bluuebunny/crossref_metadata_2025 huggingface dataset:
A systematic review on the physical and mental health risk factors of mild cognitive impairment and Alzheimer’s disease in military veterans
Authors: Akhanemhe Rebecca A , Stevelink Sharon A.M , Aarsland Dag , Greenberg Neil
Published: December 2020

Background

The connection between military service, mild cognitive impairment (MCI) and Alzheimer’s disease (AD) has been previously explored but findings remain inconclusive. With age as the greatest and unmodifiable risk factor for dementia in military veterans, there is a need to further explore specific physical and mental health factors that influence cognition and dementia in military veterans compared to the general population. We will review publications as part of a systematic review to identify if traumatic brain injury, post‐traumatic stress disorder and depression influence the risk of MCI and AD in both military veterans and non‐veterans.

Method

We aim to conduct a meta‐analysis but if we identify limited suitable studies, a systematic review will be an alternative approach. Our systematic search will be carried out using various bibliographic databases including MEDLINE and PubMed. Data will be extracted from comparative and non‐comparative epidemiological and observational studies, published between 1990 to December 2019. The study population will be restricted to adults aged ≥50 years who may or may not have served in the military and assessed the occurrence of MCI/dementia whether formally diagnosed or through self‐report.

Result

To date, we identified 135 articles without duplicates and of this, 83 (61.5%) were excluded based on their titles and a further 27 articles (20%) were excluded after reviewing their abstracts. We are currently working on this review and aim to have the full findings before the conference.

Conclusion

The potential implication of the findings could influence how health professionals utilise occupation data to identify dementia. Beyond the scientific community, the findings will raise awareness and promote health among veterans and carers.
Biogeographical factors affecting people with dementia of Alzheimer’s type and mild cognitive impairment
Authors: Rai Pooja , Singh Tara , Singh Indramani L. , Tiwari Trayambak , Joshi Deepika
Published: December 2020

Background

Dementia of Alzheimer’s type has been the most common neurodegenerative condition among elderly. The histopathological studies revealed that the formation of neurofibrillary tangles and amyloid plaque in brain have been the major factors affecting DAT. Other than intrusive protein formation there are other factors which pertains to affect DAT.

Method

The present study has accounted for different variables in with 7 mild, 8 moderate DAT and 7 MCI people.

Result

Among all the biographical variables, 10 variables viz. family size, education, smoking, exercise, alcohol, diabetes, heart problems, cholesterol, thyroid and blood pressure were the most affected biographical variables among all the patients. Further, diabetes, cholesterol, heart problem education were the most predictive among all the variables.

Conclusion

The study suggested the significance of bio‐physiological factors in assessing dementia of Alzheimer's type so that an early progression of neurodegeneration could be traced.
Investigating the contribution of an intronic variation at the trim11 locus to pathological and clinical heterogeneity in progressive supranuclear palsy
Authors: Bez Sumi , Fowler Stephanie L. , Jabbari Edwin , Morris Huw R. , Duff Karen E.
Published: December 2020

Background

Progressive supranuclear palsy (PSP) is a tauopathy that exhibits significant heterogeneity, with the three most prominently presenting subtypes showing differences in clinical symptomatology, disease progression, and tau burden. Recently, an intronic variant in the proteasome‐related gene TRIM11 was identified as a potential modifier of phenotypic diversity in PSP. Due to the role of TRIM11 as a known E3 ligase in the ubiquitin‐proteasome system, the single nucleotide polymorphism (SNP) is hypothesized to alter TRIM11 expression and/or function, thereby impacting pathological tau clearance. The current study will investigate the functional relevance of the TRIM11 intronic variant to mechanisms of pathological tau clearance.

Method

Using both full‐length, and repeat domain tau aggregation reporter assays with overexpressed or silenced TRIM11, we are determining if aggregated tau is a substrate of TRIM11 E3 ligase activity by co‐immunoprecipitation and tau ubiquitination assays. Further, we are monitoring tau inclusion formation and clearance by longitudinal imaging, coupled with the investigation of sarkosyl‐insoluble tau levels, and by cycloheximide chase assays for tau.

Result

If tau is a substrate of TRIM11 E3 ligase activity and TRIM11 is found to mediate the clearance of pathological tau, this finding could reveal the molecular mechanisms contributing to the clinical diversity observed in PSP.

Conclusion

Taken together, these experiments outline the investigation of one of the first genetic clues to phenotypic diversity in PSP, solidify the involvement of the UPS as a viable target in the processing of pathological tau, and may have wide‐reaching implications for the treatment of many other protein aggregation neuropathies.
Discovering genetic variants contributing to sleep dysfunction in presymptomatic Alzheimer’s mice
Authors: Hadad Niran , Dunn Amy R. , O'Connell Kristen M.S. , Kaczorowski Catherine C.
Published: December 2020

Background

Disordered sleep is frequently observed in Alzheimer’s disease patients. Sleep loss is associated with increased Aβ and tau accumulation in both AD patients and model organisms. Furthermore, cognitively intact individuals with impaired sleep are at higher risk for AD. Although individual differences in sleep are known to be highly heritable, little is known of the genetic factors associated with sleep dysfunction in aging and AD and if these contribute to disease development.

Method

Sleep was assessed at a presymptomatic age (6‐7 months) in a panel of genetically diverse mice carrying familial AD mutations, which better models complex etiology of human AD (AD‐BXDs; Neuner et al 2019). Sleep‐wake activity was measured for five consecutive days using the PiezoSleep tracking system across 25 AD‐BXD strains and their nontransgenic littermates (Ntg‐BXD).

Result

AD‐BXD mice slept significantly less during the dark cycle compared to Ntg‐BXDs. Additionally, reduction of sleep was observed during the transition from dark to the light cycle, suggesting disruption of circadian function. Females slept less than males regardless of AD mutation status. We identified a significant quantitative trait locus (QTL) on chromosome 9 associated with total sleep, this region is syntenic with a regions on the human chromosome 11, harboring six sleep‐associated human GWAS SNPs, demonstrating the relevance of this region to human biology. Additionally, we identified a QTL for hourly sleep at ZT14 that mapped to intron 1 of the gene Kirrel3 of chromosome 9 (∼20 mb downstream of the sleep‐QTL). Differential gene expression implicates Kirrel3 as a novel target‐gene for validation.

Conclusion

We provide the first evidence that genetic factors interact with AD mutations to influence sleep behavior, and identified two regions causally associated with variation in sleep in the AD‐BXDs. Mouse‐to‐human comparison suggest that both region are relevant to humans, demonstrating the value of the AD‐BXDs as a translational AD model. Future work will leverage genome engineering to correct sleep‐associated variants to test the delay or prevention of cognitive deficits onset apparent in the AD‐BXDs by 14 months of age. These studies may identify novel therapeutic targets to treat AD dementia.
Multifaceted pattern of longitudinal imaging changes in cognitively normal midlife adults: The PREVENT‐Dementia study
Authors: Mak Elijah , Dounavi Maria‐Eleni , Low Audrey , McKiernan Elizabeth , Carter Stephen F , Newton Coco , Williams Guy B , Ritchie Karen , Wells Katie , Sahin Zeynep , Carriere Isabelle , Terrera Graciela Muniz , Ritchie Craig W. , Su Li , O'Brien John T.
Published: December 2020

Background

First‐degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer’s disease (AD). Identifying preclinical brain changes would facilitate both early quantifiable longitudinal disease monitoring and interventional trials. However, the literature of imaging changes in FH+ remains highly controversial. We aim to investigate “estimated years to onset of dementia” (EYOD) as a surrogate marker of preclinical progression and assessed whether FH+ approaching the onset of dementia would express more severe patterns of longitudinal brain changes.

Method

89 FH+ persons underwent serial 3T‐MRI with T1‐MPRAGE, DWI and ASL (mean interval: 2 years). The longitudinal Freesurfer pipeline was used to segment hippocampal subfields and early‐AD regions. Partial‐volume corrected ASL data and DWI data were processed with FSL‐BASIL4 and DTI‐TK5. Small vessel disease was indexed with white matter hyperintensities (WMHs) (Figure 1). We applied linear mixed effects models with random intercepts to predict MRI changes relative to baseline EYOD, accounting for baseline age, gender, education and time from baseline. Secondary analyses examined the interaction of APOE‐ε4+ on proximity‐related brain changes.

Result

A shorter EYOD was associated with progressive decrease in FA, increase in MD/RD and atrophy of the fusiform gyrus over time (Figure 2). Interaction analyses revealed that APOE‐ε4+ carriers showed significant longitudinal atrophy of the hippocampal subfields with shorter EYOD. In contrast, cortical perfusion increased before plateauing ∼10 years before estimated onset. There were no associations of EYOD with mean cortical thickness or WMHs (See Figure 3 for a summary of main findings).

Conclusion

Our findings represent an extensive characterisation of longitudinal brain changes associated with proximity to dementia in FH+. Individuals who are approaching their parental age of dementia onset may be showing incipient brain abnormalities, particularly amongst APOE‐ε4 carriers. The involvement of early‐AD regions also confer support to the biological validity of EYOD as a stage marker of preclinical progression. Further clinical follow‐up of our sample would provide critical validation of these findings.
Caregiver‐centered care health workforce competencies: Taking steps to support family caregivers of people living with dementia throughout the care trajectory
Authors: Parmar Jasneet , Poole Lisa , Anderson Sharon Dorothy , Duggleby Wendy , Holroyd‐Leduc Jayna , Brémault‐Phillips Suzette , Pollard Cheryl , Charles Lesley , Haq Anwar
Published: December 2020

Background

Family caregivers [FCGs] are the backbone of the health system [1‐3]. They provide over 80% of the care for people with dementia, chronic illnesses and impairments [4 5]. Despite evidence of their contributions and consequences of caregiving, support for FCGs has not been a health system priority[6‐8]. Multi‐level interdisciplinary Alberta stakeholders recommended developing Caregiver‐Centered Care Education for the health workforce to fill this gap [9‐14]. Education to prepare health providers to effectively identify, engage, assess, and support FCGs throughout the care trajectory is an innovative approach in addressing inconsistent system of supports for FCGs [5 6 15‐17]. Objective: We report on development and validation of the Caregiver‐Centered Care Competency Framework to help with curricular design and subsequent evaluation of effectiveness of care providers working within healthcare settings to engage and support FCGs. Project description: We used a modified Delphi approach. In the first 2 rounds, multi‐level, interdisciplinary participants, rated the indicators in terms of importance and relevance. In the 3rd round consensus meeting, participants validated the final competency indicators in small group sessions. Participants: Expert panel of international, national, and provincial stakeholders were invited to a 2‐day symposium March 14‐15, 2019 and participate in the Modified Delphi Process.

Results

An expert panel of 42 international, national, and provincial stakeholders participated. Thirty‐four experts (81%) participated in the round 1, 36 (85.7%) in round 2, and 42 people (100%) in round 3. There was stable consensus across all three rounds, 96.07% of participants rated the indicators as essential or important (Round 1, 95.81%; Round 2, 94.15; Round 3, 98.23%). Six competency domains, including indicators, were validated. Discussion: FCG research has been primarily focused on educating FCGs to provide care [18‐20]. Our stakeholder engagement processes [9‐14] is critical to intervention research and practice that supports FCGs. The direct inclusion of multilevel stakeholders, particularly the FCGs, provided a robust forum for discussion and increased consensus around the value of a healthcare workforce trained to support FCGs.

Conclusions

These competencies will shape the design of educational curricula and interdisciplinary training programs aimed at supporting the health and social care workforce to provide caregiver‐centred care.
IBC‐Ab002, an anti‐PD‐L1 monoclonal antibody tailored for treating Alzheimer’s disease
Authors: Baruch Kuti , Kertser Alexander , Matalon Omri , Forsht Ofir , Braiman Shai , Shochat Eliezer , David Carol , Yoles Eti
Published: December 2020

Background

The ongoing cross‐talk between the immune system and the central nervous system plays a major role in healthy brain tissue maintenance, with critical implications to brain aging and neurodegeneration. Based on the innovative concept of “protective autoimmunity”, established by Schwartz and her group, it was shown that targeting the programmed cell death receptor (PD)‐1 / PD‐L1 pathway evokes an immune response that supports recruitment of specialized immune cells (primarily of myeloid origin) to the brain territory, where these cells act by enhancing clearance of toxic elements, improving neuronal function, and reducing inflammation in mouse models of Alzheimer's disease (AD) and dementia. Maintaining a long‐lasting effect was found to be dependent on intermittent treatment course. IBC‐Ab002 is a novel fully human anti‐PD‐L1 monoclonal antibody that was designed, by point mutations on its Fc backbone, to fulfil the pharmacokinetics (PK), pharmacodynamics (PD) and safety characteristics anticipated for treating AD. Antibody optimization and lead selection will be presented.

Methods

Correlation between PK, PD, and antibody efficacy and safety, was evaluated using different antibody variants that share the same variable region, but differ in their physical properties due to point mutations in their Fc region. These studies, in mouse models of AD and in healthy cynomolgus monkeys, were used for modeling human PK/PD properties of IBC‐Ab002.

Results

Pharmacological studies in mice revealed that treatment efficacy is primarily Cmax‐dependent, rather than exposure‐dependent. Biomarkers for biological activity were identified in the blood of both treated mice and monkeys, and PK/PD relationships were used to predict IBC‐Ab002 PK and effective dose range in humans. The ability to maintain treatment efficacy using intermittent administration regimen was evaluated in a longitudinal study, and found to be effective for up to 6 months from treatment initiation. Using a mouse model that spontaneously develops autoimmune diabetes, we also show that the chosen antibody modifications significantly improve its safety profile.

Conclusions

IBC‐Ab002 antibody was selected for clinical development based on its unique characteristics, tailored for the mechanism of action intended for treating AD, and superior safety profile in terms of immune‐related adverse events. We are currently planning the first‐in‐human study of IBC‐Ab002 in AD patients.
Impact of sex and APOE E4 on age‐related cerebral blood flow trajectories in cognitively asymptomatic middle‐aged and older adults: A longitudinal study
Authors: Wang Rui , Oh Jennifer M. , Motovylyak Alice , Ma Yue , Sager Mark A. , Rowley Howard A. , Johnson Kevin M. , Gallagher Catherine L. , Carlsson Cynthia M. , Bendlin Barbara B , Johnson Sterling C. , Asthana Sanjay , Eisenmenger Laura , Okonkwo Ozioma C.
Published: December 2020

Background

Reduced cerebral blood flow (CBF) has been considered as a potentially early biomarker of late‐onset Alzheimer’s disease (AD). We sought to detect the pattern of age‐related CBF trajectories, and to investigate how these trajectories are affected by APOE, chromosomal sex, and cardiometabolic measurements.

Method

From two ongoing longitudinal cohort studies—the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer’s Disease Research Center—we included 950 individuals (age range 40—89 years), who were cognitively unimpaired at their first visit. CBF was measured using pseudo‐continuous arterial spin labeling MRI. Demographic factors, APOE ɛ4 status, and cardiometabolic measurements were obtained during a clinic visit that included structured interviews, physical examinations, and blood sampling. We applied linear mixed‐effects models in our analyses, which focused on brain regions of relevance to AD.

Result

During the follow‐up period (median 2.17 years, range 0.13—8.24 years), increasing age was significantly associated with decreasing CBF in total gray matter (β=‐1.54) (Figure, a), hippocampus (‐1.33), superior frontal gyrus (‐1.92), middle frontal gyrus (‐2.20), posterior cingulate (‐2.71), and precuneus (‐2.32), with all p‐values<0.01. A three‐way interactive effect of age, sex, and APOE ɛ4 allele was observed on CBF trajectories. That is, compared with male ɛ4 carriers, female ɛ4 carriers showed a faster decline in global and regional CBF with increasing age (Figure, c), whereas age‐related decline in CBF was similar between male and female ɛ4 non‐carriers (Figure, b). Worse cardiometabolic profile (i.e., increased systolic blood pressure, body mass index, total cholesterol, and blood glucose) was associated with lower CBF at all the visits. When time‐varying cardiometabolic measurements were adjusted in the model, the synergistic effect of sex and APOE ɛ4 on age‐related CBF trajectories became largely attenuated.

Conclusion

Our findings demonstrate that APOE genotype and sex interactively impact CBF trajectories across the lifespan, and that this effect may be partially explained by cardiometabolic alterations.
A novel visual short‐term memory task differentiates MCI and Alzheimer’s patients from healthy ageing
Authors: Toniolo Sofia , Maio Maria R. , Tabi Younes Adam , Slavkova Elitsa , Plant Olivia , Saleh Youssuf , Attaallah Bahaaeddin , Idris Imran , Peixoto Joao , Preul Christoph , Srowig Annie , Joedecke Steffen , Butler Christopher , Thompson Sian , Manohar Sanjay , Finke Kathrin , Husain Masud
Published: December 2020

Background

We developed a novel delayed reproduction task, the “What was where?” task, which obtains a continuous measure of localization error and is more sensitive compared to conventional span measures of Short‐term Memory (STM).

Method

We recruited 44 MCI (Mild Cognitive Impairment), 41 AD (Alzheimer’s Disease) patients and 109 healthy elderly controls (EHCs) from memory clinics in Oxford, UK and Jena, Germany, where they performed the “What was where?” task (Figure 1). We extracted the following metrics: Identification Accuracy (percentage correctly identified items), Absolute Localization Error (how far the object was misplaced), Misbinding rate (erroneously localizing an item to the remembered location of another item in memory) and Guessing response rate.

Result

Absolute Localization Error and Misbinding rates were greater in MCI and AD patients (p < 0.001) compared to EHCs, while AD and MCI performed similarly on these metrics. However, Identification Accuracy as well as Guessing (p = 0.003) were greater in MCI (p < 0.001) compared to AD patients. Moreover, EHCs identified the correct object more often (p < 0.001) and guessed less (p < 0.001) than MCI patients.

Conclusion

This novel task is able to detect STM impairment in MCI cases on a continuous scale, and is a sensitive memory measure which might be a useful index of memory for future clinical trials in AD in its earliest stages.
Longitudinal changes of automated speech measures in natural connected speech in ALS
Authors: Shellikeri Sanjana , Cho Sunghye , Ash Sharon , Parjane Natalia , Elman Lauren , McMillan Corey T , Grossman Murray , Nevler Naomi
Published: December 2020

Background

Amyotrophic Lateral Sclerosis (ALS) is a multi‐system neurodegenerative disorder with motor and cognitive deficits. Speech is affected both by motor processes associated with the articulation of utterances and by cognitive processes related to conveying a linguistic message. Previous studies in ALS have reported reduced speaking rate, longer pause durations, and more pause events compared to healthy controls. However, existing studies are scarce, rarely compare the effects of motor versus cognitive deficits, and have not yet characterized longitudinal changes in this population. In this study, we analyzed longitudinal changes in speech acoustic features in ALS from 1‐minute speech samples using an objective, reproducible, fully automated method.

Method

We examined digitized Cookie Theft picture descriptions produced by 21 native English‐speakers (66.7% males, mean (SD) age (y) = 65.3 (11.2); education (y)= 15.2 (2.6)) with ALS for up to 6 years (mean inter‐sample interval= 12.8 months, median samples/subject = 3). We automatically segmented each sample into speech and pause segments and extracted total speech = sum of speech segment durations (sec); total time = sum of speech and pause segment durations (sec); average speech and pause segment durations (sec); and speech frequency and fragment rate = number of speech events per 60 sec of total time and total speech, respectively. Longitudinal changes were related to cognition (ALS‐Specific Edinburgh Cognitive and Behavioral ALS Screen scores (ALS‐sp. ECAS)), motor features (ALS Functional Rating Scale–Revised scores (ALSFRS‐R)), and progression rate (change in ALSFRS‐R over disease duration) using linear mixed‐effects models with interactions between time and the predictor of interest.

Result

Lower scores on ALS‐sp. ECAS were predictive of an increase in pause durations (p=.023) and a reduction in total time (p = .019) over time. Higher ALSFRS‐R scores were predictive of increased speech fragment rate (p=.013) over time. Faster progression rates were associated with longer pauses (p=.006) and reduced speech frequency (p=.001) over time.

Conclusion

Speech acoustic measures are differentially impacted by motor versus cognitive features over the disease course in ALS. Longitudinal speech changes in ALS can be characterized using automated methods of acoustic analysis natural speech.
Study partner perspectives on disclosure of amyloid PET scan results
Authors: Largent Emily A , Abera Maramawit , Harkins Kristin , Roberts J Scott , Karlawish Jason ,   REVEAL‐SCAN Team
Published: December 2020

Background

Alzheimer’s disease (AD) secondary prevention trials typically require cognitively unimpaired individuals to learn the results of an amyloid PET scan. Additionally, they are required to enroll with a study partner who serves as a knowledgeable informant and often learns the participant’s amyloid PET scan result. The purpose of this study is to understand how study partners understand and experience the disclosure of another person’s amyloid PET scan result.

Method

Participants in this qualitative study are study partners of cognitively unimpaired adults aged 60–75 years who learned their amyloid PET scan result as part of Risk Evaluation and Education of Alzheimer’s Disease: The Study of Communicating Amyloid Neuroimaging (REVEAL‐SCAN; NCT02959489). The sample was recruited to be balanced on the REVEAL‐SCAN participants’ amyloid PET scan results (i.e, “elevated” or “not elevated”) and the nature of participant‐study partner relationships (i.e., spousal or non‐spousal). We have interviewed 80 study partners. All interviews were recorded, transcribed, and coded in NVivo 12.0. The University of Pennsylvania IRB approved this study.

Result

Most study partners knew their REVEAL‐SCAN participant’s amyloid PET scan result and were able to explain what the result meant. For example, they generally understood that an “elevated” result indicates an increased but uncertain risk of developing dementia caused by AD. Study partners most often described feeling relief after learning a “not elevated” result, while emotions after learning an “elevated” result included sadness, concern, and resignation. Study partners felt the amyloid PET scan result gave them additional insight into the REVEAL‐SCAN participant’s memory. Nearly all study partners denied that learning the amyloid PET scan result changed their relationship with the REVEAL‐SCAN participant, but they reported changing future plans (e.g., about leisure, caregiving) in light of the result.

Conclusion

Study partners’ understanding of and reactions to another person’s amyloid PET scan result mirror those of the person. This suggests that disclosure of AD biomarkers in clinical practice will have implications not only for patients but also for their families. Looking forward, clinicians will need guidelines for how best to disclose biomarker results, including engaging and supporting patients’ family members.
Co‐designing caregiver‐centered care health workforce competencies and training: Making the leap to support family caregivers of people living with dementia
Authors: Parmar Jasneet , Poole Lisa , Anderson Sharon Dorothy , Duggleby Wendy , Holroyd‐Leduc Jayna , Brémault‐Phillips Suzette , Pollard Cheryl , Charles Lesley , Haq Anwar
Published: December 2020

Background

Family caregivers [FCGs] provide over 80% of the care for people with dementia, chronic illness and impairments. Despite evidence of their contributions and consequences of caregiving, support for FCGs has not been a health system priority. Our innovative solution to reduce caregiver distress and support caregivers to maintain their wellbeing is to educate the health workforce to identify, engage, and support family caregivers throughout the care trajectory. Education to prepare health providers to effectively identify, engage, assess, and support all FCGs is innovative approach to addressing inconsistent system of supports for FCGs. Objective: We will present the co‐design process and introduce our Health Workforce Caregiver‐Centered Care Education focused on dementia. To ensure a specific person‐centered focus on family caregivers, we created the term “caregiver‐centered care” defined as a collaborative working relationship between families and healthcare providers in supporting family caregivers in their caregiving role, decisions about services, care management, and advocacy. Project Description: We designed our Caregiver Centered Care Education using effective practices for dementia education for the health workforce. The Caregiver Centered Care Competency Framework validated in March, 2019 underpins the design and evaluation.

Methods

We engaged over 100 multi‐level, interdisciplinary stakeholders familiar with dementia care from diverse settings. We ensured that we included FCGs of people living with dementia, to co‐design Caregiver Centered Care Education for the Health Workforce.

Results

We co‐designed dementia focused competency‐based education modules aligned with the previously validated Caregiver‐Centered Competencies for the health workforce. The teaching and learning resources include competency‐aligned educational modules, multimedia resources, and facilitators guide that are designed flexibly, to be tailored to settings and learners. Discussion: The hallmark of effective education is content relevant to learners’ needs and contexts. We will pilot test the Caregiver‐Centered Care Education, for acceptability and effectiveness, in five contexts: primary care, acute care homecare, supportive living, and long‐term care.

Conclusion

Our education will support caregiver‐centered care in all settings providing dementia‐related care. Health workforce support will be essential to maintaining FCG wellbeing and sustaining the family caregiving that reduces health system costs.
Tau propagation is dependent on the genetic background in multiple mouse strains
Authors: Dujardin Simon , De Los Santos Mark , Fernandes Analiese R. , Bannon Riley N. , Kamath Tarun V. , Commins Caitlin , Hyman Bradley T.
Published: December 2020

Background

The hyperphosphorylation and deposition of tau proteins in insoluble aggregates inside neurons are a hallmark of around 20 pathologies called tauopathies including the well‐known Alzheimer’s disease (AD). In AD and other tauopathies, histopathological studies have shown that tau lesions appear progressively and hierarchically in the brain along anatomical connections. The mechanisms underlying such evolution had remained unexplained for many years, but recent evidence support the idea that the evolution across brain areas is the result of the active propagation of tau aggregation within the brain. We and others previously demonstrated in in vitro and in vivo models that tau assemblies are transferred from cell‐to‐cell and, by being taken up by a second cell, seed the aggregation of endogenous tau leading to the propagation of tau lesions in the brain. We hypothesized here that the genetic background of mice influences the propagation of tau across neural networks.

Methods

We used a model of tau propagation that we previously described consisting in the injection of adeno‐associated viral vectors (AAV) encoding the eGFP‐2A‐Tau construct into the entorhinal cortex of mice. The 2A peptide is a self‐cleaving peptide resulting in the equimolar independent expression of the eGFP and human tau. Using this model, we can therefore discriminate the neurons expressing the AAVs (GFP and tau positive) from the tau propagation recipient neurons (tau positive only). We injected mice from multiple strains (n = 5 males and 5 females per strain), with diverse genetic backgrounds, with this construct and subsequently quantified the number of neurons positive for tau propagation in each condition.

Results

In a blinded analysis we found that the propagation of tau in vivo is highly dependent of the genetic background with strains (such as C57BL/6) that are mostly resilient to tau propagation when other (such as CD‐1 or A/J) show a high degree of tau propagation.

Conclusion

these results provide an important insight to the idea that tau propagates from neuron‐to‐neuron in the human pathology. This could explain part of the human clinical heterogeneity and must be investigated further to understand the genetic factors responsible for such drastic differences.
Satisfaction with stroke care among dementia patients with stroke: A Swedish register study
Authors: Hoang Minh Tuan , Kåreholt Ingemar , von Euler Mia , von Koch Lena , Eriksdotter Maria , Garcia‐Ptacek Sara
Published: December 2020

Background

Previous studies showed that patient satisfaction with stroke care relates to age, care demands, functioning, mood, quality of life, and self‐rated health. Dementia and stroke are frequent comorbidities. It is still unknown how satisfied dementia patients are with stroke care compared to non‐dementia patients. Our study aimed to compare the satisfaction with stroke care between dementia and non‐dementia patients.

Methods

In this longitudinal observational registry study, 5,932 dementia patients (2007‐2017) who suffered a first stroke after dementia diagnosis were compared with 39,457 non‐dementia stroke patients (2007‐2017). Data on stroke was obtained through the Swedish Stroke Register (Riksstroke), linked to the Swedish Dementia Registry (SveDem), the Swedish National Patient Register and the Swedish Prescribed Drug Register. Questionnaires were completed by patients themselves, patients with the help of caregivers, patients’ family, or healthcare staffs on behalf of the patient three months after stroke. Outcomes comprised satisfaction with acute stroke care at hospital, inpatient rehabilitation, outpatient rehabilitation, healthcare staff’s attitude, communication with doctors and stroke information.

Results

Compared to non‐dementia patients, dementia patients who answered the questionnaire themselves reported lower odds of satisfaction with acute stroke care at hospital 0.72 (0.61 – 0.87), healthcare staff’s attitude 0.80 (0.67 – 0.97), communication with doctors 0.80 (0.68 – 0.95 ), and stroke information 0.63 (0.53 – 0.76); but not regarding inpatient rehabilitation 0.95 (0.77 – 1.19), or outpatient rehabilitation 0.96 (0.76 ‐1.23). When patients answered the questionnaire with the help of their caregivers, dementia patients reported significantly lower satisfaction for all items. Differences between dementia and non‐dementia patients disappeared in proxy‐reported satisfaction, except for family‐reported satisfaction with outpatient rehabilitation and stroke information, which was significantly lower in dementia group.

Conclusion

Lower satisfaction in the dementia group is a sign of unfulfilled care needs among dementia patients. Further studies on the provision of stroke care for dementia patients and their care demands should be performed.
Single‐nuclei RNA‐seq of brains carriers of high‐risk variants and Mendelian mutations
Authors: Del‐Aguila Jorge L. , Brase Logan , Benitez Bruno A. , Karch Celeste M. , Cruchaga Carlos , Harari Oscar
Published: December 2020

Background

AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. We sought to investigate the glial and neuronal pathways affected by AD at the cell specific resolution. To do so, we generated unsorted brain single‐nuclei RNA‐sequence from carrier of a Mendelian mutation and high‐risk variants associated with AD from the Knight‐ADRC and DIAN brain banks.

Methods

We sequenced 74 parietal lobe from carriers of APP, PSEN1 and PSEN2 mutations (N = 19), and high‐risk variants, including APOE e4 (N = 26) and TREM2 (N = 21), non‐carrier AD (N = 15) and neuropath‐free controls (N = 9). We employed the 10X Chromium 3’ chemistry V3, to sequence 10,000 nuclei and 40,000 reads per nuclei. In total. We generated data for more than 1,2 million nuclei. We applied stringent quality control and data cleaning procedures, including alternative methods to detect empty droplets and doublets, and used alternative clustering methods to a very large number of nuclei. We have assembled and curated a reference panel that we employ in different supervised and unsupervised methods to annotate the cell‐type of the different clusters.

Results

We have identified the expression profile of Neurons, Oligodendrocytes, astrocytes, OPC and other cell‐types in the brain (Figure 1). Our dataset includes more than 17,500 nuclei from microglia cells (minimum 100 and mean 285 nuclei per donor) that present alternative transcriptional profiles that resemble that of the Disease Associated Microglia and Human Alzheimer Microglia.

Conclusion

Single‐nuclei transcriptomic data from human brains provides a detailed molecular atlas to study the pathways dysregulated in AD. We have developed a unique resource to investigate amyloid‐beta protein clearance and degradation pathways, endolysosomal pathways, cholesterol metabolism and immune system contribution to AD etiology and pathogenesis.
Evaluating the Codesigning Dementia Diagnosis and Post‐Diagnostic Care (COGNISANCE) project
Authors: McAiney Carrie A , Vedel Isabelle , Doucet Shelley , Luke Alison , Jarrett Pamela , Team COGNISANCE
Published: December 2020

Background

Persons with dementia and their family/friend care partners often report poor experiences at the time a dementia diagnosis was given and in the supports provided following the diagnosis. Such experiences often include a lack of information, a lack of support, and limited or no hope. While there are national guidelines that outline the steps required to make a dementia diagnosis, there is limited information about how best to engage persons with dementia and their care partners and communicate this information to them. There are also few resources to support individuals and care partners in navigating this challenging journey. The "Codesigning dementia diagnosis and post‐diagnostic care" (COGNISANCE) project aims to develop and evaluate toolkits and behaviour change campaigns for: 1) members of the at‐risk public and 2) health and social care providers to improve the dementia diagnosis experience and the supports provided following a diagnosis. The purpose of this poster is to describe the process of developing an evaluation plan, together with persons living with dementia and their care partners, that will be implemented in the five countries participating in COGNISANCE: Canada, Australia, Netherlands, United Kingdom, and Poland.

Method

The evaluation plan is being informed by social marketing theories and guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE‐AIM) framework. Working collaboratively with persons living with dementia and care partners, and a large international team, we are developing a comprehensive plan to evaluate the implementation and effectiveness of the behaviour change toolkits and campaigns.

Result

We will describe the process used to develop the evaluation plan. This includes our experiences working together with persons living with dementia and their care partners, as well as our international collaborators, to develop a plan that achieves our objectives and is feasible to implement across the participating countries.

Conclusion

Findings from the COGNISANCE evaluation will inform opportunities to spread the toolkits and campaigns within the participating countries, as well as the development of an implementation playbook, a resource aimed to support developing countries in creating and implementing their own toolkits and campaigns.
The role of education in resistance against development of vascular brain pathology
Authors: van Arendonk Joyce , Yilmaz Pinar , Steketee Rebecca , Zijlmans Jendé L , Lamballais Sander , Ikram M Arfan , Vernooij Meike W
Published: December 2020

Background

Vascular brain pathology due to cerebral small vessel disease is one of the leading causes of cognitive decline and dementia in the elderly. The concept of brain resistance postulates that individuals with the same amount of risk factors show different levels of neuropathology than expected based on their risk profile. In this study, we investigate the role of education, as proxy for resistance, on the development of brain pathology due to vascular risk factors.

Method

4440 participants without stroke or dementia were included from the population‐based Rotterdam study (mean age, 62.9±10,7 years). Structural MRI was measured on a 1.5T MRI scanner and comprehensive psychometric data was obtained. Educational attainment was assessed during the baseline interview and classified in three categories. Hypertension and the Framingham Stroke Risk Profile were used as the primary vascular risk factors of interest. Vascular brain pathology as outcome was assessed by white matter hyperintensities (WMH), microbleeds and lacunar infarcts. We used multiple linear regression models to determine the relation between vascular risk factors and brain pathology, stratified by educational level.

Result

Significant interaction effects between education and hypertension were found on their association with WMH, hippocampal volume and microbleeds. The association of hypertension with hippocampal volume differed significantly across strata of education: β=0.02, 95%CI ‐0.07‐0.11 for high education compared to β=‐0.12 95%CI ‐0.21‐ ‐0.03 for low education. Moreover, the association of hypertension with WMH differed significantly between the intermediate and low education strata, and differed borderline significantly between the high and low education strata: β=0.15, 95%CI 0.08‐0.22 for high education, β=0.20, 95%CI 0.11‐0.29 for intermediate education and β=0.28, 95%CI 0.18‐0.38 for low education. Lastly, the association of hypertension with microbleeds also differed significantly across strata of education: β= 0.00, 95%CI ‐0.04‐0.03 for intermediate education compared to β=0.05, 95%CI ‐0.01‐0.10 for low education.

Conclusion

A similar vascular risk profile leads to fewer WMH, microbleeds and less hippocampal atrophy in participants with a higher education level compared to persons with lower education. This suggests that people with a higher education level are more resistant against vascular brain pathology and hippocampal atrophy due to vascular risk factors.
Development of a digital system to assess and manage unmet needs of family dementia caregivers in clinical practice
Authors: Klein Olga A , Thyrian Jochen René , Boekholt Melanie , Teipel Stefan J , Hoffmann Wolfgang , Kilimann Ingo
Published: December 2020

Background

Caregiver burden is a risk factor for negative health outcomes in carers and randomized realization in people with dementia. With the rising prevalence of dementia, it is essential to identify unmet needs of family caregivers to promote wellbeing and randomize caregiver related burden. However, validated instruments to identify unmet needs of family caregivers are scarce and it is unclear whether and to what extent existing instruments are used in clinical practice.

Aim

To develop a digital system to identify and manage unmet needs of family dementia caregivers in clinical practice.

Method

This study is part of a large, cluster randomized controlled trial (cRCT) examining the clinical use and cost‐effectiveness of a computer‐based care management programme for family caregivers. We conducted a literature search identifying existing instruments assessing medical, psychological, and social unmet needs. With the help of 25 caregivers and experts including neurologists, psychologists, psychiatrists and nurses, an initial selection of questions and existing instruments was generated and piloted. Items and response options were judged for content, clarity, interpretability, and length. The instrument was adapted and a computer‐based version was created. Questions were paired with care management recommendations which will be automatically triggered by the system if an item is identified as unmet need. Further expert interviews will examine the usability in clinical practice. This study is supported by the German Federal Joint Committee (G‐BA).

Result

The preliminary selection comprised 63 questions. Caregivers and experts commented on the content, wording and order of questions, the response options provided, the length of the instrument, and the layout of each section. Questions and response options were re‐worded to avoid ambiguity. The order and layout of questions was changed based on respondents’ comments. On average, it took 37 minutes (range 15‐90, SD=24.23) to complete the instrument. Some respondents stated that they lost focus towards the end of the assessment. As a result, the instrument was simplified.

Conclusion

The development of the digital system is currently ongoing. Results will be presented.
Deficits in emotion recognition monitoring in dementia patients
Authors: Cordero Indira Ruth Garcia , Migeot Joaquín , Aquino Alexia , Fittipaldi Sol , Rivera Mariano Díaz , Sedeño Lucas , Garcia Adolfo M. , Ibanez Agustin
Published: December 2020

Background

The capacity to ascertain other people’s emotional states is crucial for establishing and maintaining social interactions. In particular, accurate recognition of facial expressions and beliefs about whether we trust what a face transmits are fundamental for guiding and adjusting this social behavior. Yet, although emotion recognition impairments are well documented in neurodegenerative diseases, the role of monitoring skills in this domain remains poorly understood in the field of dementia.

Method

We recruited patients with behavioral variant frontotemporal dementia (bvFTD, n = 18), Alzheimer’s disease (AD, n = 27), and demographically‐matched controls (n = 38). Participants performed a classic test of facial expression recognition and, after each trial, they provided a confidence judgment about their performance. A monitoring index was calculated considering both performance on each emotion type and associated confidence ratings (with higher values of the index indicating worse monitoring). Then, whole‐brain grey matter volume was analyzed via voxel‐based morphometry (VBM) to track possible associations with the monitoring index.

Results

Compared to controls, both groups of patients exhibited difficulties in monitoring negative emotions. Monitoring of disgust was specifically impaired in bvFTD, and monitoring of sadness and neutral faces, in AD. VBM results showed that, in bvFTD, reduced grey matter volume in areas belonging to the limbic system and subcortical regions was associated with emotion recognition deficits. Monitoring impairments were also related with different subcortical and cortical areas, including the prefrontal lobe, insula and the cingulate cortex. On the other hand, in AD, temporal and parietal areas were associated with emotion recognition and parietal and frontal regions, with monitoring.

Conclusion

These results indicate that dementia patients present emotion recognition monitoring impairments and that these deficits are associated with damage of cortical and subcortical regions as well as limbic circuits. In both groups, recognition and monitoring of emotions shared several structural substrates. The monitoring impairments presented in bvFTD and AD could be related with the changes in social cognition and behavior that these patients presented in daily life. Therefore, these preliminary findings could contribute to a better understanding of emotion monitoring processes.