bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disordered ganglioside localization in the Alzheimer’s disease brain
Authors: Ollen‐Bittle Nikita , Jiang Hanyu Y , Pejhan Shervin , Pasternak Stephen H , Whitehead Shawn N 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive dementia that impairs memory and cognition. Gangliosides are glycosphingolipids enriched within the central nervous system and known to alter the secondary structure of amyloid beta deposits, a hallmark of AD (Choo‐Smith et al., 1997). The ganglioside GM1 is known to exert neuroprotective properties and was proposed as a therapeutic for AD (Svennerholm, 1994). In support of this, intraventricular administration of GM1 decreased amyloid beta deposits and provided clinical benefit (Augustinsson et al., 1997). Pre‐clinical work has since demonstrated a shift from complex GM1 species to simple GM2 and GM3 is linked to neurodegenerative pathogenesis (Wang & Whitehead, 2020). However, the ganglioside GM1 also converts amyloid beta to a toxic form with beta sheet structure (Yamamoto et al., 2007), and acts as a seed for amyloid beta fibrillogenesis (Yanagisawa et al., 1995). It is possible that different GM1 subtypes may be responsible for varying affects. Understanding the profile of GM1 subtypes in the AD brain may be a key step in capitalizing on its therapeutic potential. We investigate the ratio between 18 and 20 carbon subtypes of GM1 and simple ganglioside species in post‐mortem human AD brain tissue and non‐AD controls. Brain regions interrogated include the entorhinal cortex, basal forebrain, anterior commissure and hippocampus.MethodNeuroanatomical regions of interest (ROIs) were blocked from neuropathologically confirmed AD and non‐AD brains and stored in 10% formalin. Samples were prepared for matrix assisted laser desorption ionization imagining mass spectrometry (MALDI‐IMS) (Caughlin et al., 2017). MALDI‐IMS was performed in reflectron negative mode. Matching ROIs in AD and non‐AD samples (n = 5) were selected using TissueView software. Mass spectra were normalized by area under curve and peaks corresponding to gangliosides were statistically analyzed.ResultNon‐AD brains demonstrated distinct d20:1/d18:1 ratios of both simple and complex gangliosides between different brain regions. This expression profile was lost in the AD brain samples. Additionally, a significant decrease in this ratio was observed in AD compared to non‐AD samples in several brain regions.ConclusionGanglioside dysregulation and a decrease in the d20:1/d18:1 ratios in multiple brain regions are critical pathological biomarkers of AD.
Decline in everyday functioning in relation to cerebral tau burden across the clinical spectrum of Alzheimer’s disease
Authors: Dubbelman Mark A. , Mimmack Kayden J. , Sprague Emily H. , Amariglio Rebecca E. , Vannini Patrizia , Marshall Gad A 
Published: December 2023

AbstractBackgroundEmerging difficulty performing cognitively complex everyday tasks, or ‘instrumental activities of daily living’ (IADL) may be an early clinical sign of Alzheimer’s disease (AD). We aimed to investigate how changes over time in everyday functioning relate to tau across the AD clinical spectrum.MethodWe included 581 participants (73.9±7.6 years old; 52% female) from the Alzheimer’s Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). FAQ total scores range 0‐30, with higher scores representing more functional impairment. Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247), having either mild cognitive impairment or AD dementia. Using mixed‐effects models, we analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions. The main effect of interest was the interaction term of tau by time. We covaried for age, sex, and baseline performance on tests for memory, executive function and premorbid cognition, and corrected for multiple testing. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). Baseline amyloid PET was additionally available for a subset (n = 363), and we investigated interactions between amyloid and tau in this subset.ResultGreater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning (Table 1, Figure 1). These findings remained when adjusting for baseline global cortical amyloid; amyloid itself was only associated with change over time in FAQ scores when tau was not included (unstandardized b = 1.18, 95%CI = [0.39,1.97], t = 2.94, p = .01). When stratifying by diagnostic group, these effects were present only in the symptomatic group.ConclusionThe rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid. This aligns with previous findings that cognitive function relates more closely to tau pathology. Change in everyday functioning was only observed on the FAQ in symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease spectrum.
Proteome Analysis in Plasma and Brain Reveals a Novel Plasma Biomarker Linked to Antemortem Cognitive Impairment and Postmortem Neuropathological Traits for Alzheimer Disease
Authors: Goldstein Daniel , Aytan Nurgul , Palmisano Joseph N , Tripodis Yorghos , Turk Katherine W , O'Connor Maureen K. , Goldstein Lee E , Budson Andrew E , Qiu Wei Qiao , Kowall Neil W , McKee Ann C. , Mez Jesse B. , Alosco Michael L , Farrer Lindsay A. , Stein Thor D. , Jun Gyungah R ,   Boston University Alzheimer’s Disease Research Center
Published: December 2023

AbstractBackgroundIdentification of blood‐based biomarkers that are indicative of Alzheimer’s disease (AD) pathology may help with early detection.MethodsWe generated proteome data for ∼7,000 proteins in both antemortem plasma and postmortem brain tissue from 103 participants of the Boston University Alzheimer’s Disease Research Center. All participants completed comprehensive neuropsychological evaluations and dementia severity was measured by global cognitive dementia rating (CDR) scores. A pathological AD diagnosis was established using NIA Reagan criteria. We conducted association tests with dementia (i.e., CDR ≥1 for dementia, CDR <1 for control) and autopsy‐confirmed AD status as binary outcomes. Plasma proteins significantly associated with clinical or pathological AD (P<0.05) were tested for association with quantitative cognitive tests and AD‐related neuropathological traits in which outcomes were rank‐transformed after adjusting for sex and either age at last antemortem exam or death.ResultsOf the 103 brain donors, 43 were diagnosed with dementia and 55 had autopsy‐confirmed AD. Five proteins (ACES, AURKB, CBARP, G45IP, and MMP‐8) measured in plasma were significantly associated with both pathological AD and dementia, while 252 plasma proteins were associated with either diagnosis (P<0.05). MMP‐8 was the only protein that was significantly associated in both plasma and brain with autopsy‐confirmed AD (Pplasma = 0.005, Pbrain = 0.001) and dementia (Pplasma = 0.01, Pbrain = 9×10−5). ACES and AURKB levels in plasma and brain were significantly associated with dementia (P<0.05). Levels of these. Increased MMP‐8 level in plasma was associated with decreased animals (P = 0.03) and scores (P = 0.04), which both assess verbal fluency. Dementia and pathologically confirmed AD were associated with lower AURKB and elevated ACES levels in plasma. Decreased plasma ACES level was associated with executive function (TrailsB: P = 0.01) and language (Boston Naming Test: P = 0.02) impairment, and the reduced plasma AURKB level was associated with memory impairment (Logical Memory Immediate Recall score: P = 0.03).ConclusionMMP‐8, a neutrophil collagenase and member of the matrix metalloproteinase family, is a potential blood‐based biomarker for dementia and underlying AD pathology and is associated predominantly with impaired verbal fluency.
Change on the Repeatable Battery for the Assessment of Neuropsychological Status and its relationship to brain amyloid
Authors: Duff Kevin , Dixon Ava , Embree Lindsay , Hoffman John M. 
Published: December 2023

AbstractBackgroundThe Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer’s disease (AD), including brain amyloid plaque density. However, less is known about if changes in the RBANS across time are also related to brain amyloid deposition. The current study sought to expand on prior work by examining the relationship between changes over time on the RBANS and amyloid deposition via positron emission tomography (PET).MethodOne‐hundred twenty‐six older adults with intact or impaired cognition and daily functioning underwent repeat assessment with the RBANS across nearly 16 months, as well as had a baseline amyloid PET scan.ResultIn the entire sample, amyloid deposition was significantly related to change on all five Indexes and the Total Scale score of the RBANS (rs = ‐0.28 – ‐0.61), with greater amyloid deposition being associated with worsening cognition. This pattern was also observed in 11 of 12 subtests. In the intact individuals, this pattern was only observed on change in the Immediate Memory Index (r = ‐0.32). In the subjects with MCI, this pattern was only observed on change in the Delayed Memory Index (r = ‐0.35). There was no association between change on the RBANS and brain amyloid deposition in those with AD.ConclusionWhereas prior studies have identified a relationship between baseline RBANS and amyloid status, the current findings support that changes in the RBANS are also indicative of AD brain pathology. Although replication in a more diverse sample is needed, these results continue to support the use of the RBANS in AD clinical trials.
Investigating the role of structural variants in Alzheimer’s Disease and AD‐Related traits
Authors: Vialle Ricardo A , Lopes Katia de Paiva , Tasaki Shinya , Schneider Julie A , De Jager Philip L , Bennett David A. A 
Published: December 2023

AbstractBackgroundAlthough recent advances have led to a greater understanding of the genetics of Alzheimer’s Disease (AD), there remains a discrepancy between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability.MethodHere, we investigate the role of SVs in AD and AD‐related dementias (ADRD) by leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). We analyzed over 25,000 SVs discovered using whole genome sequencing (WGS) data of 1,106 participants and tested for association with multiple indices for AD/ADRD, including measurements of cognitive decline, amyloid beta, neuronal neurofibrillary tangles, TDP‐43, cerebral amyloid angiopathy, and resilience.ResultOur findings revealed five associations reaching genome‐wide significance. These included a 106 bp insertion (chr21:17,134,448; MAF = 0.01), located in the intronic region of the gene USP25, associated with a higher TDP‐43 burden (P‐value = 1.83×10−6). An 82 bp insertion at chr19:45,444,699 (MAF = 0.25), previously mapped as eQTL for APOC1 and sQTL for APOC2 in brain tissues, was linked to greater cerebral amyloid angiopathy (P‐value = 1.02×10−6). An 820 bp deletion chr15:26,003,040 (MAF = 0.031) overlapping a CTCF site near ATP10A was associated with greater odds of Lewy Body disease (P‐value = 1.03×10−6). A 55 bp insertion (chr12:131,797,376; MAF = 0.21) in an intergenic region was found to be associated with reduced vascular disease burden (P‐value = 2.96×10−7); and a 53 bp insertion (chr4:99,901,557; MAF = 0.014) mapped as protein QTL for ADH5 was linked to lower cognitive resilience (P‐value = 8.51×10−7).ConclusionThese findings provide evidence that common genetic variation, particularly SVs, can play a significant role in AD/ADRD traits. We are now investigating the functional impact of these SVs by integrating multi‐omics assays available from brain tissues of the same individuals. Our goal is to connect genetics to phenotype and gain a deeper understanding of the role of SVs in AD/ADRD.
Machine learning composite of remote cognitive tests for screening of preclinical AD cohorts
Authors: Liu Shu , Fedyashov Victor , Zisis Georgios , Masters Colin L , Maruff Paul , Goudey Benjamin 
Published: December 2023

AbstractBackgroundComputerized cognitive tests are critical in the screening of preclinical Alzheimer’s Disease (AD) given their ability to be conducted remotely at low cost. Here, we explore whether machine‐learning derived composites of remote cognitive tests can improve sensitivity when detecting brain amyloid (Aβ) accumulation in cognitively normal (CN) cohorts than traditional pen‐and‐paper alternatives.MethodBased on the CogState Brief Battery tests in CN individuals from the A4 dataset (n = 4230, Aβ‐ = 3094), we construct a data‐driven composite, denoted the Remote Empirical Cognitive composite for Alzheimer’s Disease (RECAD), designed to be sensitive to Aβ‐PET positivity. Specifically, the composite uses a random feature elimination logistic regression to identify a subset of predictive tests. We construct and evaluate the model using 10 repeat, 5‐fold cross‐validation in the A4 baseline data. We conduct temporal validation with the A4 second visit and external validation using CN participants from the ADNI (n = 389, Aβ‐ = 143), comparing against the pen‐and‐paper‐based PACC composite and previous computerized composites CBB and C3.ResultRECAD includes three accuracy scores (Identification, One‐Back and One‐card) and one reaction time (Detection). In cross‐validation in the A4 baseline, RECAD show a significantly higher ability to discriminate Aβ status [mean Cohen’s d = 0.26] than PACC [mean d = 0.25, t‐test p<0.001] and computerized composites CBB [median d = 0.13, p<0.001] and C3 [mean d = 0.18, p<0.001]. RECAD significantly improves beyond C3 in the A4 second visit (z‐test p<0.001). Moreover, these trends are replicated in the ADNI at baseline (RECAD d = 0.215, PACC d = 0.061) and 24 months (RECAD d = 0.295, PACC d = ‐0.026) but the small sample and effect size limits our ability to demonstrate statistical significance.ConclusionRECAD, as a machine‐learning derived composite of remotely conducted cognitive tests, shows a comparable or better sensitivity to the established pen‐and‐paper composite test when screening for Aβ+ among CN cohorts. While effect sizes are small, conducting such remote tests repeatedly may be a useful pre‐screening for downstream biofluid evaluation.
Correlation between longitudinal changes of clinical symptoms and striatal DAT uptake in DLB
Authors: Shimizu Soichiro , Takenoshita Naoto , Yamamoto Ryo , Inagawa Yuta , Inagawa Shoya , Sato Tomohiko 
Published: December 2023

AbstractBackgroundIt is widely known that there is low striatal 123I‐FP‐CIT dopamine transporter single photon emission tomography (DaT‐SPECT) uptake in patients with dementia with Lewy bodies (DLB). There are no study about the association between longitudinal changes of clinical sign and DaT‐uptake in Parkinson syndrome, especially in DLB. The aim of this study is to investigate the association between the longitudinal changes of DaT uptake and severity of parkinsonism and cognitive funtion in DLB.MethodA total of 35 outpatients with probable DLB who underwent DaT‐SPECT twice (initial and follow up period) from the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, were enrolled in this study from April 2014 until September 2020. We examined the correlation between annual changes of DaT uptake and symptoms (cognitive function decline, parkinsonism) in the patients with DLB.ResultThere was significant correlation between annual changes of severity of parkinsonism and DAT uptake in left posterior putamen (r = ‐0.39, p = 0.03), MMSE scores and DaT uptake in the entire regions except right posterior putamen (P< 0.05) in patients with DLB.ConclusionThese results may suggest clarifying the mechanism of dysfunction of nigrostriatal projection pathway in DLB.
Leptin Bioavailability and Markers of Brain Aging and Vascular Damage in Middle Age. The Framingham Heart Study
Authors: Charisis Sokratis , Short Meghan I , Aslam Asra , Himali Jayandra Jung , Habes Mohamad , Shipp Eric L. , Beiser Alexa S. , Decarli Charles , Vasan Ramachandran S , Seshadri Sudha , Maillard Pauline , Satizabal Claudia L. 
Published: December 2023

AbstractBackgroundLeptin perturbations have been associated with dementia and cognitive decline in older adults. However, given the long preclinical stages that characterize these disorders, previous findings might be confounded by reverse causality. To gain further insights into the potential role of leptin in neurodegeneration and vascular brain injury, we investigated the associations of leptin markers with cognitive function, and MRI markers of brain aging and vascular damage in cognitively‐healthy middle‐aged adults living in the community.MethodThe concentrations of leptin, soluble leptin receptor (sOB‐R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured in 2,262 cognitively‐healthy participants (mean age 40.4, standard deviation [SD] = 8.6 years; 47.6% men) from the Third Generation Cohort of the Framingham Heart Study (Table 1), that had undergone neuropsychological evaluation; of these, 2,129 also underwent brain MRI. Cognitive function was assessed using the Wechsler Adult Intelligence Scale similarities test, Trail Making Test (TMT) part A, TMT part B, logical memory delayed task, and the Hooper Visual Organization Test. The MRI protocol included T1w, FLAIR, and DTI MRI sequences. Relationships of leptin markers with cognitive and MRI measures of interest were assessed using linear regression models. The false discovery rate (FDR) was used to account for multiple testing at p<0.05.ResultHigher sOB‐R concentrations were associated with lower fractional anisotropy (FA, Beta = ‐0.11±0.02, p<0.0001), and higher free water (FW, Beta = 0.09±0.02, p<0.0001) and peak‐width skeletonized mean diffusivity (PSMD, Beta = 0.08±0.02, p<0.001), indicating an overall worse white matter (WM) microstructural integrity (Table 2). Similarly, higher FLI, reflecting an increase in leptin bioavailability, was associated with higher FA (Beta = 0.12±0.03, p<0.0001), and lower FW (Beta = ‐0.10±0.03, p = 0.001) and PSMD (Beta = ‐0.09 ±0.03, p = 0.002), indicating an overall better WM microstructural integrity. Relationships between leptin markers and cognitive measures or structural MRI markers were not significant after FDR correction (Table 3).ConclusionHigher leptin bioavailability was associated with better WM integrity in middle‐aged cognitively‐healthy adults. Considering that alterations in WM microstructure represent an early event in asymptomatic individuals who may later develop cognitive decline due to Alzheimer’s disease and/or vascular pathology, these findings support the putative role of leptin perturbations in late‐life dementia risk.
Altered Gut Microbiota in Dementia and Mild Cognitive Impairment in Community‐Dwelling Older Adults in Taiwan
Authors: Fang Chuang Yi‐ 
Published: December 2023

AbstractBackgroundThe microbiota‐gut‐brain axis has been implicated in the pathogenesis of dementia. However, research about gut microbiota changes in cognitive impairment remains scarce, and results vary with methodological differences. This study examines biodiversity and the differential abundance of gut flora associated with cognitive impairment in a community‐based cohort of older adults.MethodThe study sample of 298 older adults was derived from a community‐based prospective cohort study, the Epidemiology of Mild Cognitive Impairment in Taiwan (EMCIT). Among them, 82 were ascertained as MCI or dementia. Fecal samples were analyzed by Illumina shotgun metagenomic sequencing. The Metagenomic Phylogenetic Analysis (MetaPhlAn2) pipeline was applied to generate a relative abundance of gut microbiota.ResultIndividuals with dementia or MCI were older (76.6 ± 7.2 years vs. 67.8 ± 6.6 years) and had less education (9.3 ± 4.5 years vs.12.0 ± 3.9 years). There is no significant difference in alpha‐diversity between MCI/dementia and cognitively normal adults after adjusting for age, gender, education, and BMI. However, the PERMANOVA test revealed significant differences in beta‐diversity. The results of linear discriminant analysis (LDA) effect size (LEfSe) showed a differential abundance of taxonomy between the two groups. Increased abundance of several species, including Bacteroides thetaiotaomicron and Ruminococcus torques, and reduced abundance of Prevotella, Eubacterium, and Bifidobacterium were associated with MCI/dementia (Figure 1).ConclusionThe gut microbiota of older adults with MCI/dementia significantly altered in overall diversity and compositions. The mechanism of how altered gut microbiota contributes to the development of dementia needs to be further investigated.
Thymoquinone protects against lipopolysaccharides‐induced neurodegeneration and Alzheimer‐like model in mice.
Authors: Adeoluwa Olusegun Adebayo , Adeoluwa Gladys Onyinye , Akinluyi Elizabeth Toyin 
Published: December 2023

AbstractBackgroundChronic neuroinflammation has become a cornerstone in the study of neurodegeneration and Alzheimer’s diseases. Thymoquinone is a known anti‐inflammatory agent with a strong antioxidant activity. This study aimed at evaluating its mechanisms of neuroprotective effect against neurodegeneration, cognitive and synaptic dysfunctions in lipopolysaccharides‐induced Alzheimer‐like model in in mice.MethodsFollowing one‐week acclimatization, thirty‐five Swiss mice were distributed randomly into five groups (n = 7). Group I received vehicle (10mL/kg, p.o.), Group II (LPS) received vehicle (10mL/kg), Group III received TQ (15mg/kg), Group IV received TQ (30mg/kg, p.o) and Group V received donepezil (5mg/kg, p.o.) for seven days. Starting from day 8, sixty‐minutes after treatment with vehicle or TQ or donepezil, animals in groups II‐IV were daily injected with LPS (0.5mg/kg, i.p.) consecutively for seven days. Twenty‐four hours after the treatment on day fourteen of the study, Novel Object Recognition, (NORT), Y‐maze, were used to assess cognitive functions. Tumor necrosis factor‐α (TNF‐α), interlukin‐1β (IL‐1β), acetylcholinesterase (AChE) were assessed using ELISA techniques, microglia, amyloid‐beta, choline acetyltransferase (ChaT), synaptophysin, were quantified using immunohistochemistry, while, gene expression of interlukin‐10 and β‐secretase were measured with quantitative Polymerase Chain Reaction. Cox Golgi staining procedure was performed to evaluate morphology of the pyramidal dendrites.ResultsLPS significantly impaired performance in the Y‐maze and NORT and induced behavioural abnormalities, compared to control. These were all ameliorated by treatment with TQ (15‐30mg/kg). The TQ also significantly (P<0.05) reduced the concentration of LPS‐induced TNF‐α, IL‐1β, AChE and expressions of amyloid‐beta, microglia and β‐secretase/mRNA in hippocampus and prefrontal cortex. The TQ increased IL‐10/mRNA, ChaT, synaptophysin in hippocampus and PFC. TQ significantly (P<0.05) prevented neurodegeneration of dendrite and neuronal cells in the hippocampus of LPS‐treated mice.ConclusionOur study shows that thymoquinone possesses neuroprotective effect against LPS‐induced neurodegeneration and cognitive impairment by suppressing chronic neuroinflammation, cholinergic disruption, depleted synaptic protein and Aβ accumulation.