bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of preclinical dementia according to ATN classification for stratified trial recruitment: A machine learning approach
Authors: Koychev Ivan G , Marinov Evgeniy , Young Simon , Lazarova Sophia , Grigorova Denitsa , Palejev Dean 
Published: December 2022

AbstractBackgroundThere is a strong case for de‐risking neurodegenerative agent development through highly informative experimental medicine studies early in the disease process. These types of studies are dependent on a research infrastructure that includes volunteer registries holding highly granular phenotypic and genotypic data to allow stratified study selection. Examples of such registries include the Brain Health Registry, Great Minds and PROTECT cohorts which rely on remote cognitive, self‐reported medical history and genetic data. This requires the development of effective algorithms to predict the presence of preclinical dementia pathology. In this study we sought to address this need by building a machine learning (ML) ATN risk prediction algorithm which incorporates data typically collected in such registries.MethodsTo build a ML algorithm that is validated against an existing regression‐based model (Calvin et al. 2020), we used the EPAD LCS cohort (V1500.0). We excluded participants with 1) known diagnosis of dementia or Mild Cognitive Impairment or Clinical Dementia Rating scale ≥ 0.5 and 2) no cerebrospinal fluid biomarkers. Participants were categorised into 5 ATN categories: (i) Normal AD biomarkers: A−T−(N)−; (ii) Alzheimer’s pathologic change: A+T−(N)−; (iii) Alzheimer’s disease: A+T+(N)±; (iv)Alzheimer’s and concomitant non‐Alzheimer’s pathologic change: A+T−(N)+; (v)Non‐AD pathologic change: A−T ± (N)+; A−T+(N)−. Using a Weight of Evidence and Information Value method we identified 13 significant features for testing differences between each of the four neurodegeneration‐related groups vs. controls (A‐T‐N‐). Random Forest and XGBoost with 5‐fold cross validations were used to optimise the Area Under the Curve (AUC) metric.ResultThe study dataset included 927 individuals. Our optimal results outperformed the regression models in the Calvin et al. 2020 paper by between 2 and 12%. The optimal feature sets were not consistent across the 4 models with the A+T−(N)+ vs A−T−(N)− differing the most from the rest.ConclusionOur study demonstrates the gains offered by ML in generating ATN risk prediction over logistic regression models among pre‐dementia individuals. The reliance of the model on variables that can be collected remotely demonstrates its utility for research registers. An openly available version of the ML algorithm for use by research registries is under development.
The Brain Health Registry: Lessons learned and next steps for remote, online AD and aging clinical research
Authors: Weiner Mike W. , Truran‐Sacrey Diana , Flenniken Derek , Fockler Juliet , Camacho Monica R , Ashford Miriam T. , Howell Taylor , Kwang Winnie , Aaronson Anna , Eichenbaum Joseph , Nosheny Rachel L ,   The Brain Health Registry
Published: December 2022

AbstractBackgroundRemote, internet‐based methods for recruitment, screening, and longitudinally assessing older adults have the potential to greatly facilitate Alzheimer’s disease and related research, including clinical trials and observational studies.MethodsThe Brain Health Registry (BHR) is an online website and registry that includes a comprehensive battery of self‐ and study partner‐report questionnaires and online neuropsychological tests. Participants are asked to return at 6‐month intervals for longitudinal follow‐up. Recently, new online infrastructure for managing remote biomarker (saliva, blood) collection and for linking in‐clinic and online data were added. Multiple current initiatives aim to increase recruitment and engagement of underrepresented populations using digital, community engaged research strategies to improve generalizability of results. These include the recent launch of a Spanish‐language website, and projects focused on increasing enrollment and task completion of Black/African American and Hispanic/Latinx individuals.ResultsBHR includes >95,000 participants, >9000 of whom have enrolled study partners, 40% return for longitudinal follow up, 64% are age 55+, 80% are female, 80% identify as Non‐Latinx White, and 10% identify as Hispanic/Latinx. Participants have an average of 16.2 years of education. BHR has made >86,000 referrals to other studies, resulting in >5000 BHR participants enrolled in 25 different aging and AD observational studies and treatment trials. Over 2400 participants are co‐enrolled in BHR and collaborator studies, with online data linked to in‐clinic data. 573 participants have undergone APOE genotyping using remote saliva collection, and 629 have had blood collected using local phlebotomy for AD plasma biomarker analysis. Accumulating evidence supports the feasibility and validity of the approach, including associations with in‐clinic assessments, the ability to accurately detect MCI and enrichment for amyloid positivity.ConclusionsMajor advantages of the BHR approach are scalability and accessibility. Challenges include compliance, retention, and cohort diversity. Lessons learned from BHR, and components of the existing infrastructure, can be used to inform future remote clinical trial design. One such future effort is ADNI4. To facilitate enrollment of new participants, ADNI4 will establish an online recruitment and screening portal, with a remote phlebotomy component, to efficiently identify those from underrepresented populations, and those likely to have preclinical and prodromal AD.
Patient’s reaction to smartwatch based interventions in a controlled environment: preliminary results from the SAMi intervention study
Authors: Goerss Doreen , Köhler Stefanie , Rong Eleonora , Bieber Gerald , Teipel Stefan 
Published: December 2022

AbstractBackgroundAssistive technologies show promising features to support people with cognitive impairment in daily life, e.g. mobile sensors for falls detection or getting lost. On the other hand, smartwatches bear potential to not only monitor but also interact with the user. While sensor based monitoring in dementia care is already part of many projects, direct interaction of people with cognitive impairment with smartwatches is little investigated.MethodBased on qualitative studies, we designed interventions for a usual consumer smartwatch. We conceptualized two different tasks: A) drinking water and B) circling bells on a worksheet. Moreover, we implemented two different modes of intervention‐intensity affecting vibration patterns, alarm sounds, text sizes, display times or appearance of images and animations. We observed patients’ reactions to interventions A and B remotely via cameras. In case of failure, interventions were repeated up to three times. Here we present data of the interim analysis after completion of n = 20 patients that were equally assigned either to mode 1 (regular interventions) or mode 2 (intensive interventions). In addition to observations, participants feedback was obtained with questionnaires. Patients were diagnosed with MCI (n = 7) or dementia (n = 13) in the local memory clinic.ResultWe found it feasible to study patient‐smartwatch‐interactions with a mixed methods approach. The majority of participants (n = 18) were able to successfully complete at least one of two tasks, see Fig. 1. Circling bells (B) was completed only by 11 participants, while drinking water (A) was solved by 16 participants. The regular interventions were successful in 24%, the intensive interventions in 65%. Repetitions did not lead to an improvement of outcome in 13 cases, but in two cases. Reasons for insufficient task completion varied, e.g. patients showed unexpected reactions such as circling the picture on the smartwatch or doing arm circles. One patient fell asleep and did not react at all.ConclusionRemote observation of patients’ reaction to smartwatch based interventions is technically challenging but offers intriguing insights into human‐computer interaction. User‐centered design for patients with MCI or dementia differs from the approach for usual smartwatch users and needs to respect special needs and requirements.
The association between long‐term PM2.5 exposure and late‐life amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study cohort
Authors: Bennett Erin E , Xu Xiaohui , Lynch Katie M , Park Eun Sug , Ying Qi , Smith Richard L , Stewart James D , Whitsel Eric A , Mosley Thomas H , Yanosky Jeff D , Wong Dean F , Liao Duanping , Gottesman Rebecca F , Power Melinda C 
Published: December 2022

AbstractBackgroundA number of studies show an association between long‐term exposure to ambient particulate matter ≤ 2.5 um (PM2.5) and late‐life cognitive impairment. Mechanistic models suggest that PM2.5 may influence cognitive health through promotion of Alzheimer’s disease, which is characterized by brain amyloid accumulation. However, the association between long‐term PM2.5 exposure and brain amyloid deposition remains poorly characterized in epidemiological studies.MethodWe used data from the Atherosclerosis Risk in Communities (ARIC) study cohort. We used a chemical transport model with data fusion to estimate mean PM2.5 concentrations (ug/m3) in 36‐, 12‐, 4‐, and 1‐km grid cells in ARIC study areas. We linked the concentrations to geocoded participant addresses and calculated mean PM2.5 concentrations from 2000 to 2007. We estimated amyloid deposition using florbetapir amyloid positron emission tomography (PET) scans in 346 ARIC‐PET participants with normal cognition or mild cognitive impairment in 2011‐2014. We defined amyloid positivity as a global cortical standardized uptake value ratio (SUVR) ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and mean 2000‐2007 PM2.5 concentration after adjusting for potential confounders. We additionally explored effect measure modification by APOE e4 allele status and tested whether effect estimates were consistent using alternate PM2.5 exposure methods.ResultAfter restricting to participants with non‐missing exposure and confounder data and excluding one participant with dementia, the analytic sample included 279 participants. At the time of amyloid‐PET scans, their mean age was 78 years, 56% were female, 42% were Black, and 26% had mild cognitive impairment. After adjusting for age, sex, education, and race‐study center, we found no significant association between brain amyloid positivity and long‐term mean PM2.5 exposure. We also found no evidence of effect measure modification by APOE e4 allele status. Results were consistent when we used alternate PM2.5 estimation methods.ConclusionOur findings suggest that ambient PM2.5 may induce neurotoxic effects through non‐amyloid, potentially vascular pathways, though we note the small sample size may have made us underpowered to detect a significant association.
The Experiences of Son’s caring for a parent with Alzheimer’s Disease
Authors: DiLeone Christine , Maruca Annette T. 
Published: December 2022

AbstractBackgroundAmong primary caregivers (individuals who indicate having the most responsibility for helping their relatives) of people with dementia, over half take care of their parents. Most caregivers (66 percent) live with the care recipient in the community (Fisher, et al., 2011). The responsibilities of caring for someone with dementia often fall to women (Kasper et al., 2015). Men are underrepresented in the literature pertaining to family caregiving in dementia. Yet, they play an important role in providing care for cognitively impaired older adults in the community (Houde, 2001). While there is extensive literature on caregiving in dementia, only a few studies have emphasized the caregiving role of men (Coe & Neufeld, 1999; Kramer, 2000; Russell, 2007a, 2007b).MethodWe employed the meta‐ethnography methodology. Five electronic bibliographic databases were used to retrieve studies published from 1997‐2021 that explored son caregivers' experiences of caring for a parent with Alzheimer’s Disease. Five qualitative studies were finally included for the synthesis, based on the eligibility criteria.ResultCommon themes that emerged in the son’s experiences include a sense of loss, stress, and enduring the caregiving journey. Son’s caregiver roles included case manager, disease educator to in home paid help, and coping with sibling conflicts. Two studies showed positive outcomes.ConclusionThis review provides a deeper understanding of son’s caregivers' experiences of caring for a parent with Alzheimer’s Disease. The findings can help healthcare providers in the development and implementation of tailored interventions specific to son’s caregiver needs.
First results of the AMYPAD Prognostic and Natural History Study: amyloid‐PET centiloids predicts cognitive functioning in a pre‐dementia population
Authors: García David Vállez , Collij Lyduine E. , Mastenbroek Sophie E , Alves Isadora Lopes , Gispert Juan Domingo , Ritchie Craig W. , Boada Mercè , Marquié Marta , Grau‐Rivera Oriol , Fauria Karine , Scheltens Philip , Vandenberghe Rik , Hanseeuw Bernard J , Schöll Michael , Frisoni Giovanni B , Boecker Henning , Jessen Frank , Wolz Robin , Grootoonk Sylke , Stephens Andrew W , Buckley Christopher , Ford Lisa , Visser Pieter Jelle , Farrar Gill , Barkhof Frederik 
Published: December 2022

AbstractBackgroundThe AMYPAD Prognostic and Natural History Study aims to evaluate the value of (semi‐)quantitative amyloid PET imaging for predicting progression within an Alzheimer’s disease risk probability spectrum. The project is actively recruiting non‐demented participants from 17 sites across Europe, with a particular interest in those with emerging amyloid pathology.MethodAs of 17th January 2022, a total of 1,460 participants had been included. Of those, clinical data of 1,015 were processed, with 688 (68%) having at least a quantified amyloid PET at baseline, with [18F]flutemetamol or [18F]florbetaben. The primary metric used to assess amyloid burden was the Centiloid (CL), measured from the ratio of the GAAIN cortical target and whole cerebellum. Scans were categorized as negative (CL≤12), gray‐zone (12<CL≤50), or positive (CL>50). The distribution of these groups was assessed using a Gaussian mixture model. Independent linear mixed‐effect models were used to explore the predictive value of CL, and its interaction with time, for several cognitive outcomes: mini‐mental state examination (MMSE), memory (immediate recall, IR), attention (digit‐span forward, DSF), language, visuospatial, and executive functions. In addition, years from baseline, parent cohort, age, sex, education, APOE‐ε4, and the Clinical Dementia Rating (CDR) score were used as independent variables.ResultDemographics are shown in Table 1. At baseline, 88% of the subjects were classified as cognitively unimpaired (CDR=0). A majority of 384 (56%) was categorized as negative (1±7CL), 210 (30%) as grey‐zone (14±11CL), and 94 (14%) as positive (58±31CL) [Figure 1]. Baseline CL (‐0.007 [‐0.010; ‐0.004]) and its interaction with time (‐0.002 [‐0.003; ‐0.001]) were predictive of IR. Baseline CL, but not its interaction with time, predicted MMSE (‐0.007, 95%CI [‐0.010; ‐0.003]) and DSF (‐0.003 [‐0.005; ‐0.001]) [Figure 2]. No significant relationships were observed for executive, language, or visuospatial function.ConclusionHigher baseline CL were associated with lower global cognitive function and attention scores. Whereas, higher CL were associated with a steeper memory decline over time.Current results suggest that cerebral amyloid accumulation is predictive of future overall cognitive function, attention, and memory decline. Further analysis is assured, including more participants, longitudinal PET outcomes, and other biomarkers of the disease.
What subtypes are driving the association between hypertensive disorders of pregnancy and dementia? Findings from an 80‐year retrospective cohort study
Authors: Schliep Karen Cecilia , Shaaban C. Elizabeth , Baradaran Hediyeh , Fraser Alison , Meeks Huong , Varner Michael 
Published: December 2022

AbstractBackgroundWe recently found that women with, versus without, a history of HDP had a higher hazard of all‐cause dementia, vascular dementia (VaD), and other/unspecified dementia, but not Alzheimer’s disease (AD). Here, we assess associations of HDP subtypes with later life dementias.MethodsWe performed a retrospective cohort study among women with at least 1 singleton pregnancy (1939–2019) in Utah. Classification of HDP was done via birth certificates (text string, 1939–1977; ICD9 codes, 1978–1988; and check boxes with additional text, 1989–2013) with death certificates and inpatient records used for validation. Classification of dementia was assessed using ICD 9/10 codes via death, inpatient, and Medicare records. HDP exposed women (n=19,989) were one‐to‐two matched with unexposed women (n=39,679) by 5‐year age groups, year of childbirth, and parity at the time of pregnancy (Figure 1). Cox regression models were used to estimate adjusted Hazard Ratios (aHR) and 95% CI for HDP subtypes with all‐cause and specific dementias.ResultsHDP pregnancies were comprised of preeclampsia/eclampsia (65.9%) and gestational hypertension (33.5%). The remaining HDP cases were due to HELLP syndrome (0.6%), which we did not evaluate here due to small case count. Incidence of dementia over follow‐up (1979–2019) was 4.1%; of these, 70% were other/unspecified, 24% were AD, and 6% were VaD. Women with a history of preeclampsia/eclampsia, compared to unexposed, had a 1.38 higher hazard of all‐cause dementia, while women with gestational hypertension had a 1.36 higher hazard (Table 1). Breaking down by dementia subtypes, women with a history of preeclampsia/eclampsia had a 1.51 higher hazard of other/unspecified dementia, while women with gestational hypertension had a 1.31 higher hazard. The strength of association of gestational hypertension with VaD was 2.75, nearly double that for preeclampsia/eclampsia, which was 1.58. HDP subtypes were not associated with AD.ConclusionOur results are in line with the largest study to date conducted in Denmark that found preeclampsia to be most strongly associated with VaD compared to other dementia subtypes. Our results further suggest that risk of VaD may be just as high for women with a history of gestational hypertension as for preeclampsia.
Targeted Musashi1 knockdown leads to reduce tau pathology and improves cognitive function in aged P301L mouse model
Authors: Montalbano Mauro , Fung Leiana , Bhatt Nemil , Gaikwad Sagar , Bittar Alice , Puangmalai Nicha , Sengupta Urmi , Kayed Rakez 
Published: December 2022

AbstractBackgroundThe buildup of toxic tau species in the brain is thought to lead to the development of Alzheimer’s disease. While our current understanding of the mechanisms underlying this aggregation is limited, growing evidence has pointed to RNA‐binding proteins (RBPs) playing a role. The dysregulation of RBPs is associated with various neurodegenerative diseases. For example, during amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD), dysregulated TDP‐43 accumulates in the brain. Similarly, our recent studies showed that the RBP, Musashi‐1 (MSI1), may co‐aggregate with toxic tau oligomers in Alzheimer’s disease. Clarifying the connection between these two proteins may provide novel insights into the mechanisms behind toxic tau buildup in Alzheimer’s, allowing for new therapeutic targets in treatment development.MethodIn this study, we investigated the role of MSI1 on the aggregation and deposition of tau in aged (18‐months old) P301L mouse models, which express the P301L mutant form of tau. MSI1 expression was knocked down (KD) by performing intracerebroventricular injections of MSI1 antisense oligonucleotides into the hippocampus. The effects of MSI1 KD on tau accumulation and pathology were studied in the hippocampus, cortex, and cerebellum.ResultWestern blot and immunofluorescence (IF) analysis revealed a significant reduction in MSI1 and tau proteins levels and aggregation in the P301L mouse brain, mainly in the hippocampus. Furthermore, brain Co‐IF microscopy and Dot Blot analysis of the PBS‐ and Sarkosyl‐soluble fractions showed that there was a significant reduction of MSI1 and tau oligomeric species in the hippocampus, cortex, and cerebellum in MSI1 KD mice. In addition, phosphorylated tau forms (pSer422, pSer202/Thr205, pThr212/Ser214 and pThr231/Ser235) were significantly decreased in the cortex, cerebellum, and most prominently, in the hippocampus. Increase in synaptic marker Synaptophysin suggesting an increase of synaptogenesis. Behavioral tests, Novel Object Recognition (NOR) and Y‐Maze spontaneous alternations tests, MSI1‐KD mice showed significant improvements.ConclusionThese results suggest that MSI1 plays a major role in tau toxicity, revealing it as a possible target for treating Alzheimer’s disease.
Determining the amyloid PET and CSF inclusion criteria for the SKYLINE secondary prevention study with gantenerumab
Authors: Schiffman Courtney , Bittner Tobias , Giacobino Caroline , Hansson Oskar , Stomrud Erik , Rowe Christopher , Sperling Reisa A. , Delmar Paul , Fontoura Paulo , Ostrowitzki Susanne , Doody Rachelle S. 
Published: December 2022

AbstractBackgroundSKYLINE is a secondary prevention study in Alzheimer's disease (AD) enrolling amyloid‐positive, cognitively normal (CN) individuals at risk for clinical AD between 60–80 years and treating them with gantenerumab or placebo for 4 years. There is no gold standard for determining amyloid positivity for this purpose. Thresholds for amyloid positivity used in trials in symptomatic AD may be suboptimal in a secondary prevention setting, where amyloid positivity prevalence is lower. We compared various amyloid‐positive definitions in a CN elderly population based on how well they enrich for clinical progression over 4 years and operational feasibility.MethodFour cohorts (ADNI, BioFINDER‐1, AIBL, and HABS) were used to explore the relationship between amyloid PET visual read, centiloid values and CSF pTau/Abeta42 values in a CN population. For amyloid PET, we compared visual read with centiloid thresholds by evaluating the amyloid positivity prevalence, magnitude and variability of endpoint progression, and positive and negative predictive value (PPV and NPV). Operational advantages of CSF motivated a comparison of elevated CSF pTau/Abeta42 thresholds with amyloid PET. We interrogated which CSF thresholds were robust to preanalytical differences, had a high PPV and NPV compared with amyloid PET, and resulted in an acceptable degree of cognitive decline and variability.ResultHigher centiloid thresholds (≥40 CL) showed good agreement with visual read, but visual read resulted in a lower coefficient of variation (CV) for change from baseline in PACC5, the primary endpoint in SKYLINE (CV=118–210 vs. CV=150–336). An elevated CSF pTau/Abeta42 threshold resulted in a similar amyloid positivity prevalence to amyloid PET (14–17% vs. 10–20%), had acceptable NPV (95–97%), PPV (69–87%), sensitivity (71–82%), and specificity (95–98%) for visual read, and resulted in a similar CV for change from baseline in PACC5.ConclusionThere is no gold standard for determining the optimal amyloid positivity threshold in a secondary prevention trial. Determining patients to be amyloid‐positive if they are amyloid PET visual read‐positive or have elevated CSF pTau/Abeta42 offers not only operational advantages but also likely results in a trial population that has an acceptable level of endpoint progression and variability over the trial duration.