bluuebunny/crossref_metadata_2025 huggingface dataset:
Potentially inappropriate anticholinergic medication use interacts with memory‐enhancing treatment for patients with Alzheimer’s disease or related dementias
Authors: Vickers Lauren , Martinez Ashley I , Wallem Alexandra M , Moga Daniela C
Published: December 2020

Background

Anticholinergic medications have been consistently linked to cognitive impairment or decline, resulting in their classification as potentially inappropriate medications for older adults according to the Beers Criteria. Despite their potential for adverse effects, these medications continue to be used for individuals regardless of their cognitive status and concurrent medications. Here, we investigated risk factors for anticholinergic medication use in populations with and without Alzheimer’s disease or related dementias (ADRD). For patients with ADRD, we also investigated whether anticholinergic use may be interacting with memory‐enhancing medication therapy.

Methods

We conducted a cross‐sectional study using nationally representative data from the 2016 National Ambulatory Medical Care Survey. We included non‐perioperative office‐based visits for patients ≥ 65 years old. Visit characteristics were compared between those with and without ADRD using descriptive statistics; adjusted logistic regression was used to identify predictors of anticholinergic use.

Results

Of 218,182,131 outpatient visits, 2.2% were for patients with ADRD (N=4,651,563). 20.5% of visits for patients with ADRD reported an anticholinergic, compared to 8.1% of visits for patients without ADRD. The most common anticholinergics reported for ADRD visits were cyclobenzaprine (25.3%), benztropine (12.8%), and meclizine (12.2%). Significant predictors of anticholinergic report (aOR [95% CI]) were ADRD status (3.1 [1.2‐8.3]), female sex (2.1 [1.4‐3.1]), new problem as primary visit reason (1.8 [1.2‐2.7]), former tobacco use (1.7 [1.1‐2.7]), and polypharmacy (11.6 [6.9‐19.7]), respectively). Of the 1,633,358 visits for patients with ADRD that reported use of a cholinesterase inhibitor, 29.3% also reported an anticholinergic, which combination may negate any cognitive benefits the cholinesterase inhibitor may have been able to impart.

Conclusion

In a nationally representative sample, anticholinergic use was reported in approximately one‐fifth of visits for patients with ADRD. After adjusting for potential confounders, ADRD was an independent risk factor for report of an anticholinergic. Of those visits for ADRD patients whose cognitive impairment was being treated with a cholinesterase inhibitor, almost one‐third reported a drug‐drug interaction with an anticholinergic that may have detrimental results on cognition. Future work should investigate points of intervention to reduce anticholinergic use and inappropriate drug interactions in this population.
Improving Caregiving for Dementia (I‐CareD): Mobile health technology for dementia caregivers
Authors: Tan Zaldy S , Camarena Paul , Jennings Lee
Published: December 2020

Background

Mobile health applications represent a rapidly‐emerging technology that can improve health‐care delivery. Informal caregivers play an essential role in the care of persons with dementia; however, as a group dementia caregivers lack knowledge about the disease and available community‐based resources. Little is known about the acceptability and usefulness of mobile applications technology to provide information and resources to dementia caregivers.

Method

The I‐CareD app is a novel mobile application that provides dementia caregivers with information tailored to the care recipient’s dementia type and stage, behavioral issues, and needs for community‐based resources. Informal caregivers enrolled in a dementia care management program were provided instructions to downloaded the app.

Result

Thirteen caregivers completed a survey assessing information‐seeking behaviors/preferences and satisfaction with the app. The majority of caregivers were middle‐aged (50‐64 years; 54%), male (62%), white (83%), and college‐educated (54%). Most respondents (62%) provided care for persons with moderate‐stage dementia and 85% used a smartphone or tablet to search the web for health information. Ninety‐two percent of the caregivers preferred to receive dementia caregiving information electronically rather than by other means. The caregivers rated the app highly for ease‐of‐use, content and overall satisfaction. All of the caregivers who completed the survey stated that they would recommend the mobile app to other caregivers.

Conclusion

Informal caregivers were receptive to receiving dementia information and resources delivered via a mobile app. Although more research is needed to examine how to incorporate technology into dementia care, our study suggests that informal caregivers are likely to use technology that they perceive will help enhance their dementia caregiving.
Cerebrospinal fluid biomarker levels are not affected by aspiration or gravity drip extraction methods in Alzheimer’s disease: The AIBL study
Authors: Doecke James D , Francois Cindy , Fowler Christopher J , Stoops Erik , Rainey‐Smith Stephanie R , Li Qiao‐Xin , Masters Colin L , Martins Ralph N , Villemagne Victor LL , Vanderstichele Hugo Marcel
Published: December 2020

Background

Precise analysis of early changes in concentrations of proteins in cerebrospinal fluid (CSF) with qualified immunoassays can reflect the initiation or existence of Alzheimer’s Disease (AD) pathology in brains of affected subjects. Although CSF biomarkers are well established nowadays for use in clinical routine worldwide (eg. NIA AA guideline, FDA qualifications), there is still some ambiguity as to which method should be used to extract the CSF. We aimed to compare in detail potential differences on the most promising protein biomarkers between gravity or aspiration extraction of CSF.

Methods

Colorimetric ELISA immunoassays, developed by ADx NeuroSciences and commercialised by EUROMMUN, were used for the study. Our study assessed a panel of individual proteins (as well as their corresponding ratios) that are related to amyloidopathy (Aß1‐42, Aß1‐40), tauopathy (total tau), or synapse pathology (BACE1, Neurogranin Truncp75, a‐Synuclein). Concentration differences between using either gravity drip or aspiration extraction methods were evaluated in the same subjects in a sub‐population from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing across. Subjects included in the study were cognitively normal (CN, N = 36), mild cognitive impairment (MCI, N = 8) or AD (N = 6). All analytes were tested by a single operator in parallel on the same day to minimize bias due to the test method and using manual test procedures.

Results

Results from statistical assessments confirm high concordance in biomarker levels between extraction methods (Concordance Correlation [CC] >0.85). Bland Altman plot analyses revealed an even symmetry around the zero‐difference line for each of the individual biomarkers and their corresponding ratios. Passing Bablock regression defined low beta coefficients indicating high scalability. Results were consistent across all three cognitive groups, irrespective of sample size.

Conclusions

The consistency in CSF biomarker levels across extraction methods demonstrates that the selection of the extraction method will not affect protein concentration analysis for respectively Aβ1‐42, Aβ1‐40, total tau, Neurogranin Truncp75, BACE‐1 and α‐synuclein). This new dataset will further help the field to better understand pre‐analytical factors of the discussed biomarkers, and prepare a final consensus guidance for collection, storage, and analysis of CSF.
Individual connectome priors improve neuroimaging‐based Alzheimer’s progression modeling
Authors: Kurmukov Anvar , Zhao Yuji , Gutman Boris A
Published: December 2020

Background

Disease progression models (DPM) of Alzheimer’s disease (AD) based on non‐invasive biomarkers have received significant attention in recent years. Crucially for drug development, DPM promises to identify pre‐clinical stages of AD. However, traditional DPMs consider only a single canonical sequence of neurodegeneration, which may ignore important population clusters and individual variation. Addressing this, we propose a method to use individual dMRI‐based connectomes as an informative prior in AD DPM.

Method

We extracted regional cortical thickness measures and tractography‐based connectomes from T1 and diffusion MRI of 32 AD patients and 52 controls. We build a DPM using the event‐based (EBM) approach. EBM models AD staging discreetly. Every stage is identified with a neurodegenerative event, e.g. a regional thickness falling below some threshold. Disease stage is then defined by the last abnormal biomarker based on a canonical event order. The goal of the model is to find an event order specific to AD in a Baeysian setting. We replace the uninformative prior on the order with one based on the subject connectomes. Every regional biomarker pair is assigned a probability that one region degenerates following the other based on the shortest connectome path length between the regions. The idea follows closely the amyloid network diffusion hypothesis. We test the original EBM and our models on cross‐sectional data and test them on 12‐ and 24‐month follow‐up scans. Predicted patient stage and visit order are ordinally correlated to assess model performance.

Result

Our model outperforms the original EBM (Kendall tau=0.34 vs 0.49). Our model systematically assigns higher progression scores for AD subjects (Fig.1). We also compare DPM performance using predicted stage in disease classification. Our model again outperforms traditional EBM, achieving ROC AUC=0.88 (std=0.046) vs 0.816 (std=0.008).

Conclusion

We have developed an individualized neuroimaging disease progression model of AD based on the widely used EBM. Individual connectome variation allows the computational model to more finely pin‐point an individual’s specific stage of disease progression based on the observed pattern of neurodegeneration. The connectome‐based EBM shows significant improvement over standard EBM.
Machine learning analysis of speech and eye tracking data to distinguish Alzheimer's clinic patients from healthy controls
Authors: Field Thalia S. , Newton‐Mason Sally May , Shajan Sheetal , Barral Oswald , Jang Hyeju , Soroski Thomas , O'Neill Zoe , Conati Cristina , Carenini Giuseppe
Published: December 2020

Background

Clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD) are increasingly focused on recruiting individuals with preclinical or early‐stage disease. Artificial intelligence may help in enriching clinical trial populations with high‐risk individuals. We analyzed prospectively‐collected speech and eye‐tracking data to distinguish individuals with mild‐moderate AD, mild cognitive impairment (MCI), and subjective memory complaints (SMC) from age and sex‐matched healthy volunteers.

Method

Individuals with known clinical diagnoses of AD, MCI, and SMC from a specialty clinic, and healthy controls from the community, were prospectively recruited. Participants described the “Cookie Theft Picture” from the Boston Aphasia Battery. Their speech was recorded and manually transcribed and eye movements were assessed using an infrared eye‐tracker. Data underwent feature extraction for language‐related features including lexical and acoustic parameters (from transcripts and speech), and fixation and saccades (from eye‐tracking). Additionally, for language and eye‐tracking, features capturing spatial neglect are explored following the approach in [1]. Separate predictive models were examined using logistic regression (LR), K‐Nearest Neighbours (KNN), and random forests (RF).

Result

Recruitment and analysis are ongoing. Data from 34 clinic patients (9% SMC, 35% MCI, 56% mild‐moderate AD, mean age 7310, 44% female) and 39 controls (mean age 6811, 79% female) is reported. Best speech‐based models distinguished patients from controls with an Area Under the ROC Curve (AUC) of 79% (95% CI 0.70‐0.87). Eye‐tracking‐based models reached distinguished patients from controls with an AUC of 71% (95% CI 0.59‐0.82).

Conclusion

Machine‐learning mediated analysis of speech and eye‐tracking data achieved promising classification performance with the current cohort. Both increasing the size of the corpus with ongoing recruitment, and combining demographic and clinical data alongside multimodal feature fusion, may help to improve classification.
Sex differences in the association of APOE E4 allele and cognitive decline in a biracial population sample
Authors: Aggarwal Neelum T. , Barnes Lisa L. , Wilson Robert S. , Weuve Jennifer , McAninch Elizabeth A. , Evans Denis A. , Rajan Kumar B.
Published: December 2020

Background

Prior studies of sex differences on the association of Apolipoprotein E4 allele and cognitive decline have reported conflicting results and have been done in predominantly White populations. In this study, we tested whether the association of the APOE E4 allele and cognitive decline differs between men and women in a biracial population‐based sample of older adults.

Method

Participants (N = 5,807, 63% females and 60% Black) underwent brief cognitive assessments at 3‐year intervals from 1993 to 2012. Using linear mixed effects models, adjusted for age, education and race, we examined the rate of cognitive decline among women and men with and without the APOE E4 allele.

Result

The presence of the APOE E4 allele did not vary between women and men (32% vs. 34%). Among participants without the APOE E4 allele, the rate of annual decline in global cognition was higher in women compared to men (0.048 standard deviation units [SDU] vs. 0.033 SDU per year, p = 0.0002). Among participants with APOE E4 allele, the rate of decline in global cognitive function and episodic memory was about twice as high among White women compared to white men (0.097 SDU vs. 0.057 SDU per year, p < 0.0001; 0.077 SDU vs. 0.031 SDU per year, p < 0.0001) respectively. Black men and women with APOE E4 did not differ in rates of global cognitive decline (0.078 vs. 0.073 per year, p = 0.58), or in any domains.

Conclusion

The rates of global cognitive decline, especially in APOE E4 carriers differed significantly between White women and men, but was similar between Black women and men. Additionally, the APOE E4 genotype was associated with a faster rate of decline in global cognitive function and episodic memory in women compared to men. The reason for sex differences among Black and White participants and especially among White women needs further attention.
In preclinical AD, impaired amyloid clearance and mitochondrial function underlie associations between white matter integrity and glucose regulation deficits
Authors: Pappas Colleen , Wang Qian , Klinedinst Brandon S , Le Scott T. , Larsen Brittany , Pollpeter Amy , Willette Auriel A.
Published: December 2020

Background

White matter tract integrity is an early marker for Alzheimer’s disease (AD) risk. Adults with AD genetic risk factors, such as Apolipoprotein E ε4 (APOE4) carriage or AD parental family history (AD FH), typically show less white matter integrity in AD‐sensitive tracts. Similar loss is seen in adults with glucose regulation problems, such as type 2 diabetes (“diabetes”), and is more pronounced with APOE4 or AD FH present. By 2050, due to the obesity epidemic, over 70% of aging adults will have some form of glucose regulation deficit. The mechanisms underlying this synergistic loss in tract integrity are unknown. Impaired glucose regulation lead to mitochondrial damage and amyloid clearance, where such markers may explain how genetic and metabolic factors interact in mid‐ vs. late‐life (Figure 1).

Method

Longitudinal data were downloaded for 12,740 unimpaired UK Biobank participants (47‐81yo). Diffusion Tensor Imaging (DTI) quantified overall tract, axon, and myelin integrity. Neurite Orientation and Dispersion Density Imaging (DTI‐NODDI) quantified tract complexity, neurite density, and water diffusion. Tracts included the cingulum, uncinate fasciculus, superior longitudinal fasciculus, fornix, and corpus callosum. Linear mixed models tested the main effects of glucose‐determined diabetes status and serum insulin‐like growth factor 1 (IGF‐1), a marker of intact glucose regulation. Interactions were tested with AD genetic risk factors and age. Preacher‐Hayes moderation‐mediation analyses tested if markers of amyloid clearance and mitochondrial function, respectively cystatin c and AST:ALT ratio, drove these associations.

Result

Among all tracts, diabetes status and decreased IGF‐1 over 6 years were related to less tract and neurite density, but more tract complexity (p<.05 to .001). For APOE4 or AD FH (Figure 2), interactions indicated that among adults with genetic risk, higher IGF‐1 was related to more tract integrity in mid‐life, but much less integrity in late‐life. These interactions were fully moderated by cystatin C (indirect effect: 49.5%, p<.05) and AST:ALT (indirect effect: 51.5%, p<.05).

Conclusion

In adults with APOE4 or AD FH, excess glucose in mid‐life may temporarily increase tract density because of excess ATP conversion. This process leads to mitochondrial damage and amyloid accumulation, however, and eventually becomes neurotoxic and degrades white matter.
Tau hyperphosphorylation in the retinal ganglion cells is attenuated upon silencing of SHP2 phosphatase
Authors: Gupta Vivek K. , Chitranshi Nitin , Thananthirige Kanshika Pushpitha Maha , Rajput Rashi , Gupta Veer Bala , Mirzaei Mehdi , Basavarajappa Devaraj , Graham Stuart
Published: December 2020

Background

Human and animal studies demonstrate that both amyloid precursor protein and phosphorylated Tau which are hallmark proteins associated with Alzheimer’s disease (AD) pathology are perturbed in the retinal tissues. The accumulation of pTau in the retina in addition to the brain tissue suggests eye as a valuable structure for disease diagnosis and to study the disease mechanisms in neurodegenerative disease. Recent studies in human tissues and animal models have established a molecular overlap of AD with glaucoma in the eyes and both the diseases demonstrate altered amyloid beta and Tau phosphorylation profile. We show that Shp2 interacts with Tau protein in retina and silencing this phosphatase in the retinal ganglion cells using AAV2 mediated gene therapy can protect the retina.

Method

Animal model of ocular hypertension was generated by repeat administration of polystyrene beads into the anterior chamber of rat eyes for 8 weeks resulting in sustained elevation of intraocular pressure (20.84±1.65 mmHg). Tau expression changes were investigated both in the animal model and human tissues obtained from the Sydney Eye bank (n=3) using immunohistochemical and WB. Silencing of Shp2 expression in the inner retina was achieved using intravitreal administration of AAV2 constructs under the control of CAG hybrid promoter. The animals were monitored for 2 months after Shp2 silencing and effects on Tau protein expression studied (n=48).

Result

Increased Tau Ser404 phosphorylation was observed in both human glaucoma retinas (p<0.02; student t‐test) and in the animal model of glaucoma (p<0.05) in the WB and immunohistochemical analysis. Shp2 silencing (82±4%) was achieved using AAV2 administration and transduction was monitored using GFP staining. A 7.5±3‐fold downregulation Shp2 expression was achieved using shRNAmir that resulted in significant reduction of pTau Ser404 levels in the inner retina (p<0.028, Bornferroni post‐hoc test) indicating a regulatory effect of the phosphatase on the pTau levels.

Conclusion

This study demonstrates that TauSer404 phosphorylation in the retina in vivo is regulated by Shp2 phosphatase. Targeted gene therapy approaches to modulate Shp2 expression can be used as a novel strategy to reduce Tau pathology in the neural tissues in various neurodegenerative disorders.
Biomarkers and trial‐ready cohorts for Alzheimer’s disease clinical trials in the Down syndrome population
Authors: Fortea Juan
Published: December 2020

Background

Over the past few years, substantial progress has been made in elucidating the natural history of AD in people with DS using standard AD biomarkers such as amyloid, tau and FDG PET, volumetric MRI as well as biofluid markers in CSF and plasma. Indeed, several research groups from around the world have shown that there exist remarkable similarities between AD biomarkers in DS and the sporadic and autosomal dominant forms of AD (Fortea et al, 2020; Rafii et al, 2015; Strydom et al, 2017; Fortea et al, 2018).

Methods

We will review recent advancements in blood biomarkers,. We will discus with the recruitment of trial ready cohorts in the US and Europe will facilitate and accelerate the conduction of Alzheimer’s disease Clinical Trials in the Down Syndrome Population.

Results

Plasma amyloid, p‐tau and neurofilament light in plasma which are emerging as key AD diagnostic, prognostic and theragnostic biomarkers. There have been enormous advancements in the recruitment of trial ready cohorts. Specifically, the NIH‐funded Alzheimer’s Clinical Trial Consortium for Down Syndrome (ACTC‐DS) utilizes the existing depth and breadth of expertise of the Alzheimer’s Clinical Trial Consortium (ACTC) to conduct AD clinical trials in adults with DS across international performance sites with unparalleled expertise. The project leverages the infrastructure of the ACTC as well as the Alzheimer’s Biomarker Consortium for Down Syndrome (ABC‐DS) and Horizon21 networks.

Conclusion

Given the very high risk for AD, the potential impact of this approach on improving the lives of adults with DS cannot be overstated.
EURO‐FINGERS/UK FINGERS (Europe)
Authors: Solomon Alina , Kivipelto Miia , Ngandu Tiia , Mangialasche Francesca , Hartmann Tobias , Scheltens Philip , Molinuevo Jose Luis , Georges Jean , Middleton Lefkos T
Published: December 2020

Background

Large European pioneer trials (e.g. FINGER, MAPT, preDIVA) testing multidomain lifestyle‐based interventions for preventing cognitive impairment / dementia have highlighted the crucial need for better‐defined at‐risk groups for achieving intervention response. Although the long time between at‐risk or preclinical disease stages and dementia creates a window of opportunity for prevention, this window is still poorly defined due to the complex multifactorial nature of Alzheimer's disease (AD), and high inter‐ and intra‐individual variability in risk and prevention potential.

Method

MIND‐ADmini is a multinational 6‐month pilot trial with an optional 6‐month extension testing the feasibility of the FINGER multidomain lifestyle intervention in people with prodromal AD and vascular/lifestyle‐related risk factors. Participants are randomized into 3 groups: multidomain lifestyle intervention; multidomain lifestyle intervention + medical food; and standard care. MIND‐ADmini also provides a first template for feasibility of future combinations of lifestyle + potential disease‐modifying drugs. The recently started EURO‐FINGERS project, based on a precision prevention and early detection model adapted from cancer research, will take the first steps towards an updated FINGER 2.0 intervention model aiming to bridge the gap between pharmacological and non‐pharmacological interventions. The 2‐year MET‐FINGER‐APOE trial plans to start with a drug repurposing approach, i.e. multimodal lifestyle+metformin intervention in an APOE4 enriched (min 50%) at‐risk population.

Result

The MIND‐ADmini pilot trial was completed in December 2019. Preliminary findings will be summarized based on ongoing data analysis. MET‐FINGER‐APOE trial protocol is currently under development, and a synopsis of the study design will be shown.

Conclusion

EURO‐FINGERS aims to provide a common framework for European multimodal dementia prevention studies, with a particular focus on precision medicine approaches, and accommodating combinations of lifestyle interventions with potential disease‐modifying drugs.
CAN‐Thumbs UP (Canada)
Authors: Nygaard Haakon B. , Chertkow Howard , Feldman Howard H. , Belleville Sylvie , Montero‐Odasso Manuel
Published: December 2020

Background

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was founded in 2014 to bring together Canada's dementia research community to work together in a more synergistic manner to catalyze new important progress in dementia research in Canada. Teams are funded to work on questions and themes from basic science to clinical work. An important new initiative in Phase 2 of CCNA (2019‐24) is to set up a national study on dementia prevention. CCNA's "Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia "(CAN‐Thumbs UP or CTU) has begun with funding from the CIHR (national Canadian research fund) and the Alzheimer Society of Canada. It's building a research program that includes the recruitment of a Trial Ready Cohort (TRC) of over 2,000 non‐demented older individuals at high risk for dementia. These individuals will undergo detailed assessment focusing on cognitive level and risk factors, and be monitored and followed closely over 12 months using instrumentation such as actigraphy and activity monitoring as well as burst cognitive testing. They will also be offered a Brain Health Support Program (BHSP). The BHSP will offer internet‐based weekly modules to encourage lifestyles modification and awareness of dementia risk factors such as hearing loss and diabetes. The BHSP will become the "baseline" of best information on prevention of dementia that should be made available to the population. The initial program will focus on optimizing compliance, and fidelity of the interventions to allow that they reach the broad public with the most opportunity for effective uptake. At the same time, we will be designing a Master Trials Protocol (including a single uniform master protocol, uniform inclusion and exclusion criteria and common outcome measures) which will later be used to carry out combinations of multidomain interventions ‐ both lifestyle and pharmacological ‐ on subset populations of this Trial Ready Cohort. In these intervention trials, we plan to tailor interventions to individuals with specific risk factors (e.g., sleep interventions for those showing fragmented sleep). CAN‐Thumbs UP is still in its early stages, and is being built in conversation with scientists from WW Finger.
J‐MINT (Japan)
Authors: Arai Hidenori , Sakurai Takashi , Sugimoto Taiki
Published: December 2020

Background

Approximately 5 million people are living with dementia in Japan. Appropriate countermeasures should be established to reduce the incidence of dementia. The purpose of the Japan‐multimodal intervention Trial for prevention of dementia (J‐MINT) was to address the effect of a multimodal intervention in subjects with cognitive impairment.

Method

J‐MINT is a RCT that will recruit 440 older people (65 to 85 years old) with high risk of dementia, defined as decreased cognitive performance in at least one of the four cognitive functional domains of memory, attention, executive function, and processing speed. Subjects will be randomized to either a group that receives usual care or a group that participates in an 18‐months multidomain intervention, consisting of exercise, nutritional counseling (visits and telephone follow‐ups by health consultants with expertise in nutrition), and cognitive training using the "Brain HQ” program. In the exercise program, the intervention group participates in activities described as “cognicise”, from the combination of the words "cognition" and "exercise," (a program developed at the National Center for Geriatrics and Gerontology, NCGG in Japan) which combines physical exercise and cognitive tasks. Additionally, diabetes, hypertension and dyslipidemia are treated in accordance with the Japanese guidelines for older patients. The primary outcome of J‐MINT is cognition, while secondary outcomes include functional status, blood‐based biomarkers reflecting β‐amyloid accumulation in the brain, omics analysis and neuroimaging (MRI).

Result

We are now recruiting the participants and this study will be completed at the end of 2021. Evidence from this research is expected to inform a large‐scale, national implementation of multimodal intervention programs for older people at high‐risk of dementia.

Conclusion

N/A. This study is supported by Japan Agency for Medical Research and Development.
Imaging misfolded tau in the retina
Authors: Kayabasi Umur A
Published: December 2020

Background

Recent research suggests that Tau is the culprit lesion along with neuroinflammation in the etiology of Alzheimer' s Disease (AD). Retina is the extention of the brain and is the most easily approachable part of the central nervous system. Detection of thepathological protein accumulations may be possible by using spectral domain optical coherescent tomography (SD‐OCT) and fundus autofluorescein (FAF). There is evidence showing that retinal plaques start accumulating even earlier than the ones in the brain. Most recent Tau protein images in thebrain consist of normal or reverse C‐shaped paired hellical filaments.

Method

20 patients with PET proven AD were examined by SD‐OCT and FAF. Mean agewas 72. Hypo or hyperfluorescent retinal lesions were scanned by SDOCT and Neurofibrillary Tangles (NFT) in a masked fashion. The researchers agreed on the shape of the lesions. Both C‐shaped (normal or reverse) NFTsand thinner fibrillary structures were taken into consideration.

Result

In all the patients, NFTs that exactly corresponded with the histopathologic and cryo‐EM images of Tau (Figure 1) in terms of shape and dimension were detected along with thin fibrils and lesions similar to amyloid beta. The number of the retinal filaments and other abnormal proteins was in concordance with the severity of the disease process. The advanced retinal lesions had normal or reverse paired C shapes (Figure 2) and thin fibrils had the shape of histopathologic images seen in early developmental stages of the disease.

Conclusion

Retinal images of Tau were disclosed for the first time in live AD patients. Retinal neuroimaging is a trustable biomarker and tool for monitoring the disease.
Wisconsin ADRC research education component: Qualitative observations
Authors: Spensley Sheryl , Kohli Akshay , Puglielli Luigi , Shah Manish N , Kind Amy J , Bendlin Barbara B
Published: December 2020

Background

Increases in the prevalence of Alzheimer’s disease (AD) and related dementias (ADRD) in the coming years will require a workforce capable of addressing this health epidemic. The National Institute on Aging has introduced Research Education Components (RECs) to “support research educational activities to complement the training of a workforce to meet the nation's research needs in AD and related dementias.” By recruiting and training promising researchers, the goal of RECs are to increase the pool of researchers dedicated to studying ADRD, advance the mission of translating research advances into improved diagnosis and care, as well treating and preventing ADRD.

Method

The Wisconsin Alzheimer’s Disease Research Center (ADRC) REC was funded in 2019, and aims to SA1: Deliver a rigorous mentored training program to ensure research proficiency in AD research and preclinical biomarkers; SA2: Infuse research concepts related to AD into University of Wisconsin predoctoral, postdoctoral fellowship, and junior faculty training programs and provide training opportunities; and SA3: Measure the effectiveness of the Wisconsin ADRC REC training program using mixed methods approaches.

Result

Three REC scholars were selected. All are Assistant Professor level faculty supported by career awards. The REC provides funding to carry out a mentored, 2‐year, research project. The REC Scholars gain competency in research skills through a blend of self‐directed modules, seminars, and experiential activities. To reach a broader base of trainees, a database was created to track training needs, career goals/promotions, trainee demographics, and to communicate specific training and funding opportunities. Since the REC started its promotional activities and tracking, didactic series attendance has increased by 415%. Finally, the REC has collaborated with UW Madison PEOPLE (Precollege Enrichment Opportunity Program for Learning Excellence) to create the REC Junior Fellowship. The fellows, diverse high school students, will intern at Wisconsin ADRC research labs and learn more about career paths in AD research.

Conclusion

Qualitatively, the first year of REC funding appears to be positively impacting training. Formal evaluation of the REC will occur via the “Learning through Evaluation, Adaptation, and Dissemination” (LEAD) Center. Outcomes will include improved research competency and retention in AD‐related research fields.
Validation of a new serum anticholinergic assay using anticholinergic burden scales and cognitive assessments in older adults with mild cognitive impairment or major depressive disorder
Authors: Chandramouleeshwaran Susmita , Rajji Tarek K , Ahsan Naba , Raymond Roger , Nobrega Jose , Fischer Corinne E , Flint Alastair , Herrmann Nathan , Kumar Sanjeev , Mah Linda , Mulsant Benoit H , Pollock Bruce G
Published: December 2020

Background

A high anticholinergic burden has been associated with deleterious effects on cognition, especially in the elderly. We developed a new serum anticholinergic assay (SAA) to measure the anticholinergic burden, and report on validating this new SAA using established anticholinergic burden scales and cognitive assessments in older patients with mild cognitive impairment (MCI) or major depressive disorder (MDD).

Method

Baseline serum samples were collected from 311 participants (154 with MCI, 57 with MDD, and 100 with MCI + MDD). The new SAA assay uses radio‐ligand binding to cultured cells stably expressing the muscarinic M1 receptors, with an added procedure to remove potential confounds associated with the effects of proteins in serum. We then calculated correlations between new SAA scores and each of the Anticholinergic Burden Scale (ACB) and Anticholinergic Drug Scale (ADS) total scores. Multiple regression models assessed the relationships between SAA and cognitive performance on a comprehensive cognitive battery.

Result

Baseline serum samples were collected from 311 participants (154 with MCI, 57 with MDD, and 100 with MCI + MDD). The mean SAA value was 1.65 pmol/L, SD = 1.83). Mean age of the sample was 71.96 years, range 60‐90 years, SD=6.2. 38.7 % were males. In both the ACB and ADS scores, participants with the highest total scores had the highest SAA values. ADS: F (2,98) = 7.84, p = 0.001, SAA (3+) > SAA (1); ACB: F (2,121) = 5.89, p = 0.004, SAA (3+) > SAA (1) and > SAA (2). SAA was significantly associated with performance on executive function after adjusting for age, gender, education, diagnosis, controlling for multiple testing. (β = ‐0.152, SE = 0.024, p = 0.007) There was no association with overall cognitive composite score combining all domains.

Conclusion

The above results support the use of the new SAA as a measure of anticholinergic burden. Of note, the effect of SAA on executive function was almost equivalent, though in the opposite direction, to the effect of education on executive function.
Mining of differentially co‐expressed gene modules reveals perturbed functional network and key regulators in Alzheimer's disease brains
Authors: Xiang Shunian , Ni Dong , Huang Kun , Zhang Jie
Published: December 2020

Background

Co‐expression network module mining is an efficient approach to identify novel disease pathways, predicting new gene functions and search for disease biomarker genes. However, integrating transcriptomic data of Alzheimer’s disease (AD) patients from multiple cohorts and identified consensus (frequent) co‐expressed gene modules that are differentially expressed in AD vs. normal brains have not been explored.

Method

In this study, we analyzed eight large AD brain transcriptomic datasets from major AD cohort studies and looked for differentially co‐expressed genes that form network modules (difFGCN), through which we identified pathways and key regulators that are associated to AD pathology.

Result

We obtained six AD specific difFGCN modules which have higher co‐expression frequency in AD brains samples as compared with normal ones, and 19 such modules with higher co‐expression frequency in normal brain samples. Functional and pathway enrichment analysis revealed function categories related to AD pathology. Remarkably, we identified two transcription factors, down regulated gene EGR1 targeting the genes in AD specific module accounting for negative regulation of apoptotic pathway and up regulated gene SP1 targeting the genes in normal specific module accounting for mitochondrial pathway, which may be key regulators for AD pathological changes. Combined with differential expression analysis, we also confirmed the key regulators change in AD brains.

Conclusion

Through the differential frequent coexpression module mining, we identified several AD specific coexpressed gene modules and normal ones, which revealed functional change in the network level as well as key regulators which may cause such pathological changes in AD brains. Our results provide new insights in AD mechanism study and the key regulators we identified could be potential therapeutical targets for AD drug development.
Depression in Alzheimer’s disease: Is the combination of citalopram and rivastigmine better than rivastigmine alone? A longitudinal clinical trial
Authors: Pathak Krishna Prasad P. , Tsolaki Magda , Verikouki Eleni P.
Published: December 2020

Background

Pharmacological treatment for AD and depression are unfortunately few and of limited efficacy to cure the disease.

Method

Longitudinal clinical prospective study with 1278 AD patients on rivastigmine 9,5mg/patch and citalopram 20‐40 mg/day over 48 months was assessed on the basis of NINCDS‐ADRDA, MMSE, DSM‐IV, FRSSD, GDS, HRS‐D and follow up of the patients.

Result

Four years after the baseline assessment, there were no significant differences in MMSE, Geriatric depression scale and Hamilton rating scale for depression between patients treated with rivastigmine alone or combined rivastigmine with citalopram with or without depression (p>0.05). Functional Rating Scale for symptoms of dementia, Activities of Daily Living of patients with AD and depression treated with rivastigmine was significantly worse than patients treated with rivastigmine and no depression (p=0.027).

Conclusion

The combination of rivastigmine and citalopram had no better results than rivastigmine alone in patients with AD.
What do I really need? Assessment of caregiver support for people with intellectual and developmental disabilities (IDD) and dementia
Authors: Service Kathryn , Clifford Christine J
Published: December 2020

Background

The increased needs of people with an intellectual and developmental disability (IDD) and a dementia related disorder can strain caregivers and existing community support systems. The project team, comprised of IDD and Aging experts and funded, in part, through a federal grant, conducted a needs assessment on the awareness and use of typical community‐based resources such as senior centers. The assessment consisted of both telephone interviews and home visits with group home, shared living, and family caregivers.

Method

Nurse Practitioner (NP) conducted a total of 95 interviews with 54 site visits, and the evaluator completed 40 interviews with caregivers of people with IDD and dementia diagnosis. Analysis included both qualitative and quantitative data.

Caregivers were asked about the following: functional and health status of person with IDD since dementia diagnosis, receipt of dementia specific caregiving training, care confidence levels, perceived barriers to care, and access to community‐based aging resources.

Result

Caregiver’s most frequent concerns included lack of suitable day programming, planning for the person’s future, and caregiver burnout and stress. 78% reported feeling confident providing care currently and 68% were confident about providing care in the future. Most caregivers are aware of local community resources such as senior centers, Alzheimer’s Association Counseling and an on‐line training series on aging, but rarely used the resources.

Conclusion

Caregivers generally relied on support from provider agencies indicating a need for increased collaboration across the IDD and Aging human service support systems. Trainings, delivered to both aging advocates and caregivers of people with IDD, and designed to improve communication and collaboration focused on dementia capable care, state systems, and available community resources. In addition, a series of web‐based resources were developed with a focus on IDD and dementia. Results of the assessment will continue to guide resource and training development to improve collaboration and support the relationship between the Aging and IDD communities.
ICF‐based health and social‐needs assessment system for person‐centered dementia care
Authors: Park Myonghwa , Go Younghye , Lee Mihyun
Published: December 2020

Background

This study explained the development of health and social needs assessment system for patients with dementia based on International Classification of Functioning, Disability and Health International Classification (ICF) model to enhance person‐centered dementia community care. ICF is the WHO framework for measuring health and disability at both individual and population levels. Many countries including Korea have been participating in trials for implementation of the ICF in hospitals and community settings. The use of ICF domains as intervention targets for persons with dementia and their family members can be an innovative attempt to facilitate person‐centered community care.

Methods

Using methodological study design, the following steps were performed. First, the concepts and domains of ICF were compared with existing instruments to measure health and functional status of persons with dementia. Second, the health and social needs assessment tool sets were developed and mapped with the framework of ICF. Third, the expert validated the health and social needs assessment system tool using Delphi method and focus group interview. Fourth, the pilot test was conducted with two community social service centers and two day care centers.

Results

Six domains of health and social needs assessment were developed and embedded in the assessment tools; Health condition (diagnosis, severity of dementia), body functions and structure (health assessment, health habit, nutrition physical exercise), activity (cognitive function, daily life activities), participation (social activity, emotional function, social relationship), environmental factors (home, community, facility environment, social support) and personal factors (personal history).

Conclusion

The use of the health and social needs assessment system based ICF framework can help health care and social service professionals to evaluate person centered health and social needs. It facilitates mapping the assessed needs to individualized care plans, and guide the persons with dementia to the best services. Using a larger sample, further studies to verify reliability and validity of the developed assessment system are needed.
Development and feasibility testing of a person‐centered cognitive service manual to enhance community care for people with dementia in Korea
Authors: Park Myonghwa , Go Younghye , Lee Mihyun
Published: December 2020

Background

In order to improve the quality of life for persons with dementia and their families and to ensure the efficiency of national cost for managing dementia, there is a need to support them in their communities as long as possible. Therefore, person‐centered cognitive interventions for early detecting of dementia and delaying its progression in the community is an urgent priority at the international level. This study aimed to develop a person‐centered cognitive service manual for early dementia to use for national long‐term care agencies and test its feasibility.

Methods

This study was conducted from February to July, 2019. The theoretical rationale for the manual was developed through systematic review of previous guidelines and studies. The focus group interviews identified the needs and preferences of stakeholders. The manual consisted of assessment, intervention, and outcome based on six domains. Six domains were individuality, independence, psychological health, physical health, safety, and social support. The manual provides comprehensive needs assessment tools and algorithms to plan and provide individualized service plan. The feasibility study was conducted at 47 senior welfare centers in Korea.

Results

This study found that the manual was effective for initial consultation (63.0%), comprehensive evaluation (50.0%), service planning (72.7%), service provision (78.3%), goal achievement evaluation (50.0%), and service termination (100.0%). However, service provider’s increased workloads and the time for completing the needs assessment were identified as barriers to apply the manual. In addition, service providers experienced lack of knowledge and skills in comprehensive evaluation (55.9%) and service planning (29.4%). The continuous educational support for manual application was suggested.

Conclusion

The national manual of person‐centered cognitive service can be useful to provide the best community services to improve the quality dementia community care. Development and dissemination of ICT based care pathways into the long‐term care service system to support best practices through the manual can be suggested.