bluuebunny/crossref_metadata_2025_split huggingface dataset:
All WMH are not of purely vascular origin: existence of AD‐related WMH
Authors: Garnier‐Crussard Antoine , Chételat Gael 
Published: January 2025

AbstractWhite matter hyperintensities (WMH) are highly prevalent in aging and Alzheimer’s disease (AD) and typically attributed to vascular damage and cerebral small vessel disease. Yet, several lines of evidence from the literature emphasize the heterogeneity in the mechanisms leading to WMH, notably in AD, suggesting that WMH may be partly attributable to AD.Thus, firstly, neuropathological studies demonstrate heterogeneity in WMH histology, with indications of a link between tau pathology, Wallerian degeneration, and WMH severity. Secondly, in AD, WMH are an early event, partly independent of vascular risk factors, suggesting a specific AD‐related pathway leading to WMH. Thirdly, WMH topography in AD differs from age‐related WMH, globally mirroring patterns of neurodegeneration. Fourthly, genetic studies and biomarker analyses further support the association between AD and WMH. Potential mechanisms for AD‐related WMH are Wallerian degeneration due to proteinopathies (tau and amyloid) and neuroinflammation – in addition to vascular mechanisms, including the contribution of cerebral amyloid angiopathy.Building upon this evidence, we propose an alternative hypothesis challenging the exclusive vascular origin of WMH. This alternative hypothesis posits that, beyond purely vascular AD‐independent WMH, a subset of WMH, termed AD‐related WMH, is linked to AD pathology (see Figure 1).To test the hypothesis of distinct etiologies for WMH in AD (vascular versus AD‐related), we extracted the signal within the WMH from different neuroimaging modalities (T1 and T2 MRI, AV45 and FDG PET) in 142 participants (IMAP cohort), and i) performed cluster analyses to reveal distinct clusters representing WMH with varied properties; and ii) compared clinical groups (cognitively unimpaired/impaired) or amyloid status (positive/negative) to highlight AD‐related differences in WMH signals. Our findings offer initial support for our hypothesis; they show for instance higher T1 and lower T2 intra‐WMH signal in the frontal and parietal lobe in amyloid positive compared to amyloid negative participants (Figure 2).In conclusion, we advocate for a nuanced perspective of WMH etiology in AD, going beyond traditional vascular origins and acknowledging the potential contributions of AD‐related mechanisms. A comprehensive interpretation of WMH will undoubtedly advance our understanding of AD pathology and guide more effective diagnostic and therapeutic approaches.
The generalizability of proposed reference values of plasma neurofilament light chain level in Thai healthy population
Authors: Supaksirakol Paramee , Hemachudha Pasin , Hiransuthikul Akarin , Luechaipanit Watayuth , Haethaisong Thanaporn , Chongsuksantikul Adipa , Hemachudha Thiravat , Thanapornsangsuth Poosanu 
Published: January 2025

AbstractBackgroundAging is an established confounding factor influencing the plasma levels of neurofilament light chain (NfL). While age‐specific cutoff values for NfL in healthy Caucasian populations have been documented, the potential variations in ethnically and socioeconomically underrepresented populations remain underexplored. This study aims to evaluate the acceptability of proposed NfL cutoff values in the healthy Thai population.MethodThe study included 233 healthy participants aged 18 years and above, drawn from the Comprehensive Geriatric Clinic at King Chulalongkorn Memorial Hospital, the Cognitive Aging Cohort, and controlled participants from various studies in Bangkok, Thailand. Plasma NfL levels were quantified using the single molecule array (Simoa®) NF‐light™ Advance kit. Utilizing reference threshold from previous studies (Simrén et al., 2022 and Bornhorst et al., 2022), the proportion of participants with NfL levels exceeding the proposed cutoff values were compared with the expected values. Age‐specific cutoffs were also determined using a methodology similar to previous studies.ResultAmong the participants (72.5% females, median age 65 (IQR: 56.0‐69.0), median Montreal Cognitive Assessment 27 (IQR: 25.0‐28.0), median Mini‐Mental State Examination 29.0 (IQR: 28.0‐30.0) and median education level 16.0 years (IQR: 16.0‐18.0)), plasma NfL levels exceeded the 95th percentile reference from Simrén et al. in 12% (95% CI: 8.1‐16.9%) and Bornhorst et al. in 9% (95% CI: 5.7‐13.4%). These proportions, along with their confidence intervals, surpassed the expected values of 5%. Quantile regression was employed to provisionally visualize the age‐specific NfL threshold among the Thai population (Figure 1).ConclusionPreliminary findings suggest that age‐specific cutoff values established from healthy Caucasian populations may not be universally applicable in Thailand. Factors such as ethnicity and social determinants of health may introduce confounding factors to the blood levels or pose negative effects on brain ageing. Given the increasing significance of NfL as a biomarker for various neurological diseases, there is a critical need to establish reference values for plasma NfL in diverse settings, particularly in lower‐income countries.
Association between Blood‐based Biomarkers of Alzheimer's disease and Endothelial Function with Mild Behavioral Impairment in a Southeast Asian Population ‐ Biomarkers and Cognition Study, Singapore BIOCIS
Authors: Leow Yi Jin , Sandhu Gurveen Kaur , Vipin Ashwati , Tanoto Pricilia , Azam Mohammed Adnan , Zailan Fatin Zahra , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Kandiah Nagaendran 
Published: January 2025

AbstractBackgroundBehavioural changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. Blood‐based biomarkers could potentially be a less invasive and easily detectable biomarker for early identification of Alzheimer's disease and dementia. However, the contributions and pathobiology of blood biomarkers to disease trajectory and prevalence in Asians requires further definition. We examined the association between blood‐based markers(BBM) of Alzheimer's disease and neuropsychiatric symptoms(NPS) in a multi‐ethnic Southeast Asian population.Method1296 participants were recruited from the community living in Singapore. 713 were cognitively unimpaired (CU), 583 with mild cognitive impairment (MCI), and overall, the mean age=61.27 years, mean education=14.46years with 39.8% males. Participants underwent blood biomarker tests of Apolipoprotein (APOE) ε4, Aβ oligomers (Oaβ), Neurofilament Light Chain (NfL), Amyloid Peptides(Aβ)42, Aβ40, Phosphorylated Tau at position 181(P‐Tau181), Brain‐derived neurotrophic factor(BDNF), Vascular endothelial growth factor(VEGF) as well as self‐reported questionnaires using the Depression Anxiety Stress Scales(DASS) and Mild Behavioural Impairment‐Checklist(MBI‐C).ResultIn the MCI group, Aβ42(estimate‐0.55; 95% CI[‐0.95, ‐0.15]; p=0.01), Aβ40 (estimate ‐0.361; 95% CI[‐0.72, ‐0.01]; p=0.04), pTau181 (estimate ‐0.484; 95% CI[0.93, ‐0.04]; p=0.03), were significantly associated with overall MBI‐C. Furthermore, Aβ42 was associated with MBI‐C‐interest (estimate ‐0.341; 95% CI[‐0.568, ‐0.114]; p=0.03), and MBI‐C‐control (estimate ‐0.359; 95% CI[‐0.632, ‐0.086]; p=0.01), Aβ40 was associated with MBI‐C‐interest (estimate ‐0.279; 95% CI[‐0.475, ‐0.082]; p=0.005) and MBI‐C‐beliefs (estimate ‐0.077; 95% CI[‐0.153, ‐0.001]; p=0.046), pTau181 was associated with MBI‐C‐social (estimate ‐0.177; 95% CI[‐0.311, ‐0.043]; p=0.01), and BDNF was associated with stress (estimate ‐0.233; 95% CI[‐0.432, ‐0.034]; p=0.022). Interestingly, VEGF was significantly associated with MBIC‐interest (estimate 0.12; 95% CI[0.000, 0.239]; p=0.05) and MBIC‐beliefs (estimate 0.039; 95% CI[0.001,0.078]; p= 0.044).ConclusionBBM and NPS were elevated in the MCI group compared to CU. Aβ42, Aβ40, pTau181, NfL, BDNF and VEGF were associated with NPS in community‐dwelling individuals free of dementia. Impairments in neurovascular regulation can lead to neurological and psychiatric symptoms. VEGF might serve as a biomarker for certain neuropsychiatric conditions.
Deciphering the Synergy Between Amyloid‐Beta and Tau Pathologies in Preclinical Alzheimer's Disease
Authors: Zamani Jafar , Vahid Amirali , Gozdas Elveda , Hosseini Hadi , Lab C‐Brain ,   Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA, 94304, USA
Published: January 2025

AbstractBackgroundThe extracellular deposition of amyloid‐beta (Aβ) and intracellular aggregation of hyperphosphorylated tau proteins stand as histopathological hallmarks of Alzheimer's disease (AD). The spatial‐temporal relationship between the Aβ pathway and tau pathophysiology in AD, plays a crucial role in comprehending the pathogenesis and progression of AD. Understanding the interrelationship between Aβ and tau, is crucial to elucidate the failure of previous therapeutic strategies and understanding AD progression and will inform the next generation of clinical trials. We employed a robust machine learning approach to predict entorhinal tau levels, using Aβ SUVR‐identified pattern. Subsequently, we employed the identified Aβ SUVR pattern to predict long‐term hippocampal volume and Preclinical Alzheimer Cognitive Composite (PACC) cognitive measurement at five‐year follow‐up, as indicators of neurodegeneration and cognitive decline, respectively.MethodWe analyzed PET measures for amyloid and tau in a cohort of 509 participants, 233 participants (104 Aβ+, 129 Aβ−) from ADNI as training data and 276 participants (93 Aβ+, 183 Aβ−) from Harvard Aging Brain Study (HABS) as an independent test set. We employed support vector regression (SVR) as a machine learning regression method for predicting entorhinal tau levels based on Aβ SUVR pattern. Feature‐selection and cross validation were performed to build and train the model using ADNI training data and the performance of the model was tested using independent HABS data. We also tested if the trained SVR model can successfully predict hippocampal volume and PACC scores at 5‐year follow‐up using baseline Aβ SUVR pattern. We constructed separate predictive models for Aβ+ and Aβ‐ subjects.ResultThe SVR model trained on ADNI Aβ data successfully predicted entorhinal tau, future hippocampal volume and PACC scores in an independent HABS dataset with a correlation accuracy of 0.50, 0.68 and 0.55, respectively (Figure 1). Particularly, Aβ load in the medial orbitofrontal and rostral middle frontal regions contributed the most to predicting entorhinal tau and future hippocampal volume and cognitive outcomes (Figure 2).ConclusionOur study indicates that amyloid load in medial prefrontal regions may signal subsequent tau accumulation in the entorhinal cortex, and future neurodegeneration and cognitive decline, suggesting its potential role as a marker for AD progression.
Association of amyloid and tau pathology in longitudinal cognitive reserve
Authors: Borelli Wyllians Vendramini , Schlickmann Thomas Hugentobler , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Bieger Andrei , Schilling Lucas Porcello , Rosa‐Neto Pedro , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundHigher educational attainment is frequently associated with lower risk of cognitive decline. Many neuroprotective factors have been suggested as the biological underpinnings of cognitive reserve (CR), though the neural basis of CR is yet unclear. Herein, we aim at investigating the effect of CR using educational attainment in individuals stratified by amyloid and tau status.MethodA total of 135 participants, classified as cognitively unimpaired (CU) or Mild Cognitively Impaired (MCI), were selected from the ADNI cohort. All individuals that presented longitudinal measures and available amyloid and tau PET at baseline were included in this study. Formal years of education were selected as a proxy of cognitive reserve in this study, and individuals were classified into high CR (>17 years of education), intermediate CR (between 17 and 16), and low CR (<16 years of education) based on interquartile range. This analysis was in accordance with the most recent research framework to identify the mechanisms of cognitive reserve. A linear mixed‐effect model was performed to evaluate the interaction of cognitive reserve in the relationship between cognitive decline and AT status. The model was adjusted for age, sex, baseline diagnosis. Data is presented in mean±SD.ResultA total of 58 high CR (71.7±5, 57% males), 41 intermediate CR (70.4±6, 59% males) and 36 low CR (69.8±6.4% males) were included (Table). At baseline, these individuals were divided as A‐T‐ (n=69), A‐T+ (n=11), A+T‐ (n=27) and A+T+ (n=28). Mean follow‐up time of the sample was 3.15±0.9 years. Linear mixed‐effect model showed a significant interaction of cognitive reserve in the relationship between CDR‐SOB and A+T+ status (beta = 0.24, p‐val = 0.019), after adjusting for covariates. Sensitivity analysis adjusting for APOE status also demonstrated the same relationship.ConclusionThe neuroprotective effect of cognitive reserve was prominent in individuals with both amyloid and tau pathology, but not in the Alzheimer's pathological changes (A+T‐). Understanding the neural basis of cognitive reserve may greatly improve the advancements in therapeutic targets for secondary prevention of cognitive decline in individuals with identified Alzheimer's disease pathology.
Plasma NfL, ptau181 and GFAP as potential biomarkers for neuropsychiatric symptoms and related long‐term outcomes in a memory clinic cohort
Authors: Rabl Miriam , Zullo Leonardo , von Gunten Armin , Popp Julius 
Published: January 2025

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in older people, may occur early in developing dementia, and have been associated with worse long‐term outcomes. The objectives here were to investigate whether plasma neurofilament light chain (NfL), tau phosphorylated at threonine 181 (ptau181), and glial fibrillary acid protein (GFAP) are associated with a) current NPS, b) future NPS, c) NPS severity change and d) cognitive and functional decline over time. And whether the presence of NPS combined with plasma biomarkers are useful to predict these long‐term outcomes (b‐d).Method151 participants with normal cognition (n=67) or cognitive impairment (mild cognitive impairment and mild dementia, n=84) were examined in a longitudinal memory clinic study. Plasma NfL, ptau181 and GFAP were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI‐Q) at baseline and follow‐up, while cognitive and functional decline was evaluated trough the Clinical Dementia Rating – sum of boxes (CDR‐SB) score (mean: 22 months). Linear regression and ROC analysis were used to address the associations of interest.ResultCross‐sectionally none of the three plasma biomarkers was associated with NPS after adjusting for age, sex and cognitive impairment. Higher NfL was related to NPS at follow‐up (β = 0.24, 95% CI 0.04‐0.45, p = .022). NfL (β = 0.22, 95% CI 0.00‐0.44, p = .047) and GFAP (β = 0.26, 95% CI 0.05‐0.48, p = .017) were associated with an increase in the NPI‐Q severity at follow‐up. Furthermore, both markers were associated with increase in the CDR‐SB score (NfL: β = 0.29, 95% CI 0.06‐0.52, p = .013; GFAP: β = 0.33, 95% CI 0.11‐0.56, p = .004). Adding NPS and all three plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.75 to 0.84, p = .015) and cognitive decline (AUC 0.87 to 0.95, p = .030) but not the change in the NPI‐Q severity (AUC 0.67 to 0.71, p = .264) over time.ConclusionNfL and GFAP are associated with NPS and related long‐term outcomes. Considering the presence of NPS along with blood‐based biomarkers may improve prediction of clinical progression in memory clinic patients and improve clinical decision making.
Association between markers of brain pathology and verbal memory binding in autosomal dominant Alzheimer’s disease
Authors: Parra‐Rodriguez Mario A , Baena Ana Y , Munera Diana , Badillo‐Cabrera Alex L , Félix Nikole A Bonillas , Lopera Francisco , Quiroz Yakeel T. 
Published: January 2025

AbstractBackgroundThere is a need to develop neuropsychological measures to detect Alzheimer’s disease (AD)‐pathology and track cognitive changes along the AD trajectory. We previously showed that memory decline during word list learning (CERAD), associative memory (LAS‐FNAME test), working memory (Visual Short‐Memory Binding Test), and others, are associated with amyloid and tau pathology in members of Colombian families with autosomal dominant AD. Here we sought to determine whether associative verbal memory (Memory Binding Test ‐ MBT, (Buschke, 2014)) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal‐dominant AD from age‐matched non‐carriers.MethodsA total of 33 PSEN1‐E280A carriers (Age=37.6±6.17; 61% females) and 37 non‐carriers (Age=35.1±5.87; 54% females) from the Colombia‐Boston (COLBOS) Biomarker study were included. They were matched according to age and education. All participants completed cognitive testing, florbetapir (amyloid), and flortaucipir (tau) PET imaging. We implemented regression models to investigate the extent to which group membership, cortical amyloid burden, and regional tau pathology accounted for performance on the MBT.ResultsCarriers showed poorer performance on the MMSE (p<0.001) and higher scores on the daily living functions scale (FAST, p<0.001), suggesting they were in the early symptomatic stages. Performance on the MBT was significantly accounted for by group membership (R2=15.7%, p < 0.001) whereby carriers of the mutation exhibited significant deficits (p<0.001). Aβ and Tau pathology also accounted for performance on the MBT with the best model retaining cortical Aβ and Tau in the precuneus (R2=54.7%, p < 0.001). Controlling for disease severity (MMSE and FAST), but not for age or education, removed the above effects.ConclusionsAssociative memory (i.e., MBT) is sensitive to AD‐related brain pathology in the early stages of ADAD due to PSEN1‐E280A. These current findings, together with those reported previously, suggest that the early stages of the ADAD continuum can be traced with sensitive memory tests.
Principal Component Analysis discriminates lipid metabolites in the plasma of individuals with MCI, Alzheimer's, and Down Syndrome
Authors: Sarno Tamires Alves , Pereira Cícero Augusto Costa , Talib Leda Leme , Gattaz Wagner Farid , Forlenza Orestes Vicente 
Published: January 2025

AbstractBackgroundThere is evidence indicating that disruptions in lipid metabolism are implicated in the pathophysiology of Alzheimer's disease (AD), with systemic repercussions that can be identified in peripheral blood. Recent studies conducted by our group have identified abnormalities in lipid metabolism among patients with mild cognitive impairment (MCI) and dementia (probable AD), through the investigation of a specific panel of lipid metabolites in plasma. Although much remains to be elucidated about the complex interaction between disturbances in lipid metabolites and the pathogenesis of AD, this promising research area offers exciting opportunities for the development of new strategies for disease diagnosis, treatment, and prevention.MethodBlood plasma samples were collected from the following groups: individuals with Alzheimer's disease (AD, n=17), individuals with Mild Cognitive Impairment (MCI) showing pathological AD signature (n=17), individuals with MCI without pathological AD signature (n=17), individuals with Down syndrome (n=17), elderly (n=17), and young (n=17) cognitively healthy individuals. We used liquid chromatography coupled with mass spectrometry (LC‐MS/MS) for lipidomic analysis.ResultA total of 29 lipids were identified by principal component analysis (PCA) from a dataset consisting of 208 lipids. The lipid modules (attached image) composed of lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and sphingomyelin are differentially expressed in the samples. PCA1 (74.92%) and PCA2 (27.6%) account for the majority of variance in the sample (attached table).ConclusionOur preliminary findings suggest that the use of PCA analysis may aid in discriminating differently expressed lipids in the plasma of individuals with dementia syndromes
A novel fMRI memory paradigm designed for brain imaging studies in early Alzheimer’s Disease
Authors: Joshi Himanshu , PT Sivakumar , Venkatasubramanian Ganesan , John John P , Thompson Paul M. 
Published: January 2025

AbstractBackgroundWe present the results of a task‐based fMRI study in early Alzheimer’s disease (mild cognitive impairment, MCI and mild Alzheimer’s disease, AD) using a novel‐fMRI memory paradigm suitable for use in patients with significant cognitive impairment having difficulties with remembering complex instructions.MethodThe study samples comprised 65 patients with early AD(MCI n = 42; 21 males; mild AD n = 23; 16 males) and 26(14 males) elderly cognitively healthy control(eCHC) participants. The incidental encoding phase of the paradigm (7 minutes) comprised 110 trials of common objects (55 living and 55 non‐living trials which included 4 objects repeated 6 times each and 1 object repeated 5 times) while the intentional retrieval phase of the paradigm (7 minutes) comprised 55 trials of the 5 objects encoded during the previous phase(repeated 11 times each), and 55 new objects. Task‐based fMRI acquisitions were performed on a Philips Ingenia 3‐T MRI scannerand data was analysed using FEAT(FMRI Expert Analysis Tool) correcting for age, gender, education, and total brain volume.ResultSignificantly increased activations spread across bilateral fronto‐parietal and occipital cortices were noted during incidental encoding of both ‘living’ and ‘non‐living’ stimuli in MCI when compared to eCHC and in mild AD when compared to MCI. However, reduced activations spread across bilateral central and parietal opercular cortices as well as frontal, temporal and parietal brain regions were noted during the intentional retrieval phase in response to both ‘memory’ and ‘non‐memory’ stimuli in MCI when compared to eCHC and in mild AD when compared to MCI.ConclusionThe increased brain activations of brain regions involved in during the incidental encoding phase reflects effortful encoding of novel stimuli in patients with early AD. The brain regions that showed reduced activations during the intentional retrieval phase have been previously reported to be involved in various processes that underlie retrieval of previously encoded memory traces. The results of the study support the utility of this novel‐fMRI memory paradigm as a tool suitable for brain imaging research in cognitively impaired research participants.