bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower LC activity during high arousal conditions is related to greater plasma P‐Tau217 concentration in older individuals
Authors: Prokopiou Prokopis C. , Van Egroo Maxime , Riphagen Joost M. , Ashton Nicholas J. , Janelidze Shorena , Sperling Reisa A. , Johnson Keith A. , Blennow Kaj , Hansson Oskar , Zetterberg Henrik , Jacobs Heidi I.L. 
Published: December 2023

AbstractBackgroundThe noradrenergic locus coeruleus (LC) nucleus is critical in regulating many brain functions and processes, including arousal and emotion. Autopsy studies suggested that the LC is one of the earliest regions harboring hyperphosphorylated tau. Previous imaging work demonstrated that lower novelty‐related LC activity correlates with tau deposition in the entorhinal cortex. Here, we investigated the variability in activity across the rostro‐caudal LC under different arousal levels and its relationship with plasma markers of phosphorylated tau, including p‐tau231, p‐tau217, and p‐tau181.Method61 individuals (age range = [51,85], Male = 30) underwent a task‐based 7T BOLD‐fMRI scan and fasting blood draw. The task consisted of 100 high‐ or low‐arousing context images. The fMRI data were preprocessed using a brainstem‐specific denoising methodology to increase the LC signal‐to‐noise ratio. P‐tau181 and p‐tau231 were measured using in‐house Simoa methods, and p‐tau217 using MSD immunoassay. Voxel‐wise linear model analyses were performed to detect brainstem regions exhibiting significant high>low arousal (h>l) activation. Average h>l contrast values across activated voxels within an ex‐vivo validated LC region of interest (ROI) were extracted, and age‐ and sex‐adjusted associations between LC activity and p‐tau were evaluated using robust linear regression. Similar associations were also investigated for a control ROI defined ventral to the LC.ResultWe observed greater h>l activation of voxels in the bilateral LC (p<0.05 uncorrected–Fig.1A). We observed no regional differences in h>l activity along the LC rostral‐caudal axis (Fig.1B). Post‐hoc Mann‐Kendall trend analyses revealed a negative‐to‐positive trend in h>l LC activity across caudal‐to‐rostral LC. Lower h>l LC activity was associated with greater p‐tau217 (p = 0.042–Fig.2A). No significant associations were observed between h>l LC activity and either p‐tau231 or p‐tau181 (p>0.05–Fig.2B‐C), or between h>l activity in the control ROI and any plasma marker (p>0.05–Fig.2D‐F).ConclusionOur results show that lower h>l LC activation is associated with greater concentrations in p‐tau217. As p‐tau217 has been shown to correlate with LC neuronal loss, cortical tau‐ and amyloid‐β‐PET measures, our results suggest that LC dysfunction in higher states of arousal may signal LC degeneration. Future work includes investigating the mediating role of amyloid‐β on the observed relationship between h>l LC activation and p‐tau217.
Systematic Comparison of Reproducibility of Diffusion MRI‐Derived Free‐Water Measures Across Two Multi‐Shell Protocols
Authors: Mishra Virendra R , Sreenivasan Karthik , Cordes Dietmar 
Published: December 2023

AbstractBackgroundFree‐water (FW) measures have been widely used to understand and predict the progression of various neurodegenerative disorders1,2. However, the estimation of FW in a brain voxel needs a multi‐shell acquisition to ensure reproducible fit3,4. With the availability of multi‐shell diffusion MRI (dMRI) protocol using simultaneous multislice technique from the Human Connectome Project (HCP) and Alzheimer’s Disease Neuroimaging Initiative (ADNI‐3), such protocols can now be harmonized across various centers and MRI vendors. However, limited knowledge exists on whether the results obtained for FW measures across HCP protocols are generalizable across ADNI‐3 protocols along with which protocol is more reproducible that will assist us in understanding the variability of FW measure in an individual participant longitudinally. Hence, in this study, we compared the reproducibility of FW across major white matter (WM) tracts across both HCP and ADNI‐3 protocols.MethodsA 32‐year‐old healthy male participant was scanned over five weeks, both with Basic (2mm3, b‐value = 1000s/mm2) and Advanced ADNI‐3 protocol and 2 variants of the HCP sequence (1.5mm3 and 2mm3) both with 3 b‐values (500s/mm2, 1000s/mm2, and 2500s/mm2) and 213 directions on a clinical 3T Skyra scanner. FW dMRI measures were obtained using the original Matlab implementation (Matlab)5 and DiPY implementation6 of multi‐shell dMRI acquisition (DiPY). WM atlas from Johns Hopkins University (JHU) of 20 major WM tracts pre‐registered to MNI152 was then used as a mask to obtain FW at each WM tract, and the coefficient of variance (CoV) was computed across each protocol. The total acquisition scan time was 75 minutes.ResultFW estimated using Matlab had a mean CoV = 2.78±1.09 across all the protocols with the least CoV for Basic ADNI‐3 (CoV = 1.31±0.54) and the maximum CoV for 2mm3 HCP sequence (CoV = 4.98±1.83) (Fig.1A) while FW estimated using DiPY had a mean CoV = 6.71±2.86 across all the protocols with the least CoV for Advanced ADNI‐3 (CoV = 4.31±1.85) and the maximum CoV for 2mm3 HCP sequence (CoV = 9.66±4.15) (Fig.1A).ConclusionBoth acquisition parameters and processing techniques significantly affect the absolute quantification of FW measures. Furthermore, our data suggest that the pooling of dMRI data across various protocols should be performed with caution.
Genetic heterogeneity of Alzheimer’s disease: Evidence for disease‐relevant and disease‐specific clustering
Authors: Elman Jeremy A. , Schork Nicholas J. , Rangan Aaditya V 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) demonstrates heterogeneity across domains of cognitive impairment, atrophy, and pathological accumulation. This has led to speculations that AD may comprise several disease subtypes. AD is under substantial genetic influence, thus searching for genetic clustering may provide insight towards the origins of this phenotypic variability.MethodGenotyping data from 2,739 AD cases and 5,478 age and sex‐matched controls from the UK Biobank were used as the discovery data. A principal components analysis (PCA) was applied to AD‐associated variants (p<0.05 in the IGAPS2 GWAS of AD) to assess disease‐relevant structure. A novel biclustering algorithm was then applied to find disease‐specific genetic signatures of AD. This algorithm searches for subsets of subjects and variants that are present in cases, but importantly, not in controls. Pathway analysis was used to characterize the biological pathways implicated by disease‐relevant and specific clustering. Data from 476 AD cases and 591 controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used to test replication of clusters.ResultPCA revealed 3 distinct clusters. Each cluster contained a mix of cases and controls but these clusters only became apparent when restricting to AD‐associated variants, suggesting disease‐relevant structure. Examining clusters separately, we found 2 significant disease‐specific biclusters comprising sets of variants found more frequently in a subset of AD cases than in controls. When projecting ADNI data on UK Biobank principal components, there was almost perfect overlap of disease‐relevant clusters. Disease‐specific biclusters significantly replicated (p<0.05) across a range of parameter choices.ConclusionThese findings demonstrate a hierarchy of heterogeneity for AD genetic risk. At the first level, the three disease‐relevant clusters may indicate that different pathways are more vulnerable for different groups of individuals, but additional risk factors or insults are required to substantially increase risk for AD. At the next level, individuals assigned to the biclusters may represent subtypes of AD with different genetic signatures that significantly increase risk for AD. Replication in ADNI demonstrates that this hierarchical structure is a generalizable aspect of AD genetic risk. More broadly, this study illustrates an approach that can be extended to investigate genetic heterogeneity of other complex diseases.
Associations of Neighborhood Disadvantage, Cardiometabolic Risk, and Cognition in a Community‐Dwelling Cohort
Authors: Krishnamurthy Sudarshan , Craft Suzanne , Bateman James R. , Lockhart Samuel N. 
Published: December 2023

AbstractBackgroundSocial determinants of health (SDoH) are important environmental factors in cardiometabolic risk and cognitive aging. Area Deprivation Index (ADI) is a measure of neighborhood‐level socioeconomic disadvantage and has been studied in normal cognition (NC), but relatively less is known about impact in those with mild cognitive impairment (MCI).MethodThis study explores, in participants with NC and MCI enrolled in the Wake Forest ADRC Clinical Core, baseline measures of metabolic risk (Oral Glucose Tolerance Testing of blood glucose 120‐minute post‐challenge; OGTT‐120), cognition (Preclinical Alzheimer’s Cognitive Composite; PACC), demographics (age, education, diagnosis, race, sex), and participant national ADI rank (using baseline home address). Consensus diagnosis of NC and MCI was adjudicated by a panel of experts.ResultDemographics of community‐dwelling adults enrolled as a convenience sample in the Wake Forest ADRC with metabolic and cognitive measures by cognitive status is listed in Table 1. MCI participants, compared with CN, were older, more likely male and white, with lower education and PACC, and higher ADI (higher = more disadvantaged). Significant differences in ADI were observed when participants were stratified by race (Figure 1); post‐hoc tests indicate significantly higher ADI in Black compared to white participants, and to some degree, by higher ADI among Black participants compared with Asian participants. OGTT‐120 in participants with NC (n = 265) and MCI (n = 156) was not significantly associated with ADI national rank (Figure 2A); when controlling for age, sex, education, and diagnosis, there was still no association between OGTT‐120 and ADI. Higher ADI was significantly associated with lower PACC scores in individuals with NC (p = 0.044), but not MCI (Figure 2B); this association remained significant (p = 0.004) independent of age, sex, education, and diagnosis (all covariates p<0.001).ConclusionAmong community‐dwelling older adults, ADI national rank differs by participant race. OGTT‐120 does not correlate with ADI in participants with NC or MCI. PACC scores correlate negatively with ADI national rank in participants with NC, but not MCI; this relationship remained when controlling for covariates. Further analyses are necessary to examine the association between cardiometabolic risk and ADI.
A model for direct support of people with rare dementias, their families and practitioners
Authors: Zimmermann Nikki , Wood Olivia K , Waddington Claire , Williams Millie van der Byl , Tapson Karen , O'Hara Trish , Harding Emma , Fox Nick C , Barker Suzie , Brotherhood Emilie V , Crutch Sebastian J 
Published: December 2023

AbstractRare Dementia Support (RDS) is a UK‐based collaborative service led by the UCL Dementia Research Centre, which aims to empower, guide and inform people living with a rare dementia diagnosis and those who care about them. RDS covers familial Alzheimer’s disease (FAD), frontotemporal dementia (FTD), familial frontotemporal dementia (fFTD), posterior cortical atrophy (PCA), primary progressive aphasia (PPA), Lewy body dementia (LBD) and young‐onset Alzheimer’s disease (YOAD). Following self‐referrals and clinical referrals from memory services and specialist neurology clinics across the UK, we provide one‐to‐one support and facilitate regular opportunities for members to meet each other and the team, through large and small support groups, themed programmes and regional support groups.We will describe the practices of the one‐to‐one Direct Support Team, which provides free information, advice and support from pre‐diagnosis navigation through to post‐bereavement support. This specialist emotional and practical support encompasses compassionate listening; solution focussed outcomes (to complement the diagnosis, treatment and monitoring); helping people to understand and adapt to their condition; empowering people to use their strengths to live fulfilled lives; designing strategies and interventions to manage complex situations (including issues of safeguarding, deprivation of liberty, etc); legal rights and financial support; and supporting transitions into later stages and end of life.We will also relate the practices of direct support to the broader principles of RDS as a whole (see Figure 1), including the implications of never discharging anyone from our service, and balancing person‐centred and disease‐specific approaches (the importance of knowing which disease each person has, and what person the disease has).An evaluation of the service will be presented, including characterisation of the current 4797 members, plus data from individual support consultations in 2022 (N = 1449) relating outcomes to personal (social connectedness, wellbeing, knowledge of condition and services), disease (diagnosis, severity) and service (support usage, intensity of discussion) factors.We will conclude by discussing existing examples of and new opportunities for partnership working – with local, national and international charities, clinical services, academic institutions and funding organisations – to improve access to specialist support for those with atypical, inherited and young onset dementias.
Applications of hybrid structure light three‐dimensional scanning in neurodegenerative disease autopsy brain banking
Authors: Barannikov Savannah , Keating Mallory , Seshadri Sudha , Bieniek Kevin F 
Published: December 2023

AbstractBackgroundPostmortem magnetic resonance imaging (MRI) and three‐dimensional (3D) printing has been demonstrated to be a feasible approach for the creation of tissue matrices to aid in postmortem brain dissection. We aimed to extend this approach using hybrid structure light technology (visible and infrared) 3D scanning to generate brain models as a digital resource and operational tool for human neurodegenerative disease brain banks.MethodA consecutive series of 56 brains accessioned into the Glenn Biggs Institute Brain Bank were imaged using an EinScan H handheld 3D scanner. Five brains were selected for generation of tissue matrices, with infratentorial structures removed using 3D object post‐processing software tools. Matrices were printed using a Raise3D Pro2 printer and 1.75‐mm polylactic acid premium filament.ResultEach scan was approximately an hour to complete, including capture and alignment of a lateral and a medial surface scan for each brain. Raw scan files (DAT and BRAP‐PRJ) averaged 5.47 GB and 3D object files were 12,991 KB for 3MF and 18,067 KB for OBJ file types. For cases with tissue matrices, average print time was 42 hours with an average filament consumption of 338 g. Brain cutting with the tissue matrices was performed in a standardized manner, with superb control for section thickness and planar orientation compared to brains cut without a matrix.Conclusion3D scanning of postmortem autopsied brains is a simple and useful strategy to generate models with utility in guided tissue sectioning and storage (practice), surface area volumetric analysis (research) and virtual reality/augmented reality neuroanatomy training (education) for Alzheimer’s disease and related dementias.
Inhibition of BMP signaling delays tauopathy and cognitive deficits in P301S mouse model
Authors: Affaneh Amira , Tunc‐Ozcan Elif , Peng Chian‐Yu , Kessler John A 
Published: December 2023

AbstractBackgroundAging is the highest risk factor for sporadic Alzheimer’s disease (AD). Expression of bone morphogenic protein 4 (BMP4) increases 10‐fold with age, while expression of the BMP antagonist, noggin, decreases. We have observed that activating BMP signaling in induced human neurons increased levels of phosphorylated tau. The increase of p‐tau has been correlated with the activated non‐canonical BMP pathway leading to p38 activity. We hypothesized that modulating BMP signaling in an AD mouse model of tau would rescue disease phenotype.MethodP301S (PS19) mice were injected with lentivirus overexpressing noggin (LV‐noggin) or lentivirus mcherry (LV‐mcherry) control in the dentate gyrus. Cognitive behavioral testing was run at 7 months of age and brain tissue was collected for protein and immunofluorescent imaging.ResultWe observe that levels of BMP4, as well as BMP signaling, are increased in the brains of PS19 mice compared to littermate wildtype mice. Analysis of noggin injected PS19 brains show downregulation of BMP signaling in the DG shown by decreased pSMAD1/5/8, as well as non‐canonical signaling through p38 kinase activity. Inhibition of BMP signaling through overexpression of noggin improves cognitive ability shown through Barnes maze testing. Downregulation of BMP signaling in P301S mice led to a decrease in tau phosphorylation seen both in immunoblotting, as well as immunocytochemical analysis in the DG.ConclusionPS19 model of tauopathy show increased levels of BMP signaling. We have shown that increased levels of BMP signaling lead to increased tau phosphorylation and reduced degradation of p‐tau. We show that by inhibiting BMP signaling in vivo we can delay cognitive behavioral deficits seen in these mice by decreasing tau phosphorylation. This suggests that the age‐related increase in BMP signaling may participate in the initiation and progression of AD pathology and help to explain why age is the largest risk factor for AD.
Fast accumulators of tau have higher levels of plasma pTau and stronger associations with amyloid in later Braak regions at baseline
Authors: Servaes Stijn , Tissot Cécile , Therriault Joseph , Lussier Firoza Z , Ashton Nicholas J. , Benedet Andrea Lessa , Karikari Thomas K , Wang Yi‐Ting , Stevenson Jenna , Rahmouni Nesrine , Stevenson Alyssa , Pallen Vanessa , Arias Jaime Fernandez , Macedo Arthur C. , Nazneen Tahnia , Hosseini Seyyed Ali , Triana‐Baltzer Gallen , Kolb Hartmuth C. , Pascoal Tharick A. , Gauthier Serge , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundAccumulation of tau neurofibrillary tangles in Alzheimer’s disease (AD) follows a stereotypical pattern, known as Braak staging. As individuals show different rates of tau accumulation, depending on their initial stage, this potentially biases drug effects on tau pathology over time. We hypothesized that amyloid would be a driving force behind tau deposition in later Braak regions for those that were at earlier stages of the disease.Method79 individuals (CU: 57, MCI: 21, AD: 1) were recruited from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort. All individuals underwent baseline and 2‐year follow‐up amyloid ([18F]AZD4694) and tau ([18F]MK6240) PET imaging, as well as baseline plasma pTau181, pTau217, and pTau231 assessments. Differences in standardized uptake value ratios between the two timepoints in Braak I‐IV were used to separate fast accumulators of tau from slow accumulators, using the standard deviation of a Young group (n = 13).Pearson R’s were calculated between tau deposition in Braak regions IV‐VI and the neocortical amyloid load at baseline, within both these groups. Furthermore, a voxelwise analysis was performed to identify specific regional differences in amyloid SUVR between slow and fast progressors, while correcting for age, sex, ApoE4 carriership, as well as the individual’s Braak stage. In addition, an independent t‐test was performed to compare the levels of each pTau species at baseline.ResultFast accumulators had stronger increases (p < 0.01) in tau accumulation in Braak region V and VI, compared to slower accumulators. Furthermore, the level of tau deposition in Braak region IV and V was positively associated (p < 0.01) with the amyloid load in the neocortex, but only in the fast accumulator group (figure 1). The voxelwise analysis confirmed that faster progressors had stronger associations with amyloid‐PET (figure 2). Furthermore, those who accumulated tau at a faster rate also had higher levels of plasma pTau at baseline (figure 3).ConclusionTau deposition in later Braak regions is associated with a higher amyloid load and increased values of pTau181, pTau217 and pTau231 at baseline in individuals in early Braak stages that accumulate tau at a more rapid rate.
Distinct CSF biomarker‐associated DNA methylation in Alzheimer’s disease and cognitively normal subjects
Authors: Wang Lily , Zhang Wei , Young Juan I. , Gomez Lissette , Schmidt Michael A. , Lukacsovich David , Varma Achintya , Chen Xi , Kunkle Brian W. , Martin Eden R. 
Published: December 2023

AbstractBackgroundGrowing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease and that DNAm differences can be detected in the blood of AD subjects. Because access to human brain tissues is primarily limited to postmortem samples, most studies have correlated blood DNAm with clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Thus, the association of blood DNAm with changes in AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis.MethodCSF biomarkers are well‐established AD endophenotypes and correlate significantly with neuropathology scores measured on postmortem brain samples. In this study, we performed a comprehensive analysis to identify blood DNA methylation associated with CSF pathological biomarkers for AD in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 cognitively normal, 79 AD cases).ResultWe identified a number of novel associations between blood DNAm and CSF Aβ42, pTau181, and total tau biomarkers, demonstrating that changes in various pathological processes in the CSF are also reflected in the blood epigenome. Overall, the CSF biomarker‐associated DNAm is relatively distinct in cognitively normal (CN) and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our pathway analysis of CSF biomarker associated‐DNAm from CN subjects revealed that biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood.ConclusionOur study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.