bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex differences in neurodegeneration and memory performance in preclinical autosomal dominant Alzheimer’s disease: Baseline findings from the API ADAD trial
Authors: Vila‐Castelar Clara , Tariot Pierre N , Sink Kaycee M , Clayton David , Langbaum Jessica B , Thomas Ronald G , Chen Yinghua , Su Yi , Hu Nan , Giraldo‐Chica Margarita , Tobon Carlos , Acosta‐Baena Natalia , Luna‐Maldonado Ernesto , Londoño Marisol , Ospina Paula , Tirado Victoria , Muñoz Claudia , Henao Eliana , Bocanegra Yamile , Alvarez Sergio , Rios‐Romenets Silvia , Ghisays Valentina , Goradia Dhruman D , Lee Wendy , Luo Ji , Malek‐Ahmadi Michael H , Protas Hillary D , Lopera Francisco , Reiman Eric M , Quiroz Yakeel T ,   API ADAD Colombia Trial Group
Published: December 2020

Background

Growing evidence suggests that females have greater biological risk for Alzheimer’s disease (AD). As levels of AD pathology increase, females show greater tau accumulation, faster hippocampal volume loss, and faster cognitive decline than males. We sought to investigate sex differences in individuals with preclinical autosomal dominant AD (ADAD), who are destined to develop early‐onset dementia and have minimal age‐related confounds known to vary by sex (e.g., mortality, cardiovascular disease, or menopause). We plan to examine the role of sex in the associations among markers of pathology, neurodegeneration, and cognition leveraging baseline data from the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial.

Methods

We analyzed baseline data from 242 cognitively unimpaired 30‐53 year‐old prevention trial participants, including 167 PSEN1 E280A mutation carriers and 75 non‐carrier family members. Clinical ratings, CERAD word list delayed recall, hippocampal grey matter volume, florbetapir cortical‐to‐pontine standard‐uptake value ratios (SUVR), and precuneus 18F‐fludeoxyglucose (FDG) positron emission tomography were included in the analyses. T‐tests and multiple regressions models controlling for age, PSEN1 mutation status and amyloid burden were conducted.

Results

Across groups, females had greater hippocampal volumes (p=.05) and better delayed recall (p=.005) than males. Female carriers were younger than male carriers (p=.04). Females continued to have better delayed recall after adjusting for glucose metabolism in the precuneus (Sex: β=.562, p=.023), and showed a trend towards significance after adjusting for hippocampal volumes (Sex: β=.462, p=.059). In carriers only, as age increased, males had lower hippocampal volumes than females (Slope difference: p ≤ .05), while no differences were found in amyloid levels or metabolism. There was no sex difference in the relationship between amyloid accumulation, hippocampal volumes (Sex: β=.000, p=.094), and metabolism (Sex: β=‐.004, p=.815).

Conclusion

Findings suggest that cognitively unimpaired female mutation carriers may have greater cognitive resilience to AD‐related neurodegeneration compared to male mutation carriers. Further investigation of sex‐specific differences in AD‐related clinical and pathological markers is key to inform AD detection, prevention, and development of treatments.
Without a lifeline: Improving outcomes for patients diagnosed with dementia who do not have caregivers or family involvement in care
Authors: Sitarz Claire
Published: December 2020

Background

Healthcare providers have long depended on caregivers or family members of persons with dementia to manage care after an appointment is over. Whether it is completing follow‐up, managing medications, or ensuring testing is completed, caregivers are typically the lifeline to medical compliance and successful treatment planning. However, not all patients have the support of a caregiver or family member; how do healthcare providers ensure adequate care for persons with dementia living independently in the community? This poster presentation will include a literature review examining best practices for persons living independently, as well as case studies providing real life examples of interventions used in our Neurology practice in Philadelphia, Pennsylvania, USA. Through use of social services, care coordination, and communication among providers, patients are connected to resources and supports that allow them to remain independent in the community and build a network of care they would not otherwise have access to. The literature review synthesizes evidence based research that shows the scope of the problem, while case studies details successful interventions used, as well as difficulties and road blocks encountered in this population. Suggestions for best practices, as well as maintaining a focus on patient‐centered care are examined.
The trajectory of cognitive decline and neuropathological features among APOEɛ2 carriers
Authors: Gauthreaux Kathryn , Teylan Merilee , Culhane Jessica E. , Miller Zachary , Schwabe‐Fry Kristen , Chen Yen‐Chi , Chan Kwun Chuen Gary , Mock Charles , Kukull Walter A.
Published: December 2020

Background

Research on the APOEɛ2 allele and its role in neurodegenerative disease is sparse compared to APOEɛ4. Studies have indicated that ɛ2ɛ2 homozygosity is protective against developing Alzheimer’s disease neuropathology (ADNP). Our goal was to explore cognitive trajectories and neuropathological features among APOEɛ2 carriers versus an ɛ3ɛ3 reference group.

Method

Data were obtained from the National Alzheimer’s Coordinating Center. Participants were included if they had neuropathology data available within 2 years of their most recent clinic visit. Due to sample size, we combined the ɛ2ɛ2 and ɛ2ɛ3 genotypes into one group for our analyses. Linear regression models with generalized estimating equations were run comparing the trajectory of CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) over time between participants with ɛ2ɛ2/ɛ2ɛ3 or ɛ2ɛ4 to those with ɛ3ɛ3. Logistic regressions were run comparing the odds of having various neuropathological features in these groups. All models were stratified by baseline CDR global score (CDR) and adjusted for education, sex, race/ethnicity, smoking status, and hypercholesterolemia. Linear models additionally adjusted for age at baseline and accounted for repeated measures by individual, while logistic models examining neuropathological features adjusted for age at death.

Result

We identified 356 ɛ2ɛ2/ɛ2ɛ3, 105 ɛ2ɛ4, and 1937 ɛ3ɛ3 participants with a mean follow‐up of 3.8, 4.1 and 3.7 years, respectively. Both ɛ2 carrier groups showed significant cognitive decline in CDR‐SB regardless of baseline CDR, although the slopes were not significantly different from the ɛ3ɛ3 group. When comparing the neuropathological features present in these groups, ɛ2ɛ2/ɛ2ɛ3 participants who were mildly impaired (i.e., CDR = 0.5) at baseline had significantly higher odds of FTLD‐tau pathology (p < 0.01) and lower odds of ADNP (p < 0.01) compared to ɛ3ɛ3 participants.

Conclusion

In our sample, we found that ɛ2ɛ2/ɛ2ɛ3 participants displayed more FTLD‐tau at autopsy, but less ADNP compared to ɛ3ɛ3 participants. Our finding that ɛ2ɛ2/ɛ2ɛ3 participants had less ADNP supports the notion that ɛ2 is protective against ADNP, although when the ɛ4 allele is present it overrides the ɛ2 protective effects against ADNP. Despite this protective effect of the ɛ2ɛ2/ɛ2ɛ3 genotype against ADNP we found that the ɛ2ɛ2/ɛ2ɛ3 genotype did not prevent cognitive decline when compared to the ɛ3ɛ3 group.
Amyloid‐β oligomer‐induced, tau‐dependent dysregulation of mitochondrial DNA replication is mediated by SOD1
Authors: Norambuena Andrés , Sun Xuehan , Shivange Nutan , Bloom George S.
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by accumulation of amyloid‐β (Aβ), Tau phosphorylation, insulin resistance and mitochondrial dysfunction, but molecular mechanisms interconnecting these phenomena remain poorly understood. We recently discovered nutrient‐induced mitochondrial activity (NiMA), an inter‐organelle signaling pathway whereby activation of mTORC1, on lysosomes (lysomTORC1) by insulin or amino acids (nutrients) triggers mitochondrial oxidative metabolism (MitoOXPHOS) in cultured cells, including primary neurons, and in live mouse brain. Intriguingly, Tau was found to regulate mitochondrial DNA (mtDNA) replication in neurons through the NiMA pathway. Aβ oligomers (AβOs), which activate mTORC1 at the plasma membrane (PM), but not at lysosomes, by a Tau‐dependent mechanism (Alzheimer's & Dementia 13: 152‐167), were found to counteract nutrient effects on both MitoOXPHOS and mtDNA replication (EMBO J 37: e100241). We now report details of a mechanism by which Tau and mTORC1 regulate mtDNA replication.

Method

EdU incorporation in live neurons was used to image mtDNA replication in wild type (WT) and Tau knockout (KO) mouse cortical neuron cultures. In‐gel enzyme assays were used to evaluate Copper and Zinc superoxide dismutase (SOD1) activity.

Result

Nutrient‐induced activation of lysomTORC1 suppressed mtDNA replication in WT, but not Tau KO neurons, unless the latter expressed WT human Tau (hTau). Interestingly, expression of WT, or a 14‐site phospho‐mimetic or phospho‐null (Neuron 68:1067‐81), but not P301L hTau mutant in Tau KO neurons inhibited mtDNA replication in the absence of nutrient stimulation. Mechanistically, we found that Tau upregulates lysomTORC1, which in turn inhibits SOD1 (Mol Cell 70:502‐515). Pharmacological inhibition of SOD1 in WT neurons inhibited mtDNA synthesis, mimicking the effects of nutrients, and of WT, phospho‐mimetic or phospho‐null hTau re‐expression in Tau KO neurons. In contrast, AβO‐mediated activation of mTORC1 at the PM in WT neurons increased SOD1 activity.

Conclusion

The Tau‐mTORC1‐SOD1 signaling pathway enables nutrients to suppress mtDNA replication under non‐pathological conditions, and is required for the failure of nutrients to block mtDNA replication in the presence of AβOs. Thus, Tau is part of a nutrient‐sensing machinery that functionally couples nutrient availability to mtDNA replication under normal conditions and mechanistically links mitochondrial dysfunction to AD, independently of Tau phosphorylation at 14 sites.
Degeneration of vascular architecture associated with disease pathology in the 5XFAD mouse model of Alzheimer’s disease
Authors: Moore Shannon J. , Stevenson Tamara K. , Gyan Araba , Carrasquillo‐Morales Karina , Murphy Geoffrey G.
Published: December 2020

Background

Beta‐amyloid (Aβ) plaques have long been considered a defining hallmark of Alzheimer’s disease (AD), though the pathogenic mechanism and therapeutic efficacy of targeting plaques remain unclear. Accumulating evidence suggests that cerebrovascular abnormalities are also associated with cognitive decline and neurodegeneration in AD patients. We examined the relationship between Aβ plaque deposition and vascular architecture in different brain regions in the 5xFAD mouse model of Alzheimer’s disease.

Methods

Separate cohorts of male and female wild‐type (WT) and 5xFAD mice (C57BL/6 background) were evaluated at different time points during the progression of AD pathogenesis. First, learning and memory were assessed using a contextual fear conditioning paradigm to evaluate cognitive function. Then, blood vessels were labeled using DyLight 594 tomato‐lectin (tail‐vein injection) and a TRITC‐Dextran gelatin solution (cardiac perfusion); Aβ plaques were labeled ex‐vivo with 6‐OH‐BTA‐1 (an intervening derivative of Pittsburgh compound B). Confocal images of optically cleared (SeeDeepBrain method) sagittal sections (450 µm) were collected from four distinct regions (subiculum, dentate gyrus, cortex, and cerebellum) to analyze Aβ plaque deposition and vascular architecture.

Results

At 4 months old, 5xFAD and WT mice performed equally well in contextual fear conditioning, but by 8 months of age, 5xFAD mice exhibited lower freezing 24 hours after conditioning compared to their WT littermates. In 5xFAD mice, total Aβ plaque burden substantially increased from 4 to 8 months, but regions exhibited differential vulnerability, with the subiculum accumulating the most plaques while the cerebellum had none. Blood vessel health appeared to be more compromised in 8 compared to 4 month‐old 5xFAD mice, while it remained largely unchanged with age in WT mice. Interestingly, the regions displaying the greatest Aβ plaque burden in 5xFAD mice also had the largest reduction in the intensity of intact vascular labeling.

Conclusions

These experiments demonstrate that by 8 months of age, 5xFAD mice on a C57BL/6 background exhibit significant learning and memory impairments, increased Aβ plaque burden, and deterioration of the cerebrovasculature. They further suggest that vascular degeneration may be related to regionally specific Aβ plaque deposition and that this is an important pathological feature of disease progression.
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

Background

Heterogeneity 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.

Method

Right 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.

Result

Of 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.

Conclusion

Probable 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

Background

Microglial 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.

Methods

Autopsy 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.

Results

Across 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.

Conclusion

Overall, 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

Background

Patients 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.

Method

We 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.

Result

We 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.

Conclusion

Identifying 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

Background

Vascular 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.

Method

T2‐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.

Result

Increases 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.

Conclusion

PVWMH 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

Background

Some 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.

Objective

To compare the prevalence of affective disorders between PSEN1 E280A mutation carriers and non‐carriers at the time of API ADAD trial screening.

Method

We 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).

Result

315 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.

Conclusion

Although 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

Background

KEAP1‐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.

Method

In 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.

Result

Although 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.

Conclusion

We 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

Background

Dementia 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.

Methods

We 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.

Results

Among 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).

Conclusions

Physically 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

Background

Cerebral 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.

Method

We 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.

Result

A 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).

Conclusion

This 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

Background

Informal 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.
Peripheral nerve function and dementia in older adults with and without diabetes
Authors: Brenowitz Willa D , Robbins Nathaniel M , Strotmeyer Elsa S , Yaffe Kristine
Published: December 2020

Background

Few studies have focused on sensory peripheral nerve impairment as risk factor for or marker of dementia, although other sensory impairments are associated with cognitive decline. Peripheral nerve impairments are higher with aging, musculoskeletal injury, and conditions such as diabetes, which in turn may accelerate cognitive decline. We evaluated whether sensory nerve impairment in older adults was associated with higher risk of dementia and examined differences by diabetes status.

Method

We studied 1,923 black and white non‐demented participants from Health, Aging, and Body Composition (Health ABC) Study who were aged 70‐79 at 1998/99 enrollment (52% women; 35% black). Sensory nerve tests evaluated in Year 4 (2000/01) included monofilament (1.4‐g, 10‐g) and vibration threshold of the toe. Monofilament insensitivity was defined as unable to detect monofilament (3/4 touches) and poor vibration threshold was defined as >130μm. Incident dementia (over 11 years of follow‐up) was based on hospitalization records, dementia medications, or ≥1.5 SD decline in Modified Mini‐Mental State Exam score (race‐specific). Cox proportional hazard models with adjustment for demographics, comorbid health conditions, and health behaviors evaluated risk of dementia associated with peripheral nerve impairments. We tested for interactions with diabetes status.

Result

Of older participants, 44.7% had 1.4‐g monofilament insensitivity, 8.3% had10‐g monofilament insensitivity, and 5.9% had poor vibration threshold. 1.4‐g monofilament insensitivity was not associated with dementia (HR: 1.14, 95% CI: 0.92, 1.40), either in the combined group or by diabetes status (interaction with diabetes p=0.78). 10‐g monofilament insensitivity was associated with higher risk of dementia in those with diabetes (HR: 2.52; 95% CI: 1.53, 4.14) but not those without diabetes (HR: 1.00; 95%CI: 0.63, 1.60) (p=0.02 for interaction). Poor vibration threshold was associated with higher risk of dementia in those without diabetes (HR: 1.72, 95%CI: 1.15,2.60), estimates were elevated but not significant in those with diabetes (HR: 1.31; 95%CI: 0.48,4.49), and the interaction by diabetes was not significant (p=0.50).

Conclusion

Sensory nerve impairments were associated with increased risk of dementia although the effects differed by diabetes status. These associations may represent shared risk factors that affect peripheral and central nervous system degeneration.
Identification of genetic markers linked to accelerated brain volume changes in Aβ‐positive population
Authors: Vacher Michael , Porter Tenielle , Milicic Lidija , Peretti Madeline , Dore Vincent , Villemagne Victor LL , Laws Simon M , Doecke James D
Published: December 2020

Background

The blood‐brain barrier (BBB) is formed by a high‐density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens.

Method

This study aimed at identifying associations between longitudinal brain volumetric changes and a set of 324 BBB‐related single nucleotide polymorphisms (SNP), genotyped from 222 unrelated individuals (Ab+: N=95; Ab‐: N=127) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We focused this research on four brain regions (cortical grey matter, cortical white matter, ventricular volume, and hippocampal volume) and used a linear mixed model approach to assess if specific genotypes were linked to rates of atrophy over a 12‐year time span.

Results

We identified three genetic markers, specific to the Ab+ population, associated with accelerated volume change of the hippocampus and ventricular regions. Two markers, namely, rs17063341 (TJP2, flanking, p=1.35e‐05) and rs7975334 (SLCO1C1, non‐coding transcript variant, p=5.65e‐06) were associated with accelerated atrophy of the hippocampus. One marker, rs282984 (JAM2, intronic, p= 8.78e‐05) was linked to accelerated ventricular enlargement. These markers were independent of variation due to the APOE e4 allele and remained significant after correction for multiple comparisons. The identified associations were not seen in the Ab negative population.

Conclusions

The results suggest that specific markers in key genes involved in the regulation of BBB integrity are associated with longitudinal changes of specific brain regions. Further research is required to validate these findings and investigate how BBB functions maybe compromised by these genetic variations.
iSupport‐Portugal: Adapting an evidence‐based online intervention for dementia caregivers to a different culture
Authors: Teles Soraia , Zincke Maria do Rosário , Sosa‐Napolskij Milaydis , Ferreira Ana , Paúl Constança
Published: December 2020

Background

Informal 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.

Method

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.

Result

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.

Conclusion

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.
Who are the patients diagnosed with dementia in Brazil? A nation‐wide descriptive study
Authors: Feter Natan , Leite Jayne S , Rombaldi Airton
Published: December 2020

Background

Brazil has the second highest age‐standardized prevalence of dementia in the world. However, there are no studies that used national‐wide data to describe how this disease is distributed among Brazilian population. We aimed to describe demographic, clinical, and behavioral characteristics from people with dementia (PWD) in Brazil.

Methods

We extracted data from adults who had diagnosed dementia during the latest National Health Survey (2013), which is the most comprehensive survey with data about health status, lifestyle, and healthcare utilization among Brazilian adult population. We reported data about demographic (i.e. education, ethnicity, marital status, occupation), clinical (i.e. functional capacity, number of morbidities, hospital admission), and behavioral (i.e. physical inactivity, social interaction) aspects of PWD in Brazil.

Results

Using data from 60,202 individuals (response rate: 74.2%), we reported higher prevalence of dementia in subjects aged 60 years or older (76.1%), female (67.2%), white people (50.8%), widowed (38.3%), unemployed (60.4%), and among those with low educational level (67.1%). PWD reported higher prevalence of hearing (19.5%) and visual (34.4%) impairment, functional disability (66%), physical inactivity (90.2%), social isolation (89.3%) and diagnostic of chronic diseases (73.2%). About 75% from sample self‐rated their health as regular or worse. Although habitual activities were severally limited by dementia in about 70% of sample, only 21% frequented any type of rehabilitation service. Besides a higher incidence on hospitalizations during the last 12 months before interview (27.3%), PWD had longer hospital admissions (p<0.001), with public health system being the major provider (65.7%). In addition to 61% of PWD did not have access to any public place near their houses to perform physical activity, 97.6% did not know any public program for physical activity promotion.

Conclusion

Dementia is more prevalent in certain sociodemographic groups in Brazil. PWD have higher prevalence of morbidities, social isolation, physical inactivity, and general health rated regular or worse. Low frequency in rehabilitation services and access to physical activity practice may be associated to higher incidence and duration of hospitalizations among PWD. Strategies to reduce social inequality in dementia in Brazil should be encourage in order to reduce its burden of this disease on Brazilian healthcare system.
Association of limb length with cognitive decline in elderly
Authors: Kwon Oh Dae
Published: December 2020

Background

There are not many studies about the risk factors of dementia in Korea. Early life nutrition is very important for the body size of grown‐ups. This study investigated the associations of arm and leg length with cognitive decline in a community sample of elderly Korean.

Method

382 community residents aged 65 or over were clinically assessed for cognitive impairment. Arm length and leg length were measured. Neuropsychological tests, including Korean version of Mini‐mental state examination, Clinical Dementia Rating, and Geriatric Depression Scale were performed for all the participants.

Result

Both arm length and leg length were not associated with decreased cognitive function by correlation analysis. Correlation analysis with adjustment of age and education also did not show any significant correlation.

Conclusion

We could not find any correlation between limb length and cognition in an elderly Korean community.