bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Validation of a Structural Magnetic Resonance Imaging Metric for Tracking Dementia‐Related Neurodegeneration
Authors: Popa Emily S. , Kress Gavin T , Thompson Paul M , Bookheimer Susan Y. , Thomopoulos Sophia I , Ching Christopher RK , Zheng Hong , Merrill David A. , Panos Stella E. , Siddarth Prabha , Bramen Jennifer E. 
Published: December 2022

AbstractBackgroundCurrent research is focused on noninvasive biomarkers of neurodegeneration that can detect dementia early, benchmark disease severity, monitor disease progression, and aid in testing the efficacy of therapeutic interventions utilizing a single number1–3. The objective of this study is to create and begin to validate an intuitively meaningful biomarker called the ADNeuro‐Score.MethodCognitively normal (CN) individuals and patients with a mild cognitive impairment (MCI) or dementia diagnosis were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI)4. Eighty‐four cortical and subcortical regional volumes were estimated from T1‐weighted MR images using FreeSurfer5. To determine which regional volumes were associated with cognitive decline, we randomly selected 150 participants (N=50 each CN, MCI, and dementia) and performed an ANOVA with an alpha=0.05, Bonferroni corrected. A vector containing the resulting 41 regions, consistent with the existing literature6,7,8, was extracted for experimental and template cohorts (Table 1). To compute ADNeuro‐Score, a Hausdorff distance metric was used to estimate the differences between individual and average template vectors. ADNeuro‐Score was benchmarked using adjusted hippocampal volume (AHV), which is a NIA‐AA diagnostic biomarker for Alzheimer’s disease9, the most common form of dementia10. Both ADNeuro‐Score and AHV were harmonized for intracranial volume, age, sex, and scanner model11. Validation used an experimental cohort (N=929, mean age=72.67 years) and tested sensitivity to diagnosis using pairwise t‐tests and an alpha=0.001, Bonferroni corrected. Results were converted to a z‐score. We also tested association with disease severity, operationalized here as MMSE and ADASCog scores, using linear regression.ResultBoth ADNeuro‐Score and AHV differed between all three cognitive groups. ADNeuro‐Score (z=10.0) better differentiated MCI from dementia than AHV (z=8.9). AHV (z=7.3) was slightly better at distinguishing MCI from CN than ADNeuro‐Score (z=6.7). ADNeuro‐Score and AHV were similarly associated with MMSE (RADNS=0.41; RHA=0.41) and ADAS‐Cog (RADNS=0.49; RHA=0.47) scores.ConclusionThe newly developed ADNeuro‐Score seems to be a robust and reliable way to distinguish CN, MCI and AD patients and performs equivalently to AHV in predicting MMSE and ADAS‐Cog assessment scores. We hope ADNeuro‐Score will be highly specific to AD because of its focus on AD‐effected regions. Future research will determine if ADNeuro‐Score can improve the differential diagnosis of AD.
Collection of genetic data in ethnic‐based studies across Aymaras, Quechuas and Mestizos: the challenges of the Genetics of Alzheimer’s in Peruvian Population (GAPP) study
Authors: Reyes‐Dumeyer Dolly , Montesinos Rosa , Caipa Maritza Pintado , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Soto‐Añari Marcio , Custodio Nilton , Tosto Giuseppe 
Published: December 2022

AbstractBackgroundThe Genetics of Alzheimer’s Disease in Peruvian Population (GAPP) study aims to investigate genetic and environmental risk factors for Alzheimer’s Disease (AD) in Peru. The project is led by Columbia University (CU, New York, US) and the Instituto Peruano de Neurociencias (IPN, Lima, Peru). For the past year and a half, despite the ongoing COVID‐19 pandemic, the study has collected data on cognitive function, health, diet and numerous clinical and biological risk factors for AD. In addition, we collected blood samples for DNA extraction as well as serum and plasma to look at core AD biomarkers.MethodRecruitment prioritized populations from south Peru, the Quechuas and Aymaras, because of their high proportion of Native American ancestry (or, in other words, low admixture with European ancestry) as well as Mestizo (mixed Native‐European ancestry). Three recruitment sites were established in Lima, Puno and Arequipa. Interviewers were trained to clinically and cognitively assessed the participants and collect and ship blood samples to the main site (IPN). DNA samples were then sent to CU for processing. Serum and plasma samples were processed in Lima and stored at ‐80C for batch shipping to CU. DNA samples were sent to CD Genomics and Children’s Hospital of Philadelphia for APOE genotyping and GWAS, respectively.ResultA database with 350 participants has been created. Blood samples from all participants were collected; 268 successfully underwent GWAS and APOE genotyping. An additional 82 samples are pending QC and genotyping. No samples were dropped at extraction, and only 0.7% failed DNA quality standards for genotyping.ConclusionSample collections for genetic studies in South American indigenous populations such as Peru represent important logistic challenges. The use of blood as a main source of DNA provides an effective and reliable source for genetic data analysis. Plasma and serum biomarkers will provide additional insights into the disease manifestations and validation of the clinical diagnosis in these underrepresented populations. Ongoing recruitment will augment the analytical power of the cohort by collecting blood, serum and plasma samples from additional GAPP participants.
The synaptic interplay of Tau and Aβ oligomeric species in Alzheimer’s disease and related tauopathies.
Authors: Marcatti Michela , Fracassi Anna , Montalbano Mauro , Puangmalai Nicha , Bhatt Nemil , Natarajan Chandramouli , Guptarak Jutatip , Krishnan Balaji , Kayed Rakez , Taglialatela Giulio 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) is characterized by gradual cognitive decline driven by the targeting of synapses by small oligomers of both Aβ (AβO) and tau (TauO), which results in synaptic dysfunction that ultimately underscores disease progression. Preventing the interaction of these oligomers with synapses might be effective to treat AD. However, clinical trial failures suggest low effectiveness of targeting Aβ in late‐stage AD thus redirecting the attention onto TauO whose levels increase later in the disease timeline. Here we show that TauO and AβO target synapses with different dynamics.MethodWe used recombinant AbO and TauO as well as human brain derived tau oligomers from AD (BDTO‐AD), and from Progressive Supranuclear Palsy (BDTO‐PSP). Analyses of flow‐cytometry, western blot, immunofluorescence, and proteinase K digestion were performed to study the binding dynamic of the oligomers onto synaptosomes isolated from human frontal cortex and hippocampus. AβO and TauO were injected ICV in 3xTgAD, Tg2576 and h‐Tau mice for our in vivo experiments. The synaptic dysfunction was measured by FASS‐LTP assay.ResultWe found that recombinant TauO, BDTO‐AD and BDTO‐PSP oucompete AβO and become the prevailing synaptic‐associated species, while high concentrations of AβO facilitate the recruitment of tau oligomers at the synapses. Immunofluorescence analyses of mouse primary cortical neurons treated with AβO and/or TauO as well as in vivo experiments using 3xTgAD, Tg2576 and h‐Tau mice injected ICV with AβO or TauO supported these findings. Consistent with these observations, FASS‐LTP analyses demonstrated that TauO‐induced suppression of chemical LTP was exacerbated by AβO. Moreover, depletion of synaptosome surface proteins by PK pre‐treatment abolished the effect of TauO in reducing AβO synaptic binding without affecting the ability of high AbO levels to increase synaptic TauO recruitment. Furthermore, we observed different synaptic engagement and internalization profiles among the analyzed BDTOs.ConclusionOverall, our results suggest that, as the disease progresses, TauO outcompete AβO at the synapses, thus becoming the driver of the synaptic dysfunction responsible for the cognitive decline at the late stage of AD. Furthermore, disease‐specific differences in the dynamic of BDTOs engagement of synapses may indicate different synaptic toxicity of TauO across the tauopathies spectrum.
APOE4 blood‐brain barrier dysfunction: relation to cognitive impairment and molecular mechanisms
Authors: Zlokovic Berislav V 
Published: December 2022

AbstractBackgroundApolipoprotein E4 (APOE4), the major Alzheimer’s disease (AD) susceptibility gene, leads to accelerated BBB breakdown and degeneration of brain capillary pericytes that maintain BBB integrity both in humans and APOE4 transgenic mice. To what extent cerebrovascular effects of APOE4 contribute to preclinical and clinical decline is still understudied. Moreover, a comprehensive large‐scale analysis of cell‐specific mechanisms underlying APOE4 effects on the BBB is still lacking.MethodHere, we use neuroimaging and biomarkers approach in human APOE4 carriers and non‐carriers (ε3/ε3) and “multi‐omics” snRNAseq and proteomics analysis of the BBB in humanized APOE4 and APOE3 knock‐in mice.Result
APOE4 carriers are distinguished from APOE3 homozygotes by BBB breakdown in the hippocampus and medial temporal lobe that is not related to CSF or PET measurements of Aβ or tau pathology. High baseline CSF levels of the BBB pericyte injury biomarker sPDGFRβ predicted future cognitive decline in APOE4 carriers but not in non‐carriers. APOE4 compared to APOE3 leads to an early disruption of the BBB transcriptome in APOE4 knock‐in mice followed by dysregulation in signaling networks including proteins regulating cell junctions, cytoskeleton, clathrin‐mediated transport, and translation in brain endothelium which paralleled an early, progressive BBB breakdown.ConclusionBBB breakdown contributes to APOE4 associated cognitive decline in humans independently of AD pathology. Disruption of the BBB cell‐specific signaling mechanisms could be an initial central contributor to APOE4‐mediated cerebrovascular disorder as shown in mouse model.
A novel genetic approach to specifically target and manipulate plaque‐associated microglia in mice
Authors: Henningfield Caden M , Kawauchi Shimako , MacGregor Grant R , Neumann Jonathan , Green Kim N 
Published: December 2022

AbstractBackgroundWithin the Alzheimer’s disease (AD) brain, microglia surround extracellular plaques and mount a chronic inflammatory response. These plaque‐associated microglia (PAMs) are characterized by specific disease‐associated gene expression signatures, including Apoe, Cst7, Trem2, Clec7a, Itgax, and Csf1. Data from animal models of AD have identified that PAMs play critical roles in plaque formation and plaque compaction, but also contribute to synaptic and neuronal dysfunction and loss. To better understand the role of microglia in AD, we need precise models which directly target specific subsets of microglia, however; no such model currently exists. Here, we developed a novel genetic cre‐recombinase approach to specifically target and manipulate PAMs in AD mouse models. We identified that of PAM‐identified genes Cst7 shows no expression in the homeostatic mouse brain and is specifically and highly expressed in PAMs.MethodTo avoid caveats associated with tamoxifen inducible cre recombinase systems, we instead established a destabilized cre‐recombinase (ddCre) mouse line, in which Cre becomes stabilized and facilitates recombination in the presence of the antibiotic trimethoprim. ddCre was knocked‐in to the Cst7 locus (Cst7ddCre), followed by a P2A linker to ensure normal expression of Cst7 transcripts. We crossed these mice to a 5xFAD mouse model of AD and a loxp‐stop‐loxp‐tdTomato (Ai14tdtomato) reporter line. Upon the administration trimethoprim, cre‐recombination at loxp sites in Cst7 expressing cells occurs and tdTomato is expressed.ResultWe found that 5xFAD/Cst7
ddCre/Ai14tdtomato mice showed specific tdTomato fluorescence in PAMs with no expression present in non‐plaque associated microglia, or other cell types throughout the brain.ConclusionAltogether, we have shown that our novel Cst7
ddCre mouse line effectively targets PAMs. With this validation, we can alter any single gene specifically in PAMs.
Cardiovascular Risk, Alzheimer’s Disease Biomarkers, and Cognition: The Health and Aging Brain Study
Authors: Jiang Xiaqing , Peltz Carrie , Rissman Robert A. , O'Bryant Sid E. , Yaffe Kristine 
Published: December 2022

AbstractBackgroundsCardiovascular risk (CVR) factors (hypertension, dyslipidemia, diabetes, and smoking) and emerging plasma biomarkers including β‐amyloid (Aβ) 40/42, tau, and neurofilament light (NfL) are each associated with risk of Alzheimer’s Disease (AD), although whether CVR and AD biomarkers affect cognitive aging independently or synergistically is unclear. As part of the Health and Aging Brain Study, we assessed the association of CVR burden and cognition and if this association is modified by AD biomarkers.MethodsWe studied 1,320 dementia‐free participants (63% women, 57% Mexican Americans) aged 50‐74 years (mean age 63.7±6.7) at baseline (2017‐2021) with cognitive testing including Trail Making Tests, verbal fluency, Spanish and English Verbal Learning, and Digit Symbol Substitution. We computed a cognitive composite score by averaging the z‐standardized test scores. Plasma AD biomarkers (Aβ 40/42, tau, and NfL) were assayed using Simoa. CVR burden was assessed using the Framingham Risk Score (FRS, range ‐2 to 25 in woman, ‐2 to 19 in men). We used linear regression to assess the association of CVR (intermediate/high: FRS ≥10 vs. low: FRS <10) with cognition and effect modification by AD biomarker (high level defined as above median plasma level for ≥2 biomarkers).ResultsParticipants with intermediate/high CVR (31%) have lower composite cognitive score than those with low CVR adjusting for demographics, education, and APOE ε4 (‐0.10, 95% CI ‐0.16 to ‐0.03). The association between CVR and cognition was significantly modified by AD biomarkers (p = 0.03). Participants with intermediate/high CVR have a lower composite cognitive score only when AD biomarker level was high (‐0.15, 95% CI ‐0.24 to ‐0.07). However, participants with intermediate/high CVR were not more likely (‐0.02, 95% CL ‐0.11 to 0.08) to have worse cognition compared to low CVR among those with low level of AD biomarkers. Stratified analysis by levels of each biomarker showed similar results.ConclusionGreater CVR burden is associated with lower cognition in a diverse population, only among those with high AD biomarkers. Future longitudinal study is needed to address whether AD biomarkers modify the association between CVR and cognitive outcomes.
Cultural and ethnic differences in dementia family caregiving: A comparison of the experiences of Chinese American and non‐Chinese American dementia caregivers
Authors: Zeng Alison , Santulli Robert B 
Published: December 2022

AbstractBackgroundThe responsibilities of caring for a dementia patient are mentally and physically challenging, often resulting in adverse effects on a family caregiver’s psychological well‐being as well as the quality of care that the patient receives. While the experiences of White dementia caregivers from Western cultures have been well studied, there is a lack of understanding on how the racial, ethnic, and cultural nuances of caregivers from minority populations may influence dementia caregiving. Specifically, the research on Chinese American immigrant dementia caregivers is very sparse, which is concerning considering that Asian Americans are the fastest growing ethnic group in the United States and that Chinese Americans are the largest subgroup of Asian Americans. This study aims to explore the experiences of Chinese American dementia caregivers, focusing on processes of grief, coping mechanisms, and perceptions of stigma.MethodOver 100 adult Chinese American and non‐Chinese American dementia family caregivers were recruited across the U.S. Their experiences with grief, coping, and stigma were surveyed using adapted versions of pre‐existing validated grief, coping, and stigma scales (i.e., the Marwit‐Meuser Caregiver Grief Inventory, the Coping Strategies Inventory, and the Affiliate Stigma Questionnaire). Participants also had the option to elaborate on the ways their cultural values may have influenced their caregiving in open‐ended questions.ResultInteresting and important differences between Chinese American and non‐Chinese American participants' emotional and psychological reactions to caregiving have been observed. Thematic analysis of open‐ended questions revealed additional challenges characterizing Chinese American caregivers’ experiences with caregiving, including feelings of filial piety, language barriers, and discrimination and lack of support from medical facilities and professionals.ConclusionEmotional and psychological reactions to caregiving differ between Chinese American and non‐Chinese American dementia family caregivers. Recognition of these differences is important for those who work with this growing population.
Treatment with losartan, an AT1 receptor blocker, improves cognitive and cardiovascular function in a Dahl salt‐sensitive rat model of age‐associated vascular dementia.
Authors: Santos Carla Rocha Dos , Grigorova Yulia N , McDevitt Ross A , Long Jeffrey M , Cezayirli Defne , Zernetkina Valentina , Wei Wen , Haghkar Mahdi , Morrell Christopher H , Juhasz Ondrej , Lakatta Edward G , Spencer Richard G , Rapp Peter R. , Fishbein Kenneth W , Fedorova Olga V 
Published: December 2022

AbstractBackgroundDementia is characterized by progressive cognitive impairment (CI), which is accompanied by decline in reasoning, planning and memory. Cardiovascular diseases are the major contributors to the pathogenesis of vascular dementia and affect mainly the aging population. Even on a normal salt diet, Dahl salt‐sensitive (DSS) rats exhibit age‐associated hypertension and CI. We hypothesized, that anti‐hypertensive treatment with the angiotensin II receptor blocker losartan (LOS) would improve cardiovascular and cognitive function in aged DSS rats.MethodMale DSS rats (n=30) were kept on a normal salt diet (0.5% NaCl) for the duration of the study. Baseline measurements were taken at 6‐mo of age. After that, treatment with 30mg/kg/day of LOS, added to the drinking water (n=14), or control (n=16) was started and continued for 6‐mo. Systolic blood pressure (SBP), aortic pulse wave velocity (aPWV), a measure of aortic stiffness, and behavioral testing in a visually cued reaction task to assess attention and inhibitory control were assessed every 3‐mo. Elevated plus maze (EPM) and Morris Water Maze (MWM) tests were performed at 12‐mo of age to measure anxiety‐like behavior and to evaluate spatial memory, respectively. Data were analyzed by 2‐way repeated measures ANOVA or t‐tests as applicable.ResultPrior to the treatment, LOS and control groups did not display differences in any parameter analyzed. Control rats exhibited gradual increase in SBP and aPWV from 6 to 12‐mo of age. Following 3‐ and 6‐mo of treatment, LOS rats exhibited lower SBP and aPWV vs. controls (Table 1). At 12‐mo of age, LOS rats had improved performance in the reaction task (Figure 1), and exhibited lower anxiety levels, spending less time on the closed arm in EPM and 1.5‐fold more time in the open arm vs. control rats. LOS rats also spent less time to find a hidden platform in the MWM vs. controls, indicating that LOS treatment improved spatial memory (Table 1).ConclusionImprovement of cardiovascular function and reduction in aortic stiffness by LOS were associated with better attentional control and memory and lower anxiety levels, demonstrating an association of CI with cardiovascular changes in the DSS rat model of vascular dementia.
Association of social support with mild cognitive impairment and dementia among older women: the Women’s Health Initiative Memory Study
Authors: Posis Alexander Ivan B. , Golaszewski Natalie M. , McEvoy Linda K. , Jain Purva , Kroenke Candyce H. , Saquib Nazmus , Ikramuddin Farha , Schnatz Peter F. , Bellettiere John , Rapp Stephen R. , Espeland Mark A. , Shadyab Aladdin H. 
Published: December 2022

AbstractBackgroundWomen comprise approximately two‐thirds of older adults with Alzheimer’s disease in the United States. Social support may be a modifiable risk factor for cognitive impairment. However, few long‐term, large prospective studies have examined associations of various forms of social support with cognitive impairment. Therefore, we examined the association of perceived social support with incident mild cognitive impairment (MCI) and dementia among older women.MethodThis prospective cohort study included 6,670 older women from the Women’s Health Initiative (WHI) Memory Study (WHIMS), a sub‐cohort of the WHI hormone therapy (HT) trials, who were free of dementia upon enrollment. Perceived social support was assessed at baseline using nine items from the Medical Outcomes Study Social Support Survey. All item ratings were summed to generate a summary score (range = 9‐45), with higher scores indicating greater perceived social support. Incident MCI and dementia were ascertained using a comprehensive neuropsychological battery and central adjudication by a panel of specialists with expertise in dementia diagnosis during up to 25 years of follow‐up. Cox proportional hazards models were used to assess associations of perceived social support with incident MCI, dementia, and overall cognitive impairment (MCI or dementia). We also examined associations of four types of social support (emotional/informational, affection, tangible, and positive social interaction) with MCI/dementia.ResultOverall, (mean age at baseline = 70.0 [SD 3.8] years; 97.0% non‐Hispanic/Latina; 89.8% White) 753 women had incident MCI, 697 had incident dementia, and 1,197 had incident overall cognitive impairment. There were no significant associations of social support with MCI (HR = 0.99; 95%CI = 0.98‐1.00), dementia (HR = 0.99; 95% CI = 0.98‐1.01), or overall cognitive impairment (HR = 0.99; 95% CI = 0.98‐1.00) after adjusting for age, education, income, race, ethnicity, marital status, smoking, alcohol intake, body mass index, history of diabetes, hormone therapy trial assignment, history of hormone therapy use, history of hypertension, and depressive symptom severity. There were no significant associations between the four types of social support and MCI/dementia.ConclusionPerceived social support was not significantly associated with incident cognitive impairment among older women. Future studies should explore other social factors, such as social isolation and loneliness, particularly in larger and racially/ethnically diverse populations.