bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurodegeneration in the Longitudinal Evaluation of Early Onset Alzheimer’s Disease Study (LEADS) sample: Results from the MRI core
Authors: Collins Jessica A. , Ezzo Rania , Vemuri Prashanthi , Borowski Bret J , Iaccarino Leonardo , Joie Renaud , Lesman‐Segev Orit H. , Bourakova Viktoriya , Eloyan Ani , Aisen Paul S , Fagan Anne M. , Foroud Tatiana M. , Gatsonis Constantine , Jack Clifford R. , Kramer Joel H. , Koeppe Robert A. , Saykin Andrew J. , Toga Arthur W. , Day Gregory S. , Graff‐Radford Neill R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Salloway Stephen P. , Wolk David A. , Wingo Thomas S. , Carrillo Maria C. , Apostolova Liana G. , Rabinovici Gil D. , Dickerson Brad C. 
Published: December 2020

AbstractBackgroundApproximately 5% of the 5.6 million (∼280,000) Americans with Alzheimer’s disease (AD) develop symptoms at age 65 or younger and are classified as having early‐onset AD (EOAD). Although EOAD and late‐onset AD (LOAD) share the same pathologic substrate, there are notable differences in their clinical and biological phenotypes. The Longitudinal Early‐onset AD study (LEADS) is a multi‐site, observational clinical and biomarker study of EOAD. In the present study we utilized the currently available LEADS imaging data to explore the spatial extent and magnitude of neurodegeneration EOADMethod95 amyloid positive patients with EOAD, 37 amyloid negative cognitively impaired patients (EOnonAD) , and 55 cognitively unimpaired controls (CNs) were included in the analysis. The magnitude of cortical thinning in the EOAD and EOnonAD groups was estimated using whole‐brain GLMs compared to the CN group. In addition, w‐scores were derived for each EOAD patient for these ROIs: average cortical thickness, hippocampal volume, AD‐signature cortical thickness (typically used in LOAD), and precuneus cortical thickness controlling for age, sex, and acquisition site. The utility of each ROI to differentiate EOAD patients from CNs was assessed by calculating the percentage of patients falling below a W‐threshold of ‐1.5.ResultIn EOAD, a distributed pattern of cortical thinning was observed in lateral temporal, parietal, and frontal cortex (p<.01), and was most prominent in the precuneus (Cohen’s d’ = 1.5). In the EOnonAD group, cortical thinning was observed but was highly variable across individuals. The w‐score analysis in the EOAD group yielded the following results: Mean Cortical thickness: Mean = ‐3.34, SD = 2.97, Classification = 72%.; Hippocampal volume: Mean = ‐2.96, SD = 2.39, Classification = 74%; AD Signature: Mean = ‐4.63, SD = 3.07, Classification = 80%; Precuneus: Mean = ‐5.98, SD = 4.1, Classification = 90%.ConclusionOur results are consistent with previous findings demonstrating cortical thinning in lateral parietal, precuneus, and lateral temporal lobes in EOAD with relatively less involvement of the medial temporal lobes. Our results also suggest that the precuneus may be especially vulnerable to neurodegeneration in patients with EOAD and may serve as a useful biomarker for patient classification.
Reduced thalamic volume is associated with early brain pathology in preclinical autosomal dominant Alzheimer’s disease
Authors: Pardilla‐Delgado Enmanuelle , Torrico‐Teave Heirangi , Ramirez‐Gomez Liliana A , Baena Ana , Bocanegra Yamile , Vila‐Castelar Clara , Fox‐Fuller Joshua T. , Guzman‐Velez Edmarie , Martínez Jairo , Sanchez Justin S , Lopera Francisco , Quiroz Yakeel T. 
Published: December 2020

AbstractBackgroundSleep‐wake dysregulation may increase the risk of developing Alzheimer’s Disease (AD). In turn, AD pathology in sleep/wake regulatory brain regions may exacerbate sleep disturbances. It is unclear whether sleep dysregulation occurs before or after the onset of clinical symptoms in AD. In this study, we aimed to investigate whether the volume of brain regions known to regulate sleep/wake cycles (thalamus, brainstem sub‐regions) was different between carriers and non‐carriers of autosomal dominant AD (ADAD); and whether volume of such brain regions is associated with markers of brain pathology (amyloid and tau) and memory performance.MethodsA total of 36 non‐demented Presenilin‐1 mutation carriers and 32 age‐matched non‐carrier family members (mean age=36.3, SD=6.1) from the Colombia‐Boston (COLBOS) study underwent memory testing, and MRI and PET scanning. The CERAD word list delayed recall was used to assess memory; FreeSurfer was used to analyze bilateral volumes of the thalamus and sub‐regions of the brainstem (medulla, pons, superior cerebellar peduncle, midbrain); Pittsburgh compound‐B and flortaucipir (FTP) were used to assess cortical amyloid and entorhinal tau levels, respectively. Non‐parametric tests were used to assess group differences and correlations between brain volume, brain pathology, and memory.ResultsNo MRI volumetric differences were found between groups. In carriers, reduced thalamic volume was associated with greater mean cortical amyloid (r= ‐0.48, p=0.006) and entorhinal tau (r= ‐0.46, p=0.008). Reduced thalamic volume was also associated with worse memory performance (r= 0.38, p=0.03). When controlling for age, which is a proxy for clinical progression in this population, these associations were no longer significant. No associations were observed between memory, pathology, and any of the brainstem sub‐regions .ConclusionFindings suggest that brain regions important for sleep‐wake regulation do not show early signs of degeneration in preclinical ADAD. The association between reduced thalamic volume with both cortical amyloid and entorhinal tau supports previous work suggesting that thalamic structures are affected early in the preclinical stage of ADAD. Future research should focus on the functional abnormalities and AD‐related pathology in specific thalamic nuclei during preclinical ADAD, and their potential associations with sleep physiological features, such as thalamic spindles.
DAPT decreases the permeability of the BBB by reducing the ubiquitination and degradation of occludin during permanent brain ischemia
Authors: Ahmed Muhammad Masood , Tian Yun , Andleeb Shumaila , Zhang Gen‐Sheng , Tao Rong Rong , Ji‐Yun Huang , Shah Syed Nisar Hussain , Han Feng 
Published: December 2020

AbstractBackgroundTight junction protein degradation is a principal characteristic of the blood‐brain barrier (BBB) damage that occurs during brain ischemia.The aim of this study is to investigate the mechanisms of occludin degradation that underlie permanent middle cerebral artery occlusion (pMCAO) in rats.MethodWestern blot and Co‐immunoprecipitation data indicates ubiquitination and degradation of occludin in brain after pMCAO, which is consistent with ZO‐1 degradation in penumbra regions as observed at 24 h after pMCAO. It is further investigated that the candidate protease(s) is responsible for the degradation of occludin during pMCAO.ResultThe intraventricular administration of γ‐secretase blocker DAPT significantly inhibited the pMCAO‐induced neurovascular damage, whereas ALLM and Batimastat, which are inhibitors of calpain and metalloproteinase proteases, respectively, were less effective. Notably, it has been found that DAPT significantly inhibited BBB disruption in comparison with vehicle treatment, as assessed by Evans blue excretion. Interestingly, the confocal immunostaining revealed that activation of the E3 ubiquitin ligase Itch is associated with degradation of occludin in brain microvessels following ischemia. Furthermore, these data demonstrate that the inhibition of γ‐secretase signaling and the itch‐mediated ubiquitination of occludin likely underlie the vasoprotective effect of DAPT after pMCAO.ConclusionThe γ‐secretase blocker DAPT reduces the permeability of the blood‐brain barrier by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia, suggesting that γ‐secretase may represent a novel therapeutic target for preventing neurovascular damage.
Plasma tau is negatively correlated with frontal lobe CBF in hypertensive adults on the AD spectrum
Authors: Swinford Cecily G , Risacher Shannon L. , West John D. , Chumin Evgeny J. , McDonald Brenna C. , Unverzagt Fred W. , Gao Sujuan , Farlow Martin R. , Apostolova Liana G. , Wu Yu‐Chien , Brosch Jared R. , Tallman Eileen F. , Deardorff Rachael , Kamer Aaron P. , Wang Danny J.J. , Zetterberg Henrik , Blennow Kaj , Saykin Andrew J. 
Published: December 2020

AbstractBackgroundHypertension can lead to vascular dementia by causing cerebral hypoperfusion, and it may play a similar role in AD. Hypertensive individuals with AD have poorer cognition than normotensive counterparts (Moonga et al 2017), and CSF tau increases more quickly in at‐risk older adults with hypertension than in those without (Bos et al 2019). We investigated the relationships between cerebral blood flow (CBF), plasma tau and hypertension in two cohorts of older individuals.MethodsParticipants included 30 cognitively normal (CN), 19 subjective cognitive decline (SCD), 17 mild cognitive impairment (MCI), and 8 AD. Groups were defined by CN/SCD and MCI/AD. Participants had 3D pseudo‐continuous arterial spin label (pCASL) 3T Prisma MRI and plasma tau Simoa assay from the same visit. Multiple regression was used to assess the relationship between CBF and plasma tau on a regional and voxel‐wise basis with age, sex, diagnostic group, and total grey matter as covariates. A replication analysis between CBF from 2D pulsed ASL and plasma tau was completed in an independent sample (11 CN, 4 SCD, 15 MCI, 6 AD).ResultsHypertensive individuals had higher plasma tau than normotensive, regardless of diagnostic group (β=0.254, p=0.031), the replicate sample had the same relationship (β=0.320, p=0.086). Global CBF, however, differed by group (CN/SCD > MCI/AD; p<0.001). Multiple regression analysis revealed negative correlations between CBF and plasma tau in frontal and temporal regions but positive correlations in occipital regions. Within the frontal cortex and anterior cingulate, mean CBF and plasma tau were negatively associated in hypertensive individuals (β=‐0.503, p=0.003) but not in normotensive (β=‐0.143, p=0.283). Similar associations were found in hypertensive (β=‐1.067, p=0.001) and normotensive (β=‐0.257, p=0.183) individuals in the replicate analysis. The interaction term for hypertension by plasma tau was negatively correlated with frontal CBF in both samples (β=‐0.795, p=0.051; β=‐0.912, p=0.052).ConclusionsIncreased plasma tau is associated with decreased CBF in anterior brain regions in individuals with hypertension, suggesting that hypertension exacerbates the effect of AD pathology on cerebrovascular health.
Modeling the effects of respirasome supercomplex formation on AD progression by incorporation of mitochondrial gene expression data
Authors: Shelton Morgan , Castora Frank J. , Kerns Kimberly A. , Coleman Randolph A. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease is a specific form of dementia characterized by the aggregation of amyloid‐β plaques and tau tangles. New research has found that the formation of these aggregates occurs after dysregulation of respiratory chain activity. Proteomic and genomic data show that these changes are also related to unique gene expression patterns. Supercomplexes (SCs) are assemblages of multiple, functional respiratory complexes. After individual complexes have formed, respiratory complexes (RC) I, III, and IV begin to associate and form SCs. SCs are stable intermediates between respirasomes and individual complexes. We investigated the impact of our observed gene expression changes on new therapeutic options via metabolic flux analysis of SC assembly.MethodTotal RNA was isolated from 80‐180 mg of frozen brain tissue from 11 AD and 5 control samples. Total RNA was quantified and assessed for purity using Nanodrop and Bioanalyzer analysis. cDNA was prepared and applied to the Human Mitochondrial Energy Metabolism and the Mitochondria RT² Profiler™ PCR Arrays. The qPCR data was then analyzed using Qiagen RT2 Profiler PCR Array Data Analysis version 3.5. Gene expression changes were incorporated into the mathematical model created in CellDesigner 4.2 and these were converted into a series of mathematical equations by SBMLsqueezer. This file was imported into COPASI, a biological pathway simulation program. Treatment data were found using COPASI’s time course task. Each treatment represented a mathematical change in gene expression of a selected enzyme.ResultWe investigated 9 mitochondrial genes known to be important for efficient SC assembly. In all cases, the concentration of the gene products was decreased in the AD brain samples. After simulation of respirasome assembly using a reduced model only UQCRC1 treatment increased the percent of CI sequestration into respirasomes.ConclusionOur results indicate that protective changes in expression of UQCRCI, a component of electron transport chain respiratory complex III may serve as a potential avenue for AD therapeutics. This work also highlights the importance of metabolic enzyme activity in maintaining proper respiratory activity.We would like to acknowledge support for this work from the Alzheimer’s and Related Diseases Research Award Fund and the Commonwealth Health Research Board.
Progranulin improves memory in normal aging and Alzheimer’s disease
Authors: Farr Susan A. , Niehoff Michael L. , Nguyen Andrew D. 
Published: December 2020

AbstractBackgroundProgranulin is a lysosomal and secreted protein that has neurotrophic properties and promotes neurite outgrowth in vitro. Mutations in the progranulin gene have been found to cause frontotemporal dementia. Additionally, reduced progranulin levels may be a risk factor for the development of Alzheimer’s disease (AD). Studies in mouse models of AD support this notion: reducing progranulin exacerbates disease progression whereas increasing progranulin confers protection. However, the physiologic function of progranulin in the CNS is not known.MethodWe tested the effects of CNS‐administered progranulin in the cognition in young male CD‐1 mice, (3‐months of age), old C57/BL male mice (24 months of age) and 3xTG‐AD male and female mice (13 months of age). Immediately following T maze foot shock avoidance training, CD‐1 mice (n = 10 per group) were injected intracerebroventricularly (ICV) with progranulin (0, 0.005, 0.1 or 1.0 ug/2 ul). C57/BL 24 month old (n= 8∼9/group) and the 13 month old 3xTG‐AD mice (n = 8∼9/group) were given either 0 or 1.0 ug/2 ul immediately after training. Retention was assessed one week after training. The number of trails to reach a criterion of 5 avoidances in 6 consecutive trails was determined. Following behavioral testing, cortex, hippocampus, and plasma were harvested.ResultCD‐1 mice that received and an ICV injection of progranulin 0.1 and 1.0 ug/2 ul had significantly improved retention in T‐maze than the mice which receive vehicle. These mice took significantly fewer trials to make an avoidance than the mice which received 0 ug/2 ul. Progranulin at 1.0 ug/2 ul improved retention in the 24 month old C57/BL mice and the 13 month old 3xTG‐AD mice.ConclusionIt is becoming increasingly apparent that progranulin is involved in memory dysfunction. We found that progranulin has a direct influence on memory consolidation as its administration following foot shock avoidance training leads to improved memory retention. Our studies suggest that progranulin can directly modulate memory in both cognitively normal and AD mice, indicating that is has an important role not only in the pathogenesis of frontotemporal dementia, but in normal aged‐related cognitive decline and AD progression as well.
The virtual interface for neurodegenerative disease management: A systematic literature review on the feasibility of telemedicine in dementia care
Authors: Gosse Paula , Masellis Mario , Etchells Edward , Mitchell Sara Berman 
Published: December 2020

AbstractBackgroundAs the global population ages and the prevalence of dementia rises, telemedicine has garnered attention as a means of delivering care to a frail cognitively‐impaired population through a virtual interface. The benefits of telemedicine‐based in person patient‐physician encounters include increased access to healthcare irrespective of distance, as well as reduction in travel costs and carbon emissions. While Telemedicine has proven feasible and effective in other areas of medicine, its use in a cognitively‐impaired population is less well studied and poses unique challenges. The current literature review aims to compare and contrast the use of televisits across neurodegenerative disease, with a particular focus on dementia care.MethodWe performed a systematic review of the literature published between January 2000 and January 2020. Databases OVID Medline and PubMed were searched using keywords “Telemedicine”, “Neurodegenerative disease”, “Dementia” and their respective synonyms. Eligible articles were selected after screening the titles and abstracts. Studies were included if they examined the use of virtual healthcare visits (i.e. televisits) in the management of patients with neurodegenerative diseases.ResultThe search yielded 503 potentially eligible articles. After further screening, a total of 35 articles met inclusion criteria. Positive benefits of televisits across neurodegenerative diseases included high rates of patient satisfaction, feasibility and validity. A particular challenge that emerged as unique in dementia care is a lack of interpersonal engagement.ConclusionWhile telemedicine has clear potential benefits for neurodegenerative disease management, further research is required to assess long‐term clinical and quality of life outcomes in patients with dementia.
Occupational exposure as a risk factor for cognitive impairment in Vietnamese nail salon workers
Authors: Nguyen Thuc‐Nhi , Nguyen Mai Tram , Chen Shuai , Hinton Ladson 
Published: December 2020

AbstractBackgroundNail salon technicians are continuously exposed to neurotoxic and carcinogenic properties in nail products that may put them at risk for central nervous system impairments linked to Alzheimer’s disease. However, there are very few studies of the nail‐care workplace, and even fewer focus on Vietnamese female nail technicians, who make up the overwhelming part of the workforce. This study provides preliminary data on clinical assessments that will inform the cognitive functioning of a vulnerable population.MethodSample includes 300 Vietnamese females aged 50 or above in Northern California. The nail‐technician group (n=155) self‐identified as a current or former full or part‐time nail technician. The non‐nail group (n=145) are those who have never worked in the cosmetic industry, including nail or hair salons, but were an approximate match with the nail technicians on demographics and acculturation variables. Participants completed the Montreal Cognitive Assessment (MoCA), the Center for Epidemiologic Studies Depression Scale (CES‐D), and a self‐reported bilingual survey regarding their occupational exposure and demographics.ResultThe average MoCA score was 18.8 (SD ±4.50) for non‐nail technicians, which is significantly higher than 17.60 (SD ±4.30) for nail technicians (p = 0.017). However, there was no significant difference between the two groups on the average CES‐D score (p = 0.22). Based on results of multiple linear regression, with an increase of 100 in exposure index (i.e., years working in current nail salon x hours worked per week), the MoCA score is expected to decrease by 0.29 (95% CI: 0.05, 0.53, p = 0.017).ConclusionAfter adjusting for potential confounders, Vietnamese nail technicians were found to have lower cognitive functioning that those without occupational exposure to nail salon work. The results of this study suggest the need for future longitudinal research to better elucidate the processes underlying this association.
Comparison of digital platforms for participant recruitment in dementia research: Lessons and future directions from a global collaborative
Authors: Jeon Yun‐Hee , Fargo Keith , Smith Adam , Langbaum Jessica B , Nosheny Rachel L , Zwan Marissa D , Shin Mirim , Scheltens Philip , Weiner Michael W , Rossor Martin N 
Published: December 2020

AbstractBackgroundDelays in finding the right research participants can result in studies taking longer to deliver, often requiring funding extensions and ultimately limit the effectiveness of research and evaluation when study samples are insufficient for robust analysis and generalisation of findings. Recruitment challenges in dementia research are a global issue.MethodTo improve the effectiveness and efficiency of participant recruitment efforts in dementia research, innovative digital platforms have emerged over the past ten years: TrialMatch, Alzheimer's Prevention Registry & GeneMatch, and Brain Health Registry (USA), Join Dementia Research (UK), Hersenonderzoek (Netherlands), and StepUp for Dementia Research (Australia). Established in 2019, a global collaborative of these platforms aims to generate new insights and evidence that can help further enhance the service provision and potentially support other similar global initiatives. This paper provides an overview and comparison of the platforms, including key successes and challenges in their service delivery.ResultTrialMatch was the first platform developed to support recruitment processes in 2010. To date, collectively, the seven platforms have over 920,000 volunteer members; >50% of them had opportunities to take part in studies as a result. The services are mostly free and rely on government grants and/or philanthropic funding for their delivery. They share common features (e.g., matching volunteer demographic and clinical information with studies) although some collect and use more detailed genetic and clinical profiles than others. Examination of the matching mechanisms and volunteer data access processes across the platforms suggests various opportunities to enhance the platforms. Key outcomes of these platforms also include a positive change in the way the public perceives dementia research and a systematic way for the public to engage in research. Understanding social and economic impact and ensuring sustainability of the platform and its service delivery are crucial steps for the future.ConclusionThe seven digital platforms have been showing their power and potential impact not only in fast‐tracking dementia research but also in improving public engagement and participation. Through this global partnership, the members share practices and strategies for sustainability of the programs that can contribute to the development of ‘good’ sustainable models for dementia research recruitment services.