bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of targeted genetic variants with Alzheimer’s disease in African Americans and Nigerians
Authors: Gao Sujuan , Lai Dongbing , Lane Kathleen A. , Foroud Tatiana M. , Baiyewu Olusegun , Ogunniyi Adesola , Hendrie Hugh C 
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS) are often from populations with European ancestry (EA). To test whether the variants identified from recent GWAS are associated with age of onset for AD in an African Americans and Africans, we performed associations studies using data from the Indianapolis‐Ibadan Dementia Project (IIDP).MethodIn this longitudinal study of two community dwelling cohorts of elderly African Americans and Nigerians, 1108 African Americans and 1184 Nigerians who were dementia free at enrollment and had GWAS data were included in the analysis. During follow‐up, 104 African American individuals and 79 Nigerians developed AD. Mean follow up time was 8.8 years for both samples. Biomarkers for cardiovascular disease including lipids, homocysteine, C‐reactive protein were also measured at the time of GWAS sample collection. Cox’s proportional hazard models were used to determine the associations between previously reported genetic variants (n = 23) and the age of onset for AD, after adjusting for age, sex, education and the number APOE ε4 allele. For variants replicated in the African American and Nigerian samples, ANCOVA models were used to examine the association between the variants and blood biomarker levels.ResultIn the African American sample, one variant (rs3752246) in the adenosine triphosphate‐binding cassette subfamily A member 7 (ABCA7) gene had a significant association with earlier AD onset (Hazard Ratio (HR) = 1.84, p = 0.0306). This ABCA7 variant was not observed in the Nigerian sample. In the Nigerian sample, one variant (rs9331949) in the clusterin gene (CLU) and another variant (rs10498663) in the solute carrier family 24 member 4 gene (SLC24A4) were significantly associated with earlier onset of AD (rs9331949: HR = 2.05, p = 0.0069; rs10498663: HR = 1.55, p = 0.0401) while APOE was not significantly associated with age of onset for AD. In the Nigerian sample, rs10498663 in SLC24A4 was significantly associated with higher levels of triglycerides (p = 0.0012).ConclusionWe replicated rs3752246 in ABCA7 for increased AD risk in African American participants in the IIDP study. In the Nigerian sample, the CLU and SLC24A4 variants were associated with increased AD risk and have stronger associations with AD than APOE. Further research is needed to explore biological pathways underlying these associations.
MRI‐based automated volumetric segmentation tool in the detection of early Alzheimer’s disease
Authors: Liu Wanting , Au Lisa W.C. , Abrigo Jill , Luo Yishan , Wong Adrain , Kwan Pauline , Ma Alison Hon Wing , Ng Anthea Yee Tung , Chen Sirong , Leung Eric Y.L. , Ho Chi Lai , Chu Winnie C.W. , Ko Ho , Shi Lin , Mok Vincent C.T. 
Published: December 2020

AbstractBackgroundCognitive unimpaired (CU) and mild cognitive impairment (MCI) subjects harboring beta‐amyloid (A+) and tau (T+) are at high‐risk for incident cognitive decline. Fluoro‐deoxyglucose (FDG) positron emission tomography (PET) likely represents both cumulative loss of the neuropil and functional impairment of neurons while magnetic resonance imaging (MRI) indicates cumulative loss and shrinkage of the neuropil. As PET and CSF analysis in detecting beta‐amyloid and tau are not easily accessible (either costly or invasive nature or radiation), we compared the performance of MRI‐based automated segmentation tool with FDG PET in identifying CU and MCI subjects harboring A+T+.MethodA total of 62 subjects (CU=37, MCI=25) underwent MRI, FDG PET, 11C‐ PIB and 18F‐T807 PET. MRIs were processed by an automated segmentation tool to obtain an Alzheimer’s Disease (AD) ‐ resemblance atrophy index (AD‐RAI) which was derived from a machine learning method (AccuBrain®) that analyzed multiple brain regions relevant to AD.ResultAD‐RAI yielded the same sensitivity (0.73) among all subjects with FDG PET while they had similar specificity. AD‐RAI performed the highest sensitivity (0.91) in MCI subjects over FDG PET (0.82) with an acceptable specificity (0.79) which was slightly lower than that of FDG PET. However, both AD‐RAI and FDG PET were suboptimal in CU group. Detailed results are demonstrated in the Table.ConclusionThe volumetric segmentation tool achieves a good diagnostic profile similar to FDG PET in identifying early AD. It has the potential to be more widely used as a tool to diagnose early AD for receiving treatment or recruitment into clinical trials.
Cortisol levels and cognitive status in elderly subjects: Preliminary results from the Brazilian Aging and Memory Study
Authors: Barbosa Breno José Alencar Pires , Jesus Maria Clara Ferreira , Souza‐Talarico Juliana Nery , Buchpiguel Carlos A. , Busatto Geraldo , Nitrini Ricardo , Brucki Sonia M. D. 
Published: December 2020

AbstractBackgroundThe Brazilian Aging and Memory Study (BRAMS) is a single center, population‐based initiative to address memory and cognitive impairment in Brazil. Volunteer controls and subjects with either subjective cognitive decline (SCD) or mild cognitive impairment (MCI) are being followed up under a strict protocol that involves cognitive, general health, biomarkers and neuroimaging measures. There’s a growing body of research evaluating chronic stress as potentially preventable risk factor for dementia.Methodwe performed a transversal analysis to evaluate the relation between cortisol levels, amyloid pathology and cognitive status in a subset of BRAMS subjects. Chronic stress evaluation included anthropometric measures, serum cortisol and DHEA‐sulfate, glycated hemoglobin, total and HDL cholesterol, creatinine, fibrinogen and reactive protein‐C. Exclusion criteria included dementia and corticosteroids use.Result489 individuals were screened for the BRAMS between 2012 – 2017. A subset of 50 participants with serum cortisol levels available were included for analysis. Mean age was 71.8 years (SD ± 5.2), with 36 female patients (50%), 11.3 years of education (SD ± 5). Amnestic MCI was the most prevalent cognitive status (40%), followed by non‐amnestic MCI (28%) and SCD (21%). 24 subjects had access to amyloid status assessment with PET‐PiB (9 positive, 15 negative). In our sample the mean serum cortisol level was 9.09 mg/dL (±SD 4.1), with 12 individuals in the first tercile (24%), 30 in the middle tercile (60%) and 8 in the upper tercile (16%). Individuals in the lower cortisol tercile had more positive PET‐PiB scans, while in the middle cortisol tercile all individuals had negative scans (p = 0.007 | Fisher’s test). There was no difference in the upper cortisol tercile. No significant associations were observed regarding other chronic stress biomarkers or cortisol levels vs. cognitive status. All tests were adjusted for covariables.ConclusionDespite the modest sample size, there was a significant association between cortisol terciles and amyloid status. However, this association cannot be explained by the current hypothesis that chronic hypercortisolism is related to amyloid pathology and accelerated neurodegeneration. More longitudinal cortisol measures (ie. salivary, urinary or hair) and a larger sample size could give us more information.
Preventing loss of independence through exercise (PLIÉ) for persons with dementia: A randomized, controlled trial
Authors: Barnes Deborah E , Lee Jennifer Ann , Chesney Margaret A , Yaffe Kristine , Abrams Gary , Nicosia Francesca M , Martinez Steven , Ordonez Cherry , Woo Michele , Boscardin W John , Mehling Wolf 
Published: December 2020

AbstractBackgroundPreventing Loss of Independence through Exercise (PLIÉ) is an integrative group movement program for people living with dementia that combines exercises to maintain daily function with mindful body awareness and social engagement. We performed a randomized, controlled trial to examine PLIÉ’s effects on physical, cognitive, and social/emotional outcomes using quantitative and qualitative methods.MethodsStudy participants were persons with mild‐to‐moderate dementia (Clinical Dementia Rating: 0.5, 1 or 2) and their caregivers recruited from 4 adult day center study sites and surrounding communities. Participants were randomly assigned to immediate or delayed start in PLIÉ classes (1 hour, 2‐3 days/week, 18 weeks) at each site. Quantitative outcome data were collected at 0, 18 and 36 weeks by blinded assessors. Our primary outcomes in participants were physical performance, cognitive function, and self‐rated quality of life. Secondary outcomes included caregiver‐reported independence, behaviors, and fall concern for participants and self‐rated mood, burden, and feelings about caregiving for themselves. Caregivers also received anonymous evaluation surveys with satisfaction ratings (5‐point Likert) and open‐ended questions about PLIÉ‐related changes in participants. We used mixed effects linear models adjusting for baseline differences for quantitative data and content analysis for qualitative data.ResultsWe enrolled 88 participant/caregiver dyads, of whom 68 (77%) completed the 18‐week assessment, 55 (62%) completed the 36‐week assessment, and 47 (53%) returned evaluation surveys. Participants were 80±8 years old, 67% men, 60% Veterans and 86% non‐Hispanic White; caregivers were 67±14 years old, 83% women and 84% non‐Hispanic White. There were no significant differences between groups over time in primary or secondary quantitative outcomes, with the exception of increased caregiver burden in the immediate‐ vs. delayed‐start group (p=0.03). However, satisfaction ratings among survey respondents were high (mean: 4.5±0.9), and caregivers reported qualitative improvements in participants in 4 domains: psychological, physical, cognitive, and social. In addition, many caregivers reported improvements in multiple domains (Table).ConclusionAlthough there was no overall benefit in quantitative measures commonly used in dementia studies, a subset of caregivers reported qualitative benefits in program participants in response to PLIÉ. More sensitive measures may be needed to fully evaluate PLIÉ’s effects.
Association of Alzheimer’s disease progression with baseline clinical and genetic characteristics
Authors: Chalise Prabhakar , Sharma Palash , Hui Dongwei , Mahnken Jonathan D. , Michaelis Mary L. , Michaelis Elias K. , Swerdlow Russell H. 
Published: December 2020

AbstractBackgroundMitochondrial genetics are important in the etiology of Alzheimer’s disease (AD). Based on the polymorphisms in mitochondrial DNA (mtDNA) the population can be classified into subgroups called the haplogroups. Previous studies have explored the association of haplogroups and genetic variants in APOE ε4 with AD but the results are inconsistent. Also, patients with mild cognitive impairment (MCI) at baseline often progress differently over several years of follow up.MethodWe carried out a cross‐sectional study to examine the association of the rate of incidence of AD with APOE ε4 genotype and haplogroups. The data collected at the University of Kansas AD Center (KU ADC) consisting of 146 AD and 265 normal subjects, and the data collected by AD Neuroimaging Initiative (ADNI) consisting of 244 AD and 242 normal subjects were used for these analyses. Logistic regression and Fisher Exact tests were used to explore the associations. We also carried out the association analyses of the differences in the disease progression rates from MCI to AD among the haplogroups using both datasets.ResultRates of incidence of AD were statistically significantly different among the haplogroups (2.2 × 10−8), with differing strengths of association across haplogroups. APOE ε4 was significantly associated with AD overall (p‐value = 1.9 × 10−11) and the association further varied by haplogroups. The results of the KU ADC population were consistent with those of the ADNI data. Out of 112 MCI subjects at baseline in KU ADC, 26 progressed to AD and 20 reverted back to normal at the last clinical visit. In ADNI, 172 progressed to AD and 42 reverted back out of 482 MCI at baseline. For both datasets, the proportion of subjects who progressed to AD differed by haplogroups. APOE ε4 genotype was significantly associated with increased risk of progression from MCI to AD (p‐value = 8.6 × 10−7 KUADC and p‐value = 1.33 × 10−9 ADNI).ConclusionThe rate of incidence of AD differed by mtDNA haplogroup and the strength of association further differed by APOE ε4 genotype. The rates of progression of MCI subjects to AD also differed by haplogroups and APOE ε4 genotype.
The effects of pathogenic mutations in the APP and PSEN1 genes on in vivo G‐secretase activity are additive
Authors: Sato Kaori , Nagata Kenichi , Saido Takaomi C. , Sasaguri Hiroki 
Published: December 2020

AbstractBackgroundPathogenic mutations associated with early‐onset familial AD have been identified in the APP and PSEN genes, all of which are primarily involved in the processing of Aβ production. However, the combinatorial effects of mutations in both the genes against AD pathology in vivo remain unresolved.MethodWe generated double knock‐in mice harboring Swedish/Iberian and P117L mutations in the endogenous App and Psen1 genes, respectively, carrying a humanized Aβ sequence. We performed biological and histochemical analysis to explore additional Psen1 mutation alter the App mutations‐derived Aβ pathology or APP processing by β and γ‐secretase.ResultThe double knock‐in mice showed a drastic increase in Aβ 42 secretion more than 20‐fold compared to that of single App knock‐in mice. It is also noteworthy that Aβ plaque formation can be detected in the brains of double knock‐in mice as young as 3 months of age.ConclusionOur results indicate that the effects derived from the App and Psen1 mutations are additive and strongly accelerate production of insoluble Aβ42 prone to aggregate, and then form detectable plaques without any mutation inside the Aβ sequence at ages younger than the single App
NL‐F knock‐in mice.
Low‐dose radiation therapy: A new potential treatment targeting amyloid load and neuroinflammation in an AD rat model
Authors: Ceyzériat Kelly , Millet Philippe , Zilli Thomas , Frisoni Giovanni B. , Garibotto Valentina , Tournier Benjamin 
Published: December 2020

AbstractBackgroundLow‐dose radiation therapy (LD‐RT) has shown to be effective to decrease systemic amyloid load and has an anti‐inflammatory effect in chronic inflammatory pathologies. Consequently, we propose to use LD‐RT to decrease two central hallmarks of AD: amyloid load and neuroinflammation. Our collaborators demonstrated recently that a fractionated protocol (2 Gray in 5 fractions delivered daily) significantly reduced amyloid plaques and improved cognition in an AD mouse model (Marples et al., 2016). The aim of our study is to 1) evaluate the impact of LD‐RT on amyloid load and neuroinflammation in another animal model of AD and 2) compare the efficacy of treatment accounting for the neuropathological stage.MethodWe used TgF344‐AD (TgAD) rats developing amyloid pathology and presenting the advantage to develop endogenous tauopathy. Brains were unilaterally exposed to LD‐RT with the same fractionated radiation schedule than our collaborators (2 Gray in 5 fractions daily) at two different pathology stages: at an early (9‐month‐old) or an advanced stage (19‐month‐old). TgAD and WT littermate sham‐treated animals were used as control. At an early stage, the 18kDa translocator protein (TSPO) density in different brain regions (frontal cortex, hippocampus, striatum, cerebellum, brain residues) was measured using ex vivo [I123]‐Clinde binding. Animals underwent behavioral evaluation (general locomotion, working memory) 4 months after LD‐RT performed at an advanced AD stage. The number of amyloid plaques was quantified in the hippocampus on immunostained slices.ResultFor the first time, we observed a normalization of TSPO levels in the entire brain (‐52%, p<0.001), revealing a strong reduction of neuroinflammation. Interestingly, at an advanced stage, LD‐RT reduces hyperlocomotion (‐44%, p<0.05) and significantly improves working memory (+72%, p<0.05), without modifying the amyloid load.ConclusionWe were able to replicate, in a different animal model, the beneficial effect of LD‐RT on cognition of old animals. This could be mediated by an anti‐inflammatory effect as shown by the TSPO‐signal reduction. The LD‐RT impact on amyloid plaques previously reported could not be confirmed when the pathology has strongly progressed. Longitudinal imaging studies will allow a more in‐depth analysis of the effect of LD‐RT on amyloid and neuroinflammation over the disease course.
National Hospital Organization Dementia Registry (NHODR): A newly developed dementia registry focusing on caregivers and their situations and problems
Authors: Shigematsu Kazuo 
Published: December 2020

AbstractBackgroundCaregivers are necessary for the care of patients with dementia, which is defined as a condition needs care for daily life. However, it is getting more and more difficult for families to care one (or even more than one) of the member suffers dementia, partly because the society has changed to be a nuclear family based. The burden differs among conditions in which caregivers live. From the stand point of care, dementia patients are divided into three major groups; live alone, live with their spouses, and live with their younger generations. Care should be customized according to the groups. For patients who live by themselves, care by the non‐family members are needed, ideally by the official supports regulated by the governments. On top of that, supports by the families are often required, which causes problem for them; for example, some live far away, some have their own jobs, children and even other elderly needing care. For patients who live with their spouses, mostly spouses take care of the patients and supports for the caregivers are needed, because they often elderly and are flail as well. For patients live with their younger generations, also support for the caregivers are important to reduce the burden and keep the relationship between patients and caregivers in a good way. In NHODR, we collect data on caregivers. Who are the main caregivers, where do they live, whether they have jobs, children and elderlies to care, how long they spend on care, how much burden they feel, how well the relationships are, and so on. At the end of 2019, 837 patients were registered to NHODR. We will report the preliminary results showing the problems/difficulties of the caregivers.
Simultaneous modelling of Alzheimer’s progression via multiple cognitive scales
Authors: Kuehnel Line , Berger Anna‐Karin , Markussen Bo , Raket Lars Lau 
Published: December 2020

AbstractBackgroundThe progressive neurodegenerative nature of Alzheimer’s disease (AD) means that patients’ cognition get increasingly worse as the disease progresses. Despite of the multitude of available cognitive assessment tools, it remains a challenge to predict the disease stages and future progression of disease in AD patients.MethodA nonlinear mixed‐effects disease‐progression model was used to investigate the benefit of simultaneously using a combination of ADAS‐cog, MMSE, and CDR sum of boxes for predicting disease stage and future disease progression. The model estimated a timeline of disease progression that enable comparison of sensitivity across cognitive scales and their individual items throughout the disease. The model with multiple cognitive measures was compared to univariate models that only included one of the cognitive measures by evaluating how well they predicted future progression on the cognitive scales of unseen individuals. Individual items were compared using an ordinal analysis that estimated an ordering of item sensitivity over the disease timeline.ResultThe disease‐progression model was fitted on longitudinal data from 2144 patients from ADNI. The model incorporating multiple cognitive measures was consistently better at predicting future progression of unseen individuals compared to univariate models that only included information from one cognitive assessment. The analyses of individual item sensitivity along the disease timeline revealed a clear ordering of items with delayed memory items having the highest sensitivity in early stages of disease while language and attention related items stood out as sensitive later in disease.ConclusionConsidering multiple measures simultaneously can improve staging of patients. Methods for better staging patients can be used to design inclusion criteria for clinical trials that result in more homogeneous patient populations and thus improve statistical power. Furthermore, the comparison of item sensitivity along the disease timeline has the potential to develop new and more sensitive composite assessment tools for specific patient populations.
Depressive symptom profiles predict dementia onset and longitudinal changes in hippocampal and white matter lesion volume in older persons: The AGES‐Reykjavik study
Authors: Gerritsen Lotte , Geerlings Mirjam I , Sigurdsson Sigurdur , Jonsson Palmi V , Gudnason Vilmundur , Launer Lenore J 
Published: December 2020

AbstractBackgroundLate‐life depression (LLD) is a major risk factor for dementia, including Alzheimer’s disease. However, not every patient with LLD will develop dementia or show neurodegeneration. Since LLD is heterogeneous in symptom presentation subtypes may exist within LLD that have a higher risk of dementia than others.We aimed to 1) identify subtypes in LLD using latent class analyses (LCA), and 2) examine how these subtypes were related to dementia and MRI markers of neurodegenerative and vascular pathology over time.MethodFor 2430 participants (75±6 years; 41% male) without dementia from the population‐based AGES‐Reykjavik Study the Geriatric Depression Scale (GDS‐15) was administered and 1.5T brain MRI was performed at baseline and follow‐up after 5 years. Dementia, including AD, was assessed according to international criteria during an average follow‐up of 9 years. We performed LCA with GDS‐15 items examining 1 to 7 classes. Cox regression analyses adjusted for age, sex, and education were used to estimate the Hazard Ratios of LLD subtype with incident dementia. ANCOVA was used to examine the difference in hippocampal and white matter lesion volume (WML) from baseline to follow‐up, adjusted for age, sex, education and ICV.ResultLCA with 5 classes rendered best fitting results: no depression (57%); apathy (31%); apathy with emptiness (2%), mild depression (8%) and severe depression (2%). Severe depression (HR=1.87; 95%CI: 1.2‐2.9), mild depression (HR=1.28; 95% CI:1.1‐1.6) and apathy (HR=1.39; 95% CI:1.2‐1.6) had increased risk of developing dementia compared to the no depression group (Figure 1). Figure 2 shows the hippocampal decline(Figure 2A) and increase in WML(Figure 2B) per LLD subgroup; compared to the no depression group the subtype with severe LLD showed most hippocampal decline (F(4,2429)= 2,28; p =0.04) and increase in WML (F(4,2429)= 2,72; p =0.02).ConclusionThis study shows that different subtypes of LLD can be identified. Severe depression as well as apathy were associated with increased risk of dementia, but only severe LLD was related to progression of markers of neurodegeneration and vascular pathology.