bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between homocysteine, tau, and neurodegenerative markers in apolipoprotein ε4 non‐carriers with clinical Alzheimer’s disease
Authors: Lin William Z. , Yu Di , Xiong Lisa Y. , Goubran Maged , Ozzoude Miracle , Kumar Sanjeev , Tang‐Wai David F. , Tartaglia Carmela , Tan Brian , Bartha Robert , Haddad Seyyed M. H. , Nanayakkara Nuwan D. , Symons Sean , Lou Wendy , MacIntosh Bradley J. , Lanctôt Krista L. , Zetterberg Henrik , Black Sandra E. , Swardfager Walter 
Published: December 2023

AbstractBackgroundHomocysteine (Hcy) is an amino acid generated as a byproduct of methionine metabolism. It is a risk factor for vascular and neurodegenerative diseases. This study investigated relationships between plasma Hcy concentrations and neurodegenerative biomarkers in people clinically diagnosed with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD.MethodParticipants were identified from the Ontario Neurodegenerative Disease Research Initiative. Brain parenchymal fraction (BPF) was quantified using T1‐ and T2‐weighted structural magnetic resonance imaging with an in‐house Semi‐Automated Brain Region Extraction and Lesion Explorer package. Plasma amyloid beta (Aβ) 42, Aβ40, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) were measured with Single molecule array (Simoa) assays. Linear regression analyses were used to test associations between Hcy and neuroimaging or plasma biomarkers, controlling for age, sex, hypertension, hyperlipidemia, diabetes, cholesterol, and vitamin B12. Analyses were stratified by apolipoprotein E (APOE) ε4 carrier status (non‐carriers: n = 64, mean age = 70.9 years, 41% female; carriers: n = 62, mean age = 71.2 years, 50% female).ResultIn APOE ε4 non‐carriers, Hcy was associated negatively with BPF (β = ‐0.233, p = 0.047, 95% CI [‐0.460, ‐0.003]), notably in temporal lobe regions in exploratory regional analyses. Hcy was also associated positively with plasma concentrations of NfL (β = 0.403, p = 0.007, 95% CI [0.117, 0.688]) and p‐tau181 (β = 0.357, p = 0.023, 95% CI [0.051, 0.663]) in APOE ε4 non‐carriers. Also, in APOE ε4 non‐carriers, Hcy was associated positively with Aβ40 (β = 0.367, p = 0.015, 95% CI [0.074, 0.660]) and Aβ42 (β = 0.305, p = 0.041, 95% CI [0.012, 0.598]), but not with the Aβ42/40 ratio (β = 0.155, p = 0.339, 95% CI [‐0.166, 0.476]). None of these associations were seen in APOE ε4 carriers.ConclusionIn non‐carriers of the APOE ε4 allele clinically diagnosed with AD or MCI, homocysteine was associated with Amyloid, tau and neurodegeneration. The specificity of these relationships to ε4 non‐carriers identifies a unique risk factor profile for AD that is independent of APOE ε4 status.
Are elderly patients with atrial fibrillation sufficiently anticoagulated?
Authors: Trydal Espen Knut , Ajmi Soffien Chadli , Nygaard Benedikte Lea , Kallevag Oystein , Kurz Kathinka Dehli , Kurz Martin Wilhelm 
Published: December 2023

AbstractBackgroundEpidemiological and clinicopathological data show a significant overlap between cerebrovascular disease (CVD) and Alzheimer’s disease (AD)[1]. Atrial fibrillation (AF) is a significant risk factor for both stroke[2], and cognitive decline, and is also associated with all kinds of dementia including AD[3,4] (though a shared patho‐mecanism might be a factor in the link with AD[5]). As the elderly have a higher prevalence of cerebrovascular disease and AF, we wanted to explore the effect of age on anticoagulation status.MethodFrom 2009 to 2022, we prospectively registered all acute stroke patients treated with endovascular thrombectomy (EVT). We recorded stroke‐risk factors, including atrial fibrillation and the status of anticoagulation. To examine a possible age inequality, we analyzed the effect of age over and under 80 years on anticoagulation status.Result438 patients were treated with EVT. The median age was 74 (IQR 63‐81). The median NIHSS before EVT was 17 (IQR 11‐21). 71 patients (16%) had a history of myocardial infarction and 59 patients of previous cerebral stroke (14%). 246 patients (56%) had hypertension, 61 (14%) diabetes, and 171 (39%) were diagnosed with AF. In 80 patients (18%), AF was newly diagnosed, and 97 (22%) had known AF. 60 patients (13.7%) were inadequately anticoagulated at admission. When dichotomizing around the age of 80, significant more elderly patients with AF were insufficiently anticoagulated compared to younger patients (43% vs 26%, p<0.018). Age as a variable was significantly associated with insufficient anticoagulation (p<0.001).ConclusionIn this prospectively followed group of patients treated with EVT, a significant number of elderly patients with AF were insufficiently treated with anticoagulantia. Age was identified as a highly significant risk factor for inadequate anticoagulation. We suggest further studies addressing the association of AF with cognitive decline, dementia and AD, and especially the role of insufficient anticoagulation. We advocate improvements in the prophylactic treatment of AF in the elderly.1. Whitmer, et al. Neurology. 2005Jan;277‐81.2. Wolf, et al. Stroke. 1991Aug;983‐8.3. Diener, et al. Journal of the American college of cardiology. 2019Feb;612‐9.4. Bunch, et al. Heart rhythm. 2010Apr;433‐7.5. Myers, et al. Frontiers in aging neuroscience 2022Jul
The effect of Alzheimer’s disease pathology in corticobasal syndrome and progressive supranuclear palsy
Authors: Cordero Indira Ruth Garcia , Anastassiadis Chloe , Khoja Abeer , Morales‐Rivero Alonso , Vasilevskaya Anna , Thapa Simrika , Davenport Carly , Sumra Vishaal , Tang‐Wai David F. , Couto Blas , Multani Namita , Taghdiri Foad , Anor Cassandra Jessica , Varriano Brenda Maricela , Misquitta Karen , Fox Susan , Kovacs Gabor G. , Boxer Adam L. , VandeVrede Lawren , Lang Anthony E , Tartaglia Carmela 
Published: December 2023

AbstractBackgroundCorticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) display phenotypic heterogeneity. CBS pathology can include 4‐repeat (4‐R) tau and Alzheimer’s disease (AD) pathology/co‐pathology; while PSP involves predominantly 4‐R tau with AD co‐pathology. We evaluated whether in vivo biomarkers of AD pathology in CBS and PSP are associated with specific brain atrophy and default mode network (DMN) alterations and relates to specific clinical manifestations.MethodWe analyzed MRIs of 110 patients with a clinical diagnosis of CBS and PSP from 4RTNI‐1, 4RTNI‐2 and the Toronto Western Hospital and 30 healthy controls. Patients were separated according to AD biomarker positivity (CBS/PSP‐AD, n = 23) and negativity (CBS/PSP‐noAD, n = 87) based on blood and cerebrospinal fluid AD biomarkers. Patients’ cortical and subcortical volumes were obtained using Freesufer segmentation and compared against controls. The DMN connectivity was compared across groups using two‐sample t‐tests. In a subgroup of patients, we analyzed Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), PSP Rating Scale (PSPRS) and delayed memory on the California Verbal Learning Test (CVLT). Spearman partial correlations were performed to relate the PSPRS and CVLT scores with whole‐brain grey matter volumes. Neuroimaging analyses were controlled for age, site and total intracranial volume.ResultCBS/PSP‐AD displayed atrophy in temporal and parietal regions and hippocampus; while CBS/PSP‐noAD, in frontal and temporal regions, basal ganglia and thalamus (p<0.05, Bonferroni corrected). Reduced connectivity within the DMN was found in frontal‐temporal regions for CBS/PSP‐AD, and in frontal‐parietal regions for CBS/PSP‐noAD versus controls; and in temporal regions for CBS/PSP‐AD versus CBS/PSP‐noAD (p<0.001, uncorrected). No differences were obtained for MoCA, CDR and CVLT. The CBS/PSP‐AD group showed lower scores in the PSPRS in comparison to the CBS/PSP‐noAD [t(81) = 2.39, p = 0.02)]. Left thalamus grey matter volume negatively correlated with PSPRS scores [r:‐0.44, p = 0.02, Bonferroni corrected] in CBS/PSP‐noAD but no associations were found in CBS/PSP‐AD.ConclusionDistinct patterns of atrophy and connectivity were observed in CBS/PSP‐AD compared to CBS/PSP‐noAD, suggesting selective vulnerability to AD pathology. As well, severity of disease was related to thalamic atrophy only in CBS/PSP‐noAD. Selective vulnerability to diverse proteinopathies, leading to different atrophy and connectivity patterns, may help explain phenotypic heterogeneity in CBS and PSP.
Diagnosis patterns among diverse populations with mild cognitive impairment and Alzheimer’s disease: A large nationwide electronic health record cohort study
Authors: Sánchez‐Soliño Olga , Yue Emma Xiaomeng , Boroje Isabella , Vinikoor‐Imler Lisa C 
Published: December 2023

AbstractBackgroundWith recent advances and emerging research on diagnostic biomarkers and evolving diagnostic criteria, practitioners managing patients with cognitive complaints operate within a complex, changing environment. Although some evidence is available on the importance of prompt diagnosis, little information exists on the diagnostic process used in real‐world settings among diverse populations. This study’s objective was to characterize diagnosis patterns among adults with mild cognitive impairment (MCI), Alzheimer’s disease (AD), and/or dementia in the United States, and stratify by gender, age and race/ethnicity.MethodThis retrospective observational cohort study utilized the Optum® Market Clarity database from January 1, 2017–September 30, 2021. Eligible individuals had ≥1 diagnosis of MCI, AD, and/or dementia in their electronic health records or ≥2 diagnosis codes separated by ≥30 days in claims data, had ≥12 months of continuous enrollment before the cohort entry date, and had ≥1 day of continuous healthcare plan enrollment after the index date. Demographic information and the occurrence of diagnostic tests were also obtained from electronic medical records and insurance claims. Descriptive statistics were calculated and stratified by demographic factors.ResultA total of 179,419 newly diagnosed MCI cases, 81,267 AD cases, and 338,739 dementia cases were identified. The mean age at MCI, AD, or dementia diagnosis was similar overall for males and females. Among Caucasians, the mean age of MCI diagnosis was 70.5±14.8 for females and 69.8±14.5 for males. Among African Americans, the mean age at MCI diagnosis was 66.3±15.4 for females and 63.6±16.1 for males. PET scans and CSF biomarker screening occurred less often than MRI and CT (MCI: PET 0.6%, CSF 1.6%, MRI 16.6%, CT 17.5%; AD: PET 0.5%; CSF 0.9%; MRI 9.0%; CT 18.4%; dementia: PET 0.2%; CSF 1.6%; MRI 9.5%; CT 25.9%).ConclusionThe mean age at MCI, AD, and dementia diagnosis varied by demographic groups. The diagnosis of MCI, AD, and dementia remains largely clinical, with low use of brain imaging or CSF biomarkers. This knowledge of the patient populations and diagnostic experiences in a real‐world setting allows for greater understanding and growth to improve diagnosis across diverse groups and lead to faster support.
Education and cognitive function among older adults in Brazil and Mexico
Authors: Gonçalves Natalia G , Avila Jaqueline Contrera , Bertola Laiss , Obregon Alejandra Michaels , Ferri Cleusa P , Wong Rebeca , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundEducation is a protective factor against cognitive impairment. Research on education and cognitive function has focused on high‐income countries, where education is higher. Thus, it is important to investigate this association in a context of lower education levels, such as the one in middle‐income countries. We use nationally representative data from the two largest countries in Latin America, Mexico and Brazil, to assess the benefits of education for cognitive function, and assess how sex and country modify this relationship.MethodsThe sample included adults 50 years or older from the 2015 waves of the Brazilian Longitudinal Study of Aging (ELSI) (n = 9,412) and the Mexican Health and Aging Study (MHAS) (n = 14,779). Participants were classified as cognitively impaired or not impaired using cognitive performance scores and a regression‐based approach. Education was categorized as 0, 1‐4, 5‐8, or >8 years of education. We used logistic regression models to estimate the association of education with cognitive function adjusted for sociodemographic variables, chronic diseases, and health behaviors. We also investigated the modifying effec of sex and country by adding an interaction term in the fully adjusted model.ResultsParticipants of the ELSI had mean age 62.5±9.8 years, 54% were women, 13.3% had no formal education, and 6% were categorized as cognitively impaired. Participants of the MHAS had mean age 64.8±9.7 years, 55% were women, 18% had no formal education, and 5% were categorized as cognitively impaired (Table 1). Individuals with at least one year of education were less likely to have cognitive impairment than those with no formal education in both countries, with the highest reduction in the >8 years category, followed by the 1‐4 and the 5‐8 education categories (Table 2). We found a three‐way interaction effect of education with country and sex (p<0.001). Men in the MHAS had lower odds of cognitive impairment than men in the ELSI at all levels of education, but there was no difference for women (Figure 1).ConclusionHigher educational level was associated with lower odds of cognitive impairment in both countries. Men in Brazil had higher odds for cognitive impairment compared with men in Mexico.
Presynaptic and axonal loss are synergistically associated with longitudinal neurodegeneration and cognitive decline
Authors: Shi Dai , Lan Guoyu , Cai Yue , Li Anqi , Zhu Yalin , Zhou Liemin , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundBoth presynaptic losses measured by cerebrospinal fluid (CSF) growth‐associated protein 43 (GAP‐43) and axonal degeneration detected by plasma neurofilament light (NfL) may be related to neurodegeneration and cognitive decline. However, it is still not fully understood whether CSF GAP‐43 and plasma NfL have a synergistic effect on predicting longitudinal neurodegeneration and cognitive decline.MethodWe identified 730 Alzheimer’s Disease Neuroimaging Initiative participants (233 cognitively unimpaired (CU), 387 mild cognitive impairment (MCI), and 110 AD dementia) with concurrent (interval < 1 year) CSF GAP‐43, plasma NfL, and longitudinal memory and executive function data. Among them, 706 participants (225 CU, 388 MCI, 93 AD dementia) had longitudinal measurements of residual hippocampal volume (rHCV) and temporal metaROI cortical thickness, and 366 participants (108 CU, 235 MCI, 23 AD dementia) had longitudinal data of metaROI 18F‐fluorodeoxyglucose (FDG) standard uptake value ratio (SUVR). We investigated the interaction of baseline CSF GAP‐43 and plasma NfL at longitudinal prediction of rHCV, temporal metaROI cortical thickness, metaROI FDG SUVR, memory, and executive function, controlling for age, sex, education, and diagnosis.ResultHigher CSF GAP‐43 and Plasma NfL at baseline had significant interaction (p = 0.028) on predicting faster rates of temporal metaROI cortical thinning but not on longitudinal decreases of rHCV and metaROI FDG SUVR (Figure 1). In addition, given the same levels of CSF GAP‐43, higher baseline plasma NfL was related to more rapid rates of decline in memory (p = 0.022) and executive function (p = 0.004) over more than 4 years of median follow‐up (Figure 2).ConclusionWe found a synergistic effect between presynaptic dysfunction and axonal degeneration on predicting longitudinal cortical thinning and cognitive decline. These findings provide novel insights into understanding the association of presynaptic and axonal loss with subsequent neurodegeneration and cognitive decline in elderly adults.
Impact of sex, age, and ancestry on Apolipoprotein E‐APOE‐ risk for Alzheimer’s disease
Authors: Rodriguez Omar Garcia , Young Juan I. , Wang Lily ,   Alzheimer’s Disease Genetics Consortium (ADGC), Martin Eden R. , Kunkle Brian W. 
Published: December 2023

AbstractBackgroundPrevious studies have reported that non‐Hispanic White (NHW) females carrying the APOE ε4 allele have an increased risk for developing AD when compared to men. Recently, analyses showed that the risk for developing AD may be equivalent for males and females but may differ by age. Few studies have been done on this issue in groups other than NHW. We aimed to evaluate the association between sex, age, ancestry, APOE, and AD.MethodsWe conducted a pooled case‐control study from 45 independent databases in Alzheimer’s Disease Genetics Consortium. Individuals (age≥55 years) were included (n = 31,058). Independent variables were age, sex, ancestry/ethnicity, and APOE genotype (ε3/ε4 vs. ε3/ε3). Logistic, linear, and Cox regression models were performed by sex and ancestry.ResultsRegardless of ancestry, men and women with APOE ε3/ε4 showed no significant difference in the risk of developing AD (all age groups combined). When comparing subjects with APOE ε3/ε4 to those with ε3/ε3, East‐Asian (EA) females (OR,4.90; 95% CI: 3.46‐6.95) had the strongest OR, followed by EA males (OR, 4.09: 2.67‐6.27); and NHW females (OR,3.40: 3.14‐3.68) and men (OR,3.33: 3.03‐3.66) among all ethnicities. When stratified by age, NHW females (OR, 3.41: 2.69‐4.32 vs. NHW males: OR,2.57: 1.94‐3.39) and EA women (OR,6.51: 1.31‐32.30 vs. EA men: OR,3.41: 0.66‐17.56) with APOE ε3/ε4 showed a higher risk of developing AD between ages 55‐65; whereas African American (AA) women (OR,4.14: 3.06‐5.60 vs. AA men: OR,2.27: 1.45‐3.55) exhibited this pattern later, at the age of 66‐75 years. In Hispanics, the pattern is reversed, with males aged 55‐65 years carrying APOE ε3/ε4 (OR,6.65; 1.64‐26.89: vs. females: OR,2.27; 1.03‐4.98) had a stronger association with AD risk than their female counterpart. Case‐only and survival analyses also showed that NHW and EA female carriers of APOE ε3/ε4 had an earlier age at the onset of AD than their counterpart in men.ConclusionsOur findings suggest sex differences by age and ethnicity in the risk for developing AD and age at onset of AD for carriers of APOE ε4. Confirming these findings could lead to a better‐personalized risk assessment for AD that accounts for sex differences in APOE.
Longitudinal multi‐day learning curves (MDLCs) to capture subtle cognitive changes in preclinical Alzheimer’s disease
Authors: Jutten Roos J. , Soberanes Daniel , Weizenbaum Emma L , Hsieh Stephanie , Molinare Cassidy , Johnson Keith A. , Rentz Dorene M. , Sperling Reisa A. , Amariglio Rebecca E. , Papp Kathryn V. 
Published: December 2023

AbstractBackgroundRemote digital testing provides the opportunity to deploy memory paradigms that mimic learning in everyday life by exposing participants to repeated stimuli over frequent intervals. Here, we used the Boston Remote Assessment for Neurocognitive Health (BRANCH) multi‐day learning curve (MDLC) paradigm and investigated whether repeating MDLCs over time could capture subtle cognitive changes in preclinical Alzheimer’s disease (AD).MethodN = 223 cognitively unimpaired older adults (age = 74±8.1, 65% female, MMSE 29±1.4) with standardized cognitive testing and amyloid and tau PET from the Harvard Aging Brain Study completed a modified version of the Face‐Name Association Examination (FNAME) at‐home for seven consecutive days on a personal device. After 10.8±2.6 months a subsample (n = 54; age = 75±8.8, 61% female, MMSE = 29±1, 19% Aβ+, n = 51 with tau PET) completed a second version of the FNAME with new stimuli for seven consecutive days. A summary learning curve metric for each MDLC (baseline and follow‐up) was computed using an Area Under the Curve (AUC) method allowing for the combination of Day 1 performance and a learning trajectory over the subsequent six days. We used linear mixed effect (LME) models on the MDLC AUCs to investigate change in MDLCs and compared this to change in Day 1 performance of the MDLCs. We also ran LME models adjusting for demographic factors to examine whether baseline Preclinical Alzheimer’s Cognitive Composite‐5 (PACC5) performance and amyloid and tau burden were associated with change in MDLCs.ResultOverall, MDLCs diminished over time (Time = ‐0.028, 95%CI[‐0.056 – ‐0.001], p = 0.047) which was not detected by change in Day 1 performance of the MDLC (Time = ‐0.026, 95%CI[‐0.063 – 0.012], p = 0.117). A lower MDLC at follow‐up compared to baseline was associated with elevated amyloid (Aβ+ Group*Time = ‐.08, [95%CI = ‐0.15‐ ‐0.01], p = 0.042) (Figure 1) and worse PACC5 performance (PACC5*Time = 0.05, 95%CI = [0.01‐0.09], p = 0.029) (Figure 2). Greater entorhinal tau burden was associated with a lower baseline MDLC (Tau = ‐0.18, 95%CI[‐0.34 – ‐0.03], p = 0.025) but not with MDLC change over time.ConclusionThese results highlight how capturing multiple datapoints over days detects short‐term cognitive changes in preclinical AD that are undetectable using standard single timepoint assessments. Paradigms such as BRANCH MDLC may thereby offer more sensitive cognitive outcome measures for AD secondary prevention trials.
Retromer pathways can regulate AD‐associated neuronal and microglial phenotypes
Authors: Qureshi Yasir H 
Published: December 2023

AbstractThe relationship between retromer‐dependent pathways in neurons and neighboring glial remains unknown. To address this question, we turn to a genetic mouse model where the retromer core protein VPS35 is depleted in hippocampal neurons, and then we replete VPS35 using an optimized viral vector protocol. The VPS35 depletion‐repletion studies strengthen the causal link between the neuronal retromer and AD‐associated neuronal phenotypes, including the acceleration of amyloid precursor protein cleavage and the loss of synaptic glutamate receptors. More interestingly, the studies show that the neuronal retromer can regulate a distinct, dystrophic, microglia morphology, phenotypic of hippocampal microglia in AD. Finally, the neuronal and, in part, the glial responses to VPS35 depletion were found to occur independent of tau. Future studies are required to determine the mechanisms by which retromer‐dependent dysfunction in neurons provokes neighboring microglia.