bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundPreservation 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.MethodT2 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.ResultSites 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.ConclusionThis 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

AbstractBackgroundCGG 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).MethodHere, 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.ResultMacroscopically, 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.ConclusionWe 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

AbstractBackgroundA 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).MethodThe 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.ResultFrom 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.ConclusionUsing 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

AbstractBackgroundChanges 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.Method21 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.ResultOCT 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).ConclusionIn 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

AbstractBackgroundBehavioral 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.MethodThe 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).ResultMajority 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.ConclusionThese 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

AbstractBackgroundUnderstanding dementia patients as a source of social support for marginalized young adults.MethodThis is a qualitative research conducted via interviews and observations at Humanitas, a renowned care home in the Netherlands.ResultWhile 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.ConclusionThrough 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

AbstractBackgroundPrevious 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.Method36 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.ResultHigher 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.ConclusionThe 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

AbstractBackgroundThe 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.MethodsWe 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.ResultsMean 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).ConclusionThe 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

AbstractBackgroundWhile 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.MethodA 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.ResultsWe 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).ConclusionOur 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.