4A modifies the risk of Alzheimer disease by regulating lipid metabolism and immune response in a unique microglia state.

Genome-wide association studies (GWAS) have identified many modifiers of Alzheimer disease (AD) risk enriched in microglia. Two of these modifiers are common variants in the

Epistatic Features and Machine Learning Improve Alzheimers Risk Prediction Over Polygenic Risk Scores.

Polygenic risk scores (PRS) are linear combinations of genetic markers weighted by effect size that are commonly used to predict disease risk. For complex heritable diseases such as late onset Alzheimers disease (LOAD), PRS models fail to capture much of the heritability. Additionally, PRS models are highly dependent on the population structure of data on which effect sizes are assessed, and have poor generalizability to new data. The goal of this study is to construct a paragenic risk score that, in addition to single genetic marker data used in PRS, incorporates epistatic interaction features and machine learning methods to predict lifetime risk for LOAD. We construct a new state-of-the-art genetic model for lifetime risk of Alzheimers disease. Our approach innovates over PRS models in two ways First, by directly incorporating epistatic interactions between SNP loci using an evolutionary algorithm guided by shared pathway information and second, by estimating risk via an ensemble of machine learning models (gradient boosting machines and deep learning) instead of simple logistic regression. We compare the paragenic model to a PRS model from the literature trained on the same dataset. The paragenic model is significantly more accurate than the PRS model under 10-fold cross-validation, obtaining an AUC of 83% and near-clinically significant matched sensitivityspecificity of 75%, and remains significantly more accurate when evaluated on an independent holdout dataset. Additionally, the paragenic model maintains accuracy within APOE genotypes. Paragenic models show potential for improving lifetime disease risk prediction for complex heritable diseases such as LOAD over PRS models.

Safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel AChE inhibitor A phase I study in healthy young and elderly Chinese subjects.

The present study evaluated the safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel AChE inhibitor under development for the treatment of Alzheimers disease (AD) in otherwise healthy young and elderly Chinese subjects. The study of young subjects included the multiple ascending-dose (MAD) arm (2 and 6 mg, N24) and the food effect arm (4 mg, N12) and was followed by the study of elderly subjects who were given (2 and 4 mg, N11). The noncompartmental analysis method was employed to determine the pharmacokinetic parameters. The pharmacokinetics of fed versus fasted dose administration in the same subjects was assessed by 90% confidence interval (CI). In the MAD arm, the accumulation ratios of DC20 in vivo were 2.29 and 2.15, respectively. In the food effect arm, compared with fasting administration, an area under the concentration-time curve from zero to t (AUC

Early activation of Toll-like receptor-3 reduces the pathological progression of Alzheimers disease in APPPS1 mouse.

Toll-like receptor 3 (TLR3) plays an important role in the immuneinflammatory response in the nervous system and is a main pathological feature of Alzheimers disease (AD). This study investigates the role of early activation of TLR3 in the pathophysiological process of AD. In the experiment, the agonist of TLR3, Poly(IC), was intraperitoneally injected into the APPPS1 mouse model of AD and wild-type control mice starting from the age of 4 to 9 months. At the age of 14 months, behavioral tests were conducted. Western blot and immunohistochemistry staining were used to evaluate the level of amyloid β-protein (Aβ), the activation of inflammatory cells, and neuron loss. In addition, the levels of inflammatory cytokines were measured using a quantitative polymerase chain reaction. The results demonstrated that the early activation of TLR3 attenuated neuronal loss and neurobehavioral dysfunction. Moreover, the early activation of TLR3 reduced Aβ deposition, inhibited the activation of microglia and astrocytes, and decreased the transcription of pro-inflammatory factors in the hippocampus. The results indicated that the activation of TLR3 by Poly (IC) in the early stage of development of AD in a mouse model attenuated neuron loss and improved neurobehavioral functions. The underlying mechanisms could be attributed to its role in Aβ clearance, the inhibition of glial cells, and the regulation of neuroinflammation in the hippocampus.

Herbal Therapeutics for Alzheimers Disease Ancient Indian Medicine System from the Modern Viewpoint.

Alzheimers is a chronic neurodegenerative disease where amyloid-beta (Aβ) plaques and neurofibrillary tangles are formed inside the brain. It is also characterized by progressive memory loss, depression, neuroinflammation, and derangement of other neurotransmitters. Due to its complex etiopathology, current drugs have failed to completely cure the disease. Natural compounds have been investigated as an alternative therapy for their ability to treat Alzheimers disease (AD). Traditional herbs and formulations which are used in the Indian ayurvedic system are rich sources of antioxidant, anti-amyloidogenic, neuroprotective, and anti-inflammatory compounds. They promote quality of life by improving cognitive memory and rejuvenating brain functioning through neurogenesis. A rich knowledge base of traditional herbal plants (Turmeric, Gingko, Ashwagandha, Shankhpushpi, Giloy, Gotu kola, Garlic, Tulsi, Ginger, and Cinnamon) combined with modern science could suggest new functional leads for Alzheimers drug discovery. In this article Ayurveda, the ancient Indian herbal medicine system based on multiple clinical and experimental, evidence have been reviewed for treating AD and improving brain functioning. This article presents a modern perspective on the herbs available in the ancient Indian medicine system as well as their possible mechanisms of action for AD treatment. The main objective of this research is to provide a systematic review of herbal drugs that are easily accessible and effective for the treatment of AD.

Cancer and Alzheimers Inverse Correlation an Immunogenetic Analysis.

Numerous studies have demonstrated an inverse link between cancer and Alzheimers disease (AD), with data suggesting that people with Alzheimers have a decreased risk of cancer and vice versa. Although other studies have investigated mechanisms to explain this relationship, the connection between these two diseases remains largely unexplained. Processes seen in cancer, such as decreased apoptosis and increased cell proliferation, seem to be reversed in AD. Given the need for effective therapeutic strategies for AD, comparisons with cancer could yield valuable insights into the disease process and perhaps result in new treatments. Here, through a review of existing literature, we compared the expressions of genes involved in cell proliferation and apoptosis to establish a genetic basis for the reciprocal association between AD and cancer. We discuss an array of genes involved in the aforementioned processes, their relevance to both diseases, and how changes in those genes produce varying effects in either disease.

Validity Assessment of an Automated Brain Morphometry Tool for Patients with De Novo Memory Symptoms.

Automated volumetric analysis of structural MR imaging allows quantitative assessment of brain atrophy in neurodegenerative disorders. We compared the brain segmentation performance of the AI-Rad Companion brain MR imaging software against an in-house FreeSurfer 7.1.1Individual Longitudinal Participant pipeline. T1-weighted images of 45 participants with de novo memory symptoms were selected from the OASIS-4 database and analyzed through the AI-Rad Companion brain MR imaging tool and the FreeSurfer 7.1.1Individual Longitudinal Participant pipeline. Correlation, agreement, and consistency between the 2 tools were compared among the absolute, normalized, and standardized volumes. Final reports generated by each tool were used to compare the rates of detection of abnormality and the compatibility of radiologic impressions made using each tool, compared with the clinical diagnoses. We observed strong correlation, moderate consistency, and poor agreement between absolute volumes of the main cortical lobes and subcortical structures measured by the AI-Rad Companion brain MR imaging tool compared with FreeSurfer. The strength of the correlations increased after normalizing the measurements to the total intracranial volume. Standardized measurements differed significantly between the 2 tools, likely owing to differences in the normative data sets used to calibrate each tool. When considering the FreeSurfer 7.1.1Individual Longitudinal Participant pipeline as a reference standard, the AI-Rad Companion brain MR imaging tool had a specificity of 90.6%-100% and a sensitivity of 64.3%-100% in detecting volumetric abnormalities. There was no difference between the rate of compatibility of radiologic and clinical impressions when using the 2 tools. The AI-Rad Companion brain MR imaging tool reliably detects atrophy in cortical and subcortical regions implicated in the differential diagnosis of dementia.

Neurodegenerative disorders From clinicopathology convergence to systems biology divergence.

Neurodegenerative diseases are multifactorial. This means that several genetic, epigenetic, and environmental factors contribute to their emergence. Therefore, for the future management of these highly prevalent diseases, it is necessary to change perspective. If a holistic viewpoint is assumed, the phenotype (the clinicopathological convergence) emerges from the perturbation of a complex system of functional interactions among proteins (systems biology divergence). The systems biology top-down approach starts with the unbiased collection of sets of data generated through one or more -omics techniques and has the aim to identify the networks and the components that participate in the generation of a phenotype (disease), often without any available a priori knowledge. The principle behind the top-down method is that the molecular components that respond similarly to experimental perturbations are somehow functionally related. This allows the study of complex and relatively poorly characterized diseases without requiring extensive knowledge of the processes under investigation. In this chapter, the use of a global approach will be applied to the comprehension of neurodegeneration, with a particular focus on the two most prevalent ones, Alzheimers and Parkinsons diseases. The final purpose is to distinguish disease subtypes (even with similar clinical manifestations) to launch a future of precision medicine for patients with these disorders.

Models of precision medicine for neurodegeneration.

The clinicopathologic model that defines neurodegenerative disorders has remained unchanged for over a century. According to it, clinical manifestations are defined and explained by a given pathology, that is, by the burden and distribution of selected proteins aggregated into insoluble amyloids. There are two logical consequences from this model (1) a measurement of the disease-defining pathology represents a biomarker of that disease in everyone affected, and (2) the targeted elimination of that pathology should end that disease. But success in disease modification guided by this model has remained elusive. New technologies to probe living biology have been used to validate rather than question the clinicopathologic model, despite three important observations (1) a disease-defining pathology in isolation (without other pathologies) is an exceptional autopsy finding (2) many genetic and molecular pathways converge on the same pathology (3) the presence of pathology without neurological disease is more common than expected by chance. We here discuss the rationale for abandoning the clinicopathologic model, review the competing biological model of neurodegeneration, and propose developmental pathways for biomarker development and disease-modifying efforts. Further, in justifying future disease-modifying trials testing putative neuroprotective molecules, a key inclusion criterion must be the deployment of a bioassay of the mechanism corrected by the therapy of interest. No improvements in trial design or execution can overcome the fundamental deficit created by testing experimental therapies in clinically defined recipients unselected for their biologically suitability. Biological subtyping is the key developmental milestone needed to launch precision medicine for patients living with neurodegenerative disorders.

Biomarkers of diagnosis, prognosis, pathogenesis, response to therapy Convergence or divergence Lessons from Alzheimers disease and synucleinopathies.

Alzheimers disease (AD) is the most common disorder associated with cognitive impairment. Recent observations emphasize the pathogenic role of multiple factors inside and outside the central nervous system, supporting the notion that AD is a syndrome of many etiologies rather than a heterogeneous but ultimately unifying disease entity. Moreover, the defining pathology of amyloid and tau coexists with many others, such as α-synuclein, TDP-43, and others, as a rule, not an exception. Thus, an effort to shift our AD paradigm as an amyloidopathy must be reconsidered. Along with amyloid accumulation in its insoluble state, β-amyloid is becoming depleted in its soluble, normal states, as a result of biological, toxic, and infectious triggers, requiring a shift from convergence to divergence in our approach to neurodegeneration. These aspects are reflected-in vivo-by biomarkers, which have become increasingly strategic in dementia. Similarly, synucleinopathies are primarily characterized by abnormal deposition of misfolded α-synuclein in neurons and glial cells and, in the process, depleting the levels of the normal, soluble α-synuclein that the brain needs for many physiological functions. The soluble to insoluble conversion also affects other normal brain proteins, such as TDP-43 and tau, accumulating in their insoluble states in both AD and dementia with Lewy bodies (DLB). The two diseases have been distinguished by the differential burden and distribution of insoluble proteins, with neocortical phosphorylated tau deposition more typical of AD and neocortical α-synuclein deposition peculiar to DLB. We propose a reappraisal of the diagnostic approach to cognitive impairment from convergence (based on clinicopathologic criteria) to divergence (based on what differs across individuals affected) as a necessary step for the launch of precision medicine.

The theoretical problems of prodrome and phenoconversion in neurodegeneration.

The recognition of and approach to prodromal symptoms, those which manifest before a diagnosis can be ascertained at the bedside, are of increasing interest in neurodegenerative research. A prodrome is conceived of as an early window into a disease, a critical time when putative disease-modifying interventions may be best suited for examination. Several challenges affect research in this area. Prodromal symptoms are highly prevalent in the population, can be nonprogressive for years or decades, and exhibit limited specificity in predicting conversion versus nonconversion into a neurodegenerative category within a time window feasible for most longitudinal clinical studies. In addition, there is a large range of biological alterations subsumed within each prodromal syndrome, forced to converge into the unifying nosology of each neurodegenerative disorder. Initial prodromal subtyping efforts have been developed but given the scarcity of prodrome-to-disease longitudinal studies, it is not yet clear whether any prodromal subtype can be predicted to evolve into the corresponding subtype of manifesting disease - a form of construct validity. As current subtypes generated from one clinical population are not faithfully replicated to others, it is likely that, lacking biological or molecular anchors, prodromal subtypes may only be applicable to the cohorts within which they were developed. Furthermore, as clinical subtypes have not aligned with a consistent pattern of pathology or biology, such might also be the fate of prodromal subtypes. Finally, the threshold defining the change from prodrome to disease for most neurodegenerative disorders remains clinical (e.g., a motor change in gait becoming noticeable to a clinician or measurable with portable technologies), not biological. As such, a prodrome can be viewed as a disease state not yet overt to a clinician. Efforts into identifying biological subtypes of disease, regardless of clinical phenotype or disease stage, may best serve future disease-modifying therapeutic strategies deployed not for a prodromal symptom but for a defined biological derangement as soon as it can be determined to lead to clinical changes, prodromal or not.

Finding the falsification threshold of the toxic proteinopathy hypothesis in neurodegeneration.

A biomedical hypothesis is a theoretical assumption amenable to being tested in a randomized clinical trial. The main hypotheses in neurodegenerative disorders are based on the concept that proteins accumulate in an aggregated fashion and trigger toxicity. The toxic proteinopathy hypothesis posits that neurodegeneration is caused by toxicity of aggregated amyloid in Alzheimers disease (toxic amyloid hypothesis), aggregated α-synuclein in Parkinsons disease (toxic synuclein hypothesis), and aggregated tau in progressive supranuclear palsy (toxic tau hypothesis). To date, we have accumulated 40 negative anti-amyloid randomized clinical, 2 anti-synuclein trials, and 4 anti-tau trials. These results have not prompted a major reconsideration of the toxic proteinopathy hypothesis of causality. Imperfections in trial design and execution (incorrect dosage, insensitive endpoints, too-advanced population) but not in the underlying hypotheses have prevailed as explaining the failures. We review here the evidence suggesting that the threshold of hypothesis falsifiability may be too high and advocate in favor of a minimal set of rules that facilitate the interpretation of negative clinical trials as falsifying the driving hypotheses, in particular if the desirable change in surrogate endpoints has been achieved. We propose four steps to refute a hypothesis in future-negative surrogate-backed trials and argue that for the actual rejection to take place, refutation must be accompanied by the proposal of an alternative hypothesis. The absence of alternative hypotheses may be the single greatest reason why there remains hesitancy in rejecting the toxic proteinopathy hypothesis in the absence of alternatives, we have no clear guidance as to where to redirect or focus.

Deletion of Arrb2 down-regulates autophagy in the mouse hippocampus via Akt-mTOR pathway activation.

The cytoplasmic multifunctional adaptor protein β-arrestin 2 (Arrb2) is involved in the occurrence of various nervous system diseases, such as Alzheimers disease and Parkinsons disease. Previous laboratory studies have shown that the expression and function of the Arrb2 gene was increased in valproic acid-induced autistic mice models. However, few reports have examined the possible role of Arrb2 in the pathogenesis of autism spectrum disorder. Therefore, Arrb2-deficient (Arrb2

Understanding Alzheimers Disease in the Context of Aging Findings from Applications of Stochastic Process Models to the Health and Retirement Study.

There is growing literature on applications of biodemographic models, including stochastic process models (SPM), to studying regularities of age dynamics of biological variables in relation to aging and disease development. Alzheimers disease (AD) is especially good candidate for SPM applications because age is a major risk factor for this heterogeneous complex trait. However, such applications are largely lacking. This paper starts filling this gap and applies SPM to data on onset of AD and longitudinal trajectories of body mass index (BMI) constructed from the Health and Retirement Study surveys and Medicare-linked data. We found that APOE e4 carriers are less robust to deviations of trajectories of BMI from the optimal levels compared to non-carriers. We also observed age-related decline in adaptive response (resilience) related to deviations of BMI from optimal levels as well as APOE- and age-dependence in other components related to variability of BMI around the mean allostatic values and accumulation of allostatic load. SPM applications thus allow revealing novel connections between age, genetic factors and longitudinal trajectories of risk factors in the context of AD and aging creating new opportunities for understanding AD development, forecasting trends in AD incidence and prevalence in populations, and studying disparities in those.

Lung function and risk of incident dementia a prospective cohort study of 431,834 individuals.

Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30%) developed all-cause dementia, which consisted of 2,511 Alzheimers dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 second liter hazard ratio HR, 95%CI, 1.24 1.14-1.34, P1.10×10 Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention.

Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells.

Recently, several studies have demonstrated that low-dose radiation (LDR) therapy has positively impacts on the treatment of Alzheimers disease (AD). LDR suppresses the production of pro-neuroinflammation molecules and improves cognitive function in AD. However, it is unclear whether direct exposure to LDR causes beneficial effects and what mechanism is involved in neuronal cells. In this study, we first determined the effect of high-dose radiation (HDR) alone on C6 cells and SH-SY5Y cells. We found that SH-SY5Y cells were more vulnerable than C6 cells to HDR. Moreover, in neuronal SH-SY5Y cells exposed to single or multiple LDR, N-type cells showed decreased cell viability with increasing radiation exposure time and frequency, but S-type cells were unaffected. Multiple LDR increased proapoptotic molecules such as p53, Bax and cleaved caspase-3, and decreased anti-apoptotic molecule (Bcl

NMDAR-Arc signaling is required for Memory Updating and is disrupted in Alzheimers Disease.

Memory deficits are central to many neuropsychiatric diseases. During acquisition of new information memories can become vulnerable to interference, yet mechanisms that underlie interference are unknown. We describe a novel transduction pathway that links NMDAR to AKT signaling via the IEG Arc, and evaluate its role in memory. The signaling pathway is validated using biochemical tools and genetic animals, and function is evaluated in assays of synaptic plasticity and behavior. The translational relevance is evaluated in human postmortem brain. Arc is dynamically phosphorylated by CaMKII and binds the NMDA receptor (NMDAR) subunits NR2ANR2B and a previously unstudied PI3K adaptor p55PIK (PIK3R3) in vivo in response to novelty or tetanic stimulation in acute slices. NMDAR-Arc-p55PIK recruits p110α PI3K and mTORC2 to activate AKT. NMDAR-Arc-p55PIK-PI3K-mTORC2-AKT assembly occurs within minutes of exploratory behavior and localizes to sparse synapses throughout hippocampus and cortical regions. Studies using conditional (Nestin-Cre) p55PIK deletion mice indicate that NMDAR-Arc-p55PIK-PI3K-mTORC2-AKT functions to inhibit GSK3 and mediates input-specific metaplasticity that protects potentiated synapses from subsequent depotentiation. p55PIK cKO mice perform normally in multiple behaviors including working-memory and long-term memory tasks but exhibit deficits indicative of increased vulnerability to interference in both short-term and long-term paradigms. The NMDAR-AKT transduction complex is reduced in postmortem brain of individuals with early Alzheimers disease. A novel function of Arc mediates synapse-specific NMDAR-AKT signaling and metaplasticity that contributes to memory updating and is disrupted in human cognitive disease.

Aquaporin-4 in glymphatic system, and its implication for central nervous system disorders.

The clearance function is essential for maintaining brain tissue homeostasis, and the glymphatic system is the main pathway for removing brain interstitial solutes. Aquaporin-4 (AQP4) is the most abundantly expressed aquaporin in the central nervous system (CNS) and is an integral component of the glymphatic system. In recent years, many studies have shown that AQP4 affects the morbidity and recovery process of CNS disorders through the glymphatic system, and AQP4 shows notable variability in CNS disorders and is part of the pathogenesis of these diseases. Therefore, there has been considerable interest in AQP4 as a potential and promising target for regulating and improving neurological impairment. This review aims to summarize the pathophysiological role that AQP4 plays in several CNS disorders by affecting the clearance function of the glymphatic system. The findings can contribute to a better understanding of the self-regulatory functions in CNS disorders that AQP4 were involved in and provide new therapeutic alternatives for incurable debilitating neurodegenerative disorders of CNS in the future.

Extracellular vesicles derived from Porphyromonas gingivalis induce vagus nerve-mediated cognitive impairment.

Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimers disease (AD). PG-derived extracellular vesicles (pEVs) contain inflammation-inducing virulence factors, including gingipains (GPs) and lipopolysaccharide (LPS). To understand how PG could cause cognitive decline, we investigated the effects of PG and pEVs on the etiology of periodontitis and cognitive impairment in mice. Cognitive behaviors were measured in the Y-maze and novel object recognition tasks. Biomarkers were measured using ELISA, qPCR, immunofluorescence assay, and pyrosequencing. pEVs contained neurotoxic GPs and inflammation-inducible fimbria protein and LPS. Gingivally exposed, but not orally gavaged, PG or pEVs caused periodontitis and induced memory impairment-like behaviors. Gingival exposure to PG or pEVs increased TNF-α expression in the periodontal and hippocampus tissues. They also increased hippocampal GP Gingivally infected PG, particularly pEVs, may cause cognitive decline with periodontitis. PG products pEVs and LPS may be translocated into the brain through the trigeminal nerve and periodontal blood pathways, respectively, resulting in the cognitive decline, which may cause colitis and gut dysbiosis. Therefore, pEVs may be a remarkable risk factor for dementia.

Osmolytes Wonder molecules to combat protein misfolding against stress conditions.

The proper functioning of any protein depends on its three dimensional conformation which is achieved by the accurate folding mechanism. Keeping away from the exposed stress conditions leads to cooperative unfolding and sometimes partial folding, forming the structures like protofibrils, fibrils, aggregates, oligomers, etc. leading to several neurodegenerative diseases like Parkinsons disease, Alzheimers, Cystic fibrosis, Huntington, Marfan syndrome, and also cancers in some cases, too. Hydration of proteins is necessary, which may be achieved by the presence of organic solutes called osmolytes within the cell. Osmolytes belong to different classes in different organisms and play their role by preferential exclusion of osmolytes and preferential hydration of water molecules and achieves the osmotic balance in the cell otherwise it may cause problems like cellular infection, cell shrinkage leading to apoptosis and cell swelling which is also the major injury to the cell. Osmolyte interacts with protein, nucleic acids, intrinsically disordered proteins by non-covalent forces. Stabilizing osmolytes increases the Gibbs free energy of the unfolded protein and decreases that of folded protein and vice versa with denaturants (urea and guanidinium hydrochloride). The efficacy of each osmolyte with the protein is determined by the calculation of m value which reflects its efficiency with protein. Hence osmolytes can be therapeutically considered and used in drugs.

Study of neuropathological changes and dementia in 100 centenarians in The 90 Study.

The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90 Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

Identification of circRNAs linked to Alzheimers disease and related dementias.

Circular RNAs (circRNAs) exhibit selective expression in the brain and differential regulation in Alzheimers disease (AD). To explore the role of circRNAs in AD, we investigated how circRNA expression varies between brain regions and with AD-related stress in human neuronal precursor cells (NPCs). Ribosomal RNA-depleted hippocampus RNA-sequencing data were generated. Differentially regulated circRNAs in AD and related dementias were detected using CIRCexplorer3 and limma. circRNA results were validated using quantitative real-time PCR of cDNA from the brain and NPCs. We identified 48 circRNAs that were significantly associated with AD. We observed that circRNA expression differed by dementia subtype. Using NPCs, we demonstrated that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in the AD brain. Our study shows that differential expression of circRNA can vary by dementia subtype and brain region. We also demonstrated that circRNAs can be regulated by AD-linked neuronal stress independently from their cognate linear messenger RNAs (mRNAs).

Neuroimaging in Dementia.

Neurodegenerative diseases are significant health concerns with regard to morbidity and social and economic hardship around the world. This review describes the state of the field of neuroimaging measures as biomarkers for detection and diagnosis of both slowly progressing and rapidly progressing neurodegenerative diseases, specifically Alzheimer disease, vascular cognitive impairment, dementia with Lewy bodies or Parkinson disease dementia, frontotemporal lobar degeneration spectrum disorders, and prion-related diseases. It briefly discusses findings in these diseases in studies using MRI and metabolic and molecular-based imaging (eg, positron emission tomography PET and single-photon emission computerized tomography SPECT). Neuroimaging studies with MRI and PET have demonstrated differential patterns of brain atrophy and hypometabolism in different neurodegenerative disorders, which can be useful in differential diagnoses. Advanced MRI sequences, such as diffusion-based imaging, and functional MRI (fMRI) provide important information about underlying biological changes in dementia and new directions for development of novel measures for future clinical use. Finally, advancements in molecular imaging allow clinicians and researchers to visualize dementia-related proteinopathies and neurotransmitter levels. Diagnosis of neurodegenerative diseases is primarily based on symptomatology, although the development of in vivo neuroimaging and fluid biomarkers is changing the scope of clinical diagnosis, as well as the research into these devastating diseases. This article will help inform the reader about the current state of neuroimaging in neurodegenerative diseases, as well as how these tools might be used for differential diagnoses.

Neuropathology-based APOE genetic risk score better quantifies Alzheimers risk.

Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimers disease (AD) however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes. We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimers Prevention (WRAP), Wisconsin Alzheimers Disease Research Center (WADRC), and Alzheimers Disease Neuroimaging Initiative (ADNI). The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.

Microglia play a critical role in the pathogenic process of neurodegenerative diseases, such as Parkinsons disease (PD) and Alzheimers disease (AD). Upon pathological stimulation, microglia are converted from a surveillant to an overactivated phenotype. However, the molecular characters of proliferating microglia and their contributions to the pathogenesis of neurodegeneration remain unclear. Here, we identify chondroitin sulfate proteoglycan 4 (

CSF biomarker concordance with amyloid PET in Phase 3 studies of aducanumab.

We assessed the use of cerebrospinal fluid (CSF) biomarkers as an alternative to positron emission tomography (PET) for brain amyloid beta (Aβ) pathology confirmation in the EMERGE and ENGAGE clinical trials. EMERGE and ENGAGE were randomized, placebo-controlled, Phase 3 trials of aducanumab in participants with early Alzheimers disease. Concordance between CSF biomarkers (Aβ42, Aβ40, phosphorylated tau 181, and total tau) and amyloid PET status (visual read) at screening was examined. Robust concordance between CSF biomarkers and amyloid PET visual status was observed (for Aβ42Aβ40, AUC 0.90 95% CI 0.83-0.97 p < 0.0001), confirming CSF biomarkers as a reliable alternative to amyloid PET in these studies. Compared with single CSF biomarkers, CSF biomarker ratios showed better agreement with amyloid PET visual reads, demonstrating high diagnostic accuracy. These analyses add to the growing body of evidence supporting CSF biomarkers as reliable alternatives to amyloid PET imaging for brain Aβ pathology confirmation. CSF biomarkers and amyloid PET concordance were assessed in Ph3 aducanumab trials. Robust concordance between CSF biomarkers and amyloid PET was observed. CSF biomarker ratios increased diagnostic accuracy over single CSF biomarkers. CSF Aβ42Aβ40 demonstrated high concordance with amyloid PET. Results support CSF biomarker testing as a reliable alternative to amyloid PET.

Synthesis and In Vitro and In Vivo Evaluation of

Accurate quantification of amyloid beta (Aβ) plaques is an important indicator for Alzheimers disease diagnosis and treatment. For this purpose, new highly sensitive Aβ tracers were designed by regulating the position and number of nitrogen atoms. A series of derivatives of florbetapir (AV45) containing different numbers and positions of

Research on Diagnostic Markers for Post-Stroke Cognitive Impairment.

Post-stroke cognitive impairment (PSCI) is secondary to stroke, and is a significant burden for patients, their families and society as a whole. Our study aimed to investigate the predictive value of β-amyloid 42 (Aβ42) and hemoglobin (Hb) in the diagnosis of PSCI. 120 patients were selected and then assigned to either the PSCI group, Alzheimers disease (AD) group or post-stroke cognitive normal (PSCN) group. Baseline data were recorded. Correlation between Aβ42 and Hb and cognitive scores was evaluated. Then, the ability of these indicators to predict PSCI was compared based on logistic regression analysis and ROC curve. Aβ42 and Hb in the PSCI group were lower than in the AD and PSCN groups (P < .05). Compared with AD, hypertension (HTN) and Hb were independent risk factors for PSCI (P < .05), and Aβ42 was a relevant risk factor for PSCI (P .063). Compared with PSCN, age and Hb posed a threat to the occurrence of PSCI (P < .05). Under the ROC curve, the area under the curve (AUC) of the joint diagnosis of Aβ42 and Hb was 0.7169, specificity was 0.625 and sensitivity reached 0.800. Aβ42 and Hb in patients with PSCI were significantly lower than in the AD and PSCN groups, and were risk factors for PSCI. When the two are combined, the differential diagnosis performance may be improved.

Biomarkers Role and Scope in Neurological Disorders.

Neurological disorders pose a great threat to social health and are a major cause for mortality and morbidity. Effective drug development complemented with the improved drug therapy has made considerable progress towards easing symptoms associated with neurological illnesses, yet poor diagnosis and imprecise understanding of these disorders has led to imperfect treatment options. The scenario is complicated by the inability to extrapolate results of cell culture studies and transgenic models to clinical applications which has stagnated the process of improving drug therapy. In this context, the development of biomarkers has been viewed as beneficial to easing various pathological complications. A biomarker is measured and evaluated in order to gauge the physiological process or a pathological progression of a disease and such a marker can also indicate the clinical or pharmacological response to a therapeutic intervention. The development and identification of biomarkers for neurological disorders involves several issues including the complexity of the brain, unresolved discrepant data from experimental and clinical studies, poor clinical diagnostics, lack of functional endpoints, and high cost and complexity of techniques yet research in the area of biomarkers is highly desired. The present work describes existing biomarkers for various neurological disorders, provides support for the idea that biomarker development may ease our understanding underlying pathophysiology of these disorders and help to design and explore therapeutic targets for effective intervention.

Challenges and opportunities of diagnostic markers of Alzheimers disease based on structural magnetic resonance imaging.

This article aimed to carry out a narrative literature review of early diagnostic markers of Alzheimers disease (AD) based on both micro and macro levels of pathology, indicating the shortcomings of current biomarkers and proposing a novel biomarker of structural integrity that associates the hippocampus and adjacent ventricle together. This could help to reduce the influence of individual variety and improve the accuracy and validity of structural biomarker. This review was based on presenting comprehensive background of early diagnostic markers of AD. We have compiled those markers into micro level and macro level, and discussed the advantages and disadvantages of them. Eventually the ratio of gray matter volume to ventricle volume was put forward. The costly methodologies and related high patient burden of micro biomarkers (cerebrospinal fluid biomarkers) hinder the implementation in routine clinical examination. In terms of macro biomarkers- hippocampal volume (HV), there is a large variation of it among population, which undermines its validity Considering the gray matter atrophies while the adjacent ventricular volume enlarges, we assume the hippocampal to ventricle ratio (HVR) is a more reliable marker than HV alone the emerging evidence showed hippocampal to ventricle ratio predicts memory functions better than HV alone in elderly sample. The ratio between gray matter structures and adjacent ventricular volumes counts as a promising superior diagnostic marker of early neurodegeneration.

Simulating the multicausality of Alzheimers disease with system dynamics.

In Alzheimers disease (AD), cognitive decline is driven by various interlinking causal factors. Systems thinking could help elucidate this multicausality and identify opportune intervention targets. We developed a system dynamics model (SDM) of sporadic AD with 33 factors and 148 causal links calibrated with empirical data from two studies. We tested the SDMs validity by ranking intervention outcomes on 15 modifiable risk factors to two sets of 44 and 9 validation statements based on meta-analyses of observational data and randomized controlled trials, respectively. The SDM answered 77% and 78% of the validation statements correctly. Sleep quality and depressive symptoms yielded the largest effects on cognitive decline with which they were connected through strong reinforcing feedback loops, including via phosphorylated tau burden. SDMs can be constructed and validated to simulate interventions and gain insight into the relative contribution of mechanistic pathways.

The impact of study factors in the association of periodontal disease and cognitive disorders systematic review and meta-analysis.

The aim was to assess study factors that impact the association of cognitive disorders in people with periodontal disease (PD). Medline, EMBASE and Cochrane databases were searched until February 2022 using keywords and MeSH (periodon OR tooth loss OR missing teeth) AND (dementia OR Alzheimers Disease OR cognitive). Observational studies reporting prevalence or risk of cognitive decline, dementia or Alzheimers disease (AD) in people with PD compared with healthy controls were included. Meta-analysis quantified the prevalence and risk (relative riskRR) of cognitive decline, dementiaAD, respectively. Meta-regressionsubgroup analysis explored the impact of study factors including PD severity and classification type, and gender. Overall, 39 studies were eligible for meta-analysis 13 cross-sectional and 26 longitudinal studies. PD demonstrated increased risks of cognitive disorders (cognitive decline-RR 1.33, 95% CI 1.13-1.55 dementiaAD-RR 1.22, 95% CI 1.14-1.31). Risk of cognitive decline increased with PD severity (moderate-RR 1.14, 95% confidence interval CI 1.07-1.22 severe-RR 1.25, 95% CI 1.18-1.32). For every 10% population increase in females, the risk of cognitive decline increased by 34% (RR 1.34, 95% CI 1.16-1.55). Self-reported PD showed a lower risk of cognitive disorders compared with clinical classification (cognitive decline-RR 0.77, 95% CI 0.65-0.91 dementiaAD-RR 0.86, 95% CI 0.77-0.96). The prevalence and risk estimates of cognitive disorders in association with PD can be influenced by gender, the disease classification of PD and its severity. Further homologous evidence taking these study factors into consideration is needed to form robust conclusions.

Reverse electron transfer is activated during aging and contributes to aging and age-related disease.

Mechanisms underlying the depletion of NAD

Analysis of clinical characteristics of mirror and TV signs in Alzheimers disease and dementia with Lewy bodies.

This study explored the clinical features of dementia with Lewy bodies (DLB) and Alzheimers disease (AD) and analyzed the differences in neurologic syndromes, including mirror and TV signs, between different groups. Patients with AD and DLB (325 and 115, respectively) hospitalized in our institution were enrolled. We compared psychiatric symptoms and neurologic syndromes between the DLB and AD groups and within each subgroup, including the mild-moderate and severe subgroups. The prevalence rates of visual hallucination, parkinsonism, rapid eye movement sleep behavior disorder, depression, delusion, and the Pisa sign were significantly higher in the DLB group than in the AD group. Furthermore, within the mild-moderate subgroup, the mirror sign and Pisa sign prevalence rates were significantly higher in the DLB group than in the AD group. In the severe subgroup, no significant difference was found in any neurologic sign between the DLB and AD groups. Mirror and TV signs are rare and often disregarded because they are not usually invoked during routine inpatient or outpatient interviews. According to our findings, the mirror sign is uncommon in early AD patients but common in early DLB patients and should receive increased attention.

Protective effect of saffron carotenoids against amyloid beta-induced neurotoxicity in differentiated PC12 cells via the unfolded protein response and autophagy.

The preventive effect of saffron against Alzheimers disease (AD) has been reported. Herein, we studied the effect of Cro and Crt, saffron carotenoids, on the cellular model of AD. The MTT assay, flow cytometry, and elevated p-JNK, p-Bcl-2, and c-PARP indicated the AβOs-induced apoptosis in differentiated PC12 cells. Then, the protective effects of CroCrt on dPC12 cells against AβOs were investigated in preventive and therapeutic modalities. Starvation was used as a positive control. RT-PCR and Western blot results revealed the reduced eIF2α phosphorylation and increased spliced-XBP1, Beclin1, LC3II, and p62, which indicate the AβOs-induced autophagic flux defect, autophagosome accumulation, and apoptosis. Cro and Crt inhibited the JNK-Bcl-2-Beclin1 pathway. They altered Beclin1 and LC3II and decreased p62 expressions, leading cells to survival. Cro and Crt altered the autophagic flux by different mechanisms. So, Cro increased the rate of autophagosome degradation more than Crt, while Crt increased the rate of autophagosome formation more than Cro. The application of 4μ8C and chloroquine as the inhibitors of XBP1 and autophagy, respectively, confirmed these results. So, augmentation of the survival branches of UPR and autophagy is involved and may serve as an effective strategy to prevent the progression of AβOs toxicity.

Current understanding of metal-dependent amyloid-β aggregation and toxicity.

The discovery of effective therapeutics targeting amyloid-β (Aβ) aggregates for Alzheimers disease (AD) has been very challenging, which suggests its complicated etiology associated with multiple pathogenic elements. In AD-affected brains, highly concentrated metals, such as copper and zinc, are found in senile plaques mainly composed of Aβ aggregates. These metal ions are coordinated to Aβ and affect its aggregation and toxicity profiles. In this review, we illustrate the current view on molecular insights into the assembly of Aβ peptides in the absence and presence of metal ions as well as the effect of metal ions on their toxicity.

Reducing decoys focuses fighting microglia.

Genetic variation linked to lower levels of soluble ST2, a decoy cytokine receptor for IL-33, may protect against Alzheimers disease in female

Corrigendum to MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimers Disease.

This corrects the article DOI 10.115520218635088..

CSF-Targeted Proteomics Indicate Amyloid-Beta Ratios in Patients with Alzheimers Dementia Spectrum.

According to recent studies, amyloid- A total of 719 participants were found eligible for inclusion. Patients were then categorized into cognitively normal (CN), mild cognitive impairment (MCI), and AD and underwent an assessment of A All investigated peptides corresponded significantly to A Our research suggests potential early diagnostic and prognostic utilities for certain peptides extracted from CSF-targeted proteomics research. The ethical approval of ADNI is available at ClinicalTrials.gov with Identifier NCT00106899.

Digital phenotyping and the (data) shadow of Alzheimers disease.

In this paper, we examine the practice and promises of digital phenotyping. We build on work on the data self to focus on a medical domain in which the value and nature of knowledge and relations with data have been played out with particular persistence, that of Alzheimers disease research. Drawing on research with researchers and developers, we consider the intersection of hopes and concerns related to both digital tools and Alzheimers disease using the metaphor of the data shadow. We suggest that as a tool for engaging with the nature of the data self, the shadow is usefully able to capture both the dynamic and distorted nature of data representations, and the unease and concern associated with encounters between individuals or groups and data about them. We then consider what the data shadow is in relation to ageing data subjects, and the nature of the representation of the individuals cognitive state and dementia risk that is produced by digital tools. Second, we consider what the data shadow does, through researchers and practitioners discussions of digital phenotyping practices in the dementia field as alternately empowering, enabling and threatening.

Helicobacter pylori-derived outer membrane vesicles contribute to Alzheimers disease pathogenesis via C3-C3aR signalling.

The gut microbiota represents a diverse and dynamic population of microorganisms that can influence the health of the host. Increasing evidence supports the role of the gut microbiota as a key player in the pathogenesis of neurodegenerative diseases, including Alzheimers disease (AD). Unfortunately, the mechanisms behind the interplay between gut pathogens and AD are still elusive. It is known that bacteria-derived outer membrane vesicles (OMVs) act as natural carriers of virulence factors that are central players in the pathogenesis of the bacteria. Helicobacter pylori (H. pylori) is a common gastric pathogen and H. pylori infection has been associated with an increased risk to develop AD. Here, we are the first to shed light on the role of OMVs derived from H. pylori on the brain in healthy conditions and on disease pathology in the case of AD. Our results reveal that H. pylori OMVs can cross the biological barriers, eventually reaching the brain. Once in the brain, these OMVs are taken up by astrocytes, which induce activation of glial cells and neuronal dysfunction, ultimately leading to exacerbated amyloid-β pathology and cognitive decline. Mechanistically, we identified a critical role for the complement component 3 (C3)-C3a receptor (C3aR) signalling in mediating the interaction between astrocytes, microglia and neurons upon the presence of gut H. pylori OMVs. Taken together, our study reveals that H. pylori has a detrimental effect on brain functionality and accelerates AD development via OMVs and C3-C3aR signalling.

Mitophagy A promising therapeutic target for neuroprotection during aging and age-related diseases.

Mitochondria and mitochondria-mediated signaling pathways are known to control synaptic signaling as well as long-lasting changes in neuronal structure and function. Mitochondrial impairment is linked to synaptic dysfunction in normal aging and age-associated neurodegenerative ailments including Parkinsons disease (PD) and Alzheimers disease (AD). Both proteolysis and mitophagy perform a major role in neuroprotection by maintaining a healthy mitochondrial population during aging. Mitophagy, a highly evolutionarily conserved cellular process, helps in the clearance of damaged mitochondria and thereby maintains the mitochondrial and metabolic balance, energy supply, neuronal survival, and neuronal health. Besides the maintenance of brain homeostasis, hippocampal mitophagy also helps in synapse formation, axonal development, dopamine release, and long-term depression. In contrast, defective mitophagy contributes to aging and age-related neurodegeneration by promoting the accumulation of damaged mitochondria leading to cellular dysfunction. Exercise, stress management, maintaining healthy mitochondrial dynamics, and administering natural or synthetic pharmacological compounds are some of the strategies used for neuroprotection during aging and age-related neurological diseases. The current review discusses the impact of defective mitophagy in aging and age-associated neurodegenerative conditions, the underlying molecular pathways, and potential therapies based on recently elucidated mitophagy-inducing strategies.

Guiding safer risperidone prescribing in Alzheimers disease with therapeutic drug monitoring.

Previous analysis of pharmacokinetic data on risperidone treated patients with dementia predicted that twenty percent had concentration-to-dose (CD) ratios of the active moiety (risperidone and 9-hydroxy (OH)-risperidone) above 14ngml per mgday, which were in turn associated with a greater risk of extrapyramidal side-effects. This study aimed to further explore risperidone pharmacokinetics in a second dataset. Non-linear mixed effects modelling, using a Bayesian approach, was applied to data from a randomized controlled trial of risperidone in people with dementia. Covariates included age and glomerular filtration rate (GFR). Age had a significant effect on risperidone clearance (β -1.5) and GFR on 9-OH-risperidone clearance (β 0.2). The model predicted that 26.2% (95% CI 18.6 - 32.6%) had CD ratios above 14ngml per mgday. These findings confirm the importance of age-related risperidone dose adjustments and argue strongly for therapeutic drug monitoring in the initial stages of treatment, to identify those at greatest risk of toxicity.

DementiaBank Theoretical Rationale, Protocol, and Illustrative Analyses.

Dementia from Alzheimers disease (AD) is characterized primarily by a significant decline in memory abilities however, language abilities are also commonly affected and may precede the decline of other cognitive abilities. To study the progression of language, there is a need for open-access databases that can be used to build algorithms to produce translational models sensitive enough to detect early declines in language abilities. DementiaBank is an open-access repository of transcribed videoaudio data from communicative interactions from people with dementia, mild cognitive impairment (MCI), and controls. The aims of this tutorial are to (a) describe the newly established standardized DementiaBank discourse protocol, (b) describe the Delaware corpus data, and (c) provide examples of automated linguistic analyses that can be conducted with the Delaware corpus data and describe additional DementiaBank resources. The DementiaBank discourse protocol elicits four types of discourse picture description, story narrative, procedural, and personal narrative. The Delaware corpus currently includes data from 20 neurotypical adults and 33 adults with MCI from possible AD who completed the DementiaBank discourse protocol and a cognitive-linguistic battery. Language samples were video- and audio-recorded, transcribed, coded, and uploaded to DementiaBank. The protocol materials and transcription programs can be accessed for free via the DementiaBank website. Illustrative analyses show the potential of the Delaware corpus data to help understand discourse metrics at the individual and group levels. In addition, they highlight analyses that could be used across TalkBanks other clinical banks (e.g., AphasiaBank). Information is also included on manual and automatic speech recognition transcription methods. DementiaBank is a shared online database that can facilitate research efforts to address the gaps in knowledge about language changes associated with MCI and dementia from AD. Identifying early language markers could lead to improved assessment and treatment approaches for adults at risk for dementia.

Evaluating the neuroprotective effect of Spirulina platensis-loaded niosomes against Alzheimers disease induced in rats.

Alzheimers disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, changes in behavior, and avoidance of social bonds. Aluminum is one of the main risk factors in the development of AD. Spirulina platensis (SP) is a microalga that improves motor and cognitive skills and prevents cerebral endothelial damage. SP could be delivered in a more controlled and targeted manner using nanoparticles like niosomes. The purpose of this research was to develop a SP-loaded niosome (SPLN) formulation as a drug delivery system to investigate the effectiveness and toxicity of SP as an AD therapy using the AlCl

Elucidating the promising role of traditional Chinese medicine in neuroprotection against oxidative stress encompassing Alzheimers disease.

Medicinal plants are being used from time immemorial for their therapeutic benefits and have immense value in the therapy of neurodegenerative disorders. One of the most important neurological disorders is Alzheimers disease (AD) which is a major contributor to dementia and is accompanied by abundant oxidative stress in the brain tissue. A critical pathway to target the increased oxidative stress is to administer agents with antioxidant potential. Despite currently available clinical treatments to treat AD such as cholinesterase inhibitors or NMDA antagonists which address only the symptoms and cannot hamper disease progression, no efficient available clinical treatment can break the vicious cycle of oxidative stress and neurodegeneration till date. The main objective of presenting this review is that traditional Chinese medicine (TCM) acts as a promising candidate in breaking this vicious cycle and improves the quality of life of the debilitating patients. The active constituents of various herbs in TCM including Angelica sinensis, Radix polygalae, Polygala tenuifolia, and members of the Lamiaceae family have acquired experience of managing oxidative stress as indicated in the review for more than a thousand years now, and the preclinical and clinical evidence of their therapeutic potential has been highlighted in the review. Most importantly, Chinese herbs provide a multiple-target approach rather than a single-target approach and thus can target multiple pathways involved in AD at once. The Chinese herbs can definitely untangle the issues in the current therapy regimen of AD.

Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimers Disease.

Insight into the relationship between concepts that matter to the people affected by Alzheimers disease (AD) and the clinical outcome assessments (COAs) commonly used in AD clinical studies is limited. Phases 1 and 2 of the What Matters Most (WMM) study series identified and quantitatively confirmed 42 treatment-related outcomes that are important to people affected by AD. We compared WMM concepts rated as very important or higher to items included in COAs used commonly in AD studies. Twenty COAs designed to assess signs, symptoms, and impacts across the spectrum of AD were selected for review. Among these 20 COAs, only 5 reflected 12 or more WMM concepts Integrated Alzheimers Disease Rating Scale (iADRS), Alzheimers Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Alzheimers Disease Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI), Alzheimers Disease Composite Scores (ADCOMS), and Clinical Dementia Rating Clinical Dementia Rating-Sum of Boxes (CDRCDR-SB). Multiple symptoms and impacts of AD identified as important and meaningful in the WMM studies map only indirectly at best to 7 of the 20 most widely used COAs. While many frequently used COAs in AD capture some concepts identified as important to AD populations and their care partners, overlap between any single measure and the concepts that matter to people affected by AD is limited. The highest singly matched COA reflects fewer than half (45%) of WMM concepts. Use of multiple COAs expands coverage of meaningful concepts. Future research should explore the content validity of AD COAs planned for AD trials based on further confirmation of the ecological validity of the WMM items. This research should inform development and use of core outcome sets that capture WMM items and selection or development of new companion tools to fully demonstrate clinically meaningful outcomes spanning WMM.

Blood and cerebrospinal fluid biomarker changes in patients with HIV-associated neurocognitive impairment treated with lithium analysis from a randomised placebo-controlled trial.

HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are, therefore, prudent. Lithium treatment is known to promote neuronal brain-derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-β). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8 lymphocyte activation (CD38 HLADR ). Alzheimers Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPαβ), Aβ38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo 31 lithium 30). The age baseline mean was 40 (± 8.35) years and the median CD4 T-cell count was 498 (IQR 389-651) cellsμL. Biomarker concentrations between groups did not differ at baseline. However, both groups blood dopamine levels decreased significantly after 24 weeks (adj. p < 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size.

Gender of study partners and research participants associated with differences in study partner ratings of cognition and activity level.

Studies of Alzheimers disease (AD) typically include study partners (SPs) who report on participants cognition and function. Prior studies show SP reports differ depending on the relationship between the SP and participant, that is, spouse or adult child. Adult children SPs are typically female. Could differing reports be due to gender Knowing this may help explain variability in measurement. The Aging, Demographics and Memory Study (ADAMS) enrolled a subset of participants from the Health and Retirement Study (HRS). Each participant had a SP. Bivariate and multivariable regression models compared 718 SP-participant dyads. In analyses of four groups defined by SP and participant gender, dyads composed of two women were less likely to identify as White (75.8%, 95%CI 70.4 to 80.5) than dyads composed of two men (93.3%, 95%CI 81.2 to 97.8). In analyses adjusted for severity of cognitive and functional impairment, women SPs rated women participants as more active than they rated men, mean 2.15 (95%CI, 2.07 to 2.22) versus mean 2.30 (95%CI, 2.24 to 2.37), respectively, on a 4-point scale. Similarly, men SPs rated women participants as more active than they rated men, mean 2.1 (95%CI, 2.0 to 2.2) and mean 2.4 (95%CI, 2.3 to 2.5), respectively. In an analysis of cognitively unimpaired participants, women SPs rated participants memory worse than men SPs did (p<0.05). SP and participant gender influence SPs reports of another persons cognition and activity level. Our findings expand what is understood about how non-disease factors influence measures of disease severity.

Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimers disease.

This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloidtauneurodegeneration AT(N) framework, mild cognitive impairment (MCI) conversion to Alzheimers disease (AD), and genetic risk for AD. Using the European Medical Information Framework (EMIF)-AD cohort, we measured 696 proteins in cerebrospinal fluid (n 371), 4001 proteins in plasma (n 972), 611 metabolites in plasma (n 696), and genotyped whole-blood (7,778,465 autosomal single nucleotide epolymorphisms, n 936). We investigated associations molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR). AT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase SubtilisinKexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform. This study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates.

Examining the Lancet Commission risk factors for dementia using Mendelian randomisation.

Dementia incidence is increasing across the globe and currently there are no disease-modifying pharmaceutical treatments. The Lancet Commission on dementia identified 12 modifiable risk factors which explain 40% of dementia incidence. However, whether these associations are causal in nature is unclear. To examine the modifiable risk factors for dementia as identified in the Lancet Commission review using Mendelian randomisation (MR) to establish if, based on genetic evidence, these associations with different dementia subtypes are causal in nature. Publicly available genome-wide association study data were used for 10 risk factors and Alzheimers disease (AD), frontotemporal dementia and dementia with Lewy bodies. Two-sample MR using the inverse varianceweighted method was conducted to test for causal relationships. Weighted median MR and MR-Egger were used to test for pleiotropic effects. Genetic proxied risk for higher levels of smoking (OR 0.80 (95% CI 0.69 0.92), p0.002), obesity (OR 0.87 (95% CI 0.82 0.92), p<0.001) and blood pressure (OR 0.90 (95% CI 0.82 0.99), p0.035) appeared to be protective against the risk of AD. Post hoc analyses indicated these associations had pleiotropic effects with the risk of coronary artery disease. Genetic proxied risk of educational attainment was found to be inconsistently associated with the risk of AD. Post hoc analysis indicated that the apparent protective effects of smoking, obesity and blood pressure were a result of survivor bias. The findings from this study did not support those presented by the Lancet Commission. Evidence from causal inference studies should be considered alongside evidence from epidemiological studies and incorporated into reviews of the literature.

Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimers disease.

Neurodegenerative diseases such as Alzheimers disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional one-target, one-molecule approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H

Predicting amyloid PET and tau PET stages with plasma biomarkers.

Staging the severity of Alzheimers disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers. Participants (N 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimers Disease Research Center, had a concurrent amyloid PET, tau PET, and blood draw, and met clinical criteria for cognitively unimpaired (N 864), mild cognitive impairment (N 148), or Alzheimers Clinical Syndrome with dementia (N 124). The latter two groups were combined into a cognitively impaired group (N 272). We used multinomial regression models to estimate discrimination (concordance C statistics) among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1-2, 3-4, 5-6), and a combined amyloid and tau PET stage (nonelow vs. intermediatehigh severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aβ 1-42 and 1-40 (analyzed as the Aβ4240 ratio), GFAP, and NfL, were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (N 355) of CU participants using the Lilly MSD assay. Models with all Quanterix plasma analytes along with risk factors (age, sex, and APOE) most often provided the best discrimination among amyloid PET stages (C 0.78 to 0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C 0.72 to 0.85 vs. C 0.73 to 0.86). Discriminating a PET proxy of intermediatehigh from nonelow AD neuropathologic change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C 0.88 vs. 0.87 for unimpaired and C 0.91 vs. 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high vs. intermediate amyloid (C 0.85 vs. 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C 0.85 vs. 0.83). Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediatehigh vs nonelow neuropathologic change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination.

Illuminating neurodegeneration a future perspective on near-infrared spectroscopy in dementia research.

Dementia presents a global healthcare crisis, and neuroimaging is the main method for developing effective diagnoses and treatments. Yet currently, there is a lack of sensitive, portable, and low-cost neuroimaging tools. As dementia is associated with vascular and metabolic dysfunction, near-infrared spectroscopy (NIRS) has the potential to fill this gap. This future perspective aims to briefly review the use of NIRS in dementia to date and identify the challenges involved in realizing the full impact of NIRS for dementia research, including device development, study design, and data analysis approaches. We briefly appraised the current literature to assess the challenges, giving a critical analysis of the methods used. To assess the sensitivity of different NIRS device configurations to the brain with atrophy (as is common in most forms of dementia), we performed an optical modeling analysis to compare their cortical sensitivity. The first NIRS dementia study was published in 1996, and the number of studies has increased over time. In general, these studies identified diminished hemodynamic responses in the frontal lobe and altered functional connectivity in dementia. Our analysis showed that traditional (low-density) NIRS arrays are sensitive to the brain with atrophy (although we see a mean decrease of 22% in the relative brain sensitivity with respect to the healthy brain), but there is a significant improvement (a factor of 50 sensitivity increase) with high-density arrays. NIRS has a bright future in dementia research. Advances in technology - high-density devices and intelligent data analysis-will allow new, naturalistic task designs that may have more clinical relevance and increased reproducibility for longitudinal studies. The portable and low-cost nature of NIRS provides the potential for use in clinical and screening tests.

Plasma extracellular vesicles reveal early molecular differences in amyloid positive patients with early-onset mild cognitive impairment.

In the clinical course of Alzheimers disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aβ and p-tau-mediated neuronal injury and a mild cognitive impairment (MCI) clinical status. Because of that, most AD cases are diagnosed when neuronal damage is already established and irreversible. Therefore, a differential diagnosis of MCI causes in these prodromal stages is one of the greatest challenges for clinicians. Blood biomarkers are emerging as desirable tools for pre-screening purposes, but the current results are still being analyzed and much more data is needed to be implemented in clinical practice. Because of that, plasma extracellular vesicles (pEVs) are gaining popularity as a new source of biomarkers for the early stages of AD development. To identify an exosome proteomics signature linked to prodromal AD, we performed a cross-sectional study in a cohort of early-onset MCI (EOMCI) patients in which 184 biomarkers were measured in pEVs, cerebrospinal fluid (CSF), and plasma samples using multiplex PEA technology of Olink

Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimers disease.

Most research on glutamate spillover focuses on the deleterious consequences of postsynaptic glutamate receptor overactivation. However, two decades ago, it was noted that the glial coverage of hippocampal synapses is asymmetric astrocytic coverage of postsynaptic sites exceeds coverage of presynaptic sites by a factor of four. The fundamental relevance of this glial asymmetry remains poorly understood. Here, we used the glutamate biosensor iGluSnFR, and restricted its expression to either CA3 or CA1 neurons to visualize glutamate dynamics at pre- and postsynaptic microenvironments, respectively. We demonstrate that inhibition of the primarily astrocytic glutamate transporter-1 (GLT-1) slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic membranes. GLT-1 expression was reduced early in a mouse model of AD, resulting in slower glutamate clearance rates at presynaptic but not postsynaptic membranes that opposed presynaptic short-term plasticity. Overall, our data demonstrate that the presynapse is particularly vulnerable to GLT-1 dysfunction and may have implications for presynaptic impairments in a variety of brain diseases.

A multimodal deep learning model to infer cell-type-specific functional gene networks.

Functional gene networks (FGNs) capture functional relationships among genes that vary across tissues and cell types. Construction of cell-type-specific FGNs enables the understanding of cell-type-specific functional gene relationships and insights into genetic mechanisms of human diseases in disease-relevant cell types. However, most existing FGNs were developed without consideration of specific cell types within tissues. In this study, we created a multimodal deep learning model (MDLCN) to predict cell-type-specific FGNs in the human brain by integrating single-nuclei gene expression data with global protein interaction networks. We systematically evaluated the prediction performance of the MDLCN and showed its superior performance compared to two baseline models (boosting tree and convolutional neural network). Based on the predicted cell-type-specific FGNs, we observed that cell-type marker genes had a higher level of hubness than non-marker genes in their corresponding cell type. Furthermore, we showed that risk genes underlying autism and Alzheimers disease were more strongly connected in disease-relevant cell types, supporting the cellular context of predicted cell-type-specific FGNs. Our study proposes a powerful deep learning approach (MDLCN) to predict FGNs underlying a diverse set of cell types in human brain. The MDLCN model enhances prediction accuracy of cell-type-specific FGNs compared to single modality convolutional neural network (CNN) and boosting tree models, as shown by higher areas under both receiver operating characteristic (ROC) and precision-recall curves for different levels of independent test datasets. The predicted FGNs also show evidence for the cellular context and distinct topological features (i.e. higher hubness and topological score) of cell-type marker genes. Moreover, we observed stronger modularity among disease-associated risk genes in FGNs of disease-relevant cell types. For example, the strength of connectivity among autism risk genes was stronger in neurons, but risk genes underlying Alzheimers disease were more connected in microglia.

Effects of presenilin-1 familial Alzheimers disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.

Presenilin-1 (PS1) is the catalytic subunit of γ-secretase which cleaves within the transmembrane domain of over 150 peptide substrates. Dominant missense mutations in PS1 cause early-onset familial Alzheimers disease (FAD) however, the exact pathogenic mechanism remains unknown. Here we combined Gaussian accelerated molecular dynamics (GaMD) simulations and biochemical experiments to determine the effects of six representative PS1 FAD mutations (P117L, I143T, L166P, G384A, L435F, and L286V) on the enzyme-substrate interactions between γ-secretase and amyloid precursor protein (APP). Biochemical experiments showed that all six PS1 FAD mutations rendered γ-secretase less active for the endoproteolytic (ε) cleavage of APP. Distinct low-energy conformational states were identified from the free energy profiles of wildtype and PS1 FAD-mutant γ-secretase. The P117L and L286V FAD mutants could still sample the Active state for substrate cleavage, but with noticeably reduced conformational space compared with the wildtype. The other mutants hardly visited the Active state. The PS1 FAD mutants were found to reduce γ-secretase proteolytic activity by hindering APP residue L49 from proper orientation in the active site andor disrupting the distance between the catalytic aspartates. Therefore, our findings provide mechanistic insights into how PS1 FAD mutations affect structural dynamics and enzyme-substrate interactions of γ-secretase and APP.

Activity patterns are associated with fractional lifespan, memory, and gait speed in aged dogs.

Maintaining an active lifestyle is considered a hallmark of successful aging. Physical activity significantly reduces the risk of cognitive decline and Alzheimers disease in humans. However, pain and lack of motivation are important barriers to exercise. Dogs are a remarkable model for translational studies in aging and cognition as they are prone to Canine Cognitive Dysfunction syndrome, which has many similarities with Alzheimers disease. According to owner reports, changes in activity levels are characteristic of this syndrome, with decreased daytime activity, but also excessive pacing, especially at sleep time. We used physical activity monitors to record the activity of 27 senior dogs and evaluated the association between activity level and age, fractional lifespan, cognitive status measured by an owner questionnaire and cognitive tests. We also assessed the relationship between activity and jointspinal pain, and the offon leash gait speed ratio (a potential marker of gait speed reserve and motivation). We found that activity patterns in dogs are associated with fractional lifespan and working memory. Additionally, dogs with higher onoff leash gait speed are more active in the afternoon of weekdays. These results encourage future studies evaluating how physical activity can improve or delay cognitive impairment in senior dogs.

Investigation of Shared Genetic Risk Factors Between Parkinsons Disease and Cancers.

Epidemiological studies that examined the association between Parkinsons disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinsons Disease PD, N 16,519) and EPITHYR (differentiated thyroid cancer, N 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium PD, N 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. We confirmed a previously reported positive genetic correlation of PD with melanoma (G We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Modifications of the endosomal compartment in fibroblasts from sporadic Alzheimers disease patients are associated with cognitive impairment.

Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimers disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD. We previously found that PBMCs from AD patients have larger EEA1-positive puncta, correlating with brain amyloid load. Here we analysed the endosomal compartment of fibroblasts from a very well characterised cohort of AD patients (IMABio3) who underwent thorough clinical, imaging and biomarkers assessments. Twenty-one subjects were included (7 AD with mild cognitive impairment (AD-MCI), 7 AD with dementia (AD-D) and 7 controls) who had amyloid-PET at baseline (PiB) and neuropsychological tests at baseline and close to skin biopsy. Fibroblasts isolated from skin biopsies were immunostained with anti-EEA1 antibody and imaged using a spinning disk microscope. Endosomal compartment ultrastructure was also analysed by electron microscopy. All fibroblast lines were genotyped and their AD risk factors identified. Our results show a trend to an increased EEA1-positive puncta volume in fibroblasts from AD-D as compared to controls (p.adj 0.12) and reveal enhanced endosome area in fibroblasts from AD-MCI and AD-AD versus controls. Larger puncta size correlated with PiB retention in different brain areas and with worse cognitive scores at the time of biopsy as well as faster decline from baseline to the time of biopsy. Finally, we identified three genetic risk factors for AD (ABCA1, COX7C and MYO15A) that were associated with larger EEA1 puncta volume. In conclusion, the endosomal compartment in fibroblasts could be used as cellular peripheral biomarker for both amyloid deposition and cognitive decline in AD patients.

Rare-variant association analysis reveals known and new age-related hearing loss genes.

Age-related (AR) hearing loss (HL) is a prevalent sensory deficit in the elderly population. Several studies showed that common variants increase ARHL susceptibility. Here, we demonstrate that rare-variants play a crucial role in ARHL etiology. We analyzed exome and imputed data from white-European UK Biobank volunteers, performing both single-variant and rare-variant aggregate association analyses using self-reported ARHL phenotypes. We identified and replicated associations between ARHL and rare-variants in KLHDC7B, PDCD6, MYO6, SYNJ2, and TECTA. PUS7L and EYA4 also revealed rare-variant associations with ARHL. EYA4, MYO6, and TECTA are all known to underline Mendelian nonsyndromic HL. PDCD6, a new HL gene, plays an important role in apoptosis and has widespread inner ear expression, particularly in the inner hair cells. An unreplicated common variant association was previously observed for KHLDC7B, here we demonstrate that rare-variants in this gene also play a role in ARHL etiology. Additionally, the first replicated association between SYNJ2 and ARHL was detected. Analysis of common variants revealed several previously reported, i.e., ARHGEF28, and new, i.e., PIK3R3, ARHL associations, as well as ones we replicate here for the first time, i.e., BAIAP2L2, CRIP3, KLHDC7B, MAST2, and SLC22A7. It was also observed that the odds ratios for rare-variant ARHL associations, were higher than those for common variants. In conclusion, we demonstrate the vital role rare-variants, including those in Mendelian nonsyndromic HL genes, play in the etiology of ARHL.

A Phenome-wide Association and Mendelian Randomization Study for Alzheimers Disease A Prospective Cohort Study of 502,493 Participants From the UK Biobank.

Considerable uncertainty remains regarding associations of multiple risk factors with Alzheimers disease (AD). We aimed to systematically screen and validate a wide range of potential risk factors for AD. Among 502,493 participants from the UK Biobank, baseline data were extracted for 4171 factors spanning 10 different categories. Phenome-wide association analyses and time-to-event analyses were conducted to identify factors associated with both polygenic risk scores for AD and AD diagnosis at follow-up. We performed two-sample Mendelian randomization analysis to further assess their potential causal relationships with AD and imaging association analysis to discover underlying mechanisms. We identified 39 factors significantly associated with both AD polygenic risk scores and risk of incident AD, where higher levels of education, body size, basal metabolic rate, fat-free mass, computer use, and cognitive functions were associated with a decreased risk of developing AD, and selective food intake and more outdoor exposures were associated with an increased risk of developing AD. The identified factors were also associated with AD-related brain structures, including the hippocampus, entorhinal cortex, and inferiormiddle temporal cortex, and 21 of these factors were further supported by Mendelian randomization evidence. To our knowledge, this is the first study to comprehensively and rigorously assess the effects of wide-ranging risk factors on AD. Strong evidence was found for fat-free body mass, basal metabolic rate, computer use, selective food intake, and outdoor exposures as new risk factors for AD. Integration of genetic, clinical, and neuroimaging information may help prioritize risk factors and prevention targets for AD.

Neurodegeneration cell per cell.

The clinical definition of neurodegenerative diseases is based on symptoms that reflect terminal damage of specific brain regions. This is misleading as it tells little about the initial disease processes. Circuitry failures that underlie the clinical symptomatology are themselves preceded by clinically mostly silent, slowly progressing multicellular processes that trigger or are triggered by the accumulation of abnormally folded proteins such as Aβ, Tau, TDP-43, and α-synuclein, among others. Methodological advances in single-cell omics, combined with complex genetics and novel ways to model complex cellular interactions using induced pluripotent stem (iPS) cells, make it possible to analyze the early cellular phase of neurodegenerative disorders. This will revolutionize the way we study those diseases and will translate into novel diagnostics and cell-specific therapeutic targets, stopping these disorders in their early track before they cause difficult-to-reverse damage to the brain.

A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases.

The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - the major excitatory neurotransmitter in the mammalian brain. EAAT2 lossdysfunction triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimers disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosistherapy for ALS and AD. This perspective article describes the role of EAAT2 in physiopathological processes and provides a structure-activity relationship of EAAT2-binders, bringing two perspectives therapy (activators) and diagnosis (molecular imaging tools).

Can mixed circuit training elicit the recommended exercise intensity and energy expenditure in people after stroke

To investigate whether mixed circuit training (MCT) elicits the recommended exercise intensity and energy expenditure in people after stroke, and to establish the between-day reproducibility for the percentages of heart rate reserve (%HRR), oxygen uptake reserve (%VO Seven people aged 58 (12) yr, who previously had a stroke, performed a cardiopulmonary exercise test, a non-exercise control session, and two bouts of MCT. The MCT included 3 circuits of 10 resistance exercises at 15-repetition maximum intensity, with each set of resistance exercise interspersed with 45-s of walking. Expired gases were collected during the MCT and control session and for 40 min afterward. Control session was necessary to calculate the net energy expenditure associated with each bout of MCT. Mean %VO MCT elicited physiological strain recommended for improving health-related fitness in people after stroke and these responses demonstrated excellent between-day reproducibility.

Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimers disease.

Microglial phagocytosis is an energetically demanding process that plays a critical role in the removal of toxic protein aggregates in Alzheimers disease (AD). Recent evidence indicates that a switch in energy production from mitochondrial respiration to glycolysis disrupts this important protective microglial function and may provide therapeutic targets for AD. Here, we demonstrate that the translocator protein (TSPO) and a member of its mitochondrial complex, hexokinase-2 (HK), play critical roles in microglial respiratory-glycolytic metabolism and phagocytosis. Pharmacological and genetic loss-of-function experiments showed that TSPO is critical for microglial respiratory metabolism and energy supply for phagocytosis, and its expression is enriched in phagocytic microglia of AD mice. Meanwhile, HK controlled glycolytic metabolism and phagocytosis via mitochondrial binding or displacement. In cultured microglia, TSPO deletion impaired mitochondrial respiration and increased mitochondrial recruitment of HK, inducing a switch to glycolysis and reducing phagocytosis. To determine the functional significance of mitochondrial HK recruitment, we developed an optogenetic tool for reversible control of HK localization. Displacement of mitochondrial HK inhibited glycolysis and improved phagocytosis in TSPO-knockout microglia. Mitochondrial HK recruitment also coordinated the inflammatory switch to glycolysis that occurs in response to lipopolysaccharide in normal microglia. Interestingly, cytosolic HK increased phagocytosis independent of its metabolic activity, indicating an immune signaling function. Alzheimers beta amyloid drastically stimulated mitochondrial HK recruitment in cultured microglia, which may contribute to microglial dysfunction in AD. Thus, targeting mitochondrial HK may offer an immunotherapeutic approach to promote phagocytic microglial function in AD.

Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimers disease A 31Phosphorus MR spectroscopy study.

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimers disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi) and membrane phospholipids phosphomonoesters (PME), phosphodiesters (PDE) in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4). Women exhibited lower PCrATP and PCrPi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4 group exhibited lower PCrATP and PCrPi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4 men exhibited lower PCrATP and PCrPi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCrATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on PiATP and PMEPDE measures. Among midlife individuals at risk for AD, women exhibit lower PCrATP (e.g. higher ATP utilization) and lower PCrPi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted mens brains to a similar metabolic range as womens brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

Butyrate ameliorates quinolinic acid-induced cognitive decline in obesity models.

Obesity is a risk factor for neurodegenerative disease associated with cognitive dysfunction, including Alzheimers disease. Low-grade inflammation is common in obesity, but the mechanism between inflammation and cognitive impairment in obesity is unclear. Accumulative evidence shows that quinolinic acid (QA), a neuroinflammatory neurotoxin, is involved in the pathogenesis of neurodegenerative processes. We investigated the role of QA in obesity-induced cognitive impairment and the beneficial effect of butyrate in counteracting impairments of cognition, neural morphology, and signaling. We show that in human obesity, there was a negative relationship between serum QA levels and cognitive function and decreased cortical gray matter. Diet-induced obese mice had increased QA levels in the cortex associated with cognitive impairment. At single-cell resolution, we confirmed that QA impaired neurons, altered the dendritic spines intracellular signal, and reduced brain-derived neurotrophic factor (BDNF) levels. Using Caenorhabditis elegans models, QA induced dopaminergic and glutamatergic neuron lesions. Importantly, the gut microbiota metabolite butyrate was able to counteract those alterations, including cognitive impairment, neuronal spine loss, and BDNF reduction in both in vivo and in vitro studies. Finally, we show that butyrate prevented QA-induced BDNF reductions by epigenetic enhancement of H3K18ac at BDNF promoters. These findings suggest that increased QA is associated with cognitive decline in obesity and that butyrate alleviates neurodegeneration.

Lactococcus intestinalis sp. nov., a new lactic acid bacterium isolated from intestinal contents in Alzheimers disease mice.

A gram-positive, facultatively anaerobic, and coccoid or ovoid-shaped bacterium designated M2458

Stability of the Aβ42 Peptide in Mixed Solutions of Denaturants and Proline.

Amyloid β-peptide (Aβ) is responsible for the neuronal damage and death of a patient with Alzheimers disease (AD). Aβ42 oligomeric forms are dominant neurotoxins and are related to neurodegeneration. Their different forms are related to various pathological conditions in the brain. We investigated Aβ42 peptides in different environments of proline, urea, and GdmCl solutions (in pure and mixed binary forms) through atomistic molecular dynamics simulations. Preferential exclusion from the protein surface and facile formation of a large number of weak molecular interactions are the driving forces for the osmolytes action. We have focused on these interactions between peptide monomers and puremixed osmolytes and denaturants. Urea, as usual, denatures the peptide strongly compared to the GdmCl by accumulation around the peptide. GdmCl shows lesser build-up around protein in contrast to urea but is involved in destabilizing the salt bridge formation of Asp23 and Lys28. Proline as an osmolyte protects the peptide from aggregation when mixed with urea and GdmCl solutions. In mixed solutions of two denaturants and osmolyte plus denaturant, the peptide shows enhanced stability as compared to pure denaturant urea solution. The enhanced stability of peptides in proline may be attributed to its exclusion from the peptide surface and favoring salt bridge formation.

Phosphorylation at Ser289 Enhances the Oligomerization of Tau Repeat R2.

In tauopathies such as Alzheimers disease (AD), aberrant phosphorylation causes the dissociation of tau proteins from microtubules. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments and insoluble neurofibrillary tangles (NFTs). NFTs is a hallmark of AD, while oligomers are found to be the most toxic form of the tau aggregates. Therefore, understanding tau oligomerization with regard to abnormal phosphorylation is important for the therapeutic development of AD. In this study, we investigated the impact of phosphorylated Ser289, one of the 40 aberrant phosphorylation sites of full-length tau proteins, on monomeric and dimeric structures of tau repeat R2 peptides. We carried out intensive replica exchange molecular dynamics simulation with a total simulation time of up to 0.1 ms. Our result showed that the phosphorylation significantly affected the structures of both the monomer and the dimer. For the monomer, the phosphorylation enhanced ordered-disordered structural transition and intramolecular interaction, leading to more compactness of the phosphorylated R2 compared to the wild-type one. As to the dimer, the phosphorylation increased intermolecular interaction and β-sheet formation, which can accelerate the oligomerization of R2 peptides. This result suggests that the phosphorylation at Ser289 is likely to promote tau aggregation. We also observed a phosphorylated Ser289-Na

Unsupervised machine learning model to predict cognitive impairment in subcortical ischemic vascular disease.

It is challenging to predict which patients who meet criteria for subcortical ischemic vascular disease (SIVD) will ultimately progress to subcortical vascular cognitive impairment (SVCI). We collected clinical information, neuropsychological assessments, T1 imaging, diffusion tensor imaging, and resting-state functional magnetic resonance imaging from 83 patients with SVCI and 53 age-matched patients with SIVD without cognitive impairment. We built an unsupervised machine learning model to isolate patients with SVCI. The model was validated using multimodal data from an external cohort comprising 45 patients with SVCI and 32 patients with SIVD without cognitive impairment. The accuracy, sensitivity, and specificity of the unsupervised machine learning model were 86.03%, 79.52%, and 96.23% and 80.52%, 71.11%, and 93.75% for internal and external cohort, respectively. We developed an accurate and accessible clinical tool which requires only data from routine imaging to predict patients at risk of progressing from SIVD to SVCI. Our unsupervised machine learning model provides an accurate and accessible clinical tool to predict patients at risk of progressing from subcortical ischemic vascular disease (SIVD) to subcortical vascular cognitive impairment (SVCI) and requires only data from imaging routinely used during the diagnosis of suspected SVCI. The model yields good accuracy, sensitivity, and specificity and is portable to other cohorts and to clinical practice to distinguish patients with SIVD at risk for progressing to SVCI. The model combines assessment of diffusion tensor imaging and functional magnetic resonance imaging measures in patients with SVCI to analyze whether the disconnection hypothesis contributes to functional and structural changes and to the clinical presentation of SVCI.

Multivalent Nanobody Conjugate with Rigid, Reactive Oxygen Species Scavenging Scaffold for Multi-Target Therapy of Alzheimers Disease.

Efficient therapeutic strategies that concurrently target both Aβ aggregation and oxidative stress in the AD microenvironment emerge as a cutting-edge tool to combat the intricate pathogenesis of AD. Here we develop a multivalent nanobody conjugate with rigid, reactive oxygen species (ROS) scavenging scaffold to achieve simultaneous Aβ amyloidogenesis mitigation, ROS elimination, and Aβ plaque clearance. Grafting Aβ segment (33-GLMVGGVVIA-42) into the third complementary-determining region of a parent nanobody generates an engineered nanobody NB that can recognize Aβ and inhibit its aggregation through homotypic interactions. NB is further genetically modified with a fragment of human interleukin-1β (163-VQGEESNDK-171), so that the obtained fusion nanobody NBIL can also facilitate the Aβ clearance by microglia. Linking NBIL covalently onto a rigid, ROS scavenging scaffold poly(deca-4,6-diynedioic acid) (PDDA) creates the multivalent nanobody conjugate PNBIL, which not only boosts the binding affinity between NBIL and Aβ aggregates for nearly 100 times but also possesses a long-term capability of oxidative stress alleviation, inflammation reduction, and neuron protection. PNBIL has significantly attenuated symptoms on two AD mouse models through amyloidogenesis inhibition and AD microenvironment modulation, validating that our multivalent nanobody conjugate design based on combinatory nanobody and molecular engineering is a promising approach of multi-target therapeutic strategies. This article is protected by copyright. All rights reserved.

I lay awake at night Latino Family Caregivers Experiences Covering Out-of-Pocket Costs when Caring for Someone Living with Dementia.

The financial burden of caregiving has received less research attention than physical and emotional costs. This is especially true for underserved ethnic minorities. Financial strain affects mental and physical health and is unequally distributed across caregivers of different races and ethnicities. While caregivers overall spend, on average, one-quarter of their income on caregiving, Latino caregivers, the focus of this study, spend nearly half. To better understand this disparity, we conducted eleven qualitative interviews with fourteen Latino caregivers of persons living with dementia located in either California or Texas. Interview transcripts were thematically coded, guided by a material-psychosocial-behavioral conceptual model of financial strain. We identified three themes daily needs and costs, psychological distress caused by financial issues, and stressful barriers accessing family and societal support. Further, interviews revealed how Latino culture may influence spending patterns and management of costs. Findings suggest that preference by Latino families to care for a family member in the home may be met with financial disadvantage due to the high out-of-pocket costs of care. A better understanding of the factors contributing to high costs for Latino caregivers and how these costs affect caregivers will inform approaches at both the individual- and policy-levels and develop culturally relevant interventions to help Latino families to lower caregiving costs. This is especially important as the number of Latinos living with dementia is expected to increase over the next four decades and effective interventions are lacking.

Does statin use affect amyloid beta deposition and brain metabolism

There are contradictory findings regarding the effect of statin drugs on amyloid β (Aβ) deposition as one of the main hallmarks of Alzheimers disease (AD), along with tau pathology. We aimed to longitudinally investigate the therapeutic and preventive role of statin drugs by examining the brain Aβ deposition and metabolism rate in AD, mild cognitive impairment (MCI), and healthy controls (HC). The data of 828 subjects including 178 HC, 492 MCI, and 158 AD individuals were obtained from ADNI. The baseline and longitudinal Our results showed that there is no significant difference in baseline Aβ deposition and metabolism rate between statin users and non-users among HC, MCI, and AD subjects. While there was no significant effect of statin on metabolism rate, there was a significant difference in Aβ deposition change after 4 years (from baseline) between statin users and non-users within HC subjects (p 0.011). The change of Aβ deposition at 4 years from baseline was -2.0 ± 6.3% for statin users and 1.4 ± 4.7% for non-users. There was no significant association between statin duration use with baseline and longitudinal Aβ deposition and metabolism rate. However, statin dosage was significantly associated with Aβ deposition in 2 years (r -0.412, p 0.021) in the HC group. Moreover, our analysis showed a significant correlation between total statin exposure (duration×dosage) and Aβ deposition in 2 years visit (r -0.198, p 0.037) in HC subjects. Furthermore, we investigated the longitudinal changes within each group of statin users and non-users separately in linear mixed models. Our findings showed that there are no significant changes in AV45 and FDG SUVR among both groups. The present longitudinal analysis revealed that using statins might be beneficial in slowing down or stabilizing the Aβ deposition due to aging in subjects without cognitive impairment. However, once the clinical symptoms of cognitive impairment appear, statins fail to slow down Aβ deposition. Overall, our findings revealed that statin users might have slower Aβ aggregation than non-users.

Adult neurogenesis in the primate hippocampus.

Adult hippocampal neurogenesis (AHN) is crucial for learning, memory, and emotion. Deficits of AHN may lead to reduced cognitive abilities and neurodegenerative disorders, such as Alzheimers disease. Extensive studies on rodent AHN have clarified the developmental and maturation processes of adult neural stemprogenitor cells. However, to what extent these findings apply to primates remains controversial. Recent advances in next-generation sequencing technologies have enabled in-depth investigation of the transcriptome of AHN-related populations at single-cell resolution. Here, we summarize studies of AHN in primates. Results suggest that neurogenesis is largely shared across species, but substantial differences also exist. Marker gene expression patterns in primates differ from those of rodents. Compared with rodents, the primate hippocampus has a higher proportion of immature dentate granule cells and a longer maturation period of newly generated granule cells. Future research on species divergence may deepen our understanding of the mechanisms underlying adult neurogenesis in primates. 成年海马体神经发生过程对学习行为、记忆产生和情绪调节至关重要。成年海马体神经发生障碍可能导致认知能力下降和严重的神经退行性疾病，比如阿尔兹海默症等。目前大多数研究成年海马体神经发生过程都是基于啮齿动物模型，关于灵长类动物是否存在成年海马体神经发生现象仍存在争议。最近测序技术的发展使得可以在单细胞转录组水平深入研究成年海马体神经发生机制。该文综述了灵长类动物成年海马体神经发生的研究进展，研究结果显示不同物种间神经发生过程大体一致，但也存在重要差异之处。与啮齿类动物相比，灵长类动物海马体中未成熟齿状回颗粒细胞的比例更高，新生颗粒细胞的成熟周期更长。对于不同物种间神经发生的共同性和差异性研究，对进一步全面系统研究灵长类动物的成年神经发生机制有重要意义。.

Could exercise hormone irisin be a therapeutic agent against Parkinsons and other neurodegenerative diseases

Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers disease (AD). The pathologic hallmarks of the disease are the loss of dopaminergic neurons of substantia nigra pars compacta and the presence of intraneuronal alpha synuclein (a-syn) aggregates. Clinical features of PD include motor symptoms such as bradykinesia, rigidity, tremors, postural instability, and gait impairment, and non-motor symptoms such as constipation, orthostatic hypotension, REM sleep disorder, depression and dementia. Currently, there is no disease-modifying therapy for PD. Several human studies have shown that exercise reduces progression of motor symptoms, improves performance on cognitive tasks, and slows functional deterioration. However, regular exercise may not always be feasible in PD patients. Irisin is an exercise-induced myokine involved in metabolism modulation and body fat reduction, but it also crosses the blood-brain barrier and may mediate some of the benefits of exercise in brain function. Recent evidence has shown that irisin could be therapeutically promising in PD as an exercise-mimicking intervention. Exogenous irisin administration decreases brain a-syn pathology and loss of dopaminergic neurons, while it improves motor outcomes in preclinical models. Several other neurodegenerative disorders such as AD share common underlying pathogenetic mechanisms with PD such as protein misfolding and aggregation, neuroinflammation, brain metabolic abnormalities, and neuronal loss. Therefore, investigation of irisin as a disease-modifying therapy could be promising for PD and other neurodegenerative disorders including AD.

Agent Orange Reviewed Potential Role in Peripheral Neuropathy and Neurodegeneration.

Agent Orange, a dioxin-containing toxin, was used as an herbicide during the Vietnam War. Exposures to Agent Orange were initially linked to birth defects among Vietnamese civilians residing near aerially sprayed regions. Years later, returning South Korean and U.S. Veterans exposed to Agent Orange exhibited increased rates of malignancy, cardiovascular disease, diabetes and birth defects in their offspring. Growing evidence that herbicides and pesticides contribute to chronic diseases including neurodegeneration raises concern that Agent Orange exposures may have increased the risk for later development of peripheral or central nervous system (CNS) degeneration. This article reviews published data on the main systemic effects and the prevalence rates, relative risks, characteristics and correlates of Agent Orange-associated peripheral neuropathy and CNS dementia-associated diseases. The critical findings were that relatively high levels of Agent Orange exposure increased risk of developing peripheral neuropathy either alone or as a co-factor complication of diabetes mellitus and likely contributed to the pathogenesis of CNS degenerative diseases, including Alzheimers, Parkinsons and vascular dementias. Given the protracted intervals between the Agent Orange exposures and disease emergence, additional research is needed to identify mechanistic correlates of the related neurological disorders, including lifestyle co-factors.

Polygenic risk scores for Alzheimers disease and general cognitive function are associated with measures of cognition in older South Asians from LASI-DAD.

Genome-wide association studies (GWAS) conducted in European ancestry (EA) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with general cognitive function andor Alzheimers disease (AD). The association between these SNPs and cognitive function has not been fully evaluated in populations with complex genetic sub-structure such as South Asians. This study investigated whether SNPs identified in EA GWASs, either individually or as polygenic risk scores (PRS), were associated with general cognitive function and five cognitive domains in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). We found that SNPs identified from AD GWASs were more strongly associated with cognitive function in LASI-DAD than those from a GWAS of general cognitive function. PRSs for general cognitive function and AD explained up to 1.1% of the variability in LASI-DAD cognitive domain scores. Our study represents an important stepping-stone toward better characterization of the genetic architecture of cognitive aging in the IndianSouth Asian population and highlights the need for further research that may lead to the identification of new variants unique to this population.