bluuebunny/crossref_metadata_2025 huggingface dataset:
Doing more with less: Women’s higher brain metabolic rate compensates for early Alzheimer’s pathological changes
Authors: Sundermann Erin E , Maki Pauline M , Reddy Sarah , Bondi Mark W , Biegon Anat ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Cognitively normal women have consistently shown higher brain glucose metabolism than men across the adult life span in key Alzheimer’s disease (AD) related regions. The goal of our work was to examine whether these sex differences provide resilience to the effect of AD pathologies on cognition.

Method

1259 participants (44% women; aged 55‐90) from the Alzheimer’s Disease Neuroimaging Initiative completed the Mini Mental Status Exam (MMSE), the Clinical Dementia Rating‐Sum of Boxes (CDR‐SOB) and neuroimaging assessments of glucose metabolism (FDG‐PET) in regions of interest (posterior cingulate, angular gyrus, inferior/middle temporal gyrus), brain volumes (T1 MRI) and cortical amyloid‐β burden (AV45‐PET). First, we examined whether sex moderates the relationship between brain glucose metabolism in the grey matter and whole brain gray matter volume (WBV) in the overall sample and within cognitively normal (CN), amnestic mild cognitive impairment (aMCI) and AD diagnostic groups. Second, we divided the AD pathological markers of cortical amyloid‐β burden and hippocampal volume (HV) into quartiles and examined sex differences in MMSE and CDR‐SOB scores within biomarker quartiles before and after adjusting for brain metabolism and the covariates of age, education, APOE4 and WBV.

Result

In the overall sample and within aMCI, metabolism was higher in women versus men per unit of WBV when WBV was moderate/large but showed a steeper decrease as WBV diminished. Women showed better MMSE and CDR‐SOB scores than men (ps<.05) at mild/moderate levels of AD brain pathology (quartiles 1‐3), particularly after adjustment for sex differences in brain volume. In contrast, men and women showed similarly poor MMSE and CDR‐SOB scores within the highest quartile of severe AD brain pathology (ps>.05). The female cognitive advantage at mild/moderate quartiles of AD pathological markers was eliminated or markedly attenuated (41‐94%) after adjusting for brain metabolism

Conclusion

More efficient neural function in women versus men may provide women greater resilience against the effects of early AD pathological changes and serve as a mechanism underlying better clinical profiles in women in early disease process and faster decline thereafter. These sex‐based mechanistic differences will have important implications for disease identification and treatment.
Validity of a new brief assessment of apathy: Caregiver version of the apathy motivation index
Authors: Klar Verena S. , Ang Yuen‐Siang , Lockwood Patricia L. , Attaallah Bahaaeddin , Dickson Shannon , Drew Daniel , Kienast Annika , Maio Maria R. , Plant Olivia , Slavkova Elitsa , Toniolo Sofia , Zambellas Rhea , Irani Sarosh , Husain Masud
Published: December 2020

Background

Apathy is a common, disabling syndrome observed across neurodegenerative diseases. Self‐report of apathy from patients can be misleading so caregiver report is valuable. However, a compact instrument that does not require clinician interview, is brief but adequately detailed is lacking.

Method

We developed a caregiver version of the Apathy Motivation Index (AMI CG) which requires a short 5 minute questionnaire to be completed by an informant. Scores were validated against a more extensive caregiver interview rating (Lille Apathy Rating, LARS CG), and compared to measures of depression, anhedonia, cognitive abilities, activities of daily living and caregiver burden. 124 patients (21 Alzheimer’s; 45 Parkinson’s; 30 limbic encephalitis; and 28 with subjective cognitive impairment) were tested.

Result

The AMI CG showed good internal reliability with a significant three‐factor structure, mapping to domains of Behavioural Activation, Emotional Sensitivity and Social Motivation. It had good external validity, correlating well with other measures of apathy, but not with depression or anhedonia. A cut‐off criterion based on the LARS CG correctly classified patients as apathetic or non‐apathetic in 82% and 72% percent of cases respectively (AUC = 0.85). 20 cases identified as apathetic by the AMI CG but not the LARS CG had loss of social motivation, a dimension of apathy overlooked by traditional instruments. Patients who under‐rated their apathy compared to informants were more likely to be a greater burden to caregivers.

Conclusion

The AMI CG successfully detects clinical apathy, including cases of social apathy.
Safety and target engagement profile of two oxaloacetate doses in Alzheimer’s patients
Authors: Swerdlow Russell H
Published: December 2020

Background

Brain bioenergetics are defective in Alzheimer’s disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking.

Method

We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n=15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy (MRS) prior to and after the intervention. We also screened pharmacokinetics and cognitive performance.

Result

Both doses were well‐tolerated. Compared to the 500 mg dose, the 1000 mg dose benefited default mode network glucose utilization on FDG PET (p<0.05), and the 1000 mg dose increased frontoparietal glutathione (p<0.05). We did not demonstrate consistent changes in blood levels, and cognitive scores did not improve.

Conclusion

1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.
Validation of convolutional neural network relevance maps for revealing patterns of Alzheimer’s disease in MRI scans
Authors: Dyrba Martin , Pallath Arjun H. , Teipel Stefan J.
Published: December 2020

Background

Although machine learning approaches achieve high diagnostic accuracy for detecting Alzheimer’s disease (AD) based on MRI scans, they are not applied in clinical routine due to a lack of suitable methods for model comprehensibility and interpretability. Recently developed visualization methods for convolutional neural networks (CNN) may fill this gap. We trained a CNN model to detect AD based on T1‐weighted MRI and implemented a web application to provide an intuitive visualization of relevance maps. The aim of this study was to evaluate the association of relevance scores and hippocampus volume to validate the clinical utility of this approach.

Method

MRI scans for 254 cognitively normal controls (CN), 219 patients with amnestic mild cognitively impairment (MCI), and 189 patients with AD were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). MRI scans were tissue‐segmented and normalized using VBM8. Hippocampal volume was extracted from the gray matter (GM) maps. Subsequently, GM maps and hippocampal volume were corrected for effects of total intracranial volume, age, gender and scanner magnetic field strength using a linear model. Thirty‐two coronal slices covering the hippocampus were selected and the corresponding GM residual maps entered into the CNN. The model was evaluated using ten‐fold cross‐validation. Finally, we derived activation maps using the layer‐wise relevance propagation (LRP) algorithm and calculated the sum of hippocampus relevance scores.

Result

We obtained highly accurate results of an AUC of 93±6% for AD vs. CN. For MCI vs. CN, group separation was lower with an AUC of 74±9%. The relevance maps for four exemplary patients are shown in Fig. 1. Relevance maps confirmed that hippocampal atrophy is the most informative region for AD detection with minor contributions from other cortical and subcortical regions. Relevance scores within the hippocampus were correlated with hippocampal volume with a Pearson correlation of r=‐0.79 (Fig.2).

Conclusion

Our CNN model yielded high accuracy when detecting AD and a medium level of accuracy for mild cognitive impairment. In general, the relevance maps showed the expected regions. The high association of hippocampus relevance scores and volume indicate a high validity of the CNN model as implemented in our intuitively usable web application.
Carotid atherosclerotic calcification characteristics relate to post‐stroke cognitive impairment
Authors: Wang Yingzhe , Li Shanshan , Ding Mengyuan , Dong Qiang , Yang Yemei , Cui Mei
Published: December 2020

Background

Post‐stroke cognitive impairment (PSCI) is one of the major complications during the chronic stage of ischemic stroke. Several factors, including age, education level, vascular risk factors, extent of stroke, and cerebral small vessel disease, are considered to be main determinants of PSCI. However, the relationship between large vessel diseases and PSCI was less studied before. In this study, we aimed to investigate the association between different carotid atherosclerotic calcification characteristics and PSCI.

Method

A total of 128 patients with acute ischemic stroke admitted to Huashan Hospital from 2017 to 2018 were included consecutively in this study. All of them completed brain/neck CTA and cognitive function battery at follow‐up. The number, size, location of calcifications in bilateral intracranial/extracranial internal carotid arteries, and the presence of rim sign was recorded separately. Quantitative analysis of arterial stenosis, reconstruction coefficient (RI) and soft plaque density was assessed as well. Cognitive function was evaluated 6‐12 months within the stroke onset. Post‐stroke cognitive impairment was diagnosed according to the cognitive questionnaires and CDR scale.

Result

In our study population, we found a prevalence of 58.6% for post‐stroke cognitive impairment with no dementia (PSCIND), and a prevalence of 20.3% for post‐stroke dementia (PSD). The presence of calcification on carotid arteries increased the risk for PSCI. Furthermore, in different calcification characteristics, multiple calcifications, thick/mixed calcifications and surface calcifications were significantly associated with PSCI after full adjustment (demographics, vascular risk factors and stroke severity). Carotid artery stenosis was another strong predictor for PSCI. However, rim sign, RI and soft plaque density showed no significant relationship with PSCI.

Conclusion

The quantity and location of calcification might be independent indicators for PSCI in carotid atherosclerotic plaques.
Alzheimer pathology in the human ascending reticular activating system: Early and severe
Authors: Grinberg Lea Tenenholz
Published: December 2020

Background

The ascending reticular activating system (ARAS) is a collection of interconnected brain nuclei that regulates wakefulness, alertness and modulate behaviors. The critical components of ARAS degenerates early during Alzheimer’s disease progression in association with abnormal tau build‐up. Despite accumulating evidence, the role of AD‐related ARAS degeneration in promoting neuropsychiatric symptoms remains underappreciated. This talk will provide the state‐of‐the‐art in the knowledge of arousal system dysfunction in AD based on human studies as a framework for understanding the neuroanatomical changes underlying arousal dysfunction in AD.

Method

We reviewed authorial studies and results from other groups focusing on the isodendritic core of the reticular formation and other neuromodulatory nuclei associated with arousal in the context of AD pathology. Emphasis was given to quantitative studies, clinicopathological correlations and studies focusing on pre‐cognitive change, early AD stages.

Result

Multiple nuclei of the ARAS, including the noradrenergic locus coeruleus, show consistent and early changes associated to AD‐type neuropathology build‐up, especially but not restricted to tau protein. These neuropathological changes lead to dysregulation of the respective neurotransmitter systems (both up‐ and downregulation) besides progressive neuronal dysfunction and death.

Conclusion

The arousal neuromodulatory systems show early vulnerability to AD‐type changes. further understanding of the mechanisms leading to this vulnerability remains an unmet need and realizing this vision may point to strategies to treat neuropsychological symptoms in AD.
Noradrenergic responsiveness supports selective attention across the adult lifespan
Authors: Dahl Martin J. , Mather Mara , Sander Myriam C. , Werkle‐Bergner Markus
Published: December 2020

Background

Theories of healthy and pathological aging assume a critical role of the locus coeruleus (LC), the main cortical norepinephrine (NE) supply, in shaping late‐life cognition. Postmortem analyses identified the LC as one of the first brain sites that accumulates tau pathology. However, in‐vivo research linking the noradrenergic system to senescent cognitive decline in humans is rare.

Here we used a multimodal assessment to investigate whether individual differences in attention are related to the noradrenergic system.

Method

In younger (n = 39) and older adults (n = 38) we applied fear conditioning, an experimental manipulation known to modulate arousal‐related noradrenergic drive. Concurrently, we assessed pupil dilation, a non‐invasive proxy for noradrenergic activity, and the electroencephalogram (EEG) as indicators for successful NE manipulation. Reliable pupil and EEG signatures associated with elevated LC‐NE activity were identified in repeated conditioning sessions. We further evaluated participants’ general attention ability using a multimodal cognitive assessment. During one of the attention tasks (dichotic listening), fear‐conditioned (CS+) or perceptually matched control stimuli (CS–) were presented on a trial‐by‐trial basis to dynamically modulate arousal‐related noradrenergic drive.

Result

Relative to younger adults, older adults demonstrated compromised performance across a variety of attention tasks. On a physiological level, presentation of fear‐conditioned stimuli during dichotic listening reinstated the acquired arousal response. Relative to control stimuli (CS–), conditioned stimuli (CS+) induced a multimodal response, consisting of pupil dilation and EEG desynchronization. Crucially, greater pupil dilation in response to the CS+ was associated with a stronger transient alpha–beta desynchronization (9–30 Hz), indicating a common dependence on phasic NE release. Using structural equation modeling, we integrated over EEG desynchronization and pupil dilation markers to derive a single index reflecting the responsiveness of the noradrenergic system to arousing stimuli. Combining behavioral and physiological data, we observed that a more responsive noradrenergic system was associated with better performance across attention tasks. Finally, we found that older age is associated with lower pupil‐ and EEG‐indexed noradrenergic responsiveness.

Conclusion

Taken together, our findings indicate that (1) noradrenergic neuromodulation dynamically sculpts low frequency oscillatory dynamics in posterior brain areas and (2) this interaction supports attention across the lifespan.
Working memory and mild cognitive impairment: Digital intra‐response latency, subcortical nuclei, and neuropsychological test performance
Authors: Emrani Sheina , Baliga Satya , Lamar Melissa , Price Catherine C. , Au Rhoda , Wasserman Victor , Matusz Emily , Swenson Rodney , Baliga Ganesh , Libon David J.
Published: December 2020

Background

Digital technology offers the ability to obtain nuanced data previously unobtainable. A digital Backward Digit Span (BDT) using voice recognition was administered to memory clinic patients. Our goal was to assess the validity of this technology by (1) analyzing differences between non‐MCI versus MCI patients; (2) examining correlations with other neuropsychology tests; and, (3) analyzing test performance in relation to MRI subcortical regions of interest known to be related to working memory.

Method

Jak‐Bondi (2009) criteria classify patients into MCI (n= 67) and non‐MCI (n= 72) groups. Working memory (WM) was assessed with the Backward Digit Span Test (BDT) consisting of 7 trials of 5 digits backwards; all trials were administered; and comprehensive neuropsychological testing was obtained. Only correct test trials were analyzed. BDT variables of interest included latency for each five responses. NeuroquantTM software calculated thalamic, caudate and hippocampal volume (n= 23) controlled for intracranial volume (ICV).

Result

Between‐group difference for total time to completion was not significant (M= 55.64 + 18.91 sec.). An analysis of serial order position latencies clearly suggests two distinct epochs (Figure 1). A latency ratio (LR) for serial order 1 versus serial order 3 was calculated. Using this measure, non‐MCI patients presented with slower latency to initiate their response (serial order 1); but faster latency to sustain their response (serial order 3) compared that MCI patients (F[1,52]= 6.26, p< .016). Simple correlations were significant between the BDT‐LR and Judgement of Line Orientation Oblique test items (r= 0.325, p< .019) and WAIS‐III Digit Symbol test performance (r= 0.316, p< .017). Simple correlations were significant or near significant between the BDT‐LR and left thalamic volume (r= 0.468, p< 0.032); right thalamic volume (0.410, p< .065); total thalamic volume (r= 0.470, p< 0.032); and left caudate volume (r= 0.447, p< .042).

Conclusion

These data are remarkable for how patients allocate their time to generate a correct response. Correlations between BDT‐LR, subcortical nuclei, and neuropsychological test performance provide evidence for the validity of using discrete latency measures to assess WM in patients with MCI. Intra‐response BDT latency ratios could be a meaningful neurocognitive biomarker for emergent illness.
Repeated memory‐based assessments: Implications for clinical trials and practice
Authors: Papp Kathryn V. , Samaroo Aubryn H. , Chou Hsiang‐Chin Lori , Buckley Rachel F. , Rentz Dorene , Sperling Reisa A. , Amariglio Rebecca
Published: December 2020

Background

Detailed longitudinal neuropsychological assessment in the Harvard Aging Brain Study (HABS) and related studies has revealed that subtle decrements in associative and semantic memory, as well as reduced practice effects for repeated items may be the earliest cognitive changes in preclinical AD. Utilizing digital, repeated, and remote assessment of these cognitive functions has the potential to increase the rapidity and ease with which these subtle changes can be detected. We previously showed that diminished practice effects on a challenging iPad‐based monthly face‐name memory paradigm was associated with neuroimaging markers of amyloid and tau in normal older adults participating in HABS. These findings inspired the development of the Boston Remote Assessment of Neurocognitive Health (BRANCH), a smartphone‐based associative and semantic memory assessment using stimuli and tasks relevant to everyday life designed for serial assessment.

Method

We describe the development, feasibility, and pilot data from a smartphone‐based memory assessment administered daily (over consecutive days) in normal older adults using their own devices. BRANCH includes 2 measures of paired associative learning (faces and names, groceries and prices), an associative memory test with facilitated encoding (categories), and a continuous visual recognition task (street signs). A total of 41 pilot participants (mean age=76.1; 64% female) completed 1 version of BRANCH in clinic and 4 versions remotely on their own mobile device for 4 consecutive days. Participants also completed standard paper and pencil testing and a questionnaire about their experience completing the task.

Result

BRANCH was feasible with a total of 80% of individuals completing all assessments in the correct order. It was acceptable to participants with 64% finding the tasks at‐least somewhat to highly engaging. Older age and general cognition (e.g., MMSE) was associated with worse performance across memory tasks. Improved performance (practice effect) was observed on daily administration of paired associative memory tasks (Figure 1.).

Conclusion

A theoretically and evidence‐based digital memory assessment with ecologically‐valid tasks and stimuli is feasible for older adults to complete independently on their own devices. Digital assessment over multiple timepoints has the potential to drastically improve the efficiency with which cognitive performance and subtle decline can be captured.
NOX4 negatively regulates memory functions in APP/PS1 mice
Authors: Zhu Xiaolei , Tao Wenyuan , Yu Linjie , Jin Jiali , Xu Yun
Published: December 2020

Background

Excessive oxidative stress plays a critical role in the pathogenesis and progression of Alzheimer's disease (AD). Nox4 is constitutively active and widely expressed in the brains, and inhibition of Nox4 decreases the level of ROS and oxidative stress. Emerging evidence has shown that NOX4 inhibition protects against stoke and traumatic brain injury. However, the role of NOX4 in the pathogenesis of AD is not defined.

Method

Male APPswe/PS1dE9 (APP/PS1) transgenic mice, NOX4‐/‐ mice and wild type C57BL/6 (B6) littermates were obtained from the Model Animal Research Center of Nanjing University. GLX351322 (5 mg/kg/day, MedChemExpress, USA), was intraperitoneally injected to APP/PS1 mice for 4 weeks followed by the behavior tests. The memory function was examined by Novel‐object recognition (NOR), Fear condition (FC) and Morris water maze (MWM) tests. The amyloid load was determined by immuofluorescence assay (IFA) and ELISA. Synaptic transmission was examined by hippocampal LTP induction and synaptic proteins were determined by IFA and western blotting. The markers of lipid peroxidation 4‐HNE, protein oxidation 3‐NT, and DNA oxidation 8‐OHdG were detected using the corresponding ELISA kits. The level of ROS and H2O2 was measured using the commercialized kits.

Result

Nox4 was mainly expressed in neurons in the central nerve system, and Nox4 inhibition by GLX351322 protected against Aβ1‐42 induced neurotoxicity. In addition, GLX351322 treatment attenuated memory deficits and synaptic dysfunction of APP/PS1 mice, and decreased the amyloid load and oxidative stress in the hippocampus of APP/PS1 mice. Furthermore, Nox4 knockout APP/PS1 mice showed improved memory functions and decreased amyloid load and oxidative stress, which was consistent with the results of GLX351322.

Conclusion

Our results have demonstrated that NOX4 inhibition or knockout attenuated memory deficits in APP/PS1 mice, suggesting that NOX4 might be a potential target for AD treatment.
Activation of Nav1.1 ameliorates tau pathology and brain atrophy in a mouse model of tauopathy
Authors: Sampei Kazuaki , Seki Chie , Takuwa Hiroyuki , Maeda Jun , Ono Maiko , Tokunaga Masaki , Shimojo Masafumi , Honda Shigeyuki , Kimura Taeko , Ishikawa Taizo , Kudo Takehiro , Takado Yuhei , Sahara Naruhiko , Higuchi Makoto
Published: December 2020

Background

Several clinical studies indicate that subclinical epileptiform discharge is observed in patients with Alzheimer’s disease (AD), and neuronal hyperexcitability accelerates their cognitive decline. Previous studies indicated that the expression level of Nav1.1, which is coded by the Scn1a gene and a voltage‐gated sodium channel abundantly expressed in parvalbumin‐positive inhibitory neurons, decreased in AD patients. Because it is reported that excitatory neural activity stimulates tau release from neurons, we hypothesized that suppressing neuronal hyperexcitability by enhancing inhibitory neural activities could ameliorate disease progression in a mouse model of tauopathy. In this study, we investigated if our in‐house Nav1.1 potentiator, compound‐X, prevents the progression of tau accumulation and neurodegeneration in a mouse model of tauopathy, rTg4510.

Method

We performed electrophysiological recording to determine the specificity and potency of compound‐X in cells stably expressing various Nav subtypes, and cortical slices of Scn1a<+/‐> and rTg4510 mice. We subsequently tested the in‐vivo effects of compound‐X on Nav1.1 by examining if compound‐X can prevent hyperthermia‐induced seizure in Scn1a<+/‐> mice. To assess the effect of compound‐X on tau‐induced neuropathologies in rTg4510 mice, we orally treated rTg4510 mice with this compound from 4 months of age, and evaluated tau accumulation and brain atrophy of these animals by longitudinal tau PET with [18F]PM‐PBB3 and MRI, respectively, at 6 and 8 months of age.

Result

The auto‐patch‐clamp system using Nav stably expressing cells and current‐clamp recoding using cortical slices demonstrated that compound‐X could potentiate Nav1.1 current in a concentration‐dependent manner, leading to activation of inhibitory neurons. Scn1a<+/‐> mice administered with compound‐X showed an increased threshold of the rectal temperature of hyperthermia‐induced seizure, and prolonged latency to seizure, indicating that compound‐X can potentiate Nav1.1 in vivo. Significantly, tau accumulation and neuronal loss assessed by cerebral atrophy and lateral ventricular enlargement were profoundly suppressed in the brains of rTg4510 mice relative to vehicle‐treated controls.

Conclusion

Pharmacological enhancement of inhibitory neuronal function can be a beneficial approach to the prevention of hyperexcitability‐mediated tau pathologies and neuronal death in a mouse model of tauopathy.
Automated lexical and acoustic analysis of young and older healthy adults
Authors: Cho Sunghye , Nevler Naomi , Shellikeri Sanjana , Parjane Natalia , Ryant Neville , Ash Sharon , Irwin David J , Cieri Christopher , Liberman Mark Y , Grossman Murray
Published: December 2020

Background

Language use is affected by factors such as an individual’s age and sex. An understanding of these factors is essential to studies of speech in neurodegenerative disease. While age and sex have received considerable attention in the literature, results are mixed. Also, very few studies have considered both lexical and acoustic features at the same time, which leaves a major gap in our understanding of the effect of age and sex on language use. In this study, we analyze both lexical and acoustic features from 1‐minute speech samples using novel, objective, reproducible, fully automated methods.

Method

We examined digitized Cookie Theft picture descriptions produced by 37 older (52‐89y, mean=68y) and 76 young (18‐22y, mean=20y) participants. Using modern natural language processing and automatic speech recognition tools, we automatically annotated part‐of‐speech categories of all tokens and rated nouns and verbs for five lexical features, including word frequency, familiarity, concreteness, age of acquisition and semantic ambiguity. We automatically segmented each sample into speech and silent pause segments; extracted acoustic features such as total speech time, mean speech segment duration, and mean pause duration; and measured pitch percentiles from all speakers.

Result

Older speakers produced significantly more interjections (p=0.023), pronouns (p<0.001), and verbs (p=0.004), and fewer conjunctions (p=0.013), determiners (p=0.009), nouns (p=0.049), and prepositions (p=0.002) than young participants. Older speakers’ nouns and verbs were more familiar (nouns: p=0.008, verbs: p<0.001), more frequent (verbs only: p=0.002), and less ambiguous (nouns: p=0.049, verbs: p=0.057) compared to those of young speakers. Older speakers produced shorter utterances (p=0.001) with a lower type/token ratio for nouns (p=0.016) than young participants. Also, older participants produced shorter speech segments (p=0.017) and longer pauses (p<0.001) with increased total speech time (p<0.001) and total number of words (p=0.002). Lastly, we observed interactions of age and sex in pitch ranges (F(1,109)=4.37, p=0.039), the number of conjunctions (F(1,109)=9.52,p=0.003) and tense‐inflected verbs (F(1,109)=4.02, p=0.047).

Conclusion

These results suggest that older speakers’ lexical content is less diverse and they use shorter utterances than young participants. The findings show that lexical and acoustic characteristics of semi‐structured speech samples can be examined using automated methods.
Increased accumbens volume predicts excessive daytime sleep in subjective cognitive decline with good sleep quality
Authors: Wang Ziqi , Dong Li , Yang Jie , Zhang Songge , Zhong Dayong , Han Ying , Yao Dezhong
Published: December 2020

Background

There is evidence of excessive daytime sleep (EDS) related to future Alzheimer’s disease, but little is known about what brain alterations in the very early stage of the disease. This study examines whether EDS is associated with specific brain volume alterations in subjective cognitive decline with good sleep quality.

Method

Structural magnetic resonance imaging (MRI) was used to acquire anatomic scans from 109 community‐dwelling cognitive function normal participants (18 EDS, 91 control) and quantitative regional estimates of brain volume were derived by using volBrain. We adjusted analyses for age, sex, education, APOE, BMI, and intracranial volume.

Result

EDS had significant increased volumes in left Thalamus, total Accumbens, right Accumbens and left Accumbens. Logistic analysis showed both total Thalamus and Accumbens, both left Thalamus and Accumbens related to diagnosis EDS. Only total Accumbens (r = 0.20, p = 0.039) and right Accumbens (r = 0.23, p = 0.018) associated with Epworth Sleepiness Scale (ESS) scores.

Conclusion

At the preclinical stage, persons with increased Accumbens volume, even though had good sleep quality, predicts excessive daytime sleep.
Large‐scale plasma proteomic analysis identifies proteins and biological pathways associated with incident dementia
Authors: Walker Keenan A , Chen Jingsha , Wu Aozhou , Tin Adrienne , Mosley Thomas H , Fornage Myriam , Ballantyne Christie M , Boerwinkle Eric , Sullivan Kevin J , Zeger Scott L , Ganz Peter , Gottesman Rebecca F , Coresh Josef
Published: December 2020

Background

While plasma levels of several etiologically relevant molecules have been associated with Alzheimer’s disease and dementia more broadly, information about the full range of changes in the plasma proteome that precede dementia is lacking. Accordingly, this study used modified aptamer technology (SOMAscan) to examine the relationship between the plasma levels of 4,877 proteins and risk for incident dementia in a large community‐based sample.

Methods

Plasma levels of 4,877 proteins were measured in non‐demented participants who attended visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (2011‐2013; Figure 1A). We examined the association of log2 protein levels with incident dementia risk over 5 years using Cox proportional hazard models adjusted for demographic and cardiovascular risk factors. Dementia‐associated proteins were then measured from plasma samples collected 18 years earlier (visit 3; 1993‐1995) and related to dementia risk between visits 3 and 5 (Figure 1B). Candidate proteins were related to measures of brain structure (by MRI) and amyloid burden (by PET). Ingenuity Pathway Analyses and Mendelian randomization were used to inform biological pathways and causal relationships.

Results

Among 4,144 participants seen at visit 5 (age: 75 (SD 5)), there were 444 incident dementia cases over the next 5 years. In a proteome‐wide analysis, 50 proteins were significantly associated with incident dementia at a Bonferroni‐corrected threshold (P<1.03e‐05; Figure 2A). When these dementia‐associated proteins were measured in plasma collected almost 20 years earlier (n=11,069; 1,131 dementia cases), 21 of the 50 proteins continued to show a significant association with incident dementia (P<0.001; Figure 2B). We found causal associations with Alzheimer’s disease for two of the top five dementia‐associated proteins using Mendelian randomization, and we demonstrated a relationship between protein levels and neuroimaging measures of atrophy, white matter disease, and cerebral amyloid. A systems‐level analysis of dementia‐associated proteins implicated biological mechanisms involved in metabolic and inflammatory signaling, coagulation and prothrombin activation, and innate immune function, among others (Figure 3).

Conclusions

These findings provide insight into the plasma proteomic patterns that precede the onset of dementia in old age and middle age and highlight novel molecules and mechanistic pathways for further study.
Risk factors for dementia in Cuban older adults
Authors: Peeters Geeske , Almirall‐Sanchez Arianna , Llibre‐Guerra Jorge J , Lawlor Brian , Anne Kenny Rose , Yaffe Kristine , Llibre Juan
Published: December 2020

Background

Little is known about risk factors of dementia in Latin American countries. Findings from western countries cannot be readily translated to Latin American countries. To inform risk stratification and targeted preventive strategies, we aimed to identify risk factors of incident dementia in Cuban older adults and explores how these change with age.

Method

Data were from 1846 participants in the Cuban cohort of the 10/66 Dementia Research Group. Participants completed questionnaires, health examination and cognitive tests at baseline (2003‐06) and on average 4.5 years later (2007‐10). Univariable and multivariable associations between risk factors at baseline and incident dementia at follow‐up were examined using logistic regression for the total sample and for younger (65‐74 yrs) and older (75+ yrs) subgroups.

Result

9.2% of participants developed dementia. In the total sample, significant univariable associations with dementia were found for age, education, marital status, obesity, stroke, depression, physical activity, fish consumption and family history. In the multivariable model, associations with age (≥75 vs. 65‐74 yrs: OR=2.65, 95%CI=1.86‐3.76), marital status (widowed/divorced/separated vs. married/cohabiting: OR=1.65, 95%CI=1.12‐2.43), physical activity (inactive vs. highly active: OR=2.63, 95%CI=1.58‐4.37), and fish consumption (regular vs. rarely: OR=1.74, 95%CI=1.04‐2.91) remained statistically significant. In the younger age group, significant multivariable associations were found for stroke (OR=2.90, 95%CI=1.22‐7.90), ischaemic heart problems (OR=0.22, 95%CI=0.05‐0.95), depression (OR=1.87, 95%CI=1.05‐3.31), and physical activity (inactive vs. highly active: OR=3.09, 95%CI=1.26‐7.58). In the older age group, significant multivariable associations were found for smoking status (current vs. never/ex‐smoker: OR=2.19, 95%CI=1.17‐4.11), physical activity (inactive vs. highly active: OR=2.05, 95%CI=1.07‐3.92) and fish consumption (regular vs. rarely: OR=2.35, 95%CI=1.24‐4.45).

Conclusion

This is the first study in Cuba and one of few in Latin America to identify risk factors for incident dementia. The risk profiles were dominated by chronic conditions in 65‐74 year olds and by lifestyle factors in 75+ year olds. The important role for modifiable risk factors holds promise for future preventive strategies.
Investigating neural correlates of mild cognitive impairment using estimated clinical status from neuropsychological test battery: LASI‐DAD
Authors: Keller Brenton James , Lee Jinkook , Toga Arthur W , Jovicich Jorge ,   LASI‐DAD
Published: December 2020

Background

Having ways to quickly assess cognitive impairment is critical for developing nations. Here we examine how different combinations of neuropsychiatric tests identify cognitive impairment using the Longitudinal Aging Study in India ‐ Diagnostic Assessment of Dementia (LASI‐DAD). We then investigate for brain regions that show structural morphological differences between cognitive impairment and cognitive normal groups.

Methods

A total of 103 subjects (female = 46, age = 68 ± 6 years) were studied from three clinical 3T MRI centers using the ADNI 3 MRI protocol (NIMHANS, Bangalore, N=52, NM Medical, Mumbai, N=23, and Institute of Kolkata N=28). Cognitive impairment clinical status was missing for 62 of the subjects. Cognitive impairment status was investigated using the LASI‐DAD main dataset (clinical status n = 1486). We examined different combinations of factors from the LASI‐DAD neuropsychological assays to predict clinical impairment status. After estimating cognitive impairment status, brain morphometry data was studied with Freesurfer using volumetric ROI‐analysis and vertex‐based cluster‐corrected structural analysis.

Results

We found a combination of JORM IQCODE, Cognitive Activity Score, years of education, HMSE, and the interaction between HMSE and general cognition to best predict clinical status (AUC=0.90). Clinical status was calculated for the MRI subjects lacking a clinical diagnosis (CN=38, CI=24). Cognitive impairment was found to be associated with thickness and volumetric decline, especially the right hemisphere transverse temporal gyrus (10‐15%) and medial orbitofrontal cortex (6‐9%), and bilateral volumetric decline of the hippocampus (presubiculum and molecular layer, 5‐8%). Furthermore, age was not found to affect hippocampal volume, yet there was a significant negative effect on hippocampal volume with the interaction of cognitive impairment and age (6‐8%). A significant interaction between cognitive impairment and age was also found to reduce the curvature of the left hemisphere fusiform.

Conclusions

We investigated combinations of neurophysiological tests to predict cognitive impairment status. Using the predicted cognitive impairment status, we found significant morphological changes in the brain between groups. This demonstrates how quick neurocognitive exams can be used in areas lacking clinicians who can diagnosis dementia.
Correcting the MIR‐124/PTPN1 signal abnormality rescues tauopathy in Alzheimer’s disease
Authors: Zhou Yang
Published: December 2020

Background

MicroRNAs have been implicated in diverse physiological and pathological processes.

Method

Cell Culture and Treatment, RNA Isolation and Quantitative Real‐Time PCR (qRT‐PCR), Preparation of Soluble and Insoluble Fraction.

Result

We demonstrated that disturbance of the miR‐124/PTPN1 signal induced animbalance of the phosphatase/kinase system by enhancing the tyrosine phosphorylation of GSK‐3β and PP2A, which then caused the activation of GSK‐3β and inactivation of PP2A and ultimately led to AD‐like tauopathy.

Conclusion

We first replicated the alteration in the miR‐124/PTPN1 signal in AD by artificially upregulating miR‐124 or silencing PTPN1 in the hippocampus of C57 mice and found that disturbance of miR‐124/PTPN1 signal resulted in AD‐like tauopathy, including hyperphosphorylation, aggregation and missorting, as well as learning and memory deficits.
Implication of healthy lifestyles and the taking of Fortasyn Connect© in the cognitive impairment evolution
Authors: Zea‐Sevilla María Ascensión , Palomo María Sagrario Manzano
Published: December 2020

Background

There is increasing evidence that beyond modifiable risk factors there are modifiable factors associated with Alzheimer's disease, including those related to cardiovascular risk ‐ high blood pressure, hypercholesterolemia, diabetes, smoking and overweight. And with a diet lifestyle, physical exercise and cognitive and social activity. Based on this premise, we analyze on a series of patients treated with Fortasyn connect (Souvenaid®) their “healthy life” habits.

Method

On 39 patients with mild cognitive impairment or mild Alzheimer's disease in treatment with Souvenaid®, life habits questionnaires were completed in daily and leisure activities, in social and food participation.

Result

We studied 39 subjects around the age of 81.1 years (± 4.5), in treatment with Souvenaid ® (53.8% associated with IAch and 10.3% with memantine). Compliance with Souvenaid ® treatment was 79.5% (due to intolerance dropped 7.7%). The mean treatment follow‐up of patients who finished the study was 12.9 months (± 8.0). The adherence to the Mediterranean diet was moderate. 37.8% of the subjects maintained or improved the MMSE score at the time of follow‐up. The loss of the monthly MMSE score tended to be greater in the elderly (p = 0.082) and was significantly lower in those who regularly drove (p = 0.009), read (p = 0.036) or engaged in light physical activity (p = 0.018). In the multivariate study, driving and light physical activity was associated with a lower monthly loss of MMSE.

Conclusion

The study of healthy lifestyles could help elucidate the best combination of pharmacological and non‐pharmacological treatments, in order to develop a "precision medicine" approach and an individual and multimodal strategies, in order to prevent, diagnose and develop therapies more precise and effective against AD.
An integrative, hypothesis‐free, multi‐omics approach uncovers biological pathway alterations in Alzheimer’s disease
Authors: Clark Christopher , Dayon Loic , Masoodi Mojgan , Popp Julius
Published: December 2020

Background

In recent years, different ‘omics approaches have identified multiple pathway alterations in Alzheimer’s disease (AD). However, the pathogenic mechanisms are still not fully understood. Here, we test an integrative approach combining multiple ‘omics results to identify and explore in depth central nervous system (CNS) pathway alterations in AD.

Methods

Multi‐omics data were obtained from a well‐characterised cohort of community‐dwelling elder subjects including healthy volunteers with normal cognition and memory clinic patients with either mild cognitive impairment or mild AD dementia. Inflammatory biomarkers were quantified by sandwich immunoassays in cerebrospinal fluid (CSF) samples; metabonomics (covering amino acids, carboxylic acids, and central energy metabolism), ionomics, proteomics, and lipidomics were performed using nuclear magnetic resonance or mass spectrometry coupled to liquid, supercritical fluid or gas chromatography. Alterations associated with AD were identified using Elastic‐Net regression at single ‘omics level and Multi‐Omics Factor Analysis, a hypothesis‐free Bayesian approach, for multi‐omics integration. Pathway enrichment analysis was performed in the Reactome database for selected analytes.

Results

We identified five major dimensions of heterogenicity (latent factors, LFs) within the cohort. We evaluated the performance of this model by separating participants in the cohort with low vs. high CSF expression levels of amyloid, tau and phosphorylated tau (P‐tau). Best performance was obtained for tau and P‐tau with 93 and 96% sensitivity, respectively. Using these LFs we could furthermore identify analytes associated with either amyloid pathology (21) or neurodegeneration (37). We also identified specific patterns of expression of these analytes across LFs, revealing interactions between multiple ‘omics modalities. Pathway enrichment analysis also revealed an over representation of the hemostasis, immune response and extracellular matrix signalling pathways.

Conclusions

In this proof‐of‐principle work, we demonstrate that integrating expression from multiple ‘omics levels allows for a more comprehensive exploration of alterations related to AD pathology at CNS level. We identify novel metabolic alterations at molecular and pathway levels, and describe their relationships with amyloid pathology, neuronal injury, and tau hyperphosphorylation.
Single cell RNA sequencing of human microglia uncovers a subset that is associated with Alzheimer’s disease
Authors: Olah Marta , Menon Vilas , Habib Naomi , Taga Mariko , Ma Yiyi , Khairallah Anthony , Yung Christina J. , Coronas‐Samano Guillermo , Vonsattel Jean P , Teich Andrew F. , Schneider Julie A. , Bennett David A. , Regev Aviv , De Jager Philip L.
Published: December 2020

Background

The extent of microglial heterogeneity in the aging human brain remains a central, yet poorly explored question in light of the development of therapies targeting this cell type in age related neurodegenerative diseases, such as Alzheimer’s disease.

Methods

Using single cell RNA sequencing, we investigated the population structure of microglia purified from human cerebral cortex of aged donors with and without Alzheimer’s disease.

Results

We describe the population structure of microglia in the aged human brain and establish the divergent association of the different microglia subsets to age related neuropathologies and measures of cognitive decline. We confirm the presence of the identified microglial subpopulations histologically and explore their topological relationship to histopathological hallmarks of aging and AD in situ. Based on our data we prioritize one microglial cluster, cluster 7, which is enriched for genes involved in endosomal/vacuolar pathway. Interestingly we find that the signature gene set of cluster 7 is depleted in the cortical transcriptomic profile of individuals with AD. Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data.

Conclusions

Thus, single cell transcriptomic profiling of live human microglia identifies a range of microglia subtypes in the aged human brain, and we prioritize one of these as being altered in AD.
A common risk variant in the MTHFR gene contributes to age‐related cerebrovascular dysfunction in VCID
Authors: Reagan Alaina M. , Christensen Karen , Haber Annat , Rozen Rima , Carter Gregory W. , Sasner Michael , Howell Gareth
Published: December 2020

Background

Cerebrovascular damage occurs during aging, Alzheimer’s disease and Vascular Dementia, commonly referred to as Vascular Contributions to Cognitive Impairment and Dementia (VCID). However, few mouse models currently recapitulate human cerebrovascular deficiencies in disease. The C677T variant in methylenetetrahydrofolate reductase (MTHFRC677T
) is commonly associated with VCID. MTHFR codes for an enzyme involved in production of folate, homocysteine, and methionine metabolism. The MTHFRC677T
polymorphism is predicted to result in hyperhomocysteinemia, a condition that causes vascular inflammation and vascular damage. Additionally, methionine deficiency can result in DNA hypomethylation and has been confirmed in MTHFRC677T
carriers. Despite the fact that, in some populations, MTHFRC677T
is more common than APOE
E4, mechanisms by which MTHFR
C677T increases risk for VCID are not known.

Methods

CRISPR technology was employed to engineer the Mthfr
C677T allele into C57BL/6J (B6) mice. Vascular health is being assessed in 6, 12, 18 and 24 months‐old mice using leakage assays (FITC‐dextran and presence of extravascular fibrin) and immunofluorescence (IF) to examine blood brain barrier integrity in the cerebrovascular unit: endothelium (CD31) smooth muscle (aSMA) pericytes (PDGRFb) basement membrane (ColIV) and tight junctions (Claudin‐5, Occludin, ZO‐1). Functional MRI is used to determine in vivo vascular reactivity. Bulk RNA sequencing and Reduced Representation Bisulfite Sequencing (RRBS) were performed on half brains to assess differential gene expression and DNA methylation, respectively.

Results

Mice with the Mthfr
C677T risk variant have significantly reduced liver enzymatic activity, significantly increased plasma homocysteine levels and decreased methionine levels, recapitulating the human phenotype. Transcriptional profiling of brain tissue revealed genes regulating circadian rhythm, neurogenesis, ER stress and GABA signaling are differentially expressed (DE) in B6.Mthfr
C677T compared to B6 samples. RRBS data demonstrated significant genome‐wide DNA hypomethylation in these mice. Hypomethylated and DE genes are expressed in astrocytes, microglia and endothelial cells and are predicted to regulate apoptosis/proliferation, inflammation and glucose transport across the blood brain barrier. Validation by IF is underway.

Conclusion

We have created a novel mouse strain to determine the precise mechanisms by which MTHFR
C677T increases risk for VCID. This work aims to identify novel therapeutic approaches that preserve cerebrovascular health throughout aging to prevent VCID.