bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of obesity, diabetes, hypertension and depression in two parallel, aging study cohorts from rural and urban India: SANSCOG study and TLSA
Authors: Sundarakumar Jonas , Sivakumar Palanimuthu T , Rao Naren P , Ravindranath Vijayalakshmi ,   SANSCOG and TLSA Investigators
Published: December 2020

AbstractBackgroundPopulation aging has contributed to high global prevalence of dementia, particularly in developing countries like India. Increasing evidence indicates that the pathogenesis of dementia starts several decades before its symptoms become manifest, thus making it important to identify the risk and protective factors even before the onset of its clinical features. Longitudinal, population‐based, aging studies offer an excellent opportunity to do this.MethodSrinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) study and Tata Longitudinal Study on Aging (TLSA) are parallel, prospective, community‐based, cohort studies in India – rural and urban, respectively – for comprehensive evaluation of risk and protective factors associated with cognitive changes due to normal ageing, dementia and other related disorders. Both the study cohorts comprise of cognitively healthy individuals aged ≥ 45 years. However, they have distinct population characteristics with respect to socio‐economic status, migration, literacy and lifestyle. Participants in the SANSCOG study are recruited from the villages of Srinivaspur Taluk in Kolar District in southern India, through an area sampling strategy, whereas, those in TLSA are recruited through convenience sampling, from urban Bangalore, India. Participants undergo detailed clinical and neuro‐psychiatric assessments that provide valuable data on a variety of health parameters, including vascular risk factors. Harmonization in clinical evaluations across the two studies enable head‐to‐head comparison of clinical outcome measures. Preliminary analysis was done on parameters such as obesity, hypertension, diabetes and depression that are assessed in the above two cohorts.ResultThere was a statistically significant difference in BMI between the two cohorts – the urban cohort had substantially higher proportion of those with obesity than the rural cohort. Diabetes was over two‐fold more common in the urban cohort than the rural cohort. The proportion of persons with Hypertension was also much higher in the urban than in the rural cohort. Depression (Geriatric Depression Scale score ≥ 10) was slightly higher in the rural cohort than the urban cohort.ConclusionVascular risk factors were strikingly higher in the urban cohort than the rural cohort. Long‐term follow‐up of these risk factors along with parallel monitoring of cognitive changes will help in predicting risk factors for dementia in this population.
The association between mesial temporal tau with age, cognition and neocortical tau in Aβ cognitively unimpaired individuals using MK‐6240
Authors: Krishnadas Natasha , Groot Colin , Dore Vincent , Burnham Samantha C. , Huang Kun , Masters Colin L. , Martins Ralph N. , Maruff Paul T. , Ames David , Fripp Jurgen , Bourgeat Pierrick , Goh Anita M.Y. , Villemagne Victor L.L. , Rowe Christopher C. 
Published: December 2020

AbstractBackgroundIt has been proposed that tau deposition in the mesial temporal lobe (MTL) is an age‐related occurrence. We investigated the effects of high mesial temporal tau on age, cognition and neocortical tau in Aβ‐ cognitively unimpaired individuals (CU).Method187 Aβ‐ cognitively unimpaired older adults (≥60 years) from the AIBL cohort were included in this study. MK‐6240 retention was assessed in the amygdala, hippocampus, parahippocampus and entorhinal cortex and in a composite mesial temporal (Me) region. We assessed the association between regional and neocortical retention, age and cognition (MMSE, composite memory scores (CMS), composite non‐memory scores (CNMS) and the AIBL preclinical Alzheimer cognitive composite (AIBL‐PACC)). Two thresholds were used to stratify the cohort into two groups according to Me tau SUVR: 1) using the 95th percentile of the cohort; and 2) using two standard deviations (SD) above the mean.ResultsMK‐6240 Me retention was correlated with age (rs = 0.19, p = 0.01). Those with higher Me retention also had higher retention in all other neocortical regions, as well as higher retention in all four Me sub‐regions. Using the 95th percentile cut‐point, those with higher Me retention performed significantly worse on the CMS (t = 1.89, p = 0.03, Cohen’s d = 0.66) and the CNMS (t = ‐1.90, p=0.03, d = 0.69), which remained significant for the CMS after correction for age. There was a trend toward significance on the MMSE (t =‐1.40, p = 0.08, d =0.43) and PACC (‐1.37, p= 0.09, d = 0.47). These findings should be interpreted with caution, given the small sample of participants above the cut‐off (n =10). When stratified using the 2 SD cut‐point, the resulting sample size of the higher retention group was too small (n =5) to be reliably interpreted.ConclusionThese findings demonstrate an association between mesial temporal tau with age and neocortical tau deposition. The relationship to cognition should be further validated in a larger cohort.
Amyloid‐positive individuals with subjective cognitive decline present increased CSF neurofilament light levels that relate to hippocampal volume
Authors: Sánchez‐Benavides Gonzalo , Suárez‐Calvet Marc , Milà‐Alomà Marta , Arenaza‐Urquijo Eider M. , Grau‐Rivera Oriol , Operto Greg , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Sala‐Vila Aleix , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Simon Maryline , Kollmorgen Gwendlyn , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

AbstractBackgroundNeurofilament light chain (NfL) is a biomarker of neurodegeneration. While cerebrospinal (CSF) NfL is increased in individuals with AD dementia as compared to controls and mild cognitive impairment, studies in cognitively unimpaired individuals with subjective cognitive decline (SCD) are scarce. SCD may represent the first clinical symptom of AD. We aimed at investigating the association between presence of SCD and CSF NfL levels, the interaction between SCD and amyloid‐β (Aβ) status on NfL, and their relationship to hippocampal volume.MethodWe analyzed 78 SCD and 200 controls from the Alfa+ cohort [mean age 61(4.6)] with Roche NeuroToolKit. We defined SCD as a positive answer to the question “Do you perceive memory or cognitive difficulties?” from the SCD‐Questionnaire. We assessed vascular risk factors and mood with the CAIDE score and the Hospital Anxiety and Depression Scale (HADS), respectively, and calculated hippocampal volumes using FreeSurfer V6.0. ANCOVA models accounting for covariates (age, gender, and HADS) were used to test the association between log10(NfL) levels and SCD status, and between log10(NfL) and bilateral total intracranial volume (TIV)‐adjusted hippocampal volume. The interactions SCD*Aβ42/Aβ40 and SCD*hippocampal*dichotomized amyloid status [Aβ+ (n=88) vs Aβ‐ (n=190), defined by the cut‐off of 0.071 for Aβ42/Aβ40] were also tested, and within group analysis performed when interactions were significant.ResultSCD subjects displayed higher NfL (p=0.002, Partial Eta2=0.033) and lower Aβ42/Aβ40 (p=0.044, Partial Eta2 =0.015) than controls, after adjusting by age, gender and HADS (Table 1, Figure 1). Adding the cardiovascular risk factor score CAIDE as a covariate did not change these associations. We observed a significant SCD*Aβ42/Aβ40 interaction (p=0.028) on NfL. A sensitivity analysis stratifying for Aβ‐status showed that the association between SCD and NfL was significant only in Aβ+ individuals (p=0.006, A‐ p=0.21) (Figure 2). Further, the association between hippocampal volume and NfL was only significant in the Aβ+ individuals with SCD (p=0.04, age‐adjusted r=0.38, n=30) (Figure 3).ConclusionAβ+ individuals with SCD displayed increased levels of CSF‐NfL. This association was independent of age, gender, anxiety/depression and vascular risk, and was related to hippocampal atrophy. The presence of SCD in Aβ+ may represent an early symptom related with neurodegeneration.
Educational video increases patients’ knowledge regarding the lumbar puncture procedure: Results of a randomized controlled trial in clinical practice
Authors: Mofrad Rosha Babapour , Fruijtier Agnetha D , Visser Leonie NC , Hoogland Nina , Bouwman Femke , Smets Ellen , Teunissen Charlotte E , van Der Flier Wiesje 
Published: December 2020

AbstractIntroductionPatients’ LP‐related anxiety was previously associated with a higher risk for post lumbar puncture (LP) complications. Since better understanding of the LP procedure might reduce anxiety, we developed an educational video explaining the LP procedure and potential complications. Here, we assessed the impact of the video on patients’ LP‐related knowledge, anxiety, uncertainty, and post‐LP complications.MethodsConsecutive participants (n=148, n=94 underwent LP) who visited the Alzheimer center Amsterdam (table 1, data collection ongoing) were randomly assigned to one of three conditions: 1) home‐provision of the video (home‐viewers), 2) viewing the video in the clinic (clinic‐viewers), or 3) care as usual (controls). Questionnaires measured LP‐related knowledge (self‐developed), anxiety (STAI‐s) and uncertainty (MUIS) prior to (T0), at the start (T1) and end (T2) of participants’ visit (figure 1). Post‐LP complications were reported via telephone‐consultation two weeks thereafter. The video was viewed after T0 and prior to T1. LP‐related knowledge, anxiety, uncertainty, and post‐LP complications were compared between conditions using either one‐way (LP‐ knowledge, post‐LP complications) or repeated measures ANOVA (anxiety, uncertainty) adjusted for age, sex and diagnosis. Since information processing can be affected in dementia patients, analyses were repeated in a subgroup (n=64) of non‐demented participants who underwent an LP.ResultsPreliminary results show that viewing the video resulted in more LP‐related knowledge compared to controls at T1 (F(2,131)=14.0, p<0.001,η2p=0.18) and T2 (F(2,131), p=0.001,η2p=0.11; figure 2A). Anxiety levels decreased over time (F(2,248)=5.8, p=0.004, η2p=0.04) irrespective of condition (figure 2B). Within non‐demented participants who underwent an LP, knowledge was highest in clinic‐viewers compared to controls at T1 (F(2,58)=7.6, p=0.001, η2p=0.21), but not T2 (F(2,58)=0.73,p=0.49,η2p =0.03; figure 2C). In this subgroup, there was an interaction between condition and time (F(4,108),p=0.03, η2p=0.09): anxiety levels increased in controls in anticipation of their memory clinic visit, whereas this decreased in clinic‐viewers after viewing the video (figure 2D). Change in uncertainty (F(4,228)=1.8,p=0.13,η2p=0.03) or post‐LP complications (F(2,89)=0.58,p=0.56, η2p=0.01) did not differ between conditions.DiscussionPreparing patients for an LP through an educational video increased patients’ knowledge about the LP procedure and its potential complications. The benefits of watching the educational LP‐video might even be greater for non‐demented subjects.
Safety, tolerability and immunogenicity of an active anti‐Aβ40 vaccine (ABvac40) in patients with amnestic mild cognitive impairment (A‐MCI) or very mild alzheimer’s disease (VM‐AD): A randomized, double‐blind, placebo‐controlled, phase II trial
Authors: Molina Elisabet P. , Pesini Pedro , Sarasa‐SanJose Manuel , Marcos Ivan , Lacosta Ana M. , Allué Jose A. , Fandos Noelia , Sarasa Manuel , Boada Mercè ,   ABvac40 Phase 2 Study Group
Published: December 2020

AbstractBackgroundAlzheimer's disease is one of the biggest burdens of society with a dramatic and growing worldwide incidence rate. Notwithstanding scientific and medical advances, the condition remains incurable. Immunotherapies intended to act on the amyloid cascade are currently among the most hopefully disease modifying approaches Αβ40 is in the core of the amyloid plaques and is the main component of vascular amyloid deposition which is associated with earlier dementia onset in AD. These data leads further the hypothesis that it should be targeted in treatment strategies. Araclon Biotech is developing an active vaccine directed specifically against the Aβ‐40 peptide.MethodThis is a phase II, double‐blind, randomized, placebo‐ controlled study in patients with amnestic mild cognitive impairment (a‐MCI) or very mild Alzheimer’s Disease (Vm‐AD). The study will last for 104 weeks (from V0 to V25) during which the patients will receive five monthly (every four weeks) immunizations plus a booster shot. The primary objective of this trial is to confirm the safety, tolerability and biological activity (immunogenicity) results obtained in phase I and to explore the effect of the treatment on disease biomarkers (neuroimaging, CSF and plasma) and cognition as secondary efficacy variables.ResultRecruitment has been completed. 124 patients aged 55 to 80 have been included in the study (a‐MCI, n= 80; Vm‐AD, n= 44). Baseline demographics and characteristics were balanced. To date, fifty patients have completed the first year study (treatment period).ConclusionInterim findings to be presented at the congress.
Working memory modulation using multifocal transcranial direct current stimulation in stable and decliner older adults
Authors: Vaqué‐Alcázar Lídia , Abellaneda‐Pérez Kilian , Solé‐Padullés Cristina , Bargalló Nuria , Sala‐Llonch Roser , Bartres‐Faz David 
Published: December 2020

AbstractBackgroundThe combination of transcranial direct current stimulation (tDCS) with functional magnetic resonance imaging (fMRI) is able to provide original data about how brain change in aging. Furthermore, tDCS procedures might moderate age‐related brain functional changes associated to cognitive decline. In the present study, we aimed to investigate in which manner two multifocal tDCS procedures based on two distinct working memory (WM) patterns entail capability to modulate neural activity in older adults showing cognitive stability or decline.MethodTwo multifocal tDCS montages were designed to generate two distinct electric field distributions fitting either ‘compensatory’ or ‘maintenance’ fMRI patterns underlying high WM performance, described in a previous publication from our group (Fernández‐Cabello et al., Neurobiol Aging, 2016). A sham‐controlled crossover study was undertaken on three separate experimental sessions, where 24 healthy elders (mean age: 71.73±2.65 years, 14 females) performed a verbal N‐back task while fMRI data was acquired. During the fMRI acquisitions, tDCS was applied using ‘compensatory’, ‘maintenance’ or sham stimulation in a randomized counter‐balanced order. Each subject was retrospectively classified as showing WM stability (N=12) or decline (N=12) at baseline (i.e. during sham condition) based on the WM scores obtained 4 years before. We studied differences in fMRI between group’ trajectories and across the different tDCS montages.ResultThere was a significant time*group interaction, where the decliners evidenced a longitudinal progression marked by an over‐activation of non‐related WM areas. Focusing on the stimulation intervention, we identified a significant interaction group (stables vs. decliners) * condition (‘compensatory’ vs. sham). Regarding the specific effects for each group and montage, only in the decliner group, the ‘compensatory’ tDCS induced an activity reduction overlapping posterior cortical regions, whose longitudinal hyperactivation was characteristic of this group.ConclusionThe present results reinforce the notion that tDCS effects depend on the underlying age‐related functional organization and that these effects might be larger as more compromised is a system. Moreover, our findings are also in accordance with the hypothesis that tDCS is able to normalize functional patterns subtending cognitive decline in aging.
Morphological alterations of the choroid plexus epithelium in Alzheimer’s disease
Authors: Van Cauwenberghe Caroline , Vandendriessche Charysse , Kremer Anneke , De Rycke Riet , Borghgraef Peter , Van Imschoot Griet , Van Wonterghem Elien , Lippens Saskia , Vandenbroucke Roosmarijn E 
Published: December 2020

AbstractBackgroundThe choroid plexus (CP), is a complex structure localized in the ventricles of the brain, which mainly consist of tightly connected choroid plexus epithelial (CPE) cells surrounding fenestrated capillaries. These CPE cells form the blood‐cerebrospinal fluid barrier and play a vital role in the maintenance of brain homeostasis. During Alzheimer’s disease (AD) several CPE related processes are severely affected (Brkic, 2015) and evidence indicates that CP‐derived extracellular vesicles play an important role in AD pathogenesis. In this study morphological alterations of the CPE cells were characterized in two distinct AD mice models (APP/PS1tg/wt and APPNLGF/NLGF). Additionally, we investigated the subcellular localization and performed quantification of multivesicular bodies (MVBs) and intraluminal vesicles (ILVs) using transmission electron microscopy (TEM) and 3D‐scanning electron microscopy (3D‐SEM).MethodCP tissue was isolated from APPwt/wt, APP/PS1tg/wt, APPNLGF/NLGF mice at different timepoints (age 10w, 20w, 30w and 40w). Isolated CP was processed for TEM and 3D‐SEM imaging as previously described in (Balusu, 2016; Kremer, 2015). Visualization of the samples was performed using a TEM (JEOL) and FIB‐SEM (Zeiss) and manual segmentation of 3D‐SEM images was done using Microscopy Image Browser (Belevich, 2016).ResultIn both APP/PS1tg/wt and APPNLGF/NLGF mice morphological alterations of the CP are visible at the age of 20 weeks, the ultrastructure is damaged. The CPE cells lose their typical cuboidal shape, are more point‐shaped, the cytoplasm becomes more translucent, the nuclei are irregularly shaped and the mitochondria are more condensed. These changes become increasingly prominent as the mice age. In APPwt/wt mice, the same morphological alterations of the CP become visible at later age. Early during disease progression (10 w), we observed higher levels of ILVs in the CP of APP/PS1tg/wt compared to age‐matched APPwt/wt mice, while levels normalized at later stages. In APPNLGF/NLGF mice higher MVB and ILV levels are observed early during disease progression.ConclusionUltrastructural changes of the CP epithelium are present in different AD mice models. Furthermore, we observed differences in levels of ILVs in the CP early during disease progression. Further research might give insights into the role of the CP and ILVs in AD pathogenesis.
Comparative diagnostic performance of plasma P‐tau217 and P‐tau181 in Alzheimer’s disease and frontotemporal lobar degeneration and correlations with [18F]Flortaucipir‐PET uptake
Authors: Thijssen Elisabeth H. , La Joie Renaud , Strom Amelia , Teunissen Charlotte E. , Dage Jeffrey L. , Rojas Julio C. , Rabinovici Gil D. , Boxer Adam L. 
Published: December 2020

AbstractBackgroundPlasma P‐tau181 has previously been shown to be associated with tau pathology in Alzheimer’s disease (AD). P‐tau217 is a novel blood‐based biomarker. We assessed the diagnostic value of plasma P‐tau181 and P‐tau217 in the same cohort of patients across the AD and frontotemporal lobar degeneration (FTLD) spectrum.MethodThis retrospective study of 617 participants included 119 healthy controls, 74 cases in the clinical AD spectrum (57 amnestic, 15 lvPPA, 2 PCA; all biomarker‐confirmed) and 294 in the FTLD spectrum. The cohort included 15 AD and 67 FTLD autopsy‐confirmed cases and 66 Microtubule‐Associated Protein Tau (MAPT) mutation carriers. P‐tau concentrations were measured using custom electrochemiluminiscence‐based assays at Lilly. P‐tau217 was available in 513 cases, P‐tau181 in 614 cases, and both in 509. Amyloid‐PET was available in 352 cases and [18F]Flortaucipir (FTP)‐PET in 227 cases. The differentiating power of P‐tau181 and P‐tau217 was assessed across clinical and autopsy‐confirmed phenotypes, amyloid‐ and FTP‐PET status, and type of tau pathology in MAPT mutation carriers.ResultPlasma P‐tau217 concentrations were increased 5.2‐fold in clinical AD (n=74) relative to controls (AUC=97%, p<0.001) and 3.8 fold relative to clinical FTLD (AUC=93%, p<0.001). P‐tau217 was increased 4.9 fold in autopsy‐confirmed AD compared to autopsy‐confirmed FTLD (AUC=92%, p<0.001). Plasma P‐tau181 was increased 2.6 fold in clinical AD compared to controls (AUC=93%, p<0.001) and 2.4 fold relative to clinical FTLD (AUC=89%, p<0.001). P‐tau181 was increased 2.5 fold in autopsy‐confirmed AD compared to autopsy‐confirmed FTLD (AUC=87%, p<0.001). There was no change in P‐tau217 concentrations in MAPT mutation carriers with mixed 3R/4R tau pathology compared to 4R tau pathology, whereas P‐tau181 was 1.4 fold increased (p<0.01). FTP‐PET SUVR was associated with P‐tau217 (ρ=0.78, p<0.001) and P‐tau181 (ρ=0.64, p<0.001). P‐tau217 could identify amyloid‐PET positive cases (n=317, AUC= 86%, p<0.001), and FTP‐PET positive cases (AUC= 96%, p<0.001, n=213) across diagnoses, with similar accuracy to P‐tau181 (amyloid‐PET AUC=81%, n=351, FTP‐PET AUC=90%, p<0.001, n=227).ConclusionPlasma P‐tau217 is comparable to P‐tau181 for differential diagnosis of AD and potentially superior for identifying FTP‐PET positivity. Additional investigations are necessary to explain potential differences in assay performance in MAPT mutation carriers that produce mixed 3R/4R tau, whose pathology is similar to AD.
Epitope prediction for oligomer‐selective antibodies in tau and Aβ
Authors: Plotkin Steven S. , Hsueh Shawn Ching‐Chung , Adekunle Aina , Peng Xubiao , Gibbs Ebrima , Roman Andrei , Zhao Beibei , Louadi Sarah , Kaplan Johanne , Cashman Neil R. 
Published: December 2020

AbstractBackgroundPrevious studies of Alzheimer’s disease (AD) pathology point to cytotoxic tau as a cause of neuronal cell death, which is induced or exacerbated by soluble misfolded Aβ oligomers. Soluble misfolded species of both tau and Aβ are both observed to propagate cell‐to‐cell. A method for identifying antibodies to tau and Aβ that are conformationally‐selective to propagative misfolded oligomeric forms, and which also have low affinity to isolated monomers or, particularly for Aβ, low affinity to fibrils, is thus a highly desired goal that holds significant promise for AD therapy.MethodWe have developed a novel computational platform to identify epitopes that may be selectively exposed on oligomers. Epitope prediction ideally uses an experimentally determined fibril structure as input, but the method alters this structure using molecular dynamics, to more accurately model the regions that may be exposed on soluble oligomers. Both primary sequence and structural conformation are taken into account: The epitope should be conformationally‐distinct from those conformations presented in the functional healthy protein. Epitope scaffolding is then employed to optimize the presentation of the epitope in animal immunizations, so that the resulting antibodies are predicted to be selective to misfolded oligomeric forms.ResultOligomer‐specific epitope predictions for tau and for Aβ have been used to raise preclinical antibodies that have selectivity for pathogenic tau and Aβ species. In vitro SPR measurements confirmed selective binding to synthetic oligomers and soluble pre‐formed fibrils (PFFs), vs. native healthy protein. As well, the antibodies showed little immunoreactivity toplaque or vascularAβ deposits via immunohistochemistry, while SEC fractionation of AD brain homogenate shows selective binding to toxic dimers, tetramers and dodecamers, in contrast to aducanumab and bapineuzumab. Tau antibodies recognized tau from AD brain extract, and inhibited seeding activity in a FRET assay. Aβ antibodies alleviated the cognitive deficits caused by oligomers in mouse NOR studies.ConclusionLead antibodies to tau and Aβ developed using rationally designed conformational epitopes are likely to achieve greater therapeutic potency by selectively targeting soluble toxic oligomers, and reducing the risk of target distraction and ARIA.