bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period
Authors: Robb W Hudson , Gogniat Marissa A. , Zhang Panpan , Shah Krish U , Houston Michelle L , Pechman Kimberly R. , Liu Dandan , Landman Bennett A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values>0.31) nor p‐tau (p‐values>0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values>0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values<0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation.
Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082
Cellular Energy Metabolism is Altered in the Trem2R47h NSS Mouse Model of AD
Authors: Bishop Joseph , Vu Michael M , Malhas Rond , Cheema Amrita K , Milinkeviciute Giedre , MacGregor Grant R , Green Kim N , Tenner Andrea J , LaFerla Frank , Mapstone Mark , Consortium MODEL AD 
Published: December 2023

AbstractBackgroundHuman GWAS have identified variants of the triggering receptor expressed on myeloid cells 2 (TREM2) gene as a major genetic risk factor for Alzheimer’s disease (AD). TREM2 is necessary for maintaining microglial metabolic fitness and may be critical for providing cellular energy demands for microglial‐dependent β amyloid phagocytosis. Here, we examine the plasma metabolome of Trem2 R47H NSS mice in the presence of β amyloid plaques to examine alterations of cellular energy metabolites.MethodWe examined the abundance of plasma metabolites obtained from homozygous Trem2 R47H NSS (Jax #034036), 5xFAD x Trem2 R47H NSS, 5xFAD hemizygous, and control (WT) mice (n = 10 each group) at 4 months of age. We measured 762 lipids and 204 polar metabolites from peripheral plasma using liquid chromatography mass spectrometry (LC‐MS). We conducted differential abundance (DA) analysis for the individual metabolites and compared the groups using FDR correction (q < 0.05). We used DA metabolites in pathway analysis to examine which metabolic pathways were impacted by TREM2 R47H and the presence of amyloid (5xFAD hemizygous background).ResultHomozygous Trem2 R47H NSS mice, both in the presence and absence of amyloid plaques (i.e. 5xFAD hemizygous or non‐transgenic background), had significantly lower abundance α‐D‐glucose and lactate compared to their relevant control groups (q’s < 0.05). 5xFAD x Trem2 R47H NSS mice also showed significantly lower phosphatidylethanolamine (PE) abundance relative to 5xFAD hemizygous mice (q’s < 0.05) and this was especially apparent for female mice (q’s < 0.05). KEGG pathway analysis using DA features revealed enrichment on Glycerophospholipid Metabolism and Glycolysis/Gluconeogenesis pathways.ConclusionWe report lower levels of the entry substrate to glycolysis (Glucose) and an end product metabolite (Lactate) in homozygous Trem2 R47H NSS mice, especially in the presence of amyloid. The depletion of these energy metabolites in circulating blood may reflect failure of the immunometabolic switch from oxidative phosphorylation to glycolysis in support of increased energy demands of activated microglia. We also find significant depletion of glycerophospholipids in Trem2 R47H NSS mice, which was more pronounced for female mice. These results suggest cellular energy dyshomeostasis associated with microglial activation which can be measured in peripheral blood.
Cerebral amyloid angiopathy and neuritic plaques impact tangle burden and cognitive decline in a heterogeneous clinical population
Authors: Godrich Dana , Pasteris Jeremy , Martin Eden R. , Schellenberg Gerald D. , Pericak‐Vance Margaret A. , Cuccaro Michael L. , Scott William K. , Rundek Tatjana , Kukull Walter A. , Montine Thomas J. , Beecham Gary W. 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) presents with two primary pathologies: neurofibrillary tangles (NFT) and neuritic plaques (NP). However, these hallmark pathologies typically co‐occur with pathologies from AD‐related dementias like cerebral amyloid angiopathy (CAA) [Godrich, 2022; PMID: 35142102]. While CAA is known to impact cognitive impairment, the role of CAA in AD dementia is still not well described [Rabin, 2022; PMID: 35759327]. Here we present an analysis of CAA, NP, and NFT to assess the interplay of these pathologies with cognitive decline and genetic risk factors for AD.MethodData come from 4,915 autopsied individuals from the National Alzheimer’s Coordinating Centers (NACC). NFT, NP, and CAA were measured ordinally. We used ordinal logistic regression to model and compare independent and interactive effects of CAA and NP on NFT and cognitive decline while adjusting for sex, AAD, and APOE. We also evaluate models with an APOE and NP interaction as a comparison to gauge whether it is more informative than CAA. Finally, we replicate causal mediation analysis from Rabin et al. and extend the path model to include APOE, stratifying both models by NP severity (Fig.1).ResultThe model with CAA and NP interactions best explained NFT burden outcome (per AIC, pseudo‐R2, and F‐test), even when compared to models with APOE. We replicated Rabin et al. findings that CAA does not directly affect cognitive decline but rather indirectly via NFT mediation, but only in individuals in the high NP group. We saw this in a larger clinical cohort with ordinal measures of neuropathology, which are more commonly obtained than linear ones. We also extended the mediation analysis to include APOE and findings held.ConclusionWe replicated the relationship between CAA, AD pathologies, and cognitive decline [Rabin, 2022] and extend the findings to a more heterogeneous clinical population. Even when accounting for APOE, CAA still had an indirect effect on cognitive decline in the high NP group as mediated by NFT severity, showing that the findings are likely not due to APOE confounding. These findings continue to underscore the importance of the consideration of co‐occurring neuropathologies like CAA when developing novel AD therapeutics.
Relationships between CYP450‐sEH oxylipins, small vessel disease markers, and regional neuroimaging in Alzheimer’s disease and mild cognitive impairment
Authors: Lin William Z. , Yu Di , Xiong Lisa Y. , Anita Natasha Z. , Liang Nuanyi , Shen Qing , Ozzoude Miracle , Fischer Corinne E. , Frank Andrew R , Freedman Morris , Kumar Sanjeev , Pollock Bruce G. , Tang‐Wai David F. , Tan Brian , Haddad Seyyed M. H. , Nanayakkara Nuwan D. , Ramirez Joel , Symons Sean , Arnott Stephen R. , Lou Wendy , Rabin Jennifer S. , Taha Ameer Y. , Swardfager Walter 
Published: December 2023

AbstractBackgroundCytochrome P450 (CYP450) derived epoxides are vasoactive lipid mediators that may confer neuroprotective and anti‐inflammatory effects. CYP450 epoxides are degraded by soluble epoxide hydrolase (sEH) into diols. This study investigated relationships of these CYP450‐sEH “oxylipins” with regional small vessel disease (SVD) markers, atrophy, and white matter microstructural integrity in people with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD.MethodParticipants with clinical AD or MCI were identified from the Ontario Neurodegenerative Disease Research Initiative. Fasting serum oxylipins were quantified using ultra‐high performance liquid chromatography‐tandem mass spectrometry. White matter hyperintensities (WMH), lacunes, perivascular spaces (PVS), and brain parenchymal fraction (BPF) were quantified using structural magnetic resonance imaging. Fractional anisotropy (FA) and mean diffusivity (MD) were measured using diffusion tensor imaging. Spearman correlations were performed between oxylipin species and imaging measures, controlling for demographic factors, ApoE4 status, glucose, cholesterol, systolic blood pressure, and waist circumference. Results were corrected for multiple comparisons using a 5% false discovery rate.ResultIn both the AD (n = 73) and MCI (n = 28) groups, fatty acid epoxide concentrations were generally associated with higher FA. Diol concentrations were generally associated with lower FA in AD, but with higher FA in MCI. Epoxide concentrations were associated with greater MD in AD but with less MD in MCI. There were multiple associations between diols and greater regional BPF in AD that were less pronounced and less widespread in the MCI group; however the trend was consistent between AD and MCI for the left middle inferior frontal region (greater diols, greater BPF). In AD, it is notable that the 14(15) arachidonic acid epoxide was associated with lower WMH volumes (Spearman’s ρ: ‐0.234 to ‐0.577); the 9(10) linoleic acid epoxide was associated with greater temporal lobe BPF (Spearman’s ρ: 0.204 to 0.499).ConclusionDifferential correlations between plasma oxylipin concentrations and regional neuroimaging measures between AD and MCI suggest that the involvement of the CYP450‐sEH pathway may differ across stages of AD progression.
Optimizing Subjective Cognitive Concern Assessment to Predict Cognitive Decline in Motoric Cognitive Risk Syndrome: Results from the Einstein Aging Study
Authors: Nester Caroline O. , Gao Qi , Wang Cuiling , Emmeline Ayers , Katz Mindy J. , Derby Carol A. , Lipton Richard B. , Verghese Joe , Rabin Laura 
Published: December 2023

AbstractBackgroundMotoric Cognitive Risk Syndrome (MCR) is a predementia condition that combines slow gait speed and subjective cognitive concerns (SCC), and predicts incident dementia in diverse global populations. MCR status is simple and inexpensive to ascertain, facilitating assessment in low resource settings. Though the slow gait component of MCR diagnosis is well operationalized, there is no standardized approach to SCC assessment. We hypothesized that in older adults with slow gait, the SCC questions that best predicted cognitive decline would most successfully operationalize SCC.MethodEinstein Aging Study participants (n = 324; Mage = 70.4; Meducation= 15; 67%women; 46.3%White) completed the Cognitive Change Index Supplement (CCI‐40) as part of a comprehensive neuropsychological assessment (which included the Clinical Dementia Rating Scale [CDR]) at baseline and over up‐to‐5 annual follow‐ups (Mwave= 1.48). The CCI‐40 queries SCC across cognitive domains, including memory (21 items), language (4), executive functioning (5), attention/concentration (4), visuospatial functioning (2), calculation (1), mental clarity (2), and orientation (1). Slow gait was diagnosed based on established MCR criteria (1 SD below age/sex adjusted means). We used linear mixed effects models (LME) for continuous, and generalized LME for binary longitudinal cognitive outcomes, to examine how various definitions of SCC at baseline predict cognitive changes in older adults with slow gait, adjusting for covariates including age, sex, education, race/ethnicity, and depression. We report the interaction terms between SCC and time. The final sample included 43 participants (13%) who met slow gait criteria at baseline.ResultAmong participants with slow gait, the CCI‐40 total score was associated with decline on neuropsychological measures of attention/processing speed (β = ‐0.09, p = 0.05), verbal fluency (β = 0.03, p = 0.01), and a global dementia rating scale (β = 0.04, p = 0.02). Item‐by‐item analysis revealed a subset of items that were significantly associated with decline in key neuropsychological domains, including executive functioning, language, and memory.ConclusionOur findings suggest that attention to SCC assessment in older adults with slow gait may provide key insight into individuals at greatest risk for cognitive decline. SCC in MCR may be best operationalized through comprehensive assessment across broad cognitive domains. Future work will develop a brief SCC screen optimized to predict cognitive decline in this population.
Associations between brain TSPO and [18F]FDG‐PET signals in neurodegenerative disorders
Authors: Machado Luiza Santos , Vidor Pedro , Limberger Christian , de Carvalho Lavínia Perquim , Machado Leonardo , Carvalho Guilherme Da Silva , da Rocha Andreia Silva , Bellaver Bruna , Soares Carolina , Ferreira Pamela C.L. , Pascoal Tharick A. , Rosa‐Neto Pedro , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Zimmer Eduardo R. 
Published: December 2023

AbstractBackgroundRecent evidence indicates that activated microglial cells contribute to the brain FDG‐PET signal changes in neurodegenerative disorders. Radiopharmaceuticals targeting the 18‐kDa translocator protein (TSPO) have been used to measure microglial activation. The combination of FDG‐PET and TSPO‐PET allows for assessing, in‐vivo and non‐invasively, whether they associate in brain regions vulnerable to neurodegeneration. So far, multiple studies have used FDG‐PET and TSPO‐PET concomitantly, but to our knowledge, no systematic evaluation has been conducted to assess whether they are associated. We aimed to systematically summarize the current data on brain TSPO‐PET and FDG‐PET signals in individuals with neurodegenerative disorders.MethodStudies performing TSPO‐ and FDG‐PET in neurodegenerative disorders were searched in PubMed and Web of Science. Included articles must have performed PET images concomitantly with both tracers in healthy controls and individuals presenting with neurodegenerative disorders. This review complied with PRISMA (2020) guidelines and was registered at PROSPERO (CRD42022354523).ResultA total of 272 articles were found after a search on PubMed and Web of Science, with eight meeting the inclusion criteria. We included clinical studies with individuals presenting Alzheimer’s Disease (AD), Parkinson’s Disease (PD), corticobasal syndrome and progressive supranuclear palsy, behavioral variant frontotemporal dementia, and progressive nonfluent aphasia. In AD, five studies presented negative associations, and one presented a positive association between TSPO and FDG signals in brain regions vulnerable to AD. In PD (3 studies) and the other related neurodegenerative disorders (2 studies) evaluated, we found a negative correlation between FDG‐PET and TSPO‐PET signals in vulnerable regions.ConclusionAll studies presented associations between FDG‐ and TSPO‐PET signals. These findings suggest that microglia, indexed by TSPO binding, negatively impacts brain glucose metabolism indexed by FDG‐PET. Further studies are needed to address associations between TSPO‐PET and FDG‐PET in the asymptomatic and early stages of neurodegenerative disorders.
Adults with Down syndrome show quantitative sleep electroencephalogram patterns similar to those observed in patients with Alzheimer’s disease
Authors: Giménez Sandra , Clos Susana , Serna Leidy Y. , Carmona‐Iragui Maria , Benejam Bessy , Rojas Monica , Bejanin Alexandre , Arranz Javier , Videla Laura , Barroeta Isabel , Aranha Mateus Rozalem , Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Mañanas Miguel Angel , Lleo Alberto , Romero Sergio , Fortea Juan 
Published: December 2023

AbstractBackgroundDown syndrome (DS) is a genetic form of Alzheimer’s disease (AD) with a preclinical AD biomarker changes similar to euploid forms of AD. In sporadic AD, sleep electroencephalogram (EEG) changes have been related to cognitive decline and AD progression. However, whether DS follows a similar pattern of sleep EEG changes has not been investigated. Here, we aimed to quantify sleep EEG pattern in adults DS using spectral analysis and entropy changes.MethodCross‐sectional study, 67 adults with DS (41.1±11.4 yo) without signs of AD cognitive decline, and 24 euploid adults (58.3±12.4 yo) performed a polysomnography with extended 19 channels EEG setup. For data analysis, EEG was segmented into 5s epochs and preprocessed by an automatic artifact rejection procedure based on amplitude and kurtosis. Power spectra at the common EEG bands were calculated separately for wake, for NREMS: N1, N2, N3 stages, N2 stage, slow wave sleep (SWS:N3 stage) and REM stage. Sample entropy was also calculated for each epoch. Differences in EEG power across sleep stages between groups were calculated and represented by statistical percentage differences in one channel (Fz‐derivation) and by statistical topographic maps in all 19 EEG channels. For the dynamic of the EEG spectrum, the average of delta and entropy activity was calculated in Fz for each NREM cycle, and for sigma activity in NREM‐REM cycles.ResultAs compared to the control group, subjects with DS presented overall and significant increments in the delta and theta band for all sleep stages, and across sleep cycles(p<0.01). Topographic maps showed also a generalized increase in the beta band (13‐35Hz) compared to controls, mainly for N2 and N3 stages. A general decrease in the sample entropy (p<0.01) was also observed for all the sleep stages, implying that Down subjects have more regular and deterministic EEG rhythms.ConclusionSubjects with DS present a high activity in the low frequency bands, detected in all EEG channels and all sleep and wake stages. These results follow the same tendency observed in the sleep EEG changes in preclinical AD, which evidence the suitability of adults with DS to study sleep EEG changes as possible AD biomarker.
Regulation of meningeal lymphatic function by APOE
Authors: DELIVANOGLOU NIKOLETA , Todd Kennedi , Barber Megan J , Neves Sofia Pereira , Schrader Racquelle , Sanchez Guadalupe , Rego Shanon , Martens Yuka A , Bu Guojun , Fryer John D. , Mesquita Sandro Gabriel (Sandro Da Mesquita) Ferreira Da 
Published: December 2023

AbstractBackgroundThe meningeal layers form a unique interface between the central nervous and peripheral immune systems. The lymphatic vasculature that is present in the meningeal dura and drains cerebrospinal fluid (CSF) becomes dysregulated during aging and in models of neurodegenerative disorders such as Alzheimer’s disease (AD). Apolipoprotein E (APOE), and the isoform APOE4 in particular, increases the risk for late‐onset sporadic AD. However, it is still poorly understood whether changes in meningeal lymphatic morphology and drainage are mediating the deleterious effects of APOE4 expression. In the present study, we investigate the effects of human APOE3 or APOE4 on meningeal lymphatic function and immunity.MethodWe evaluated the morphology of lymphatic vessels in dural whole mounts of age‐matched wild type, Apoe‐KO, APOE3, and APOE4 mice at 2‐3, and 11‐12 months. This assessment was performed in both male and female mice. The drainage function of meningeal lymphatics is being assessed in the same mice by in vivo imaging of CSF‐derived fluorescent tracers into the deep cervical lymph nodes. We have also performed RNAscope and protein measurements using murine meningeal tissue to investigate the main cellular source(s) of Apoe, and single‐cell RNA sequencing to explore the cell‐specific transcriptomic signatures linked to the changes in meningeal lymphatic function.ResultLymphatic vessel length is increased in 11‐12‐month‐old APOE4 male mice, when compared to their APOE3 counterparts. Interestingly, the same was not detected in female mice. Dural myeloid cells, expressing Itgam (encoding for CD11b), are the main source of Apoe mRNA transcripts, and one of the main sources of apoE protein in the brain dura mater. APOE4 expression and age markedly alter the transcriptional profile of meningeal myeloid cells, which show overexpression of lysosomal, antigen presentation, and complement genes.ConclusionAPOE4 expression leads to a sex‐dependent meningeal lymphatic vascular remodeling, which is associated with an exacerbated activation of meningeal macrophages. In future studies, we will test whether the changes in meningeal lymphatics observed in mice expressing APOE4 are mediated by myeloid cell derived APOE.