bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of [18F]SNFT‐1, a novel tau PET tracer with little off‐target binding
Authors: Ishiki Aiko , Harada Ryuichi , Lerdsirisuk Pradith , Yiqing Du , Michinori Ezura , Yanai Kazuhiko , Furumoto Shozo , Kudo Yukitsuka , Arai Hiroyuki , Okamura Nobuyuki
Published: December 2020

Background

[18F]THK‐5351, which was originally designed to detect tau aggregates, bound to monoamine oxidase B (MAO‐B) with high affinity. Lead optimization toward selective binding profiles to tau has resulted in the development of novel selective tau PET tracer named [18F]SNFT‐1 (THK‐5562). Here we present the preclinical characteristics of this tracer.

Method

In vitro competitive binding assays against MAO‐A, MAO‐B, amyloid, and tau were performed. In vitro autoradiography of the human brain tissues of various neurodegenerative diseases was performed. Receptor panel screen was performed to confirm the binding selectivity of this compound. Biodistribution study was performed in mice. In addition, an acute toxicity with intravenous administration of a single dose of this compound in mice was also investigated.

Result

SNFT‐1 showed high affinity (K
d = 0.47 nM) and selectivity for tau aggregates over other misfolding proteins as well as MAO enzymes. In vitro autoradiography demonstrated the intense laminar binding of [18F]SNFT‐1 to tau pathology in AD and less off‐target binding than currently available tau PET tracers. No remarkable binding inhibition on various receptors ion channels, and transporters was observed at 1 μM concentration. [18F]SNFT‐1 showed good initial brain uptake and rapid washout without defluorination and troublesome radiolabeled metabolites in mice. In acute toxicity study, no drug‐related changes were noted after intravenous administration of this compound in mice.

Conclusion

[18F]SNFT‐1 is highly selective tau PET tracer, which will enable accurate monitoring of abnormal tau pathology in AD brain.
Effect of disproportionately enlarged subarachnoid space hydrocephalus (DESH) on cognition
Authors: Cogswell Petrice M. , Weigand Stephen D. , Gunter Jeffrey L. , Graff‐Radford Jonathan , Jones David T. , Schwarz Christopher G. , Senjem Matthew L. , Knopman David S. , Petersen Ronald C. , Jack Clifford R.
Published: December 2020

Background

Disproportionately enlarged subarachnoid‐space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. Although this imaging phenotype was originally described in normal pressure hydrocephalus (NPH), it has since been more widely recognized in the aging population with a prevalence of 6‐7% in the Mayo Clinic Study of Aging (MCSA) 1. The clinical significance of DESH with regards to cognitive decline outside of NPH is not yet well‐defined. The goal of this work is to determine if DESH is associated with risk of cognitive impairment.

Method

Participants in the population‐based MCSA who met the following criteria were included: age ≥ 65 years, 3T MRI, cognitively unimpaired at enrollment, and at least one follow‐up visit. A support vector machine based method to detect the DESH imaging features on T1‐weighted MRI was used to calculate “computational DESH” or CDESH scores2 (Figure 1). Cox proportional hazard models were fit with events defined as progression from cognitively unimpaired to mild cognitive impairment or dementia. Time was defined as years from MCSA enrollment to the first visit with cognitive impairment with censoring at last follow‐up. CDESH was modelled as a spline to allow for non‐linear effects. Covariates included age, sex, education, APOE status, cortical thickness, white matter hyperintensity (WMH) volume, and total intracranial volume.

Result

Participant demographics are summarized in Table 1. The model including the above co‐variates showed a significant CDESH effect (p=0.02) with an approximately 20% greater hazard of progression for a CDESH score of +1 versus −1 (HR 1.2, 95% CI 1.0‐1.4) (Figure 2).

Conclusion

Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well‐known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically and also used as a selection stratification variable for clinical trials. References: (1) Graff‐Radford et al doi:10.1212/WNL.0000000000008616; (2) N. Gunter et al doi:10.1016/j.nicl.2018.11.015.
Untangling neuropathological changes in a large clinicopathological population younger than 65: Correlations with clinical scores
Authors: Socher Karen L.R. , Rodriguez Roberta Diehl , Suemoto Claudia K. , Brucki Sonia M.D. , Leite Renata Elaine Paraizo , Ferretti‐Rebustini Renata Eloah de Lucena , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Grinberg Lea Tenenholz , Nitrini Ricardo
Published: December 2020

Background

Clinical symptoms in early‐onset dementia occurs before than 65 years of age and represents around 10% of the dementia cases. The evidence of tau lesions in young individuals from nonselected autopsy studies supports that AD‐type pathology can start much earlier than previously thought. However, the majority of studies in dementia are focused in caucasians older than 60 years. Here we analyze demographics and neuropathological features of individuals between 30 to 65 years of age.

Method

The Biobank for aging studies has a unique collection of brain samples of a large mixed population spanning all AD‐Braak stages. To explore the presence of AD‐type pathology, we analyzed 275 younger individuals. All cases have a complete semistructured interview performed to obtain data about sociodemographic, lifestyle, past medical history, and cognitive and neuropsychiatric symptoms (NPS). Presence of cognitive impairment (CI) was defined according the Clinical Dementia Rating Scale (CDR≥0.5) and the Neuropsychiatric inventory was used to evaluate the presence of NPS. Internationally accepted neuropathological criteria were used for pathological staging and diagnosis.

Result

The mean age at death was 58 ± 5.4 years, 58% were men and 67.3% white. The mean education was 5.1 ± 4.1 years. High frequency of cerebrovascular risk factors such as hypertension (63.9%), smoking (58.5%) and alcohol intake (27.5%) was noted. Presence of CI was found in 22.5%, while some degree of NPS was noted in 59%. The most prevalent NPS was anxiety (25.5%) followed by appetite changes (24.4%). Some degree of cortical neurofibrillary tau pathology was observed in 53.5% (147), while neuritic plaques was found only in 9.5% (26). There were no significant differences in AD‐type pathology burden between individuals with and without CI. Vascular lesions were observed in 5.1% of all individuals, and those with CI and NPS showed more vascular pathology (p < 0.001 and <0.005 respectively). In addition, CI individuals had more history of alcohol abuse (p = 0.02), meanwhile the same association was not noted with the presence of NPS (p = 0.13).

Conclusion

In younger individuals vascular pathology seems to play an important role in cognitive and neuropsychiatric symptoms. The high frequency of cerebrovascular risk factors highlights the importance of early prevention strategies.
Influence of social networks on Alzheimer’s disease biomarkers and subjective cognitive decline among elders without dementia: A CABLE study
Authors: Ma Ya‐Hui , Wang Ya‐Yu , Tan Lan , Yu Jin‐Tai , Xu Wei
Published: December 2020

Background

The social networks has been recommended as a moderator of incident Alzheimer’s disease (AD) and aggravated cognitive deficits. Still few data are available about the effect of social networks on cerebrospinal fluid (CSF) AD biomarkers.

Method

Participants without dementia were recruited from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) study. Multiple‐adjusted analyses were performed to explore the association of social networks with CSF biomarkers, pre‐AD stage and subjective cognitive decline (SCD).

Result

Total eight hundred and twenty‐two individuals without dementia were included in current study. Moderate to high social network scores were significantly associated with CSF low levels of β‐amyloid (Aβ)40 (moderate, β=‐0.198; close, β=‐0.127), Aβ42/Aβ40 (moderate, β=0.227; close, β=0.184) and phosphorylated tau (p‐tau)/Aβ42 (moderate, β=‐0.106; close, β=‐0.1). In addition, moderate and high scores associated with low p‐tau (β=‐0.076) and total‐tau(t‐tau)/Aβ42 (β=‐0.111) respectively. Mostly significant associations of social network scores with biomarkers persisted in advanced age group, males and SCD group after stratified analyses. Moderate to high social network scores decreased risk for A+ (moderate:odds ratio (OR)=0.519, 95% confidence intervals (CI)=0.302‐0.890; high: OR=0.516, 95%CI=0.305‐0.874), A+T+ (moderate: OR=0.208, 95% CI=0.089‐0.488; high: OR=0.228, 95%CI=0.098‐0.528) and A+T+N+ (moderate: OR=0.144, 95% CI=0.055‐0.378; high: OR=0.141, 95%CI=0.054‐0.370)). In addition, close social ties and high social network scores decreased the risk of SCD (p < 0.05). There were no significant associations of moderate social ties and social network scores with SCD (p > 0.05).

Conclusion

Social networks weaken the deleterious effect of AD neurodegenerative biomarkers. Furthermore, favorable influences of social networks on early neurobiological alterations of preclinical stage of AD and self‐reported SCD were suggested.
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

Background

Genome‐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).

Method

In 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.

Result

In 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).

Conclusion

We 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

Background

Cognitive 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+.

Method

A 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.

Result

AD‐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.

Conclusion

The 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

Background

The 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.

Method

we 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.

Result

489 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.

Conclusion

Despite 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

Background

Preventing 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.

Methods

Study 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.

Results

We 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).

Conclusion

Although 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

Background

Mitochondrial 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.

Method

We 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.

Result

Rates 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).

Conclusion

The 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

Background

Pathogenic 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.

Method

We 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.

Result

The 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.

Conclusion

Our 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

Background

Low‐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.

Method

We 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.

Result

For 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.

Conclusion

We 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

Background

Caregivers 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

Background

The 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.

Method

A 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.

Result

The 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.

Conclusion

Considering 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

Background

Late‐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.

Method

For 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.

Result

LCA 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).

Conclusion

This 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.
Energy intake and expenditure in patients with Alzheimer’s disease and mild cognitive impairment: The NUDAD project
Authors: Doorduijn Astrid S , de van der Schueren Marian , van de Rest Ondine , de Leeuw Francisca A , Hendriksen Heleen MA , Teunissen Charlotte E , Scheltens Philip , van Der Flier Wiesje , Visser Marjolein
Published: December 2020

Background

Malnutrition is common in patients with Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) and is associated with institutionalization and increased mortality. Malnutrition is the result of a negative energy balance, which could be due to reduced dietary intake and/or higher energy expenditure. To study underlying mechanisms for malnutrition, we investigated dietary intake and resting energy expenditure (REE) of patients with AD dementia, MCI and controls. In addition, we studied associations of global cognition (Mini‐Mental State Examination (MMSE)) and AD biomarkers with dietary intake and REE.

Method

We included 219 participants from the NUDAD project, 71 patients with AD dementia (age: 68 ± 8 years, 58% female, MMSE 24 ± 3), 52 with MCI (67 ± 8 years, 42% female, MMSE 26 ± 2) and 96 controls (62 ± 7 years, 52% female, MMSE 28 ± 2). We used a 238‐item food frequency questionnaire to assess dietary intake (energy, protein, carbohydrate and fat). In a subgroup of 92 participants (30 patients with AD dementia, 22 with MCI and 40 controls) we measured REE with indirect calorimetry. Between‐group differences in dietary intake and REE were tested with ANOVAs. In the total sample, linear regression analyses were used to explore potential associations of MMSE score and AD biomarkers with dietary intake and REE. All analyses were adjusted for age, sex, education, and body mass index or fat‐free mass.

Result

Patients with AD dementia and MCI did not differ from controls in total energy intake (1991±71 and 2172±80 vs 2022±61 kcal/d, p>0.05) nor in protein, carbohydrate or fat intake. Patients with AD dementia and MCI had a higher REE than controls (1704±41 and 1754±47 vs 1569±34 kcal/d, p<0.05). We did not find an association of MMSE score or AD biomarkers with dietary intake or REE.

Conclusion

We found a higher resting energy expenditure, despite similar energy intake in patients with AD and MCI compared to controls. These findings suggest that elevated metabolism rather than reduced energy intake explains malnutrition in AD. These results could be useful to optimize dietary advice for patients with AD dementia and MCI.
Magnetic resonance imaging subtypes in subjective cognitive decline
Authors: Diaz‐Galvan Patricia , Poulakis Konstantinos , Grothe Michel J. , Fripp Jurgen , Maruff Paul T. , Rowe Christopher C. , Dore Vincent , Barroso Jose , Ferreira Daniel , Westman Eric
Published: December 2020

Background

Older adults who do not meet clinical criteria for mild cognitive impairment (MCI) or dementia, but who report progressive change in their cognitive abilities (i.e. subjective cognitive decline, SCD) are at increased risk for developing Alzheimer’s disease (AD). However, SCD can be associated to other conditions and its heterogeneity needs to be investigated further. In patients with AD dementia, data‐driven approaches to biological information have been useful in disentangling heterogeneity. We therefore utilized a data‐driven clustering method on regional structural magnetic resonance imaging (MRI) data to identify subtypes of SCD.

Method

Cognitively normal adults with SCD (n=86) and without SCD (n=68) from the AIBL cohort were studied. Clusters of SCD were determined based on 82 cortical and subcortical grey matter volumes using random forest pairwise similarity, multidimensional scaling, and distance‐based hierarchical clustering. The number of clusters was decided according to Carlinski‐Harabasz index. We also studied neuroanatomical, clinical, cognitive, and genetic characteristics at baseline, and clinical and cognitive progression over 7.5 years of follow‐up.

Results

The data driven analyses yielded four SCD subtypes. The largest proportion (49%) showed regional volumes equivalent to those without SCD. Nonetheless, this group could be divided into two subtypes depending on the volume of the thalamus (no atrophy + low thalamic volume, 35%; and no atrophy + high thalamic volume, 15%). We also identified a Hippocampal‐sparing SCD subtype (32%), which displayed reduced cortical volumes but normal volume of the hippocampus; and a Diffuse SCD subtype (16%), which displayed reduced volume in both the hippocampus and cortical regions. Diffuse, Hippocampal‐sparing, and no atrophy + low Thalamic volume SCD subtypes were each associated with increased risk for MCI or dementia over 7.5 years, and showed faster decline in MMSE. The Diffuse SCD subtype was also characterized by an increased amyloid‐PET burden, small vessel disease (white matter hypointensities), and worse CDR scores at baseline.

Conclusions

Data‐driven analyses of structural MRI data revealed that SCD characterized by a Diffuse, Hippocampal‐sparing, or no atrophy with a low Thalamic volume pattern were at increased risk for MCI or dementia. Thus, these data‐driven methods show great potential for disentangling biological heterogeneity within SCD.
Dietary patterns and cognitive decline among older adults: Findings from Sydney Memory and Aging Study
Authors: Chen Xi Sophie , Oleary Fiona , Liu Zhixin , Brodaty Henry
Published: December 2020

Background

Evidence suggested dietary patterns that may protect against cognitive decline among older adults, are mostly plant‐based, rich in poly‐/mono‐ unsaturated fatty acids, and low in processed foods. We aim to examine associations between diet with cognition and cognitive decline among older adults over a 6‐year period in Sydney Memory and Aging Study.

Method

Community dwelling participants (n=1037) were non‐demented and aged 70‐90 years at baseline. Diet was assessed using the 80‐item Cancer Council of Victoria FFQ at baseline, Mediterranean diet scores and DASH diet scores were generated based on dietary intake for individuals. Using PCA we have derived a‐posterori patterns. Neuropsychological tests assessed global cognition and 6 cognitive domains for 4 times, at baseline and followed up every two years. Linear mixed model analyses were conducted to examine the relationship between dietary scores, cognitive health, and cognition change over time, with adjustment for age, gender, education, BMI, cardiovascular risk factors, history of stroke, smoking, depression and APOE ε4 genotype.

Result

No significance was found between adherence to Mediterranean diet or DASH diet, and cognitive decline over 6 years. However, a total intake of legumes and nuts, was positively associated with better overall performance in cognitive domains including language (β=0.058; 95% CI: 0.028, 0.113; P=0.040), visuospatial (β=0.048; 95% CI: 0.008, 0.089; P=0.019) and global cognition (β=0.059; 95% CI:0.005, 0.112; P=0.033). The prudent healthy diet pattern was associated with cognitive health in women over time, in domains of memory (β=0.332; 95% CI: 0069, 0.596 ; P=0.014), verbal memory (β=0.313; 95% CI:0.056 ,0.569 ; P=0.017), visuospatial (β=0.271; 95% CI: 0.005,0.440; P=0.009), executive (β=0.352; 95% CI:0.073, 0.631; P=0.014), attention processing speed (β=0.273; 95% CI: 0.039,0.507 ; P=0.022) and global cognition (β=0.426; 95% CI: 0.141,0.711 ; P=0.004).

Conclusion

In this longitudinal analysis, a prudent healthy diet and high total intake of legumes and nuts, were associated with better cognitive performance over 6 years in various domains among older adults. Adherence to Mediterranean or DASH diet was not associated with cognitive change overtime.
Analysis of users' needs for developing a mobile health–based lifestyle care application for health promotion in elderly
Authors: Park Kang‐Hyun , Park Ji‐Hyuk , Won Kyung‐A , Yang Min Ah , Lim Seungju
Published: December 2020

Background

Recently, Individuals who want to be provided mobile based health services for improving their health and quality of life are increasing. The demand regarding mobile health care services and wearable device are increased gradually in order to monitor their health wherever they are. Therefore, the purpose of this study is to analysis of user’s needs for developing mobile health based lifestyle care application for health promotion in elderly.

Method

Participants who lived in their community and used mobile phone were recruited. Finally, a questionnaire survey was conducted to 84 people. Data was anlaysized using descriptive statistics and t‐test with the SPSS version 25.0.

Result

As a result, the important functions for lifestyle care app which consumers are need are the number of daily steps, physical activities, blood pressure, sleep, nutrition and activity participation. Interestingly, in terms of the importance of activity participation as a function of the app, there was a significantly differences between age groups.

Conclusion

This study investigated user’s needs and preference in order to develop and design mobile health based lifestyle care application for health promotion in elderly. Therefore, findings from this study could be valuable resource for developing lifestyle care app.
A polygenic risk score for Alzheimer’s disease determines the risk of incident dementia in APOE ɛ4 negative individuals over the age of 95: A population‐based cohort study
Authors: Najar Jenna , Joas Erik , Van Der Lee Sven J. , Wetterberg Hanna , Guerreiro Rita , Bras Jose , Hardy John A. , Waern Margda , Kern Silke , Zetterberg Henrik , Blennow Kaj , Skoog Ingmar , Zettergren Anna
Published: December 2020

Background

The combined effect of common genetic variants (SNPs) into polygenic risk scores (AD‐PRS) have been shown to have a strong influence on incident AD between ages 60 and 95 years, especially in carriers of the APOE ϵ4 genotype. However, few studies have investigated the effect of AD‐PRS on incident dementia in the general population and among the oldest old (≥ 95 years).

Method

A population‐based sample of 2053 participants aged 70‐108 years, from the Gothenburg H70 Birth Cohort Studies, Sweden, was followed for incident dementia. An AD‐PRS (39 SNPs) were constructed using effect sizes from large genome‐wide association studies. Dementia was diagnosed according to DSM‐III‐R based on information from neuropsychiatric examinations and close informant interviews. Cox regression models adjusted for sex, birth year, age at blood sampling, and APOE ϵ4 status, were used to analyse the associations between AD‐PRS and incident dementia in the total sample and in the oldest old (n = 338). Additionally, we stratified the analysis by APOE ϵ4 carriership and tertiles of the AD‐PRS.

Result

During mean follow‐up of 7.19 years (SD 4.68; 14,775.25 person‐years), 607 participants developed dementia (220 over the age of 95 years). In the total sample, AD‐PRS was associated with incident dementia (HR per increased point of the score 1.38; 95%CI 1.12‐1.73, p = 0.003), especially among APOE ϵ4 non‐carriers (HR 1.72; 95%CI 1.33‐2.23, p < 0.0001). Among the oldest old, AD‐PRS was associated with incident dementia in APOE ϵ4 non‐carriers only (HR 1.80; 95%CI 1.20‐2.69, p = 0.004). Further, in this age group, APOE ϵ4 carriership was associated with increased risk of dementia only among those in the low‐risk tertile of AD‐PRS (HR 1.84; 95%CI 1.08‐3.12, p = 0.004).

Conclusion

We found an association between AD‐PRS and dementia in the general population up to very old ages, especially among APOE ϵ4 non‐carriers. In the oldest old, an effect of APOE ϵ4 carriership on dementia risk was observed among individuals in the low‐risk tertile of the AD‐PRS. These results could provide additional information to identify individuals at risk for dementia.
Genetic risk of Alzheimer’s disease is linked to short sleep duration
Authors: Leng Yue , Ackley Sarah F , Glymour M Maria , Yaffe Kristine , Brenowitz Willa D
Published: December 2020

Background

Sleep disturbances including short sleep duration are common in older adults, especially in those with Alzheimer’s disease (AD). However, it is unclear to what extent sleep duration is a manifestation of AD disease process. We examined whether genetic variants related to AD influence sleep duration in middle‐aged and older adults using a Mendelian randomization (MR) approach.

Method

We examined 406,687 UK Biobank participants without dementia at enrollment, with Caucasian genetic ancestry, and who self‐reported sleep duration at baseline (2006‐2010). Sleep duration was assessed by asking: “About how many hours sleep do you get in every 24 hours? (please include naps).” A genetic risk score for AD (AD‐GRS) was calculated as a weighted sum of 23 previously identified AD‐related single nucleotide polymorphisms in individuals of European ancestry. AD diagnosis was assessed over follow‐up (to 2018) based on ICD‐9/10 codes. We evaluated whether genetic risk for AD influenced sleep duration using two steps: first we used linear regression to examine the association between AD‐GRS and sleep duration, adjusting for age, sex and principle components for genetic ancestry. Next, we conducted a two‐stage least square regression using AD‐GRS as an instrumental variable for AD diagnosis to estimate the magnitude of the effect of AD on sleep duration. We also stratified the analysis by age at baseline (≤55y or >55y).

Result

Participants (aged 56.91±8.00y) had an average sleep duration of 7.2 (Standard deviation [SD]=1.1) hours and AD‐GRS of 0.11 (SD=0.40; range:‐1.15∼1.85). Higher AD‐GRS score predicted shorter sleep duration (b= ‐0.013, 95%CI:‐0.022,‐0.005), mainly among those aged over 55y (b= ‐0.023, 95%CI:‐0.034,‐0.012) and not in those 55y or younger (b= 0.006, 95%CI:‐0.012,0.013); p for interaction by age=0.02. Analysis using AD‐GRS as an instrumental variable for AD diagnosis suggested that participants with AD diagnosis had 1.76 hrs (b=‐1.76, 95%CI: ‐2.62, ‐0.90) shorter sleep duration in those aged >55y.

Conclusion

Using a novel analytical approach, we found that higher genetic risk for AD predicted shorter sleep duration among older adults. This suggests shared genetic pathways; the biologic processes that lead to AD may also affect sleep duration.