bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel type of amyloid‐beta plaques discovered in early‐onset AD patients
Authors: Boon Baayla D.C. 
Published: December 2020

AbstractBackgroundThe clinical presentation of Alzheimer’s disease (AD), including age at onset, is remarkably heterogeneous. Besides clinical heterogeneity, we recognize distinct Aβ deposits in AD pathology. These deposits are called plaques when located in brain parenchyma or cerebral amyloid angiopathy (CAA) when located in cerebral vessels. Recently, we described a novel Aβ plaque‐type, referred to as ‘the coarse‐grained plaque’. In this study, we evaluate its clinical relevance and perform in‐depth morphological characterization.MethodThe coarse‐grained plaque’s presence was investigated in the frontal cortex of Aβ‐pathology‐positive cases (N = 74), including non‐demented controls (n = 15), early‐onset (EO)AD (n = 38), and late‐onset (LO)AD (n = 21), using a semi‐quantitative approach. Main plaque characteristics were compared to other well‐defined Aβ deposits; the classic cored plaque, the cotton wool plaque, and CAA. In‐depth characterization was done by studying the coarse‐grained plaque’s Aβ isoform (Aβ40, Aβ42, AβN3pE, and pSer8Aβ) composition, neuroinflammatory component, and vascular association using immunohistochemistry and 3D confocal laser scanning microscopy imaging.ResultThe plaque was only observed in cases with clinical symptoms, it was more prominent in EOAD (95%) than in LOAD (66%) and was associated with a homozygous ApoE4 status (Figure 1). The coarse‐grained plaque showed a multi‐cored Aβ morphology and was seen in the proximity of CAA‐affected sulci. Its predominant Aβ40 composition was distinct from other plaques, but showed similarities to that of CAA (Figure 2A). 3D imaging revealed a unique hollow Aβ40‐shell structure (Figure 2B) with microglia in Aβ‐devoid holes (Figure 3). Furthermore, the plaque’s immunoreactivity for the CAA‐Type 1 specific marker norrin suggests – although having a different morphology ‐ a close etiological relation with CAA.ConclusionThe coarse‐grained plaque is a clinically relevant Aβ deposit as it occurs only in clinical AD and is more frequent in EOAD. The plaque is strongly associated with neuroinflammatory and vascular changes. Differences in presence of coarse‐grained plaque among AD subtypes, contributes to the compiling evidence that also pathophysiology in AD is heterogeneous.
Structural brain network efficiency and cognitive processing speed in healthy aging
Authors: Seiler Stephan , Fletcher Evan , Beiser Alexa S , Himali Jayandra J , Satizabal Claudia L , Seshadri Sudha , Maillard Pauline , DeCarli Charles 
Published: December 2020

AbstractBackgroundTo test the hypothesis that structural brain network efficiency relates to cognitive processing speed and executive function, we computed structural brain networks of 2,278 healthy adults and conducted graph theoretical analyses.Method2,278 healthy adults from the cross‐sectional Framingham Heart Study, aged 26‐91 years, were included. We used the trail making test (TMT) parts A and B to assess processing speed. To assess executive function, we subtracted the TMT A from the TMT B score to obtain the TMT difference score. We computed structural brain networks from MRI, using diffusion tensor imaging (DTI) probabilistic tractography. Graph theory was then applied to assess global network efficiency (GE) and nodal efficiency (NE) of 72 nodes (gray matter regions). Global‐ and nodal relationships between efficiency measures and age, white matter hyperintensities (WMH), and processing speed scores were tested using linear models. All linear models were adjusted for confounding variables. Node‐wise p‐values <0.05, corrected for multiple comparisons, were considered statistically significant.ResultHigher age was significantly associated with lower GE (β=‐0.143, p<0.001, figure 1.1). Higher WMH volumes related to lower GE, independent of age (β=‐0.069, p<0.001, figure 1.2). Node‐wise regression analysis revealed that associations of age and WMH with NE were differentially distributed across the brain. Efficiencies of widespread cortical and subcortical nodes correlated negatively with age and WMH (figure 2), while nodes including the posterior and caudal cingulate cortex and precuneus correlated positively with age (figure 3), but not WMH (p<0.05, corrected). GE related positively to TMT B (β=0.046, p=0.006, figure 4.1) and the TMT difference score (β=0.039, p=0.012, figure 4.2). Efficiencies of mainly fronto‐temporal, but also subcortical nodes were associated with TMT B and the TMT difference score (p<0.05, corrected, figure 5).ConclusionAging and WMH negatively impact efficiency of the structural brain network. Regional efficiency losses, mainly in fronto‐temporal, but also subcortical nodes, relate to reduced processing speed and executive function. Positive nodal relationships with age might represent a compensatory effect, but this hypothesis needs further exploration.
Different relationship of cross‐regional correlations of progression of local cortical thickness and local SUVR 18F‐Flortaucipir PET values to strength of connectivity
Authors: Soucy Jean‐Paul , Mohammadi Fatameh , Boulier Thomas , Hortelan Valentine , Rosa‐Neto Pedro , Pascoal Tharick A. , Savard Melissa , Kang Min Su , Mathotaarachchi Sulantha , Therriault Joseph , Benali Habib 
Published: December 2020

AbstractBackgroundWe have demonstrated in vivo in humans that spatial progression of tau distribution and atrophy in Alzheimer’s is largely driven by connectivity (Soucy et al, HAI2020). Nevertheless, local tau accumulation and atrophy should not progress in parallel during disease evolution. Atrophy keeps worsening, while local tau density (SUVRs estimated with PET) initially increases but could then decline because of tissue loss. Therefore, despite the impact of connectivity on progression of both local atrophy and SUVRs, it likely will not remain the same for both over time. This is what we tested in this work.MethodWe studied 35 AD subjects from ADNI with 2 PET studies (18F‐florbetapir) at times Ta/Tb (mean elapsed time = 438 days, median = 454), and a T1 MRI at Ta. Eighteen subjects were non‐progressors (NP) and 17 were progressors (P) based on change between Ta/b hippocampal SUVRs values. This criterion was considered to represent how far advanced patients were in their disease. Moran I statistic was used to measure autocorrelations between connectivity and T1 MRI‐defined cortical thickness at Ta or tau PET SUVR values at both times Ta and Tb in NP and P subjects in regions separately analyzed based the “intensity” of their connectivity as defined by a standard connectivity map (Human Connectome Project). We defined 3 groups of regions from thresholds separating poorly connected from moderately connected (0.01) and moderately connected from highly connected ones (0.021).ResultIn both NPs and Ps, regions with high connectivity showed higher Z‐score (4.06) of the Moran I value for correlations between regions’ cortical thickness than those with low (2.64)/moderate (2.17) connectivity. For SUVR values however, in both NPs and Ps and at both time points, Z‐scores were always lower for the highly connected regions than for those with moderate/low connectivity.ConclusionThe way connectivity influences correlations of atrophy across regions is indeed different from the way it affects correlations of tau deposition, likely for the reasons we hypothesized above to guide the progression of each parameter. Models of tau propagation across the brain will need to factor in ongoing atrophy but reversible accumulation of tau.
Within and between person effects of sleep quality on daily cognitive performance: Data from the Einstein Aging Study (EAS)
Authors: Derby Carol A , Zhaoyang Ruixue , Jiao June L , Sliwinski Martin J , Buxton Orfeu M 
Published: December 2020

AbstractBackgroundEvidence suggests that sleep disturbance may precede cognitive decline and may thus be a target for early intervention. Few studies have examined the short term (day to day) associations between sleep quality and cognitive performance in older adults. The Einstein Aging Study (EAS) provided the opportunity to examine ambulatory measures of sleep (actigraphy) and smartphone based ecological momentary assessments of cognitive performance to examine between‐ and within‐person effects of sleep quality on cognitive performance the following day.MethodsAnalyses involved 224 participants enrolled in the Einstein Aging Study, a community based longitudinal cohort of older adults free of dementia at enrollment (Mean age 77.3 years; 33% male; 47% White, 39% African American, 13% Hispanic). Participants wore an actiwatch, and completed brief smartphone based cognitive assessments 6 times per day over an 18‐day period. Multilevel models were used to examine between‐person and within‐person associations between objective measures of sleep quality (wake after sleep onset (WASO)), and duration with daily mean cognitive performance, adjusted for age, gender, race/ethnicity, education (years), and learning effects. Cognitive performance was assessed using previously validated smartphone based cognitive tests of processing speed (Symbol Match), working memory (Color Dot) and memory binding (Color Shape).ResultsBetween person results show that older adults with less nightly WASO on average had better processing speed (b=7.18, p=0.001), better working memory (b=0.001, p=0.005), and better memory binding (b= ‐0.003, p<0.001). Within‐person results showed that higher WASO was significantly associated with worse processing speed the next day: A thirty‐minute increase in nightly WASO predicted a 13 millisecond increased response time on the Symbol Match Test (p=0.001). There were no significant within‐person associations between WASO and working memory or memory binding. Sleep duration was not associated with cognitive performance in any of the analyses.ConclusionsWithin individuals, poor sleep quality is associated with worse cognitive processing speed the following day. The cumulative effects of poor sleep may lead to long term cognitive decline. Future work will determine whether individuals susceptible to the adverse effects of sleep from day to day are at increased risk for long term cognitive decline.
Central nervous system‐active polypharmacy among community‐dwelling persons with dementia in the United States
Authors: Maust Donovan T , Kim H Myra , Strominger Julie , Chang Chiang‐Hua , Langa Kenneth M , Bynum Julie , Kales Helen C , Zivin Kara , Marcus Steven 
Published: December 2020

AbstractBackgroundPsychotropic prescribing and central nervous system (CNS)‐active polypharmacy are increasing among community‐dwelling older adults in the United States.1 While psychotropic prescribing to persons living with dementia (PLWD) in long‐term care has received significant regulatory attention, there are no recent estimates of use among PLWD in the community. The aim of this analysis is to determine the prevalence of CNS‐polypharmacy (“CNS‐poly”)—potentially inappropriate for older adults given risks of associated falls and overdose2—among community‐dwelling PLWD.MethodThe cohort included beneficiaries: 1) enrolled in fee‐for‐service Medicare with Part D (prescription drug); 2) with a dementia diagnosis from 10/1/14 – 9/30/15 (the baseline); and 3) who were community‐dwelling (determined by Minimum Data Set). CNS‐poly was defined as receipt of ≥3 medications for ≥31 consecutive days from the following classes: opioids, antipsychotics, antidepressants, benzodiazepines, “z‐drugs”, anti‐epileptics. The CNS‐poly observation period was 10/1/15–9/30/16; as with baseline, those with time in LTC were excluded. We determined CNS‐poly overall and by demographic characteristics, then by state.ResultAmong 740,274 beneficiaries, 14.8% experienced CNS‐poly. The prevalence was higher among: females versus males (16.1% vs 12.2%); younger persons (24.2%, 14.6%, 10.2% for those 65‐74, 75‐84, and ≥85); and non‐Hispanic white and Hispanic beneficiaries compared to non‐Hispanic black and other (15.6%, 15.6%, 9.4%, and 8.8%); but comparable for urban and rural (15.8% vs 15.8%). The Figure presents state‐level prevalence by quintile. The state‐level median was 14.4%, with Hawaii lowest (5.4%) and North Carolina highest (19.1%).ConclusionCNS‐poly is widespread among PLWD in the U.S.—much higher than among the general population of older adults1—and varies widely by patient demographics and by state. Future work is needed to understand drivers of this high rate of CNS‐poly and to develop patient, provider, and policy‐level interventions to more appropriately target psychotropic use.
Differential effects of apolipoprotein E on the molecular and cellular phenotypes associated with Alzheimer’s disease in isogenic human iPSC‐derived neurons
Authors: You Yang , Poon Wayne W. , Jun Gyungah R. , Farrer Lindsay A. , Ikezu Tsuneya 
Published: December 2020

AbstractBackgroundApolipoprotein E4 (APOE4) is an established AD risk gene, while APOE2 is considered protective. Recently, several studies demonstrated that APOE4 can induce AD‐related pathological phenotypes including tau phosphorylation (p‐tau), neuroinflammation, and tau‐mediated neurodegeneration in both mouse models and human neurons. However, the underlying mechanism of APOE4 in AD pathology and how other APOE isoforms affect the molecular and cellular phenotypes associated with AD are not well understood in human cells. In this study, we used isogenic human induced pluripotent stem cell (iPSC)‐derived neurons to explore the differential effects of APOE isoforms on AD‐related pathology.MethodsIsogenic human APOE2/2, APOE3/3, APOE4/4 and APOE knock‐out (APOE‐/‐
) iPSC lines were generated by CRISPR‐Cas9 editing and characterized by immunocytochemistry. Functional excitatory neurons were induced from isogenic iPSCs by overexpressing neural fate‐driven gene neurogenin2, and tested for the expression of AD and neuroinflammation‐related genes, p‐tau, and neuronal firing and synchrony in vitro.ResultsFour isogenic iPSC lines were successfully differentiated into functional excitatory neurons with >99% purity. We found significantly reduced gene expression of C4A and C4B, which have been implicated in AD pathology, in APOE2/2 neurons compared to APOE3/3 (p=0.0377) or APOE‐/‐
neurons (p=0.0284). We also observed an upregulated expression of PPP2CB in APOE‐/‐
neurons compared to three other APOE isogenic neurons (one‐way ANOVA, F=3.863, p=0.0249), suggesting a possible APOE‐dependent suppression of PPP2CB expression. Further, the ratio of the level of p‐tau at both Thr 231 and Thr 181 sites to total tau was significantly lower in APOE3/3 neurons than APOE4/4 or APOE‐/‐
neurons (Thr 231: APOE3/3 vs APOE4/4, p<0.0001; APOE3/3 vs APOE‐/‐
, p=0.0033; Thr 181: APOE3/3 vs APOE4/4, p=0.0071; APOE3/3 vs APOE‐/‐
, p=0.0115). The expression of C4A/B but not PPP2CB was found inversely correlated with the level of p‐tau at the Thr 231 site. Finally, APOE3/3 neurons showed significantly higher neuronal firing activity and synchronization compared to other APOE isogenic neurons, which were resistant to excess glutamate treatment.ConclusionOur findings in isogenic iPSC‐derived neurons describe the differential effects of APOE on the expression of AD‐related genes, p‐tau and neuronal functions, which provide new insights into the potential role of the APOEvariants in AD.
Functional indicators of a decline in the noradrenergic locus coeruleus in ageing
Authors: Hammerer Dorothea , Hopkins Alexandra , Ludwig Mareike , Yi Yeo‐Jin , Lüsebrink Falk , Liu Kathy , Femminella Grazia Daniela , Betts Matthew J , Callaghan Martina F , Howard Robert J , Düzel Emrah 
Published: December 2020

AbstractBackgroundPostmortem studies show that the locus coeruleus (LC), the major source of cortical noradrenergic projections, exhibits evidence of neurodegeneration early in Alzheimer’s disease (AD). Indeed, the noradrenergic system is more affected than the dopaminergic or cholinergic ones. Albeit to a smaller extent, neuronal loss in the LC is also seen in cognitively normal older adults, which can in some cases reflect the earliest stages of AD neuropathology before cognitive changes are clinically detectable. These postmortem findings have been corroborated in recent years by in vivo assessments of LC integrity using anatomical MRI (magnetic resonance imaging) approaches. Before measurable neuronal loss occurs, functional LC decline should be observable. I will present the results of a series of studies involving pupillometry, high‐resolution fMRI (functional) as well as cognitive paradigms targeting noradrenergic function, which investigated whether a decline in LC function can be detected in cognitively normal older adults.MethodWe examined LC function during an emotional memory task known to rely on the noradrenergic system in 22 healthy younger adults (18‐30 years) and 22 healthy older adults (62‐83 years) with pupillometry (a proxy for LC function) (Study 1), as well as 22 healthy younger adults (20‐31 years) and 28 healthy older adults (65‐84 years), using high resolution fMRI (Study 2).ResultOur studies reveal both, a) evidence for a decline in functional LC responses with ageing (Figure 1, pupillometric data), as well as, b) evidence for no decline in functional LC responses in older adults (in pupillometry and fMRI). Specifically, reduced LC responses with ageing were observed in experimental conditions that allowed for a more selective assessment of LC function, independent of the engagement of other brain areas, underlining the need for a careful selection of cognitive paradigms when investigating functional indicators of LC decline.ConclusionOur results show that fMRI and pupillometry are promising methods for assessing changes in LC function in ageing and early AD. We provide recommendations for cognitive paradigms, experimental setups as well as data analysis methods for researchers interested in assessing functional changes in the noradrenergic system in AD and other disorders.
Dementia care in rural areas: A cross‐sectional study from the Wisconsin Alzheimer’s Institute (WAI) Dementia Diagnostic Clinic Network
Authors: Pinzon Maria C Mora , Krainer Jody , Houston Stephanie , Green‐Harris Gina , Norris Nia , Walaszek Art , Johnson Sterling C , Carlsson Cynthia M 
Published: December 2020

AbstractBackgroundThe Wisconsin Alzheimer’s Institute (WAI) Dementia Diagnostic Clinic Network includes 38 affiliated clinics across 24 healthcare systems in Wisconsin. Its purpose is to promote the use of evidence‐based strategies to provide high quality care for people with dementia across the state. The clinics follow a set of guidelines that are tailored to address the challenges of providing specialized care in rural areas (e.g. travel burden, transportation, limited resources, lack of trained healthcare providers, social isolation, among others). The purpose of this study is to describe the characteristics of patients seen in rural areas of Wisconsin, the care provided and how it compares to the models of care seen in urban areas.MethodsCross‐sectional study including the patients seen at the WAI’s Clinic Network between September 2018 and January 2020. Demographics, clinical diagnosis, and quality of care provided were compared according to rurality (metropolitan, micropolitan, rural) using the Urban‐Rural Classification Scheme for Counties (URCSC) which was assigned using the location of the submitting clinic.ResultsOver the study period, 1,769 patients were identified: 61% female, 69% between 65 and 84 years old, and 78% diagnosed with dementia or mild cognitive impairment. Overall, 15% of the patients were seen in rural areas, 8% in micropolitan areas, and 76% in metropolitan areas. Patients in rural areas were older, drove longer distances to the clinic, had lower educational attainment level, and were more likely to be self‐referred than those in metropolitan areas. Clinics in rural areas were more likely to provide educational materials, referrals to local resources in the first visit, and to refer patients for further neuropsychology or specialty evaluation before an etiology was identified. As a result, these clinics were less likely to provide a complete diagnosis in the first visit, but provide more caregiver support and management of behavioral symptoms.ConclusionsWAI’s affiliated clinics in rural areas of Wisconsin use referral patterns that differ from their counterparts in metropolitan areas, including making more connections to local resources. More research is needed to identify additional resources and clinic models to improve dementia care in rural areas.
Characterizing chromogranin and secretogranin proteoforms in dementia pathophysiology
Authors: Quinn James P. , Kandigian Savannah E. , Trombetta Bianca A. , Arnold Steven E. , Carlyle Becky C. 
Published: December 2020

AbstractBackgroundChromogranins and secretogranins are neurotransmitter‐like molecules (neuropeptides) that are processed into functional peptides (proteoforms) by proteases. Full‐length chromogranins and secretogranins and their peptide proteoforms are involved in diverse neuronal and synaptic functions, but their specific processing pathways and contribution to dementia remain largely unknown. This project aims to investigate chromogranin and secretogranin proteolytic processing and validate if specific proteoforms may be useful cerebrospinal fluid (CSF) biomarkers of synaptic health in dementia.MethodMass spectrometry (MS) of intact processed peptides was used to produce a detailed map of identified proteoforms arising from chromogranins and secretogranins in the CSF of 5 control and 5 Alzheimer’s disease (AD) patients. This CSF profile was compared against known processed peptides and those used in CSF‐targeted MS assays. Proteasix was used to identify potential proteases involved in the production of identified proteoforms and the human cell atlas was used to identify whether they were expressed in the brain. The cleavage specificity was assayed in vitro using recombinant proteins, analysed by gel electrophoresis and western blotting with chromogranin and secretogranin antibodies.ResultUsing tryptic versus non‐tryptic MS techniques, we detected distinct chromogranin and secretogranin proteoform profiles, suggesting that tryptic digestion underestimates the complexity of proteoform profiles. We are now developing a targeted MS assay to characterize the profile of chromogranin and secretogranin proteoforms in CSF samples spanning controls, different stages of AD and other neurodegenerative diseases. Using Proteasix; members of the calpain, cathepsin, caspase and MMP families were identified to cleave chromogranins and secretogranins. These protease families are known to be expressed in the brain as shown by the human cell atlas and have been previously identified to be dysregulated in dementia. Recombinant assays identified that these proteases can cleave chromogranins and secretogranins to produce different proteoforms.ConclusionOur results show that (i) standard tryptic digestion methods underestimate the proteoform complexity of chromogranins and secretogranins, and (ii) that chromogranins and secretogranins are proteolytically processed by proteases relevant to dementia pathophysiology. This work improves our mechanistic understanding of chromogranin and secretogranin processing and further establishes them as a potential synaptic health biomarker in dementia pathophysiology.