bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated [Primary +] Memory Care Clinic
Authors: Clevenger Carolyn K 
Published: December 2022

AbstractBackgroundThe Integrated Memory Care Clinic (IMCC) is a model of care for people living with dementia directed by advanced practice registered nurses. The post‐diagnosis model incorporates the expertise of nursing, social work and nurse practitioners certified in gerontology, palliative care and/or geriatric psychiatry.MethodThe Clinic nurse practitioners provide comprehensive and coordinated primary care for dementia and other stable chronic conditions and episodic care for minor acute illnesses. Care delivery is structured to maximize ongoing dialogue with patients and their caregivers during office visits and by phone and patient portal access. The Clinic provides a number of services to care partners, including an after‐hours line, stage‐based educational groups, and a monthly support group. The IMCC aims to reduce the overall burden of dementia by partnering with affected individuals and their caregivers in the co‐production of care.ResultNow at full capacity, the IMCC serves 525 active patients and their care partners with 1.3 FTE primary care nurse practitioners. The mean age is 78.6 years; most are female (63%); and 42% identify as a racial minority. The majority of patients are moderate (27% early‐moderate; 36% late‐moderate) stage of dementia clinical syndrome. The mean monthly rate of hospital admissions for ambulatory care sensitive conditions in 2022 is 1.42%. The published rate for this population is 13‐15%. Finally, the model is financially neutral in a fee‐for‐service environment.ConclusionOpen in 2015, the IMCC has combined primary care and dementia care in one clinical practice. The IMCC developed strong rapport and trust with patients and families to achieve outstanding health outcomes. The model is an American Academy of Nursing Emerging Edge Runner, recognized by NCQA as a Patient Centered Medical Home, recognized as a Level 2 Age‐Friendly Health System participant, and a Best Practice Exemplar by the Institute for Patient‐ and Family‐Centered Care.
Blood‐brain barrier permeability is increased in early Alzheimer’s disease and correlates with brain microstructure
Authors: Reas Emilie T. , Tsiknia Amaryllis A. , Banks Sarah J. , Rostowsky Kenneth A , Andrews Murray , Brewer James B. , Bolar Divya S 
Published: December 2022

AbstractBackgroundVascular dysfunction frequently accompanies Alzheimer’s disease (AD), and its suspected contributions to AD pathogenesis may be partly mediated by disrupted blood‐brain barrier (BBB) function. Despite consistent evidence for increased BBB permeability in AD, it remains unclear whether BBB damage occurs in preclinical stages, when therapeutic interventions may be most effective. Furthermore, the relationship between BBB breakdown and microstructural neurodegenerative changes have not been well characterized.MethodDynamic contrast‐enhanced MRI and restriction spectrum imaging (RSI) were conducted to measure BBB permeability and brain microstructure, respectively, among 24 cognitively normal controls and eight individuals with mild cognitive impairment or mild AD (aged 77±5 years, 41% women). Participants were enriched for AD risk, with 72% amyloid‐positive as determined by cerebrospinal fluid amyloid‐B42/40 and 50% APOE4 carriers. The volume transfer coefficient Ktrans, an estimate of vascular permeability, and RSI measures of restricted, hindered, and free water diffusion, were computed in the hippocampus, entorhinal cortex, and across all white matter. Differences in Ktrans were examined between impaired and control subjects, and between APOE4 carriers and non‐carriers. Correlations between Ktrans and brain microstructure were computed to examine associations between BBB permeability and microstructure. Analyses adjusted for age, sex, and education. Subgroup analyses were conducted within cognitively normal controls.ResultEntorhinal cortex Ktrans was higher for cognitively impaired subjects than controls. Higher Ktrans correlated with lower education, but was not associated with age, sex, amyloid‐B42/40, hypertension, or APOE genotype. Among controls, white matter Ktrans was higher for APOE4 carriers versus non‐carriers. Ktrans correlated with restricted, hindered, and free water diffusion in the hippocampus, entorhinal cortex, and white matter within controls in an APOE‐dependent manner. Results were essentially unchanged by adjustment for amyloid‐B42/40 or hypertension.ConclusionBBB permeability increases in individuals with mild cognitive impairment and in cognitively normal individuals at elevated genetic risk for AD, independent of amyloid pathology. BBB breakdown is associated with microstructural abnormalities that may reflect cell loss or dystrophy, or neuroinflammation, in an APOE‐dependent manner. Our findings suggest that BBB breakdown may occur in early AD and promote neurodegeneration via APOE‐dependent avenues, warranting further examination of the mechanisms underlying AD‐related BBB compromise.
Subcortical brain structure and APOE genotype: An analysis of 43,000 participants from the UK Biobank
Authors: Ching Christopher RK , Thomopoulos Sophia I , Santhalingam Vigneshwaran , Gleave Emma J , Zhu Alyssa H , Islam Tasfiya , Abaryan Zvart , Jahanshad Neda , Thompson Paul M 
Published: December 2022

AbstractBackgroundCarriers of the ε4 allele of the apolipoprotein (APOE) gene are at higher risk for developing Alzheimer’s disease (AD). In individuals with mild cognitive impairment or AD, the ε4 allele is associated with lower hippocampal and amygdala volumes. How ε4 affects brain structure in healthy individuals before AD symptom onset is less clear. APOE ε2 allele carriers may show slower rates of hippocampal volume loss, suggesting protection against AD. In this large‐scale analysis, we plot normative regional brain volume trajectories in adults (45‐82 years) and map regional subcortical volume differences between APOE genotypes.MethodWe used FreeSurfer 7.1 to segment average left and right accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus and lateral ventricle volumes from T1‐weighted brain MRI (N=43,000). Comparisons between APOE genotypes (ε2ε2, n=257; ε2ε3, n=5,479; ε3ε3, n=26,016; ε3ε4, n=10,263; ε4ε4, n=985) were made using linear mixed effect models, correcting for population structure, age, sex, and intracranial volume (ICV) as fixed effects, and site as a random effect. Results were adjusted for multiple comparisons (FDR q<0.05). Nomograms were derived by adjusting subcortical volumes for population structure, ICV, and site then fitting normative quantile regression models based on the standardized residuals for each region stratified by genotype.ResultNomograms showed similar age‐related trajectories for all APOE genotypes, with smaller gray matter volume and larger ventricle volumes with increasing age. Significantly smaller amygdala and hippocampal volumes were found in ε4ε4 compared to ε3ε4, ε3ε3, and ε2ε3 carriers, and smaller amygdala volumes in ε2ε2 versus ε3ε3 carriers. Smaller accumbens volumes were found in ε4ε4 carriers versus ε2ε3 and ε3ε3, and in ε3ε4 versus ε3ε3 and ε2ε3. Smaller thalamus volumes were found in ε3ε4 versus ε2ε3 and ε3ε3, ε4ε4 carriers had smaller volumes versus ε2ε3 and ε3ε3, and ε2ε2 carriers had smaller volumes versus ε2ε3 and ε3ε3.ConclusionIn this large sample of generally healthy individuals, APOE ε4 allele carriers exhibited lower subcortical volumes compared to those with more neutral AD genetic risk background (ε3ε3). Carriers of ε2ε2 had smaller thalamus and amygdala volumes compared to ε3ε3, suggesting differential effects of AD genetic risk across brain structures known to play a role in AD pathophysiology.
Analytical performance overview of the Lumipulse G pTau 181 Plasma RUO
Authors: Vandijck Manu , D'hont Jelle , Dekeyser Filip , Bastard Nathalie Le , Vandenbroucke Ina 
Published: December 2022

AbstractBackgroundStudies have shown that changes in Alzheimer’s disease (AD) biomarker levels occur in blood at approximately the same time as in cerebrospinal fluid (CSF). Therefore, plasma‐based testing could be used as a simple, accessible, and scalable approach to help support the diagnosis of AD, avoiding the complexity of CSF sampling, and the high costs and limited availability of PET imaging. It was demonstrated that plasma pTau181 has the potential to be a good predictor of amyloid PET positivity, has proven to differentiate between AD and non‐AD neurodegenerative diseases, and is able to predict progression to AD. The aim of this study was to determine the preliminary analytical performance of the newly developed Lumipulse G pTau 181 Plasma RUO assay.MethodThe LUMIPULSE G System is a chemiluminescent enzyme immunoassay platform that allows fully automated processing of samples using ready‐to‐use immunoreaction cartridges. Time to result in these single use test cartridges takes about 30 minutes. The assay uses AT270 for capturing and HT7/BT2‐conjugate for detection in a 2‐step set‐up. Parameters analysed were precision, sensitivity, linearity, and potential impact of interfering substances. The studies included a series of buffer– and K2EDTA plasma samples at different concentration levels, each tested in several replicates sized to the different parameters tested.ResultThe total within‐lab variability of the assay was found to be <5% CV for each of the samples tested, confirming the high precision of the LUMIPULSE G platform. Using low pTau181 concentrated plasma samples, the LoD was found to be <0.20 pg/mL, and the LoQ <0.50 pg/mL. The high sensitivity was confirmed by a formal concentration assignment to each tested samples of a cohort of healthy elderly subjects. Linearity was shown across the measurement range of the assay (0 – 60 pg/mL), and no significant impact of rheumatoid factor and human anti‐mouse antibodies was observed.ConclusionThis preliminary verification of the analytical performance of the Lumipulse G pTau 181 Plasma RUO indicated promising results in terms of low variability, good dilutional linearity, and high sensitivity. The assay is now ready for full analytical verification and clinical validation towards the identified contexts of use.
White Matter Disease is Associated with Widespread Grey Matter Atrophy in APOE4 non‐carriers with Early‐Stage Dementia
Authors: Vipin Ashwati , Kumar Dilip , Soo See Ann , Zailan Fatin Zahra , Leow Yi Jin , Koh Chen Ling , Ng Adeline Su Lyn , Ng Kok Pin , Kandiah Nagaendran 
Published: December 2022

AbstractBackgroundThe APOE‐ε4 (APOE4) allele and cerebrovascular disease (CVD), represented by surrogate MRI measures involving white matter hyperintensities (WMH) are key dementia risk factors [Tosto et al.,2015; Mahley et al.,2006]. They relate to grey matter volume (GMV) and cognitive decline, and demonstrate increased occurrence with lowered age of dementia onset [Boyle et al.,2016; Brickman et al.,2014]. Whether APOE4 is a key effect modifier in the relationship between WMH and GMV needs further exploration. Therefore, we examined independent and interactive effects of WMH and APOE4 on GMV and cognition in cognitively unimpaired (CU) and early‐stage dementia (ESD) participants. We hypothesized that participants with higher WMH load would demonstrate worse GMV atrophy and greater cognitive impairment, especially among APOE4 carriers.MethodWe studied 259 CU and 192 ESD (mild cognitive impairment, mild dementia) from a Singapore research cohort with neuroimaging, APOE genotyping and neuropsychological assessment data (Table 1). We investigated independent and interactive effects of WMH and APOE4 on whole‐brain voxel‐wise GMV using voxel‐based morphometry (uncorrected p<0.001; minimum cluster size=100 voxels). Multiple linear regression models assessed APOE4 and WMH interactive effects on global cognition (mini‐mental state examination–MMSE), memory (Alzheimer’s disease assessment scale‐delayed word recall) and executive function (Color Trails 2) in ESD.ResultHigher WMH load associated with widespread voxel‐wise grey matter atrophy across frontal, parietal, temporal and occipital lobes in CU and ESD (Fig.1). When stratified by APOE4 status, APOE4 carriers showed regions of GM atrophy in frontal, temporal and parietal regions. When examining the interaction between WMH and APOE4 on GMV, contrary to our hypothesis, APOE4 non‐carriers showed more extensive derogatory effects of WMH on GMV than APOE4 carriers (Fig.2). These effects extended into ESD cognitive performance with APOE4 non‐carriers displaying deteriorating global and executive function with increasing WMH load than APOE4 carriers (Fig.3).ConclusionWe illustrate APOE4 status as likely a key moderator in the relationship between WMH and GMV in both preclinical CU and ESD stages. With differential effects of WMH on GMV and cognition between APOE4 carriers and non‐carriers, interventions targeting WMH may need a differential approach depending on the APOE4 status.
Impact of CSF pTau/Aβ42 ratio on brain structure and metabolism in middle‐aged cognitively unimpaired individuals
Authors: Cacciaglia Raffaele , Milà‐Alomà Marta , Shekari Mahnaz , Operto Grégory , Falcon Carles , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Quevenco Frances‐Catherine , Gispert Juan Domingo 
Published: December 2022

AbstractBackgroundThe cerebrospinal fluid (CSF) pTau/Aβ42 ratio has emerged as a promising biomarker to monitor the pathological progression of Alzheimer’s disease (AD), even at preclinical stages. To date, no studies have assessed the impact of this continuous biomarker on the brain structure and metabolism in cognitively unimpaired (CU) individuals.MethodWe included 243 CU participants from the ALFA study (mean age=61.68 years) who underwent a lumbar puncture, magnetic resonance imaging (MRI) and 18F‐Fluorodeoxyglucose (FDG) positron emission tomography (PET). CSF Aβ42 and pTau181 were measured with the Elecsys® immunoassay (Roche Diagnostics International Ltd). After image preprocessing, we applied a voxel‐wise linear regression to test the impact of CSF pTau/Aβ42 ratio, as well as its interaction with age, sex and APOE‐ε4, on both gray matter volume (GMv) and brain metabolism. The statistical significance threshold was set to p<0.005, with a cluster extent correction of 100 voxels.ResultThere were no main effects of pTau/Aβ42 on either GMv or brain metabolism. However, a significant interaction with age indicated that for older individuals, a higher pTau/Aβ42 was associated with reduced GMv in the middle cingulum, the middle and superior frontal gyrus, and the angular gyrus (Fig. 1a). An interaction with sex indicated that for females, a higher pTau/Aβ42 was associated with reduced GMv in the precuneus, superior frontal and fusiform gyrus (Fig. 1b). For FDG, we found a significant interaction with sex indicating that females exhibited a metabolism reduction with increasing levels of pTau/Aβ42, in the hippocampus and anterior cingulum (Fig. 1c). Finally, an interaction with APOE‐ε4 indicated that ε4‐carriers showed lower metabolism in the bilateral striatum, as a function of increasing pTau/Aβ42 ratio (Fig.1 d).ConclusionIn CU individuals, the impact of the progression of AD pathophysiology as indicated by a higher CSF pTau/Aβ42 ratio, on both brain structure and metabolism is modulated by AD risk factors. These data suggest that each of these risk factors confers a higher vulnerability to the progression of AD pathology in asymptomatic individuals, as manifested by an early impact on brain structure and metabolism in brain areas which are known to be affected in clinical AD stages.
Rescuing impaired cortical‐hippocampal interactions during sleep with 40Hz stimulation targeted to hippocampus in 3xTg‐AD/PVcre mice
Authors: Benthem Sarah Danielle , Moseley Shawn C , Dixon Jessica R , Silk Ashley L , Stimmell Alina C , Wilber Aaron A 
Published: December 2022

AbstractBackgroundIn preclinical Alzheimer’s disease (AD), spatial learning and memory is impaired. We previously reported similar impairments in 6‐month 3xTg‐AD female mice on a virtual spatial reorientation task that requires learning to use landmarks for spatial orientation. Memory replay during sleep is critical for learning related plasticity, and hippocampal‐cortical dysfunction during sleep is a potential mechanism for memory impairments in AD. Consistent with this, we previously found that prior to emergence of significant pathology there were deficits in hippocampal‐parietal cortex (PC) coordination during sleep which predicted performance on the virtual spatial reorientation task. Gamma‐stimulation (40Hz) has been shown to clear AD pathology in mice, and improve functional connectivity in preclinical AD patients. Thus, we assessed hippocampal‐PC coordination in 6‐month female 3xTg‐AD/PVcre (4xTg) mice that were learning the same spatial reorientation task.MethodWe implanted a 16‐tetrode recording array targeting PC and hippocampus and an optical fiber aimed at hippocampus. Daily recording sessions of rest‐task‐rest commenced as mice learned to locate the unmarked reward zone. During the same surgery, cre‐dependent AAV was used to express channel rhodopsin 2 in hippocampal interneurons. This allowed for daily stimulation sessions after recording sessions, with either 40Hz or SHAM hippocampal stimulation. We assessed sleep quality metrics, and cortical spindles, and delta waves (DW) in PC during slow wave sleep. In hippocampus we assessed markers of memory replay (SWRs) during SWS.ResultAnimals with 40Hz entrainment showed increased REM sleep compared to SHAM animals. There was also a significant increase in SWR rate from pre‐ to post‐sleep, opposite a decrease in post‐sleep in SHAM mice; however, there was no difference in the absolute number or rate of DW or . Finally, in SHAM stimulated mice SWR‐DW temporal‐correlations were significantly reduced, similar to our previous findings in 3xTg‐AD mice; while in the 40Hz mice, this phase locking was rescued. .ConclusionThus, 40Hz stimulation of hippocampus may rescue learning and memory related functional interactions in the hippocampal‐PC network during sleep and as a consequence at least partially rescue impairments in spatial navigation.
What is the practical utility of the MyCognitionPRO platform for monitoring and preventing cognitive decline in a real‐world context of people over 50years‐old experiencing cognitive ageing?
Authors: Sandford‐james Anna , Parkes Jacqueline , Campbell Jackie 
Published: December 2022

AbstractBackgroundMyCognitionPRO is a CE‐marked digital health platform, offered as a subscription product by Beingwell Ltd; designed to help users self‐manage their cognitive health by combining cognitive assessment with personalised gamified training games. Reviews have highlighted computerised cognitive training as an effective non‐pharmacological intervention for enhancing cognitive functioning and quality of life of people with MCI or mild‐dementia (Hill et al., 2017; Bahar‐Fuchs et al., 2019). In a recent RCT, a now obsolete desktop version of MyCognitionPRO was used effectively by 21 Parkinson’s‐MCI patients (aged 40‐70 years) and caused a reversal in cognitive decline as compared to matched controls (van de Weijer et al., 2020). However, several real‐world trials investigating the effectiveness of the app‐based platform for people experiencing cognitive decline outside laboratory conditions indicate high rates of non‐adoption and non‐adherence in target users. The value of a digital health intervention is multi‐dimensional, relying on the willingness of end‐users, the capacity of features as well as its successful implementation in wider healthcare pathways (Kolasa & Kozinski, 2020).MethodThis mixed‐methods feasibility study explores the differing needs, opinions and variability of core stakeholders, representing multiple perspectives (people over 50 years‐old with early‐stage cognitive decline and their carers). Guided by digital‐health evaluation frameworks, quantitative data (app engagement and performance data) and qualitative data (e.g. observation of user‐experience and interviews) are analysed to assess feasibility.ResultAnalysis indicates key issues with acceptability, usability and accessibility of the MyCognition apps in this context, modelling factors that predict poor engagement as well as reporting the characteristics of subpopulations for which the MyCognitionPRO platform works best. Results are synthesised into a user‐centred product roadmap, providing recommendations for app developments, further user trials, coproduction and efficacy research.ConclusionA staged evidence‐generation strategy is necessary to ensure the effective launch of a usable, evidence‐based version of the platform that is tailored to user‐needs and implementation into relevant markets for the purpose of monitoring and preventing cognitive decline in people over 50years‐old.
Higher allostatic load is associated with poorer structural integrity in the limbic network in cognitively unimpaired elderly
Authors: Palix Cassandre , Chocat Anne , Ferment Victor , Coulbaut Laurent , Felisatti Francesca , Haudry Sacha , Gonneaud Julie , Collette Fabienne , Mézenge Florence , Landeau Brigitte , De la Sayette Vincent , Vivien Denis , Chetelat Gael , Poisnel Géraldine 
Published: December 2022

AbstractBackgroundAllostatic load (AL) is a cumulative measure of dysregulations across multiple physiological systems of the body occurring over time. AL was originally developed to explain how chronic stress damages physiologic systems and accelerates aging. Studies exploring the relationship between AL and brain health in older adults using a multimodal approach are limited. Our objective was to provide a comprehensive overview of the brain substrates of AL in cognitively unimpaired elderly using complementary multimodal neuroimaging techniques.MethodBaseline data of 111 cognitively unimpaired older adults (mean age, 68.9years) from the Age‐Well study (NCT02977819) were included. They underwent multimodal neuroimaging (T1‐weighted and diffusion MRI, FDG‐PET and amyloid‐PET). A global measure of brain integrity was obtained for each modality by extracting the averaged signal across the whole gray matter (GM) or white matter (WM) for diffusion. AL was computed based on 19 markers of health. First, we examined the relationships between AL and sex or age. Second, we performed multiple regression and voxel‐wise analyses to predict AL from each neuroimaging modality and to highlight the brain regions involved. Finally, we conducted forward stepwise multiple regressions including the 19 AL‐components to determine the prognostic components of each of these associations; correcting for age, sex and education.ResultAL was associated with sex (men>women) but not with age. Higher AL was associated with lower global GM volume and WM mean diffusivity. Adjusting for alcohol consumption, smoking habits, treatments or comorbidities, these associations remained unchanged. Association with lower GM volume was found in the parahippocampus, hypothalamus, anterior insula and prefrontal gyrus and with WM diffusivity in the corona radiata and corpus callosum. Stepwise regressions revealed that these associations with GM volume and WM diffusivity were mainly explained by the body mass index (BMI) and waist‐hip‐ratio (WHR), respectively.ConclusionHigher AL is associated with poorer structural integrity in regions of the limbic network, which is implicated in memory, emotion and stress processes and known to be particularly vulnerable to Alzheimer’s disease. Our results further suggest that maintenance of a healthy weight (by monitoring BMI and WHR) might help to prevent AL increase, thus promoting brain health.