bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain and cognitive changes in memory systems vulnerable to Alzheimer’s disease following targeted multiday repetitive transcranial magnetic stimulation applied to healthy young adults
Authors: Phipps Connor J. , Rangel Anthony , Heller Abi M. , Phatak Vaishali S. , Murman Daniel L. , Warren David E. 
Published: December 2020

AbstractBackgroundAging processes — healthy and pathological — contribute to age‐related memory decline, and current treatments offer limited remediation. Targeted non‐invasive brain stimulation (NBS) of memory networks vulnerable to Alzheimer’s disease is a novel approach which can enhance memory in healthy young adults by 20% (Wang et al., 2014). To test generalizability of this finding, we are administering a clinical trial (ClinicalTrials.gov #alz045244) applying targeted NBS to healthy young adults, healthy older adults, and patients with amnestic mild cognitive impairment (aMCI). Here, we report preliminary findings from the trial arm studying healthy young adults.MethodOur approach replicates methods from Wang et al. (2014). Healthy young adults (N = 16) completed two interventions which combined pre/post‐stimulation brain and cognitive measurement with NBS (treatment or sham for five consecutive days) in the form of repetitive transcranial magnetic stimulation (rTMS). The two interventions were identical except for rTMS parameters. Pre‐/post‐stimulation, brain measures included structural and resting‐state functional MRI data; cognitive measures included cognitive abilities (e.g., hippocampal‐dependent memory). Intervention formats applied rTMS using β‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min; the stimulation location was constant (left lateral parietal cortex coactive with a hippocampus‐centered network). Stimulation intensity was tailored to participants’ resting motor threshold (RMT) and varied by condition: treatment, 100% RMT; sham, 10% RMT. Participants completed both conditions in a counterbalanced order.ResultWe successfully mapped hippocampus‐centered functional networks in each participant and localized left lateral parietal targets for rTMS. Furthermore, we observed changes in brain and cognitive measures related to the stimulation condition. Brain measures including resting‐state functional connectivity (RSFC) revealed changes in patterns of RSFC between several areas of the hippocampus‐centered network targeted with rTMS in the treatment condition.ConclusionOur ongoing clinical trial measures changes in brain and cognitive variables associated with NBS of a functional brain network supporting memory. The current trial arm focused on healthy young adults, and we found evidence consistent with plasticity in the intrinsic brain network supporting memory. Findings from the remaining arms (older adults, healthy or aMCI) will inform the generalizability of our observations to populations vulnerable to Alzheimer’s disease.
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

AbstractBackgroundSubclinical 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.MethodUsing 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.ResultAmong 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.ConclusionWe 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

AbstractBackgroundShorter 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.MethodWe 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.ResultThe 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.ConclusionIncreased 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

AbstractBackgroundCortical 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.MethodThe 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.ResultThe 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).ConclusionIn 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

AbstractBackgroundAn 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.MethodParaffin 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).ResultIn 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.ConclusionThese 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

AbstractBackgroundSleepiness 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.MethodWe 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.ResultHigher 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).ConclusionIncreased 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

AbstractBackgroundThe 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.MethodTwenty‐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.ResultBaseline 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).ConclusionModerate 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

AbstractBackgroundYoga 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.MethodsParticipants 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.ResultsThere 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).ConclusionsAlthough 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.