bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic potential of niacin in Alzheimer's disease
Authors: Moutinho Miguel , Tsai Andy P. , Puntambekar Shweta S , Patel Jheel , Lin Peter B. , Jadhav Vaishnavi , Williams Roxanne Y , Shekhar Anantha , Landreth Gary E. 
Published: December 2020

AbstractBackgroundDietary intake of niacin reduces the risk of Alzheimer's disease (AD) and protects against age‐related cognitive decline. Niacin is a ligand for the niacin receptor HCAR2, which, in the brain, is selectively expressed by microglia. HCAR2 activation has been shown to be neuroprotective in stroke and demyelination models. Therefore, we hypothesized that niacin administration could have beneficial effects in AD pathology.Method5 month‐old 5xFAD mice, an animal model of AD, were treated with a FDA‐approved formulation of niacin (Niaspan®) daily, by oral gavage for 30 days with 100 mg niacin/kg. After treatment, the animals were sacrificed and the brains were collected for immunohistochemistry and biochemical analysis. Gene expression and Aβ uptake efficiency were analyzed in primary cultures of microglia incubated with 1.25 nM of Niaspan®.ResultOur results indicate there is an induction of HCAR2 expression in the AD brain, prominently in activated microglia. Niaspan® treatment significantly reduced Aβ burden and number of compact plaques in 5xFAD brain. Accordingly, Niaspan® induced phagocytic genes and Aβ uptake in primary cultures of microglia. Importantly, Niaspan® exerted a neuroprotective effect evidenced by reduced neuronal loss in the subiculum and cortical layer 5 of Niaspan®‐treated mice, accompanied by a rescue of working memory deficits.ConclusionThese preliminary data suggest that Niaspan® treatment has neuroprotective effects in AD, even after the onset of severe amyloid pathology, through an induction of Aβ cleareance by microglia. Niaspan® is a FDA‐approved drug, thus there is a translational potential of this strategy into clinical practice, supporting further study of this therapeutic approach.
Plasma‐free amino acid (PFAA) profile is a potential blood‐based biomarker for detection of mild cognitive impairment (MCI)
Authors: Yano Yuki , Sato Wataru , Kasuga Kensaku , Tokutake Takayoshi , Kitamura Hitomi , Kanda Mayuka , Arashida Naoko , Nagao Kenji , Morikawa Fumiyoshi , Toru Shuta , Nishimura Chika , Miyazawa Nobuhiko , Kuroha Yasuko , Kitamura Akihiko , Kaneko Eiji , Yamakado Minoru , Ikeuchi Takeshi 
Published: December 2020

AbstractBackgroundPrimary prevention of cognitive decline is important while development of disease modifying drugs for early Alzheimer's Disease (AD) is progressing rapidly. As a screening tool for early detection of cognitive decline, blood‐based biomarkers prior to invasive testing such as cerebral spinal fluid examination and positron emission tomography scanning could be beneficial. In our small‐scale pilot study, plasma‐free amino acid (PFAA) profiles of AD patients and mild cognitive impairment (MCI) due to AD were shown to be significantly different from those of cognitively healthy elderly. In order to examine the clinical significance of PFAAs as a novel biomarker, we started an MCI cohort study that enrolls hundreds of MCI subjects to determine practical biomarkers for MCI screening among generally healthy subjects, and to distinguish stable MCI and AD‐converted MCI. The results of interim baseline analysis regarding MCI screening will be presented here.MethodMCI subjects from 6 medical sites in Japan (MCI, n=117) and age‐gender‐matched community dwellers in 3 different cities in Japan (healthy control, n=117) were included in the current analysis. At baseline visit, plasma samples were collected under fasting condition. The concentrations of PFAAs and plasma amines were analyzed with LC/MS or LC/MS/MS and serum biochemistry tests were done. Observation of the clinical status of MCI subjects for 3 years after the blood collection is ongoing.ResultSeveral PFAAs including essential amino acids of MCI subjects were significantly lower than those of healthy control. There were no significant differences in plasma amine concentrations between MCI and control group. In addition, several serum biochemistry parameters including serum albumin of MCI subjects were significantly lower. These differences were independent of age and gender.ConclusionBoth PFAAs including essential amino acids and serum biochemistry including albumin were shown to be potential biomarkers for MCI screening. The validation of this results will be conducted in another subset in this MCI cohort study. For further investigation, we will conduct multivariable analysis and create the robust algorithm for MCI screening. Also, observation of the clinical status of MCI subjects will continue to distinguish stable MCI and AD‐converted MCI.
The evidence for the effects of physical exercise training on cognitive function for those with mild cognitive impairment
Authors: Cox Kay L , Lautenschlager Nicola T 
Published: December 2020

AbstractBackgroundThe evidence supporting the view that physical activity (PA) and exercise training in particular aerobic or resistance training improves cognition for those with mild cognitive impairment (MCI) is accumulating. ‘PA’ usually refers to any bodily movement whereas ‘exercise’ refers to planned and/or structured activity which may be aerobic exercise, resistance training or a combination (multimodal) or mind‐body exercise. Systematic reviews and meta‐analyses report inconsistent results, highlighting methodological issues including variations in study design; the type duration and frequency of the exercise utilised; the cognitive outcome and the heterogeneity of the target group. In order to minimise the effects of these issues, in utilising the treatment framework, we limited our summary to focus on the effects of aerobic training and resistance training separately on cognition in participants 60 years and over with MCI.MethodSeveral databases were searched to identify systematic reviews or meta‐analyses of RCT’s conducted in the last 5 years evaluating the effects of aerobic or resistance exercise on cognition. Reviews relevant to each regime were summarised to identify the ingredients and dosing parameters.ResultsFive systematic reviews and meta‐analyses reported positive effects of aerobic exercise on global cognition with small to medium effect sizes and one with weak significant benefits on memory. Session duration ranged between 20‐60 minutes, frequency between 2‐5 times/week and intensity between 60‐80% of maximum heart rate. The evidence for resistance training is more limited with 4 recent reviews. Evidence for global cognition with small to moderate effects was strongest with limited effects for executive function. Higher intensity and more frequent sessions appear to be more effective but have low adherence rates. Formats are progressive using one’s own body weight, free weights, dumbbells, resistance bands, weight machines or a combination, supervised with sessions of 60‐75 minutes in duration 2‐3 times/week.ConclusionThe evidence for an effect of aerobic training on cognition is growing and the evidence for resistance training is promising. Refinement of the treatment specifications for optimal cognitive outcomes requires further investigations of interventions with clearly defined mode, frequency, duration and intensity of exercise and crucial reports of adherence to the treatment.
AAV mediated gene therapy as local treatment modality directed against amyloid beta oligomers in the brain using a high affinity, high specificity antibody
Authors: Blits Bas , Gouwenberg Yvonne , Gebuis Titia , van der Loo Rolinka , van Kesteren Ronald E. , Smit August B. , Preusting Hans , Scheefhals Guus 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by formation of amyloid beta (AB) plaques in the brain. Intermediate aggregates such as oligomers are considered to be the most toxic. Using AAV gene therapy, we express an antibody specifically directed against these AB oligomers. Local expression in the brain avoids the challenge of inefficient blood brain barrier transfer, and AAV vector administration would be needed only once for a long‐lasting effect. In this project, we are designing and characterizing AAV‐5 based vectors for the development of a gene therapeutic immunotherapy for AD.MethodAAV‐5 vectors were chosen as safe and effective delivery system for antibody expression and secretion in the brain. To test whether the generated recombinant AAV is functional, primary hippocampal neurons were infected and analyzed for transgene expression. Oligomer‐binding functionality of the expressed antibody was analyzed using ELISA. Moreover, AAV vectors were administered in vivo, either directly into the hippocampus or intracerebroventricular of wild type mice.ResultRecombinant AAV‐5 particles were able to infect and transduce primary hippocampal neurons. Western blot analysis revealed presence of antibody both in cell homogenate and secreted in medium. Functionality of the antibody was demonstrated by binding AB oligomers in an ELISA. In vivo, both routes of administration resulted in transduction patterns that could well be used to target an AD diseased brain.ConclusionRecombinant AAV‐5 vector encoding for the antibody is tested positive in vitro and in vivo, suggesting that the antibody can be expressed and secreted in the brain to target AB oligomers at the site where it is needed. Future studies should reveal whether native AB oligomers are also recognized and efficiently neutralized in an appropriate mouse model of AD resulting in enhanced cognitive performance.
Subtypes of Alzheimer’s disease and the ATN biomarker scheme
Authors: Cedres Nira , Ekman Urban , Ferreira Daniel , Westman Eric 
Published: December 2020

AbstractBackgroundUnderstanding the association between two popular classification schemes: AD subtypes (based on patterns of brain atrophy) and the ATN (based on dichotomous categories of amyloid‐beta deposition (A), tauopathy (T) and neurodegeneration (N)) might increase our current understanding of the neurobiological heterogeneity within AD. We aimed to evaluate the association between the AD subtypes based on brain atrophy patterns and the ATN scheme, in the context of other relevant disease measures such as a marker of small vessel disease (white matter changes, WMC) and the source of the patients: ADNI vs. a memory clinic (KIDS).MethodsAD patients from two large cohorts were investigated: Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Karolinska Imaging Dementia Study (KIDS). The ATN categories were entirely based on cerebrospinal fluid (CSF) biomarkers, and the subtypes on atrophy patterns were based on visual ratings from magnetic resonance imaging. Clustering analysis was used to further investigate associations with demographic and clinical factors.ResultsThe clustering analysis showed different distributions of ATN profiles and brain atrophy patterns in ADNI as compared with KIDS. Typical AD was the most frequent AD subtype in both cohorts, while limbic‐predominant and minimal atrophy AD were more frequent in KIDS than in ADNI. The A+T+N‐ profile was more frequent in ADNI, while A+T‐N+ and A+T‐N‐ profiles were more frequent in KIDS. The distribution of AD subtypes was associated with age in ADNI while in KIDS, it was also associated with MMSE as a measure of global cognition.ConclusionsThe distribution of and association between AD subtypes and ATN profiles depends on the source of the patients, aligning with different demographic and clinical characteristics depending on whether the cohort is more selective (ADNI) or more naturalistic and heterogeneous (KIDS). In ADNI we found a distribution of ATN profiles that seems to mainly reflect AD staging (i.e. A+T‐N‐, A+T+N‐, and A+T+N+). In KIDS, which is a heterogeneous memory clinic cohort, the ATN distribution seem to be determined by very early disease stages, either more “pure” (i.e. A+T‐N‐) or also including comorbidities contributing to unspecific neurodegeneration in the absence of a T+ biomarker (i.e. A+T‐N+).
Impact of the disclosure of amyloid‐PET results to patients with subjective cognitive decline: the AMYPAD Diagnostic and Patient Management Study (DPMS)
Authors: Poitrine Léa , Altomare Daniele , Moro Christian , Collij Lyduine , Alves Isadora Lopes , Barkhof Frederik , Saint‐Aubert Laure , Delrieu Julien , Jessen Frank , Félez‐Sánchez Marta , Lee Lean , Walker Zuzana , Démonet Jean‐François , Nordberg Agneta K , Gismondi Rossella , Farrar Gill , Stephens Andrew W , Molinuevo Jose Luis , Frisoni Giovanni B , Wuthrich Sonia Plaza , Escher Claus , Lee Ho‐Yun , Scheltens Philip 
Published: December 2020

AbstractBackgroundAmyloid‐PET is increasingly used for diagnostic purposes in patients with cognitive impairment due to suspected Alzheimer’s disease. However, cognitively unimpaired individuals are frequently included in research studies involving amyloid‐PET scan. Even if amyloid‐PET is not clinically recommended in these cases, these patients often want to know their amyloid status, a strong risk factor for incident dementia. Currently, evidence on the impact of the disclosure of amyloid‐PET results on patients’ psychological well‐being is scanty. The aim of this sub‐study is to assess how a positive amyloid‐PET result affects the psychological well‐being of patients with subjective cognitive decline plus (SCD+) enrolled in a prospective study on the diagnostic utility of amyloid PET (AMYPAD‐DPMS).MethodThe impact of the disclosure of amyloid‐PET results on patient’s psychological well‐being was investigated using the Impact of Event Scale–Revised (IES‐R). IES‐R is used to detect potential changes from the current time point and a previous time point preceding up to 7 days an event (the amyloid‐PET result disclosure in this case). IES‐R was administered 1‐3 days post‐disclosure, and consists of one total score (0‐88) and three sub‐scores (0‐4): avoidance (avoidance of thoughts, feelings, memories or situations), intrusions (intrusive memories, thoughts, or feelings causing distress), and hyperarousal (hypervigilance, feeling watchful and on guard, difficulty concentrating). IES‐R total score between 12‐32: symptoms of post‐traumatic stress, patient monitoring is required; ≥33: probable presence of a post‐traumatic stress disorder.ResultSo far, 36 SCD+ participants of AMYPAD‐DPMS, who received their amyloid‐PET results, have accepted to participate in this sub‐study. Amyloid‐positive patients (n=9) had higher IES‐R total score (median=10, lower‐upper quartiles=1‐14) than amyloid‐negatives (1, 0‐6), albeit at trend level (p=0.052). We also observed higher avoidance scores in amyloid‐positives compared to amyloid‐negatives (0, 0.00‐0.62 vs. 0, 0.00‐0.00, p=0.004), but no differences in the other two sub‐scores (p>0.05).ConclusionThese preliminary data on 36 participants suggests that the disclosure of positive amyloid scan to an SCD+ patient is associated with the avoidance of thoughts and memories of the news. Future analyses will address additional outcome measures (e.g. post‐disclosure anxiety and depression) and factors associated with a milder psychological impact in amyloid‐positive patients.
Astrocyte cholesterol is essential for amyloid beta production
Authors: Kulas Joshua A. , Wang Hao , Hansen Scott B. , Ferris Heather A. 
Published: December 2020

AbstractBackgroundSeveral variants of genes involved in cholesterol metabolism are risk factors for the development of Alzheimer’s disease (AD). We disrupted the master regulator of cellular cholesterol metabolism, SREBP2, and assessed the impacts of this disruption in neuron‐glia primary cell co‐cultures and in the 3xTg mouse model of AD.MethodGlial SREBP2 ablation was induced in neuron‐glia cultures by treatment of Aldh1l1‐CREERT2xSREBP2flox mixed primary cell cultures with 4OH tamoxifen. Amyloid precursor protein (APP) trafficking to lipid raft domains was quantified by dSTORM imaging. SREBP2 was ablated in the brains of 3xTg AD mice by crossing to an SREBP2‐flox and then a GFAP‐CRE. Aged (40 week old) mouse brains were then assessed for Aβ and pTau burden by ELISA.ResultDisruption of glial SREBP2 was sufficient to significantly alter localization of APP from α‐secretase rich disordered membrane regions to β‐ and γ‐secretase enriched lipid raft domains (Figure A). In 3xTg‐AD animals, SREBP2 ablation did not alter total levels of APP or Tau, but significantly reduced both Aβ 1‐42 peptide burden and P‐T181 Tau abundance in 40‐week hippocampus (Figure B).ConclusionDisruption of astrocyte‐mediated cholesterol metabolism is sufficient to robustly reduce Aβ and pTau burden in a mouse model of AD, which likely occurs in part through reduced APP localization to lipid rafts.
Long‐term exposure to ambient air pollution and risk of dementia: Results of the prospective Three‐City Study
Authors: Mortamais Marion , Gutierrez Laure Anne , de Hoogh Kees , Benmarhnia Tarik , Helmer Catherine , Tzourio Christophe , Dartigues Jean‐François , Letellier Noemie , Jacquemin Benedicte , Berr Claudine 
Published: December 2020

AbstractBackgroundChronic exposure to air pollution (AP) is associated with cardiovascular morbidity and mortality. Emerging epidemiological evidence suggests a relationship between exposure to various air pollutants (fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2)) and dementia. However, most of existing studies relied on population‐based health administrative databases to obtain a dementia diagnosis. In a large French population‐based cohort (the Three‐City Study) and using state‐of‐the‐art models for AP exposure, we aimed at assessing the effects of different air pollutants on dementia risk using reliable diagnosis tools.MethodsParticipants aged ≥65 years were recruited between 1999 and 2001 and followed for 12 years. At baseline and every 2 years, dementia diagnoses were preliminary made using DSM‐IV criteria and validated by an adjudication committee. Levels of NO2, O3, Black Carbon and PM2.5 were obtained at the residential addresses of participants using land‐use regression models developed for Europe in the ELAPSE project (de Hoogh et al., Env Int 120 (2018) 81‐92). For each year of follow‐up, we estimated for each subject a 10‐year moving window of mean past exposure to each pollutant. We used a Cox Proportional Hazard model where exposure to AP was included as a time‐varying variable. Analyses were adjusted for individual (age, sex, education, APOE4 genotype, vascular risk factors, depression, respiratory diseases) and contextual (neighborhood’s deprivation index) level confounders.ResultAt baseline, the mean (SD) age of the 7956 participants was 73.2 (5.4) years‐old. Sixty‐one percent of them were women. The mean time of follow‐up was 9.2 (3.6) years. Over the follow‐up period, the mean annual PM2.5 levels ranged from 15 to 33 µg/m3 and 910 participants developed dementia. We observed a positive association between levels of PM2.5 and dementia risk [HR=1.16, 95%CI (1.02‐1.32) for a 5µg/m3 increase in PM2.5]. We did not observe any relationship between exposure to the other air pollutants and dementia risk.ConclusionIn this large cohort with reliable diagnosis of dementia and individual estimates of AP exposure, we observed that long‐term exposure to PM2.5 was associated with higher dementia incidence. These results suggest that PM2.5 exposure might be a modifiable risk factor of dementia.
Creating a patient‐centered guide to navigating cognitive change in Parkinson’s disease
Authors: Dolhun Rachel , Amodeo Katherine , Goldman Jennifer , Ruhlin Susan , Butler Ava , Iverson Dave 
Published: December 2020

AbstractBackgroundThe Michael J. Fox Foundation for Parkinson’s Research (MJFF) regularly gathers feedback from patients and families about their experiences with Parkinson’s disease (PD). We often hear that cognitive changes are among the most feared and troublesome symptoms. Participants in Fox Insight, MJFF’s online observational study, reported cognition as their third most bothersome symptom1 and in an informal survey of 797 webinar attendees, more than 40 percent said cognitive changes always or often affect daily life, confirming known research.2 Mild cognitive impairment affects 25 percent3,4 and dementia impacts 40 percent5 of people with Parkinson’s. Yet honest, relatable, actionable information on this topic is lacking. To fill this information gap, MJFF’s on‐staff movement disorder specialist facilitated question‐driven discussion with three groups: 1. Providers — four movement and cognitive specialists; 2. Patients — 23 people with PD; 3. Care partners — two social workers and seven care partners of people with Alzheimer’s disease or Lewy body dementia. Care partners also completed a 17‐item questionnaire. Sessions focused on understanding how participants think and talk about cognitive changes as well as what patients and care partners want to know about cognitive changes and how to manage them. Patients and families want early, honest information so they can be proactive and plan. Clinicians recognize the need to mitigate fear and denial and to address cognitive changes in compassionate, reassuring and useful ways. We used these insights to create accessible, practical resources including a 35‐page guide, a webinar and a video. These materials offer information on how thinking and memory can change in Parkinson’s, tips and treatments to promote brain health and ease cognitive symptoms, strategies for talking with loved ones and providers about cognitive changes, and connections with the latest research. Demonstrating the urgent need for this information, the guide and associated materials have been downloaded over 325,000 times in less than four months and over 3,400 people attended the webinar. MJFF’s resources convey a sensitive topic in a relatable and empathic manner to decrease fear and stigma, stimulate discussion, promote research participation, and help patients and families maintain quality of life with cognitive changes.