bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel specific Aβ42 oligomer antibody ameliorates the neurotoxicity of patient‐derived brain extracts
Authors: Sandberg Anders , Rodriguez Rosa Crespo , Correa Ernesto Berenjeno , Morrema Tjado , Hoozemans Jeroen J. , Scheper Wiep 
Published: December 2021

AbstractBackgroundIn Alzheimer’s disease (AD), the neurotoxicity of amyloid‐β 1‐42 (Aβ42) stems mostly from soluble oligomeric aggregates of this peptide. However, the study of these aggregates has been hampered by their unstable and elusive nature, thus questioning the very definition of them as distinct targets for drug development. Here, we assess the toxicity of physiologically‐derived Aβ using extracts from deceased patients and controls in primary neuron cultures. By using a monoclonal antibody with a unique binding profile, ALZ‐201, we demonstrate that all of the Aβ toxicity observed in human‐derived brain extracts stem from soluble Aβ42 aggregates.MethodBrain tissue samples from 10 individuals were confirmed as AD (n=7) and non‐AD (n=3) cases using IHC staining for Aβ and p‐Tau aggregates. Extracts were prepared as described in Hong et al. 2018 (doi:10.1007/s00401‐018‐1846‐7) and immunodepleted with either the antibody 4G8 (removes all Aβ), ALZ‐201 (100% specific for non‐fibrillar soluble Aβ42 aggregates) or an isotype control to ALZ‐201 (does not bind any Aβ). Fractions were biochemically characterized, and toxicity assays were performed in primary mouse neuronal cultures using an automated cell imaging platform.ResultThe total Aβ content was higher in AD cases, as expected. The toxicity of the patient extracts exceeded those obtained from non‐AD cases with respect to neuronal loss and morphological determinants such as synapse density and measures of neurite complexity. Immunodepletion using 4G8 dramatically reduced Aβ in the AD patient samples and the control samples. This is in contrast to immunodepletion using ALZ‐201 or the isotype control, for which there was no detectable difference. Despite this remarkable difference in Aβ content, the therapeutic effect of depletion with 4G8 and ALZ‐201 was comparable, whereas there was no effect after depletion using the isotype control.ConclusionThe results demonstrate that very small amounts of soluble aggregated Aβ42 likely account for a large part of the toxicity in AD patients. The unique antibody, ALZ‐201, is capable of depleting these without targeting other forms of Aβ. Since this natural toxic form of Aβ is extremely low in abundance, this feature may be a critical attribute for achieving a true therapeutic effect in actual patients.
Centiloid harmonisation strategies across longitudinal studies: Evaluation on AIBL, ADNI and OASIS3
Authors: Bourgeat Pierrick , Li Shenpeng , Tosun Duygu , Benzinger Tammie L.S. , Burnham Samantha C , Weiner Mike W. , Morris John C. , Masters Colin L , Rowe Christopher C , Fripp Jurgen , Dore Vincent , Villemagne Victor L 
Published: December 2021

AbstractBackgroundThe Centiloid (CL) was proposed to harmonise the quantification of Amyloid PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners. In this study, we aim to evaluate the impact of different pre/post‐processing harmonisation steps on the consistency of longitudinal data across multiple large studies.MethodAll Amyloid PET data in AIBL (N=3830), ADNI (N=3453) and OASIS3 (N=1398) were quantified using the Centiloid SPM pipeline. SUVR were converted into Centiloids using each tracer’s respective transform. All images were smoothed to a uniform 8mm FWHM PSF. Both Raw and 8mm FWHM smoothed images were quantified. For Florbetapir, we evaluated using both the standard Whole Cerebellum (WC) and a Composite WM+WC reference region, which has been previously shown to improve longitudinal consistency. Additionally, our recently proposed Non‐negative Matrix Factorisation quantification (NMF: Neuroimage 2021) was applied to all spatially and SUVR normalised images. Longitudinal consistency was evaluated using: fitting error when fitting a regression line to each subject; percentage of longitudinal changes exceeding 95th percentile of changes seen with PiB when using a single scanner (6.56CL/y in the negative and 17.06CL/y in the positive); Spearman rank correlation ρ between the baseline Centiloid and the rate of change.ResultFigure 1 illustrates the longitudinal consistency, while the fitting error and percentage of outliers are presented in Table 1. These results indicate that the 8mm FWHM smoothing reduced some of the variability, but its impact was limited. Using the Composite reference region on Florbetapir had a bigger impact in reducing the variability. The best results were however obtained when using the NMF method, compared to SPM. Figure 2 shows the baseline vs rate of CL changes. These plots also show a moderate influence of the FWHM smoothing, and a stronger influence of the Composite reference region. They also show that the NMF method produced the highest Spearman and peak CL/y regardless of the pre‐processing or normalisation method used.ConclusionFWHM smoothing has moderate impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for Florbetapir longitudinal Centiloids. NMF improves consistency over SPM.
Adherence to the MIND diet and cognitive performance in the ELSA‐Brasil study
Authors: Ferreira Naomi V , Lotufo Paulo A , Bensenor Isabela M , Barreto Sandhi Maria , Viana Maria Carmen , Caramelli Paulo , Marchioni Dirce Lobo , Suemoto Claudia K 
Published: December 2021

AbstractBackgroundAdherence to healthy dietary patterns such as the MIND diet has been associated with better cognition, but little is known about this relationship in studies from low‐ to middle‐income countries. This study aims to investigate the association between adherence to the MIND diet and cognitive performance in the ELSA‐Brasil study baseline.MethodAdherence to the MIND diet score was assessed using a food frequency questionnaire and cognitive performance was evaluated using three cognitive domains: memory domain (immediate word list recall, late word list recall, word list recognition), fluency domain (semantic and phonemic verbal fluency) and executive domain (Trail Making test version B). We used z scores for the three domains and created a standardized global composite score. We used linear regression to investigate the association between MIND diet adherence and cognitive performance adjusted for sociodemographics and clinical variables. We also investigated interactions between adherence to the MIND diet and age, race, and education.ResultMIND diet adherence was associated with better cognitive performance in all three domains and with global cognition in unadjusted analysis. However, adherence to the MIND diet was related to a worse performance in the executive domain in a full adjusted model (Table 1). Adherence showed significant interaction with age, race and education, suggesting better cognitive performance with higher adherence in older people (Figure 1), white participants (Figure 2) and those in higher levels of education (Figure 3), but a lower cognitive performance with higher adherence in those in lower levels of education (Figure 3).ConclusionMIND diet adherence was associated with worse performance in an executive function test. Older, white and high‐educated participants had better performance with higher adherence scores.
An investigation of HCV as a predictor of cognitive decline: The Bio‐Hermes protocol
Authors: Wolz Robin , Bork Jason , Cordell Cyndy , Hughes Lynne , Bullock Roger Alan , Cerroni Giulio , Dwyer John , Mohs Richard 
Published: December 2021

AbstractBackgroundA 2018 NIA‐AA Research Framework extended the biological definition of Alzheimer’s disease (AD) from biomarkers of amyloid (A) and tau (T) to include measures of neurodegeneration (N) thus enabling more detailed staging and identification of participants potentially closest to clinical decline (N+) (AlzheimersDement.2018;14(4):535‐562). This framework is only partially implemented in clinical trials as N is rarely considered a selection criterion. Hippocampal volume (HCV) measured from magnetic resonance imaging (MRI) has been proposed as a widely available, robust tool to define N+ (AlzheimersDement.2014;10(4):421‐429.e3).MethodParticipant selection through N+ will be validated in a sub‐study of the Bio‐Hermes trial planned by the Global Alzheimer’s Platform Foundation®. The Bio‐Hermes trial will assess biomarkers of Aβ, phospho‐tau, and neurofilament light in approximately 1,000 participants in three cohorts: cognitively normal, mild cognitive impairment, probable AD. A baseline MRI will be performed in approximately 200 additional participants randomized in a substudy. A pre‐defined HCV cut‐off from the Learning Embeddings for Atlas Propagation (LEAP) algorithm was identified to define N+ status (NeuroImage.2010;49(2):1316‐1325). The sub‐study will enrol participants willing to forgo treatment studies for 12 months to allow standardized measures of progression. Correlation with clinical measures and clinical decline will be compared in N+ and N‐ populations in the three cohorts to validate the benefit of full ATN staging in trial design.ResultWhile most publications using the LEAP algorithm for N+ AD patient stratification define N+ cut‐offs based on HCV percentiles in the analysed dataset (Neurobiology of Aging. 2012;33:2272–2281, Neurology. 2013;80(12):1124‐1132, , Neurology. 2016; 87(12):1235–124, Alzheimers Dement. 2018;14(7):1076, Alzheimers Dement. 2020; 10.1002/alz.037912), one study deployed percentiles from a healthy reference cohort (Neurobiology of Aging. 2014;35:808‐818). Based on prior work and simulations of the Bio‐Hermes trial cohorts, the N+ cut‐off was set at HCV=5.4cm3.ConclusionThe presented study design validates the use of MRI as inclusion criterion in AD clinical trials to fully implement ATN staging. As MRI is a standard tool during screening for AD clinical trials, additional participant characterisation can be achieved at minimal extra cost and burden, significantly improving trial power.
The association between long term blood pressure variability with incident dementia and cognitive impairment: A systematic review and meta‐analysis
Authors: Jia Pingping , Lee Helen WY , Chan Joyce YC , Tsoi Kelvin KF , Yiu Karen KL 
Published: December 2021

AbstractBackgroundDementia cases continues to grow in the era of ageing population, with its number approaching 50 million. Accumulating evidence has shown that high blood pressure increases the risk of dementia and cognitive decline. In recent decades, some studies demonstrate that blood pressure variability (BPV) may contribute to cognitive decline and incident dementia independent of the blood pressure level. However, due to the inconsistence of statistical results and clinical methodology, the magnitude of this relationship remains ambiguous. A clear understanding of the role of BPV in dementia may shed light to etiology and early prevention of dementia. This study aims to assess the association between BPV with incident dementia and cognitive impairment.MethodWe searched MEDLINE, Embase, PsycINFO, CINAHL and Web of Science from December 2020 for articles describing trials, retrospective and prospective cohort studies in adults that assessed the association of long‐term BPV (measured through clinic blood pressure monitoring) with incident dementia and cognitive impairment. 5681 papers were identified and eventually 12 articles with full text and 3 abstracts with enough information were included in the quantitative analysis. Of these 15 studies, 2 articles report both dementia and cognitive decline or dysfunction as outcomes, while 5 studies report dementia as an outcome and 8 studies report cognitive decline or dysfunction.ResultHazard Ratio and linear regression coefficient were converted to a standardized one. We found that increased long‐term variability in systolic blood pressure was associated with higher risk of all‐cause dementia [pooled standardized HR of 1.1 (95%CI, 1.01, 1.19)]. Compared to people in lower BPV group, people in higher BPV group was 1.17 times more likely to develop dementia [pooled HR 1.17 (95%CI,1.12, 1.22)]. Cognitive decline was associated with higher SBPV [pooled linear coefficient for MMSE score is ‐0.11(95%CI, ‐0.17, ‐0.05)],which means MMSE score decreases by 0.11 per SD increase in SBPV.ConclusionOur findings suggested that higher long‐term blood pressure variability increases both the risk for incident dementia and cognitive decline.
Capturing functional change in early Alzheimer’s disease: Comparing instruments and scoring techniques to detect subtle decline
Authors: Dubbelman Mark A. , Jutten Roos J. , Harrison John E , Ritchie Craig W. , Aleman André , de Jong Frank Jan , Scheltens Philip , Sikkes Sietske A.M. 
Published: December 2021

AbstractBackgroundFunctional decline is a gradual process occurring along the Alzheimer’s disease (AD) continuum, starting years before dementia onset. Different instruments, such as the ADCS‐ADL and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) aim to capture early functional changes. In the current study, we compared measurement instruments and scoring techniques to find the optimal measurement technique for detecting functional impairment in early AD.MethodStudy partners of participants from the international ‘Capturing Changes in Cognition’ study cohort completed both the A‐IADL‐Q and ADCS‐ADL over the course of one year (mean follow‐up 10.8±2.3 months). For both measures, we computed the following scores: (1) sum score, (2) weighted average, and (3) number of items with maximum score. For the A‐IADL‐Q, we also computed item response theory (IRT) scores, using predetermined parameters that take into account varying difficulty of included items (see Jutten et al., 2017). To compare the ability to detect changes over time for each scoring method, we performed linear mixed modeling, adjusted for sex and baseline age.ResultWe included 159 individuals (72.2±8.4 years old, 45% female) with subjective cognitive decline (SCD, N=12), mild cognitive impairment (MCI, N=66) or mild dementia (N=81). Overall, a significant decline in functioning was detected with all scoring techniques (all p<.01), except the technique of the number of items with most impairment for the ADCS‐ADL (see Table 1). When comparing decline in the diagnostic groups (see Figure 1 and Table 1), linear mixed models showed functional decline in all scoring techniques of both instruments in mild dementia. In MCI, all A‐IADL‐Q scoring methods showed a significant decline over time (p<.05), whereas the ADCS‐ADL scores did not. No decline was detected in SCD.ConclusionThe A‐IADL‐Q showed greater sensitivity to functional decline over one year than the ADCS‐ADL in those with MCI. Our findings suggest that the ability to detect subtle functional changes appears to be mostly dependent on instrument, and to a lesser extent on the scoring technique used. These findings imply that the selection of appropriate instruments is pivotal for optimal longitudinal study design, and clinical trial design in patients with MCI.
Healthcare expenditure attributable to dementia with Lewy bodies in Japan: LIFE Study
Authors: Ono Rei , Nakatsuka Kiyomasa , Uchida Kazuaki , Fukuda Haruhisa 
Published: December 2021

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia, yet scarce evidence is available about healthcare expenditure after diagnosis. This study aimed to quantify the healthcare expenditure attributable to DLB using claims data.MethodThis study design was the prospective cohort study. The analysis was conducted using the LIFE Study database, which comprises municipality‐level information centred on claims data. Claims data from April 2014 to March 2019 were obtained from ten rural cities (n=170,919, mean age: 73.4 years, woman: 99,210). The study subjects were individuals who had received new diagnoses of DLB (ICD‐10 code G31.8 and F02.8) in October 2014 or later. The healthcare expenditures for three years were estimated for subjects with adequate follow‐up data for the respective periods. Using the expenditures incurred during the six‐month period before DLB diagnosis as a comparator, the expenditures trend incurred after DLB diagnosis were estimated through fixed‐effects models.ResultOf them, 277 individuals with new diagnoses of DLB were identified. Their mean age was 82.0 years, 188 (67.9%) were women. The fixed‐effects model estimated that the first, second months after DLB diagnosis were associated with higher expenditures of US$1,766.7 (US$1 = ∖103.8, P < 0.001) and US$1,366.3 (P < 0.001), respectively, when compared with the pre‐DLB period (US$663.6). The expenditures stabilized in the first, second, third years (US$524.9, US$440.5, US$609.0).ConclusionHealthcare expenditure in first and second months after DLB onset were much higher than those of the pre‐DLB period.
Impaired recognition of disgust is related to subcortical volume loss in amyotrophic lateral sclerosis
Authors: Canu Elisa , Leocadi Michela , Castelnovo Veronica , Magno Maria Antonietta , Riva Nilo , Poletti Barbara , Silani Vincenzo , Filippi Massimo , Agosta Federica 
Published: December 2021

AbstractBackgroundThe impairment in detecting disgust in Amyotrophic Lateral Sclerosis (ALS) has been hypothesized to be related with the integrity of subcortical structures. However, this has not been demonstrated yet and was the aim of the study.MethodTwenty ALS patients without cognitive/behavioural symptoms and 52 matched healthy controls (HC) underwent a brain MRI scan and a neuropsychological assessment including the Comprehensive Affect Testing System (CATS) investigating emotion recognition. Composite scores were calculated by summing up the correct answers for each emotion. Gray matter (GM) volumes of the subcortical structures were obtained using FIRST in FSL. Sociodemographic, cognitive and MRI data were compared between groups. In ALS patients, CATS significant findings were correlated with the subcortical volumes, ECAS performances, patients’ mood and behaviour.ResultALS patients performed significantly worse than HC at the CATS, and they were significantly less able to recognize disgust. No GM volume differences were observed between groups. In ALS patients, a low performance in disgust recognition was related with a reduced volume of the left pallidum and with low performances at the ECAS.ConclusionIn a sample of cognitively/behaviourally unimpaired ALS, we demonstrated an altered ability to correctly recognize disgust and a potential role of basal ganglia in the altered processing of this emotion. These findings, together with the relationship between the altered disgust recognition with lower ECAS performances in patients, suggest that disgust could be the first emotion to be hit in ALS cognitive decline. These findings offer new potential markers for monitoring extra‐motor progression in ALS. Supported by: Italian Ministry of Health (GR‐2013‐02357415); European Research Council (StG‐2016_714388_NeuroTRACK).
Unfulfilled potential for secondary prevention of cognitive decline in individuals with covert brain infarcts: A population‐based study
Authors: Wolters Frank J , Ikram M Arfan , Bos Daniel , Raso Francesco Mattace , Vernooij Meike W 
Published: December 2021

AbstractBackgroundModifiable cardiometabolic risk factors account for about 25% of all dementia, including Alzheimer’s disease. Risk factor control is therefore pivotal, particularly in patients with high risk of dementia after stroke. However, 15‐20% of elderly individuals have brain infarcts on routine MRI that have not produced notable stroke symptoms (‘covert brain infarcts’ [CBI]), and in whom risk factors consequently may not be treated optimally.MethodWe included 5934 participants of the population‐based Rotterdam Study who underwent routine brain MRI and cognitive assessment between 2005‐2016 (mean age 65 years, 55% women). Clinical stroke symptoms were ascertained through interview and medical records review. In individuals with CBI, we determined the extent to which cardiometabolic risk factors (systolic blood pressure, LDL‐cholesterol, serum glucose) are managed according to AHA/ASA guidelines for secondary stroke prevention.ResultOf 507 patients with brain infarction on MRI, 395 (78%) had not had prior clinical stroke. Prevalence of CBI increased steeply with age, from 2% at age 45‐49 to 20% after age 85, and was associated with worse performance on a cognitive assessment battery (β[95%CI]=‐0.19[‐0.32;‐0.06]). 34% of participants >60 years with CBI had one or more untreated, modifiable cardiometabolic risk factors, compared to 9% of participants with prior clinical stroke, and optimal risk factor control was twice as likely after clinical stroke than with covert brain infarcts (28 vs. 13%). Among individuals with CBI, those with suboptimal cardiometabolic risk management did worse on cognitive testing, notably in the memory domain (global cognition– β[95%CI]=‐0.27[‐0.65;0.12]; memory– β=‐0.40[‐0.73;‐0.08]). Similar differences were seen when additionally examining lifestyle factors (obesity and smoking). Of participants with CBI, less than half (45%) were using antithrombotic medication, compared to 88% after clinical stroke. The percentage of undertreated individuals was similar when comparing the earlier (2005‐2010) with the later years of the study (2011‐2016).ConclusionIn one third of individuals with covert brain infarcts, cardiometabolic risk factor management does not align with secondary stroke prevention guidelines, potentially resulting in poorer cognitive function. These findings should prompt further study into the optimal secondary preventive strategies for this large group of elderly individuals with undiagnosed covert brain infarcts.