bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain imaging and neuropsychiatric profiles associated with plasma cortisol level among nondemented older adults
Authors: Oh Hwamee , Leung Hoi‐Chung , Canli Turhan , Slifstein Mark 
Published: December 2020

AbstractBackgroundA predisposition to stress or expression of chronic stress‐related symptoms has been considered as a risk factor for Alzheimer’s disease (AD). To elucidate a neural mechanism underlying the risk of AD, we examined the relationship between glucocorticoids, glucose metabolism, hippocampal volume, and subsequent amyloid deposition among nondemented older adults.MethodWe assessed plasma cortisol level (cortisol), FDG counts in AD signature cortical regions, adjusted hippocampal volume, cognitive and neuropsychiatric measures and subsequent amyloid accumulation in 58 cognitively normal older adults (CNs) and 396 participants with mild cognitive impairment (MCIs) in the Alzheimer’s Disease Neuroimaging Initiative. Multiple regression models were applied to assess the relationships between these measures across all groups, followed by within‐group analyses. For psychological measures, neuropsychiatric inventory (NPI) scale total scores were assessed in relation with cortisol and neuroimaging measures.ResultHigher cortisol was associated with smaller adjusted hippocampal volume and greater NPI scores. With glucosemetabolic rates in AD signature regions, higher cortisol was associated with lower glucose metabolism in the MCI group, but with increased glucose metabolism in the CN group. Smaller hippocampal volume, but not higher cortisol, at baseline, was related to higher brain amyloid burden over time.ConclusionIndividuals’ susceptibility to stress as measured by plasma cortisol levels may confer risk for neurodegeneration and the development of AD pathology among nondemented older adults.
Brain network dysfunction associated with blood neurofilament light chain in autosomal dominant Alzheimer disease
Authors: Wheelock Muriah D. , Strain Jeremy F. , Ances Beau M. , Preische Oliver , Morris John C. , Bateman Randall J. , Jucker Mathias , Benzinger Tammie L.S. , Eggebrecht Adam T. , Gordon Brian A. ,   Dominantly Inherited Alzheimer Network
Published: December 2020

AbstractBackgroundAlzheimer disease is characterized by accrual of amyloid‐b and tau, cortical thinning, and disruptions in brain connectivity. Recent reports suggest neurofilament light chain (NfL), a measure of brain damage and atrophy, is measurable in the blood and is predictive of presymptomatic cognitive decline in individuals with autosomal dominant Alzheimer Disease. We sought to investigate the relationship between serum blood estimates of NfL and functional brain connectivity. We hypothesized that increasing NfL levels would be associated with increasing disruption of within and between network connectivity.MethodWe performed neuroimaging and blood serum NfL assessments in a longitudinal sample of 78 mutation non‐carriers (NC) and 112 mutation carriers (MC) age 20‐65 enrolled in the Dominantly Inherited Alzheimer Network. Serum blood samples were collected and assayed in duplicate for NfL. Resting state‐functional MRI (rs‐fMRI) data were acquired on 3T Siemens scanners. For each subject, five minutes of low‐motion rs‐fMRI data were included (scrubbing with FD <0.2 mm). Functional connectivity (FC) was estimated using zero‐lag Pearson correlations calculated between 246 regions of interest (Figure 1A). NfL values were compared between mutation carriers and non‐carriers using non‐parametric Mann‐Whitney U tests (Figure 1B). We examined associations between FC and NfL using a Network Level Analysis (NLA) approach. Briefly, NLA uses non‐parametric test statistics and permutation testing to determine FC networks associated with NfL scores (Figure 1A).ResultNfL was correlated with a wide‐range of within and between‐network connectivity in MC but not NC subjects (Figure 2A). The five strongest associations with NfL were within the DMN, cingulo opercular (CO) and dorsal attention (DAN) networks. Specifically, greater levels of NfL were associated with reduced magnitude of within‐ and between‐network connectivity (Figure 2D&E).ConclusionOnly in the MC group was NfL correlated with deterioration of the DMN and reduced connectivity between the DMN and other brain systems. Reduced connectivity between DMN and CO and DAN with increasing atrophy may be associated with executive and cognitive decline following full progression to Alzheimer’s disease. The present study suggests that indirect measurement of cell death and brain atrophy with serum NfL corresponds to reduced functional connectivity in presymptomatic Alzheimer’s disease.
Care ecosystem training: Developing a free online dementia course for a growing lay health workforce
Authors: Dulaney Sarah , Allawala Mahnoor , Thoma Mark , Merrilees Jennifer , Lynch Shalini , Chodos Anna H , Huffman Sara , Chiong Winston , Hooper Sarah M , Possin Kate L 
Published: December 2020

AbstractBackgroundThe Care Ecosystem is a telephone‐based dementia care program that is delivered by trained lay heath workers called Care Team Navigators (CTNs) who are supported and supervised by a clinical team with expertise in dementia (Possin, et.al., 2019). We hypothesized that health systems interested in implementing the Care Ecosystem would benefit from an asynchronous online training course to help prepare a dementia‐capable workforce.MethodWith a grant from the Merck Foundation, faculty and staff from the UCSF Memory and Aging Center and UC Hastings College of Law developed a series of brief videos (∼10min). Content was adapted for a lay, adult‐learner audience. Multiple choice post‐test questions were written to reinforce content. A Likert scale and an open‐ended question were used to collect feedback for each video. Presentations and quizzes were reviewed by our multidisciplinary team in monthly meetings and over email. Audio was recorded using a smartphone application and spliced with slides into an mp4 video using basic movie editing software. The Canvas Network platform was selected for ease of use, broad availability, and free user account options.ResultThe Care Ecosystem Training was released in September 2019 with a link embedded on the Care Ecosystem website (memory.ucsf.edu/care‐ecosystem) and email distribution to three implementation sites. By January 2020, 44 students enrolled in the course, 130 quizzes on 34 topics were completed with an average quality rating of 4.6 (out of 5).ConclusionThe Care Ecosystem Training demonstrates that simple, broadly available technology can be used to increase access to dementia care training. A peer review process helps tailor content for a lay health workforce. The Care Ecosystem Training is designed to be used with the Care Ecosystem Toolkit, and supplemented by clinical observation and case discussions with local clinicians. By prioritizing ease of access for users, the ability to collect user data may be limited. Feedback from quizzes will be used to improve the course.
MRI measures of neurodegeneration in the LEADS cohort
Authors: Dickerson Brad C. 
Published: December 2020

AbstractBackgroundAlthough early‐onset AD (EOAD) and late‐onset AD (LOAD) share the same pathologic substrate, there are notable differences in their atrophy patterns compared with LOAD. EOAD is associated with greater baseline cortical atrophy, less medial temporal lobe involvement and often more severe AD pathology than LOAD. In addition, MRI measures can be informative about likely etiology in patients with a clinical phenotype suggestive of EOAD who turn out to have biomarkers not consistent with EOAD.MethodIn LEADS, the goals of the MRI core are to 1) collect and perform quality control procedures using the ADNI 3 protocol; 2) collect and analyze T1‐ and T2‐weighted MRI data to obtain measures of atrophy (neurodegeneration) and white matter signal abnormalities; 3) collect and analyze advanced diffusion, perfusion, resting‐state functional MRI, and high‐resolution medial temporal lobe sequences. At present, we are focusing on the Freesurfer‐based analysis of T1‐weighted MRI data for the purposes of evaluating atrophy patterns to compare patients with elevated amyloid vs. those with low amyloid, and furthermore to try to identify patterns suggestive of non‐AD pathologies. Furthermore, we are comparing several methods for defining neurodegeneration from T1‐weighted MRI scans, including whole brain volume, hippocampal volume, average cortical thickness, and AD‐signature cortical thickness.ResultAs a group, the T1‐derived atrophy pattern relative to controls from patients with elevated amyloid show prominent lateral temporoparietal and posterior cingulate/precuneus atrophy. The low‐amyloid group do not show a clear pattern of atrophy, as a group. AD‐signature cortical thickness differs between EOAD and controls but not between EO‐nonAD and controls, while hippocampal volume differs between both patient groups and controls. In some patients with low amyloid, atrophy patterns are suggestive of likely FTLD pathology.ConclusionThe initial MRI data from LEADS support the observations reported from smaller studies of EOAD. Analyses are ongoing to determine whether MRI‐based definitions of neurodegeneration previously developed in LOAD are generalizable to EOAD.
MAPT mutations cause rapid progressive frontal temporal dementia: A case report
Authors: Mao Chenhui , Li Jie , Zhou Liangrui , Huang Xinying , Lei Dan , Liu Caiyan , Dong Liling , Gao Jing 
Published: December 2020

AbstractBackgroundFrontal temporal dementia (FTD) was a heterogeneous disease entity which was divided into behavior variant FTD (bvFTD), semantic dementia and none fluent progressive aphasia. The pathologic and genetic mechanism was much more complicated and intercrossed. Mutations in the microtubule‐associated protein tau (MAPT) gene were the first to be associated with inherited FTD and the clinicopathological phenotypes depended on tau isoform composition, relative disposition of abnormal tau in neurons and glia, as well as different anatomic distribution of tau pathology and neuronal loss.MethodWe reported a proven case of rapid progressive FTD with detail clinical description, neuroimaging, neuropathology and genetic data. Then we discussed the diagnosis and differential diagnosis thoughts.ResultIt was a 31 years old female patient admitted with behavior and psychiatric symptoms as well as rapid progressive dementia for 10 months. The onset symptoms included abnormal behavior, changed personality and apathy. Then she had cognitive disorder, declined memory, however, the ability of housekeeping, taking care of herself and daily life was kept. About 4 months later, she got dysarthria. No family history was found. Encephalitis was suspected. Brain MRI showed unilateral atrophy of right frontal and temporal lobe with white matter lesions. Lumber puncture revealed no inflammation reactions. Systemic screening for antibodies, abnormal metabolites, tumors was negative. Brain biopsy of right frontal lobe revealed severe loss and degeneration of neurons with extensive proliferation of glial cells. No active inflammation or necrosis was seen. Neurodegeneration was suspected. Genetic sequencing suggested MAPT (NM_005910.5) exon8 c.796C>G p.leu266val, which was a definite pathogenic mutation. The final diagnosis was MAPT related FTD.ConclusionWe reported an atypical case of bvFTD caused by MAPT mutation which was difficult in the diagnosis process, because of the short and rapid course and atypical neuroimaging manifestation.
Automated hippocampal segmentation improved by convolutional neural network approach in participants with a history of cerebrovascular accident
Authors: Zavaliangos‐Petropul Artemis , Tubi Meral A , Zhu Alyssa , Haddad Elizabeth , Jahanshad Neda , Thompson Paul M , Liew Sook‐Lei 
Published: December 2020

AbstractBackgroundCerebrovascular accidents (CVA) are risk factors for dementia, including Alzheimer’s disease (AD; Arvanitakis et al., 2016). Hippocampal atrophy is observed in both CVA (Gemmel et al., 2012) and AD (Braak & Braak, 1991) patients. Thus, the hippocampus may be an important biomarker for CVA patients with high AD‐risk. FreeSurfer, a commonly used automated hippocampal segmentation method to study post‐CVA hippocampal volume (Khlif et al., 2019), uses an atlas‐based approach, making it more likely to fail in the presence of CVA lesions (Yang et al., 2016). Two recent convolutional neural network‐based (CNN) hippocampal segmentation algorithms, Hippodeep (Thyreau et al., 2018) and Hippmapp3r (Goubran et al., 2019), are more flexible for post‐CVA anatomical changes since they do not rely on a single atlas. However, they have not been widely tested in CVA populations. Here, we compare the segmentation accuracy of FreeSurfer, Hippodeep, and Hippmapp3r in participants with a history of CVA.Method30 T1‐weighted structural brain MRIs from CVA participants with varying lesion sizes (0.43‐181.5 cc) in the Anatomical Tracings of Lesions After Stroke dataset (Liew et al., 2018) were used to compare FreeSurfer, Hippodeep, and Hippmapp3r to manual segmentations. Accuracy was measured as spatial overlap between each automated and manual segmentation using the Dice Coefficient (DC). An ANOVA was used to test for DC differences across methods.ResultDC significantly differed by segmentation method (F‐value=178.3;p‐value<2.10x‐16). Ipsilesional results: Hippodeep DC was significantly greater than FreeSurfer DC (p‐value=1.03x10‐17;t‐value=18.7) but not significantly different from Hippmapp3r DC. Contralesional results: Hippmapp3r DC was significantly greater than both Hippodeep (p‐value=9.53x10‐4;t‐value=4.52) and FreeSurfer (p‐value=4.68x10‐21;t‐value=24.8;Figure 1).ConclusionHippodeep and Hippmapp3r segmentations had significantly better accuracy than FreeSurfer, although all methods had a DC >0.7 (recommended threshold for good segmentation overlap; Zou et al., 2004). For ipsilesional segmentation accuracy, the two CNN methods did not significantly differ, while for contralesional segmentations, Hippmapp3r performed best. Future studies may benefit from using CNN approaches to more accurately estimate hippocampal volumes in patients with CVA with high AD risk.
Tau microtubule binding region in cerebrospinal fluid as a biomarker to differentiate tau pathology in Alzheimer’s disease
Authors: Horie Kanta , Barthelemy Nicolas R , Sato Chihiro , Bateman Randall J 
Published: December 2020

AbstractBackgroundTau deposition in brain is a pathological hallmark of some neurodegenerative disorders including Alzheimer’s disease (AD). Braak staging of post‐mortem tissue suggests pathological tau spreads through the brain via synaptically connected pathways, and specific tau isoforms containing the microtubule binding region (MTBR) are thought to be essential to form extracellular seeds that propagate pathology. Tau is cleaved at the mid‐domain and the N‐ter to mid‐domain species are actively secreted extracellularly, whereas MTBR‐tau show faster turn‐over and deposition in brain. Recently, we identified the MTBR regions (residues 299‐317 (HVPG) and 354‐369 (IGSL)) and the nearby region (residue 243‐254 (LQTA)) were specifically enriched in AD brain aggregates. However, if and how these species change in extracellular spaces under pathophysiogical conditions were not known. This work describes the behavior of the pathological species in extracellular spaces by analyzing human cerebrospinal fluid (CSF) with changes of disease progression.MethodWe established a method to quantify MTBR‐tau in CSF, consisting of chemical extraction followed by tryptic digestion and mass spectrometry analysis. This method was applied to the CSF analysis of AD participants (n=50 amyloid negative with CDR=0‐1, n=50 amyloid positive with CDR=0‐2). A subset of these participants was followed longitudinally (2‐9 years).ResultOur method revealed that (1) MTBR‐tau were specifically increased in amyloid positive group and HVPG was the most significantly increased even in clinically asymptomatic stages, (2) the increases of HVPG and IGSL were saturated after symptomatic onset, whereas LQTA continued to increase even after the clinical onset, and (3) the concentration of LQTA showed the highest correlation with tau pathology as measured by positron emission tomography (PET) for tau (Pearson r=0.84, n=35) as well as cognitive testing measures.ConclusionMTBR‐tau enriched in AD brain aggregates are increased in AD CSF. These findings suggest HVPG and LQTA in CSF could be promising biomarkers to recapitulate amyloid status and tau pathology in AD, respectively. Notably, only LQTA showed the continuous increase along to disease progression in terms of tau‐PET as well as amyloid status and cognitive decline, which suggests the region is key to differentiate tau pathology in AD.
Change in renal biomarkers and in structural MRI outcomes in chronic kidney disease (CKD) patients over three years
Authors: Murray Anne , Vemuri Prashanthi , Davey Cynthia , Reid Robert I. , Wille Samantha M. , Thostenson Kaely , Jack Clifford R. , Knopman David S. 
Published: December 2020

AbstractBackgroundWe report the associations between change in renal biomarkers in CKD and non‐ CKD participants and change in structural MRI outcomes over 3 years in the BRain IN Kidney disease (BRINK) study MRI cohort. The imaging outcomes were cortical thickness in Alzheimer’s disease signature regions, white matter hyperintensities (WMH), and fractional anisotropy in the corpus callosum (FA CC), an early marker of cerebrovascular disease.MethodsParticipants were ≥ 45 years with CKD (estimated glomerular filtration rate (eGFR) in mL/min/1.73 m2< 60; non‐ dialysis) or non – CKD (eGFR ≥ 60) in Minneapolis/St. Paul. CKD severity was measured by the eGFR and urine albumin creatinine ratio (UACR‐albuminuria, a measure of microvascular disease). Brain images were obtained on a 1.5 T Phillips Ingenia machine at baseline and 3 years. Linear regression models measured the associations between 3 year change in eGFR and UACR, as predictors of change in MRI measures: AD cortical thickness, WMH, and FA CC over 3 years. Adjusted models included age, gender, AA race, education years, cerebrovascular disease risk factor score (CVD RF), smoker/alcohol use, and pulse pressure as covariates, and TIV for change in WMH models.ResultsAt baseline, mean age of the 97 participants was 67 years, and mean eGFR was 37 for the CKD group vs. 83.2 for non‐ CKD (Table 1). Mean change in eGFR and UACR in the CKD group were ‐3.6 and +212, respectively compared with ‐ 8.5 and +1.7 in the non‐ CKD group. Mean WMH volume increase (+5.8 cc) and mean FA CC decrease (‐0.012) were significant in CKD (p < 0.001) for both (Table 2). In adjusted models both a 1% decrease and a ≥ 3 unit/year decline in eGFR were associated with a decline in FA CC over 3 years in the CKD group (β (SE) =‐0.020 (0.007); p = 0.004) and ‐0.0097 (0.0042); p = 0.025, respectively). Cortical thickness models were not significant. Unexpectedly, change in UACR was not associated with change in any MRI outcomes.ConclusionsDecreased eGFR was associated with decreased FA CC in CKD, suggesting that CKD progression exerts its influence largely through cerebrovascular mechanisms.
Hormetic effects of alcohol in an astroglial cellular model and its proteomics signature
Authors: Khorshidi Fatemeh , Poljak Anne , Jayasena Tharusha , Sachdev Perminder S. 
Published: December 2020

AbstractBackgroundHormesis or the adaptive stress response is a biphasic dose response to a factor which has a beneficial effect on cells or an organism at low doses while having a toxic effect at higher doses (1). Alcohol has been considered both a cause and protective factor for dementia (2) and arguably has a biphasic effect on brain cells. This study evaluated the dose‐ response relationship of ethanol on astrocytes in vitro, considering the importance of astrocytes in the support, maintenance and repair of neurons and the blood brain barrier (3). Cellular proteomics was performed to examine likely mechanisms underlying the effect.MethodsAn astrocyte cell line (U‐251) was used, incubating cells with increasing concentrations of ethanol. Cell viability and toxicity were evaluated by MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) and LDH (Lactate Dehydrogenase) Assay assays respectively. Proteomic profiling was performed (LC‐MS/MS) to assess differential protein expression in response to ethanol in the hormetic range, and at different timepoints after exposure (12 and 24hrs).ResultsAt low concentrations (0.1% to 1%) ethanol was stimulatory to U‐251 cell growth, and at high doses (5% to 20%) toxic effects were observed, demonstrating a biphasic curve in response to ethanol (Figure 1 & 2). Proteomic evaluation using cells exposed to hormetic doses of ethanol showed significant upregulation of proteins involved in DNA repair and cellular response to stress and DNA damage functions at 12 hours (Figure 3), while at 24 hours protein expression changes mostly related to apoptosis and regulation of reactive oxygen species (Figure 4).ConclusionThese results show that at low doses ethanol has a hormetic effect on the U‐251 astrocyte cell line, and a biphasic dose response curve is observed across the full ethanol concentration range. Proteomics profiling suggests that mechanisms of cellular protection within the hormetic range include upregulation of stress response proteins, DNA protection and factors which promote cell growth.
Cortical cerebral microinfarcts and risk of stroke, dementia and mortality: The Rotterdam study
Authors: Rojas‐Saunero Liliana Paloma , Doolabi Arwin , Vrooman Henri A , Ikram M Kamran , Ikram M Arfan , Vernooij Meike W , Hilal Saima 
Published: December 2020

AbstractBackgroundCortical cerebral microinfarcts (CMIs) –a novel MRI marker of cerebral vascular pathology have been linked with dementia and impaired cognition in cross‐sectional studies. However, it is unknown if cortical CMIs are an indicator of further cognitive decline and incident clinical outcomes. We examine the risk factors of CMIs on 1.5T MRI and their association with cognitive decline and risk of stroke, dementia and mortality.Method2156 participants (median age: 74.6 (range: 70.7‐79.3 years, women 55.6%) with baseline MRI (acquired between January 2009‐December 2013) and no prevalent dementia were included. Data on incident clinical outcomes were available (until January 2016) were included. CMIs on 1.5T were graded based on a previously validated criterion on 3T and were defined as the hypointense lesions on T1‐weighted images, <5mm in diameter, restricted to cortex and perpendicular to the cortical surface Markers of cerebrovascular disease (cortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds) and neurodegeneration (volumes of total brain and hippocampus) were collected. Cognition was assessed using a detailed neuropsychological test at baseline and at follow‐up after five years.Result227 individuals (10.5%) had one or more cortical CMIs. The main risk factors of cortical CMIs were male sex (OR: 1.86, 95%CI: 1.23‐2.82), heart disease (OR: 1.81, 95%CI:1.24‐2.63), cortical infarcts (OR: 6.03, 95%CI:3.79‐9.58) and lacunes (OR: 1.12, 95%CI: 1.03‐2.29). Persons with cortical CMIs showed cognitive decline albeit non‐significant. During a mean follow‐up of 5.2 years, 14 (6.5%) individuals with cortical CMIs developed incident stroke, 10 (4.6%) incident dementia and 76 (3.5%) died. People with cortical CMIs at baseline had an increased risk of strokes (Risk Ratio (RR): 1.66, 95%CI:0.8‐3.11), mortality (RR: 1.18, 95%CI:0.97‐1.43) compared to individuals with no CMIs, unlike the risk of dementia (RR: 0.72, 95%CI: 0.27‐1.30) albeit non‐significant.ConclusionCortical CMIs are highly prevalent in a population‐based setting and are associated with cardiovascular risk factors and increased risk of stroke and mortality albeit non‐significant. These findings provide new insights into the etiologic and prognostic significance of cortical CMIs. Future investigations will have to show whether screening and treating persons with cortical CMIs can effectively reduce the burden of stroke.