bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late, but not too late, is better than never: late‐life literacy is not associated with lower prevalence of dementia and cognitive impairment no dementia
Authors: Bertola Laiss , Suemoto Claudia Kimie , Ferri Cleusa P 
Published: December 2023

AbstractBackgroundEducation is a major modifiable risk factor for dementia and is usually considered an early‐life intervention. However, low‐ and middle‐income countries usually have high rates of illiteracy among older adults, and some became literate after childhood. Therefore, we aimed to investigate whether there were any associations between the age of literacy with the prevalence of cognitive impairment no dementia (CIND) and dementia, compared to illiteracy, regardless of the educational attainment.MethodWe used baseline data from the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), a population‐based nationally representative cohort of people aged 50 years or older, and the first Health and Retirement Studies (HRS) partner study in South America. For this study, we restricted our analysis to those aged 60 years or older, who had been classified as cognitively normal, CIND, or dementia. Participants were stratified into five groups: four according to their age when started schooling (early‐life literacy (EL) (<11 years), adolescent literacy (AdL) (11‐19 years), adulthood literacy (AhL) (20‐59 years) and late‐life literacy (LL) (≥60 years)) and illiteracy (IL). CIND and dementia classification prevalence ratios (PR) according to literacy status were assessed using Poisson regression, and adjusted for sociodemographic (age, sex/gender, educational attainment, race/ethnicity) and clinical confounders (memory complain, depressive symptoms, heavy drinking, smoking status, hypertension, and diabetes).ResultOur final sample comprised 5,244 older adults (mean age 70.1±7.8 years, mean education 4.6±4.4 years, 60% female, 55% Black/Brown, 6% with dementia and 8% with CIND) (Table 1). Fifteen percent of the sample started their literacy after childhood, and 21% remained illiterate. EL and (PR = 0.22, 95%CI = 0.09;0.53) and AdL (PR = 0.42, 95%CI = 0.18;0.98) groups had lower dementia prevalence compared to IL group (Table 2). However, there was no prevalence difference between IL and those who started literacy after adolescence.ConclusionWe found a lower prevalence of dementia among participants with early‐life and adolescent literacy compared to illiteracy. Adulthood and late‐life literacy were not associated with lower dementia prevalence. Literacy after childhood might have same beneficial impact if it is not started too later in life. Further studies should be conducted to better understand the impact of late‐life literacy interventions on reducing dementia risk.
Modifiable dementia risk and protective factors in persons with subjective cognitive decline or mild cognitive impairment: a systematic literature review and Delphi study
Authors: Truin Lotte S. , Heger Irene , Deckers Kay , de Vugt Marjolein , Köhler Sebastian 
Published: December 2023

AbstractBackgroundMany studies showed that addressing modifiable risk factors has an impact on dementia prevalence and incidence. Most studies have focussed on universal prevention, irrespective of individual risk stage, with risk factors for dementia mainly identified in the general population. Less is known about the most important target risk factors in persons with subjective cognitive decline (SCD) or mild cognitive impairment (MCI), and hence, whether they have a similar potential for risk reduction as the general population. Therefore, this study aims to identify modifiable risk and protective factors for cognitive deterioration and dementia in persons with SCD or MCI.MethodWe use a mixed‐methods approach combining findings from a systematic literature review and an online Delphi study. Four electronic databases (PubMed, EMBASE, PsycINFO, Web of Science) were searched to review relevant literature. A broad search term was developed in consultation with an experienced librarian and consisted of terms linked to SCD, MCI, dementia, modifiable risk factors and disease progression. Observational studies with at least 50 participants and 1 year of follow‐up were considered for inclusion. Twenty international dementia prevention experts were invited to participate in the online Delphi study. In two rounds, experts were asked to spontaneously name, rank and weigh modifiable risk and protective factors in order of importance for the target population.ResultOur search yielded 19,128 abstracts in total. After removal of duplicates, 9,862 abstracts were considered for inclusion and 203 full‐texts were read, of which 69 were included in our review. Several risk and protective factors were encountered including somatic, lifestyle and neuropsychiatric factors, and they are further scrutinized. Eighteen experts named 31 risk and protective factors in the first Delphi study round, of which physical activity, social isolation and hypertension were ranked highest. Results of round two are being collected.ConclusionFindings from the current study will result in an inventory of relevant modifiable risk and protective factors linked with clinical progression in persons with SCD or MCI. Results will serve as the basis for the development and testing of an online dementia risk reduction tool for use in clinical populations with SCD and MCI.
Pooling trial data to identify heterogeneity and characteristics of patients most likely to respond to treatment: a causal forest approach
Authors: Dubbelman Mark A. , Vromen Eleonora M. , Tijms Betty M. , Ottenhoff Lois , Vijverberg Everard G.B. , Prins Niels D. , van der Flier Wiesje M. , Sikkes Sietske A.M. 
Published: December 2023

AbstractBackgroundA potential explanation for the limited success of past therapeutic trials for Alzheimer’s disease (AD) lies in disease heterogeneity. We set out to pool and jointly analyze data from completed trials using a hypothesis‐free machine learning approach, aiming to identify participant characteristics related to increased responsiveness to treatment. Considering methodological difficulties, we also aim to describe the pooling and analytical process.MethodWe requested data from fifteen completed phase I–III trials investigating several compounds in AD individuals and were granted access to six trial datasets using compounds LY450139 (semagacestat), GSK933776, and BI409306 (with donepezil) with 2,397 participants (73.3±7.8 years old, 55% female, Table 1), through the Vivli platform. Causal Forest analyses, a machine learning technique that extracts a minimal subset of patient characteristics that can explain heterogeneity in outcomes, were used with change on (1) ADAS‐Cog and (2) MMSE as outcome, accounting for treatment group (placebo vs. compound).ResultThe included trial datasets showed considerable differences in available variables and data structure, constraining the amount of data that may be used in joint analysis. We were able to pool and analyze twenty‐seven characteristics shared across trial datasets in the model, covering demographics, vital signs, MRI volumetrics, baseline cognitive and functional performance, apolipoprotein ε4‐carriership and drug compound. Causal forest analyses did not reveal heterogeneity in pooled treatment effects on ADAS‐Cog (estimate for differential forest prediction: ‐2.25, p = 0.96) or MMSE (‐2.97, p = 0.98), indicating that these patient characteristics were not predictive for increased responsiveness to treatment. Stratifying by compound, similar results were found.ConclusionWe took an innovative approach and provided a methodological basis to examine heterogeneity in treatment effects by pooling existing trial datasets. Our results imply that responsiveness to treatment may not be well‐explained by the patient characteristics to our disposal, or that different compounds should be investigated. More research into other factors possibly related to treatment response is needed, e.g., fluid biomarkers and genetics. Based on our experience, we recommend that trial sponsors improve collaboration and data access, as we work towards personalized medicine by identifying which therapeutic approach works best for whom.
AMYPAD: Correlation of Amyloid PET results with anxiety and depressive symptoms in SCD+, MCI and dementia patients
Authors: Zeyen Philip , Sannemann Lena , Escher Claus , Maier Franziska , Rostamzadeh Ayda , Drzezga Alexander , Giehl Kathrin , Bischof Gerard N , Hönig Merle C. , Altomare Daniele , Garibotto Valentina , Barkhof Frederik , Scheltens Philip , van Berckel Bart N.M. , Collij Lyduine E. , Molinuevo Jose Luis , Grau‐Rivera Oriol , Gispert Juan Domingo , Delrieu Julien , Payoux Pierre , Nordberg Agneta K , Savitcheva Irina , Walker Zuzana , Edison Paul , Demonet Jean‐François , Stephens Andrew W. , Gismondi Rossella , Farrar Gill , Frisoni Giovanni B , Jessen Frank 
Published: December 2023

AbstractBackgroundDepression and anxiety are two frequent neuropsychiatric symptoms in Alzheimer’s disease (AD). Moreover, depressive symptoms and anxiety are frequently associated with greater amyloid deposition and risk of Alzheimer’s dementia. The aim of the present study is to assess the association between anxiety and depression and amyloid burden.MethodIn the AMPYAD study, participants with subjective cognitive decline (SCD+, n = 244), mild cognitive impairment (MCI, n = 341) and dementia (n = 255) were enrolled in eight European memory clinics between 2018 and 2020. They underwent three study visits (baseline, six months, thirteen months) with collection of cognitive data and symptoms of depression and anxiety (Hospital Anxiety and Depression Scale, HADS) as well as measures of quality of life and coping strategies. Amyloid burden was obtained as the standardized centiloid values (CL). Correlation analyses were carried out for HADS‐Scores and CL. We analyzed the progression of depressive and anxiety symptoms over time between patients with and without presence of amyloid (CL≥21) using mixed‐model‐ANOVA. All analyses were corrected for time of PET result disclosure.ResultA total of 840 patients (46.2% female; mean age of 70.9 (SD = 7.8)) were included. Among SCD+ patients, CL values were positively correlated with baseline anxiety scores (r(216) = .14, p = .038). In contrast, MCI and dementia patients showed a negative correlation between CL and depressive symptoms (r(296) = ‐.16, p = .005; r(209) = ‐.23, p<.001). In SCD+, there was no significant interaction between time and CL status for anxiety (p = .512), but a significant main effect of time (F(2,302) = 3.4, p = .036, η² = .02), indicating a decline in anxiety symptoms over time. A trend indicated higher anxiety for amyloid positive participants, but the effect missed statistical significance (p = .068). For depressive symptoms, we found no main effects and no significant interaction of time and CL status.ConclusionThe AMYPAD study contains a large amyloid‐PET data set of patients from eight European memory clinics. We observed an association of increased anxiety scores with amyloid load in SCD+, but reduced symptoms of depression with higher amyloid load in the MCI and dementia group. These findings and their longitudinal development over time will be put into a broader context of patient characteristics.
Discriminative power of multi‐PET tracer approach targeting reactive astrogliosis, tau pathology, and dopaminergic impairment in 4R primary tauopathies
Authors: Malarte Mona‐Lisa , Gillberg Per‐Göran , Kumar Amit , Nordberg Agneta K 
Published: December 2023

AbstractBackgroundThe 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are described as dementias with parkinsonian syndrome. Even if they are proven to represent clinically different entities, their complex neuropathology and common hallmarks often make the differential clinical diagnosis of CBD and PSP challenging. The highly entangled astrocytic and tau pathologies observed in these diseases are however displaying unique disparities which might unravel specific neuropathological profiles for each disease. The multi‐PET tracer approach applied in the present study in postmortem brain tissue might provide new mechanistic insights. We recently demonstrated that the second‐generation tau PET tracer, 3H‐PI2620 had a discriminative potential in CBD, PSP, and Alzheimer’s disease (AD) brains (Malarte et al. Mol. Psychiatry. 2022). To further understand the interaction between tau spatial distribution and its potential effects on astrocytic reactivity, we conducted a comparative multi‐tracer investigation in CBD, PSP, AD, and control brains using novel tau and astrocytic tracers. To gain a deeper insight into the relationship between tau, astrogliosis, and concomitant motor impairments, we also studied the interaction with the dopaminergic system.MethodWe performed autoradiography studies on large frozen hemispherical brain tissue of CBD, PSP, AD, and control cases using the tau PET tracer 3H‐PI2620, in comparison to astrocytic tracers (3H‐BU99008 and 3H‐Deprenyl) and dopaminergic tracers (3H‐Raclopride and 3H‐FE‐PE2I). We also analyzed the regional distribution of these tracers in small adjacent frozen brain sections of pathologically specific brain regions (globus pallidus, putamen, caudate, frontal cortex, medulla oblongata). We also performed saturation studies with 3H‐BU99008 and 3H‐Deprenyl on CBD and PSP brain homogenatesResultOur preliminary results are promising and suggest high astrogliosis measured by 3H‐BU99008 and 3H‐Deprenyl in large frozen autoradiography in CBD and PSP brains, and with different binding intensities in different brain regions comparable with regional 3H‐PI2620 binding. 3H‐BU99008 and 3H‐Deprenyl both highlighted two binding sites in the putamen of CBD cases, but only one site in PSP.ConclusionOngoing multi‐PET tracer studies targeting different pathological hallmarks of CBD and PSP tauopathies will improve differentiation and provide new knowledge regarding the spatial distribution of tau and its correlation with astrogliosis and the dopaminergic system in primary tauopathies.
Correlations in hippocampal subfield volume and pathological hallmarks in Alzheimer’s and Parkinson’s disease
Authors: Bouwman Maud M.A. , Frigerio Irene , Reijner Niels , Lin Chen‐Pei , Bouwman Femke H. , Berg Wilma D.J. , Jonkman Laura E. 
Published: December 2023

AbstractBackgroundThe hippocampus is highly vulnerable to protein aggregations and often severly atrophic in Alzheimer’s disease (AD) and related neurodegenerative disoders such as Parkinsons’ disease (PD) with dementia (PDD). This study aims to define the association between MRI‐measured hippocampal subfield volumes and pathology load using a cross‐disease and within‐subject post‐mortem MRI‐pathology approach in clinically‐defined and pathologically‐confirmed AD and PD brain‐donors.MethodWe included 17 typical (amnestic) and 13 atypical (non‐amnestic) AD, 10 PD, 9 PDD and 14 age‐matched control donors. 3T in‐situ MRI 3D‐T1 images were obtained for FreeSurfer‐based subfield segmentation. Hippocampus tissue sections were immunostained for amyloid‐beta (Aβ), p‐tau, and pSer129‐α‐synuclein. Immunoreactivity in manually segmented subfields (DG, CA1 to CA4, (para)subiculum and entorhinal cortex) was quantified as area% load. Clinical Dementia Rating (CDR) scores were obtained from clinical reports. Group differences were analysed with general linear models and regional assocations with partial correlations, corrected for age, sex, postmortem delay and intracranial volume.ResultTotal hippocampal, CA1 and subiculum MRI‐volumes were lower in typical AD compared to all other groups (p<0.03). PD and PDD showed higher volumes in all subregions compared to typical AD, except for CA2/3 and parasubiculum (Fig.1).Typical and atypical AD showed similar p‐tau burden, which was higher compared to other groups in most subfields. CA1 and entorhinal cortex showed the highest Aβ pathology load in AD compared to controls and PD. No significant differences in pSer129‐α‐synuclein pathology were seen between PD and PDD (Fig.2).Cross‐disease, p‐tau negatively correlated with volume in total hippocampus and all subfields (all r←0.30, p<0.025) (Fig.3). In typical AD, no disease‐specific correlations between pathology and volume could be observed. In PD(D), pSer129‐α‐synuclein was negatively associated with volume in CA4, whereas p‐tau negatively correlated with volume in total hippocampus, DG and CA4 in PDD.CDR scores correlated negatively with volume in total hippocampus, subiculum and entorhinal cortex cross‐disease, and in typical AD with p‐tau in total hippocampus, CA1 and CA2.ConclusionAlthough similar pathological burden is observed in typical and atypical AD, typical AD showed more severe hippocampal MRI‐atrophy. Furthermore, p‐tau load is associated with MRI‐atrophy of hippocampal subfields cross‐disease, and is regionally associated with impaired cognition.
Identifying modifiable psychosocial outcomes to maintain physical ACTIVity and promote independence in DEMentia: the ActivDem study
Authors: Ardle Ríona Mc , Din Silvia Del , Hicks Ben , Kingston Andrew , Banerjee Sube , Thomas Alan J , Robinson Louise , Rochester Lynn 
Published: December 2023

AbstractBackgroundPromoting habitual physical activity (HPA; e.g. walking) may help decelerate dependency and disability in people with dementia (PwD). HPA refers to any movement the skeletal muscles make which requires energy expenditure, including daily tasks (e.g. gardening/housework). Research regarding physical activity in PwD mainly focuses on exercise‐based activities, which may not be feasible for people with chronic health conditions or frailty, or who cannot afford or travel to exercise classes. Promoting participation in HPA may be an inclusive, accessible strategy to support PwD to remain physically active and mobile. PwD participate in less HPA than recommended and disease‐specific factors (e.g. cognition) do not sufficiently explain this. In healthy ageing, HPA participation is associated with multiple socio‐ecological factors (e.g. psychosocial wellbeing/social support/environment) but this has not been explored in dementia. The ActivDem study aims to identify key socio‐ecological influences on HPA change over time in community‐dwellers with dementia. Figure 1 presents ActivDem’s core objectives.MethodPwD and their carers will be recruited from the ongoing cohort study, DETERMIND, they will participate in a continuous seven‐day HPA assessment. This involves wearing an inertial measurement unit on their lower back at baseline and one‐year follow up. Digital mobility outcomes relating to volume (e.g. steps per day), pattern (e.g. mean ambulatory bout length), and variability (i.e. of bout length) will be derived via validated algorithms. PwD will also complete the LASA Physical Activity Questionnaire and Falls Efficacy Scale. Carers will complete the Dementia Management Strategies Scale. Demographic, clinical and psychosocial characteristics and information on care support will be assessed as part of the DETERMIND study (1).ResultLongitudinal statistical methods will identify key predictors of HPA change in PwD, and examine the relationship between HPA and independenceConclusionThe ActivDem study will identify key socio‐ecological predictors of HPA change, these will inform key interventional components to support PwD to remain physically active and mobile following diagnosis of dementia.References1. Farina et al., 2020. DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers (DETERMIND): A protocol paper. Int. J. Geriatr.
Blood‐brain barrier disruption measured by dynamic contrast‐enhanced MRI in Alzheimer’s disease
Authors: Rauchmann Boris‐Stephan , Toth Hannah , Üstün Guersel Selim , Schirge Philine , Schweiger Meike , Brendel Matthias , Franzmeier Nicolai , Lamby Niclas , Burow Lena , Kurz Carolin Isabella , Koriath Carolin , Tato Maia , Papazov Boris , Moussiopoulou Joanna , Pogarell Oliver Michael , Keeser Daniel , Dietrich Olaf , Stöcklein Sophia , Seelos Klaus , Perneczky Robert 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Blood‐brain barrier (BBB) dysfunction has been associated with AD. Aβ‐plaques have been found to disrupt the BBB, leading to increased permeability and invasion of immune cells into the CNS and triggering an inflammatory response, and contributing to neurodegeneration. In this study, we investigated BBB disruption in Alzheimer’s disease and its associations with amyloid deposition and clinical severity, and cognitive decline.MethodIn this cross‐sectional study, n = 16 AD patients were included. AD patients were defined as amyloid positive by CSF amyloid‐β42/amyloid‐β40 ratio < 5,5% and a Mini‐Mental‐State Examination (MMSE) score < 27. Dynamic contrast‐enhanced magnetic resonance imaging (DCE MRI), a non‐invasive imaging technique that uses intravenously injected gadolinium to quantify the permeability of the BBB has been acquired. DCE‐MRI quantification was quantified using the Patlak method. To analyse the regional degree of BBB disruption the AAL atlas was warped onto the Patlak maps and the median of each ROI was calculated. The cortical amyloid deposition has been quantified using 18F]flutemetamol β‐amyloid‐PET and cognitive performance was assessed using the Alzheimer’s Disease neuropsychological battery (CERAD‐NB). Associations were tested using linear regression models adjusted for age and sex in SPSS.ResultThe highest Ktrans values were measured in the orbitofrontal cortex (mean: 1,6×10−3 min−1). BBB dysfunction in median Ktrans values in the bilateral temporal lobe and particularly the right hippocampus were associated with decreases in the CSF amyloid‐β ratio. Furthermore, BBB dysfunction was negatively associated with cognitive decline measured by the CERAD‐NB. BBB dysfunction overlapped with amyloid PET accumulation in the parietal and temporal brain regions.ConclusionDCE MRI shows spatially localized BBB dysfunction in AD. The BBB dysfunction seems to be more severe in regions of the brain that are affected by Aβ plaques. This could support the idea that Aβ plaque contributes to BBB dysfunction in AD. BBB dysfunction also tends to be pronounced in patients with more severe cognitive impairment, suggesting that it may play a role in the progression of AD.