bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the causal mediating role of cardiovascular disease on the relationship between subclinical cardiovascular disease and cognitive impairment: The Cardiovascular Health Cognition Study
Authors: Andrews Ryan M , Carlson Michelle C , Didelez Vanessa
Published: December 2020

Background

Subclinical cardiovascular disease (sCVD) is associated with an increased risk of incident Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD). However, relatively little is known about the mechanisms by which sCVD leads to MCI or AD. One hypothesis is that cardiovascular disease (CVD) mediates the relationship between sCVD and MCI or AD.

Method

Using data from the Cardiovascular Health Cognition Study (N=3,602) and the R package medflex, we fit natural effects causal mediation models to test the hypothesis that CVD is a causal mediator of the effect of sCVD on the risk of MCI or AD within 10 years. All models were adjusted for age, sex, race, education, diabetes status, smoking status, and body mass index, and we excluded those with baseline CVD. We also stratified our analyses by apolipoprotein (APOE)‐4 carrier status and conducted several sensitivity analyses to assess the robustness of our results to violations of our assumptions.

Result

Among those in our analytic sample (N=2,377), sCVD significantly increased the odds of MCI or AD by 35% (OR: 1.35, 95% CI: (1.14, 1.56)) in total. Both the natural direct effect (OR = 1.31, 95% CI: (1.10,1.52)) and the natural indirect effect (OR=1.02, 95% CI: (1.01, 1.05)) were significant as well. CVD mediated approximately 9.5% of the total effect. Among APOE‐4 allele noncarriers, we also found a significant total effect (OR = 1.50, 95% CI: (1.25, 1.76)), natural direct effect (OR=1.44, 95% CI: (1.17, 1.70)), and natural indirect effect (OR=1.04, 95% CI: (1.01, 1.08)) of sCVD on MCI or AD risk through CVD, with approximately 11% of the total effect being mediated. Among APOE‐4 carriers, however, we failed to see any significant effects. Multiple sensitivity analyses showed our results were robust.

Conclusion

We found that CVD causally mediates the relationship between sCVD and the risk of MCI or AD within 10 years for APOE‐4 noncarriers, provided that our analytic and causal assumptions hold. Interestingly, the proportion mediated by CVD was only 9‐11% in our analyses, indicating that there are other, possibly substantial, etiological pathways by which sCVD increases the risk of MCI or AD; future research is needed.
Greater REM sleep associates with lower subcortical gray matter in APOE4 carriers
Authors: Baril Andree‐Ann , Beiser Alexa S. , DeCarli Charles , Sanchez Erlan , Mysliwiec Vincent , Seshadri Sudha , Pase Matthew P. , Himali Jayandra J.
Published: December 2020

Background

Shorter rapid‐eye movement (REM) sleep has been associated with an increased risk of Alzheimer’s disease (AD) and accelerated cognitive decline. In this study, we evaluated the association between REM sleep duration and brain structure in adults without stroke or dementia; and whether the presence of an apolipoprotein E4 (APOE4) allele modified this association.

Method

We studied participants in the Framingham Heart Study Offspring cohort aged at least 40 years who were without significant neurological diseases such as dementia and stroke. Participants underwent in‐home overnight polysomnography and brain MRI. REM sleep duration was calculated as a proportion of total sleep time. Cortical gray matter (GM) and subcortical GM volumes were segmented by semi‐automated procedures and investigated in statistical models as a percentage of intracranial volume. We used linear regression models to assess the association between REM sleep and brain structure, adjusted for age, age squared, sex, depression, and time between the polysomnography and MRI. We included an interaction term to evaluate potential modification by APOE4 allele status.

Result

The final sample included 492 participants (58.8 ± 8.8 years, 49.4%M). The average time between the polysomnography and MRI was 3.3 ± 1.0 years. We did not observe any direct associations between REM sleep percentage and GM volumes. The APOE4 allele interacted with REM sleep percentage in association with subcortical GM volume (p = 0.045). In APOE4 carriers, more REM sleep was associated with lower subcortical GM volumes (b = ‐0.009; SE = 0.004; p = 0.021), while no association was observed in non‐carriers. Consistent associations were observed when repeating analysis with REM sleep duration rather than percentage.

Conclusion

Increased REM sleep duration and percent were associated with lower subcortical GM volume in persons with genetic vulnerability to late‐onset AD. Persons with genetic susceptibility to AD and subcortical GM atrophy may have a compensatory increase in their REM sleep, given the role of this sleep stage in memory. On the other hand, hypertrophic GM has been reported in preclinical stages of AD, and this might be the case in those with a genetic susceptibility to AD and shorter REM sleep.
The role of dietary fatty acids intake in the association between cortical thickness and global cognitive function: The MIND trial
Authors: Aggarwal Neelum T. , Dhana Klodian , Agarwal Puja , Arfanakis Konstantinos , Barnes Lisa L. , Carey Vincent , Sacks Frank , Morris Martha Clare
Published: December 2020

Background

Cortical thickness has been associated with cognitive functioning and the risk of Alzheimer’s dementia. Macronutrients, such as fatty acids, are modifiable dietary factors known to be important in brain development. Whether fatty acid intake moderates the relationship between cortical thickness and cognitive performance deserves examination.

Method

The study population included 261 cognitively‐ healthy adults at risk of Alzheimer’s dementia from the ongoing MIND trial (NCT02817074) that studies the role of the MIND diet on cognition. Cortical thickness was measured on 34 regions of each hemisphere of the brain using FreeSurfer. Dietary fatty acids, including good fats, omega‐3, monounsaturated, polyunsaturated, and bad fats such as saturated and trans‐fatty acids, were assessed through a validated, interviewer‐administered 142‐item food‐frequency‐questionnaire. Participants grouped into high (n=130) or low (n=131) intake of fatty acids based on the median of the study population. Global cognition was composed as a summary measure of 4 cognitive domains from 12 cognitive tests. Linear regression models adjusted for age, sex, site, caloric intake, education, and cognitive activities were used to examine associations between cortical thickness and global cognition according to the dietary intake of fatty acids.

Result

The average age of study participants was 70 years (range, 65‐83), and 57% were women. Cortical thickness was significantly associated with higher global cognition (beta=1.046, p=0.02). Fatty acids modified the association between cortical thickness and global cognition. Among individuals with a higher intake of omega‐3 or polyunsaturated fatty acids, cortical thickness was associated with higher global cognitive functioning [beta (p‐value): 1.49 (0.032) and 1.366 (0.062), respectively]. In contrast, there was no association between cortical thickness and global cognitive function in individuals with a lower intake of these good fatty acids. In individuals with low consumption of saturated or trans‐fatty acids (bad fats), cortical thickness was associated with higher global cognitive functioning [beta (p‐value): 1.737 (0.009) and 1.467 (0.024), respectively], but not in individuals with high intake of these fatty acids (all p’s>0.3).

Conclusion

In cognitively healthy individuals at risk of Alzheimer’s dementia, higher cortical thickness was associated with better cognitive performance, but the dietary intake of fatty acids modified the relationship.
VAMP2 is a cerebrospinal fluid marker of selective hippocampal synapse loss and episodic memory performance in Alzheimer’s disease
Authors: Belbin Olivia , Molina Beatriu , Núñez‐Llaves Raúl , Goossens Julie , Dewit Nele , Alcolea Daniel , Estellés Teresa , Querol‐Vilaseca Marta , Dolcet Sonia Sirisi , Muñoz Laia , Clarimon Jordi , Blesa Rafael , Fortea Juan , Vanmechelen Eugeen , Lleó Alberto
Published: December 2020

Background

An early objective cerebrospinal fluid (CSF) marker of cognitive decline in preclinical Alzheimer’s disease (AD) would be a useful addition to the current AD biomarker arsenal. We recently identified VAMP2 as a potential CSF marker of AD‐related synapse loss. The aim of this study was 1) to evaluate the regional brain expression of VAMP2 in human postmortem tissue and 2) to assess the correlation of CSF VAMP2 levels with cognitive performance in cognitively normal controls and AD patients.

Method

Paraffin fixed brain sections from hippocampus, frontal, posterior‐cingulate and temporal inferior cortices from AD cases (n=10) and non‐pathological controls (n=10) were stained with anti‐VAMP2 (Cell Signaling) and an HRP‐conjugated (Dako) secondary antibody. VAMP2 was quantified using MATLAB software (MA, USA). CSF from the Sant Pau Initiative in Neurodegeneration (SPIN) cohort was selected from cognitively normal controls (n=68), preclinical AD stages 1 (n=31) and 2 (n=8), prodromal AD (n=80) and AD dementia patients (n=39). Cognitive performance was evaluated using the total score in the Free and Cued Selective Reminding Test (Buschke et al). We quantified VAMP2 in CSF by Single MOlecule Array (SIMOA).

Result

In control and AD brains, VAMP2 showed a neuropil‐like expression pattern consistent with a synapse marker and was widely expressed in cortical and subcortical regions (hippocampus>frontal cortex>cingulate cortex>temporal cortex). VAMP2 expression in AD brains was reduced 0.6‐fold compared to controls in the hippocampus (p=0.01) but comparable to controls in all other regions tested (all p>0.1). Reduced hippocampal VAMP2 levels correlated with increased Braak (r2=0.4, p=0.006) and CERAD (r2=0.3, p=0.03) staging. In CSF, VAMP2 levels were decreased compared to controls in preclinical AD and sequentially elevated over the course of AD, plateauing at the prodromal stage. Worse episodic memory was associated with increased CSF VAMP2 in controls (r2=0.09, p=0.009). In AD, the best fit was a nonlinear model (r2=0.07, p=0.0009) in which worse episodic memory was associated with increased CSF VAMP2 in preclinical AD but decreased VAMP2 in clinical AD.

Conclusion

These data support VAMP2 as a promising CSF marker of selective hippocampal synapse loss and episodic memory performance in Alzheimer’s disease and healthy controls.
Increased self‐reported sleepiness is associated with larger brain volume and less ischemic brain injury in a community sample
Authors: Baril Andree‐Ann , Beiser Alexa S. , DeCarli Charles , Sanchez Erlan , Mysliwiec Vincent , Seshadri Sudha , Himali Jayandra J. , Pase Matthew P.
Published: December 2020

Background

Sleepiness has been associated with an increased risk of Alzheimer’s disease (AD) and vascular dementia, but few studies have investigated its association with markers of accelerated brain aging. We evaluated the association between sleepiness and MRI measures; and whether the apolipoprotein E4 (APOE4) allele status moderates this relationship.

Method

We studied 492 participants (58.8 ± 8.8 years, 49.4%M) in the Framingham Heart Study aged >40 years without significant neurological diseases, such as dementia and stroke. We used the Epworth Sleepiness Scale (ESS) to assess sleepiness. Brain MRI metrics were volumes of white matter hyperintensities (WMH), total brain, cortical gray matter (GM) and subcortical GM, all investigated as a percentage of total intracranial volume; we also identified covert brain infarcts (CBI). Linear and logistic regressions were used to assess the association between ESS scores and brain structure. Model 1 adjusted for age, age squared, sex, and time between the ESS and MRI (3.3 ± 1.0 years). Model 2 additionally adjusted for APOE4 allele carrier status, Framingham Stroke Risk Profile scores, sleep medication, body mass index, and depression. We included an interaction term between APOE4 allele status and ESS score, adjusted for model 1 covariates, to evaluate potential effect modification.

Result

Higher ESS scores, indicating greater sleepiness, were associated with higher total brain volume (b = 0.33; SE = 0.13; p = 0.02), higher cortical GM volume (b = 0.26; SE = 0.12; p = 0.03), and a lower risk of CBI (OR = 0.57; 95%CI = 0.36‐0.93; p = 0.02) adjusted for both models 1 and 2 covariates. These associations were present when further adjusting for the apnea‐hypopnea index, education and habitual sleep duration. A significant interaction was observed between APOE4 and ESS scores (p = 0.008), where higher ESS was associated with higher cortical GM in non‐carriers (b = 0.43; SE = 0.14; p = 0.002). Conversely, in carriers, higher ESS was associated with lower cortical GM (b = ‐0.36; SE = 0.22; p = 0.09, trend).

Conclusion

Increased self‐reported sleepiness was associated with findings of better brain health, including higher cortical GM volume and less CBI. Genetic susceptibility to AD modified this relationship, where increased sleepiness was associated with higher cortical GM volume only in APOE4 non‐carriers. Better brain health may be associated with higher self‐reported sleepiness via better cognition and self‐awareness in those who are not at increased risk of developing AD.
Improved memory learning behavior in AD mice following 21‐day intermittent hypoxia training
Authors: Shi Xiangrong , Chen Xiaoan , Cai Ming , Wang Hong , Jung Marianna E , Metzger Daniel B , Mallet Robert T , Ryou Myoung‐Gwi
Published: December 2020

Background

The intensity and cumulative dose of intermittent hypoxia (IH) exposures are critical determinants of beneficial vs detrimental effects on the brain. This study tested if moderate, low‐dose IH training (IHT) is safe and effective to improve memory‐learning behavior and to augment neuroprotective trophic/growth factors in mice with transgenic Alzheimer’s disease (AD) traits.

Method

Twenty‐four triple‐transgenic (JAX MMRRC Stock# 034830) and wild‐type (WT) 12‐month‐old female mice were assigned to 4 groups: WT (n = 8), AD (n = 6), AD+IHT (n = 6), and AD+sham‐IHT (n = 6). Cerebrocortical and hippocampal amyloid‐β (Aβ) 40 and 42 were determined by ELISA. Cerebrocortical contents of brain‐derived neurotrophic factor (BDNF) and erythropoietin (EPO) were quantified by immunoblotting and ELISA. Memory‐learning behavior was tested using Morris water maze (MWM). IHT was conducted between 9AM‐12:00 by exposing AD+IHT mice to alternating 10% O2 for 6‐min and room‐air for 4‐min, for 10 cycles daily for 21 consecutive days. AD+sham‐IHT group was exposed to room‐air. These protocols were IACUC‐approved. Two‐factor ANOVA was applied to test the significance of age‐factor (12‐ vs ∼13‐month‐old) and IHT‐factor. Tukey’s post hoc analysis was applied if a factor showed significance at P<0.05. The table presents group mean values ±SD.

Result

Baseline body‐weight and swimming time and distance to find the submerged platform were not different between AD+IHT vs. AD+sham‐IHT, or between WT vs. AD. Cerebrocortical and hippocampal Aβ42 contents were lower (P<0.01) in WT than in AD (table). However, neither age‐factor nor IHT‐factor significantly modified Aβ40 or Aβ42. Cerebrocortical BDNF and EPO tended to be increased following 21‐day IHT. In the AD+IHT mice, overall swimming distance decreased by 1.60±4.36m and distance swum in the opposite quadrant decreased by 0.85±1.13m after 21‐day IHT, but in the AD+sham‐IHT mice, these distances increased by 5.78±6.38m (P=0.041 vs. AD+IHT) and by 0.99±1.35m (P=0.028 vs. AD+IHT). The changes in body weight did not differ between AD+IHT (‐2.3±0.8g) and AD+sham‐IHT (‐1.1±1.0g).

Conclusion

Moderate low‐dose normobaric IHT is potentially beneficial for enhancing memory‐learning behavior and expressions of cerebrocortical BDNF and EPO contents in AD mice.
A pilot trial of a yoga intervention versus healthy living education for mild cognitive impairment
Authors: Tremont Geoffrey , Davis Jennifer D , Britton Karysa , Kenney Lauren , Sanborn Victoria , Uebelacker Lisa , Ott Brian R
Published: December 2020

Background

Yoga is a low risk intervention that is accessible, adaptable for older adults, easily incorporated into daily life, and potentially sustainable. It combines mental and physical practice and includes instruction on breathing, stress reduction, and mindfulness meditation. Previous research documents that yoga can target modifiable risk factors for Mild Cognitive Impairment (MCI) progression, including stress, depression, cardiovascular health, insulin resistance, and inflammation. We describe a pilot randomized trial of yoga for individuals with MCI.

Methods

Participants were 37 individuals with amnestic MCI who were randomly assigned to receive 12 weeks of twice‐weekly yoga intervention (YI; n = 18) or healthy living education classes (HLE; n = 19). The yoga classes were 60‐min, designed for safety (using props and chairs), and followed a fixed sequence of breathing practices, meditation, warmups, standing and seated postures, simple inversions, and relaxation. HLE classes involved interactive discussion and presentations addressing topics relevant to aging and cognitive impairment. Participants completed neuropsychological and mood measures at baseline and immediately post‐intervention.

Results

There were no group differences for age, education, race, sex, class attendance rates, or percent taking dementia medications. Results of ANCOVA, controlling for baseline scores, did not show any statistically significant differences in neuropsychological domains between the groups. However, medium effect sizes in favor of the YI were seen for visuospatial skills (Cohen’s d = 0.47) and executive functioning/working memory (Cohen’s d = 0.58). Minimal to small effects were found for attention/speed, language, and learning and memory. The yoga group showed significant declines in perceived stress compared to HLE (p<0.05; Cohen’s d = 0.74). Surprisingly, HLE resulted in significantly greater reductions in depressive symptoms after the intervention compared to the YI (p<0.05; Cohen’s d = 0.78).

Conclusions

Although small sample sizes likely impacted our ability to detect statistically significant results, these findings indicate that the YI was feasible and may improve aspects of neuropsychological functioning in individuals with MCI. Results support stress reduction as a possible mechanism for the YI. The interactive nature of HLE class may explain its effect on mood. Future studies should address a yoga intervention in a larger sample.
Search for protective genetic variants in Alzheimer disease in the U.S. Midwestern Amish
Authors: Main Leighanne R. , Song Yeunjoo E. , Laux Renee A. , Miskimen Kristy , Cuccaro Michael L. , Ogrocki Paula , Lerner Alan J. , Vance Jeffery M. , Fuzzell M. Denise , Fuzzell Sarada L. , Sewell Jane L. , Lynn Audrey , Caywood Laura J. , Prough Michael , Scott Bill , Adams Larry D. , Clouse Jason E. , Herington Sharlene D. , Pericak‐Vance Margaret A. , Haines Jonathan L.
Published: December 2020

Background

Most genetic studies on Alzheimer’s disease (AD) have focused on finding risk genes and variants. Taking into account the 30+ loci identified to increase risk of AD, still only around 40‐50% of the estimated heritability of AD is explained. Our goal is to identify genetic variants that delay the onset or protect against the development of AD and to find novel gene interactions or pathways associated with AD.

Method

Our study focuses on the Amish communities in Ohio and Indiana due to their homogeneous genetics and environment. Studying genetics in the Amish increases our ability to find rare protective variants for AD that do not exist at a detectable frequency in the general population. Our focus is to identify individuals who are cognitively normal (CN), but at high risk for developing AD (i.e. have an affected sibling). Each of these individuals is retested every two years to assess their cognition status.

Results

Using the extensive genealogical data of families in the Amish population, we have generated a large ∼5,000 person, 13‐generation pedigree. As of January 2020, we have ascertained 652 individuals and are examining over 300,000 SNPs that were retained after preliminary QC. Out of the recently adjudicated enrollments, 55 percent are cognitively normal, 33 percent are borderline or cognitively impaired, and the remainder have been sampled and are awaiting a consensus diagnosis. The frequency of the APOE‐e2 allele in our enrollments is at 5%, while the APOE‐e4 allele is at 14%, is lower than the general European population. We are currently using KING and GENESIS software to QC the data since they take into account more relatedness in a population structure, which is needed for working with the Amish. Association and linkage analyses, taking into account the complex pedigree relationships, is ongoing.

Conclusion

We are using a founder population to have an increased chance of finding protective genetic variants in AD. We are specifically targeting individuals who are at high risk for developing AD, but seem to be resilient. This is important in discovering novel pathways in which AD functions, which can lead to further functional and pharmaceutical studies.
Alpha‐frequency synchronization deficits during life predict postmortem neurofibrillary tangle burden in Alzheimer’s disease
Authors: Ranasinghe Kamalini G , Petersen Cathrine , Kudo Kiwamu , Srivatsan Srivatsan , Beagle Alexander J , Mizuiri Danielle , Findlay Anne , Houde John F , Rankin Katherine , Rabinovici Gil D , Seeley William W. , Spina Salvatore , Gorno‐Tempini Marilu , Kramer Joel H , Miller Bruce L , Vossel Keith A , Grinberg Lea Tenenholz , Nagarajan Srikantan S
Published: December 2020

Background

Using a multimodal imaging approach with neurophysiological assessments incorporated alongside molecular markers in patients with AD, we have previously demonstrated frequency‐specific neural synchronization deficits distinctly associated with tau and Aβ tracer uptake. Reduced alpha (8‐12 Hz) synchrony (alpha hyposynchrony) closely mapped onto regional patterns of tau uptake and was modulated by the degree of tau uptake. In contrast, increased delta‐theta (2‐8 Hz) synchrony (delta‐theta hypersynchrony) showed strong associations with Aβ tracer uptake. Here, we examined the associations between regional neurofibrillary tangle (NFT) pathology and frequency‐specific neuronal synchrony in patients with AD.

Methods

In a well‐characterized clinicopathological cohort of AD (n=13; Figure 1), we quantified the postmortem NFT density using thioflavin‐S fluorescent microscopy within six selected neocortical and hippocampal regions including, angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1 and subiculum. In the same patients, using resting‐state magnetoencephalography (MEG) we quantified the degree of alpha and delta‐theta neural synchrony abnormalities, compared to an age‐matched control group (n=23). We used linear mixed effects statistical models to investigate the associations between frequency‐specific neurophysiological indices and NFT burden. The duration between MEG scan and death, Clinical Dementia Rating (CDR) at death, and the difference of CDR‐Sum‐of‐Boxes between MEG scan and death were included into the mixed models as additional variables, together with the subject identity as a repeated factor.

Results

We found that alpha hyposynchrony negatively predicted the NFT burden in patients with AD, in contrast, delta‐theta hypersynchrony did not show significant associations with the NFT burden (b=‐7.42, F=10.17, P=0.01 for alpha‐hyposynchrony; b=0.73, F=0.07, P=0.8 for delta‐theta hypersynchrony; Figure 2). Results were similar with a restricted analysis on neocortical regions after exclusion of subcortical regions (b=‐13.13, F=8.75, P=0.02 for alpha‐hyposynchrony; b=‐1.79, F=0.00, P=0.97 for delta‐theta hypersynchrony).

Conclusions

The current study characterizes the frequency‐specific nature of neurophysiological signatures in AD pathophysiology and demonstrates that alpha hyposynchrony is a sensitive index of network disruptions mediated by abnormally phosphorylated tau proteins. These findings suggest that neurophysiological indices may be useful biomarkers to detect earliest manifestations of dysfunctional neural networks as well as to gauge therapeutic efficacy in clinical trials.
Exploring the causes of MMSE scoring and administration errors in the clinical trial screening period
Authors: Miller David S. , Wang XIngmei , Kott Alan
Published: December 2020

Background

Audio recording of eCOA MMSE administration enables identification of both administration and scoring errors. Either can result in incorrect MMSE scores, potentially leading to inclusion of inappropriate subjects and/or biased assessment of change after randomization. Our current analysis explores the effect of protocol design, MMSE scores close to inclusion criteria and visit type on MMSE scoring and/or administration errors.

Method

Data were pooled from 2 types of early dementia protocols – Type A where MMSE inclusion criteria need only be met at screening, and type B where they needed to be met at both screening and baseline. All assessments were audio recorded and reviewed by independent clinicians for the presence of administration and scoring errors. Operationally, subjects were defined as close to inclusion criteria if their MMSE scores were within 2 points of specified thresholds. Logistic regression with 3‐way interaction was used to explore the hypotheses.

Result

11,391 MMSE assessments were reviewed, and 2,706 (23.8%) had either an administration and/or scoring error. In both protocol types, administration errors were significantly less likely at baseline than screening, regardless of MMSE score proximity to inclusion threshold. In type A protocols, administration errors were more likely if scores were close to inclusion criteria. For type B protocols this was true only at screening. Scoring errors were significantly less likely at baseline, if MMSE scores were close to inclusion (both protocol types) or not (type A). Scoring errors were significantly more likely at screening but not baseline when scores were close to inclusion (only type A). No direct effect of protocol design was observed on the likelihood of either scoring or administration errors.

Conclusion

Our data indicate that scoring and administration errors occur more frequently at screening and in subjects with scores close to inclusion criteria. Despite some differences, the effect of protocol design seems less likely to result in errors to the same extent as the other 2 parameters. Given that data coming from subjects close to inclusion criteria at screening are at the highest risk of having a scoring or administration error indicates that data may be manipulated to meet inclusion criteria.
Timing of school desegregation experience and late‐life cognition in the Study of Healthy Aging in African Americans (STAR) cohort
Authors: Peterson Rachel , George Kristen M. , Barnes Lisa L. , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , Whitmer Rachel A.
Published: December 2020

Background

Prior studies suggest segregated school experiences are associated with poorer late‐life cognition among African Americans. However, less is known about how the timing of school desegregation in the individual’s lifecourse or historically is associated with cognition for younger cohorts.

Method

The Study of Healthy Aging in African Americans (STAR) is a cohort of community‐dwelling Kaiser Permanente members residing in the San Francisco Bay area and Sacramento valley. The study has enrolled 722 African Americans (half ages 50‐64, half 65+) and aims to understand lifecourse processes that contribute to cognitive aging disparities. Experiences of segregation were self‐reported and modeled three ways: 1) having attended only segregated schools vs. only integrated; 2) by life stage when first transitioned to a desegregated school (i.e. 1st‐6th, 7th‐9th or 10th‐12th grades); and 3) the historical timing of school desegregation relative to the 1954 Brown vs. Board of Education decision mandating school integration (many districts were reluctant to integrate in a timely manner). Executive function, semantic memory and verbal memory measured with the Spanish and English Neuropsychological Assessment Scales (SENAS) were z‐standardized and averaged for overall cognition. Linear regression was used for analysis; models controlled for age, gender, and education.

Result

Participant mean age was 68 (8.7) and 69% were female. Compared with participants who only attended integrated schools (ref.; n=438), those who only attended segregated schools (n=145) had significantly lower overall cognition, executive function and semantic memory (see table). Those who transitioned from segregated to integrated schools between 7th and 9th grade (n=51) had worse executive function and semantic memory than those who only attended integrated schools; we did not observe significant associations for those who transitioned to integrated schools in 1st‐6th grades (n=44), or 10th‐12th grades (n=43). We observed no differences in cognition by historical timing of desegregation.

Conclusion

Older African Americans who attended only segregated schools or experienced desegregation in 7th‐9th grades had worse later‐life cognitive test scores than those who attended racially integrated schools. Our findings suggest that only attending segregated schools and the timing of school desegregation in the lifecourse may have implications for understanding cognitive aging among African Americans.
Variability in every day pain is associated with mild cognitive impairment (MCI): Results from the Einstein Aging Study (EAS)
Authors: Lipton Richard B , Wang Cuiling , Hyun Jinshil , Katz Mindy J , Derby Carol A , Pavlovic Jelena
Published: December 2020

Background

Half of older adults have chronic pain. Pain is a common, biologically plausible, remediable risk factor for cognitive decline and incident dementia. The relation of pain and MCI is under‐explored. Commonly measured dimensions of pain include intensity (how severe is the pain) and interference (how much does pain interfere with activities). Traditional pain measures use recall intervals of 1 week to 3 months, are subject to recall bias, and cannot measure pain variability.

Methods

The EAS enrolled a systematically‐recruited, community residing sample of adults, age 70+. Annual in‐person visits included neuropsychological and neurologic assessments, and recall‐based pain measures (Table 1). MCI was diagnosed using Jak‐Bondi criteria. Ecological Momentary Assessment (EMA) via smartphone was used to measure pain intensity and pain interference with activities and concentration 6 times per day for 14 days. We calculated mean daily pain (DP) intensity and mean DP interference as well as the standard deviations of these measures across days (i.e., variability). Logistic models were used to calculate odds ratios for associations between pain indices and MCI status, adjusting for age, sex and education.

Results

The study sample included 243 individuals (mean age 77.5, 65.4% females) including 68 with MCI and 175 normal controls (NC). On average, participants completed 84% of the daily EMA assessments (86% in NC, 78 % in MCI). There were no differences in the mean recall‐based pain measures between MCI and NC participants (Table1). Variability in DP intensity and interference with concentration were significantly higher in the MCI group compared to NC, while variability in DP interference with activities did not differ between groups (Table1). In logistic regression models, higher variability of DP intensity and DP interference with concentration was significantly associated with higher odds of having MCI status in logistic models (Table 2).

Conclusion

EMA‐based measures of variability in DP intensity and interference with concentration are associated at cross‐section with MCI while recall‐based pain measures are not. Future work will assess the predictive validity of pain intensity and interference for cognitive decline and incident MCI.
Klotho‐VS decreases probability of amyloid pet positivity in APOE4+ controls
Authors: Eger Sarah J. , Belloy Michael E. , Guen Yann Le , Napolioni Valerio , Deters Kacie D. , Mormino Elizabeth C. , Greicius Michael D.
Published: December 2020

Background

Klotho‐VS heterozygosity (KL‐VSHET) has been linked to increased longevity and decreased rate of cognitive decline. In Alzheimer’s disease (AD), KL‐VSHET was recently shown to decrease both AD risk and amyloid burden, specifically, in APOE4+ controls of Northwestern European descent within the age range of 60 to 80 years (Belloy et al., 2020). We investigated whether this protective effect of KL‐VSHET could be replicated in a larger, independent cohort of cognitively normal subjects.

Method

The A4 study provides genotypic data and cross‐sectional amyloid PET cortical composite standard uptake value ratios (SUVr) of a large group of cognitively healthy older controls (CDR = 0 and MMSE 25‐30). We performed identity‐by‐decent analysis and SNPweights ancestry determination to select only unrelated individuals of Northwestern European ancestry (n = 2453) (Figure 1). With this sample, we examined the association between KL‐VSHET and amyloid positivity (SUVr equal to or greater than 1.17, as determined by a Gaussian Mixture Modeling approach with a 2‐cluster solution), for each of the age strata (60‐80, 80+, full sample) and within the APOE4+ and APOE4‐ groups. A logistic regression model was implemented using the amyloid positive phenotype as the target outcome variable, KL‐VSHET as the covariate of interest, adjusting for age, sex, and the first three genetic principal components to account for population structure.

Result

As predicted, KL‐VSHET significantly reduced the odds of being amyloid positive for APOE4+ controls within the age range of 60 to 80 years (OR = 0.72 [0.53, 0.98]; p = 0.041) (Table 1). This was not the case in APOE4‐ controls in the same age range (OR = 0.93 [CI = 0.65, 0.13]; p = 0.703), nor in either of the 80+ age‐stratified analyses (Table 1). Figure 2 shows the logistic model for amyloid positivity and demonstrates the difference in probabilities of amyloid positivity between the APOE4+ KL‐VSHET carriers and non‐heterozygotes (wild type homozygotes and minor allele homozygotes combined).

Conclusion

These findings provide additional evidence that for APOE4+ controls KL‐VSHET is associated with decreased amyloid burden. Elucidating the molecular mechanisms underlying this protective effect may lead to novel drug targets for AD.
White matter hyperintensities in Alzheimer’s disease: Topography of lesions and association with cognition
Authors: Garnier‐Crussard Antoine , Bougacha Salma , Wirth Miranka , Paly Léo , Sherif Siya , Landeau Brigitte , Gonneaud Julie , Sayette Vincent De , Vivien Denis , Salmon Pierre Krolak , Chetelat Gael
Published: December 2020

Background

White matter hyperintensities (WMH) are frequent in the older adults and are associated to worse cognitive performances and to dementia. Alzheimer’s disease is associated with greater brain WMH volume, particularly in posterior regions, compared to cognitively unimpaired older adults. The aim of this study was to assess in details the topography of brain WMH and their links with cognition in amyloid‐positive cognitively impaired older adults, i.e. patients in the Alzheimer’s continuum (ALZ), compared to amyloid‐negative cognitively unimpaired adults (controls).

Method

Fifty‐four ALZ and forty controls matched for age and cardiovascular risk factors were included in the IMAP cohort (Caen, France). Amyloid status was based on Florbetapir PET scans. In addition, each participant underwent 1) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of WMH in the frontal, parietal, temporal, occipital lobes and in the corpus callosum (CC) region and subregions; 2) a comprehensive neuropsychological assessment of global cognition, episodic memory, working memory and executive functions. The regional volumes of WMH were compared between groups and the relationship of regional WMH to cognition was assessed within the ALZ patients.

Result

WMH volumes were significantly higher in ALZ patients than in controls in all brain regions, with highest differences in the splenium of the CC (p= 0.00005, size effect r = 0.42) and lowest effects in the frontal lobe (p = 0.025, size effect r = 0.23) (Figure 1). Within the ALZ patient group, WMH volumes of the CC, particularly in the splenium, were negatively associated with global cognition, working memory and executive functions (Figure 2). Total and frontal WMH volumes were also negatively associated with working memory, but this relationship did not survive correction for multiple comparisons.

Conclusion

WMH in the splenium of the CC most specifically characterize amyloid‐positive patients in the Alzheimer’s continuum and correlate to worse cognition especially in frontal cognitive functions. These specific ALZ‐related WMH are probably not only due to small vessel disease and could be secondary to neurodegenerescence.
Tau‐dependent regulation of neuronal activity by the Alzheimer’s disease risk gene BIN1
Authors: Voskobiynyk Yuliya , Roth Jonathan R. , Cochran J. Nicholas , Rush Travis , Carullo Nancy V.N. , Waqas Mohammad , Vollmer Rachael , McMahon Lori L. , Day Jeremy J. , Roberson Erik D.
Published: December 2020

Background

Alzheimer’s disease (AD) affects about five million Americans and the underlying causes of the disease remain uncertain. Genome wide association studies (GWAS) have identified bridging integrator 1 (BIN1) as one of the leading genetic risk factors in AD. Neurons express unique BIN1 isoforms, but their function is unknown. Thus, one key question that may contribute to a deeper understanding of AD pathophysiology is how BIN1 affects neuronal function.

Methods

To address this question, we determined the effects of expressing human BIN1 neuronal isoform 1 in primary hippocampal cultures.

Results

First, we observed that higher BIN1 increased spike and burst frequency using multielectrode arrays. On patch‐clamp recordings of transduced neurons, higher BIN1 increased frequency of both excitatory and inhibitory synaptic transmission. Higher BIN1 also increased calcium spikes in neurons co‐transfected with the calcium indicator GCaMP6f. To understand the potential mechanism of increased calcium influx, we explored potential interactions with L‐type voltage gated calcium channels (LVGCCs). BIN1 interacted with LVGCCs in neurons in a Tau‐dependent manner, assessed by both co‐immunoprecipitation and proximity ligation assay. Finally, using a high throughput multielectrode array system, we showed that Tau reduction prevents network hyperexcitability induced by BIN1.

Conclusions

Together, these data show Tau‐dependent regulation of neuronal activity by the Alzheimer’s disease risk gene BIN1 and generate fundamental insights about the mechanistic role BIN1 may play in AD.
Caregiver’s position creating dementia care networks in a rural area in Mexico
Authors: Ibarrola Mariana Longoria , Acosta‐Castillo Gilberto Isaac , Cañongo Guadalupe , Sosa‐Ortíz Ana Luisa , Institute Global Brain Health
Published: December 2020

Background

Dementia prevalence in Mexico is 9% over 65 years old, 28% of those patients live in rural areas, dementia care in rural communities face special challenges due to often geographical, economical, sociocultural, functional and inaccessibility1. Although in the country dementia care is mostly family dependent and locally integrated there is a scarcity of data about their networks2.

Objective

To describe the dementia caregiver´s position given the possibility of creating a network of care in a rural area in Mexico.

Method

We analyzed information from 13 dyads (patient and primary caregiver), evaluated in incidence phase of Dementia Research Group 10/66 protocol in Mexico. Dementia was established according to the 10/66 algorithm. We asked about: 1) relationship with neighbors, 2) with other relatives, 3) willingness to spend time with relatives of other dementia patients, 4) and to participate in a scheme of rotation of care among other families with dementia patients.

Results

Mean age of patients was 84.4±4.2 years and 61.5% were women. Caregiver´s mean age was 54.8±16.0 years, 69.2% were female. Regarding employment, 38.5% merchants, and 53.8% homemakers, 23.7% were widowers, single or separated, and 69.2% were married. 93.2% have economic dependents and their average monthly income was 146±84 USD. There were no differences by gender in spend‐time and relationships with neighbors and relatives. 66.7% spend‐time with their neighbors, 83.3% believe their relationship with the neighbors is good or very good. Half of the relatives say they do not know other families of dementia patients, 66.7% would spend‐time with these families and 91.7% are willing to share their experiences. 83.3% would be willing to spend time in group sessions, but only 41.7% would be willing to care for other patients and only 25.0% would leave others take care of their patients.

Conclusion

Dementia care networks are highly influenced by caregivers, patients, and community surrounding their characteristics. In our study, despite a good relationship within the community and the desire to share experiences, the provision both to care and to let care is low, understanding this phenomenon could be crucial in the implementation of strategies for dementia care in these rural areas.
Self‐reported sleep duration is not associated with pet amyloid deposition in the oldest‐old: The 90+ Study
Authors: Melikyan Zarui A. , Mander Bryce A , Greenia Dana E. , Fletcher Evan M. , DeCarli Charles , Phelan Michael , Kawas Claudia H. , Corrada Maria M.M.
Published: December 2020

Background

Some, but not all cross‐sectional studies have suggested a relationship between sleep and PET‐measured amyloid burden in older adults without cognitive impairment. It is hypothesized that amyloid clearance from the brain is related to sleep duration. Our aim is to examine the cross‐sectional association between self‐reported sleep duration and amyloid accumulation in the oldest‐old (90+ years), a group with high prevalence of amyloid burden and sleep changes.

Method

We analyzed data on 115 participants of The 90+ Study, a longitudinal study of aging and dementia, who reported their monthly average nocturnal sleep duration using the Medical Outcomes Study Sleep Scale (MOS) and had 18F‐florbetapir (amyloid) PET. Sleep duration was categorized as <8, 8 (reference, mean sleep duration) and >8 hours. Standardized uptake value ratio (SUVr) was computedfor the posterior cingulate/precuneus (region affected early by Alzheimer’s neuropathological changes) and analyzed both as continuous and binary (SUVr <0.8 vs. ≥0.8) variables. Cognitive diagnosis from the clinical evaluation closest to PET was used to categorize participants as normal vs. cognitively impaired (dementia or cognitive impairment without dementia). We analyzed sleep duration in relation to SUVr using multiple linear regression and logistic regression, controlling for age, Geriatric Depression Scale score, sleep medications, and cognitive diagnosis at the time of MOS; and additionally sex, education, APOEe4 status, and time between MOS and PET.

Result

At the time of MOS, average age was 95 years, 60% were women, 65% had normal cognition. The average sleep duration was 8 hours. Average PET SUVr was 0.77 and 33% of participants were amyloid positive. Amyloid burden was higher (0.80 vs. 0.75) and sleep was longer (8.14 vs. 7.51 hours) in cognitively impaired compared to cognitively normal participants (Table 1). Sleep duration was not associated with amyloid accumulation in the entire group analysis or when stratified by cognitive diagnosis (Tables 2 and 3, Figure 1).

Conclusion

In this group of oldest‐old individuals, self‐reported sleep duration was not associated with amyloid accumulation in the posterior cingulate/precuneus. It is possible that amyloid accumulation is not associated with sleep in this age group or it is associated with other sleep‐related measures.
Role of extracellular vesicles in early synaptic dysfunction in AD
Authors: Prada Ilaria , Gabrielli Martina , D'Arrigo Giulia , Arancio Ottavio , Verderio Claudia
Published: December 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with amyloid‐β (Aβ) and tau protein accumulation. Synaptic dysfunction is an early mechanism in AD which involves progressively larger areas of the brain over time. However how synaptic dysfunction starts and propagates is unknown. The hypothesis we are testing is that extracellular vesicles (EVs) released by microglia exposed to and carrying Aβ42 (Aβ‐EVs) may be responsible for these early events in AD.

Method

Combining optical manipulation and time lapse imaging to place single EVs on RFP‐positive cultured neuron dendrites and test their effects on the synapse, we show that Aβ‐EVs rapidly alter dendritic spine morphology (a structural correlate of synaptic strength) locally at the site of interaction.

Result

Aβ‐EVs induce a significant increase in the density of immature protrusions around the contact site (<7 µm from the contact point) starting 2 min after EV adhesion, compared to EVs released by microglia not exposed to Aβ42 (ctrl‐EVs). Almost no alteration was detected far from the contact site (>60 µm).

Conclusion

Employing the same methodologies, we are currently monitoring Aβ‐EV‐neuron dynamics at the neuronal surface, to test whether Aβ‐EVs may propagate dendritic spine alterations to adjacent regions over time, contributing to the spreading of synaptic deficits. Our data provide evidence of the involvement of microglial EVs in early synaptic dysfunction in AD, paving the way for novel therapeutic strategies.