bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Viruses Detected in Human DNA are Associated with Alzheimer Disease Risk
Authors: Tejeda Marlene , Farrell John , Zhu Congcong , Wetzler Lee , Lunetta Kathryn L. , Bush William S. , Martin Eden R , Wang Li‐San , Schellenberg Gerard D. , Pericak‐Vance Margaret A. , Haines Jonathan L. , Farrer Lindsay A. , Sherva Richard 
Published: December 2022

AbstractBackgroundMultiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer disease (AD) by independent lines of evidence.MethodWe mapped and quantified DNA sequence reads from whole exome and whole genome sequencing data in 37,000 AD cases and controls from of the Alzheimer Disease Sequencing Project that did not align to the human genome to 318 viral reference sequences. After quality control, the sample included 1,696 samples derived from brain (cases=1,314, controls=382) and 14,588 derived from blood (cases=5,813, controls=8,775). We tested individual and cumulative normalized viral read counts, both free and inserted in the host genome, for association with AD using multiple machine learning (ML) classifiers, selecting the top 27 viral species according to an algorithm based on the species’ predictive rank weighted by the model’s overall predictive accuracy across models. These top 27 viruses were tested for association with AD using logistic regression models adjusted for PCR amplification, sequencing site, sex, APOE genotype, and ancestry. Analyses were stratified by tissue source.ResultWe detected sequence reads from 175 unique viral species, herpes simplex virus 1 (HSV‐1) being the most common. Viral read counts varied significantly by sequence center, tissue source, sex, PCR use, and ancestry in both the WES and WGS datasets. ML results indicated that herpes viruses (1, 2, 4, 5, 6A, 6B, 7, and 8), HIV, Hepatitis C, Molluscum contagiosum, several Torque Teno virus species (TTV), HPV‐71, Coronavirus 229E, Tick‐borne encephalitis, human Mastedenovirus, human polyomavirus 2, variola virus, primate t‐lymphotropic virus 1, human endogenous retrovirus K, and total normalized mapped viral reads were significant predictors of AD. Subsequent meta‐analyses of results stratified by tissue source showed that AD was significantly associated with HSV‐1(OR=4.07, P=2.22x10‐5), Human papillomavirus type 71(OR=3.26, P=0.006), TTV‐10 (OR=22.11, P=0.004) , and cumulative viral read count (OR=7.34, P=0.03). After multiple testing correction, HSV‐1 remains significant.ConclusionThese results support the hypothesis that viral infections, especially HSV‐1, is associated with AD risk and demonstrate the potential of using deep sequencing technology to detect microbial agents in multiple tissues and discerning here‐to‐for unrecognized associations of infectious agents and AD.
Factors Associated to Progression of Hippocampal Sclerosis: Contribution of a New Staging System
Authors: Heras Alicia Uceda , Villalón Diego , Zea Marian , López Mª José , Rabano Alberto 
Published: December 2022

AbstractBackgroundHippocampal sclerosis (HS) is a neuropathological condition with 5% to 30% of prevalence in the elderly (Nelson et al., 2013). HS is mostly associated with TDP‐43 proteinopathy, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (Nelson et al., 2019), and usually coexists with other neurodegenerative disorders like Alzheimer´s (AD) and Lewy body disease (LBD). LATE is a progressive pathology that may combine with HS (LATE_HS+) in its advanced phases. We have developed a staging scheme for HS with a high correlation with TDP‐43 staging. Here we analyze the contribution of this classification system to understand the progression of HS in the context of focal TDP‐43 pathology in the medial temporal lobe (MTL).MethodA full postmortem neuropathological study was performed in 161 brains from a clinicopathological cohort of institutionalized dementia patients (Vallecas Alzheimer’s Center Study) (age at death = 87.4±6.6, sex ratio = 79% females) with a predominant primary diagnosis of AD (77.4%), followed by vascular dementia (11%) and LBD (7.3%), and a high prevalence of comorbid pathologies (TDP‐43 and various tauopathies). Four stages (1‐4) of HS, including early phases (pre‐HS), were applied based on histologic criteria. Demographic, clinical, and neuropathological variables showing correlation with HS stages were analyzed through factorial analysis.ResultSome stage of HS was present in 71.1% of patients, and 24% of them displayed an early HS stage. TDP‐43 inclusions were detected in 67.5% of the patients. Variables associated to HS stages were grouped in 4 factors. While age at death, survival time and MTL atrophy, grouped together (factor 1) explained 23% of total co‐variability, other factors included Braak tau and NIA‐B stages (20%) or alpha‐synuclein stages‐HS stages (4.5%). Interestingly, HS and TDP‐43 stages were also included in factor 1 and seggregated together into a further single factor (18%) as well.ConclusionOur staging scheme for hippocampal sclerosis identifies patients with LATE in early stages of HS, and suggests a complex interaction of factors involved in conversion of LATE_HS‐ to LATE_HS+. While TDP‐43 stages, age, survival time and atrophy stay closer to HS in the explanation of variability, Alzheimer’s tau and Lewy body pathologies appear as secondary co‐factors.
Bilingualism Appears to be Protective Against Cognitive Decline Related to Cerebral Tau in Mexican Americans: An HABS‐HD Study
Authors: Petersen Melissa , Hall James , Johnson Leigh , Braskie Meredith N , Yaffe Kristine , Rissman Robert A. , Toga Arthur W. , O'Bryant Sid E. ,   Health and Aging Brain Study‐ Health Disparities (HABS‐HD) Study Team
Published: December 2022

AbstractBackgroundBilingualism is thought to provide protective effects from neurodegeneration and age‐related diseases such as Alzheimer’s Disease (AD). The protective effect is considered to be due to differences in grey and white matter between monolingual and bilinguals; however, no work to date has looked at differences in additional AD brain pathology. The aim of this study was to examine among Mexican Americans the impact of cerebral tau levels on cognitive functioning stratified by language status.MethodData were analyzed on a combined sample of n=44 Mexican American (n=15 Monolingual [n=9 Cognitively Normal; n=6 Cognitively Impaired {Mild Cognitive Impairment/Dementia}]; n=29 Bilingual [n=19 Cognitively Normal; n=10 Cognitively Impaired]) participants. One outlier case (Cognitively Impaired, Monolingual participant) was removed from subsequent analyses. All participants underwent cognitive testing and PET tau imaging using Siemens Biograph Vision 450 PET/CT scanner with PI‐2620. PET scans were co‐registered with 3T MRI scans (Siemens Vida). PET tau scans were processed using FreeSurfer‐defined regions of interest (ROIs) focused on the medial temporal lobe (average across entorhinal, hippocampus and amygdala), posterior cingulate cortex (isthmus cingulate and posterior cingulate) and lateral parietal cortex (inferior parietal, superior parietal and supramarginal). Linear regression models were generated for each language status group (monolingual, bilingual) examining the impact of each ROI on cognitive outcomes covarying for age, sex, and education.ResultAmong monolingual Mexican Americans, higher Medial Temporal SUVR was significantly related to poorer performance across measures of global cognition (MMSE p<0.001), processing speed (DSST p=0.038), episodic learning and memory (WMS‐III LM I p<0.001; WMS‐III LM II p<0.001) as well as rote verbal learning (SEVLT Immediate Recall p=0.004). Posterior Cingulate and Lateral Parietal SUVRs were not found to be significantly related to cognitive functioning among monolinguals. Additionally, among bilinguals, cerebral tau (derived from select ROIs) was not found to be significantly related to cognition.ConclusionHigher cerebral tau, specifically in the Medial Temporal ROI, was found to be related to poorer cognitive functioning across multiple domains but only among those who were monolingual. Results provide further support for the protective effect of bilingualism.
Unexpected Findings from 8,205 Brain Magnetic Resonance Imaging Examinations of Research Volunteers ≥ 40 years old
Authors: Rowley Howard A. , Rowley Paul A , Field Aaron S , Johnson Sterling C. , Carlsson Cynthia M. , Asthana Sanjay , Chin Nathaniel A. , Bendlin Barbara B. , Okonkwo Ozioma C. 
Published: December 2022

AbstractBackgroundBrain MRI is used routinely to study morphology in normal aging and dementia. Expert image review for clinically significant findings varies across sites and best practice is unsettled. We describe unexpected findings from 8,205 research brain MRIs from adults 40 years and older, comparing neuroradiologist presumptive diagnoses versus lesions flagged as concerning by scanning staff.MethodN=8,205 consecutive brain MRIs were prospectively reviewed by neuroradiologists from April 2002 to March 2020 under an IRB directive intended to identify clinically relevant unexpected findings. The final study population (M= 3,625, F= 4,580; ages 40–94 years (y); median 62 y) included normal volunteers and subjects with known diagnoses. Neuroradiologists detailed their findings using a structured reporting form, using only the scans included for research purposes. Scans were categorized normal, abnormal without follow‐up recommended, or abnormal with follow‐up recommended. Only the last category was considered to have a clinically relevant, unexpected abnormality and was referred for notification. Scanning staff and research personnel were also instructed to document concerns they noticed at the time of scanning, a common screening approach at other sites, usually followed by referral for expert reading. Scans were subcategorized and compared by presumptive abnormality type, both for the neuroradiologists and scanning staff.ResultUnexpected findings of potential clinical significance were discovered by neuroradiologists in 442/8,205 (5.4%) research volunteers ≥40 years. The most common abnormalities prompting follow‐up were vascular (204/439 (46%)), neoplastic (117/439 (27%), and inflammatory lesions (35/439 (8%)). Fewer than 2% of these 442 concerning abnormalities were prospectively reported by scanning staff, who most commonly flagged normal anatomic variants for further review.ConclusionFive percent of research volunteers ≥40 years who undergo brain MRIs have an unexpected, potentially clinically significant finding reported by a neuroradiologist. Very few relevant abnormalities are detected using spontaneous reports by scanning staff. This result could be predicted based on personnel training and roles in research protocols. Our results clarify how often significant abnormalities may be missed if scans are not formally interpreted. Ideally, neuroradiologist review should be included in aging research protocols using brain MRI.
Investigating the functional significance of presynaptic tau in ageing and disease
Authors: Groves Emily E , Sung Katherine , Flores‐Dominguez Diana , Pollack Saskia J , Croft Cara L , Golde Todd E , Hanger Diane P , McAdam Robyn , Giese Karl Peter , Noble Wendy 
Published: December 2022

AbstractBackgroundSynaptic dysfunction is an early pathological feature of neurodegenerative disease and is a close correlate of cognitive decline. Modified tau mislocalises to the synaptic compartment in disease, where some forms of tau interact with synaptic proteins and disrupt synapse function. This study seeks to further explore synaptic tau accumulation, and the impact on synaptic health and tau release, during ageing and tauopathy progression.MethodPost‐mortem Brodmann area 9 (BA9) pre‐frontal cortex from control or Braak stage I‐VI tissues were obtained. Formalin‐fixed paraffin‐embedded sections were subject to immunohistochemistry. Total lysates, cytosolic and synaptoneurosome fractions were isolated for western blotting, imaging and analysis of synaptic protein interactions.Organotypic brain slice cultures were prepared from P9‐10 wild‐type mice and Tau35 mice in which a disease‐associated tau fragment is expressed. In addition, some wild‐type slices were transduced with AAV2/TM8‐WT‐htau0N4R‐EGFP (WT) or AAV2/TM8‐P301L/S320F‐htau0N4R‐EGFP. Slices were cultured for 21‐28 DIV. Total lysate, cytosolic, and synaptoneurosome fractions were isolated for western blot, immunocytochemistry, or immunoprecipitation. Culture medium was used for tau sandwich ELISA.ResultWe observed progressive neurodegenerative changes, including the accumulation of sarkosyl‐insoluble tau, in organotypic brain slices expressing Tau35 and mutant (AAV‐expressed) human tau. Mislocalisation of phosphorylated and aggregated tau to the synaptic fraction in the tauopathy slice models mirrors, at least in part, changes observed in postmortem AD brain. Tau mislocalisation was associated with significant loss of specific pre‐synaptic proteins in Tau35 mice and AD brain. Mutant AAV‐expressed tau, but not WT AAV‐expressed tau, interacts with specific presynaptic vesicle proteins. Furthermore, alterations in basal tau release from slices was observed when disease‐like tau was expressed.ConclusionSlice cultures from mice in which disease‐associated tau is expressed at physiological levels (Tau35) or in which mutant tau is virally induced recapitulate key elements of human tauopathy. These long‐term brain slice cultures allow sensitive characterisation of presynaptic alterations that occur early in tauopathy. These models are now being used to determine if interactions between tau and pre‐synaptic proteins are essential for tau‐mediated synaptic dysfunction and/or tau release.
Comparison of plasma amyloid, tau, and astrocyte biomarkers to identify AD pathophysiology
Authors: Ferreira Pamela C.L. , Tissot Cécile , Ferrari‐Souza João Pedro , Bellaver Bruna , Brum Wagner S. , Leffa Douglas Teixeira , Therriault Joseph , Benedet Andréa Lessa , Servaes Stijn , Lussier Firoza Z , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Tudorascu Dana L , Klunk William E , Villemagne Victor L , Cohen Ann D , Zimmer Eduardo R. , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A 
Published: December 2022

AbstractBackgroundAlthough it has been alredy demonstrated that plasma amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillar protein (GFAP) can predict with high accuracy Alzheimer's disease (AD) pathophysiology, no previous study has compared their performance in the same set of individuals. Here, we compare the performance of plasma Aβ42/40, p‐tau, GFAP, and NfL against Aβ and tau PET across the AD spectrum.MethodWe used the ROC curve to test the predictive performance of Simoa plasma Aβ42/40, p‐tau (at threonine 181 and 231), NfL, and GFAP to identify Aβ and Pau PET positivity in 138 cognitive unimpaired (CU) and 87 cognitive impaired (CI) from the McGill TRIAD cohort. Pearson correlation and linear regression tested the association between markers.ResultWe showed that plasma p‐tau231, p‐tau181, GFAP, and NfL correlated with each other (Figure 1), while Aβ42/40 did not. In CU, voxel‐wise linear regressions (Figure 2A) showed that p‐tau231, p‐tau181, and GFAP concentrations were significantly associated with Aβ‐PET (Figure 2A). While for Tau‐PET (Figure 2B), there was a significant association only with p‐tau231 and p‐tau181 (Figure 2B). P‐tau231 outperformed the other plasma biomarkers to identify both Aβ‐ and Tau‐PET positivity (AUC 0.877 and 0.796, respectively) in CU individuals. In CI, Aβ‐ and Tau‐PET were significantly associated with p‐tau231, p‐tau181, and GFAP, whereas NfL was only associated with Tau‐PET. The discriminative accuracy of GFAP in identifying both Aβ‐PET and Tau positivity (AUC 0.936 and 0.944, respectively) outperformed the other plasma biomarkers in CI individuals (Figure 3, Table 1).ConclusionWe showed that plasma p‐tau231, a novel biomarker of early AD, best depicted AD pathophysiology in CU individuals. Interestingly, GFAP, an astrocyte reactivity marker, was better associated with brain Aβ and tau pathologies than plasma p‐tau and Aβ markers in CI individuals. Our results highlight that the performance of the novel plasma biomarkers of amyloid, tau and neuroinflammation to detect brain AD pathophysiology is disease stage specific.
Longitudinal genetic and environmental relationships between structural‐ and diffusion‐based Alzheimer’s disease neuroimaging signatures
Authors: Williams McKenna E. , Gillespie Nathan A. , Bell Tyler Reed , Dale Anders M. , Elman Jeremy A. , Eyler Lisa T. , Fennema‐Notestine Christine , Franz Carol E , Hagler Donald J. , Lyons Michael J. , McEvoy Linda K. , Neale Michael C. , Panizzon Matthew S. , Reynolds Chandra A. , Sanderson‐Cimino Mark E. , Kremen William S. 
Published: December 2022

AbstractBackgroundComposite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures,' are tools developed to identify brain changes specific to mild AD. In recent work from our group, we found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s aided prediction of 12‐year progression to MCI beyond age and polygenic risk for AD. Results held up after accounting for general brain age. In contrast, a cortical thickness/hippocampal volume‐based signature did not improve prediction. Given the importance of genetic influences on brain structure and AD, here we examined the phenotypic and genetic relationships among diffusion and structural AD signatures and brain age, and how those relationships change across midlife and early old age.MethodOur validated thickness/volume signature, novel MD signature, and a validated brain age measure were used in biometrical twin analyses to examine phenotypic, genetic, and environmental relationships both cross‐sectionally and longitudinally across 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA; baseline age=56.1, SD=2.6, range=51.1‐60.2). Subsequent waves were at approximately 5.7‐year intervals.ResultBoth AD signatures and brain age are heritable (56%‐72%), but each signature captured unique phenotypic and genetic variance that is also not explained by general brain aging. Genetic correlations across time within each signature were high (0.77‐0.98). Baseline MD signatures (age=56 years) predicted thickness/volume signatures over a decade later (r= ‐0.53, 95% CI: ‐0.62, ‐0.42), but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures (r= ‐0.13, 95% CI: ‐0.24, ‐0.01). Interestingly, by wave 2 (average age=62 years), the thickness/volume signature appears to have caught up with the MD signature in terms of predictive ability.ConclusionFindings lend further support to the idea that a signature based on brain microstructure captures very early AD‐related changes that are later reflected in the macrostructural signature. This MD signature explains substantial genetic variance that is consistent throughout midlife and into early old age, supporting the utility of the MD signature as a very early AD‐related neuroimaging biomarker and its potential role in clinical trials.
Plasma biomarkers contribution to the structural alteration of perivascular spaces in Alzheimer’s disease
Authors: Sibilia Francesca , Sheikh‐Bahaei Nasim , Mack Wendy J , Choupan Jeiran 
Published: December 2022

AbstractBackgroundPerivascular spaces (PVSs) are fluid‐filled spaces in the brain surrounding blood vessels. Their function is to facilitate the cerebrospinal fluid (CSF) drainage between the interstitial space and the blood vessel space, allowing the outflow of waste soluble proteins in the brain. Aging leads to the increase of PVS number and volume, especially in basal ganglia and centrum semiovale. Stress was found to alter the cerebral flow of metabolites in the brain and to accelerate Aβ accumulation. High level of cortisol causes hypertension, contributing to increase of blood pressure. Angiotensin‐II raises arterial blood pressure quickly, and its production is associated to levels of Angiotensin‐converting enzyme (ACE). This study objective is to investigate the relationship between plasma biomarkers and the PVS volume fraction, and their effect on cognitive impairment process.MethodOlder adults from the ADNI‐1 population (n=108, age range= 56‐89 years old, http://adni.loni.usc.edu), were divided into healthy control, mild cognitive impairment (MCI) and Alzheimer’s (AD) patients. MRI T1w images were acquired at 3T for all participants. PVS volume fraction was obtained by using parcellation and quantitation within white matter volume at global and regional levels. Linear regressions were run considering PVS volume fraction as dependent variable, calculated both in the total white matter and in the basal ganglia. Levels of cortisol, ACE and matrix metallo‐proteinases (MMPs) 2 and 9 were treated as independent variables. Pulse, age, sex, apolipoprotein E4, and diagnosis were included as covariates.ResultA main effect of MMP‐9 was seen on the PVS of the total white matter (p=0.046), with the covariates age and diagnosis showing a significant effect. Mediation analyses showed that diagnosis was the factor leading such relationship (p<0.05). PVS in the basal ganglia had a trend of being significantly associated to decreases of MMP‐2 (p=0.052). No significant effect was seen between PVS and cortisol, nor ACE.ConclusionThis study shows for the first time that there is a significant relationship between higher levels of MMP‐9 and alterations in PVS, when considering the cognitive impairment in older adults. This confirms previous findings that associated increase levels of MMP‐9 to faster Aβ accumulation.