bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEG spectral patterns in the progression from MCI to AD
Authors: Cuesta Pablo , García María Eugenia López , Pusil Sandra Angelica , Bajo Ricardo , Maestú Fernando , Fernandez Alberto 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) is the most prevalent type of dementia. The relevance of the symptomatic pre‐dementia or mild cognitive impairment (MCI) is central to stablishing a prognosis of the disease. Considering the scarcity of studies within this field and its potential clinical relevance, we conducted a longitudinal magnetoencephalography (MEG) study in two groups: stable (sMCI) and progressive (pMCI) MCIs during a 4‐years followed‐ up.MethodWe compared the power spectra in source space measured by MEG during 5 minutes of resting state eyes‐closed from 49 MCIs (24 pMCI and 25 sMCI) within three frequency bands: delta (1,5‐4Hz), theta (4‐8Hz) and alpha (8‐12Hz). The procedure for statistical comparisons relied on the cluster‐based permutation test (CBPT) and was carried out independently for each frequency band. As both groups did differ in age and educational level, both factors were included as covariates in the statistical tests. Finally, we performed Spearman correlation analyses between the significant power differences and the neuropsychological scores and hippocampal volumes.ResultpMCI patients showed a significant power increase within theta range (4‐8Hz), compared with the sMCI group (CBPT p <0.05). The significant cluster within this frequency band mainly involved right medial temporal regions, including inferior temporal gyrus, fusiform gyrus, parahippocampal gyrus, hippocampus and amygdala. Besides, the pMCI group exhibited a power shift to lower frequencies than the sMCI group. The correlation analysis carried out with all participants showed a direct association between power results and general cognitive status (Mini‐mental state examination; rho= ‐0.344; p= 0.021), working memory (inverse digit span test; rho= ‐0.285; p= 0.049) and episodic memory (immediate recall; rho= ‐0.405; p= 0.004; and delayed recall; rho= ‐0.358; p= 0.016).ConclusionOur results are aligned with previous reports with (EEG)/MEG spectral analysis performed in those MCI that finally progressed to AD. The Progression to AD involved the electrophysiological disruption of the medial temporal lobe structures. Besides, we found that this slowness pattern was related with worse performance in several cognitive measures, such as global cognitive status, episodic and working memory, entitle this MEG profile to be considered as AD‐progression biomarker.
A multivariate model of time to conversion from mild cognitive impairment to Alzheimer’s disease
Authors: García María Eugenia López , Turrero Agustín , Cuesta Pablo , Rojo Inmaculada Concepción Rodríguez , Barabash Ana , Dolado Alberto Marcos , Maestú Fernando , Fernandez Alberto 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) is a neurodegenerative disorder, clinically defined by a progressive loss of memory and other cognitive and functional abilities. One of the most studied phases in the prognosis of AD is the Mild cognitive impairment (MCI) since it entails a higher risk of developing this type of dementia. The majority longitudinal studies from MCI to AD utilize both a reduce number of potential prediction markers and a shorten length of follow‐up. Therefore, the present study was aimed at determining which combination of demographic, genetic, cognitive, neurophysiological (i.e. magnetoencephalography, MEG), and neuroanatomical (i.e. magnetic resonance imaging (MRI) volumetry) factors may predict differences in time to progression from MCI to AD during an extended follow‐up.MethodTo this end, a sample of 121 MCIs was followed‐up during a 5‐years period. According to their clinical outcome, MCIs were divided into two subgroups: (i) the “progressive” MCI (pMCI; n= 46); and (ii) the “stable” MCI group (sMCI; n= 75). Kaplan‐Meier survival analyses were applied to explore each variable’s relationship with the progression to AD. Once potential predictors were detected, Cox regression analyses were utilized to calculate a parsimonious model that may allow the estimation of differences in time to progression.ResultResults indicated that the final model included three variables (in order of relevance): Left parahippocampal volume (corrected by intracranial volume, LP_ ICV), Delayed recall (DR), and Left Inferior Occipital lobe individual alpha peak frequency (LIOL_IAF). Those MCIs with LP_ ICV volume, DR score and LIOL_IAPF value lower than the defined cutoff had 6‐times, 5.5‐times and 3‐times higher risk of progression to AD, respectively. Besides, when the categories of the three variables were “unfavourable” (i.e. values below the cutoff), a 100% of cases progressed to AD at the end of follow‐ up, while a combination of “favourable” categories yielded a 94.7% of stable cases at the end of follow‐up.ConclusionOur results highlighted the relevance of neurophysiological markers as predictors of conversion, and the importance of multivariate models that combine markers of different nature to predict time to progression from MCI to dementia.
Cerebrospinal fluid fatty acid binding protein 3: A screening biomarker for preclinical Alzheimer’s disease
Authors: Dhiman Kunal , Martins Ralph N , Gupta Veer Bala 
Published: December 2020

AbstractBackgroundPreclinical Alzheimer’s disease (AD) is a silent, asymptomatic stage of AD, classified into three sub‐stages based on amyloid positivity, neuronal injury and presence of subtle cognitive decline. Pathophysiological biomarkers are needed to effectively screen cases of preclinical AD based on the specific stage. Fatty acid binding protein 3 (FABP3) is a biomarker of neuronal membrane disruption, associated with lipid dyshomeostasis. The current study evaluated the potential of cerebrospinal fluid (CSF) FAPB3, as a stage‐specific screening biomarker of preclinical AD.MethodThe levels of FABP3 were quantified in CSF samples of healthy participants (n = 159) from the Australian Imaging, Biomarkers and Lifestyle studying of ageing (AIBL), on the Meso Scale Discovery platform using Human FABP3 Kit (Meso Scale Diagnostics, USA). A sub‐set of participants, (n = 142) had undergone positron emission tomography (PET) brain amyloid imaging. These participants were dichotomised into PET amyloid positive (n = 49) and negative (n = 93) based on the PET derived standardized uptake value ratio (SUVR) cut‐off of 1.4. Diagnostic differences in CSF FABP3 levels were assessed among amyloid positive and negative participants. Cox proportional hazards model was used to identify individuals likely to progress to an early stage of cognitive impairment, by assessing the risk of conversion from clinical dementia rating (CDR) of 0 to CDR ≥ 0.5. CDR assessments were done over 4.5 years; participants who had at least two follow‐up assessments were included in the analysis.ResultCSF FABP3 levels were significantly higher in PET amyloid positive healthy participants as compared to negatives (p = 0.001). CSF FABP3 levels were significantly higher in healthy participants who converted from CDR 0 to CDR ≥ 0.5, over 4.5 years, against non‐converters (p = 0.039). In an unadjusted analyses, CSF levels of FABP3 significantly predicted the risk of conversion from CDR 0 to CDR ≥ 0.5, with a hazard ratio (HR) of 1.58 (CI 1.03‐2.43, p = 0.035).ConclusionFABP3 is a biomarker of early neurodegenerative changes, which can be used to screen cases of preclinical AD with asymptomatic amyloidosis, as well as identify individuals likely to progress to a clinical stage of AD.
Effects of early surgical menopause on sleep, memory, and medial temporal lobe structure at midlife
Authors: Gervais Nicole J , Lauzon Claire , Brown Alana , Gravelsins Laura , Nicoll Gina , Baker‐Sullivan Elizabeth , Almey Anne , Reuben Rebekah B , Duchesne Annie , Mendoza Leanne , Perovic Mateja , Kannampuzha Courtney , Grady Cheryl , Olsen Rosanna , Einstein Gillian 
Published: December 2020

AbstractBackgroundWomen bear the greatest burden of Alzheimer’s disease (AD) with menopause‐associated estrogen (E) loss becoming increasingly implicated. Surgical menopause <45 years of age (via bilateral salpingo‐oophorectomy, BSO) is thought to further increase the risk (Rocca et al., 2007). Neurodegeneration and atrophy in medial temporal lobe (MTL) structures including the perirhinal (PRC) and entorhinal (ERC) cortices occur in the very early stages of AD (e.g. Khan et al., 2013; Wolk et al., 2017). Further, sleep disturbance is also implicated in AD progression (Lim et al., 2013). Unknown is whether BSO‐associated sleep disturbance contributes to reduced memory performance and MTL atrophy via sleep disturbance, and whether E2 supplementation influences this relation. Our study aimed to determine the effect of early hormone deprivation (via BSO) on MTL volume, visual recognition memory, and whether this is correlated with sleep disturbance.MethodDemographic and cognitive measures were administered to women with an oophorectomy <45 years who were either taking estradiol‐based hormone therapy (BSO+E2: n=19), or not taking E2 (BSO no E2: n=15). Data was also collected from age‐matched premenopausal women (AMC: n=27). High‐resolution T2‐weighted scans were acquired using a Siemens 3T Prisma scanner, and hippocampal subfields, PRC, ERC, and parhippocampal cortex were manually segmented (Olsen et al., 2017) in FSLView. The interference match‐to‐sample (IMTS) task was used to asses and recognition memory (Watson et al., 2013). Sleep was assessed using an at‐home polysomnography device (Vitaport‐5/REMbo‐234, Temec Technologies).ResultRelative to AMCs, the BSO no E2 group had smaller volumes in the dentate gyrus, CA2, and CA3 (DGCA23) (p<.05, d=1.03). Relative to BSO+E2 women with BSO no E2 had reduced recognition memory performance (p<.05; d=1.36) and their sleep was more disrupted, indicated by increased sleep latency (p<.05, d=.71), and cortical arousals ( p<.05, d=.87]. DGCA23 volume and nighttime arousals were correlated negatively (r=‐.503, p<.05).ConclusionOur findings demonstrate that HPC, recognition memory, and sleep are sensitive to E2 loss and suggest that reduced HPC volume relates to disrupted sleep. Taken together these findings begin to explicate the path from early menopause to late‐life dementia and the importance of E2 for women’s brain health.
Novel proteomic molecular signatures of brain endothelial cells and microglia in the aging mouse brain
Authors: Rayaprolu Sruti , Duong Duc , Xiao Hailian , Carter Emma Kathleen , Cheng Lihong , Levey Allan I , Seyfried Nicholas T , Rangaraju Srikant 
Published: December 2020

AbstractBackgroundImmune and vascular mechanisms of aging and Alzheimer’s disease (AD) are mediated by microglia and endothelial cells, respectively. Transcriptomic studies of endothelial cells and microglia have revealed distinct and overlapping molecular features between these cell types while brain endothelial proteomic signatures remain unknown. Using concurrent isolation of microglia and endothelial cells from adult mouse brain along with multiplex quantitative proteomics, we contrast the proteomic profiles of these cell‐types and define their unique age‐related proteomic characteristics, for the first time.MethodThe study cohort consisted of 3 and 7‐month‐old C57BL/6J mice (N = 6/age, 3M and 3F). Endothelial cells and microglia were concurrently isolated from fresh, whole mouse brain using fluorescence‐activated cell sorting (FACS). On average, 14,000 endothelial cells and 20,000 microglia were sorted directly into 8M urea and digested. Peptides from each sample were randomized into four batches and labeled using 16‐plex tandem‐mass‐tag (TMT) kits. After high pH fractionation, peptides were analyzed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) with synchronous precursor selection MS3 based quantification (SPS‐MS3). Raw files were processed using Proteome Discoverer. The spectra were searched against UniProt mouse proteome database. Differential expression analysis and Gene Ontology analysis (GO) was performed.ResultQuantitative proteomics of endothelial cells and microglia from adult mice identified 512 proteins. Of these, 199 proteins differentiated microglia from endothelial cells (Fig.1A) of which 20 proteins had >4‐fold higher expression in microglia (e.g., Rgs10) and 60 proteins had >4‐fold higher expression in endothelial cells (e.g., Hspa12b). 51 proteins demonstrated age‐dependent changes in microglia (Fig. 1B; 18 increased and 33 decreased). 35 proteins demonstrated age‐dependent changes in endothelial cells (Fig.1B; 15 increased and 20 decreased). GO analysis showed age‐dependent increase in structural, morphogenesis, and intermediate filament proteins and decrease in cell motility and macromolecular biosynthetic proteins in microglia. Age‐dependent changes in endothelial cells included increased gene transcription, splicing, and subcellular transport and decrease in chromatin organization and cytokine production proteins.ConclusionIn this direct comparison of proteomic profiles of adult mouse microglia and endothelial cells, we report proteomic signatures that differentiate microglia and endothelial cells and identify unique age‐dependent changes in microglia and endothelial cells.
Entry of extracellular tau to human neurons is functionally analogous to virus infection
Authors: Evans Lewis D , Livesey Rick 
Published: December 2020

AbstractBackgroundIn tauopathies, including Alzheimer’s disease, the disease progresses through the brain in a defined spatial and temporal pattern, with the deposition of protein aggregates in brain regions mirroring the clinical symptoms of disease. Progression of tauopathies through the CNS is thought to be mediated by intercellular transfer of disease‐associated forms of the microtubule‐associated protein tau between diseased and healthy neurons. We report here the use of whole genome CRISPR screens to understand the cell biology of entry and processing of extracellular monomeric and aggregated tau by human neurons.MethodsWhole genome, loss of function CRISPR screens in human iPSC‐derived excitatory neurons were performed to identify genes that regulate uptake and intracellular processing of extracellular monomeric and aggregated tau (MAPT P301S), using a lentiviral library of 100,000 gRNAs targeting 20,000 protein‐coding genes. Neurons that took up transferrin were FACS purified into populations with either low or normal levels of internalised tau and gRNA libraries sequenced from each population to identify genes required for tau uptake, using the MAGeCK data analysis algorithm.ResultsFor both monomeric and aggregated tau, multiple genes involved in endosomal sorting and those regulating receptor recycling are required for tau uptake. Aggregated tau uptake is dependent on several other intracellular vesicular trafficking systems, including trafficking between organelles and surface protein glycosylation. In addition, monomeric tau uptake requires the newly identified low‐density lipoprotein receptor LRP1 and the endocytosis regulator LRRK2, mutations in which are causal for monogenic PD. Comparison of the protein networks involved in tau uptake demonstrates a striking similarity to genes identified as host factors required for viral infection, particularly for viruses that enter cells via receptor‐mediated endocytosis.ConclusionsMonomeric and aggregated tau enter human neurons via overlapping but distinct pathways, dependent on specific surface receptors, the endolysosomal‐autophagy system, the Golgi network and other vesicle trafficking pathways. The similarity of the cell biology of extracellular tau uptake and processing by neurons with that of viral entry suggests that tauopathy spreading is a quasi‐infectious process, analogous to viral infection, suggesting potential therapeutic strategies to prevent disease progression.
APOE genotype and sex influence memory and dendritic spine density in an EFAD mouse model of Alzheimer’s disease
Authors: Taxier Lisa R , Philippi Sarah M , York Jason , LaDu Mary Jo , Frick Karyn M 
Published: December 2020

AbstractBackgroundWomen carriers of the APOE4 genotype, which is the leading genetic risk factor for late‐onset Alzheimer’s disease (AD), are more likely than women carriers of other APOE genotypes and men of any APOE genotype to develop AD. However, factors underlying the interaction between APOE genotype and sex are not well characterized. The goal of this study was to examine the effects of sex and APOE genotype on memory function and dendritic spine density in a mouse model of AD.MethodsSix month‐old gonadally‐intact male and female transgenic (Tg) mice expressing 5 familial AD mutations (5xFAD+/‐) and human APOE3
+/+ (E3FAD) or APOE4
+/+ (E4FAD) were trained on object recognition (OR) and object placement (OP) tasks designed to test object recognition and spatial memory formation. Memory for previously seen objects or locations was tested 24 or 4 hours later, respectively. Two weeks after the conclusion of behavioral testing, mice were retrained with novel objects, and brains were collected for Golgi staining. Following staining, apical and basal dendritic spines in the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) were counted and classified by morphological type.ResultsMale E3FAD mice exhibited intact memory for previously seen objects or locations, whereas male E4FADs and female E3FAD or E4FAD mice did not. The density of total, mushroom, and stubby spines on basal CA1 and mPFC dendrites was lower for E4FAD mice of both sexes compared to E3FAD mice. Preliminary data suggest a similar pattern for mPFC apical spine density.ConclusionsThese data suggest that APOE genotype and sex influence object recognition and spatial memory formation, and that APOE4 genotype is associated with reduced density of mature and immature spines in CA1 and the mPFC.
Network analysis of the brain proteome of GRN knockout mice reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations
Authors: Kukar Thomas , Huang Meixiang , Modeste Erica S , Dammer Eric B , Holler Christopher J , Deng Qiudong , Taylor Georgia L , Merino Paola , Seyfried Nicholas T 
Published: December 2020

AbstractBackgroundMutations in the GRN gene, encoding the progranulin (PGRN) protein, are a common cause of Frontotemporal dementia (FTD) and induce haploinsufficiency of PGRN. PGRN is composed of 7.5 repeating domains called granulins (GRNs 1‐7). PGRN is processed into GRNs within the lysosome, where we hypothesize they are critical for lysosome homeostasis and function. However, it is unclear how decreased levels of lysosomal PGRN/GRNs cause FTD, Alzheimer’s disease, and related neurodegenerative disorders.MethodsWe performed quantitative proteomic analysis of whole‐brain tissue from wild‐type (Grn
+/+) and PGRN knockout (Grn
‐/‐) mice at 3‐ and 19‐months of age using 10‐plex Tandem Mass Tag (TMT) isobaric labeling mass spectrometry. Protein changes were validated using immunobloting, immunohistochemistry, and ELISAs.ResultsDeep proteome analysis of mouse brains detected 8,695 proteins. Weighted correlation network analysis (WGCNA) of the brain proteome of Grn
‐/‐ compared to Grn
+/+ mice identified 29 modules of highly co‐expressed proteins. In particular, 3 modules strongly correlated to Grn deficiency, increased with age, and were enriched with lysosomal proteins (Gpnmb, Ctsd, Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44). Immunohistochemistry revealed age‐dependent increases in multiple lysosomal proteins and inflammation throughout the Grn
‐/‐ brain, particularly in the thalamus. Importantly, we discovered similar changes in the brain and cerebrospinal fluid (CSF) of individuals with GRN mutations that cause FTD (FTD‐GRN). GPNMB and galectin‐3 (LGALS3) were significantly elevated in the lysates of FTD‐GRN brain. Further, GPNMB levels were significantly increased in human FTD‐GRN CSF compared to controls and other genetic forms of FTD (MAPT and C9orf72).ConclusionsThese data suggest that common pathogenic pathways are dysregulated in human FTD cases with GRN haploinsufficiency and Grn
‐/‐ mice. Moreover, GPNMB is a novel, potential biomarker for FTD. Our findings support the idea that insufficiency of PGRN and GRNs in humans cause FTD, AD, and related neurodegenerative diseases through lysosomal dysfunction and neuroinflammation and suggest novel therapeutic approaches.
Rapidly progressive dementia in the COVID‐19 era
Authors: Dubey Shubham , Ramakrishnan V , Naveen P , Dubey Ayush 
Published: December 2020

AbstractBackgroundRapidly progressive dementias(RPD) are conditions that typically cause dementia over weeks or months.1 Due to the current COVID‐19 pandemic, it has become difficult for dementia caregivers on the one hand, and relevant detailed examination and management in the hospitals worldwide, on the other. Recent studies shows that ApoE e4 genotype is associated with both dementia and delirium2. Hence further research into the possible genetic link between dementia and COVID‐19 is the need of the hour.MethodWe studied two elderly male patients, aged 66 and 68 years, presenting with memory decline of recent events, untimely and non‐sequential Activities of Daily Living and apathetic alongwith way finding difficulty and errors in money transactions. One patient also had forgetfulness of handwashing and face hygiene measures, and of using preventive face masks in public places as advised for public health during COVID‐19 outbreak. On examination, vitals were stable and normal fundus examination with no fever, dry cough or tiredness, and no evidence of Increased Intracranial Pressure(ICP). MMSE score was 16/30 and 17/30 respectively, recent memory and visuospatial skills were impaired and slowness of activities were present. Motor examination was normal, with no focal or non‐focal neurological deficit or sensory impairment. All routine tests were normal. Neuroimaging with contrast in one patient showed well defined hyperdense mass lesion of size 4.0*3.5*3.0 cms. showing heterogenous contrast enhancement in left parieto‐occipital lobes with moderate perilesional edema suggestive of astrocytoma (intermediate type).ResultHigh index of suspicion of Space occupying lesions should be made in the background of RPD even in the absence of focal or non focal neurological deficit or without signs of raised ICP.ConclusionMost of the etiologies causing RPD especially surgical causes, if diagnosed early and promptly are reversible and treatable. The double hit of dementia and COVID‐19 pandemic necessitates further research globally. References: 1) Paterson RW, Takada LT, Geschwind MD. Diagnosis and treatment of rapidly progressive dementias. Neurol Clin Pract. 2012;2(3):187–200. 2) Kuo C‐L, Pilling LC, Atkins JL, Kuchel GA, Melzer D. ApoE e2 and aging‐related outcomes in 379,000 UK Biobank participants. medRxiv [Internet]. 2020: 2020.02.12.20022459.