bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive reserve among potentially inappropriate medication users with and without preclinical Alzheimer’s disease
Authors: Martinez Ashley I. , Jicha Gregory A. , Khouli Riham H. El , Schmitt Frederick A. , Abner Erin L. , Beech Brooke F. , George Rosmy , Hall Megan , Eckmann Lynne , Huffmyer Mark , Moga Daniela C.
Published: December 2020

Background

Augmenting cognitive reserve (CR) may delay the progression from preclinical Alzheimer’s disease (pAD) to symptomatic AD. Because studies have shown that potentially inappropriate medication (PIM) use may lower CR,1 optimizing individual medication regimens may protect against AD dementia symptomatic onset. We investigated the association between baseline measures of CR and PIM use among participants enrolled in a randomized medication therapy management trial.2

Methods

Participants completed cognitive tests –Trail Making Tests A and B (TMT) and California Verbal Learning Test Trials 1‐5 (CVLT) – while wearing a 1.5mg scopolamine patch (“challenged”) and again four weeks later under normal conditions (“unchallenged”). Change scores between the challenged and unchallenged tests (standardized for age, sex, and education) were used as a surrogate for CR. The Medication Appropriateness Index for medications considered potentially inappropriate for older adults based on the 2015 Beers Criteria3 served as a measure of PIM use (MAI‐PIM). pAD was defined as total brain relative standardized uptake values > 1.4 using amyloid PET.4Spearman correlation coefficients (rs) assessed the relationship between MAI‐PIM and CR.

Results

Included participants (N=79) had mean age 73.9 years [SD 5.9] and were 66% female; 31.6% met pAD criteria. The median (IQR) PIMs reported at baseline was 2 (2‐3). Participants with and without pAD had similar mean (SD) baseline change scores for TMT B minus A (‐0.17 [1.37] and ‐0.13 [1.10] respectively; p=0.90), but lower total CVLT change scores (‐0.85 [0.84] and ‐0.29 [0.83]; p=0.01). Higher MAI‐PIM was also correlated with lower baseline CVLT change scores (rs=‐0.16), driven by the participants with pAD (rs=‐0.33). TMT B minus A change scores and MAI‐PIM were uncorrelated (rs=0.02).

Conclusion

Among community‐dwelling non‐demented older adults, executive function and total learning CR was operationalized via participants’ abilities to compensate for anticholinergic challenge. There was a moderate negative correlation between MAI‐PIM and low total learning CR among participants with pAD, but not for those without. These results support the hypothesized relationship between CR and medication appropriateness. References: 1. Moga DC et al. Alzheimers Res Ther. 2017;9(1):36. 2. Moga DC, et al. Trials. 2019;20(1):806. 3. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246.4. Jack CR et al. Brain. 2015;138(12):3747‐3759.
Validity of tau as both a biomarker and target for AD and the dynamics of tau over the course of the disease
Authors: Barthelemy Nicolas R. , Horie Kanta , Sato Chihiro , Li Yan , McDade Eric , Bateman Randall J.
Published: December 2020

Background

Brain tau aggregates are, together with amyloid plaques, hallmarks of Alzheimer Disease (AD). Structural characterization of tau aggregates in AD, Pick’s disease and Chronic Traumatic Encephalopathy demonstrate distinct folds leading to tau aggregation. However, initiation and propagation mechanisms involved are still unknown. One hypothesis includes modification in tau metabolism affecting tau isoforms abundance and clearance. Understanding these mechanisms can both identify potential targets for treatment, biomarkers for monitoring disease stages and response to tau‐directed therapies.

Method

Recent developments in characterizing tau species by Mass Spectrometry in brain and biofluids have provided new insights on the diversity of tau isoforms and their changes associated to Alzheimer’s disease over the course of the disease. We will review past and new results from these techniques and discuss which tau isoforms are the most promising biomarkers to identify and stage AD. We will then discuss how these changes can be related to abnormal tau metabolism and, potentially, aggregation.

Result

In brain, soluble tau is phosphorylated at more than 30 sites and tau phosphorylation occupancy is modified in AD in a site‐dependent manner and appears to occur decades before substantial tau aggregation. Contrarily, AD brain aggregates are hyperphosphorylated compared to AD soluble tau at specific sites. In cerebrospinal fluid (CSF), the longitudinal monitoring of 11 phosphorylated sites in autosomal dominant AD demonstrates different behavior of these sites over disease trajectory. The CSF tau truncation profile, particularly in the protein domain enriched in brain aggregates, changes with disease. This suggests brain tau aggregates may impact the nature of tau isoforms released extracellularly. Yet, initial stages of tau hyperphosphorylation appears to occur many years before substantial tau aggregation. Critically, certain tau hyperphosphorylation sites observed in CSF are recapitulated in plasma tau in the preclinical stages of disease.

Conclusion

Both CSF tau phosphorylation and tau truncation profiles can serve as biomarkers to complement p‐tau and tau levels for AD diagnosis and staging. For target validation, the multiplicity of tau isoforms complicates the identification of the most relevant species to target. Notably, the uncertain role of abnormal tau phosphorylation as the initiator or a consequence of tau aggregation remains to be addressed.
Trust thyself: How older black and white adults consider Alzheimer’s disease research participation
Authors: Howell J. Christina , Wharton Whitney , Hodge David A. , Warren Reuben C. , Hu William T.
Published: December 2020

Background

Black or African Americans (B/AA) are twice as likely to develop Alzheimer’s disease (AD) but significantly under‐represented in AD research studies, particularly those involving cerebrospinal fluid and PET biomarkers. We previously did not find potential participants to reference Tuskegee Study of Untreated Syphilis (TSUS) as a common reason for non‐participation, but B/AA adults who expressed an interest in research participation were much less likely to follow through than White adults in the Atlanta area. The reason for this is not clear.

Method

We electronically surveyed 158 older B/AA and 216 older non‐Hispanic Whites from Georgia, Alabama, Pennsylvania, and Missouri to assess their trust in AD research and their local academic medical centers (AMC); motivating factors and sources of counsel for participating in a hypothetical AD research study; and knowledge of ethical violations including TSUS and the case of Henrietta Lacks.

Result

Compared to White respondents, B/AA respondents were more likely to provide accurate (OR=2.51, 95%CI=1.42‐4.44 p=0.002) as well as inaccurate (OR=3.95, 95%CI=2.37‐6.56, p<0.001) details about TSUS, perceive less equity in AD research (proportional OR 2.10, 95%CI=1.43‐3.09, p<0.001), and report less equity in healthcare at researcher‐affiliated AMCs (proportional OR=2.63, 95%CI=1.73‐3.98, p<0.001) even if they themselves can receive quality care there. State of residence did not greatly influence accuracy of knowledge or perception of equity in research and healthcare. Personal or family history of dementia, altruism, support from a friend or family, and support from a trusted physician were top factors considered by both older B/AA and White adults prior to research participation. Knowledge of TSUS – not Lacks – among older B/AA adults was associated with a shift of trust from community leaders to one’s own healthcare experience at AMCs.

Conclusion

Familiarity with TSUS – but not accuracy – impacted factors of mid‐ to low importance in older B/AA adults when considering research participation and, to a lesser degree, perception of healthcare equity. Positive personal healthcare experience can potentially enhance B/AA research participation even if it poorly improves perception of inequity in research and healthcare.
A pilot clinical trial of adapted tango to improve negative health impacts in middle aged African‐American women caregivers of persons with Alzheimer’s disease
Authors: Wharton Whitney , Shin Ryan , Hu William T. , Jeong Leanne , Bay Allison A. , Hart Ariel R. , Ni Liang , Hackney Madeleine E
Published: December 2020

Background

Dementia caregivers have increased risk for psychological and physiological illness including depression, stress, hypertension, diabetes, diminished QOL, low‐grade inflammation and increased mortality. Dementia risk factors include gender, race and family history.

Method

This phase I pilot study evaluated the potential physiological, cognitive, motor, and psychosocial benefits of a 12 week, 20‐lesson adapted Argentine Tango intervention (N=30) to a no‐contact control group (N=10) in middle‐aged (45‐65 years) African American women caregivers of their parent with AD. Blood draw for inflammatory markers was done pre/post intervention/control.

Result

Women were middle age (60.0 yrs), slightly overweight (BMI 30.7) and highly educated (16.3 yrs of education). Significant reductions were noted in pre/post visit change for the Tango group in inflammatory markers including TNFα, interleukin‐7 and interferon‐gamma; maintenance of 30s chair stand performance, balance, and performance on the Tower of London and Stroop interference tests. Other non‐significant trends were noted in caregiving quality of life, gait speed, spatial cognition and executive function.

Conclusion

The Tango dance intervention is a promising, non‐pharmaceutical intervention for African American women AD caregivers, for preservation of physiological, psychological and cognitive health.
Analysis of copy number variation in a Turkish dementia cohort
Authors: Dehghani Nadia , Kun‐Rodrigues Celia , Foster Kalina , Hanagasi Hasmet , Lohmann Ebba , Guven Gamze , Bilgiç Başar , Gurvit Hakan , Bras Jose , Guerreiro Rita
Published: December 2020

Background

Copy number variations (CNVs) arise from copied or deleted regions of the genome. These regions vary in size and may span genes known to play a role in human disease. For example, duplications and triplications of SNCA have been shown to cause forms of Parkinson’s disease, while extra copies of APP are associated with early onset Alzheimer’s disease (AD). We have previously studied a Turkish dementia cohort for variants in known disease‐causing genes for both AD and frontotemporal dementia (FTD) and have also reported variants in the new AD‐associated genes TREM2 and NOTCH3. The goal of the current study was to perform a systematic analysis of CNVs in order to further characterize the genetic causes of dementia in this Turkish dementia cohort.

Method

Ninety‐nine Turkish individuals, either at risk of dementia due to family history, diagnosed with mild cognitive impairment, AD or FTD, were whole‐genome genotyped using Illumina HumanOmniExpress chips. We used GenomeStudio cnvPartition v3.2.1 plug‐in (Illumina, Inc) to analyze the data.

Result

We did not identify any CNVs segregating with disease in any of the four dementia families present in the studied cohort. We also did not observe any CNVs across our entire data set overlapping genes which have been previously associated with neurodegenerative diseases. We identified 9 distinct CNVs overlapping regions previously reported to have potential disease‐associated gene dosage alterations in patients with dementia phenotypes using PennCNV‐1.0.5; these were confirmed by manually checking CNVs on GenomeStudio. We observed potential disease‐associated CNVs in single individuals overlapping LOC286367, ABCA1, NIPSNAP3A, NIPSNAP3B, OR13C2, OR13C5, OR13C8, OR13C9, OR13D1, CNTN6, NIPA1, CYFIP1, GALNTL6, NLGN1, XPO1, SNORA70B, USP34, and HLA‐G. Additionally, two identical heterozygous duplications spanning MICA were identified in two AD patients; CNVs spanning this gene have been previously reported in four AD patients and no controls.

Conclusion

In this study, we integrated whole‐genome genotyping results from a Turkish cohort with previously reported findings and data publicly available to add further evidence to the role of specific CNVs in the pathogenesis of dementia.
Key developmental milestones for tau therapeutics
Authors: Cummings Jeffrey L.
Published: December 2020

Background

There have been few breakthroughs and slow progress toward development of disease‐modifying treatments for Alzheimer’s disease (AD) and other neurodegenerative diseases. A biology/biomarker framework is captured in the AD‐disease specific framework focused on amyloid, tau, and neurodegeneration (ATN).

Method

Recent developments in basic research — involves advances in both fluid‐ and neuroimaging‐derived biomarkers — has strengthened the foundation of clinical AD research.

Results

While much of the focus in recent years has been on amyloid, contemporary studies analyzing the temporal dynamics of tau have suggested that tau pathology better corresponds to the clinical features of AD and may be a viable therapeutic target. As a component of the ATN framework with a known association with AD cognitive impairment, tau and its regulation are well‐positioned for drug discovery programs. Although no disease‐modifying agents are currently approved, approximately 120 potential disease‐modifying anti‐AD agents are in clinical trials. Of these, about 55% incorporate tau and/or inflammatory activity in their mechanisms of action, including at least 4/28 candidates in Phase 3 trials.

Conclusion

Improved biomarkers, trial designs, outcomes, and population definitions will assist in advancing tau therapeutics.
Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer's disease
Authors: Therriault Joseph , Pascoal Tharick A. , Savard Melissa , Mathotaarachchi Sulantha , Benedet Andréa Lessa , Chamoun Mira , Tissot Cecile , Lussier Firoza Z , Soucy Jean‐Paul , Massarweh Gassan , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

Preclinical models suggest that tau pathology spreads intracellularly, thought to explain the topographical distribution of tau observed in Alzheimer’s disease (AD). However, these findings have yet to be extended to humans.

Method

We assessed 131 cognitively unimpaired elderly and 63 AD individuals who underwent amyloid‐PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, fMRI and diffusion‐weighted MRI. Of the subjects with AD, 11 had behavioural/ dysexecutive AD, 18 had PCA and 11 had Logopenic variant PPA, while 23 subjects had an amnestic presentation (all were Ab+/Tau+). A voxelwise multivariate regression model was employed to determine the peak difference in [18F]MK6240 SUVR between each AD variant and CU elderly, with each clinical diagnosis entered as a different categorical variable and correcting for age, gender and MMSE score. Within each AD variant, the peak voxels derived from the regression model were used to compute the correlation between [18F]MK6240 SUVR in the seed voxel and [18F]MK6240 SUVR in every voxel, thus generating an [18F]MK6240 covariance network for each AD group. The same seeds were also employed in functional connectivity and diffusion tractography analyses in the CU elderly group. To determine whether the topographical distribution of tau pathology is related to connectivity properties of the human brain, we applied regression models to assess the relationship between functional/structural connectivity values from the CU population and [18F]MK6240 in each variant of AD.

Result

Tau organization differed between AD groups, reflecting clinical phenotypes and organizing within distinct brain networks. Furthermore, structural (Figure 1) and functional (Figure 2) connectivity patterns of the human brain predicted in vivo [18F]MK6240 SUVR across the cerebral cortex in each variant of AD.

Conclusion

These results support a framework in which the intrinsic connectivity of the human brain provides a scaffold for tau pathology to spread to anatomically distant regions.
Mild behavioral impairment associates with Alzheimer’s disease biomarkers and greater risk of incident dementia in patients with MCI
Authors: Ismail Zahinoor , Gill Sascha , Wang Meng , Naude James , Smith Eric E.
Published: December 2020

Background

Mild behavioral impairment (MBI) is characterized by later life onset of sustained neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. Here we assess differences in sustained NPS versus transient NPS versus no NPS, on neuroimaging markers and cognitive scores, and the risk of progression to dementia.

Method

Data from 764 individuals with MCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed. NPI‐Q items were transformed to MBI domains using a published algorithm. MBI requires sustained NPS for 6 months, thus we grouped individuals based on two visits 6‐months apart as sustained (present at both visits, n=258), transient (present at one visit, n=346), and no NPS (present at neither visit, n=160). For the cross‐sectional analyses, outcomes of interest were matched to the clinical visits assessing NPS. We investigated differences in brain metabolic activity by [18F] fluorodeoxyglucose (FDG)‐PET, and composite scores of executive functioning and memory in these groups using multiple linear regression adjusted for age, sex and education. Time‐varying cox regression models were constructed, adjusting for age, sex, and education to assess if time to dementia is associated with MBI.

Result

In these participants with MCI, compared to individuals with no NPS, sustained NPS was associated with reduced [18F] FDG uptake [Adjusted‐=‐0.06 (SE=0.02); p value=0.003], lower executive functioning scores [Adjusted‐=‐0.28 (SE=0.08); p value=0.001], and memory impairment [Adjusted‐=‐0.38 (SE=0.08); p value=<.001]. Compared to individuals with transient NPS, sustained NPS was also associated with reduced glucose metabolism [Adjusted‐=‐0.03 (SE=0.01); p value=0.018], and lower memory scores [Adjusted‐=‐0.17 (SE=0.06); p value=0.007], but not executive functioning. Compared to no or transient NPS, the risk for incident dementia was highest in the sustained NPS group (HR 1.87, 95% CI 1.50 to 2.34).

Conclusion

In a cohort of individuals with MCI, baseline NPS are associated with biomarkers of dementia risk and predict progression to dementia. MBI, as operationalized here by sustained NPS, was associated with worse memory, lower glucose metabolism, and higher risk of incident dementia compared to transient NPS. There is diagnostic and prognostic utility in determining if NPS are sustained or transient, further validating the MBI construct.
The Oxford Brain Health Centre: Embedding dementia research in clinical practice
Authors: O'Donoghue M Clare , Raymont Vanessa , Fossey Jane , Semple Juliet , Griffanti Ludovica , Zokaei Nahid , Nobre Anna Christina , Martos Lola , Mackay Clare
Published: December 2020

Introduction

The Oxford Brain Health Centre (BHC) is an ambitious and innovative joint clinical‐research service that aims to bring UK NHS memory services into the 21st century by addressing gaps between clinical practice and research advances into dementia. This NIHR‐funded partnership between Oxford Health NHS Foundation Trust and the University of Oxford will be the first psychiatry‐led service of its kind, developing the model for a specialist service that can be adopted throughout the UK health service.

Methods and Materials

The BHC will augment current NHS memory services by providing high‐quality assessments not routinely available in clinical service, e.g. MRI rather than CT brain scans, and developing novel diagnostic tools sensitive to earlier pathological changes. Enhanced information will be fed into clinical notes, improving the quality of information available to clinicians empowered to make more confident and accurate timely diagnoses. The BHC will increase opportunities for patients and relatives to participate in research by embedding research in the clinical service, through use of clinical data for research, completion of additional research assessments, and re‐contact about future research opportunities. All research data collected at the BHC will be made openly available to the scientific community through the BHC Research Database, encouraging collaborative and transparent research. The BHC actively involves public contributors with lived experience at all stages of the development and evolution of the service.

Results

A six‐month pilot of 150 patients from a single memory clinic will launch in early 2020 to demonstrate feasibility and refine procedures, before expanding to other memory clinics. The pilot will incorporate evaluation of service‐user and clinician feedback and health economic measures.

Conclusions

To prepare the UK health system for the future of dementia treatment and ultimately prevention, the BHC will provide a translational interface, enabling new advances in diagnosis, risk reduction and treatment to be rapidly implemented in clinical practice to provide better care for patients.
T2 protect AD: Achieving a rapid recruitment timeline in a multi‐site clinical trial for individuals with mild‐to‐moderate Alzheimer’s disease
Authors: LaCroix Andrea Z. , Shadyab Aladdin H. , Matthews Genevieve , Bennett Daniel , Shadyab Alexandre , Donahue Lia , Qureshi Irfan , Feldman Howard H.
Published: December 2020

Background

Preservation or improvement in cognition in Alzheimer’s disease (AD) is a public health priority. In 2018, there were 30 drugs in phase II and III AD trials1, increasing to 50 in 20192. However, AD trial recruitment is oft‐cited as slowing down research advancements3,4. The T2 Protect AD Trial (T2), is a multi‐site, randomized, placebo controlled, 52‐week trial testing troriluzole, a glutamate modulator. T2 was designed as a proof of concept clinical trial with an estimated sample size of 336 participants.

Method

T2 is coordinated by the ADCS, and includes 44 US academic and private medical clinics specialized in AD research, treatment, and care. The trial (NCT03605667) includes participants with mild‐to‐moderate AD, 50‐85 years old, stable on AD medication(s), with MMSE 14‐24 and MRI findings consistent with AD. There are no AD biomarker inclusion criteria. The trial recruitment toolkit included flyers, brochures, press release, FAQ, infographics, video, and a website. The recruitment budget was divided between the central ADCS effort and individual sites. The ADCS effort included creative design services, social media outreach, telephone prescreening, development of news stories, and advertising placement.

Result

Sites screened 736 individuals, randomizing 350. Fourteen sites exceeded their enrollment goal of 10 participants and the top two sites randomized 25 and 20 participants. 98% of participants were randomized during an intensively supported 10‐month rapid recruitment period, that was initiated when 21/44 sites were actively recruiting (Figure). The randomization rate, defined as the number randomized, divided by the number of active site recruitment months, ranged from 0 (1 site) to 4.0 per month, with an overall rate of 0.87 per month. Sites enrolled 75% of the cohort through their existing site recruitment infrastructure, including waiting lists and internal referrals. 25% came from news media reports, paid advertising, word‐of‐mouth, and outside physician/organizational referrals. Social media advertising was not a significant source of participants.

Conclusion

This trial in mild‐to‐moderate AD achieved among the highest site recruitment rates reported in ADCS investigational new drug trials in the last 20 years. Its success was primarily achieved through site network resources, however central recruiting efforts contributed significantly.
Neuropathology of FMR1‐premutation carriers presenting with dementia and neuropsychiatric symptoms
Authors: Dijkstra Anke A. , Haify Saif , Verwey Nicolaas A. , Prins Niels D. , van der Toorn Esmay , Rozemuller Annemieke J.M. , Bugiani Marianna , den Dunnen Wilfred , Todd Peter K. , Charlet‐Berguerand Nicolas , Willemsen Rob , Hukema Renate , Hoozemans Jeroen J.M.
Published: December 2020

Background

CGG repeat expansions in the premutation range (55‐200) of the FMR1 gene can lead to Fragile‐X associated tremor/ataxia syndrome (FXTAS). Clinically, FXTAS is characterized by progressive tremor and ataxia, however psychiatric symptoms can also manifest as part of the syndrome, termed Fragile‐X associated neuropsychiatric disorders (FXAND) (1). Pathology of FXTAS/FXAND include ubiquitin‐positive intranuclear inclusions in both neurons and glia cells. Recently, FMRpolyG RAN‐translation product has been identified in the majority of the inclusions (2).

Method

Here, we describe two cases with predominantly FXAND symptoms with mild movement disturbances. One donor was diagnosed with vascular dementia and frontotemporal dementia during life carrying an 107 CGG repeat expansion in the FMR1 gene. Donor two, carrying an 77 repeat expansion, presented with dementia and behavior alterations, and suffered from several infarcts throughout the brain.

Result

Macroscopically, both donors showed no FXTAS‐characteristic white matter lesions on MRI, but vascular infarcts in cortical‐ and subcortical regions were identified. At microscopic level, vascular pathology was observed throughout the brain. A high number of p62‐positive intranuclear inclusions were observed predominantly in cortical regions in neuronal, glial, ependymal, choroid plexus and endothelial cells. The majority of these inclusions were positive for FMRpolyG as well. Dopaminergic neurons in the substantia nigra contained p62‐positive intranuclear inclusions, but were FMRpolyG negative.

Conclusion

We conclude that in these patients with FXAND, no characteristic MRI abnormalities are seen and that the inclusion pathology of FXAND also affects the vasculature of the brain. Inclusions were present in large numbers throughout the brain, and often positive for FMRpolyG. The described donors clinically resemble other types of dementia, and in absence of genetic testing or family history, FMRpolyG can be used post‐mortem to identify premutation carriersHagerman et al. Fragile X‐Associated Neuropsychiatric Disorders (FXAND) Front. Psychiatry. 2018. (2) Krans et al. Neuropathology of RAN translation proteins in fragile X‐associated tremor/ataxia syndrome Acta Neuropathol Commun. 2019.
A genetic enrichment strategy for delay of onset of Alzheimer’s disease clinical trials
Authors: Lutz Michael W. , Burns Daniel K. , Alexander Robert , Culp Meredith , Yarnall David , Haneline Stephen , Chiang Carl , Lai Eric , Metz Craig , Sundseth Scott , Guennel Tobi , Marshall Scott , Andruss Bernard F. , Latham Gary J. , Hall Bradley , Statt Sarah N. , Swanson Tom , Ratti Emiliangelo , Saunders Ann M.
Published: December 2020

Background

A challenge with AD prevention is the timely identification of subjects at risk of cognitive symptom onset, mitigating prohibitive costs associated with the trial size and duration. A biomarker risk assignment algorithm (BRAA) consisting of genotypes at the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) rs10524523 loci (‘523) and current age was developed to enrich the TOMMORROW delay of AD onset clinical study. ‘523 is a poly‐T homopolymer of 14 to 50 residues. For the BRAA, the alleles were categorized by T length as “short” (S: <21), “long” (L: 21‐29), or “very long” (VL: >29).

Method

The TOMMORROW study (NCT 01931566) provided a large dataset to assess APOE‐‘523 haplotypes to improve the performance of the BRAA. The original BRAA used phased genetic information to determine risk categories (developed in 150 individuals, verified in 1018 individuals). Because phased haplotype data were not available from the samples genotyped in the TOMMORROW study, an optimized calibration was performed using APOE 3/3 and 4/4 homozygous individuals (n=1625). By maximizing the genetic congruency between the APOE and ‘523 genotypes, the calibration of the ‘523 categorical boundaries was optimized.

Result

From these haplotype data, the ’523 categorical assignments were optimized to S: <19; L: 19‐31; and VL: >31. When these optimized categorical assignments were applied retrospectively to the TOMMORROW study cohort (n=1803), the hazard ratio for the time‐to‐event comparison between the high and low risk placebo groups improved from 3.3 (95% confidence interval [CI] 1.2‐9.0, P=0.023) to 4.3 (95%CI 1.3‐13.7, P=0.015). Applying the refined BRAA to a future delay of AD onset clinical trial would reduce enrollment by 26% for a 5‐year interventional study versus an all‐comers enrollment strategy. Furthermore, a streamlined, kit‐based genotyping assay for APOE and TOMM40 ‘523 was evaluated and found to yield congruent results with the sequencing‐based method used for genotyping in the TOMMORROW clinical trial.

Conclusion

Using phase 3 clinical trial data, the TOMMORROW BRAA demonstrated the ability to enrich delay of onset/prevention of AD studies for subjects more likely to develop cognitive symptom onset during an acceptable timeframe with significant clinical trial cost savings.
Assessing changes in choroidal vasculature in the eye in Down’s syndrome
Authors: Csincsik Lajos , Nelson Rachel , Walpert Madeleine , Little Julie‐Anne , Doyle Lesley , Saunders Kathryn , Peto Tunde , Holland Tony , Lengyel Imre
Published: December 2020

Background

Changes of choroidal vasculature in the eye have been reported in Alzheimer’s disease (AD) and this is positively correlated with declining cognitive status. Patients with Down’s syndrome (DS) are at a high risk of developing AD and also show signs of premature ageing. Both AD and ageing have been associated with thinner choroid, measured on optical coherence tomography (OCT) scans, however, there are currently no studies in the literature to evidence whether choroidal thinning occurs in DS. Our study, for the first time, investigated choroidal thickness (CT) in DS using OCT imaging.

Method

21 DS and 9 controls (Ctrl) were imaged using Enhanced Depth Imaging Spectral Domain OCT (Heidelberg). The choroid was manually segmented, and thickness values calculated using conventional grading grid (ETDRS). Statistical analysis was conducted in SPPS using only the right eye. The analysis was controlled for age, image quality, refractive error and time of the scan as covariates.

Result

OCT imaging in DS proved to be challenging due to some participants having difficulties maintaining the fixation for an extended period. In this preliminary cohort the DS group was older than the Ctrl group (39.5±6.9 vs 31.2±6.0 years, p=.004) but there was no difference in gender (χ2=0.7, df=1, p=.376). Sub‐foveal (SF) and Superior‐inner (SI) CT was significantly increased in DS compared to Ctrl (SF: 363.2µm±25.9µm vs 237.3µm±45.8µm, p=.046; SI: 381.8µm±26.2µm vs 253.6µm±46.3µm, p=.044) but no differences were found in other sectors of the ETDRS grid. Increase in SF CT showed a moderate, positive correlation with cognitive status in the 14 participants whose cognitive score was available (ρ=.539, p=.047). Suprachoroidal space (SCS) as a hypo‐reflective band at the choroidal scleral interface, was only visible in DS in 13 (61.9%) out of the 21 participants. Those with SCS were older than those without (41.9±1.7 vs 35.6±2.2 years, p=.040).

Conclusion

In this study we found that there is an increase in choroidal thickness in DS which is in contrast to the thinning observed in AD; this might be an anatomical feature of DS or may reflect inflammation. The increased prevalence of SCS in DS is likely to be associated with the accelerated ageing.
Feasibility of clinical research studies reported by patients with behavioral variant frontotemporal dementia and their caregivers
Authors: Nery Flavia C. , DeVico Danielle , Matzopoulos Mark , Wilson Kate , Huang Ellen , Von Rosenstiel Philipp , Ratti Elena
Published: December 2020

Background

Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by progressive, profound behavioral changes plus loss of insight and independence, leading to significant burden for affected families both in daily life and clinical research participation. FORWARD study aimed to estimate disease‐related decline in patients with early‐stage bvFTD (NCT03088956) over 1 year (consisting of 6 in‐clinic and at least 4 at home study visits), using a battery of cognitive tests, functional, behavioral, and quality of life assessments. Participants were asked to complete an end‐of‐study questionnaire with the purpose to identify aspects of the study considered as potentially burdensome, challenging and/or positive.

Method

The one‐time end‐of‐study questionnaire consisting of 10 questions was completed by 29 bvFTD subjects and their 29 caregivers at their last study visit (Month 13 or Early Termination).

Result

Majority of participants were very satisfied in taking part in the study (66% bvFTD; 72% caregivers). The top motivators to participation included contributing to dementia research (79% bvFTD; 93% caregivers) while the main drivers to complete the study included their commitment to be in the study (83% bvFTD; 86% caregivers) as well as the amount of care and attention received from the study doctor and staff (76% bvFTD; 79% caregivers). In terms of study design, home visits were considered useful (76% bvFTD; 83% caregivers) and not burdensome (79% bvFTD; 86% caregivers) by the majority of participants. Most participants did not find every 3‐months clinic visits (55% bvFTD; 62% caregivers), clinic visit length (62% bvFTD; 76% caregivers), and study duration (59% bvFTD; 72% caregivers) as burdensome. However, bvFTD patients considered burdensome cognitive assessments done either in paper forms (55%) or on iPAD (55%). Use of iPAD was considered useful (48% bvFTD; 64% caregivers) and not burdensome (69% bvFTD; 93% caregivers) mainly by caregivers and less so by patients. Financial travel support was deemed useful (69% bvFTD; 66% caregivers) and 62% of caregivers found the overall study experience not burdensome for bvFTD patients.

Conclusion

These insights are useful to minimize the degree of burden for participants with improved clinical trial design in the bvFTD indication with limited drug development precedence.
From liability to asset: Understanding senior citizens with dementia as a source of social support for marginalized young adults
Authors: Zheng Chengwen (Kevin)
Published: December 2020

Background

Understanding dementia patients as a source of social support for marginalized young adults.

Method

This is a qualitative research conducted via interviews and observations at Humanitas, a renowned care home in the Netherlands.

Result

While many researches look at dementia using a critical lens, the senior citizens with dementia are also found to be genuine, welcoming and peaceful. Derived from these changes, this population have distinct needs for security (i.e. attention, consistent presence of familiar faces), diverse ways of communication (i.e. physical, emotional, but less verbal) and a preference of interaction with young people. These factors make them a nonjudgmental source of support for marginalized young adults, who need such social connections to recover from depression, autism, drug addiction, etc.

Conclusion

Through interactions with senior citizens with dementia, marginalized young adults in Humanitas have reported more empathy, self‐control and efficacy. Bonding the two groups is therefore a mutually beneficial process. While the senior citizens' well‐beings are better taken care of, the marginalized young adults can eventually join the workforce and lead a normal life. Considering the size of the two populations, future interventions based on this model can have immense social value.
Docosahexaenoic acid oxylipins are associated with white matter microstructural integrity in a cohort of cognitively normal, hypertensive young‐old
Authors: Silbert Lisa C , Wall Rachel C , Lahna David , Dodge Hiroko H , Hagen Kirsten , David Jason C , Kaye Jeffrey , Shinto Lynne
Published: December 2020

Background

Previous studies investigating potential beneficial effects of Omega‐3 Polyunsaturated Fatty Acids (PUFA) on vascular health have shown inconsistent results. Oxylipins, produced from the oxidation of PUFAs, have potent vascular effects shown to be relevant to human disease. We have previously reported the cytochrome P450‐derived Omega‐3 PUFA Docosahexaenoic acid (DHA) oxylipin 16,17‐EpDPE to be associated with less cerebral white matter hyperintensities (WMH), while a ratio of its soluble epoxide hydrolase (sEH) products, 19,20‐DiHDPE/19,20‐EpDPE were associated with higher WMH. Relationships between DHA and its oxylipin products and microstructural white matter integrity is unknown.

Method

36 cognitively intact subjects with low blood omega‐3 levels, controlled hypertension, 55 years or older, enrolled in a study investigating fish oil and lipoic acid on preserving cognitive function, underwent baseline MRI and plasma PUFA oxylipins measured by liquid chromatography tandem mass spectrometry. Voxel‐wise associations between Diffusion Tensor Imaging (DTI) metrics, including fractional anisotropy (FA), radial (RD) and axial (AD) diffusivity, and DHA and oxylipins were examined using Tract‐Based Spatial Statistics, adjusted for age and sex.

Result

Higher DHA oxylipin 16, 17‐EpDPE was associated with increased FA clusters within the inferior frontal‐occipital fasciculus, and the cingulate and anterior thalamic radiation tracts. Higher DHA oxylipin ratio 19, 20‐DiHDPE/19, 20‐EpDPE was associated with decreased FA in those same regions, as well as in the superior and inferior longitudinal fasciculi and corticospinal tract. Increased RD clusters were observed in some corresponding regions in relation to 19, 20‐DiHDPE/19, 20‐EpDPE. DHA was not related to DTI measures.

Conclusion

The oxylipin 16,17‐EpDPE, an epoxide, is associated with greater DTI white matter integrity, while a ratio of 19,20‐DiHDPE/19,20‐EpDPE , is associated with decreased DTI white matter integrity, in a hypertensive young‐old cohort. Protective epoxides are converted to diols by sEH, the ratio of diol/epoxide is an indirect measure of sEH activity. Affected areas were found largely in long‐range association fibers, important for intrahemispheric cortical connectivity, with extension beyond areas of macrostructural WMH lesions. DHA‐derived cytochrome P450 oxylipins, not DHA, are associated with DTI white matter integrity with differential effects observed. Targeting specific DHA oxylipin products is warranted for the effective prevention of cerebrovascular disease.
Impact of cortical and subcortical atrophy in the diagnosis and prognosis of bvFTD: A multicenter longitudinal study
Authors: Illán‐Gala Ignacio , Falgàs Neus , Castro‐Suárez Sheila , Keret Ophir , Friedberg Adit , Rogers Nicole , Oz Didem , Nigro Salvatore , Quattrone Aldo , Wolf Amy , Rojas Julio C , Santos‐Santos Miguel A , Borrego‐Écija Sergi , Sanchez‐Valle Raquel , Fortea Juan , Lleó Alberto , Karydas Anna M , Cobigo Yann , Miller Bruce L. , Grinberg Lea Tenenholz , Spina Salvatore , Kramer Joel H , Rabinovici Gil D , Boxer Adam L , Gorno‐Tempini Marilu , Seeley William W , Rosen Howard J , Perry David C
Published: December 2020

Background

The behavioral variant of frontotemporal dementia (bvFTD) presents with variable patterns of cortical and subcortical atrophy on Magnetic Resonance Imaging (MRI). We aimed to assess the clinical utility of two reproducible measurements of cerebral atrophy (Harper's visual atrophy scale [HVAS], and the Magnetic Resonance Parkinsonism Index [MRPI]) in a large multicenter sample of bvFTD with longitudinal follow‐up.

Methods

We included 466 participants from three centers: 241 bvFTD (according to the International bvFTD Criteria Consortium), and 225 healthy controls (HC). Clinical deterioration was assessed with Mini‐Mental State Examination (MMSE) and the Clinical Deterioration Scale Sum‐of‐boxes (CDR‐sb). bvFTD participants were considered to have an increased certainty of underlying Frontotemporal Lobar Degeneration (+FTLD) when: (i) FTLD was confirmed at autopsy (n=72); (ii) a secondary FTLD‐related phenotype was identified during follow‐up (n=47) or (iii) a FTLD‐related mutation was found (n=49). Six raters blinded to clinical data were first asked to dichotomize participants according to the presence of "a clear pattern of atrophy suggestive of probable bvFTD", and then applied the HVAS (ICC(2,k)=.86 to .96). The MRPI was calculated with a fully automated algorithm.

Results

Mean age of bvFTD participants was 63.3 ± 10, 68% were male (MMSE=23 ± 7 and CDR‐sb=6.7 ± 3.5). Blinded raters had 52% sensitivity and 97% specificity for the identification of bvFTD participants (AUC=.74, p=.001). All HVAS measures with the exception of posterior atrophy discriminated between bvFTD and HC (AUC=.77 to .83, p<.001). The composite bvFTD score (average score of orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe and frontal insula regions) showed the best diagnostic accuracy for the differentiation of bvFTD from HC (AUC=.91, p<.001 in +FTLD). This composite score also differentiated between bvFTD participants that were not considered to have a clear pattern of atrophy suggestive of probable bvFTD (blinded raters) and HC (p<.001). We hypothesized that HVAS and MRPI scores may be independent predictors of clinical deterioration and survival in bvFTD (definitive results pending).

Conclusion

The combination of HVAS and MRPI may provide valuable diagnostic and prognostic information in the behavioral syndromes verifying bvFTD criteria. These measures represent reliable, reproducible and affordable imaging biomarkers.
A blood cholesterol polygenic score in two independent AD cohorts
Authors: Nilsson Nathalie I.V. , Picard Cynthia , Labonte Anne , Poirier Judes ,   PREVENT‐AD
Published: December 2020

Background

While blood total cholesterol (TC) levels is a recognized factor contributing to Alzheimer’s disease (Alz. Ass., 2017), its role is debated (Wood et al., 2014). E.g. several studies have shown that midlife hypercholesterolemia is associated with increased risk of developing AD (Reiman et al., 2010; Solomon et al., 2009; Toro et al., 2014), but others have shown no association (Li et al., 2005; Tan et al., 2003). High TC has also been associated with increased amyloid load in the hippocampus (Pappolla et al., 2003) and hypometabolism in brain regions affected by AD (Reiman et al., 2010). Studies with statins have shown similar discrepancies with retrospective studies indicating a protective effect but have had no consistent positive effects in randomized controlled trials (Shobab et al., 2005). Thus, in an attempt to address these discrepancies, we constructed a polygenic score (TC‐pgs) capturing some of the variance in peripheral TC levels and evaluated it for associations with AD risk and biomarkers.

Method

A weighted TC‐pgs was constructed using summary data from Willer et al., (2013; http://lipidgenetics.org/) in two AD cohorts; PREVENT‐AD (https://preventad.loris.ca/) and ROSMAP (https://www.radc.rush.edu/home.htm). The TC‐pgs was optimized for correlation with TC levels in the PREVENT‐AD cohort, and then evaluated for correlations with AD risk and CSF biomarkers using both cohorts.

Results

We found that by stratifying for statin use and sex we more than doubled the amount of variance explained by the score (from ∼7.5% to ∼17.5%) specifically in statin free females. Furthermore, the TC‐pgs improved the prediction of hypercholesterolemia (AUC 0.805 vs 0.646, p = 0.0016) in the same group. The TC‐pgs were evaluated for associations with CSF Aβ42, p‐tau and tau in PREVENT‐AD and for clinically and pathologically defined AD in ROSMAP. We did not find any significant associations, but for a trend towards a positive association between TC‐pgs and CSF p‐tau levels (p = 0.09).

Conclusion

Our TC‐pgs did improve prediction of hypercholesterolemia but failed to correlate with AD or AD biomarkers. Thus, the findings do not support that an increased cumulative genetic risk of hypercholesterolemia influence the risk of AD.
One year tau progression measured with F‐18 MK6240 PET
Authors: Rowe Christopher C , Dore Vincent , Krishnadas Natasha , Mulligan Rachel S , Tyrrell Regan , Burnham Samantha C , Villemagne Victor LL
Published: December 2020

Background

For optimal design of anti‐tau trials, an understanding of the rate of tau progression in Alzheimer’s disease (AD) is important. Studies with Flortaucipir (F‐18 AV1451) PET have reported no detectable annual increase in beta‐amyloid (Ab) ‐ve cognitively normal (CN), 0.5%/yr increase in Ab +ve CN, mainly in entorhinal and posterior cingulate areas, and widespread cortical 3%/yr increase in Ab +ve MCI or dementia. Increase was greater with higher baseline tau and younger age. F‐18 MK6240 is a new tau tracer with higher target to background binding and no choroid plexus uptake, making it attractive for use in clinical trials. We aimed to define regional rates of MK6240 accumulation in CN, MCI and AD.

Method

PET acquisition was performed 90‐110 minutes post injection of 200 MBq F‐18 MK6240 at baseline and 12 months later in 15 Ab ‐ve CN and 23 Ab +ve subjects (13 CN, 6 MCI, 4 mild AD). SUVR was calculated for the medial temporal region (Me) (i.e. entorhinal, amygdala, hippocampus, parahippocampal cortex) and temporoparietal cortex (Te) (i.e. inferolateral temporal and parietal cortex) using cerebellar grey matter as reference.

Results

MCI and AD were younger than CN (67.0 ±5 yrs vs 77.2 ±4). Ab ‐ve CN showed no change, Ab +ve CN showed a trend increase of 1.5%/yr in the medial temporal region, while MCI and AD showed an increase of 7%/yr in temporoparietal cortex with lesser increase in the medial temporal region of 4%/yr. (Table 1, Figure 1).

Conclusion

In comparison to published data for AV1451, we found greater increase over one year in MK6240 binding in both the medial temporal and temporo‐parietal regions in Ab +ve CN, MCI and AD patients. However, given the strong relationships of age and baseline tau level to rate of increase, some of these comparative findings may be due to younger age in our MCI and AD participants. Future recruitment will address this issue.
Liraglutide treatment sustains neuronal glycolysis and prevents hyperinsulinemia‐induced neuronal senescence
Authors: Chow Hei‐Man , Herrup Karl
Published: December 2020

Background

We previously reported hyperinsulinemia during prediabetes could lead to neuronal insulin resistance and cell cycle‐induced senescence. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age‐related neurodegeneration and cognitive decline. Here we attempted to investigate if Liraglutide‐the FDA approved diabetes drug‐can prevent insulin‐induced senescence in neurons.

Method

Toxicity and optimal treatment strategies were first performed in primary neuronal culture (n=9). After that, optimal dosages of Liraglutide was co‐treated with long‐lasting insulin glargine for 72 hours. A series of post‐treatment biochemical, immunocytochemistry and electrophysiology analyses were performed.

Result

Liraglutide treatment did not reveal toxicity to neurons even at micro‐molar dosage. Liraglutide co‐treatment with insulin substantially preserved glycolysis capacity in primary neuronal cultures. Initiation of drug treatment prior or simultaneously with insulin revealed almost equal protective on neurite morphology; synaptic protein abundance and distribution; electrophysiology properties and be able to suppress cell‐cycle associated senescence.

Conclusion

Liraglutide effectively prevents the entire range of structural and functional abnormalities in neurons induced by chronic exposure of insulin.