bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence, clinical characteristics, and association between chronic obstructive lung disease (COPD) and cognitive status in a cohort of elderly adults
Authors: Choate Radmila , Jicha Gregory A , Abner Erin L 
Published: December 2022

AbstractBackgroundThe burden of age‐related conditions, like COPD and dementia, including Alzheimer’s disease, has been increasing. COPD prevalence is highest in women aged 65‐74 (10.4%) and in men aged 75‐84 (11.2%). We hypothesized that COPD, which may lead to chronic brain hypoxia, could increase the risk for late‐life dementia. By examining the association between COPD and cognitive status, we sought to better understand potential shared risk factors associated with these highly prevalent conditions.MethodThis study examined data from the University of Kentucky Alzheimer’s Disease Research Center (UK‐ADRC) cohort, a convenience sample of community‐based older adults followed longitudinally until death and subsequent brain autopsy. Individuals with available history of COPD were included in the study. Demographics and clinical characteristics of the cohort were assessed at the last available follow‐up visit. Descriptive and comparative statistical analyses were performed for participants with and without COPD.ResultOverall, 692 individuals were included (8.5% with COPD, mean age 77.5±7.9 years, 62.9% female, 84.3% white). The majority of those with COPD (67.8%) vs. 36.0% of those without COPD had a history of smoking (mean duration 31±15.8 vs. 21.1±14.6 years, respectively). Individuals without COPD (n = 633) did not differ demographically from those with COPD (Table 1). Hypertension and diabetes were more common in the participants with COPD compared to those without COPD (73.7% vs. 64.2%, and 20.7% vs. 15.5%, respectively). At least one APOE ε4 allele was found in 32.0% of individuals with a history of COPD and 38.7% of those without COPD. At the last available follow‐up visit, the prevalence of dementia and MCI were similar in the participants with COPD compared to those without COPD (17.0% % vs. 16.3% %, and 25.4% vs. 23.1%, respectively).ConclusionWe found no association between the history of COPD and impaired cognitive status in this cohort. COPD may be underdiagnosed and underreported in this group of older individuals, given its lower prevalence than expected in this age group. Further research relying on more objective pulmonary function data and longitudinal studies are needed to fully understand the potential associations of COPD with risk for impaired cognitive status in this population.
Development and Validation of a clinical scale for defining RBD severity in participants of the North American Prodromal Synucleinopathy (NAPS) consortium
Authors: Choudhury Parichita , Busicescu Andrea , Lee‐Iannotti Joyce , Rangan Pooja , Shprecher David , Ju Yo‐El , Boeve Bradley F. , Postuma Ronald B ,   North American Prodromal Synucleinopathy (NAPS) Consortium
Published: December 2022

AbstractBackgroundREM Sleep Behavior Disorder (RBD) is a prodromal marker of α‐synucleinopathies with no standardized tool for assessing severity in clinical or research practice. RBD severity may have implications in measuring risk of phenoconversion, monitoring response to treatment and clinical trial design. This study assessed the validity of the RBD symptom severity scale (RBDSSS) and its correlation to the clinical global impression of severity (CGI‐S) in a cohort of participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium.MethodParticipants and their bedpartners enrolled in the NAPS cohort filled out an 8‐item questionnaire, developed by the International RBD Study Group, assessing frequency and severity of dreams, vocalizations, movements, and injuries associated with RBD, with higher scores indicating more severe symptoms. The CGI‐S is a 7‐point scale ranging from normal (1) to most severely ill (7) and was completed by a clinician based on an independent interview with the participant ± their bedpartners. Total scores for participant (RBDSSS‐PT) and bed partner (RBDSSS‐BP) questionnaires were derived by multiplying frequency and severity scores for each feature, then summing the products for possible maximum scores of 54 and 38 respectively.ResultThis cohort (n = 212) was predominantly male (82.5%) with a mean ± SE age of 65.16 ± 1.46 years. The median (interquartile range) for RBDSSS‐PT, RBDSSS‐BP and CGI‐S was 11 (4‐17), 8 (4‐14.3) and 3 (3‐4), respectively. Spearman’s rank correlation coefficients (rs) were as follows: RBDSSS‐PT vs. RBDSSS‐BP, rs = 0.579; RBDSSS‐PT vs. CGI‐S, rs = 0.642; RBDSSS‐BP vs. CGI‐S, rs = 0.487 (all P<0.0001). RBDSSS‐BP scores were significantly lower in women (6 vs. 9, Chi‐Square p = 0.009) while there were no differences in RBDSSS‐PT scores by sex. (9 vs. 11, p = 0.473).ConclusionA moderate correlation was observed between RBDSSS‐PT and RBDSSS‐BP suggesting good construct validity for the scale. CGI‐S correlated most with RBDSSS‐PT and had a weaker association with RBDSSS‐BP. Women had lower severity scores as reported by bed partners unlike their self‐reported scores, indicating possible sex differences in perceived RBD severity.
Mechanism of gamma‐secretase modulators
Authors: Luo Joanna E. , Wagner Steven L , Li Yueming 
Published: December 2022

AbstractBackgroundAmyloid‐beta (Aβ) peptides are believed to be integral to Alzheimer’s disease (AD) pathogenesis through their role in the “amyloid hypothesis,” in which the accumulation of Aβ peptides initiates a cascade of pathological events leading to neurodegeneration and AD. γ‐Secretase is a transmembrane aspartyl protease which cleaves APP to generate Aβ peptides, making γ‐secretase an attractive drug target. However, inhibitors failed in clinical trials due to their unwanted side effects on other γ‐secretase substrates such as Notch. ɣ‐Secretase modulators (GSMs) selectively reduce levels of the pathogenic Aβ species without affecting Notch and overall APP processing. However, many questions on their mechanism still remain. Here we investigate the molecular mechanism of GSMs by (1) investigating the binding site of imidazole GSM E2012 using photoaffinity labeling and molecular docking and (2) investigating combination therapy with different GSMs on reducing Aβ production.MethodPart I: We incubated clickable GSM photoaffinity probes with cell membranes in the presence or absence of competitors, followed by UV irradiation to initiate photo‐crosslinking to nearby proteins and conjugation to biotin via click chemistry. Labeled proteins were isolated with affinity chromatography by streptavidin beads, eluted, and analyzed by western blot. Probes were docked onto γ‐secretase (PDB 7D8X) using tools from Schrodinger Suite 2021‐2. Part II: We treated N2a‐APP cells with GSM‐1 (acid GSM), E2012, or BPN‐15606 (imidazole GSMs) individually or in combination for 12h. Afterwards we collected cell culture media and measured secreted Aβ38, Aβ40, and Aβ42 levels using MesoScale Discovery.ResultWe demonstrate that GSM photoprobe E2012‐BPyne labels presenilin‐1 and nicastrin in the presence of transition state analog L‐685, 458, consistent with structural observations. From molecular docking studies we observe that GSM photoprobes differentially interacted with γ‐secretase and docking scores aligned with probe labeling efficiency. Furthermore, we demonstrate that acid and imidazole GSMs synergistically inhibit cellular Aβ production.ConclusionOur findings have revealed insight into the binding of GSMs and the effects of two GSM classes in combination. We are currently examining the effects of combined GSMs in primary neurons and on Notch production. These studies aim to better understand the mechanisms of GSMs to target γ‐secretase in AD.
Neuroinflammation connecting amyloid‐beta and p‐tau pathology, may explain clinical heterogeneity in Alzheimer’s disease
Authors: Boon Baayla D.C. , Hoozemans Jeroen J.M. , Rozemuller Annemieke J.M. , Bouwman Femke H. , Frigerio Irene , Jonkman Laura E. , Kouri Naomi , Dickson Dennis W. , Murray Melissa E. 
Published: December 2022

AbstractBackgroundOther than the typical (memory‐dominant) variant, Alzheimer’s disease (AD) can present as posterior cortical atrophy (PCA) and behavioral/dysexecutive AD. Tangle distribution differs amongst clinical variants. Neuroinflammation is important in AD pathogenesis and may contribute to Aβ and p‐tau distribution. The relationship between pathological hallmarks, neuroinflammation and, APOE genotype in (a)typical AD is still largely unknown.MethodI will discuss our most recent studies on neuroinflammation in (a)typical AD from cohorts derived from the Netherlands Brain Bank and the Mayo Clinic. Atypicality is investigated from both a neuropathological perspective(N=19) and a clinical perspective (N=30, unpublished data). Additionally, the association ofAPOE ε4 with specific Aβ deposits (i.e., the ‘coarse‐grained plaque’ and the classic cored plaque) and their underlying neuroinflammatory response is investigated (N=60, unpublished data).ResultIn neuropathologically‐defined atypical AD, microglia, and complement show an atypical distribution across regions, resembling that of p‐tau. Clinical atypical AD variants show in addition to a distinct distribution for p‐tau and Aβ, a distinct distribution for activated microglia (CD68, MHC‐II), complement (C4b), and astrocytes (GFAP) (p<.05) (Fig. 1). Furthermore, when investigating Aβ in detail, we observed an atypical plaque, defined as the ‘coarse‐grained plaque’. This APOE ε4+ plaque is associated with increased neuroinflammation and p‐tau burden (ρ(58)=0.5 and 0.6;p<.05) in contrast to the classic cored plaque.ConclusionOur data supports that not all types of Aβ deposits are associated to p‐tau damage. Neuroinflammation, a process that is differently activated within AD variants, may be the link between Aβ aggregation and subsequent neurodegeneration and contribute to clinical variability.
Implementation of the Alzheimer’s blood‐based biomarker panel in clinical practice: the development of cutoffs for plasma Abeta1‐42/1‐40, P‐tau181, GFAP and NfL across the clinical continuum
Authors: Verberk Inge M.W. , van Harten Argonde C. , Gouda Mariam , Hussainali Zulaiga , van Engelen Marie‐Paule E. , Wilson David , Lemstra Afina W. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundSeveral blood‐based biomarkers for Alzheimer’s disease (AD) can now be reliably measured. It is not yet clear how those markers should be interpreted in a real‐world clinical setting, where a heterogeneous group of patients presents in different syndromal stages and with different symptoms. We aim to establish a ready‐to‐implement blood‐based biomarker panel including Abeta1‐42/1‐40, P‐tau181, GFAP and NfL with cutoffs for clinical application among subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD‐dementia, frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB).MethodWe included n=1132 individuals of the Amsterdam Dementia Cohort (table 1) with known baseline amyloid‐beta (Aβ) status, who had SCD (n=237 Aβ‐, n=66 Aβ+), MCI (n=108 Aβ‐, n=151 Aβ+), AD‐dementia (n=297, all Aβ+), FTD (n=162 of whom n=121 Aβ) or DLB (n=111 of whom n=53 Aβ‐). Plasma markers were measured with Simoa (neurology 4‐plex E, P‐tau181 V2). We applied ROC analysis and subsequently LASSO regression to identify panels among the plasma markers.ResultROC analysis (table 2, figure 1) showed that among SCD and MCI, AUCs of the individual plasma markers to predict Aβ status were 0.738–0.799 (lowest for NfL, highest for P‐tau181). LASSO regression (table 2, figure 1) selected Abeta1‐42/1‐40, P‐tau181 and GFAP, but not NfL as the optimal panel (AUC=0.846, 95%CI: 0.812–0.880). Stratifying for SCD or MCI stage resulted in largely similar findings (not shown). When discriminating AD from FTD, AUCs of the individual plasma markers were 0.643–0.820 (lowest for Abeta1‐42/1‐40, highest for P‐tau). LASSO regression selected P‐tau181, GFAP and NfL as the optimal panel (AUC=0.889, 95%CI: 0.850–0.927). For AD versus DLB, AUCs were 0.514–0.741 (lowest for NfL, highest for P‐tau181). LASSO regression selected only P‐tau181 (AUC=0.741, 95%CI: 0.683–0.800). Plasma marker cutoffs at Youden’s indices differed depending on the diagnostic groups, with higher cutoffs for P‐tau181, GFAP and NfL in AD versus FTD or DLB analyses, compared to the SCD and MCI analyses (table 2).ConclusionWe showed that depending on the clinical question at hand, the four biomarkers add valuable information with their own cutoffs. Decision trees might lead to ready‐to‐apply cutoffs for daily clinical practice.
GABAergic system in Alzheimer’s disease: a systematic review with meta‐analysis
Authors: Carello‐Collar Giovanna , Bellaver Bruna , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Ramos Vanessa G. , Pascoal Tharick A , Rosa‐Neto Pedro , Zimmer Eduardo R. 
Published: December 2022

AbstractBackgroundCholinergic and glutamatergic dysfunctions have been widely described in Alzheimer’s disease (AD). However, the role of other neurotransmitter systems, such as the GABAergic, remains poorly understood. In fact, studies evaluating GABAergic neurotransmission in AD patients have provided contradictory results, pointing to a need for a consensus in the literature regarding the GABAergic system in AD. Thus, we aimed at examining whether the GABAergic system is altered in AD.MethodWe systematically reviewed and meta‐analyzed the literature following the PRISMA 2020 guidelines (PROSPERO #alz064082). We searched in the PubMed and Web of Science databases for studies reporting quantitative or semi‐quantitative data of GABA, and GABAergic transporters, receptors, and synthesis enzymes. The participants included were AD subjects and age‐matched cognitively unimpaired (CU) individuals. The effect sizes were determined via the standardized mean difference (SMD) using Hedge’s g method with random effects. The percentage of heterogeneity between studies was estimated using I2 test. Data are presented as SMD [95% CI], I2 %.ResultThe search identified 3,223 papers (Figure 1). Forty‐nine records met the inclusion criteria (a total of 667 AD patients, mean age 75.4, and 584 CU subjects, mean age 72.4). Here, we present results obtained in the CSF, blood, and different brain regions in which more than five studies have been meta‐analyzed. GABA levels were decreased in the CSF (‐0.42 [‐0.74, ‐0.1], p<0.0001, 0%), temporal cortex (‐0.97 [‐1.38, ‐0.55], p<0.0001, 54.6%), occipital cortex (‐1.03 [‐1.86, ‐0.2], p=0.015, 78%), and striatum (‐0.58 [‐1.09, ‐0.07], p=0.025, 0%), but not in the blood (‐0.64 [‐1.39, 0.11], p=0.092, 64.2%), frontal cortex (‐0.49 [‐1.06, 0.08], p=0.09, 73.1%), and hippocampus (‐0.39 [‐0.8, 0.03], p=0.068, 24.7%); GABA A receptor availability was decreased in the frontal (‐0.74 [‐1.44, ‐0.05], p=0.037, 50.5%) and temporal cortices (‐0.73 [‐1.15, ‐0.3], p=0.001, 7.4%), but not in the hippocampus (‐0.79 [‐1.64, 0.06], p=0.068, 66.9%). Figure 2 provides a summary of our findings.ConclusionOur results demonstrated a decrease of GABAergic system components in multiple brain regions and low levels of GABA in the CSF of AD subjects compared to age‐matched CU individuals, pointing to an important role played by GABAergic neurotransmission in the pathophysiology of AD.
Precision estimates of Relative and Absolute Cerebral Blood Flow in Alzheimer’s disease and Cognitively Normal individuals
Authors: Heeman Fiona , Visser Denise , Yaqub Maqsood , Verfaillie Sander C.J. , Timmers Tessa , van der Flier Wiesje M. , van Berckel Bart NM , Boellaard Ronald , Lammertsma Adriaan A. , Golla Sandeep SV 
Published: December 2022

AbstractBackgroundAlzheimer’s disease is characterized by regional reductions in cerebral blood flow (CBF) and the gold standard for measuring CBF is [15O]H2O PET. Recently, proxies of relative CBF, derived from the early distribution phase of amyloid‐β and tau tracers, have gained attention. It has been hypothesized that relative CBF is likely to have higher precision (but not accuracy) than absolute CBF, as global variations in CBF are cancelled out. The present study assessed precision of [15O]H2O PET derived relative and absolute CBF measures, and compared them with relative CBF proxies estimated from [18F]florbetapir and [18F]flortaucipir scans.MethodDynamic [15O]H2O, [18F]florbetapir and [18F]flortaucipir test‐retest (TRT) PET datasets were included, consisting of eleven cognitively normal (CN) individuals for [15O]H2O, four CN and five AD participants for [18F]florbetapir, and six CN and eight AD participants for [18F]flortaucipir. [15O]H2O data were analysed using the standard single tissue compartment model and [18F]florbetapir and [18F]flortaucipir using the simplified reference tissue model (SRTM). Relative CBF (i.e. K1/K1’) was derived from absolute CBF (i.e. K1 of [15O]H2O) or estimated using SRTM (i.e. R1), in all cases using cerebellar cortex as reference tissue. CBF values were obtained for 22 cortical grey matter regions and TRT variability (eq.1) was calculated for all metrics. Differences (%) between test and retest measures were assessed using Bland‐Altman analysis and TRT variability for different tracers and between diagnostic groups were compared using Wilcoxon Signed‐Rank and Mann‐Whitney U‐tests.ResultAverage differences (M±SD) between test and retest measures were small for relative measures, [15O]H2O K1/K1’:‐2.0±7.8%, [18F]florbetapir R1:‐1.7±4.1%, [18F]flortaucipir R1:‐0.1±4.2%, but somewhat larger for [15O]H2O K1:‐5.7±14.6%,(Fig.1). In case of [15O]H2O, TRT variability was lower for K1/K1’ than for K1 (p<0.001). Furthermore, [18F]florbetapir and [18F]flortaucipir derived R1 showed lower TRT variability than [15O]H2O K1/K1’ (p<0.001). Only for [18F]flortaucipir, TRT variability was higher in the AD compared with the CN group.ConclusionRelative CBF has higher precision than absolute CBF derived from [15O]H2O PET scans. Furthermore, relative CBF proxies derived from commonly used amyloid‐β and tau tracers appear to have an even higher precision, possibly due to the compensatory effect of extraction fraction and/or the older scanner used for [15O]H2O scans.
COVID‐19‐related loneliness, social isolation and burden in informal caregivers worldwide
Authors: Chen Yaohua Sophie , Almirall‐Sanchez Arianna , Ilinca Stefania , Grycuk Emilia , Higgins Dawn , Leon Tomas , McGlinchey Eimear , Rogan Carol , Saha Sanjib , Tjin Anna , Galvin Miriam , O'Sullivan Roger , Lawlor Brian , Leroi Iracema 
Published: December 2022

AbstractBackgroundInformal caregivers may experience high levels burden. Prior to COVID‐19, loneliness and social isolation, and especially the discordance between them, were recognized for rapid aging‐related cognitive decline. The COVID‐19 has significantly increased social isolation and loneliness in caregivers. Thus, we aimed to explore the variables that were associated with higher care burden among all caregivers and only among caregivers for people living with dementia, and whether the increased burden could be associated with a discrepancy between loneliness and social isolation.Method‘Comparing Loneliness and Isolation in COVID‐19’ was an online global survey of over 20,000 respondents, including 5243 caregivers across 50 countries with enduring brain or/and physical health conditions. We first used a multilevel modelling to identify risk factors associated with higher burden. Then, we defined profiles of discrepancy between loneliness and social isolation, based on the differences between standardized score on a scale of loneliness and of social connectedness and estimated the association between the discrepancy and higher burden.ResultIn our sample, 74% of caregivers were female, 44% were caring for people with dementia, and 22% for people with multiple conditions, including dementia. The most prevalent age group was 60‐69 years old. Factors significantly associated with higher care burden were being female, having poorer financial situation, worse mental health during the pandemic, caring for people with dementia or intellectual disabilities, caring in the same home, being diagnosed with COVID, and changes of care abilities. 40% of caregivers consistently reported high level of loneliness and social isolation, 38% reported consistent lower levels of both, and two groups reported discordance (low levels of loneliness and high social isolation in 13%; high levels of loneliness and mild social isolation in 12%). The latter group was at the highest risk of self‐reported increased and intense care burden.ConclusionThis represents the largest, most widespread survey on the impact of the COVID‐19 pandemic on caregivers of people with long‐term conditions to date and reflects the importance of capturing the nuances in the relationship between loneliness and social isolation in caregivers. It will be an important resource for support agencies and to inform policy.
Experiences of English‐speaking care partners of individuals with brain health conditions during COVID‐19: a qualitative analysis
Authors: Rogan Carol , Higgins Dawn , Chen Yaohua Sophie , Grycuk Emilia , Wormald Andrew , Leroi Iracema , Galvin Miriam 
Published: December 2022

AbstractBackgroundPublic health restrictions due to the COVID‐19 pandemic have affected care partners of people living with dementia and/or mental health conditions. This qualitative study explores care partners’ ability to offer care, and changes and interruptions to care provision during the period of the COVID‐19 pandemic (2020) in English‐speaking regions worldwide.MethodAs part of an international cross‐sectional online survey, qualitative data were collected from over 1,000 English‐speaking care partners of people living with dementia and/or mental health conditions. Responses to an open‐ended question about ability to care were coded and analysed thematically. The analysis was undertaken by three independent interdisciplinary coding dyads.ResultA number of main themes and subthemes were generated through the analysis. Reduced in‐person contact with the person with a brain health condition and restrictions in health and social care services created practical, psychological and emotional impacts for care partners. The lack of adequate information from health/social care services, deterioration in the condition of the person living with a brain health condition, and additional care hours/duties were identified. Care partners also mentioned the fear of virus transmission and increased awareness of public health measures as factors that changed or interrupted their ability to provide care.ConclusionThe ability of care partners to provide care was changed or interrupted, and disruption to routines and services available impacted on their well‐being. These findings reflect the complexity of the care partner role and highlight the importance of supporting care partners, in particular during periods of service restrictions such as those experienced as a result of the pandemic. Findings will be of interest to policymakers and service providers.