bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physical activity delayed the onset of cognitive impairment in middle‐aged and older adults with diabetes ‐ Findings from the ELSA‐Brasil Study
Authors: Feter Natan , Schmidt Maria Inês , Santos Danilo , Duncan Bruce 
Published: December 2023

AbstractBackgroundPhysical inactivity and diabetes are known risk factors for cognitive impairment. Yet, few studies in large samples of cognitively diverse populations have been reported to assess this joint effect on cognitive function. Therefore, this study aimed to characterize the joint association of baseline diabetes and physical activity with cognitive decline and the risk of cognitive impairment in middle‐aged and older adults.MethodsLongitudinal data of the Estudo Longitudinal da Saúde do Adulto (ELSA‐Brasil, Longitudinal Study on Adult’s Health), an occupational cohort of Brazilian adults aged 35‐74, were analyzed. A standardized questionnaire distinguished physically active (≥150 min/week) from inactive participants. Cognitive function was examined using standardized tests to assess memory, language, and executive function at baseline and during follow‐up visit. Global cognitive function summed all three aspects and was described as z‐score differences from the sample average over follow‐up. Linear mixed models, Cox proportional regression models, and Laplace regression models, adjusted for sociodemographic and behavioral variables, were used to assess the relationship of diabetes and physical activity with change in cognitive function over time.ResultsParticipants (n = 12,214; 55.5% women; age [SD]: 51.4 [8.8]) had median follow‐up of 8.2 (0.6) years. During follow‐up, those physically active at baseline showed a slower less than average global cognitive decline (z‐score difference 0.22; 95%CI: 0.19, 0.24) and those with diabetes greater than average decline (z‐score difference ‐0.22; 95%CI: ‐0.26 ‐0.19). In those with diabetes, active adults aged 80 or older showed global cognitive function (z‐score ‐0.80; 95%CI: ‐0.90, ‐0.69) similar to inactive adults aged 70 (z‐score ‐0.69; 95%CI: ‐0.74, ‐0.65). While inactive participants had an increased risk of incident cognitive impairment independent of diabetes status (no diabetes: HR: 1.31; 95%CI: 1.13, 1.53; diabetes: HR: 1.21; 95%CI: 1.02, 1.44), among active adults, diabetes was not associated with incident cognitive impairment (HR: 0.93, 95%CI: 0.69, 1.27) compared to active participants with no diabetes. In participants with diabetes, physical inactivity anticipated in 3.15 (95%CI: 1.60, 4.69) years the onset of cognitive impairment. Results remained consistent after multiple sensitivity analyses.ConclusionPhysical activity attenuated the impact of diabetes on cognitive function in middle‐aged and older adults.
Meta‐analysis on Individual Patient Data from Randomized Controlled Trials of Fortasyn Connect in Early Alzheimer’s Disease
Authors: van Hees Anneke MJ , Cetinyurek‐Yavuz Aysun , Counotte Danielle , Rudka Tomasz , Sijben John W.C. 
Published: December 2023

AbstractBackgroundThe specific nutrient combination Fortasyn Connect (available in Souvenaid®), has been shown to bring benefits to subjects with various stages of Alzheimer’s disease (AD). The objective of this meta‐analysis was to investigate the effect of Souvenaid on cognition and memory using individual patient data (IPD) from all published RCTs in the early phases of AD ranging from mild cognitive impairment (MCI) due to AD (prodromal AD) to mild AD.MethodThe study population comprised all drug‐naïve subjects with a diagnosis of prodromal or mild AD included in double‐blind, randomised controlled clinical trials (RCTs) testing the efficacy of orally administered Souvenaid. Electronic databases and Google Scholar were searched to find all relevant RCTs. This meta‐analysis compared differences between Souvenaid and control groups using the IPD of analogous scales measuring overall cognition and episodic memory domains that were specified as either primary or secondary endpoints.ResultIn total, 779 subjects from three separate RCTs were included (Souvenir I, Souvenir II, and LipiDiDiet). The IPD meta‐analysis showed a significant favorable effect of Fortasyn Connect on episodic memory; the mean difference (MD) was 0.211 (95% confidence interval: 0.05, 0.37); p = 0.01, which was confirmed when corrected for possible confounders and effect modifiers (MD: 0.24 [0.07, 0.41]; p = 0.006) (Figure; Table). The IPD meta‐analysis for overall cognition suggested participants receiving Fortasyn Connect performed better than controls in the combined dataset (MD: 0.16 [−0.00, 0.32]; p = 0.055), which was confirmed when corrected for possible confounding effects and effect modifiers (MD: 0.23 [0.06, 0.41]; p = 0.01) (Figure; Table).ConclusionThe total body of evidence available from RCTs suggests that Fortasyn Connect has a favorable effect on cognition and memory in early AD without any safety concerns, and consequently that this intervention is a viable option in the management of MCI due to AD (prodromal AD) and mild AD.Trial registration: clinicaltrialregister.nl (Souvenir I: NTR702; Souvenir II: NTR1975; LipiDiDiet: NTR1705).
Processing of acoustically degraded emotional prosody in Alzheimer’s disease and primary progressive aphasia
Authors: Jiang Jessica , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Johnson Jeremy , Sivasathiaseelan Harri , Chokesuwattanaskul Anthipa , Nelson Annabel , Warren Jason D , Hardy Chris JD 
Published: December 2023

AbstractBackgroundAccurately interpreting a speaker’s nonverbal emotional vocal signals (their prosody) is often essential for successful communication. In the noisy conditions of daily life, this presents the brain with a difficult computational challenge that may be vulnerable to neurodegenerative pathologies. However, processing of acoustically degraded prosody has not been studied in these diseases.MethodHere we addressed this issue in patients representing all major syndromes of primary progressive aphasia (N = 33) and Alzheimer’s disease (N = 18) versus healthy age‐matched controls (N = 24). As a model paradigm for the degraded ‘noisy’ speech signals of everyday life, we used noise‐vocoding: digital division of the speech signal into a variable number of frequency channels constituted from amplitude‐modulated white noise, such that fewer channels convey less spectrotemporal detail and reduce intelligibility. We assessed the impact of noise‐vocoding on recognition of three canonical prosodic emotions (anger, surprise, sadness) at three noise‐vocoding levels. Correlations were also conducted with perception of degraded emotional prosody and measures of social cognition.ResultCompared with health controls, all patient groups were impaired in the identification of ‘clear’ emotional prosody. This impairment in all groups was sustained when the emotional prosody stimuli were vocoded, with differences seen between 18 and six channels, and 12 and six channels. Cost analyses conducted showed a significantly larger cost of noise‐vocoding in lvPPA than in healthy controls. Accurate identification of degraded emotional prosody in patients was significantly correlated with measures of social cognition.ConclusionOur findings open a window on a dimension of real‐world emotional communication that has often been relatively overlooked in dementia, and suggest a novel candidate paradigm for investigating and quantifying this systematically.
Using GENFI participant engagement to inform observational research and clinical trials
Authors: Russell Lucy L. , Greaves Caroline V , Bocchetta Martina , Heller Carolin , Rinaldi Daisy , Mueller Doreen , Bessi Valentina , Ber Isabelle Le , Synofzik Matthis , Borroni Barbara , Rohrer Jonathan D. 
Published: December 2023

AbstractBackgroundIt is vital that we include the views of individuals with frontotemporal dementia (FTD) and their families in the design of clinical trials. This study aims to establish what types of trials and treatments individuals with familial FTD would like to participate in.Methods135 participants from the GENFI cohort of at‐risk genetic FTD family members (34% of whom were known mutation carriers) completed a structured online questionnaire about clinical trials via Qualtrics. There was a total of 27 questions with a mix of multiple choice and free text questions. Topics included willingness to participate, understanding about likely proximity to symptom onset, and willingness to undertake different methods of therapeutic drug delivery including gene therapies.Results54% of individuals were definitely willing to participate in clinical trials with 39% stating it would depend on what the specific trial involved. Only 6% said they would not take part in a trial. The presence of a placebo group was a factor in trial participation with 31% stating they would decline to take part if there was a chance they did not receive the active drug. In light of a recent study suggesting plasma neurofilament light chain (NfL) may be a marker of proximity to symptom onset, we asked people if they would be willing to find out their NfL level as part of the trial, and 85% said they would. Most individuals said they would be willing to have IV infusions or lumbar punctures as part of the trial, although this did depend on the frequency with which they were required. For trials where drug administration would require more invasive measures, e.g. injections directly into the cisterna magna or the brain itself, only about 50% of people said they would be willing to take part. Lastly, if participation in a gene therapy trial precluded an individual from participating in future studies, only 30% said they would definitely consider being involved.ConclusionsObservational studies and clinical trials are designed to make a difference to people’s lives, and it is important to consider patients and family members throughout the development pipeline of treatments.
Plasma biomarkers rates of change across the preclinical stage of Alzheimer’s disease: a longitudinal study
Authors: González Escalante Armand , Milà‐Alomà Marta , Ashton Nicholas J. , Shekari Mahnaz , Salvadó Gemma , Ortiz‐Romero Paula , Montoliu‐Gaya Laia , Benedet Andrea Lessa , Karikari Thomas K , Rodriguez Juan Lantero , Vanmechelen Eugeen , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Zetterberg Henrik , del Campo Marta , Gispert Juan Domingo , Blennow Kaj , Vilor‐Tejedor Natalia , Suarez‐Calvet Marc 
Published: December 2023

AbstractBackgroundWhether plasma biomarkers steadily increase during the preclinical stage of Alzheimer’s disease (AD) is unknown. Herein, we aimed to determine the rate‐of‐change of plasma biomarkers throughout preclinical AD. This may be important to determine the optimal time window for treatment.MethodWe included baseline and follow‐up plasma biomarkers measurements (follow‐up: 3.37±0.40 years) of 240 cognitively unimpaired participants of the ALFA+ cohort (mean age: 60.75±4.85 years). Plasma Aβ40, Aβ42, GFAP and NfL were measured with the Simoa N4PE Advantage Kit, and plasma p‐tau231 with a Simoa‐validated in‐house assay.For each participant we calculated the difference between follow‐up and baseline levels, and corrected for sex, time between measurements, and age. We computed z‐scores from the corrected values, and we applied a bootstrapped regression approach to model the rate‐of‐change of each plasma biomarker as a function of baseline age or Aβ PET centiloids (CL).Moreover, we also computed the plasma biomarkers rate‐of‐change in three stages of preclinical AD: (I) CSF/PET Aβ‐negative group, (II) CSF Aβ‐positive/PET Aβ‐negative (CL < 30), and (III) CSF/PET Aβ‐positive.Significance was determined if the 95% confidence interval of the rate‐of‐change did not overlap with zero.ResultSignificant acceleration in the rate‐of‐change of plasma GFAP was observed with ageing (Fig. 1), becoming significant at 60 years. There was also a significant accelerated change of p‐tau231 from 55 to 68 years.Plasma NfL was the only biomarker whose rate‐of‐change accelerated with Aβ accumulation, and that rate became significant at 40CL (Fig. 2). Consistently, we observed a significant acceleration of plasma NfL when there was overt Aβ pathology (CSF/PET Aβ‐positive group; Fig. 3)The rest of plasma biomarker rates‐of‐change did not significantly increase, some were even deaccelerating (plasma Aβ42/40 and p‐tau231), as Aβ accumulated (Fig. 2 and 3).ConclusionPlasma biomarkers rate‐of‐change throughout the preclinical AD continuum differ. Plasma NfL rate‐of‐change accelerates in the later stage of preclinical AD, when overt Aβ pathology is present. The deceleration on the rate‐of‐change of plasma Aβ42/40 and p‐tau231 may explain why their early increase in the preclinical AD continuum tends to plateau in later stages.
Life course rural/urban place of residence, depression and cognitive impairment among older adults: Findings from the Longitudinal Aging Study in India
Authors: Muhammad T. 
Published: December 2023

AbstractBackgroundGiven the unique socioeconomic structures and rural/urban differentials in mental health outcomes in the country, this study aimed to explore the associations of childhood, adulthood and late‐life place of residence with mental health outcomes of depression and cognitive impairment among older adults in India. The study also examined the relationship between older individuals’ life‐course rural/urban place of residence and late‐life mental and cognitive health.MethodUtilizing data from the Longitudinal Aging Study in India (n = 28,041 older adults age 60 years and above), I employed multivariable logistic and linear regression models to examine the association between urban/rural residential status, life‐course residence, depression and cognitive impairment among older adults.ResultChildhood and adulthood place of residence was not associated with depression in older men and women. Current rural place of residence was positively associated with depression in older women [OR: 1.37, CI: 1.05‐ 1.80] but not men. Childhood [OR: 1.88, CI: 1.16‐ 3.04], adulthood [OR: 2.00, CI: 1.26‐ 3.16] and current rural residence [OR: 1.93, CI: 1.27‐ 2.91] was positively associated with cognitive impairment in men. Only current rural residence [OR: 1.71, CI: 1.29‐ 2.27] was associated with cognitive impairment in women. There was no significant association between life‐course place of residence and depression except in case of lifetime rural residence Respondents with urban‐urban‐urban place of residence were less likely to be depressed [Coef.: ‐0.14, CI: ‐0.21‐ ‐0.07] compared to those with rural‐rural‐rural place of residence. There were significant associations between life‐course residence and cognitive impairment except among rural‐urban‐rural and urban‐rural‐rural migrants, showing a urban advantage in cognitive function among older adults.ConclusionThis study showed significant associations between life‐course residence and depression among permanent rural/urban residents. The study also showed significant associations between life‐course residence and cognitive impairment except among rural‐urban‐rural and urban‐rural‐rural migrants. Considering the rural disadvantage, the government should continue to support policies that can promote education among people residing in rural areas. The findings also urge social scientists and gerontologists, in particular, to consider the importance of lifetime historical context while evaluating mental and cognitive health of older persons.
Diffusion MRI track cortical microstructural changes over time during the early stages of the Alzheimer’s disease continuum
Authors: Spotorno Nicola , Strandberg Olof , Stomrud Erik , van Westen Danielle , Hansson Oskar 
Published: December 2023

AbstractBackgroundMarkers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Previous cross‐sectional investigations suggested that diffusion MRI (dMRI) can provide metrics sensitive to cortical microstructural alteration linked to multiple aspects of the AD pathological cascade including Aβ‐accumulation and astrocytic activity. However, currently little evidence is available regarding the ability of dMRI in tracking changes over time.MethodsMean diffusivity (MD) was computed from dMRI data acquired from 363 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐1 study. Each participant underwent multiple dMRI scan (range 2‐4 scans) and was classified as Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on CSF levels of Aβ42/40 and ptau‐181. Rates of changes in MD, cortical thickness and plasma level of GFAP were computed in a linear mixed effect framework. Cortical regional values of MD were compared across biomarkers‐defined groups as well as to rates of change of GFAP.ResultsAnalyses of MD revealed widespread differences in rates of change already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation (fig.1). Further, analyses focusing on two composite ROIs, one encompassing regions that accumulate Aβ early in the disease process and a temporal meta‐ROI, confirmed that rates of change in MD significantly differed between groups even when cortical thickness was included in the model (Ps<0.05,fig.2). Regional MD rates of change in both neocortical temporal areas and key regions for Aβ‐accumulation, were also positively correlated with rates of change in GFAP (fig.3). Such result was supported by the analysis based on the two meta‐ROIs which confirmed the positive association between rates of change GFAP and MD.ConclusionMean diffusivity from dMRI is able to track cortical microstructural changes over time and to differentiate trajectories even during the early stages of the AD pathological cascade. The association between rates of change of MD and rates of change of GFAP suggested dMRI might reflect microstructural changes related to the astrocytic response to AD pathology. dMRI might help monitoring the effects of disease‐modifying therapies (e.g. Ab immunotherapies) in clinical trials.
Challenges with phenotyping dementia in a low resource setting; Frontotemporal dementias (FTDs) as a case study in Nigeria
Authors: Elugbadebo Olufisayo Oluyinka , Olawuyi Cynthia Olapeju , Farombi Temitope Hannah , Baiyewu Olusegun 
Published: December 2023

AbstractBackgroundPhenotyping dementia is a major problem in low resource settings like Nigeria and it has implication for research and management of people with dementia. Challenges associated with phenotyping dementia are embedded in poor health financing and lack of health personnel. This study aimed at scoping studies on dementia in Nigeria to identify those related to frontotemporal dementia (FTD) and describe the pattern of its presentation in a memory clinic as a means of highlighting challenges of phenotyping.MethodA literature search of studies on dementia that reported FTDs as a phenotype and or described profile or pattern of FTDs in Nigeria was conducted. In addition, a review of hospital records of all persons clinically diagnosed with dementia (PWD) using the ICD 10 criteria was conducted. Those with FTD phenotypes were identified. The cohort comes from a memory clinic in University College Hospital, Ibadan, Nigeria. Records of these individuals with FTDs were reviewed and data (including sociodemographic details, clinical profile and pattern of presentation) extracted for case series report.ResultsLiterature search yielded 2 studies; a retrospective study that reported dementia phenotypes including FTD and a case report. From a total of 216 PWD, we identified and included 14 persons with FTDs (6.5%) in this case series. Initially, 32 records of tentative diagnosis of FTD were identified, however, 18 persons with incomplete evaluation after the initial assessment were excluded. The mean age (±S.D) of those included (n = 14) is 67.7(±8.4). The main presenting complaints were behavioral with 57.1% presenting to the hospital at least a year after onset of symptoms. The most common behavioral problem identified was personality change accompanied with disinhibition in 9 persons (64.3%). Symptoms started before age 60 years in only one person. Two of the 14 persons had an initial diagnosis of schizophrenia until subsequent review with neuroimaging. Delay in carrying out neuroimaging due to financial constraint was a major challenge in making a diagnosis.ConclusionThere is paucity of data on FTDs in Nigeria. Out‐of‐pocket payment for assessment is a major setback in phenotyping dementia and it has implication on both clinical practice and research.
Development of a targeted proteomic assay for the quantitation of neurofilament light in cerebrospinal fluid: Correlation with Simoa‐based quantitation across neurodegenerative diseases and centres
Authors: Leckey Claire A. , Coulton John , Barthélemy Nicolas R. , He Yingxin , Laban Rhiannon , Heslegrave Amanda , Giovannucci Tatiana A. , Byrne Lauren M , Swift Imogen J , Esteve Aitana Sogorb , Rohrer Jonathan D. , Schott Jonathan M , Wild Edward J , Zetterberg Henrik , Wray Selina , Mills Kevin , Bateman Randall J. , Paterson Ross W. 
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) neurofilament light (NfL) is a dynamic biomarker of neurodegeneration that is used for supporting clinical diagnosis and monitoring disease‐modifying therapies. Development of new analytical tests has been limited, with quantitation of NfL in biomarker studies largely restricted to immunoassay methods. Targeted mass spectrometry is a highly specific technique that can be easily translated into existing proteomic and clinical pathology laboratories. In this multi‐centre study, we have developed two targeted mass spectrometry assays which were compared to Simoa, the gold standard method for NfL quantitation. The developed methods included immunocapture of intact NfL protein or specific peptides (immune‐peptide capture) prior to targeted proteomic analyses. We discuss the development, validation and merits of each technology to quantitate NfL in CSF from healthy controls and several neurodegenerative diseases.MethodCSF was collected from patients with a range of neurological diseases at the National Hospital for Neurology and Neurosurgery (London, UK). Clinical diagnosis was determined by their treating clinician according to consensus clinical criteria. NfL concentrations were measured by Simoa (Quanterix, USA) and two immunoprecipitation‐targeted mass spectrometry (IP‐MS) assays developed by a collaboration between UCL and Washington University in St Louis. To evaluate replication of results across centres and mass spectrometry approaches, results were compared using Spearman’s correlation analysis and Bland‐Altman testing.ResultsA high correlation was observed for CSF NfL levels between Simoa and both IP‐MS assays (immune‐peptide capture, r = 0.90, P<0.0001 and immune‐protein capture, r = 0.88, P<0.0001). Relative differences in mean NfL concentration between clinical groups remained the same across the analytical methods, with the highest and lowest NfL concentrations observed in the Huntington’s disease and the healthy control groups respectively. Interestingly, differences in the extent of correlation between Simoa and IP‐MS were observed between the different clinical groups (r = 0.37 ‐ 0.94).ConclusionImmunoprecipitation‐targeted mass spectrometry quantitation of NfL correlates highly with NfL Simoa measures across a range of neurodegenerative and neuroinflammatory diseases, and is replicable between laboratories using different immunoprecipitation‐targeted mass spectrometry approaches.