bluuebunny/crossref_metadata_2025_split huggingface dataset:
A synergistic association of diabetes and AD biomarkers on cognitive decline in persons without dementia?
Authors: van Gils Veerle , Jansen Willemijn J. , Hort Jakub , Martinez‐Lage Pablo , Ramakers Inez H.G.B. , Rouaud Olivier , Zetterberg Henrik , Dalsgaard Søren , Verhey Frans R.J. , Visser Pieter Jelle , Vos Stephanie J. B. , Consortium EMIF‐AD MBD , Consortium EPAD 
Published: December 2022

AbstractBackgroundTo improve prognostic procedures, we aimed to explore whether diabetes mellitus and Alzheimer’s disease (AD) biomarkers are synergistically associated with cognitive decline in persons without dementia.MethodWe included 1.737 persons with normal cognition (NC) and 634 with mild cognitive impairment (MCI) from 8 European memory clinic and aging cohorts as part of the PRIME project. We examined cognitive decline in MMSE (raw scores), memory (delayed recall), attention, executive functioning, and language domains (Z‐scores). AD biomarkers included CSF amyloid‐beta42 (data‐driven cut‐offs) or amyloid PET (center‐specific cut‐offs) as measure of amyloid positivity, CSF p‐tau as measure of tau tangle positivity and CSF t‐tau as measure of neurodegeneration (both center‐specific cut‐offs). We performed generalized linear mixed models with random intercepts and slopes, all adjusted for demographics.ResultMean age was 65.9 (SD=8.9) years, 54% were women, and diabetes was diagnosed in 7% of NC and 12% of MCI. Mean follow‐up time was 1.8 years (range 0.5‐8).In NC, we found decline in memory and attention in persons with both diabetes and t‐tau positivity. This was not shown in persons with only diabetes or only t‐tau positivity (Figure 1). We also found this interaction between diabetes and p‐tau on attention decline (Table 1). When stratifying for amyloid status, we found that this was only significant in amyloid negative individuals (memory t‐tau: p=0.005, attention p‐tau: p=0.033, attention t‐tau: p=0.039). A higher baseline language performance was found in persons with both diabetes and p‐tau or t‐tau positivity (p=0.011; p=0.034) compared to those with only diabetes or tau positivity. We found steeper decline in language in persons with both diabetes and amyloid positivity, compared to other groups (Figure 2). A similar synergism with diabetes was found for p‐tau. No interaction was found for executive functioning.In persons with MCI with both diabetes and t‐tau positivity, we found higher baseline MMSE scores (p=0.041) compared to other groups. Diabetes was not associated with cognitive decline in any domain in MCI.ConclusionDiabetes may affect non‐AD‐related decline in memory and attention as well as AD‐related decline in language at an early clinical stage. This may help improve prognostic procedures.
Five pathophysiological Alzheimer’s disease subtypes detected with unsupervised clustering of CSF proteomics
Authors: Tijms Betty M. , Wesenhagen Kirsten E. J. , Teunissen Charlotte E. , Scheltens Philip , Birkeland Even , Berven Frode , Visser Pieter Jelle 
Published: December 2022

AbstractBackgroundWe previously identified three CSF proteomic Alzheimer’s disease (AD) subtypes: one with increased amyloid metabolism and aberrant neuronal plasticity, one with innate immune activation and one with blood‐brain barrier dysfunction. We studied their replicability in another cohort, and whether increasing the number of proteins (from 556 to 1059) would enable detecting more subtypes.MethodWe selected 419 AD individuals with abnormal CSF abeta42 and 187 controls (normal cognition and normal AD biomarkers) from Alzheimer center Amsterdam studies. With 16‐plex TMT‐MS we detected 3987 proteins in CSF, of which we clustered 1059 proteins with complete observations that were associated with AD (all p<.05). Subtypes were compared on all 2906 proteins with at least 10 observations per subgroups. Potential upstream drivers of molecular subtypes were identified with ENRICHR.ResultWe found 5 subtypes with distinct protein profiles, of which three subtypes were highly concordant with our previously observed subtypes (figure1: subtype 1a, 2a and 2b) and two were new (1b and 1c). Compared to controls, subtype 1a, 1b and 1c had high levels of neuronal plasticity proteins, and subtype 2a and 2b had low levels of plasticity proteins. Thirty‐one proteins were increased in all subtypes (figure 2). Subtype 1a individuals (n=137, 32%) also showed increased amyloid processing. Their 827 proteins associated with REST and SUZ12 as potential upstream drivers. Subtype 1b individuals (n=124, 30%) also showed increased levels of inflammation proteins. Their 988 proteins converged on SOX2 as potential upstream driver. Subtype 1c individuals (n=24,6%), also showed proteasome dysfunction. Their 517 proteins were associated with TAF1 and MYC as potential upstream drivers. Subtype 2a individuals (n=78, 19%) showed increased levels of 469 proteins, of which 45% is expressed by the choroid plexus. These converged on NFE2L2. Subtype 2b individuals (n=56, 13%) showed high levels of 649 proteins that associated with blood‐brain barrier (BBB) leakage. These proteins converged on ERG1 and ESR1 as potential upstream drivers.ConclusionIn this new dataset we replicated three AD subtypes, and detected two new subtypes. Subtypes differed on plasticity proteins, immune activation, choroid plexus function and BBB function. Each AD subtypes may require a different treatment.
A multimodal pilot study of default mode network (DMN) connectivity across the lifespan in healthy volunteers using functional imaging, CSF, and plasma Alzheimer's disease biomarkers
Authors: Shapiro Noah L , Galler Jake A , Trombetta Bianca A. , LaCasse Kathryn , Ramirez Christopher E. , Riley Misha M. , Williams Victoria J. , Kivisäkk Pia , Salat David H , Rashid Barnaly , Arnold Steven E. 
Published: December 2022

AbstractBackgroundNormal aging is associated with decreased functional connectivity (FC) in the brain’s default mode network (DMN). Additionally, cerebral burden of both amyloid‐β (Aβ) and tau proteins further contribute to decreased DMN FC in the course of the normal aging process (Wales and Leung, 2021). However, the current literature is sparse and unclear as to the independent actions of Aβand tau on FC of DMN, with tau being associated with general hypoconnectivity (Wales and Leung, 2021). The current pilot study examines resting state fMRI (rsfMRI) data in conjunction with Alzheimer’s Amyloid/Tau/Neurodegeneration (ATN) biofluid biomarkers in healthy individuals, using the isthmus cingulate of the retrosplenial cortex as seed for FC analysis of the DMN.MethodrsfMRI scans are collected in the LifeSPAN Biobanking project [ongoing]. Scans are preprocessed utilizing standard FreeSurfer pipeline. Standard parcellations are assigned using the Desikan‐Killiany atlas. In initial analyses, isthmus cingulate served as the seed for DMN analysis using the FSFAST processing stream within FreeSurfer. ATN biomarkers are obtained from cerebrospinal fluid (CSF) and the following biomarker ratios were computed: Aβ42/Aβ40 (Aβ ratio) and phosphorylated tau‐181 (pTau181) / total Tau (tTau) (pTau181/tTau ratio).ResultIn the initial 14 participants (aged 26‐82 years) [Table 1], General Linear Models (GLMs), adjusted for age, were utilized to evaluate the associations between DMN FC and the following AD biomarkers: Aβ40, Aβ42, Aβ ratio, tTau, pTau181, and pTau181/tTau ratio [Table 2; Figure 1]. After correcting for multiple comparisons (p<0.05), significant association between tTau, and the FC between the DMN and the right inferior temporal region was observed [Table 3].ConclusionThe pilot analysis indicates at least tTau has an association with DMN FC, but sample size precludes conclusion or interpretation. Preliminary data obtained in this exploratory analysis provides a framework for examining the effect of AD biomarkers on the DMN and other functional networks. Future research will incorporate synaptic, inflammatory and other markers into similar statistical models and report preliminary associations.
Reference
Wales R, Leung H‐C. The Effects of Amyloid and Tau on Functional Network Connectivity in Older Populations. Brain. 2021;142(8):2483‐2491. doi:10.1093/brain/awz162
Novel peptide‐driven global proteomics platform to identify unique peptide profiles linked to Alzheimer’s disease
Authors: Saxena Satya , Devanarayan Viswanath , Ye Yuanqing , Reyderman Larisa , Koyama Akihiko , Sachdev Pallavi 
Published: December 2022

AbstractBackgroundThere is a growing need for new biomarker signature(s) to further improve the predictive values of currently used markers for Alzheimer’s disease (AD) staging, monitoring, and prognostic prediction of disease progression. Most AD biomarker discovery studies have not focused on peptide level alterations despite unquestionable importance of abnormal proteolysis in AD. Here we present a peptide‐focused unbiased global proteomics platform to identify unique peptide profiles associated with amyloid pathology in cognitively impaired subjects.MethodWe used the mass spectrometry (MS) data from a recently published multi‐cohort study (PRIDE archive PXD016278) using cerebrospinal fluid (CSF) from cognitively impaired AD (classified based on t‐tau > 400 ng/l, Aβ1–42 <550 ng/l and Aβ1–42/Aβ1–40 ratio <0.065) and non‐AD control participants. Data from the Sweden cohort was used for “discovery” and Magdeburg and Kiel cohort for “validation”. RAW MS files were analyzed using a novel platform integrating a de novo‐based workflow with comprehensive project‐specific hybrid spectral libraries to enable the identification of non‐tryptic and microbial peptides missed in traditional proteomics workflows. Raw intensities were quantile normalized and log transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, at 20% false discovery rate.Result1199 peptides identified as significant for amyloid positivity in discovery cohort were confirmed in an independent validation cohort. Most of the confirmed peptides demonstrate strong separation of amyloid (+) and amyloid (‐) subjects; 270 out of 1199 peptides had area under receiver operating characteristic curve (ROC‐AUC) over 90%, and 975 peptides had ROC‐AUC over 80%. Interestingly, 64.4% of CSF proteins identified as significant for amyloid positivity were altered only at the peptide‐level, including recently reported markers of AD progression such as VGF and PTPRN, underscoring the importance of tracking peptide‐based alterations in biomarker discovery.ConclusionOur unbiased peptide‐focused global proteomics platform has yielded a unique profile of over 1000 novel peptide signatures linked to amyloid pathology. Further evaluation is ongoing to study the pathways and interactions associated with these unique peptide profiles, and their potential utility for disease staging, monitoring, and progression.
Normative data for the Digit Symbol Substitution Test for diverse Hispanic/Latino adults: Results from the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Paredes Alejandra Morlett , Tarraf Wassim , Gonzalez Kevin A , Stickel Ariana M , Graves Lisa V. , Salmon David P. , Kaur Sonya , Gallo Linda C , Isasi Carmen R , Lipton Richard B. , Lamar Melissa , Goodman Zachary T , Zeng Donglin , Garcia Tanya P , González Hector M 
Published: December 2022

AbstractBackgroundNeuropsychological assessment plays an important role in identifying mild cognitive impairment and dementia; demographically appropriate norms are essential for interpreting test performance and maximizing diagnostic accuracy. Limited availability of normative data for cognitive tests administered to older Hispanic/Latino adults can lead to diagnostic error. Executive functioning and information processing speed are crucial elements of neuropsychological assessment. To meet the needs of the Hispanic/Latino population, we investigated the associations of age, education, ethnic background, gender, and language on the Digit Symbol Substitution (DSS) test – a subtest of the WAIS‐R – and to provide demographically adjusted norms for a diverse group of Hispanics/Latinos.MethodThe target population for the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA; 2015–2018) included individuals from Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American backgrounds (n = 6,172). Average age was 63.4±8.3 years, 54.5% were female, and mean education was 11.0±4.6 years. The DSS was administered as part of a larger cognitive protocol in participants’ preferred language (English or Spanish). Lower scores on the DSS are associated with slower processing speed. Demographic adjusted DSS scores, and percentile cut‐points were created using survey‐adjusted regression and quantile regression models.ResultIn covaried regression models, each year increase in age was associated with B = ‐0.54 (p<0.001) units decrease in DSS scores, and each additional year of education with B = 1.42 (p<0.001) units increase in performance. Males had, on average, lower DSS scores than females (B = ‐2.41; p<0.001), and individuals with English as their preferred language performed better than those preferring Spanish (B = 6.18; p<0.001). DSS performance varied significantly by Hispanic/Latino background with, predominantly, Mexicans scoring highest and Dominicans lowest on the DSS.ConclusionWhile other norms for Hispanic/Latino populations exist, results from this study represent the largest and only norms for Hispanic/Latinos living in the US. Representative DSS test norms for diverse groups of US‐based Hispanics/Latinos will advance cognitive assessment and the accuracy of neurocognitive disorder diagnosis in this country. We have developed an online dashboard to facilitate potential clinical use and interpretation (https://solincalab.shinyapps.io/DSST/)
Disentangling selective vulnerability underlying sleep disfunction in neurodegenerative diseases: differential gene expression in neuromodulatory subcortical system in Alzheimer’s disease vs. Progressive supranuclear palsy vs. controls
Authors: Satpati Abhijit , Pereira Felipe Luiz , Mladinov Mihovil , Seeley William W. , Spina Salvatore , Neylan Thomas C. , Walsh Christine M , Grinberg Lea Tenenholz 
Published: December 2022

AbstractBackgroundSleep‐wake disturbance precedes the prodromal stage of Alzheimer’s disease (AD) and is characterized by excessive daytime sleepiness and sundowning. In contrast, hyper‐insomnia is seen in progressive supranuclear palsy (PSP), a pure 4‐repeat tauopathy. The wake‐promoting histaminergic (HA) neurons of the tuberomamillary nucleus (TMN) together with the orexinergic (OX) neurons of the lateral hypothalamic area (LHA) modulate the sleep‐wake cycle. Previously, we reported wake‐promoting nucleus (WPNs) are selectively vulnerable to AD‐tau toxicity than PSP, and neuronal loss in TMN is specific to AD. In the present study, we investigated changes in RNA expression in the TMN and LHA to understand the selective vulnerability of WPNs in AD at the molecular level.MethodLHA and TMN were dissected from serial histological sections from the postmortem brains of AD, PSP, and healthy control (HC) subjects. 50ng total RNA was extracted using RNeasy Micro Kit, and RNA integrity was accessed using Nanodrop. Cases with RIN > 5 were included for RNA sequencing. The nCounter Neuropathology panel and nSolver software (NanoString Technologies) was employed to obtain and analyze the data.ResultMolecular profiling of TMN in AD demonstrated 13 upregulated genes associated with angiogenesis, apoptosis, chromatin modification, disease‐association, and transcription factor, and 12 genes in PSP. The proto‐oncogene RELA, RNA binding protein FUS and oligodendrocyte specific NKX6‐2 genes were upregulated in AD and PSP. Further, in the LHA, we identified 17 differentially expressed genes associated with circadian rhythm, inflammatory cytokines, apoptosis, autophagy, and angiogenesis in AD over HC and 72 genes in PSP over HC. Both IL4 and CRY2 genes demonstrated downregulation in the AD and PSP.ConclusionDifferential gene expression in the WPNs revealed a significant upregulation of genes associated with pro‐inflammatory cytokines, activated microglia, apoptosis, oxidative stress, and autophagy in AD over PSP. The neuromodulatory subcortical system shows different vulnerability patterns in AD vs. PSP making it an excellent candidate to interrogate the molecular bases of vulnerability.
Potential Savings in Caregiver Time and Societal Costs Associated with Slowing Disease Progression over 36 months in Patients with Early Alzheimer’s Disease: Findings from GERAS‐US
Authors: Chandler Julie , Ye Wenyu , Johnston Joseph , Mi Xiaojuan , Doty Erin 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is associated with significant costs that increase with disease progression. These analyses describe the relationship between cognitive decline and measures of caregiver time and societal costs and estimate the impact of slowing disease progression over 36 months.MethodsAmyloid positive patients with mild cognitive impairment (MCI) and mild AD dementia (MILD) from the GERAS‐US study1 were included. Assessments included: Mini Mental State Examination (MMSE‐ cognition); Resource Utilization in Dementia (RUD‐ caregiver time, societal costs). The generalized linear model (GLM) with normal distribution was performed for caregiver time and with log link and gamma distribution for total societal cost. The associated outcome savings over 36 months were calculated based on least squares mean change (LSMC) in MMSE and coefficient of MMSE change from baseline to month 36.ResultsTable 1 shows baseline characteristics of 617 patients (300 MCI, 317 MILD, 47.3% male) with a mean (SD) age of 71.0 (7.8) years. MILD vs. MCI patients had greater cognitive impairment, higher caregiver time, and higher monthly societal cost. Over 36 months, MILD patients had significantly greater disease progression compared to MCI (MMSE LSMC 4.1 vs. 2.1). A 2.1‐point worsening in MMSE over 36 months for MCI was associated with an increase of 35.7 hours in total caregiver time and an increase of $8,084 per patient in total societal costs (Table 3). Delaying progression by 20% ‐30% could lead to a savings 7.2 to 10.7 hours for caregiver time and $1,675 to $2,502 in total societal costs. For MILD, a 4.1‐point worsening in MMSE was associated with an increase of 77.3 hours in total caregiver time and $12,807 per patient in total societal costs. Delaying progression by 20%‐30% could save 15.5 to 23.2 hours in caregiver time and $2,665 to $ 3,978 in total societal cost.ConclusionCaregiver time and total societal costs are higher in MILD than in MCI; caregiver time increases over 3 years for both MCI and Mild. Treatments that slow cognitive decline have the potential to keep patients in earlier disease stages longer with a resulting savings in caregiver time and societal cost. 1J Alzheimers Dis. 2019;72(1):279‐292
Hippocampal volume mediates the association between depression and cognitive function differently by sex
Authors: Ortega Nancy E , Aslanyan Vahan , Pa Judy 
Published: December 2022

AbstractBackgroundSex differences are prominent features of both depression and Alzheimer’s disease, with women showing an increased lifetime risk relative to men. However, the neural mechanisms that explain sex differences in the relationship between depression and cognition are poorly understood. The goal of this study was to evaluate whether smaller brain volumes mediate the relationship between higher depression symptom severity and poorer cognition, and whether this association differed by sex.MethodUK Biobank participants were included in the sample based on availability of demographic variables, mental health assessments, structural MRI scans, and four cognitive measures (Fluid Intelligence, Numeric Function, Pairs Matching, and Symbol Digit Substitution). Depression symptom severity was evaluated using the Patient Health Questionnaire (PHQ‐9). The indirect effect of depression symptom severity on cognition via hippocampal volumes was evaluated using causal mediation analyses. Models were adjusted for age, sex, APOE‐e4 status, and Townsend Deprivation Index, a measure of material deprivation (Fig.1). A priori sex‐stratified models evaluated sex differences. Exploratory analyses assessed the indirect effect of depressive symptom severity on cognition with amygdalar and total brain volumes as separate mediators. The significance of indirect effects was evaluated using bootstrapping procedures.ResultThe study sample consisted of 39,692 middle‐aged and older adults (53% women, mean age±SD = 64.1±7.6 years, 28% APOE‐e4 carriers). Hippocampal and amygdalar volumes mediated the effect of depression symptom severity on cognition, for Fluid Intelligence, Numeric Function, and Symbol Digit Substitution, but not Pairs Matching. Total brain volume mediated the effect of depression symptom severity on Symbol Digit Substitution performance (Fig.1, Table1). In sex‐stratified analyses, the effect of depression symptom severity on Fluid Intelligence, Numeric Function, and Symbol Digit Substitution was mediated by hippocampal and amygdalar volumes in women. In men, the effect of depression symptom severity on Symbol Digit Substitution was mediated by total brain volume (Table2).ConclusionDepression symptom severity influences cognition via hippocampal and amygdalar volumes in women, while in men, total brain volume mediated the relationship with cognition. These data suggest sex‐specific neural pathways for the relationship between depression and cognition.