bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE ε4 is associated with reduced myelin and thus faster rate of tau PET accumulation
Authors: Rubinski Anna , Zheng Lukai , Dewenter Anna , Franzmeier Nicolai , Stephenson Henry G. , Deming Yuetiva , Bendlin Barbara B , Ewers Michael 
Published: December 2023

AbstractBackgroundMyelin is the cholesterol‐rich layer ensheathing axons in the white matter (WM). The APOE ε4 allele has been associated with both reduced cholesterol transport to myelin layers in mice and with faster tau progression in individuals with AD. Here we asked the questions whether 1) APOE ε4 is associated with lower myelin and 2) any myelin decreases mediate the association between APOE ε4 and the rate of tau‐PET accumulation in Aβ+ individuals. To assess myelin, we repurposed florbetapir‐PET tracer binding, previously shown to be sensitive to myelin binding protein in the WM (Stankow et al. Annals Neurol 2011).MethodWe included 43 Aβ‐ cognitively normal (CN, global florbetapir SUVR < 1.11) and AD‐spectrum participants (56 CN Aβ+, 32 MCI Aβ+, and 20 AD Aβ+) from ADNI. To extract individual myelin levels, we averaged each participant’s florbetapir SUVR within individual T1‐MRI based WM masks (global myelin) or 58 fiber‐tracts generated from multishell DTI (fiber‐tract myelin). To control for a putative influence by grey‐matter florbetapir levels, we adjusted the individual WM‐florbetapir SUVRs for grey‐matter florbetapir SUVR via linear regression analysis and computed z‐scores of the adjusted WM‐florbetapir SUVRs across all participants (Moscoso et al. EJNNMI, 2022). For tau‐PET, flortaucipir SUVRs were extracted in Braak‐stage GM ROIs or in the tracts’ cortical projection zones, and mixed effect linear regression was used to estimate the rate of regional flortaucipir change.ResultHigher APOE ε4 score was associated with both lower WM‐florbetapir z‐score (β = ‐0.329, p<0.001) and faster tau‐PET increase in Braak stage 3+4 ROIs (β = 0.224, p = 0.01) in Aβ+ participants (Fig. 1A&B). Using bootstrapped mediation analysis, we found that the WM‐florbetapir z‐score mediated the effect of APOE dosage on the rate of tau‐PET accumulation in Braak 3+4 (b = 2´10‐4 [95% CI: 2´10‐5, 3´10‐4], p = 0.02, Fig 1C). At the fiber‐tract level, APOE ε4 dosage exacerbated the association between decreased fiber‐tract florbetapir and faster tau‐PET increase in the tracts’ projection zones (p<0.001).ConclusionAPOE ε4 may contribute to the accumulation of tau pathology in a myelin dependent manner. Myelin impairment is treatable by several known drugs and therefore an attractive therapeutic target in AD.
White matter changes in the cholinergic system in Alzheimer’s disease and dementia with Lewy bodies
Authors: Schumacher Julia , Ray Nicola , Hamilton Calum Alexander , Bergamino Maurizio , Donaghy Paul C , Firbank Michael J , Watson Rosie , Roberts Gemma , Allan Louise M , Barnett Nicola , O'Brien John T , Thomas Alan J , Taylor John‐Paul 
Published: December 2023

AbstractBackgroundThe early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD.MethodsNBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data.ResultsFree water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls).ConclusionOur cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations.
Longitudinal white matter integrity alterations as a function of Preclinical Alzheimer’s Pathology: findings from the EPAD non‐demented cohort
Authors: Lorenzini Luigi , Tranfa Mario , Ingala Silvia , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Ewers Michael , Payoux Pierre , Martinez‐Lage Pablo , Ritchie Craig W , Gispert Juan Domingo , Brunetti Arturo , Mutsaerts Henk‐Jan , Wink Alle Meije , Barkhof Frederik 
Published: December 2023

AbstractBackgroundCross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progression.We investigated trajectories of WM alterations in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and their relationship with AD biomarkers.MethodEPAD inclusion criteria were age>50 years and Clinical Dementia Rating≤0.5. We selected participants with baseline CSF samples, and longitudinal DTI scans. After defining AT groups(Ingala et al. 2021), A‐T+ participants were excluded (final N = 283).MRI acquisition and preprocessing was previously described(Lorenzini et al. 2022). We extracted fractional anisotropy (FA) in 14 regions(Mori et al. 2005) from DTI as a marker of WM integrity. Site harmonization of MRI‐derived data was performed with ComBat toolbox(Fortin et al. 2018).Age‐ and sex‐corrected linear mixed models with random intercepts on participants were used to estimate time‐effect on MRI‐derived phenotypes, and their interaction with AT status. Results were corrected for multiple testing.ResultAt baseline, A+T‐ participants showed lower FA in body/columns (ß = ‐0.04, p<0.01) and crus of fornix (ß = ‐0.01, p = 0.04), and in splenium (ß = ‐0.007, p = 0.04) and body of CC (ß = ‐0.01, p = 0.03) compared to A‐T‐. In the whole group, FA decreased over time in splenium (ß = ‐0.003, p<0.01), body (ß = ‐0.002, p<0.01) and genu of CC (ß = ‐0.009, p<0.01), body/columns (ß = ‐0.004, p<0.01) and crus of fornix (ß = ‐0.005, p<0.01), and inferior longitudinal fasciculus (ß = ‐0.007, p<0.01). Compared to A‐T‐, A+T+ participants showed steeper FA reduction in superior (Interaction:ß = ‐0.004, p = 0.03) and anterior corona radiata (Interaction:ß = ‐0.006, p = 0.02).ConclusionOur results suggest that WM integrity in key AD regions may degenerate early in the AD continuum, showing greater impairment over short‐time intervals in individuals with higher AD‐specific pathological burden.
Transition in the cognitive continuum from normal cognition to dementia: the interplay of lifelong cognitive reserve with brain aging and genetic predisposition
Authors: Li Yuanjing , Dekhtyar Serhiy , Grande Giulia , Kalpouzos Grégoria , Laukka Erika J , Fratiglioni Laura , Qiu Chengxuan 
Published: December 2023

AbstractBackgroundHigher cognitive reserve (CR) has been associated with lower risks of cognitive decline and dementia. In this study, we sought to investigate associations of lifelong CR capacity with transitions of cognitive phenotypes in older adults, while accounting for age, sex, APOE genotype, and pathological load of brain aging.MethodThis population‐based Swedish National study on Aging and Care‐Kungsholmen included 2631 participants (age≥60 years, 61.4% female) free of dementia at baseline (2001‐2004); among them 517 had brain MRI. At baseline, lifelong CR capacity was assessed by integrating early‐life education, midlife occupational complexity, later‐life social network and leisure activity. The load of pathological brain aging was assessed using volumes of grey matter (GM), white matter, hippocampus, and white matter hyperintensity, and count of perivascular space and lacunes. Cognitive impairment no dementia (CIND) and dementia were defined at baseline and across up to 15 years until 2016‐2019. Data were analyzed using the Markov multi‐state model.ResultDuring the mean 10.7 years of follow‐up, 9.0% had incident dementia (95%CI: 7.8%–10.3%). Among people free of CIND at baseline (n = 2023), 27.4% had incident CIND during follow‐up (25.3%–29.6%). Higher lifelong CR capacity (mean value of composite CR score = 0.2; range: ‐4.2‐3.6) was associated with a lower risk of direct transitions from non‐dementia (normal or CIND) to dementia (multivariable‐adjusted HR = 0.84; 95% CI 0.73–0.95) and from normal cognition to CIND (0.79; 0.73–0.85), but not with the direct transitions from normal cognition to dementia (0.86; 0.72–1.03), from CIND to dementia (0.93; 0.76–1.14), or from CIND to normal cognition (1.15; 0.98–1.35). Higher lifelong CR capacity was associated with a lower risk of direct transition from normal cognition to dementia in people with APOE‐ε4 and those with high GM volume (2nd‐4th quartiles), but not in those without APOE‐ε4 or with low GM volume (1st quartile) (P‐for‐interaction<0.05). There was no statistical interaction of CR with age, sex, or other brain MRI markers on cognitive transitions.ConclusionHigher lifelong CR capacity may benefit late‐life cognitive status by reducing the risk of cognitive deterioration to dementia, especially in people with genetic predisposition or with low neurodegenerative load.
Eye movements during the judgment of line orientation test in patients with Alzheimer’s disease and amnestic mild cognitive impairment
Authors: Akkoyun Müge , Koçoğlu Koray , Boz Hatice Eraslan , Tüfekci Işıl Yağmur , Ekin Merve , Akdal Gülden 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by early impairment of memory. However, recent studies have revealed early abnormalities in other cognitive functions, such as visuospatial functions, the ability to process visual information, and visuospatial attention. The Judgment of Line Orientation (JLO) is a neuropsychological test commonly used to measure visuoperceptual and visuospatial abilities. Eye movements are a practical method for assessing cognitive processes during visual tasks. This study aimed to investigate eye movement patterns during the JLO test in AD and amnestic mild cognitive impairment (aMCI).MethodThe study sample consisted of 16 patients with AD (mean age 72.2±7.9 years), 34 patients with aMCI (mean age 70.3±6.5 years), and 37 HC (mean age 67.7±6.7 years). Eye movements during the 30‐item Benton JLO test were recorded with the EyeLink 1000 Plus. Fixation duration (FD), the response time (RT), and the total number of correct and incorrect responses were calculated.ResultThe mean of JLO scores was significantly lower in aMCI and AD than in HCs (p<0.001). In the correct responses, Patients with AD had a statistically significantly less FD on the test lines compared HCs (p = 0.019). Moreover, FD on the reference lines of correct responses was significantly decreased in AD (p = 0.006) and aMCI (p = 0.016) compared to HCs. In the incorrect responses, FD on the test lines was significantly increased in aMCI (p = 0.009) and AD (p = 0.008) compared to the HCs. The FD on the reference lines of the incorrect responses was increased in AD (p = 0.021) and aMCI (p = 0.013) groups compared to HCs. Additionally, AD (p = 0.001) and aMCI (p = 0.004) groups showed significantly increased RT in incorrect responses compared to HCs.ConclusionThis study showed that the AD and aMCI groups looked at visual stimuli with less fixation duration than HCs. The patient groups looked at the target for a longer time in incorrectly answered trials and had a delay in making decisions. The findings may indicate difficulties in visual‐spatial processing and visual‐attention deficit in these patient groups and provide insight into the underlying cognitive processes involved in visual perception in AD and MCI.
Cognitive Reserve proxies for individuals with intellectual disabilities: a Scoping Review
Authors: La Face Annalisa , Pucci Veronica , Mondini Sara , Gasteiger‐Klicpera Barbara 
Published: December 2023

AbstractBackgroundDementia in people with Intellectual Disability (ID) has a prevalence three times greater (Strydom et al., 2007) and with an earlier onset (Dodd et al., 2015) than in the general population. Despite the fact that virtually all adults with ID display neuropathology consistent with dementia by the age of 40, many of them never show the clinical symptoms (Strydom et al., 2009): there is no linear link between degree of brain damage and severity of the symptomatology (Arvio & Bjelogrlic‐Laakso, 2021). This discrepancy could be attributed to a difference in Cognitive Reserve (CR, Stern, 2009). However, CR has never been systematically studied specifically in relation to ID. To fill this gap, we aimed to identify potential indicators (“proxies”) of CR specifically relevant for people with ID to be included in future instruments. Indeed, activities potentially promoting and enhancing CR in people with ID may not overlap with those considered by the instruments for the general population (see CRIq, Nucci et al., 2012).MethodA Scoping Review was conducted in PubMed and Scopus. N = 1239 potentially relevant papers were identified, 104 papers were assessed for eligibility and 17 studies matched our inclusion criteria.ResultWe consider as proxies of CR all lifestyle factors and life experiences proven in past studies to be positively correlated with the cognitive performance or with the everyday functioning of adults with ID, even if not explicitly labeled as proxies of CR. Some proxies found are partly overlapping with the ones used to quantify CR in the general population: Education, Occupation, Leisure and Physical activity. Yet, others are uniquely suitable for the population with ID: Type of schooling, Parental educational level, Environmental stimulation and Living place. Those should be incorporated within the instruments developed and validated in the future to assess the CR of people with ID.ConclusionThis Review is the first step toward the development of the first instrument to measure CR in people with ID. The hope is that it will be integrated among the instruments routine used in the clinical practice and assure people with ID an early and accurate diagnosis of dementia.
Which intrinsic and extrinsic factors predict decline of activities of daily living in dementia?
Authors: Puthusseryppady Vaisakh , Bregola Allan , Camino Julieta , Backhouse Tamara , Mioshi Eneida 
Published: December 2023

AbstractBackgroundVarious intrinsic and extrinsic dementia factors have been suggested to contribute separately to disability in people with dementia (PwD). Objective: To investigate if the combination of specific intrinsic and extrinsic factors at baseline can predict longitudinal declines in activities of daily living (ADL) performance of PwD at 12‐month follow‐upMethod141 community‐dwelling PwD‐carer dyads were assessed on their global cognition (ACE‐III), apathy (CBI‐R), carer management styles (DMSS), medical comorbidities (CCI), and ADL performance (DAD) at baseline, and for a subset of participants (n = 53), at 12‐month follow‐up. Multiple linear regression models were run to assess: 1) the relationships between PwD’s DAD scores and the remaining variables at baseline and 2) whether these variables’ scores at baseline can predict longitudinal change in the PwD’s DAD scores.ResultAt baseline, having lower ACE‐III (β = 0.379, p<0.001), higher CBI‐R (β = −0.287, p<0.001), higher DMSS criticism (β = −0.409, p = 0.003), lower DMSS encouragement (β = 0.387, p = 0.006), and higher CCI scores (β = −2.660, p = 0.008) were significantly associated with having lower DAD scores. The PwD’s DAD scores significantly declined from baseline to follow‐up (p<0.001, d = 1.15), however this change could not be predicted by the baseline scores of any of the independent variables. This change was instead predicted by declines in the PwD’s ACE‐III scores from baseline to follow‐up (β = 1.021, p = 0.001).ConclusionIn our limited sample, cognitive changes seem to be the main factor underlying longitudinal decline in ADL performance for PwD. Carer management styles appear relevant in predicting current ADL performance but not in predicting longitudinal ADL decline.
DEPRESCRIBING IN OLDER POLY‐TREATED PATIENTS AFFECTED WITH DEMENTIA: A SHARED EXPERIENCE BETWEEN UNIVERSITY AND TERRITORY
Authors: Gareri Pietro , Gallelli Luca , Palleria Caterina , Gareri Ilaria , De Sarro Giovambattista 
Published: December 2023

AbstractIntroductionThe present study aimed to assess geriatric poly‐treated patients of the Center for Cognitive Disorders and Dementia of Catanzaro Lido, in collaboration with the School of Pharmacology, University of Catanzaro, Faculty of Medicine. We used the Beers, and STOPP & START criteria for assessing poly‐treatment and deprescribing in the population under investigation.Patients and MethodsIn the time range between October 2021 and September 2022, we randomly assessed 205 patients, 114 outpatients, and 91 home care patients.The primary outcomes were: 1) deprescribing inappropriate drugs through the Beers and STOPP & START criteria;2) assessing duplicate drugs, and the risk of iatrogenic damage due to drug‐drug and drug‐disease interactions.Results69 men and 136 women, mean age of 82.7±7.4 years old, were studied. Of these, 91 patients were home care patients and 114 were outpatients. The average of the drugs used in the sample was 9.4 drugs/patient; after the first visit and the consequent deprescribing process, the average dropped to 8.7 drugs/patient (p = 0.04). Potentially inappropriate drugs were overall 74(36.1%). Of these, long half‐life benzodiazepines (8.8%), non‐steroidal anti‐inflammatory drugs in chronic use (> 15 days) (3.4%), tricyclic antidepressants (3.4%), first‐generation antihistamines (1.4%), anticholinergics (11.7%), ticlopidine (1.4%), prokinetics in chronic use (1.4%), digoxin at dosage > 0.125 mg (1.4%), amiodarone (0.97), a‐lytics (1.9%). The so‐called “duplicate” drugs were overall 26 (12.7%). 10 potentially dangerous prescriptions were found for interactions (4.8%).Discussion and conclusionsApplying the Beers and STOPP&START criteria can improve the use of drugs in the poly‐treated patient. We underline the importance of checking all the drugs taken periodically, discontinuing drugs with the lowest benefit/harm ratio and the lowest probability of adverse reactions due to withdrawal. Currently, there are no guidelines to properly address the management complexities of the older patient. Computer tools and properly trained teams (doctors, nurses, pharmacists) could identify, treat and prevent possible drug interactions.
Relationships between KLOTHO and APOE4‐associated β‐amyloid and tau alterations across AD continuum
Authors: Cook Noah R. , Driscoll Ira , Gallagher Catherine L. , Johnson Sterling C , Asthana Sanjay , Hermann Bruce P , Sager Mark A. , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Carboni Margherita , Wang Dan , Dubal Dena B. , Okonkwo Ozioma 
Published: December 2023

AbstractBackgroundApolipoprotein E ε4 allele (APOE4) is the leading genetic risk factor for Alzheimer’s disease (AD). APOE4 carriers (APOE4+) exhibit greater accumulation of the two AD neuropathological hallmarks, beta‐amyloid (β‐amyloid) and tau. KLOTHO KL‐VS heterozygosity (KL‐VSHET) attenuates APOE4‐related β‐amyloid and age‐related tau burden in cognitively normal individuals. It remains unclear whether this holds true for individuals with mild cognitive impairment (MCI) and AD. Here we investigate whether KL‐VSHET attenuates APOE4‐related cerebrospinal fluid (CSF) AD‐biomarker burden across the AD continuum.MethodMiddle‐aged and older adults (N = 396; MeanAge = 65) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center who were genotyped for KLOTHO and APOE and underwent CSF sampling were included in analyses. General linear models, covarying for sex, age, and AD family history, examined whether APOE4 yielded expected outcomes on β‐amyloid and tau burden. Follow‐up regression analyses, stratified by KL‐VS genotype [non‐carriers(KL‐VSNC,N = 293); KL‐VSHET (N = 103)], evaluated whether the APOE4 associations with β‐amyloid and tau differed between KL‐VSHET and KL‐VSNC. Analyses were stratified further by diagnosis [cognitively normal (N = 308) or MCI/AD (N = 88)] to investigate whether the relationships between APOE4 and β‐amyloid or tau differed among KL‐VSHET and KL‐VSNC in cognitively normal and MCI/AD participants.ResultResults for the entire sample, as well as stratified by KL‐VS status and diagnosis, are presented in Table 1. When the analysis was stratified by KL‐VS status, the APOE4+ effect on both β‐amyloid and tau burden was seen among KL‐VSNC but not KL‐VSHET. When further stratifying by diagnosis, the same pattern of attenuation among KL‐VSHET was observed for β‐amyloid burden in both cognitively normal individuals and MCI/AD whereas for tau burden, we only observed a non‐significant trend among cognitively normal persons (KL‐VSNC: p = 0.10; KL‐VSHET: p = 0.74).ConclusionKL‐VSHET attenuates both APOE4‐related CSF β‐amyloid and tau burden in cognitively normal individuals. This attenuation extends to CSF β‐amyloid but not tau accumulation in MCI/AD. These results add to the literature suggesting that KL‐VS heterozygosity is protective against APOE‐related biomolecular alterations that confer AD risk.