bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance to amyloid plaque pathology in the oldest‐old: Results from the 90+ study
Authors: Greenia Dana E , Yan Rui , Paganini‐Hill Annlia , Corrada Maria MM , Kawas Claudia H 
Published: December 2020

AbstractBackgroundAlthough cerebral amyloid deposition is highly associated with age, many elderly individuals show apparent ‘resistance’ to amyloid pathology, with little or none at autopsy. Our objective was to examine factors associated with resistance to amyloid pathology in people 90 years and older.MethodParticipants were 287 deceased individuals who had agreed to brain autopsy as part of The 90+ Study, an ongoing investigation of aging and dementia. We examined demographic factors, ApoE genotype and past medical history reported by participants or, if cognitively impaired, their surrogates. Participants were evaluated every 6 months with neurological examination and neuropsychological testing. Cognitive status (normal, cognitively impaired no dementia [CIND], or dementia) was assigned postmortem during a multidisciplinary case‐conference without knowledge of pathological findings. Amyloid plaque pathology was scored according to CERAD (Consortium to Establish a Registry for Alzheimer’s disease staging) and dichotomized as absent (Stage 0) or present (sparse, moderate, frequent). We used logistic regression with absence of amyloid plaques (CERAD Stage 0) as the outcome of interest. Education was dichotomized as <college degree vs. >college degree. All analyses adjusted for sex and age at death. We repeated analyses stratifying by cognitive status.ResultAt death, participants’ median age was 97 years (range:90‐108), 72% were women, 50% were college graduates, and 75% had amyloid plaque pathology. Among all participants, the odds for absence of amyloid plaques (resistance) was 75% greater in college graduates compared with those with less education (OR=1,75) (Figure). When stratified by cognitive status, education was related to absence of amyloid plaques in individuals with normal cognition (OR=4.02), but not in those with cognitive impairment. ApoE genotype and medical history variables were not related to absence of amyloid plaques (Table).ConclusionIn our study of oldest‐old participants, high education (college degree or more) was associated with absence of amyloid plaque pathology in those with normal cognition. Education may contribute to amyloid resistance in late life through a variety of potential biological mechanisms related to cerebral health and neural efficiency, or through associated lifestyle, activities and other factors.
Intracellular signal changes in the anterosuperior medial temporal lobe associated with early cognitive decline
Authors: Crawford Malcolm S. , Cabeen Ryan P. , Toga Arthur W. , Sepehrband Farshid ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundHippocampal degeneration and loss of white matter integrity both play a role in AD pathology. The anterosuperior part of the medial temporal lobe (MTL) acts as a white matter connecting point between the fontal and temporal lobes. Loss of white matter integrity in tracts passing through this region has been associated with AD [1,2]. Our aim was to use diffusion MRI to investigate changes in microstructure of white matter tracts passing through this region corresponding with cognitive impairment.Method120 subjects from the ADNI 3 cohort with multi‐shell diffusion MRI were analyzed [3]. Tractography through the anterosuperior MTL (asMTL) tracts were performed using the Quantitative Imaging Toolkit (QIT), using HCP‐derived atlas data [4,5]. Three tracts were selected for analysis including the uncinate and inferior fronto‐occipital fasciculi and the anterior commissure. . Subjects with global clinical dementia rating of 0 (N=71) and 1 (N=39) were grouped as cognitively normal (CN) and mild cognitive impairment (MCI), respectively. Intracellular signal fraction, isotropic signal fraction (free water) were obtained using NODDI [6] and mean diffusivity were obtained using DTI [7] estimated using QIT. The association between cognitive impairment and imaging features were assessed using logistic regression with age, sex, and brain volume as covariates.ResultThe intracellular signal fraction was reduced to a significant extent bilaterally in the uncinate and inferior fronto‐occipital fasciculi and anterior commissure among MCI compared to CN individuals (Figure 2.a). No significant difference in isotropic signal was observed (Figure 2.b). We also observed significantly increased mean diffusivity among MCI bilaterally in the uncinate fasciculi and the anterior commissure and trended towards significance bilaterally in the inferior fronto‐occipital fasciculi (Figure 2.c).ConclusionWe found significant microstructural alteration in early cognitive decline in tracts passing through the asMTL region. Among these tracts, the left inferior fronto‐occipital fasciculus showed the largest microstructural changes (Cohen’s D=0.525721). Identifying early white matter changes could aid early diagnosis or disease progression monitoring, as it has been suggested that white matter atrophy precede symptom onset [2]. Results suggest that decreased intracellular signal fraction in these tracts passing through the asMTL as a potential driving factor of this increased diffusivity.
Carbonic anhydrase inhibition ameliorates Aβ‐induced neurovascular dysfunction in vivo
Authors: Canepa Elisa , Vazquez‐Torres Rafael , Debure Ludovic , Fossati Silvia 
Published: December 2020

AbstractBackgroundCerebral amyloid angiopathy (CAA) is present in about 90% of Alzheimer's disease (AD) cases and is characterized by the vascular accumulation of amyloid beta (mainly Aβ40), or specific mutated variants (such as the Dutch‐Q22) in familiar forms of the disease. Our laboratory has previously demonstrated that brain vascular amyloidosis triggers mitochondrial dysfunction and caspase‐mediated apoptotic pathways activation in neuronal, glial and endothelial cells, in vitro. We have shown that these pathological processes can be prevented by acetazolamide (ATZ) and metazolamide (MTZ), FDA‐approved carbonic anhydrase inhibitors (CAIs) with a well‐known profile of brain delivery. Carbonic anhydrases (CAs) represent a family of enzymes catalyzing the reaction CO2 + H2O ⇄ HCO3− + H+. Amongst 15 known isoforms in humans, CA‐VA and ‐VB are solely expressed in mitochondria, while CA‐II translocates to the mitochondria from the cytosol in aging and neurodegeneration.MethodsWe fed Tg‐SwDI (APP‐Swedish, Dutch, Iowa) mice, which develop fibrillar amyloid deposits primarily in the cerebral microvasculature starting at 6 months, with a CAI‐diet for 8 months (from 8 to 16 months of age). Following behavioral analysis, brains have been harvested for both biochemical and immunohistochemical analysis.ResultsBrain CA‐VB expression is dramatically increased in Tg animals compared to WT, and the treatment with ATZ and MTZ significantly decreases it. Moreover, CAIs reduce the number of vasculotropic amyloid deposits and GFAP+ astrocytes, main pathological features of the disease. In Tg mice, our preliminary data show that Aβ deposition occurs in both endothelial and glial cells, leading to cell‐specific apoptosis detectable as caspase‐3 cleavage. Interestingly, CAI treatment attenuates brain Aβ load measured by Thioflavin S, as well as endothelial and astrocytic Aβ overload and the resulting caspase activation. Furthermore, the pronounced increase of cerebral CD68+ cells in CAIs‐fed animals suggests a boost of the perivascular phagocytic activity that might explain the observed reduction of Aβ deposition.ConclusionsThis study supports the role of CAs in the endothelial and astrocytic Aβ‐induced cell death and inflammation pathways associated with CAA and AD, indicating CAIs as potential drugs to improve vascular health and provide neuroprotection.
Posterior cortical atrophy in Southeast Asia: Clinical and biomarker profile
Authors: Lim Levinia , Wong Benjamin , Vipin Ashwati , Silva Eveline , Lay Hoon Lim Linda , Vanessa Chua Esther , Yuen Oi Choong Tanya‐Marie , Mei Nyu Mei , Chiew Hui Jin , Hameed Shahul , Seng Ting Simon Kang , Lyn Ng Adeline Su , Ng Kok Pin , Kandiah Nagaendran 
Published: December 2020

AbstractBackgroundPosterior Cortical Atrophy (PCA) has been widely studied internationally, but there is limited data on its clinical and biomarker characteristics among Southeast Asians. We aim to describe a case series of PCA patients in this part of the world and explore how the new PCA consensus classification (Crutch et al., 2017) could be applied in this cohort.MethodA retrospective review of the Singapore Young Onset Dementia (YOD) research database from a tertiary neurology center was performed. Available demographic, clinical and biomarker data of patients with a clinical diagnosis of PCA were extracted.ResultOf 290 patients with YOD, ten patients (5 males; 5 females) with a clinical diagnosis of PCA were identified. Mean (SD) age of onset was 54.70 (4.11), duration between symptom onset and neurological consultation was 3.90 (1.45) years. All patients reported insidious onset and gradual progression of symptoms.Upon neurological examination, principle types of cognitive deficits seen were acalculia (80%), finger agnosia (70%), simultagnosia (60.0%) and agraphia (50%).In another sub‐group with available MRI scans (n=7), all showed biparietal cortical atrophy, five (71.0%) had concomitant bilateral medial temporal lobe atrophy and white matter hyperintensities of varying severity was noted in four (57.0%) patients.Among patients with known APOE genotyping (n=8), there was one e2e3 six e3e3 and one e4e4. Findings on cerebrospinal Ab‐42 and tau levels was available (n=7), mean (SD) of Ab‐42, phosphor‐tau and total tau levels were 525.1 (195.5)pg/ml, 72.1 (22.9)pg/ml and 611.3 (246.9)pg/ml respectively. Based on the new consensus classification for PCA (Crutch et al., 2017) and incorporating the CSF Ab‐42 criterion cut‐off for AD by Dubois et al. (2014), our series consists of one PCA‐AD (10.0%) and nine PCA‐pure (90.0%) However, if the CSF tau/ Ab‐42 ratio >0.52 (Duits et al., 2014) for biomarker diagnosis of AD is used, there would be seven PCA‐AD (70%) and three PCA‐plus (30%).ConclusionPCA patients tend to present late in clinic and greater awareness on the presentation of PCA is needed for earlier diagnosis and timely intervention. Also, the sensitivity of the different CSF criteria for AD in diagnosing PCA‐AD would require further analyses in larger cohorts.
Validity of the severe impairment battery, brief praxis test, and dementia questionnaire for persons with intellectual disabilities in differentiating dementia status in individuals with Down syndrome
Authors: Wallace Elizabeth , Harp Jordan , Pelt Kathryn L. , Koehl Lisa , Caban‐Holt Allison M. , Anderson‐Mooney Amelia J , Robertson William , Lightner Donita , Jicha Gregory A. , Head Elizabeth , Schmitt Frederick A. 
Published: December 2020

AbstractBackgroundIndividuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer’s disease (AD). However, many measures regularly used for the detection of AD in the general population are not suitable for individuals with DS. Some measures, including the Severe Impairment Battery (SIB), Brief Praxis Test (BPT), and Dementia Questionnaire for Persons with Intellectual Disabilities (DMR), have been used in clinical trials and other research with this population. Validity research is limited, however, particularly regarding identification of predementia symptoms in the DS population. The current project presents baseline cross‐sectional SIB, BPT, and DMR performance in order to characterize their ability to discriminate normal cognition, possible AD, and probable AD in DS.MethodBaseline SIB, BPT, and DMR performances from 117 individuals were analyzed as part of a large longitudinal cohort of aging individuals with DS. Receiver operating characteristic (ROC) curves were calculated to investigate accuracy in differentiating levels of dementia status.ResultIn comparing no/possible AD vs. probable AD, the SIB and BPT exhibited fair discrimination ability (AUC = .78 and .79, respectively). In comparing no/possible AD vs. probable AD, the DMR exhibited good discrimination ability (AUC = .89), with qualitatively similar performance of the DMR‐Cognitive and DMR‐Social subscales (AUC = .89 and .83, respectively). In comparing no AD vs. possible AD, the SIB and BPT failed to differentiate these groups (AUC = .53 and .55, respectively), whereas the DMR exhibited good differentiation (AUC = .80).ConclusionResults suggest that the SIB, BPT, and DMR are able to discriminate between levels of dementia status in individuals with DS, supporting their continued use in the clinical assessment of dementia in DS. Specifically, the DMR, based on informant ratings of social and cognitive behaviors of daily living, outperformed the SIB and BPT, tests of cognitive performance, in discriminating no/possible AD vs. probable AD as well as no AD vs. possible AD. Such findings suggest that the DMR is better equipped to identify symptoms of overt dementia as well as predementia in this population. Findings reinforce the importance of including informant behavior ratings in assessment of this population.
Regulation of amyloid‐beta pathology by CNS amylin receptors in APP/PS1 mice
Authors: Corrigan Rachel , Grizzanti John , Casadesus Gemma 
Published: December 2020

AbstractBackgroundAmylin is a pancreatic amyloid protein, known to regulate glucose homeostasis and satiety through its ability to sensitize insulin and leptin. Importantly, the amylin receptor (AMYR) is expressed throughout the brain, including areas important in both cognition and Alzheimer’s disease (AD) pathology, like the hippocampus. We and others have previously shown that an analogue of amylin, Pramlintide (PRAM), reduces Aβ plaque burden and recuses hippocampal‐dependent cognitive decline in AD‐mouse models. However, the mechanisms underlying the therapeutic benefits of PRAM are not known.MethodAPP/PS1 mice were treated with PRAM, or saline, chronically via a subcutaneous pump for eight weeks. Additionally, a second subcutaneous pump connected to an ICV cannula delivered an AMYR antagonist, AC187 or aCSF during the last four weeks of peripheral treatment. Radial Arm Water Maze was performed at the end of study to measure spatial memory. Soluble‐Aβ1‐42 hippocampal levels were measured via ELISA and APP processing enzymes were evaluated by Western Blot.ResultPreliminary data suggests central blockade of amylin receptors may exacerbate Aβ burden and prevent learning of spatial‐memory tasks; while PRAM treatment showed increased protein expression of certain Aβ degradation enzymes.ConclusionEvaluation of AMYR blockade in AD‐modeled mice has supported a deeper knowledge of amylin signaling in the brain.
Hybrid resting state structural connectome reveals disruption of excitation‐inhibition balance in APOE ε4 carriers
Authors: Fortel Igor , Morrissey Zachary , Korthauer Laura E , Zhan Liang , Ajilore Olusola , Driscoll Ira , Schonfeld Dan , Leow Alex 
Published: December 2020

AbstractBackgroundMultimodal neuroimaging modalities may improve detection of early brain changes associated with Alzheimer’s disease (AD). We investigated cognitively intact middle‐aged individuals to determine whether male and female APOE‐ε4 carriers demonstrate altered connectivity using a novel multimodal connectomics technique to probe excitation‐inhibition balance.MethodFor 38 cognitively intact APOE‐ε4 carriers aged 40‐60 (μ=50.8) and 38 age (μ=50.9) and sex‐matched (16M/22F) non‐carriers, imaging included: T1‐weighted MRI, resting‐state fMRI and diffusion‐weighted MRI (Korthauer et al, 2018. NeuroImage, 178, 295‐305). Functional connectomes (rs‐FC), constructed with 80 regions of interest (ROIs) used correlation‐based methods on BOLD activity. The hybrid resting state structural connectomes (rs‐SC), constructed using a recently proposed multimodal connectome technique, leverages statistical mechanics to infer connectome‐level excitation‐inhibition balance (Fortel et al, 2019. MICCAI Conference. 503‐511, Springer). Positive edges in this rs‐SC indicate excitatory relationships between ROI pairs, while negative indicate inhibitory relationships. For each ROI, a hyperexcitation indicator (HI) was defined as the percentage of positive edges.ResultUsing rs‐SC and rs‐FC, figure 1 presents a comparison for each sex between group‐averaged HI for ROIs of carriers and non‐carriers. For each sex, we compared carriers and non‐carriers using 2‐sample T‐tests. Functional connectivity shows no significant difference for percentage of positive BOLD correlations for both genders (P > 0.05). By contrast, using rs‐SC, females have a significant increase in HI compared to non‐carriers (P < 0.001), suggesting female APOE‐ε4 carriers have globally disrupted E‐I balance that may confer greater vulnerability to AD neuropathology. Figure 1. Average HI for each ROI computed using the rs‐SC (1A) and rs‐FC (1B). Line x = y is a reference for equal HI between groups. While a strong linear relationship exists between carriers and non‐carriers for both genders using functional connectivity, the HI is comparable. Using rs‐SC, female ε4 carriers show a significant increase in HI compared to non‐carriers.ConclusionWe demonstrated a global shift towards hyperexcitation in a group of cognitively intact female ε4 carriers, less so in the male carriers. Our findings are consistent with known AD sex differences, suggesting that novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not.
Transforming growth factor β1 differently modulates wild‐type and TgF344‐AD astrocyte cultures' function
Authors: de Souza Débora Guerini , da Rocha Andreia Silva , Salles Giovanna Bortoluzzi , Oliveira Ana Cristina Laydner Joly , Limberger Christian , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Zimmer Eduardo R. , Souza Diogo O. 
Published: December 2020

AbstractBackgroundAstrocytes are key players involved in several functional aspects of the brain. They manage extracellular neurotransmitters and ions, regulate blood flow and energy substrates. Additionally, they produce and release growth factors, with autocrine and paracrine reach. Recently, the beneficial effects of Transforming Growth Factor β1 (TGF‐β1) have been shown in some experimental models of neurodegenerative diseases. However, the effects of TGF‐β1 in experimental models of Alzheimer’s Disease (AD) are still a matter of debate and further mechanistic investigation is needed. Here, we used adult astrocyte cultures prepared for the first time from Fischer TgF344‐AD (TG) rats to verify whether exogenous TGF‐β1 would affect astrocyte function.MethodCortices of adult (4‐month‐old) Fischer wild‐type (WT) and TG rats were aseptically dissected and digested with trypsin and papain. Cells suspensions were plated in 24‐well plates and cultivated for 3 weeks in DMEM/F12 supplemented with 10‐20% fetal bovine serum (FBS). At confluence, cells were treated with TGF‐β1 10 ng/mL for 1, 4 or 24h in DMEM/F12 1% FBS. Glutamate uptake was measured by radioactive assay and cellular morphology was evaluated with glial fibrillary acidic protein (GFAP) antibody and with rhodamine‐phalloidin for actin staining.ResultAstrocytes from WT and TG rats take up the same amount of glutamate in basal conditions. WT astrocytes, however, respond to TGF‐β1 treatment increasing the levels of glutamate uptake nearly two‐fold after been treated for 4 or 24h (p<0.05), while TG astrocytes are not affected. GFAP and actin staining of the astrocytes shows extensive expression of the glial marker in the cytoskeleton and typical morphology (Figure 1 ‐ representative of TG astrocytes).ConclusionTGF‐β1 enhanced glutamate uptake in WT but not in TG astrocytes. This may be related to an intrinsic lesser ability to fulfill neuroprotective roles and decreased plasticity presented by TG astrocytes. Impaired astrocyte function is thought to be a decisive component of AD and here we show preliminary data that suggests decreased capacity of TG astrocytes to respond to neuroprotective compounds such as TGF‐β1. Whether the decreased response to TGF‐β1 is contributing to neurodegeneration or it is a consequence of neurotoxic stimulus in TG cells remains to be determined.
Genome‐wide profiling of the noncoding regulatory mechanisms in Alzheimer’s disease
Authors: Kleidermacher Lauren , Kuksa Pavel , Lee Chien‐Yueh , Amlie‐Wolf Alexandre , Schellenberg Gerard D. , Wang Li‐San , Leung Yuk Yee 
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS) have identified genetic variants associated with Alzheimer’s Disease (AD), but the majority are noncoding and may affect transcriptional regulatory elements such as enhancers. While prior post‐GWAS analyses focused on analyzing only top GWAS signals, this study focuses on a systematic genome‐wide analysis of all significant GWAS signals aimed at identifying a more complete set of causal variants given a complex linkage disequilibrium (LD) genome structures and the regulatory mechanisms, and tissues/cell types.MethodTo perform genome‐wide analysis of GWAS summary statistics (NIAGADS NG00036) from the IGAP study [Lambert et al., 2013], we adopted INFERNO (http://inferno.lisanwanglab.org), a recent method for post‐GWAS analysis of non‐coding variants. INFERNO integrates GWAS data with hundreds of publicly available functional genomics datasets (e.g., ENCODE, FANTOM5, GTEx, HOMER) across 485 tissues and cell types to facilitate identification of the regulatory mechanisms and tissue/cell types affected by noncoding genetic variants.ResultsGenome‐wide INFERNO analysis identified 168 distinct loci by pruning all genome‐wide significant (p‐value < 5e‐8) GWAS variants using LD structure, a significant increase compared to original top‐SNP analysis (19 loci). Across these 168 distinct loci, INFERNO identified 1,358 candidate potentially causal variants in LD. Around 6% of these variants were localized in coding exons, 67% overlapped enhancers in at least one tissue and 57% overlapped transcription factor binding sites. Co‐localization analysis of GWAS and eQTL data (GTEx_v6p) identified tissue‐specific effects of 53 variants on 43 genes across 16 INFERNO tissue categories, with 12 variants affecting expression of 16 genes in the blood (RP11‐1036E20.9, ZNF223, ZNF285B, RP11‐286H15.1, FAM115D, EPHA1‐AS1, TAS2R60, TAS2R62P, PTK2B) and brain (CR1, ABCA7, POLR2E, EML2, PPM1N, RP11‐385F7.1, FAM115C). These INFERNO‐identified genes include both novel and genes previously implicated in AD. E.g. EPHA1‐AS1 activity was confirmed by luciferase reporter assay [Amlie‐Wolf et al., 2019]. Additionally, our analysis found that PTK2B gene, an early marker of Tau pathology [Dourlen et al., 2016], is regulated by rs28834970 that also disrupts binding motif of HLF(bZIP) in blood.ConclusionGenome‐wide INFERNO analysis confirmed experimentally validated and discovered additional plausible biological mechanisms related to AD. These can help to inform the development of better AD therapeutic targets.