bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha‐synuclein N‐ and C‐terminal regions have distinct in vivo roles in mitochondrial fragmentation and oxidation: Implications for a pathogenic mitochondrial pathway for Parkinson’s disease (PD)
Authors: Gunawardena Shermali 
Published: December 2020

AbstractBackgroundMitochondrial health depends on a critical balance between fission via dynamin‐related protein 1 (DRP1) and fusion via mitofusin (MFN) in concert to mitochondrial motility, and defects in fission‐fusion and motility are linked to neuronal dysfunction. In Parkinson’s disease (PD) which is characterized by progressive neuronal loss and α‐syn‐rich Lewy bodies, the presence of impaired mitochondrial function, fragmentation, and high oxidative stress are also seen.MethodsUsing genetics, in vivo reporters of mitochondrial health and biochemical analysis, here we test the physiological relevance of α‐syn in mitochondrial homeostasis using a Drosophila model of PD.ResultsExcess human α‐syn cause fragmented mitochondria, which are rescued by excess/depletion of DRP1, but not by excess MFN. Contrary to previous knowledge, α‐syn aggregation did not contribute to mitochondrial fragmentation as rescue of α‐syn accumulations by excess HSP did not eliminate fragmentation. Further, deletion of the C‐terminus (α‐syn1‐120) or the NAC did not affect mitochondrial fragmentation. α‐syn‐mediated mitochondrial fragments were oxidized as assayed by the in vivo oxidation markers mitotimer, mito‐roGFP2‐ORP1 and mito‐roGFP2‐GRX1, which were rescued by deletion of the C‐terminus. While α‐syn‐mediated oxidized mitochondrial fragments showed biased retrograde motility, α‐syn1‐120‐mediated healthy fragments did not. Intriguingly, α‐syn‐mediated fragmentation was rescued by PINK1/PARKIN expression, but not the fragmentation caused by deletion of the C‐terminus.ConclusionOur study demonstrates that under physiological conditions, α‐syn N‐ and C‐terminal regions have distinct functions on mitochondrial fission and oxidation, opening up a previously unknown α‐syn‐mediated mitochondrial defective pathogenic pathway for PD.
Epigenetic measurement of biological age associates with tau load in normal brain aging
Authors: Maroni Marissa J , Wolk David A , Das Sandhitsu R , De Flores Robin , Wisse Laura , Xie Long , Yushkevich Paul A , Lee Eddie B , McMillan Corey T 
Published: December 2020

AbstractBackgroundAging is the most established risk factor for sporadic Alzheimer’s Disease (AD). However, relative risk of AD varies greatly across individuals. One potential explanation for this heterogeneity is that chronological age may not reflect differences in biological aging. One measure of biological age is the “epigenetic clock” which utilizes a weighted statistical model from >350 CpG sites that captures the cumulative work of an individual’s epigenetic maintenance system and has been demonstrated to relate to age, mortality, and survival. In this study, we test the hypothesis that the epigenetic clock will be related to two regional brain aging signatures associated with AD, including neurofibrillary tau tangle (NFTs) load and reduced cortical thickness.MethodsWe evaluated 40 cognitively normal, amyloid‐negative (PET‐Aβ <= 1.11) individuals from the Alzheimer’s Disease Neuroimaging Initiative dataset with DNA methylation, 18F‐Flortaucipr PET, and volumetric MRI data. 18F‐Flortaucipr PET and volumetric MRI data were processed using ANTs Cortical Thickness in 100 neocortical regions of interest (ROI) from the BrainColor/MindBoggle parcellation. 18F‐Flortaucipr PET and T1‐weighted MRI data was additionally processed using ASHS to derive 12 hippocampal subfield parcellations. Regression analyses related chronological age and Horvath’s “epigenetic clock” measurement of biological age to 18F‐Flortaucipr SUVR, mean cortical thickness, and hippocampal subfield volumes.ResultsIn healthy adults, we observed a positive association with increasing epigenetic age related to increased tau SUVR in the entorhinal cortex and the hippocampus (p = 0.029, R = 0.36; p = 0.028, R = 0.397). There was no association of epigenetic age with any of the neocortical tau SUVR ROIs and chronological age was not associated with tau SUVR in any of the hippocampal subfields or neocortical ROIs. In contrast, both epigenetic age and chronological age both trended toward associations of reduced cortical thickness in the neocortex.ConclusionsThis study suggests that epigenetic changes that occur with age may provide a risk factor for tau accumulation, more so than chronological age, and that is more tightly linked with age‐related tau pathological accumulation than age‐related cortical neurodegeneration.
Deficiency of WFS1 increases vulnerability to pathological tau in vitro and in vivo
Authors: Chen Shuo , Venkaraman Lalitha , Liang Jiawen , Nakano Yoshi , Villegas Nancy E. Hernandez , Brown Cris , Urano Fumihiko , Koks Sulev , Serrano Geidy E. , Beach Thomas G. , Davies Peter , Diamond Marc , Duff Karen E. , Fu Hongjun 
Published: December 2020

AbstractBackgroundPathological tau accumulates in patients with Alzheimer’s disease (AD) and related tauopathies. However, it remains unclear why specific neuronal subtypes and brain regions are vulnerable to pathological tau in early AD. Recently we found excitatory neurons expressing the Wolframin (WFS1) in the entorhinal cortex and the CA1 of hippocampus are particularly vulnerable to pathological tau in tau transgenic mice and human AD. However, the role of WFS1 in mediating this selective neuronal vulnerability is unknown.MethodThe tau aggregates in live cells were imaged as individual tiles and stitched via the Zeiss Observer 7 fluorescent microscope, and then the area with tau aggregates in each stitched image was quantitated by Image J. The tau pathology in mouse brain was visualized by MC1‐positive and conformation‐dependent tau via the immunofluroscent staining. The protein interaction between WFS1 and tau was measured by the Duolink Proximity ligation assay (PLA) and co‐immunoprecipitation (CO‐IP) assay.ResultHere we reported that overexpression of human WFS1 significantly reduced DS9 tau seeding in SH‐SY5Y cells stably transfected with P301S mutant tau, while overexpression of mutant P724L WFS1 did not. Also, overexpression of human WFS1 significantly reduced exogenous tau aggregation in primary mouse mixed neurons treated with P301S tau‐YFP lentivirus, while overexpression of mutant WFS1 did not. Furthermore, the heterozygotes of PS19 tau;NestinCre/+; Wfs1f/+
brain‐specific knock‐out mice and PS19 tau;Wfs1+/‐
knock‐out mice have much more tau pathology in the Dentate gyrus, CA1 and entorhinal cortex compared with PS19 tau and PS19 tau;Wfs1f/+
mice. The homozygotes of PS19 tau;NestinCre/+;Wfs1f/f
brain‐specific knock‐out mice and PS19 tau;Wfs1‐/‐
knock‐out mice have even more tau pathology than those heterozygotes. We further identified that WFS1 interacts with both total tau and pathological tau in primary cultured neurons, wild‐type and tau transgenic mice, and human non‐AD and AD cases. The interaction is first enhanced as tau pathology increases, however, it is reduced as tau pathology further increases.ConclusionTaken together, we demonstrate that deficiency of Wfs1 increases vulnerability to pathological tau in vitro and in vivo, indicating WFS1 may be a therapeutic target for preventing or delaying the tau pathology in AD.
Plasma YKL40 as a biomarker for brain aging and injury in three community cohorts
Authors: Pase Matthew P , Himali Jayandra J , Bis Joshua C , Beiser Alexa S , Satizabal Claudia L , Aparicio Hugo J , Maillard Pauline , DeCarli Charles , Ghosh Saptaparni , Gudnason Vilmundur , Psaty Bruce M , Tracy Russell P , Launer Lenore J , Fornage Myriam , Seshadri Sudha 
Published: December 2020

AbstractBackgroundYKL40 is expressed in reactive astrocytes and microglia and is upregulated in numerous neurological conditions associated with heightened neuroinflammation. We explored the utility of circulating YKL40 as a biomarker of accelerated brain aging and subclinical brain injury.MethodYKL40 was measured using the Mesoscale Discovery (MSD) multi‐array assay system from stored plasma in three community‐based cohorts: the Atherosclerosis Risk in the Communities Study (ARIC), the Coronary Artery Risk Development in Young Adults (CARDIA), and the Framingham Heart Study (FHS). MRI‐derived outcomes of total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) were expressed as a percentage of total intracranial volume. We derived a general cognitive factor from multiple neuropsychological tests capturing multiple domains using cohort‐specific principal component analysis with a forced single factor solution. We examined the association between log‐transformed and standardized YKL40 levels and MRI and cognitive phenotypes separately in each cohort using linear regression. Cohort specific results were then pooled in random‐effects meta‐analysis. Analyses were cross‐sectional and adjusted for age, age squared, sex, education (for cognition), and the time interval between the blood draw for YKL40 and outcome assessment. A second model included additional adjustments for vascular risk factors and presence of the APOE ε4 allele.ResultAcross cohorts, there were 2782 dementia‐free participants (mean age, 64 years; 45% male; Mean(SD) YKL40 levels = 50689(7114)pg/mL; YKL40 Coefficient of Variation = 7.5%). In random‐effects meta‐analysis, higher YKL40 levels were associated with smaller total brain volume (β±SE, ‐0.24±0.05 per percentage change in brain volume, p<0.0001) and poorer cognitive function (β±SE, ‐0.04±0.02 per unit change in cognitive composite, p=0.03). The association between YKL40 levels and total brain volume remained significant following full multivariable adjustments (β±SE, ‐0.23±0.05 p<0.0001) whereas the association between YKL40 and cognition was attenuated (β±SE, ‐0.04±0.02, p=0.06). YKL40 levels were not associated with hippocampal volume or WMHV (P>0.05).ConclusionHigher plasma YKL40 levels were associated with MRI and cognitive markers of accelerated brain aging, suggesting involvement of astrocytic or microglial mediated neuroinflammation in subclinical brain atrophy and cognitive impairment.
Defective axonal motility of a unique Huntingtin‐Rab4 vesicle causes synaptic defects and behavioral deficits seen in Huntington’s disease
Authors: Gunawardena Shermali 
Published: December 2020

AbstractBackgroundHuntington’s disease (HD) is a progressive neurodegenerative disease characterized by expansion in the polyQ region of Huntingtin (HTT). HTT is ubiquitous but the native function of HTT remains elusive. HTT is required for neuron survival and viability, as loss of HTT causes early embryonic lethality. Although HTT has been implicated to have numerous binding partners involved in a wide array of cellular processes, the significance of these interactions in neurons remain allusive. HTT moves bi‐directionally within axons. However, the specific vesicle types that HTT is present on and the cargoes that HTT‐containing vesicles carry to/from synapses are unknown. Here we test the hypothesis that HTT is involved in the motility of Rab4 whose function remains ambiguous.MethodsSimultaneous dual‐view imaging and computational analysis coupled with Drosophila genetics is used to isolate moving HTT‐Rab4 vesicles in vivo. Findings are validated in mouse brains and in neurons differentiated from iPSCs from WT and HD individuals.ResultsWe found that a sub‐population of moving Rab4‐containing vesicles contained HTT. Reduction of HTT disrupts the bi‐directional motility of Rab4, prompting axonal and synaptic accumulations. Simultaneous dual‐color in vivo imaging revealed that HTT and Rab4 are present on a unique class of vesicles that contain synaptotagmin, synaptobrevin, and/or Rab11, but not APP or Rab3. The HTT‐Rab4 vesicle uses kinesin‐1 and dynein for its bi‐directional movement within axons and is aided by HTT‐interacting protein HIP1 and Rab‐interacting protein Rip11/Rab11‐FIP5, but not HAP1. While pathogenic HTT disrupts Rab4 motility causing larval locomotion defects, synaptic morphological defects and decreased adult lifespan, expression of Rab4 rescues these pathogenic phenotypes. Consistent with these observations, Rab4 motility was perturbed in human neurons derived from HD patient iPSCs, likely due to disrupted associations between the polyQHTT‐Rab4 vesicle and motor proteins.ConclusionsOur observations propose a model in which HTT links unique Rab4 vesicles to motors for their motility to synapses. Pathogenic HTT perturbs the axonal transport of the HTT‐Rab4 vesicle causing synaptic and behavioral defects. The rescue of these pathogenic defects by excess Rab4 highlight a potential novel therapeutic target for early intervention prior to neuronal loss and behavioral defects observed in HD.
ACSS2 and the metabolic‐epigenetic axis in Alzheimer’s disease
Authors: Egervari Gabor , Berger Shelley L. 
Published: December 2020

AbstractBackgroundWe examine the contribution of the metabolic‐epigenetic regulatory axis1to protective histone acetylation in the brain, which is impaired in Alzheimer’s disease (AD). ACSS2 (acetyl‐CoA synthetase 2) is a key metabolic enzyme that is chromatin‐bound in neurons2. ACSS2 is recruited to specific promoters and maintains a local pool of acetyl‐CoA that fuels histone acetylation and drives the expression of key neuronal genes that regulate learning and memory.MethodWe characterize the genomic distribution of neuronal histone acetylation and ACSS2 in post‐mortem human brains from young, old and AD subjects. We also assess dynamic changes in chromatin localization and function of neuronal ACSS2 in mouse models of AD that rely on intra‐cerebral injection of human pathological AD‐tau in non‐transgenic mice3. To further establish the role of ACSS2 in AD etiology, we perform AD‐tau injections in mice lacking or overexpressing ACSS2 and assess consequent changes in AD neuropathology and phenotype.ResultWe showed that ACSS2 is required for brain histone acetylation as well as learning and memory in vivo
4. Intriguingly, we recently showed that loss of protective histone acetylation potentially underlies AD and related dementia in humans5. In post‐mortem human brains from young, old and AD subjects, we found that while normal aging is characterized by increased neuronal histone acetylation, this enrichment is lost in AD. We thus hypothesize that impaired function of ACSS2 could underlie the loss of protective histone acetylation in AD and consequent neuropathological and cognitive impairments. We anticipate that chromatin‐bound ACSS2 is lost during the development of AD and that this loss underlies subsequent changes in histone acetylation, chromatin accessibility and transcription of key neuronal genes required for learning and memory. We expect a more severe disease phenotype in ACSS2 knock‐out mice while ACSS2 overexpression might have a protective effect.ConclusionOverall, we expect this study to be of significant interest to the field as positive results could establish ACSS2 as a key neuroprotective metabolic enzyme and a potential new therapeutic target for humans suffering from AD. Acknowledgements: G.E. is supported by the Alzheimer’s Association Research Fellowship (AARF‐19‐618159).
Does verbal fluency test administration order impact performance?
Authors: Dominguez Antonella Yael , Aragón Irina , Sanjurjo Natalia Sierra , O´Neill Santiago 
Published: December 2020

AbstractBackgroundVerbal Fluency Tests measure the ability to produce words in a given time. Semantic fluency (SF) is related to the production of words within a category and phonological fluency (PF) with words that start with the same letter1. These tests are frequently used in the standard neuropsychological evaluation. Age, education2,3 and the order of administration4,5 can affect the performance. This study aims to evaluate the impact in the order of administration on verbal fluences performance in spanish.MethodCross‐sectional analytical study.52 healthy adults participated in this study. Participants were divided into two groups (G1 and G2) matched by age (M 64.48 DS 9.37), education (M 13.21 SD 4.65), gender (F: 31 M: 17) and estimated CI level based on years of education and their performance on a word accentuation test (WAT‐R)6. In G1 it was applied first SF and later PF. In G2 the order of presentation was inverted. T test and Pearson correlations were calculated in SPSS statistical program.ResultTwo outliers were found in G1. Taking out outliers and their matches, no significant effect in the order of application was observed when comparing both groups in the SF (t= 888 p = .379) and PF (t = ‐1.510 p = .138). When analyzing whether the order of fluencies administration varied the performance in G1 and G2, no differences were found for gender but a correlation with education was observed (SF: r = .30 p = .037; PF: r = .60 p <.001) and age (SF: r = .40 p = .005; PF r = .32 p = .027). When making a more detailed analysis of the groups, significant effect was observed for the years of education and FP (p = .002): the group with less than 7 years of schooling differed from groups from 8 to 12 (p =. 012) and more than 12 years of schooling (p =. 003).ConclusionThe results suggest that the performance in verbal fluences of older adults may be influenced by normal aging and years of education. This must be taken into account when choosing standards and interpreting the results of neuropsychological tests.
Assessment of naming by auditory confrontation in adults
Authors: Aragón Irina , Dominguez Antonella Yael , Sanjurjo Natalia Sierra , O´Neill Santiago , Rojas Galeno 
Published: December 2020

AbstractBackgroundOne of the most frequent symptoms in normal aging and in some neurodegenerative diseases is the difficulty to find words. Naming assessment is fundamental in a standard neuropsychological assessment. Even though visual difficulties have a high prevalence in older adults, visual confrontation tests have been utilized as the gold standard to detect the word finding impairment. In the Auditory Naming Test (ANT) different descriptions of objects are presented orally, and the patient should name the object described. Although there have not been published norms for adults for this test so far, the ANT has shown to be more sensitive than visual naming tests in mixed etiology dementia. The aim of this study was to analyze the ANT performance in older adults and generate normative data in Argentinian population (Spanish first language speakers).MethodCross‐sectional descriptive‐observational study. The participants were assessed with Spanish adaptation of ANT and Beck Depression Inventory. SPSS program was used and Pearson correlations, ANOVA, means and standard deviations were calculated.Result115 adults (79 women, mean age: 66.57 SD: 10.36, mean education: 13,86 SD: 5.04) without concomitant pathologies that potentially affect cognition participated were assessed (table 1). There were no differences in performance according to sex. A negative correlation with age was found (r ‐.289, p = .002). A positive correlation was found with education (r .308, p = .001). A later analysis revealed that this correlation only occurs in the group of 50‐59 years (r .605, p < .001) and 60‐69 years (r .405, p = .022).ConclusionIn the present study, the performance in the ANT of older adults was analyzed and normative data were generated. Age and education influence the performance of this test.
Subcortical atrophy in dementia with Lewy bodies
Authors: Philippi Nathalie , Noblet Vincent , Botzung Anne , Blanc Frédéric 
Published: December 2020

AbstractBackgroundDementia with Lewy bodies (DLB) is typically associated to less pronounced cortical atrophy than Alzheimer’s disease (AD). However, our clinical experience suggests that DLB patients have a prominent subcortical atrophy, contrasting with overall preserved neocortical and hippocampal regions. Therefore, the objective of the present study was to test the existence of a subcortical atrophy in DLB patients as compared to AD patients and normal controls. We hypothesized that patients with DLB would have larger ventricular volumes than AD patients and controls, at least when considering the ventricular volume relatively to the global cortical volume.MethodWe included 55 DLB patients (30 mild to moderate [d‐DLB], 25 prodromal [pro‐DLB]), and compared their cerebral volumes to those of 51 AD patients (31 mild to moderate [d‐AD], 20 prodromal [pro‐AD]), matched for age, educational level and MMSE scores, and to those of 17 healthy control subjects (CS), matched for age and educational level. Total ventricular volume (TVV) volumes were extracted using freesurfer. We also examine the ratio of the TVV against the total cortical volume (Cortex). We included Total intracranial volume and age as nuisance covariates.ResultWe found that both d‐DLB group(p = 0.003) and pro‐DLB group (p = 0.006) had significantly higher TVV compared to the CS. Compared to the AD patients, TVV was significantly higher in the d‐DLB group vs. the d‐AD group (p = 0.03), though, only at the level of a trend in the pro‐DLB group vs. pro‐AD group (p = 0.055). As for the TVV/Cortex ratio, a significant difference was found for the DLB groups compared to both CS (d‐DLB: p = 0.002; pro‐DLB: p = 0.004) and AD groups (d‐DLB vs. d‐AD: p = 0.03; pro‐DLB vs. pro‐AD: p = 0.04).ConclusionDLB patients have higher ventricular volumes compared to healthy controls and AD patients, reflecting a larger subcortical atrophy. This was more particularly the case when considering the ventricular volume relatively to the global cortical volume, which suggests it could serve as a potential biomarker for the differential diagnosis between DLB and AD patients, even at the prodromal stage.