bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing everyday functioning using a novel smartphone app in cognitively normal adults: A pilot study of the Assessment of Smartphone Everyday Tasks (ASSET)
Authors: Dubbelman Mark A. , Hall Tia C. , Levesque Isabella M. , Mimmack Kayden J. , Sikkes Sietske A.M. , Fischer Shira H. , Tatar Daniel , Rentz Dorene M. , Sperling Reisa A. , Papp Kathryn V. , Amariglio Rebecca E. , Marshall Gad A 
Published: December 2022

AbstractBackgroundCognitively complex everyday tasks may be affected in early stages of Alzheimer’s disease. Performance‐based digital assessments could facilitate more precise measurement of subtle changes in everyday functioning. We piloted a novel smartphone app ‘Assessment of Smartphone Everyday Tasks’ (ASSET), to investigate its utility for measuring everyday functioning in cognitively normal older adults. ASSET consists of Patient Portal and Calendar tasks for renewing prescriptions, making payments, and scheduling urgent and recurring appointments (Figure1). It tracks response time and accuracy.MethodASSET was piloted in 34 participants (n = 20 cognitively normal young adults (YN): 21.3±2.6 years, 85%female, median 14.5 years of education; n = 14 cognitively normal older adults (ON), 75.1±4.8 years, 71%female, median 18 years of education). At baseline, participants completed the first version of ASSET and the Preclinical Alzheimer’s Cognitive Composite (PACC5) in the research clinic. ON participants and their study partners completed the Alzheimer’s Disease Cooperative Study Activities of Daily Living – Prevention Instrument (ADCS ADL‐PI). We calculated accuracy rates (correct responses/task duration) for both tasks and computed Pearson’s r correlation coefficients between subtasks (internal consistency) and with PACC5 and ADCS ADL‐PI (construct validity). To investigate test‐retest reliability, participants subsequently completed the first and five alternate versions of ASSET remotely on a fixed, biweekly schedule.ResultAt baseline, the Patient Portal and Calendar tasks were highly correlated (r = 0.78, 95% confidence interval (95%CI) = [0.60,0.89]). YN performed better on both tasks than ON, completing them faster and making fewer errors (Patient Portal: Cohen’s d = ‐3.0, 95%CI = [‐4.2, ‐1.8]; Calendar: d = ‐1.6, 95%CI = [‐2.4, ‐0.7]). Performance was moderately correlated with PACC5 (Patient Portal: r = 0.59, 95%CI = [0.49,0.67]; Calendar: r = 0.48, 95%CI = [0.37,0.58]). Among ON, performance on ASSET was not significantly correlated with either self‐ or study partner‐reported ADCS ADL‐PI. Over repeated assessments, Patient Portal accuracy increased, while Calendar accuracy increased but dropped at the last assessment among all participants (see Figure2).ConclusionInitial results show that ASSET may have good internal consistency and good ability to distinguish young from older cognitively normal adults. Future research should aim to corroborate current findings and extend with Alzheimer’s disease biomarkers to better understand the value of ASSET in detecting early changes in everyday functioning.
Comparison of midlife offspring cohorts based on family history of Alzheimer’s Disease: multi‐domain risk factors and cognitive function
Authors: Zhang Xuan , Mbangdadji Djass , Li Zhiguang , Sigurdsson Sigurdur , Gudnason Vilmundur , Meirelles Osorio , Launer Lenore J. 
Published: December 2022

AbstractBackgroundMaintaining healthy clinical indicators and behavior is positively related to cognitive protection from midlife. However, limited population‐based studies have explored the role of family history on these factors in midlife. Therefore, we examined cognitive‐related risk factors in two midlife cohorts from the same source population in the Age, Gene/Environment Susceptibility‐Reykjavik Study.MethodWe included 446 offspring (aged 61, 49% women) from the random sample (RS) without Alzheimer’s Disease (AD) and 499 offspring (aged 63, 49% women) to AD cases at baseline and during follow up from the main study. Accordingly, we labeled the offspring with and without AD family history as offspring AD and offspring RS, respectively. Clinical factors included BMI, systolic (SBP) and diastolic blood pressure (DBP), cholesterol, fasting glucose, inflammatory factors, and medication. Socio‐behavioral factors included education, smoking, problems of doing usual activities. Cognitive function was evaluated by MMSE and STROOP. To address the potential correlation between siblings within one family, we compared these characteristics with the random effects intercept mixed model by family ID. We also did a sensitivity analysis by comparing people under age 65 to assess reverse causation for specific traits. All models were adjusted for age and sex. Fasting glucose, triglycerides, and inflammatory factors were log‐transformed due to skewness. We consider p<0.05 as statistically significant.ResultAs shown in the table, socio‐behavioral factors, cognitive function, or most clinical characteristics did not differ in the two groups. The Offspring AD had 2.71‐unit lower SBP and 0.03‐unit higher log(glucose) (3% increased glucose) than the RS (p<0.05). The sensitivity analysis among people under age 65 showed a similar pattern, except for the insignificant difference in fasting glucose between offspring AD and RS.ConclusionIn general, there was no difference in AD‐related health profile among midlife offspring with and without AD family history. This analysis of standard cardiovascular and cognitive impairment‐related risk factors suggests that these variables alone will not help identify at‐risk individuals for later‐life cognitive impairment.
The Care Ecosystem: The Effectiveness and Implementation of Telephone‐Based Collaborative Dementia Care
Authors: Possin Katherine L , Sideman Alissa Bernstein , Dulaney Sarah , Lee Kirby , Merrilees Jennifer , Bonasera Steve , Chiong Winston , Hooper Sarah M , Kiekhofer Rachel , Robinson‐Teran Joanne , Allen Isabel Elaine , Braley Tamara , Guterman Elan , Rosa Talita D , Harrison Krista L , Hunt Lauren , Kahn James G , Lanata Serggio , Miller Bruce L. , LaRoche Ashley , Sawyer Robert John , Brungardt Adreanne , Lum Hillary , Hess Mailee , Ward Katie , Kuebrich Mary Beth , Hodges Marian , Olney Nicholas , Barclay Michelle , Rosenbloom Michael H 
Published: December 2022

AbstractBackgroundHealth systems are increasingly interested in collaborative dementia care. Implementation challenges include the limited dementia specialist workforce, time pressures of high‐volume care, increasing use of telemedicine, and inadequate reimbursement. The Care Ecosystem is a telephone‐based collaborative dementia care model designed to augment existing healthcare services and be amenable to scale. Here we present the latest evidence for the Care Ecosystem, including the effects among subpopulations at risk for health disparities (rural and Hispanic/Latino), and facilitators from the early phase of Care Ecosystem implementation at 6 diverse health systems.MethodEffectiveness was evaluated in a single‐blind, randomized clinical trial (N = 804). Persons with dementia (PWD)‐caregiver dyads were randomized to receive 12 months of the intervention (N = 527) or usual care (N = 277). Outcomes were measured via telephone surveys at 6 and 12 months after randomization and medical record review. Subgroup analyses were performed for the 124 dyads who identified as Hispanic/Latino, and the 66 who lived in rural Nebraska or Iowa. The intervention was primarily delivered by an unlicensed, trained care team navigator, who provided education, support and care coordination with supervision and help from a dementia specialist team (advanced practice nurse, social worker, and pharmacist). Implementation facilitators were evaluated through observation and qualitative interviews with clinical teams at 6 health systems implementing the model.ResultsThe PWD‐caregiver dyads lived in California (n = 476), Nebraska (n = 286), or Iowa (n = 42). Compared with usual care, the Care Ecosystem improved PWD quality of life, reduced emergency department visits, reduced the use of potentially inappropriate medications, and decreased caregiver depression and caregiver burden. Effect sizes were similar or greater in Hispanic/Latino and rural subgroups on most outcomes. Facilitators of Care Ecosystem implementation included open‐access implementation tools (online training, care protocols), the adaptability of the care model, the care team navigator role, and remote care delivery.ConclusionEffective dementia care can be delivered by care team navigators via telephone to mitigate the burdens of dementia, including for underserved PWD living in rural areas or who identify as Hispanic/Latino. Implementation is a challenge although features of the care model appear to facilitate adoption.
Pleiotropic effect of LRRK2 on Parkinson‐associated proteins and processing of pathological alpha‐synuclein in myeloid cells
Authors: Nykanen Niko‐Petteri , Yang Chengran , Harari Oscar , Davis Albert A , Cruchaga Carlos , Benitez Bruno A. 
Published: December 2022

AbstractBackgroundMutations in the LRRK2 gene, which encodes leucine‐rich repeat kinase 2 (LRRK2), are a cause of autosomal dominant Parkinson’s disease (PD). Single‐nucleotide polymorphisms (SNP) in the LRRK2 locus are one of the most consistently replicated in multiple genome‐wide association studies in sporadic PD and with inflammatory diseases. We recently found that a PD‐associated risk SNP (rs76904798, p = 2.0×10−28) in the LRRK2 locus is also associated with cerebrospinal fluid (CSF) levels of granulins (PGRN, p = 8.6×10−9), glycoprotein nmb (GPNMB, p = 2.3×10−9), Ectonucleoside triphosphate diphosphohydrolase‐1 (ENTPD1, p = 2.3×10−9) also known as CD39 and Cathepsin B (CTSB, p = 2.5×10−4). Yet, functional validation in cellular models is lacking.MethodsHuman monocytic cells (U937) were differentiated (dU937) into macrophages to test the effect of LRRK2 on CTSB, CD39, GPNMB, PGRN and alpha‐synuclein (aSyn). LRRK2 kinase activity and expression level were modulated using pharmacological inhibitors and lentivirus‐mediated overexpression. Protein levels were assessed using western blotting and ELISA. dU937 cells were treated with human aSyn pre‐formed fibrils (haSyn PFFs). We analyzed CSF somaLogic data from the Parkinson’s Progression Marker’s Initiative (PPMI) cohort (Data accessed November 2021).Results
LRRK2 mutation (G2019S and R1441G) carriers from the PPMI cohort exhibit significantly increased CSF levels of PGRN (p = 2.1×10−22), GPNMB (p = 1.6×10−29), CTSB (p = 2.5×10−16) and CD39 (p = 1.8×10−18) compared to age and gender‐matched non‐carriers (N = 1158). dU937 cells overexpressing LRRK2 showed an increase in the phosphorylation of LRRK2‐Ser935 and Rab10‐T73 and intracellular levels of lysosomal proteins CTSB and Saposin D without affecting LAMP1 or M6PR. LRRK2 also reduced extracellular CD39, PGRN and GPNMB levels and the levels of intracellular endogenous aSyn dimers in dU937 cells. HaSyn PFF treatment induced a time‐dependent reduction of CTSB and GPNMB levels, increased PGRN levels and altered intracellular aSyn processing pattern in dU937 cells overexpressing LRRK2. Pharmacological LRRK2 kinase inhibition decreased intracellular CTSB levels. LRRK2 co‐immunoprecipitates with PGRN in cells and in human brain.ConclusionsLRRK2 modifies lysosome‐associated proteins and regulate aSyn proteostasis. Pathogenic LRRK2 mutations increased CSF levels of PGRN, GPNMB, CTSB and CD39 in the PPMI cohort. Our in vivo and in vitro data supports a pleotropic role of the LRRK2 locus as a genetic modifier of PD‐associated proteins.
Lipid oxidation as a marker of apathy and executive dysfunction in patients at risk of vascular cognitive impairment
Authors: Bawa Kritleen Kaur , Ba Joycelyn , Kiss Alex , Wang RuoDing , Feng Vivian , Swardfager Walter , Andreazza Ana C. , Gallagher Damien , Marotta Giovanni , Herrmann Nathan , Lanctôt Krista L. 
Published: December 2022

AbstractBackgroundApathy and executive function decline are hallmarks of vascular dysfunction in neurodegeneration and cognitive impairment. People with mild vascular cognitive impairment (mVCI) display a combined etiology of both cognitive impairment and vascular comorbidities; hence, patients with vascular risk factors are at risk for mVCI. The co‐occurrence of apathy and executive dysfunction is prevalent; however, the physiological pathway underlying these manifestations is yet to be investigated. Oxidative stress is often present in vascular dysfunction. This study investigated the relationship between oxidative stress, specifically markers of lipid oxidation, apathy, and executive dysfunction in patients at risk of mVCI.MethodPatients at risk of mVCI were recruited from a population of patients with coronary artery disease in a Cardiac Rehabilitation Program. Apathy was assessed using the Apathy Evaluation Scale and executive function with Trial Making Test B, phonemic fluency test and animal naming test. Fasting blood was collected and serum concentrations of early and late lipid oxidation markers, lipid hydroperoxides (LPH) and 8‐isoprostane (8‐ISO) respectively, were measured.ResultParticipants (n=206, Age= 63.0±7.5, 80% men, total years of education= 15.9±3.4, AES score= 28.3±8.8, composite z score for EF= 0±1) demonstrated significantly different ratios of late to early lipid oxidation markers (8‐ISO/LPH) between groups (F(3, 202) = 10.915, p <0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction, only apathy, and both apathy and executive dysfunction. A multivariate linear regression model adjusting for demographics found that lipid oxidation was significantly associated with apathy (B= 4.63, p < 0.001) and executive function (B= ‐0.19, p= 0.018); however, when controlling for both demographics and vascular risk factors, lipid oxidation was significantly associated with apathy alone (B= 3.11, p= 0.002).ConclusionThe results highlight an important involvement of lipid oxidation in the co‐occurrence of apathy and executive dysfunction in patients at risk of mVCI. Our results show that increased oxidative stress may contribute to the development of apathy, which may relate to why apathy is a strong risk factor for progression to dementia in at‐risk populations.
Variability of response to exercise‐primed tDCS in those with mild cognitive impairment and Alzheimer’s disease (the EXPRESS study): a preliminary analysis
Authors: Koo Grace KY , Herrmann Nathan , Gallagher Damien , Rapoport Mark J. , Charles Jocelyn , Papneja Purti , Rajji Tarek K. , Andreazza Ana C. , Oh Paul I. , Marzolini Susan , Kiss Alex , Swardfager Walter , Vieira Danielle , Song Bing Xin , Rivet Luc , Lanctôt Krista L. 
Published: December 2022

AbstractBackgroundStudies investigating the use of transcranial direct current stimulation (tDCS) to improve outcomes in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) have reported mixed findings. Such variability may be explained by inter‐individual differences such as demographics or disease pathology. Given the increased prevalence of cardiovascular risk factors with aging and the potential changes in neurobiology of those exhibiting additional vascular etiology, we evaluate the influence of etiology on tDCS outcomes in patients with mild AD or MCI.MethodParticipants were diagnosed with mild or major neurocognitive disorder due to AD or mixed AD/vascular disease according to The Diagnostic and Statistical Manual of Mental Disorders (DSM–5) criteria. Participants completed a 2‐week, blinded, randomized trial examining the effects of exercise primed tDCS where they were randomized to receive either exercise with tDCS, exercise with sham tDCS, or tDCS only. Cognitive tests assessing episodic memory (ADAS‐Cog Word Recognition and Word Recall Tasks) and working memory (N‐Back) were administered before and after intervention. Independent t‐tests were used to assess for differences in demographics between groups, and paired t‐tests were used to evaluate the influence of etiology on tDCS outcomes.ResultOf the 28 participants (17 males [58.6%], mean [±SD] age 74.8±8.9 years, education 16.3±2.2 years) included, 17 participants had mixed vascular/AD etiology and 11 participants had AD (without vascular) etiology. Both groups did not differ significant in demographics. Participants with mixed vascular/AD etiology showed significant improvement in episodic memory (Word Recognition 1.71±2.97, t(16) = 2.365, p = 0.031; Word Recall 0.65±1.12, t(16) = 2.257, p = 0.038), while those without vascular etiology did not (Word Recognition 0.36±2.80, t(10) = 0.43, p = 0.676; Word Recall ‐0.09±0.63, t(10) = ‐0.472, p = 0.647). No significant improvement in working memory in either group was observed.ConclusionFactors such as etiology should be taken into consideration when considering the efficacy of tDCS on improving cognition in patients diagnosed with AD/MCI. Further analyses upon unblinding will confirm whether patients with mixed AD/vascular etiology respond differently to tDCS.
Antidepressant use in relation to long‐term dementia risk and imaging markers of neurodegeneration: a population‐based study of potential adverse effects
Authors: vom Hofe Ilse E. M. , Stricker Bruno , Vernooij Meike W. , Ikram M. Arfan , Wolters Frank J. 
Published: December 2022

AbstractBackgroundIn Europe, one in five adults uses antidepressants, with an increase in prescriptions of 20% per year. It has been suggested that antidepressant use might ultimately lead to adverse cognitive outcomes due to their anticholinergic properties. However, this impact remains largely undetermined, as randomised trials have limited follow‐up duration. We aimed to determine the association between antidepressant use and the long‐term risk of dementia in a population‐setting. In addition, we assessed the effect of antidepressant use on change in brain volume as measured with MRI.MethodBetween 2005‐2008, we included 5551 cognitively healthy participants of the population‐based Rotterdam Study (57.6% women, mean age 70.5 years). Detailed information on type of antidepressant (ATC‐coded), number of prescriptions, days of use and daily dose was extracted from pharmacy dispensing records from 1991 until baseline. Participants underwent neuropsychological testing and brain MRI every 2‐4 years. We determined the association of antidepressant use with incident dementia until 2018 using a Cox model, and with change in cognitive performance and brain MRI measures using linear mixed‐effects modelling. Models were adjusted for demographics, lifestyle variables, comorbidity and comedication. Furthermore, we explored the effect of slowed metabolization of antidepressants based on CYP2D6 genotype.ResultDuring a mean follow‐up of 10.2 years, 640 participants developed dementia. Antidepressant use was not associated with risk of all‐cause dementia (hazard ratio (HR) [95% confidence interval (CI)]: 0.87 [0.70;1.08]). This was similar for tricyclic antidepressants and serotonin‐reuptake inhibitors, and regardless of dose and duration. Antidepressant use was not associated with decline in general cognition (mean difference [95% CI] per standard deviation: 0.01 [0.00;0.01], nor with change in brain volume (mean difference [95% CI] per mm3; total volume: 15.19 [‐210.22;240.60], grey matter: ‐52.23 [‐179.45;74.99], white matter: 71.49 [‐93.03;236.01], hippocampus: ‐3.70 [‐8.18;0.78], amygdala: ‐0.60 [‐3.49;2.30], thalamus: 0.87 [‐6.14;7.88]). Similarly, among antidepressant users only, CYP2D6 genotype was not related to dementia risk (HR [95% CI] for amitriptyline users: 0.88 [0.76;1.02], paroxetine users: 0.83 [0.67;1.02]).ConclusionIn this population‐based study, antidepressant use was not associated with long‐term adverse effects on cognition or subclinical brain injury. These results are reassuring regarding safe prescription of antidepressive medication with respect to cognitive decline.
Diverse representation in Frontotemporal Dementia research studies: implications for clinical trials.
Authors: Piña‐Escudero Stefanie Danielle , Franco Teresita Ramos , Slachevsky Andrea , Yokoyama Jennifer S. 
Published: December 2022

AbstractBackgroundThe Multi‐Partner Consortium to Expand Dementia Research in Latin America (RedLat) study is a niche for the implementation of clinical trials on Frontotemporal Dementia in Latin America. We identified that one of the main limitations of recruitment was a lack of clinicians with comprehensive knowledge on Frontotemporal Dementia in the region. We aimed to fill these gaps by creating an online training for physicians.MethodA group of American and Latin American brain health experts trained at the Global Brain Health Institute at the University of San Francisco California is delivering an abridged online behavioral neurology training project to a pilot group of 30 neurologists, geriatricians, and psychiatrists from Latin America. The training highlights important aspects such as culturally appropriate neuropsychological assessment and functional assessment to adequately classify participants under the frontotemporal dementia umbrella. A component about the importance of research including clinical trials is also being delivered. Baseline evaluations about the quality of their medical training regarding dementia and a dementia knowledge evaluation were conducted and we are expecting to conduct an evaluation in the third and sixth months.ResultOn the baseline evaluation, 80% classified the information they received as “poor”, 12% classified the information as “sufficient” and 8% classified it as “good”. Regarding baseline dementia knowledge, the mean score was 5.2 (SD ± 2.5) out of a maximum score of 10 points. We expect an increase in these numbers during the upcoming evaluations. As a side outcome, participants from this project are building pipelines to increase recruitment in RedLat.ConclusionOvercoming existing educational barriers of diagnosis of Frontotemporal Dementia as well as generating awareness of the importance of clinical trials in Latin America will hopefully be a key tool to increase the representation of persons with Frontotemporal Dementia. We will discuss the importance of adequate diagnosis and classification of frontotemporal dementia by the professionals who serve these underrepresented populations and the importance that this first step has to adequate recruitment into clinical trials.