bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of novel candidate gene ameliorates dendritic simplification in hippocampal neurons from APP/PS1 mouse model of AD
Authors: Verma Aditi , Gnanabharathi Barathan , Kumar Sunny , Gowaikar Ruturaj , Ramachandran Arathy , Kommaddi Reddy Peera , Rupanagudi Khader Valli , Palkovits Miklos , Renner Eva , Csiba Laszlo , Hortobagyi Tibor , Bennett David A. , Ravindranath Vijayalakshmi
Published: December 2020

Background

Imaging and neuropathological studies have revealed the entorhinal cortex (EC) and hippocampus (HP) circuitry to be affected early on during Alzheimer’s disease (AD) progression. Changes in the EC‐HP circuitry also correlate with the episodic memory deficits that have been reported in AD. Using bulk RNA sequencing, we studied the gene expression changes in the EC and HP of adolescent (1‐month old) and young adult (3‐months old) APPswe/PS1ΔE9 (APP/PS1) mice. The analysis of RNA‐seq data revealed a single common gene, the expression of which was perturbed at both ages and both regions. We further studied the physiological implication of this gene in the transgenic mouse model of AD.

Method

Total RNA was isolated at 1 month and 3 months of age from the EC and HP of male APP/PS1 transgenic (Tg) and wild type (WT) control mice as an input for Illumina paired end sequencing. The reads were aligned to mouse genome after adapter trimming and read counts were generated and normalized using DESeq2 for differential gene expression analysis. qRT‐PCR based validation was performed for the differentially expressed genes. Over‐expression of novel candidate gene on primary hippocampal cultures from Tg and WT APP/PS1 mice was achieved using lentiviral transduction. Imaging of neurons was performed on Zeiss confocal microscope and morphometry and spine analysis was done using Neurolucida software.

Result

APP was found to be upregulated in both EC and HP at 1 month and 3 months of age in APP/PS1 mice, which served as a positive control. A single gene was consistently down‐regulated at both 1 and 3 months of age in both EC and HP, which was validated through qRT‐PCR. Over‐expression of this gene using lentiviral transduction on APP/PS1 Tg hippocampal neurons in vitro rescued the loss of dendritic complexity observed in these neurons but not spine loss. Finally, we show the down‐regulation of this gene in prefrontal cortex from human AD autopsy tissue as compared to controls.

Conclusion

In conclusion, our study identified a novel gene candidate that is involved in loss of dendritic complexity in AD pathogenesis early in the disease.
Association between cognition and gait in elderly people: The putamen as a shared substrate
Authors: Li Peixi , Wang Yingzhe , Jiang Yanfeng , Chen Xingdong , Dong Qiang , Cui Mei
Published: December 2020

Background

Cognitive impairment and gait disturbance are both prevalent in elderly people. However, few studies have focused on the underlying mechanisms in the relationship between cognition and gait. The aim of our study is to contrast the strength of correlations between each cognitive domain and gait parameters in a community‐dwelling population, as well as giving a new insight into the shared neuroimaging signature of cognitive impairment and gait disturbance.

Method

In the cross‐sectional population‐based Taizhou Imaging Study, 733 older adults with a mean (SD) age of 63.9 (3.1) years accepted brain MRI, neuropsychological tests and wearable gait tracking devices for quantitative gait analysis. Global cognitive function and individual cognitive domains (memory, executive function, language, visuospatial skill) were assessed using the Mini‐Mental State Examination, auditory verbal learning test (with>6 years of education), modified Fuld Object Memory Evaluation (with≤6 years of education), conflicting instructions task, clock drawing test and animal fluency test. Dementia and mild cognitive impairment (MCI) were diagnosed according to DSM‐5 criteria and the Petersen criteria. The volume of brain regions was analyzed by Freesurfer.

Result

Of the 733 participants, 500 (68.2%) were cognitive normal, 182 (24.8%) were diagnosed as MCI, 51 (7.0%) were diagnosed as dementia. Gait parameters, including gait velocity, stride length and cadence, were significantly different among three cognition groups (P<0.001). In fully adjusted linear regression models, global cognitive function and each cognitive domain were significantly associated with gait parameters. Executive function demonstrated the strongest association with gait (β: 0.149‐0.206, P<0.001), which remained significant when adjusted for memory, language and visuospatial skill. The volume of putamen was the only region that was related to both executive function (β=0.103, P=0.007) and gait velocity (β=0.107, P=0.007). Mediation analysis confirmed a mediating role of putaminal atrophy in the association between executive function and gait velocity.

Conclusion

Cognitive function is associated with gait performance in community‐dwelling elderly individuals. Executive function had the strongest association with gait among cognitive domains, which is supported by a shared substrate including putaminal atrophy. Future longitudinal studies with neuroimaging techniques are needed to further confirm our findings.
An association study of Alzheimer’s disease risk genes in a Chinese population
Authors: Xiao Xuewen , Jiao Bin , Yuan Zhenhua , Liao Xinxin , Tang Beisha , Shen Lu
Published: December 2020

Background

Genome‐wide association studies (GWAS) and whole‐exome sequencing have identified a number of risk genes playing a significant role in the pathogenesis of Alzheimer’s disease (AD). However, most of the genetic studies are from Caucasian populations and relatively rare in Chinese population.

Method

We sequenced 33 AD risk genes using Targeted panel sequencing in 721 AD patients and 365 normal controls in Han population of Southern China. A series of bioinformatic methods including common‐variant (0.01≤MAF≤0.5) based association analysis and gene‐based association analysis on rare variants (MAF<0.01) were performed between AD patients and normal controls.

Result

We identified nine common variants with significant differences, three of them had been reported, including rs429358 in APOE, rs4147929 in ABCA7 and rs3752246 in ABCA7, while other six variants were novel, including rs3752229 in ABCA7, rs4147935 in ABCA7, rs17125497 in SORL1, rs2282647 in SORL1, rs11218355 in SORL1, and rs11682128 in BIN1. The area under the ROC (AUC) of the nine significant loci model was 0.670. Gene‐based association analysis on rare variants showed that the p value of RIN3 was less than 0.05 both in the Sequence Kernel Association Test‐Optimal (SKAT‐O) test and logistic regression analysis (age, gender and APOE ε4 as covariates) between AD patients and normal controls (p = 0.0399, corrected P = 0.0346).

Conclusion

We conclude that APOE, ABCA7, SORL1, BIN1 and RIN3 are risk factors for AD in Chinese population.
Sex‐specific differential gene expression changes in young AD transgenic (APPswe/PS1ΔE9) mice through RNA‐seq
Authors: Verma Aditi , Ramachandran Arathy , Rupanagudi Khader Valli , Ravindranath Vijayalakshmi
Published: December 2020

Background

Women and men are differently affected in Alzheimer’s disease (AD). However, the factors that contribute to this differential AD epidemiology are not well understood. We, therefore, examined how gene expression changes could work differently in females and males in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD using RNA sequencing (RNA‐seq).

Method

Total RNA was isolated from EC and HP from 3‐month‐old female and male APP/PS1 transgenic (Tg) and wild type (WT) control mice (n=4). Depletion of ribosomal RNA was performed on the total RNA before cDNA library preparation which was followed by Illumina paired end sequencing. The raw reads were processed to remove reads with low quality and adapters. The reads were then aligned to mouse genome and read counts for all the files were generated from aligned reads using htseq‐count. The counts were then name sorted using samtools and differential gene expression analysis was performed after normalisation using DESeq2 which was followed by pathway analysis using the online application DAVID.

Result

In both EC and HP in the female and male APP/PS1 mice, APP was found to be upregulated. In the EC, we observed that while 55 genes were upregulated in males, 418 genes were upregulated in female Tg mice as compared to WT with only 10 common genes. Further, while 153 genes showed downregulation in males, 152 genes were downregulated in EC in female Tg mice as compared to WT mice with 10 common genes. In HP, 40 genes were found upregulated in males while only 2 genes in females. The number of downregulated genes in male HP was 46, while it was 3 in female HP. Further, biological pathways such as synapse, cell junction, postsynaptic membrane, calmodulin binding, gap junction, cytoskeleton were perturbed in female Tg mice while in male Tg mice the pathways perturbed were synapse, cell junction, SH3 domain, transcription regulation and neurogenesis.

Conclusion

Our analysis of transcriptomic data reveals a significant difference between male and female APP/PS1 transgenic mice. Our study therefore, highlights the importance of studying sex‐specific mechanisms of AD pathogenesis.
Effect of soluble interleukin‐10 receptor expression in mouse models of Alzheimer’s disease
Authors: Koller Emily J. , De La Cruz Elsa Gonzalez , Weinrich Mary J. , Antezana Gustavo , Ibanez Kristen R. , Ryu Daniel H. , Lewis Jada , Chakrabarty Paramita
Published: December 2020

Background

Alzheimer’s disease (AD) is a neurodegenerative disease characterized pathologically by intracellular neurofibrillary tangles (NFT), extracellular amyloid β (Aβ) plaques, and neuroinflammation. Interleukin 10 (IL10) is an anti‐inflammatory cytokine released by immune and glial cells. Since IL10 is anti‐inflammatory, it has the potential to be a therapy for neurodegenerative diseases with an inflammatory component. However, contrary to what we expected, an earlier study from our group showed that overexpression of IL10 actually led to an increase in Aβ plaque burden in a mouse model of Aβ plaques. Therefore, we proposed to assess the effect of overexpression of the soluble extracellular portion of the IL10 receptor (sIL10R) on disease pathogenesis in both an Aβ mouse model and tau mouse models. The premise was that this soluble form of the receptor would attenuate IL10 signaling, thus reversing its anti‐inflammatory properties.

Method

To investigate the effect of sIL10R expression on Aβ plaques, we used adeno‐associated virus (AAV) to express sIL10R in neonatal TgCRND8 mice and aged them 3 or 6 months. We next investigated whether sIL10R also affected tau pathology in two tau mouse models: a slowly‐progressing spinal cord tauopathy model (JNPL3) and a rapid model with primarily cortical and hippocampal tauopathy (rTg4510).

Result

Assessment of Aβ plaque burden revealed decreased Aβ plaque load in the younger TgCRND8 cohort, but this effect was not observed in the 6 month old mice. We observed a significant reduction of phosphorylated tau and a trend towards reduced p62 levels in the JNPL3 mice. However, we did not observe changes in phosphorylated tau or p62 levels in 4 month old or 6 month old rTg4510 mice. Quantification of neuroinflammatory markers in APP and tau mouse models showed distinct patterns of neuroinflammation specific to each model.

Conclusion

Our study demonstrates that a decoy receptor may be a potential therapeutic for Alzheimer’s disease and that attenuation of Aβ and tau pathogenesis may occur at different rates and at different disease stages. Future experiments will center around characterizing possible mechanisms underlying these changes.
Intrathecal antibodies against herpes simplex virus are associated with tau pathology in humans with Alzheimer’s disease
Authors: Goldhardt Oliver , Freiberger Robert , Ortner Marion , Müller‐Sarnowski Felix , Förstl Hans , Diehl‐Schmid Janine , Ramirez Alfredo , Magdolen Viktor , Thaler Markus , Grimmer Timo
Published: December 2020

Background

Recurrent infection with herpes simplex virus type 1 (HSV1) has been discussed as contributing to Alzheimer’s disease (AD) pathology. HSV1 infection has been shown to induce beta‐amyloid (Aβ) accumulation and tau pathology in cell culture and animal models. Aβ limits the activity of the virus and might be part of the innate immune system. Both hyperphosphorylated tau (pTau) and HSV1 are associated with intracellular kinase activity. In this study, we investigated the association of serological HSV biomarkers with CSF biomarkers for Aβ and tau pathology as well as neuronal injury in humans with AD.

Method

In 117 patients at early stages of AD, total Tau (tTau), pTau, Aβ42 and Aβ40 were measured in CSF. All patients were positive for amyloid pathology in amyloid PET or exhibited an Aβ42/Aβ40 ratio <0.05 (in‐house cut‐off). Seral anti‐HSV1‐IgG, anti‐HSV1‐IgM titer and anti‐HSV1/2‐IgG CSF to serum antibody index (HSV‐AI) were determined by ELISA. In HSV1‐seropositives (defined by HSV1‐IgG ≥ 25 U/ml), serological HSV parameters and CSF AD biomarkers were correlated. The association between CSF pTau with serological HSV biomarkers modulated by amyloid was investigated in linear regression models.

Results

In the HSV1‐positives (n= 92), no serological HSV parameter was significantly correlated with CSF amyloid biomarkers. The HSV‐AI, was significantly correlated with tTau (Rho= 0.276, p= 0.012, n= 82) and pTau concentrations (Rho= 0.296, p= 0.007, n= 82), but not the seral anti‐HSV1‐IgG or IgM titer. In a linear regression model, HSV‐AI significantly and positively predicted pTau variability (adj. R²= 0.140, p<0.001, beta‐coefficient (β) = 0.389). Including Aβ42/Aβ40 ratio in the model increased the explained variability: adj. R²= 0.352, p< 0.001, βHSV‐AI= 0.374 (p< 0.001), βAβ‐Ratio= ‐0.467 (p< 0.001). A significant and negative interaction between the Aβ42/Aβ40 ratio and the HSV‐AI was retrieved (adjusted R²= 0.395, p< 0.001, βHSV‐AI= 1.560 (p =0.001), βAβ‐Ratio= 0.339 (p=0.304), βAβ‐Ratio*HSV‐AI= ‐1.430 (p= 0.013)). All models were controlled for APOE genotype, sex and age.

Conclusion

In AD, CSF pTau is associated with intrathecal HSV activity. This association is modulated by Aβ. The results support the hypothesis of HSV infection contributing to AD pathology.
Association of traumatic brain injury with late life neuropathological outcomes in a community‐based cohort
Authors: Gibbons Laura E , Power Melinda C , Walker Rod L , Kumar Raj G , Murphy Alia , Latimer Caitlin S , Melief Erica J , Beller Allison E , Keene C Dirk , Larson Eric B , Crane Paul K , Dams‐O'Connor Kristen
Published: December 2020

Background

Despite extensive interest in risk for dementia following traumatic brain injury (TBI), there is scant research on neuropathological outcomes among community‐dwelling elders with TBI exposure. We previously reported an association of TBI resulting in loss of consciousness (LOC) with microinfarcts and Lewy body pathology, but TBI exposure data were limited to a single self‐report question. With expanded ascertainment data from medical records and structured interview on lifetime TBI exposure, we conducted a comprehensive investigation of neuropathological associations of TBI in a large autopsy cohort.

Method

780 older adults from the Adult Changes in Thought (ACT) study underwent brain autopsy (Table 1). Participants were members of Kaiser Permanente Washington who completed biennial clinic visits including self‐reported head trauma with LOC exposure. These data were supplemented with medical record abstraction, and, for 244 people, with structured interviews, increasing the sensitivity for TBI‐LOC in that sample from 16% to 20% (see Figure 1). Neuropathology outcomes included neurofibrillary tangle distribution (Braak), neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral cortical atrophy. Exposures of interest included TBI with or without LOC. We used Poisson regressions with robust standard errors adjusted for age, sex, education, and APOε4 genotype, weighted back to the full cohort (n=5546; Table 2) in a bootstrapping procedure accounting for errors in estimating weights.

Result

TBI with LOC was associated with increased cortical atrophy (Table 3). In those with the structured interview (including TBI without LOC), the neuropathological associations of TBI were attenuated; no outcomes were statistically significant (Table 4). These findings apply to the full ACT cohort, not just people with TBI data in the autopsy sample.

Conclusion

Cerebral cortical atrophy results from chronic brain parenchymal injury, potentially including vascular brain injury and tauopathy. Understanding mechanisms underlying associations of TBI with microvascular brain injury and pathological tau are poorly understood; future studies deploying new techniques to better quantify these lesions and differentiate between TBI‐related, age‐related, and ADRD‐related pathways are needed.
Potential for primary prevention of dementia in low‐ and middle‐income countries: A cross‐sectional analysis of population attributable risk of dementia using twelve modifiable factors in population surveys of aging
Authors: de Langavant Laurent Cleret , Bayen Eleonore , Bachoud‐Levi Anne‐Catherine , Yaffe Kristine
Published: December 2020

Background

The World Health Organization recently assessed twelve modifiable risk factors that could be targeted to prevent future dementia but did not find sufficient evidence for recommending prevention programs for each of them. Several groups estimated the population attributable risk of dementia for seven to nine of these risk factors and suggested that one third of dementia cases could be prevented worldwide (Barnes & Yaffe, 2011; Norton, 2013). This proportion of avoidable dementias might be even higher in low‐ and middle‐income countries (LMIC) based on 10/66 data surveys (Mukadam, 2019). Our goal is to expand this research in ten population‐based surveys of aging on four continents using twelve modifiable risk factors.

Method

We previously identified probable dementia cases based on unsupervised machine learning (Cleret de Langavant, 2018, AAIC 2019, and submitted) in the following studies from LMIC: MHAS (Mexico, 2015), ELSI (Brazil, 2016), CHARLS (China, 2015), IFLS (Indonesia, 2015), LASI (India, 2016), SAGE‐Ghana wave 1 (2007), SAGE‐South Africa (2007), SAGE‐Russia (2007) and from high income countries (HIC): HRS (USA, 2014) and SHARE (Europe and Israel, 2015). In the different cohorts, we first estimate the communality between twelve risk factors (when available): hypertension, diabetes, dyslipidemia, low education, low physical activity, social isolation, depression, poor diet, smoking, alcohol abuse, unhealthy weight gain and hearing loss. We calculate the overall weighted population attributable risk of dementia to estimate avoidable dementia proportion in each cohort. We then compute the individual weighted population attributable risk of dementia for each factor in each cohort to identify the most important targets for dementia prevention.

Result

Our preliminary results suggest that the population attributable risk of dementia vary according to the country of origin of the cohort. According to our approach, the proportion of avoidable dementias might be higher than expected in HIC, and much higher in LMIC compared to HIC. We will present an overview of the most important risk factors of dementia in each cohort.

Conclusion

Our investigation confirms a huge potential for primary prevention of dementia in both HIC and LMIC. Health policy makers should adapt their prevention efforts according to country specificities.
PIN1 is an indicator of age‐ and sex‐associated risk of mild cognitive impairment and subsequent Alzheimer’s disease
Authors: Mastroeni Diego F.
Published: December 2020

Background

Women have a higher incidence of Alzheimer’s disease (AD) than men, even after correction for the greater longevity of women. It is also known that AD on the maternal side increases risk for offspring more than does AD on the paternal side. Considerations such as these have led to intense interest in potential molecular differences between the male and female brain, with special emphasis on aging in many studies. Thus, there is an urgent need to identify molecules that identify gender risk early in disease. Excessive post‐translational modifications (e.g. phosphorylation) are known early events in AD. Phosphorylation events are critical intermediates of “normal” protein function, but excessive phosphorylation (e.g. hyperphosphorylation) is unfavorable. Hyperphosphorylation of tau and amyloid triggers the formation of neurofibrillary tangles (NFTs) and toxic Aβ aggregates, both of which have been descried as classical hallmarks of AD. Recent efforts have identified the peptidyl‐prolyl cis/transisomerase (Pin1) as a key regulator of the phosphorylation signaling pathway.

Method

Here, we demonstrate using Laser Capture micro‐dissection, Affy‐Microarray, RNA sequencing and 450K methylation array that Pin1 is significantly down‐regulated as a function of age (22yrs‐99yrs) and AD, and up‐regulated in MCI limbic and neocortical brain regions.

Results

Analysis revealed a significant sex and aging effect. In order to confirm, further analysis in a larger AD and matched control cohort (630 patients) from the Religious Orders Study and Memory and Aging Project (ROSMAP) study revealed that the significant decreases in Pin1 levels in AD are wholly driven by female subjects.

Conclusion

These results set the stage for the development of therapeutic strategies to target Pin1 in females in preclinical AD as a method of preventing, and monitoring the progression of healthy aging to AD.
Impact of video decision aids for caregivers of people with young‐onset dementia
Authors: Brandt Katie , Quimby Megan , Quintiliani Lisa M , Wong Bonnie , Paasche‐Orlow Michael K , Krahn Erin , Krivensky Samantha , O’Chander Raseeka , Volandes Angelo , Dickerson Brad C
Published: December 2020

Background

Young‐onset (age < 65) dementias, especially the Frontotemporal Dementia spectrum of diseases and young‐onset Alzheimer’s disease, are often rapidly progressive and have unique caregiving demands. Educational tools for caregivers often are inconsistent and may not adequately help people envision future challenges . The study objective is to examine the acceptability of video decision aids for caregivers of people with young‐onset dementia.

Method

We conducted focus groups of caregivers for people with young‐onset dementia, separated by early, moderate, and late stage. Eleven video decision aids total (six per group), each focused on a caregiving topic, were shown. After each video, participants answered six questions about acceptability and then responded to open‐ended questions to explain their ratings. Descriptive statistics were calculated, and themes were summarized.

Result

Four focus groups have been completed (n=8, 4 mild, 4 moderate). On a scale of 1 (strongly disagree) to 5 (strongly agree), the mean (SD) ratings were 3.4 (0.43) for learning something new, 2.1 (0.65) for made me feel uncomfortable, 3.7 (0.35) for made me want to learn more, 4.2 (0.58) for how much already knew about this topic, 4.1 (0.42) for important to learn more, 4.4 (0.36) for recommend to others. Videos about talking to your loved one about not driving, choosing a skilled nursing facility, goals of care in advanced dementia, and thinking about medical decisions had the most positive mean ratings. Caregivers reported preferring visual images that match their loved one’s age group, wanting access to information earlier, and preferring to receive access to videos from their healthcare provider. While similar overall, caregivers in the moderate stage reported learning more from an introduction to caregiving video (moderate M=3.25; mild M=2) and more discomfort for the video about stopping driving (moderate M=2.75; mild M=1.75) compared to caregivers in the mild stage.

Conclusion

Video decision aids may be an acceptable way to convey information about the unique caregiving demands of those caring for loved ones with young‐onset dementia. Empowering caregivers with information about anticipated medical decisions may reduce caregiver burden and stress, allowing for higher quality of care for loved ones.
The electronic person‐specific outcome measure (ePSOM) development programme: Overall approach
Authors: Saunders Stina , Terrera Graciela Muniz , Evans Alison , Sheehan Shane , Luz Saturnino , Ritchie Craig W.
Published: December 2020

Background

The ePSOM development programme is a collaboration between the University of Edinburgh and Alzheimer’s Research UK prompted by the recognition that outcome measures currently used in clinical trials in prodromal and preclinical neurodegenerative diseases do not capture the research participants’ views of effectiveness. A better understanding of earlier manifestations of Alzheimer’s disease and the drive for relevant outcome measures, allied to technological advances in artificial intelligence, have mediated the electronic Person‐Specific Outcome Measure (ePSOM) development programme. The group took the view that ‘maintenance of brain health’ as opposed to ‘avoidance of symptoms’ would form the underpinning narrative in the ePSOM programme and ultimately app design.

Method

There are 4 sequential stages in the ePSOM programme (the first three completed): (1) literature review, (2) focus group study, (3) national survey, and (4) development of an app for capturing person‐specific outcomes. The survey data was analysed using clustering and natural language programming techniques and the results are presented separately. Here, we report the overall approach to the ePSOM programme.

Result

Our literature review on patient‐reported outcome measures in the Alzheimer’s disease population showed trials currently do not use any patient‐reported outcome measures. Our focus groups with people living with memory problems; healthy volunteers and health care professionals (n=41) yielded five key domains in relation to what matters to people when developing new treatments for Alzheimer’s disease: Everyday Functioning; Relationships and Social Connections; Enjoying Life; Sense of Identity; and Alleviating Symptoms. Our online survey, which was created based on the literature review and focus groups, was completed by 5807 individuals. 30 clusters of themes emerged from the survey responses.

Conclusion

The ePSOM development programme is building evidence in order to deliver the methodology for incorporating personally meaningful outcome measures in Alzheimer’s disease clinical trials. The completed three stages will underpin the ePSOM app, which will be using natural language processing methodologies, and have good psychometric properties enabling the app to be use in regulatory trials.
Viewing some people living with dementia through a lens of complicated grief
Authors: Ione Adrienne
Published: December 2020

Background

The concept of human flourishing holds tremendous global value for policy makers and individuals alike, and in no just society should people living with dementia be excluded. Rather than promoting what is commonly discussed as the most disturbing sequala of neurological disorders and related dementias, a few researchers have flipped BPSD (e.g., agitation, ruminating, pacing, etc.) on its head, arguing that these are expressions of agency (Boyle, 2014; Orulv, 2012; Finkle, 2000 and Kales et al., 2015). Regulation of BPSD needs to be relegated to the background, reframed as a form of agency, and therapeutic techniques aimed at increasing flourishing brought into the foreground (Ryan et al., 2013). One challenge with developing a coherent and systematic therapeutic approach for people living with dementia is determining individual needs (Smith et al., 2013). A view of BPSD, expanding on the notion of exercising one’s agency, is the human need for an attachment figure (Walsh et al., 2019). It has long been established that complicated grief leads to negative overall health and life quality consequences (Prigerson et al., 2008). Grounded in attachment theory, Complicated Grief Treatment (CGT) (Shear et al., 2014), one of the only evidence‐based techniques that has been applied to older adults, holds promise for bridging attachment gaps (Meichsner, 2020).

Method

Active Capabilities Therapy (ACT), an exploratory, non‐judgmental, integrative, person‐centered approach used to increase flourishing among people living with dementia, incorporates CGT principles.

Result

The 5‐item brief grief questionnaire (BGQ) is used to assess prolonged grief and is included in the intake assessment of people receiving ACT (Shear and Essock, 2002). The BGQ was used as an interview instrument throughout therapy sessions to measure change in grief. To maintain consistency in the evaluation cycle of CGT component of ACT, data were collected through an unbiased random selection of 6 time points, over 3 years of data collection, from a single case study.

Conclusion

The efficacy of CGT in people living with dementia, was evidenced by a continued point improvement on the Inventory of Complicated Grief (Prigerson et al., 1995) as well as decreased severity of items listed on NPI‐Q (Cummings, 1994).
Natural genetic variation alters Alzheimer’s‐related gene expression modules in mice
Authors: Wells Ann E. , Raghupathy Narayanan , Robledo Raymond F. , Gatti Daniel M. , Munger Steven C. , Phillips Charles , Ndukum Juliet , Wilcox Troy , Graber Joel , Hibbs Matthew , Langston Michael A. , Churchill Gary A. , Carter Gregory W. , Chesler Elissa J
Published: December 2020

Background

Understanding the genetics of Alzheimer’s disease (AD) has proven difficult in human populations. Using mouse models enables researchers to dissect the genetics of AD‐related pathways. The Diversity Outbred (DO) mice are a heterogenous multi‐parental population created using eight founder strains, mimicking human population structure. The DO provide a new resource to investigate complex diseases, such as AD. Comparing the genetics of individuals with AD to DO mice will enable us to identify AD‐related pathways in mice that can be dissected to better understand AD.

Method

Genes identified in the hippocampus of 258 male and female DO mice were grouped into 145 paracliques, unique clusters of correlated genes that are closely related. Paracliques were compared with 30 human gene modules related to AD from the Accelerating Medicines Partnership for Alzheimer’s disease (AMP‐AD). Gene content overlaps were calculated between the AMP‐AD modules and DO paracliques by Jaccard index. Additionally, we mapped and characterized quantitative trait loci (QTL) to determine if summary eigengenes from each paraclique were associated with genetic factors. Both SNP associations and database searches were performed to identify potential genes of interest within the QTL. Paracliques and DO genes identified for significant QTL were compared to the AMP‐AD modules and AGORA to determine their relevance to AD.

Result

Significant QTL were identified for paraclique 56 on chromosome 16. IL6ST, a nominated target in AGORA, was identified within paraclique 56. Additionally, KALRN, a gene that plays a role in decreased anxiety‐related behavior, contextual conditioning, and synapse formation, was identified within the QTL for paraclique 56. KALRN was a member of the AMP‐AD neuronal modules. Furthermore, variants in KALRN were identified in brain eQTL from Alzheimer’s study cohorts and determined to be a candidate gene in AGORA, adding to its potential relevance. Mediation analysis revealed that KALRN is potentially locally regulated by ROGDI. A loss‐of‐function mutation in ROGDI results in Kohlschutter‐Tonz syndrome, which can result in dementia as a symptom.

Conclusion

This study identified potential candidate genes in DO mice that have relevance to AD. In sum, this study showcases the potential of utilizing DO mice to translationally investigate AD‐related pathways.
Dementia with Lewy bodies: A differential diagnosis of normal pressure hydrocephalus
Authors: Durand Hélène , Baloglu Seyyid , Bilger Mathias , Ollivier Irène , Cretin Benjamin , Anheim Mathieu , Proust François , Blanc Frédéric , Philippi Nathalie
Published: December 2020

Background

The diagnosis of idiopathic normal pressure hydrocephalus (NPH) is challenging and remains overestimated because of the absence of specific clinical, imaging or biological features. It relies on association of classical triad of symptoms (gait disturbance, cognition impairment, urinary symptoms) associated to a ventricular enlargement. Several differential diagnoses should be considered with an initial presentation suggestive of NPH, such as dementia with Lewy bodies (DLB), Alzheimer disease (AD) and vascular dementia (VD). The aim of this study was to identify NPH differential diagnosis as well as to highlight clinical and radiological features that could help questioning this diagnosis, before performing invasive procedures.

Method

In this monocentric retrospective study, we included 42 patients fulfilling the criteria of possible NPH on initial presentation. At the end of the follow‐up, we classified the sample into patients with probable NPH (NPH group ; n = 13), differential diagnosis of NPH (NPH‐ group; n = 21) and dual pathology with criteria of probable NPH (NPH+; n = 8), depending on their outcome after cerebrospinal fluid (CSF) drainage. We collected clinical data, including results of cognitive assessment, as well as results of CSF biomarkers, EEG, functional and morphological neuroimaging. Ventricular enlargement profile was analyzed using different visual measures on MRI.

Result

The main differential diagnosis of NPH was DLB (21/21), mixed with vascular dementia in four cases. None of the patient had a CSF profile suggestive of AD. Regarding clinical features, asymmetric parkinsonism, fluctuations, agitation during sleep, visual hallucinations and visuospatial impairment were significantly more frequent in NPH‐ patients, compared to NPH patients (p=0.033). The callosal angle was significantly more acute (<104° ; p <0.01) and fourth ventricular dilatation greater (>17 mm ; p<0.01) in NPH patients than in NPH‐ patients, while there was no significant difference in the dilatation of lateral ventricles and third ventricle.

Conclusion

DLB appeared as the main differential diagnosis of NPH. Our results indicate that the existence of asymmetric parkinsonism, fluctuations, agitation during sleep, visual hallucinations or visuospatial impairment, as well as the absence of acute callosal angle or fourth ventricular dilatation should lead to consider DLB as a differential diagnosis of NPH.
Reflective pondering is associated with a global cognitive marker of Alzheimer’s disease risk
Authors: Demnitz‐King Harriet , Whitfield Tim , Schlosser Marco , Barnhofer Thorsten , Collette Fabienne , Klimecki Olga , Lutz Antoine , Schild Ann‐Katrin , Wirth Miranka , Chetelat Gael , Marchant Natalie L , Group Medit‐Ageing Research
Published: December 2020

Background

Reflective pondering is an introspective mechanism conceptualised as actively seeking a solution to one’s problems. Literature has consistently demonstrated positive associations between reflective pondering and improved mental health outcomes in clinical populations. Given that poor mental health (e.g. depression, anxiety) has been associated with increased dementia risk, and that reflective pondering improves mental health, we asked whether reflective pondering could also act as a protective factor against dementia, measured by cognitive function, in older adults.

Method

Baseline data from 145 older adults with subjective cognitive decline (SCD; mean age = 72.2) from the SCD‐Well clinical trial and 135 healthy older adults (mean age = 70.5) from the Age‐Well clinical trial were included in this study. All participants completed the reflective pondering subscale of the Rumination Response Scale and a modified version of the Preclinical Alzheimer’s Cognitive Composite (PACC; Donohue et al., 2014). Linear regressions were run to determine the association between reflective pondering and PACC scores in each cohort independently. Analyses controlled for available prognostic characteristics known to be associated with Alzheimer’s disease (e.g. age, sex, education, depressive symptoms and APOE genotype).

Result

In SCD‐Well reflective pondering was positively associated with PACC scores after controlling for age, sex, education and depressive symptoms (β = 0.05, p <.01), with higher levels of reflective pondering associated with better cognition. Similarly, in Age‐Well reflective pondering was also positively associated with PACC scores (β = 0.04, p = .03) aftercontrolling for age, sex, education, depressive symptoms and APOE genotype.

Conclusion

In two independent cohorts that included healthy older adults and individuals with SCD, levels of reflective pondering were positively associated with a global cognitive marker of Alzheimer’s risk. Our results introduce preliminary support for reflective pondering as a protective factor for cognitive function. Both SCD‐Well and Age‐Well are clinical trials, thus future work will evaluate the association between changes in reflective pondering due to intervention and cognitive function.
Awareness of dementia risk and of brain‐healthy lifestyles in medical students implementing new brain health classes in French schools
Authors: Bayen Eleonore , de Langavant Laurent Cleret , Gouriou Clémentine , Pradat‐Diehl Pascale , Canoui‐Poitrine Florence , Yaffe Kristine , Lawlor Brian
Published: December 2020

Background

Research projects that up to 35% of dementia cases may be preventable by targeting modifiable risk factors. Yet, there is currently a low awareness among citizens of all ages about the link between lifestyles and dementia risk. MyBrainRobbie is a public health non‐profit initiative launched in 2019 to promote brain health among children aged 6 to 12 with support from the Global Brain Health Institute (GBHI) and the Alzheimer's Association. MyBrainRobbie includes 1)a video that helps children and teenagers learn about eight neuroprotective/risky lifestyles in a gentle and appropriate language (over 80000 YouTube views) 2)a website with scientific and educational resources: www.mybrainrobbie.org/ ,(1&2 freely available in four languages) 3)an implementation strategy to integrate brain health classes in schools’ curriculum 4)an international outreach development thanks to GBHI. Implementations of new brain health classes in French elementary and middle schools leveraging MyBrainRobbie’s tools were carried out during 2018‐2019 and 2019‐2020 academic years. Pilot monitoring of 303 school children showed a high satisfaction and a significant memorization of neuroprotective lifestyles after the class (AAIC2019). We now report on the monitoring of medical students who implemented these classes.

Method

Over 400 students in second, third or fourth year of their medical studies were trained in three medical universities including 1) 2‐hours lecture on dementia risk 2) 2‐to‐6 hours of coaching in small groups to prepare their school interventions. Dyads of students then carried out their preventative educational class in schools. Before this training, medical students were asked 1) whether they thought that they could modify their own dementia risk 2) what neuroprotective/risky brain habits they were spontaneously aware of 3) to sort out a list of dementia risk factors. At the end of the training they were asked whether they thought they would now modify their personal behavior to protect their brain (and how). Six months later, after their practical teaching experience in schools, they were asked whether they had modified their behavior (how/why not) in order to protect their brain.

Result

Pre‐post results will be presented.

Conclusion

We aim to evaluate how brain health promoted by medical students might ricochet on their own personal awareness and behaviors.
Haploinsufficiency of progranulin causes impairments in PINK/PARKIN mitophagy
Authors: Casey Jackie M. , Melandri Daniela , Arber Charles , Soutar Marc , Holler Christopher J. , Kukar Thomas , Isaacs Adrian M. , Rohrer Jonathan D. , Plun‐Favreau Helene , Wray Selina
Published: December 2020

Background

GRN mutations, resulting in haploinsufficiency of progranulin, cause frontotemporal dementia (FTD) with TDP‐43 pathology. Impairments in mitophagy, the selective autophagy of damaged mitochondria, have been identified in several neurodegenerative diseases, and multiple neurodegenerative disease genes, including PINK1, Parkin, VCP and TBK1, have been shown to play a role in this pathway. A role for progranulin in the regulation of neuronal mitophagy has not been explored, however progranulin deficient mice exhibit reduced xenophagy (selective clearance of bacteria). We therefore hypothesised that loss of progranulin could lead to defective mitophagy.

Method

We used two in vitro models to investigate PINK1/Parkin mitophagy: SHSY5Y cells overexpressing Parkin (PoE‐SHSY5Y) +/‐ siRNA against GRN, and induced pluripotent stem cell (iPSC) derived cortical neurons from two patients with FTD‐associated GRN mutations (R493X and C31fs). PINK1/Parkin mitophagy was induced using a combination of Antimycin A (respiratory complex III inhibitor) and oligomycin (ATP synthase inhibitor), and PINK1 accumulation and levels of S65 phosphorylated ubiquitin (the substrate of PINK1 and a marker of its activity) were examined using western blot and immunofluorescence. Subsequent mitophagy was assessed by examining Mitofusin‐2 ubiquitination and degradation, and TIM23 levels by western blot.

Result

A reduction in progranulin levels resulted in reduced accumulation of PINK1 and lower levels of mitochondrial phospho‐ubiquitin following oligomycin/antimycin treatment in both PoE‐SHSY5Y and iPSC‐neurons with GRN mutations. Ubiquitination and degradation of mitofusin‐2 was also decreased in cells with reduced progranulin.

Conclusion

These results suggest that progranulin plays a role in mitophagy by regulating stability and/or activity of PINK1. Ongoing work aims to understand the mechanisms by which progranulin and/or individual granulins contribute to this process and to dissect cell‐type specific contributions of progranulin to mitophagy in iPSC‐ derived neurons, astrocytes and microglia.
Physical activity and brain volumes in older adults: The Washington Heights‐Inwood Columbia Aging Project (WHICAP)
Authors: Gu Yian , Manly Jennifer J , Schupf Nicole , Mayeux Richard , Brickman Adam M
Published: December 2020

Background

Leisure time physical activity (LTPA) has been shown to be protective against cognitive decline, dementia, and Alzheimer's disease. Understanding whether LTPA is associated with MRI‐assessed brain measures will help elucidate the underlying mechanisms.

Method

This cross‐sectional study included 1557 older participants of the Washington Heights‐Inwood Columbia Aging Project study, a community‐based, multi‐ethnic elderly cohort. Current LTPA level was measured using metabolic equivalent of energy expenditure (MET‐minutes/2‐wk), calculated from self‐reported Godin Leisure Time Exercise Questionnaire. Total brain volume, gray matter volume, white matter volume, hippocampal volume, and white matter hyperintensity volume were derived from MRI scans with established methods and were adjusted for intracranial volume. We examined the association of LTPA with these imaging markers using multivariable regression models.

Results

The participants of the study had a mean (SD) age of 74.9(6.0) years, 64% were women; 26%, 34% and 38% were non‐Hispanics whites, African‐Americans, and Hispanics, respectively; and 28% carried Apolipoprotein ɛ4 allele. One SD (2860 MET‐minutes/2‐wk) increase in LTPA was significantly associated with 4.02 (95%CI=1.15‐6.88; p=0.006), 2.87 (95%CI=1.13‐4.62; p=0.001), and 0.043 (95%CI=0.004‐0.082; p=0.032) cm3 larger total brain, gray matter, and hippocampal volumes, respectively. Compared to those in the lowest tertile of LTPA, those with the highest tertile of LTPA had larger (in cm3) total brain volume (b=13.23, p=0.001; p‐trend=0.001), total gray matter volume (b=8.41, p<0.0001; p‐trend=0.001), and total white matter volume (b=7.25, p=0.005; p‐trend=0.013), hippocampal volumes (b=0.11, p=0.04; p‐trend=0.08), after adjusting for age, sex, race/ethnicity, education, Apolipoprotein E4 status, intracranial volume, and recruitment waves. The effect size comparing the highest to the lowest tertile LTPA was equivalent to about 3 years of aging (b for 1‐year older=‐3.14, ‐2.72, ‐2.16, ‐0.059 for total brain, gray matter, white matter, and hippocampal volumes, respectively). The associations were attenuated slightly but remained similar after further adjusting for body mass index and vascular comorbidities. LTPA was not associated white matter hyperintensity volume. The results remained similar after excluding 296 participants with mild cognitive impairment.

Conclusion

More physical activity is associated with larger brain volumes in the elderly. Future longitudinal studies are needed to establish a temporal relationship between physical activity and brain health.
Quantitative sodium imaging using ultra‐high field magnetic resonance imaging in patients with Alzheimer's disease
Authors: Haeger Alexa , Coste Arthur , Lerman‐Rabrait Cécile , Lagarde Julien , Schulz Jörg B. , Vignaud Alexandre , Sarazin Marie , Bottlaender Michel , Reetz Kathrin , Romanzetti Sandro , Boumezbeur Fawzi
Published: December 2020

Background

In Alzheimer’s disease (AD), energy deficit is suspected to occur before clinical symptoms arise. Therefore, neuroimaging methods sensitive to metabolic alterations are attractive to improve diagnostics, therapeutics and follow‐ups of AD patients. An indirect measure of deficient Na+/K+‐ATPase‐activity during neurodegeneration is provided by the tissue sodium concentration (TSC) measured by Sodium‐(23Na)‐MRI.

Method

16 patients (7 Male, 71.7±8 years) diagnosed with AD (MoCA 15.1±7) were recruited from Ste. Anne Hospital in Paris as well as 16 cognitively healthy age‐matched control subjects (7 Male, 69±3.1 years; MoCA 28.1±1.8). Each subject underwent 23Na and 1H MRI examinations at the 7T MRI scanner (Siemens) at Neurospin, CEA. A dual‐resonance 1H/23Na volume coil (Rapid Biomedical) was used for a 23Na MRI protocol acquiring ultra‐short echo‐time images (3mm isotropic resolution) at two flip‐angles (a1=25º/a2=55º) (Coste et al., 2019). Briefly, processing steps comprised image reconstruction, denoising, motion‐ and B1‐inhomogeneities‐corrections, and a calibration step using 4 external references. Individual TSC maps were co‐registered to their T1‐weighted anatomical reference (MP2RAGE, 750 µm isotropic resolution) and a partial‐volume‐effect correction (Thomas et al., 2016) was implemented to limit the influence of sodium from cerebrospinal fluid. Anatomical and TSC images were normalized to the OASIS template using ANTs. A parameter free permutation analysis was performed voxel‐wise on normalized TSC images and on the LogJacobian of the deformation fields. After, region‐of‐interest‐analyses on hippocampus from VolBrain‐Atlas followed.

Result

The voxel‐based analysis showed significant widespread increases in TSC of AD patients, particularly in parietal, temporal and frontal regions. Interestingly, the observed TSC changes were located in areas not directly associated to significant structural changes (Fig 1). Furthermore, TSC in the hippocampus was found significantly higher in AD than in controls (42.9±4.3mmol/l; 35.8±3.9mmol/l; Wilcoxon‐rank‐sum; p=0.00015, z=3.8) and was correlated, after controlling for age, with both the MoCA‐scores (r=‐0.62; p=0.0002) and hippocampal volumes (r=‐0.39; p=0.032).

Conclusion

High‐field quantitative 23Na MRI in AD shows increased TSC values across a wide range of brain regions. These results may provide a deeper insight into metabolic alterations occurring during neurodegeneration. 23Na MRI could therefore serve as a useful tool to characterize disease progression or the impact of therapeutic intervention.