bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different profiles of cognitive deficits predict progression rate in probable AD
Authors: Sood Ajay , Pavlik Valory N. , Darby Eveleen , Chan Wenyaw , Doody Rachelle 
Published: December 2020

AbstractBackgroundHeterogeneity in the pattern of cognitive deficits seen in probable AD patients is well recognized. Two reliably reproducible profiles are ones that have an extreme deficit in either visuo‐spatial (Vis‐D) or language (Lang‐D) domains compared to all other domains, independent of memory performance. Information on variability in progression rates and overall survival associated with these profiles is lacking.MethodRight handed probable AD patients followed longitudinally in a memory clinic, 50‐90 years old with baseline MMSE score ≥10, were classified as Vis‐D or Lang‐D if their scores on tests of visual and language function varied by ≥ 2 standard deviations. Proportional hazards analysis was used to compare time to reach an MMSE < 10, CDR global score=3, and survival time from diagnosis to death in Vis‐D, Lang‐D and balanced deficits (Bal‐D) groups, adjusting for age, sex, education, ethnicity, baseline co‐morbidity, and APOE genotype.ResultOf 540 patients meeting inclusion criteria, 86 (15.9%) were Vis‐D and 61 (11.3%) were Lang‐D. Median follow‐up time after baseline was 3.30 years (range 0.9, 13.3) and median time to death was 5.50 years (range=1.0, 16.8). The Vis‐D group was younger at diagnosis and had a higher prevalence of APOE e4 homozygosity than the Lang‐D and Bal‐D groups (69.8±8.5 vs 76.3±7.1 and 75.0±7.5 years and 25.9% vs 10.2% and 14.1% APOE e4 homozygosity respectively). Lang‐D patients reached a severe stage on the MMSE more rapidly than Vis‐D and Bal‐D (HRLang‐d vs Bal‐D=1.68, 95% CI=0.99‐2.73, p=.054; HRLang‐D vs Vis‐D=2.04, 95% CI=1.06‐3.78, p=.032). Results for the CDR endpoint were similar (HRLang‐D vs Bal‐D=1.64, 95% CI=1.04‐2.56, p=.032; HRLang‐D vs Vis‐D=2.32, 95%CI=1.40‐4.57, p=.002). Cognitive profile did not affect time to death.ConclusionProbable AD patients with a Lang‐D cognitive profile decline faster on the MMSE and CDR than those with other cognitive profiles. Cognitive profile at diagnosis does not affect overall survival. Understanding the neuropathology underlying these cognitive profile differences could have implications for development or selection of disease modifying treatments.
Microglial phenotypes in the brains of aging people with Down syndrome and Alzheimer disease
Authors: Martini Alessandra Cadete , Helman Alex M. , McCarty Katie , Lott Ira T. , Doran Eric , Schmitt Frederick A. , Head Elizabeth 
Published: December 2020

AbstractBackgroundMicroglial cells play an important role in maintaining normal brain function, but changes in microglia morphology may reflect the functional state of the cell, and potentially contribute to the development and progression of Alzheimer disease (AD). People with Down syndrome (DS) inevitably develop AD neuropathology by 40 years of age, but little is known about microglial phenotypes in this population.MethodsAutopsy tissue from the posterior cingulate cortex (PCC) from six groups were included in the study: DS (<40 years), DS with AD (>40 years), sporadic non‐DS AD and young, middle‐aged and aged non‐DS controls. Sections were stained with the microglia marker Iba1 and scanned with the Aperio ScanScope XT digital slide scanner Five microglia morphological types were assessed: ramified, hypertrophic, dystrophic, rod‐shaped and amoeboid.ResultsAcross all groups, individuals with DS have higher numbers of hypertrophic microglial cells in their white matter. In the gray matter, the numbers of ramified microglial cells declines with age across controls and individuals with DS. Individuals with DSAD had significantly fewer ramified microglia than controls and the younger individuals with DS. Higher numbers of dystrophic microglia were also observed in individuals with DSAD relative to the other groups. Interestingly, individuals with DSAD also exhibited more rod‐shaped and amoeboid cells than the AD group.ConclusionOverall, individuals with DS and DSAD are associated with a microglial phenotype that distinguishes them from non‐DS controls. Our findings suggest a progressive change in microglia patterns over time as people with DS are aging with a trend towards more dystrophic microglial cells. These results reinforce the differences observed in the neuroinflammation phenotype in individuals with DS, and contribute to our understanding of the role that microglia cells play in the development and progression of AD neuropathology and dementia in people with DS.
Shared genetic etiology underlying late‐onset Alzheimer’s disease and post traumatic stress syndrome
Authors: Lutz Michael W. , Luo Sheng , Williamson Douglas E. , Chiba‐Falek Ornit 
Published: December 2020

AbstractBackgroundPatients with late‐onset Alzheimer’s Disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms (NPS) with depression and anxiety being most prevalent. Posttraumatic stress disorder (PTSD) is a neuropsychiatric condition that is highly comorbid with depression and anxiety and PTSD patients also have an increased risk for developing dementia. These evidences suggest the possibility of shared etiologies and intersecting pathways between LOAD and PTSD. We investigated genetic pleiotropy between LOAD and PTSD.MethodWe assessed genetic pleiotropy by using a conditional false discovery rate framework based on GWAS summary statistics: LOAD (IGAP, ADG Consortium study of genetic risk for Alzheimer’s disease in African Americans); PTSD (Psychiatric Genomics Consortium PTSD GWAS (discovery), the Genetic and Environmental Predictors of Combat‐Related PTSD study (replication). Functional bioinformatics and gene expression analysis was completed for genes that replicated in the discovery and replication cohorts.ResultWe found enrichment of 2.2‐5.6 fold for SNPs associated with LOAD across increasingly stringent levels of significance with PTSD association. The reverse conditional association showed a modest enrichment of approximately 1.3‐5.0 fold. Similar fold enrichment was observed for the African American samples. Six genes were identified as FDR significant for the association with LOAD conditional on PTSD for both the discovery and replication cohorts. Four genes in the MS4 gene family replicated in the two independent PTSD datasets, pointing to a role for genes associated with immunity in the shared genetic signature. These genes showed a shared, consistent expression pattern in the cerebellar hemisphere and cerebellum and a similar expression pattern in the amygdala, hippocampus, cortex and frontal cortex. Cross‐brain‐tissue analysis identified a significant association (P = 2.9 × 10−7) for the MS4A6A gene. There were no FDR significant results in either direction for the African American dataset.ConclusionIdentifying common genetic signatures for LOAD and PTSD advances understanding of shared genetic etiologies and impaired pathways between these conditions. Our data suggest that immune function genes may play a role in both PTSD and LOAD, implicating common pathways. This knowledge provides insights for actionable targets to treat NPS earlier in life to delay or ultimately prevent the onset of LOAD.
Increases in periventricular white matter hyperintensities associate with Alzheimer disease biomarkers
Authors: Kilgore Collin B. , Strain Jeremy F. , Benzinger Tammie L.S. , Morris John C. , Ances Beau M. 
Published: December 2020

AbstractBackgroundVascular dysfunction can compound white matter damage in an Alzheimer disease (AD) cohort, leading to the formation of white matter hyperintensities (WMHs). The spatial distribution of WMHs at various stages of the disease is of interest, as previous work has found that patients with late‐onset AD show the earliest changes in posterior regions. We evaluated whether volumetric and microstructural changes within WMHs and normal‐appearing white matter were associated with biomarkers for AD.MethodT2‐weighted‐Fluid‐Attenuated Inversion Recovery (T2‐FLAIR) MRI images and diffusion tensor imaging (DTI) were obtained from 199 biomarker (amyloid PET) negative in centiloid, cognitively normal; 48 biomarker positive, cognitively normal (preclinical AD); and 19 biomarker positive, cognitively impaired participants (symptomatic AD) followed by the Knight Alzheimer Disease Research Center. Cognitively normal was defined as having a clinical dementia rating (CDR) of 0. Masks demarcating periventricular (PVWMHs) or deep (DWMHs) WMHs were created based on their proximity to the lateral ventricles and quantified as singular values representing the extent of lesion burden. PVWMHs were further dichotomized as anterior or posterior based on their location relative to the mid‐slice of the corpus callosum. Each WMH map was overlaid onto the corresponding diffusivity map, and mean diffusivity (MD) was used to evaluate white matter tract integrity within WMHs. Volumetric and DTI data were compared among disease groups using a Mann‐Whitney test of medians.ResultIncreases in PVWMH but not DWMH volume were associated with AD progression in a stepwise manner – symptomatic AD participants had the largest PVWMH volume compared to preclinical AD (p=0.003) and biomarker negative participants (p<0.001). MD within PVWMHs was significantly increased for preclinical and symptomatic AD participants when compared to biomarker negative controls. Within PVWMHs, posterior but not anterior PVWMH volumes were significantly increased (p=0.029) among preclinical AD participants compared to biomarker negative controls.ConclusionPVWMH volume associated with AD biomarkers and posterior regions showed increases in PVWMHs among participants with preclinical AD. Increases in MD within WMHs were present in asymptomatic individuals, suggesting potential for measurable changes in axonal integrity prior to symptom onset. These results suggest a more direct link between AD and WMHs.
Depression and anxiety disorder along life in familial Alzheimer’s disease in the API ADAD Colombia trial
Authors: Ramos Claudia , Rios‐Romenets Silvia , Giraldo‐Chica Margarita , Acosta‐Baena Natalia , Tobon Carlos , Lopez Hugo , Aguirre‐Acevedo Daniel C. , Langbaum Jessica B. , Reiman Eric M. , Tariot Pierre N. , Lopera Francisco 
Published: December 2020

AbstractBackgroundSome late‐onset Alzheimer’s disease studies suggest that affective disorders begin before cognitive impairment and promote decline. Nevertheless, it has been observed that in Autosomal Dominant Alzheimer’s Disease (ADAD), asymptomatic mutation carriers have a lower risk of disorders such as depression compared to non‐carriers. The relationship between affective disorders and Alzheimer’s disease would be clearer if there were more studies in preclinical Alzheimer’s disease. Currently, the biggest population of familial Alzheimer’s disease, caused by the PSEN1 E280A mutation, is located in Colombia. The Alzheimer’s Prevention Initiative (API) ADAD Colombia trial is being conducted with PSEN1 E280A carriers and non‐carriers, cognitively unimpaired at baseline. During screening, investigators asked about antecedents of mental health disorders. We examined whether asymptomatic mutation carriers reported a different rate of affective disorders compared to non‐carriers.ObjectiveTo compare the prevalence of affective disorders between PSEN1 E280A mutation carriers and non‐carriers at the time of API ADAD trial screening.MethodWe performed a retrospective analysis to understand the history of affective disorders (reported by participants), after screening 315 mutation carriers and non‐carriers aged 30 ‐60 years. The comparison between carriers and non‐carriers was made by a generalized linear regression model. Results were adjusted by age, gender, educational level and the Clinical Dementia Rating (CDR) scale. Odds ratios (OR) were used as measure of association, with a 95% confidence interval (95%CI).Result315 candidates underwent screening: 210 carriers and 105 non‐carriers. Of people with antecedent of affective disorders, 65 (30.9%) were mutation carriers and 32 (30.5%) were non‐carriers. Comparing carriers with non‐carriers, the OR for depression was 1.010 (95%CI 0.492 – 2.113) and for anxiety was 1.325 (95%CI 0.485 – 3.938). Results were similar after excluding 15 participants with CDR of 0.5.ConclusionAlthough there were no differences between groups, the prevalence of affective disorders through life was high in carriers and non‐carriers, compared to the adult Colombian population (30.8% vs 6.7%). Possible reasons include: 1) Concern about having a family with an elevated risk of AD; 2) observing the progressive decline of close relatives; 3) living with or caring for persons with dementia.
Establishment of a transgenic mouse line for monitoring exposure history to electrophilic stress
Authors: Kitamura Hiroshi , Oishi Tetsuya , Yamada‐Kato Tomoe , Okunishi Isao , Motohashi Hozumi 
Published: December 2020

AbstractBackgroundKEAP1‐NRF2 system is a major response mechanism against electrophilic stress. In normal condition, NRF2 is ubiquitinated by the KEAP1‐CUL3 ubiquitin E3 ligase complex in the cytoplasm, resulting in degradation through the proteasome. On the exposure to electrophilic stress, KEAP1 is inactivated leading to nuclear translocation of NRF2 and inducible expression of antioxidant proteins and detoxification enzymes. NRF2 activation caused by electrophilic phytochemicals has been shown beneficial for various human disorders including neurodegeneration such as Alzheimer’s disease. However, due to the transient and fluctuating nature of the NRF2 activation, it has not been easy to detect the electrophilic response, i.e., NRF2 activation, at a single‐cell resolution.MethodIn order to establish an in vivo detection system of NRF2 activation at a single‐cell resolution, we generated a unique mouse model by utilizing Neh2 domain of NRF2. Neh2 domain is located at the N‐terminus of Nrf2 and known as a degron mediating ubiquitination and degradation of NRF2 in KEAP1 dependent manner. We first established a transgenic mouse line expressing Neh2‐Cre recombinase fusion protein ubiquitously under the regulation of mouse Mafg gene regulatory region (MGRD‐Neh2‐Cre mouse). Secondly, we crossed the transgenic mouse with Rosa‐CAG‐LSL‐tdTomato mouse and obtained MGRD‐Neh2‐Cre:Rosa‐CAG‐LSL‐tdTomaato (Neh2‐Cre:tdTomato) mouse. In this mouse, Neh2‐Cre was expected to be stabilized under electrophilic stress and subsequently induce expression of tdTomato by recombining the Rosa locus.ResultAlthough a single dose of an electrophilic compound, CDDO‐Im, did not induce tdTomato expression in Neh2‐Cre:tdTomato mice, repeated administration of CDDO‐Im gradually increase the number of cells expressing tdTomato in various organs. Furthermore, the mice continuously treated with 6‐methylsulfinylhexyl Isothiocyanate (6‐MSITC) in drinking water for 4‐5 months, which is a weak electrophile compared with CDDO‐Im, exhibited tdTomato expression in various organs including brain. These results suggest that 6‐MSITC as well as CDDO‐Im activates KEAP1‐NRF2 system in the central nervous system.ConclusionWe consider that the established Neh2‐Cre:tdTomato mouse is especially useful to monitor the cumulative weak response to chronic/repetitive electrophilic stimuli. Our study suggests that 6‐MSITC as well as CDDO‐Im can be applied for therapeutic approaches of aging‐related neurodegenerative disorders by activating NRF2 in the central nervous system.
Trajectory of physical activity and risk of dementia: A national‐based cohort study
Authors: Feter Natan , Leite Jayne S , Smith Emily , Coombes Jeff , Rombaldi Airton 
Published: December 2020

AbstractBackgroundDementia is a leading cause of morbidity and mortality worldwide. Physical activity (PA) appears as an alternative approach to reduce the burden of this disease especially among older adults. We aimed to identify the effect of changes in PA status among older adults on risk of dementia.MethodsWe analyzed data from wave 1 (2002‐2003) to wave 8 (2016‐2018) of the English Longitudinal Study of Aging. PA level were categorized in sedentary, low, moderate, and high. We only considered dementia diagnosed from wave 2 (2004‐2005) to wave 8. The probability of being diagnosed with all‐cause dementia was calculated using multiple logistic regression adjusting for age, sex, educational level, economic status, body mass index (BMI), alcohol consumption, smoking, hypertension, diabetes, and stroke.ResultsAmong 12,099 participants at baseline, the mean age of 60.1 ±10.5 years, 55.9% were female, and 69.1% were classified as overweight or obese. Also, 65.7% were at moderate or high PA categories at baseline. Between the second and the latest wave, 571 (2.1%) individuals were diagnosed with any type of dementia, with difference between education level (p<0.001), economic status (p<0.001), and age (p<0.001). No statistical difference was reported between sex (p=0.112) and BMI groups (p=0.378). Participants who were sedentary or had low level of PA at baseline but became physically active at moderate or high level in the latest wave had 81.4% (95%CI: 0.04‐0.80; p=0.02) lower odds of being diagnosed with dementia compared to those who kept sedentary behavior between the two periods. Also, a protective effect was observed between those participants who sustained PA practice during cohort period (OR=0.24; 95%CI: 0.12‐0.50; p<0.001). There was no observed protective effect for participants that were physically active at baseline and became sedentary or had reduced level of PA at wave 8 (OR=1.34; 95%CI: 0.79‐2.28; p=0.272).ConclusionsPhysically active behavior is associated with decreased risk for all‐cause dementia even if started at later stages of life. Our findings highlight the importance of PA promotion for older adults as a low‐cost and non‐pharmacological approach to protect against all‐cause dementia.
Genome‐wide association study identifies two novel chromosome loci associated with cerebral white matter hyperintensity volume in Japanese population
Authors: Kokubo Manabu , Ozaki Kouichi , Ohta Hidetaka , Nakanishi Hiroki , Shimizu Atsuya , Arai Hidenori , Sakurai Takashi 
Published: December 2020

AbstractBackgroundCerebral white matter hyperintensity (WMH) is highly prevalent in the elderly population, and increases the risk of dementia and stroke . The genetic underpinnings of WMH are still incompletely characterized, especially in Asian. To identify novel genetic variants influencing WMH burden, we conducted a genome‐wide association studies (GWAS) in Japanese population.MethodWe included outpatients who visited National Center for Geriatrics and Gerontology (NCGG) without symptomatic heart failure, ischemic heart disease, atrial fibrillation or stroke. The clinical data and blood samples used in this study were distributed from the NCGG Biobank, which collects and stores biological material and associated clinical information for biomedical research. WMH volume were analyzed by an automatic segmentation application (SNIPER). To identify WMH associated loci, we conducted a GWAS with linear regression analysis adjusted with age and gender as covariates using approximately 4,300,000 single nucleotide polymorphisms (SNP) imputed based on reference panel from large Japanese sequences. This study was approved by the Ethics Review Board of NCGG.ResultA total of 813 patients were enrolled in the present study (mean age 75.4 ± 8.1 years), including 503 female patients (61.9%). The clinical profiles of the study participants are normal control: n = 184; Alzheimer’s disease: n = 375; other: n = 254. The mean MMSE score was 24.2 ± 4.5.In the GWAS, we have identified two novel loci on chromosome 1 and 2 associated with WMH volume with GWAS significance (P < 5 × 10‐8). We also identified several WMH volume associated loci with suggestive significance (P < 1 × 10‐6).ConclusionThis GWAS of WMH burden in outpatients of our hospital identifies 2 novel genetic loci with GWAS significance and several candidate loci. This is the first report on WMH associated loci of Japanese population. Further characterization of these loci may provide novel insights into the pathogenesis of cerebral WMH in Japanese population.
iSupport‐Portugal: Adapting an evidence‐based online intervention for dementia caregivers to a different culture
Authors: Teles Soraia , do Rosário Zincke Maria , Sosa‐Napolskij Milaydis , Ferreira Ana , Paúl Constança 
Published: December 2020

AbstractBackgroundInformal dementia caregivers often struggle with several stressors that place them in a position of greater risk to develop physical and mental health problems in comparison to the general population. iSupport is an online training programme developed by the World Health Organization to prevent or minimize mental and physical health problems and improve the quality of life of dementia caregivers. Caregivers’ well‐known needs for information and skills training are addressed in twenty‐three lessons organized in five modules. Problem‐solving and cognitive behavioural therapy techniques are evidence‐based methods used in iSupport to change thoughts, feelings, and behaviours and improve overall functioning and life satisfaction. iSupport design choices are grounded on good practices for digital engagement including customization, interactivity and immediate feedback as interface features. Provided its web‐based delivery, iSupport is an ubiquitous and convenient solution, with the potential of scalability. A scalable tool to relieve caregivers’ psychological distress is a necessity in Portugal, given the country’s high share of very old people, high dementia prevalence and rate of informal home care. iSupport was culturally adapted to Portugal using an eight‐step methodological approach comprising: needs assessment from primary (web‐survey; N=180 caregivers) and secondary data collection; content translation; technical accuracy check by health professionals; cultural adaptation; expert panel appraisal; fidelity check by WHO; focus groups with caregivers and professionals; and usability testing. The needs assessment study suggested the potential utility and acceptance of online intervention programmes in Portugal. Findings from the adaptation process revealed the need for adjustments of the original iSupport programme in terms of content and interface. Contents were adapted for language semantic and conceptual equivalence, and adjustment to cultural habits. Definitions, designations, recommendations and case studies were modified to match local knowledge and practices. Findings from usability testing and focus groups resulted in recommendations to improve learnability, efficiency, memorability, and satisfaction with iSupport interface. iSupport‐Portugal introduces adjustments needed to achieve a culturally‐meaningful version of an evidence‐based programme aimed at lessening the psychological distress of dementia caregivers. As the only online programme for dementia caregivers available in Portugal, iSupport studies are instrumental in assessing the feasibility of similar resources in this context.