bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of a 3‐Dimensional Exergame to Promote Integrated Cognitive and Physical Activity in Aging Adults
Authors: Carlson Michelle C , Moored Kyle D. , Crane Breanna M , Ahmad Ohmar , Chan Thomas , Krakauer John 
Published: December 2022

AbstractBackgroundEvidence suggests that bi‐directional associations exist between cognition and mobility that magnify with increasing age. Both cognition and mobility are important to maintaining independent function in daily life. These and other findings suggest that cognition and mobility may share common neural substrates that can be trained simultaneously through real‐world simulations that safely promote navigation through complex virtual environments. However, few interventions explicitly train on cognition and mobility simultaneously. We optimized an immersive, 3‐Dimensional (3‐D) exergame to simultaneously train cognitive and motor functions in a community‐based setting for older adults.MethodWe recruited 16 older adults from an independent living community, with varying levels of physical function. Participants completed one‐hour sessions three times each week for five weeks for a total of 15 sessions. The customized game provides an immersive virtual oceanic environment in which the participants control a simulated dolphin (“Bandit”) that responds to the participant’s desired direction in 3‐D space and amid other oceanic fish, including sharks, orcas and small pods of fish. Participants used their dominant hand, tracked by motion sensors, to navigate this world to help “Bandit” eat fish, avoid being bitten by sharks, and jump out of the water. Players advanced in levels after mastering the preceding level. After completing all 110 game levels, participants switched to their non‐dominant hand to remaster all levels of the exergame again.Before and after the program, participants completed tests of memory, executive function, and speed of processing.ResultAll participants successfully completed the intervention, with the exception of one participant, with a vestibular disorder. In adjusted models (age, sex, education), post‐intervention improvement in processing speed was marginally significant (p = 0.06). No other cognitive improvements were found.ConclusionOur feasibility study demonstrated that we can effectively use this innovative exergame platform as a clinic‐ or community‐ based tool for individuals to safely practice and promote integrated skills related to complex, real‐world navigation.
Natural Killer Cells Improve Cognitive Function and Support to Induce Amyloid Beta Clearance by Functional Recovery of Impaired Microglia in Natural Killer Cell‐treated Alzheimer’s Diseases Mouse Model
Authors: Hwang Do Won , Sohn Dae‐Hee , Ki Young Wook , Kim Shin‐Il , Choi Yoori , Ko Min Kyung , Lee Sung Chang 
Published: December 2022

AbstractBackgroundDysfunction of microglia that plays a pivotal role in amyloid beta clearance is recognized to be involved in pathological progression of the Alzheimer’s diseases. Natural killer (NK) cells participate in homeostatic immune‐modulation and immune‐surveillance by secreting immune‐boosting signaling molecules. These molecules can serve as cell‐based therapeutics for AD. In this study, we found that the activated NK cells eliminated Aβ plaques, resulting in a marked improvement in behavior in mice with AD. This improvement may be associated with the recovery in microglial function due to the upregulation of phagocytic activity and autophagy genes.MethodNK cells were isolated, using a negative selection process, from the spleens of BALB/c mice and subsequently expanded to 1×108 cells.ResultThe cultured NK cells were intravenously administered into APP/PS1 mutant mice. There was dramatic reduction of Aβ deposition in the cortex and dentate gyrus areas of the brain in these mice following the NK cell treatment. While phosphate‐buffered saline APP/PS1 control mice exhibited learning deficits in the escape platform, the NK cell‐treated mice showed reduced escape latency in the Morris water maze test. Mouse microglia, in the AD model, were isolated using CD11b positive magnetic activated cell sorting method. RNA sequencing was performed using total RNA isolated from mouse brain hippocampus tissue, to explore differential gene expression levels. Hierarchical cluster heat maps revealed the recovered gene populations in the NK‐treated microglial group. The percentage of genes upregulated in the total gene ontology groups were significantly altered in NK treated/sham ratio group (i.e., 171 upregulated immune response‐related genes). The homeostatic and disease‐associated microglia (DAM)‐related genes that were increased in microglia isolated from APP/PS1 mouse brain were downregulated after NK treatment. KEGG pathway analysis projected the autophagy signaling pathways as critical pathways associated with amyloid beta clearance. Our analysis showed that treatment of mice with NK cells recovered gene signatures involved in phagocytic activity.ConclusionThese findings show that NK cells, which are known to have low in vivo toxicity, could be a potential therapeutic option for AD that could be rapidly translated to the clinic.
UK Biobank imaging adapted for a real‐world memory clinic sample
Authors: Griffanti Ludovica , Gillis Grace , O'Donoghue M Clare , Blane Jasmine , Pretorius Pieter M , Mitchell Robert , Aikin Nicola , Lindsay Karen , Campbell Jon , Semple Juliet , Martos Lola , Raymont Vanessa , MacKay Clare 
Published: December 2022

AbstractBackgroundThe Oxford Brain Health Centre (BHC) provides real‐world research data, aligned with the UK Biobank imaging study (UKB), routinely captured in a clinical service from patients under‐represented in dementia research. In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for memory clinic patients, 2) modified the imaging analysis pipeline to extract measures that are in line with radiology reports and 3) compare measures from BHC patients to the biggest brain MRI study in the world (ultimately 100,000 participants).MethodAdaptations of the UKB acquisition protocol for BHC patients include dividing the scan into core and optional sequences to improve patients’ tolerance. We adapted the UKB structural MRI analysis pipeline to extract quantitative measures from the scans, taking into account the characteristics of a memory clinic population (e.g. high level of white matter hyperintensities, WMH, causing misclassifications in tissue‐type segmentation). We compared the measurements extracted from the scans to visual ratings from radiology reports and to reference distributions derived from UKB data.ResultOf the 108 BHC attendees since August 2020 (average age 78.5 years, range 65‐101 years, 50.9% female), 100 (92.6%) completed the clinical scans, 100 (92.6%) consented to use of data for research, and 69 (63.9%) consented to additional research sequences, demonstrating that the protocol is well tolerated. Modified tissue‐type segmentation improved grey matter volume estimation, which showed stronger correlation with visual ratings of global atrophy after correction (r=‐0.34; p=0.001) than with the original analysis pipeline (r=‐0.31; p=0.002). Correlations between hippocampal volumes and MTA scale (r(L)=‐0.59, r(R)=‐0.71) and between WMH volume and Fazekas scale (r=0.78) were also significant (p<0.001). Because UKB participants are younger than memory clinic patients, additional scans on elderly healthy controls are planned to improve reference distributions to detect pathological deviations. Measures from BHC patients within UKB age range are comparable to those from UKB participants, with several patients falling in the lower percentiles.ConclusionWe adapted UKB research imaging for clinical practice. Current and future work aims to integrate automated quantitative measures in the radiology reports and evaluate their clinical utility.
Diabetes and hypertension are associated with elevated beta‐amyloid burden: evidence from the population‐based Rotterdam Study
Authors: Neitzel Julia , van Arendonk Joyce , Steketee Rebecca M.E. , van Assema Daniëlle , Segbers Marcel , Ikram M. Arfan , Vernooij Meike W. 
Published: December 2022

AbstractBackgroundHigher vascular risk increases the likelihood of developing dementia. Better understanding the association between vascular risk and Alzheimer’s disease (AD) pathology at the pre‐dementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of vascular risk on the presence and severity of in‐vivo measured brain beta‐amyloid (Aβ) plaques in participants from the population‐based Rotterdam Study.MethodVascular risk factors (hypertension, hypercholesterolemia, diabetes, obesity, physical inactivity, and smoking) were assessed twelve and seven years prior to 18F‐florbetaben positron emission tomography (PET) in 506 dementia‐free participants. Vascualr risk factors were associated with binary amyloid PET status or continuous PET readouts (SUVr values) using logistic and linear regression models respectively, adjusted for age, sex, education, APOE4 risk allele count, and time between vascular risk and PET assessmentResultParticipants’ mean age at time of amyloid PET was 68 years (range: 60‐90), 262 (51.8%) were women and 158 (31.2%) carried at least one APOE4 risk allele (Figure 1). The adjusted prevalence estimates of an amyloid‐positive PET status markedly increased with age (12% in 60‐69y vs. 45.5% in 80‐89y age‐groups) and APOE4 allele count (8.3% in non‐carriers vs. 34.8 to 58.8% in carriers of one or two risk allele(s); Figure 2). A diagnosis of diabetes seven years prior to PET assessment was associated with a higher risk of a positive amyloid status (OR[95%CI] = 4.07[1.66‐9.71], P = 0.002; Figure 3) and higher SUVr values, indicating more severe Aβ pathology (standardized beta = 0.478[0.205–0.750], P = 0.001; Figure 4). We found evidence for an association between hypertension and higher SUVr values in APOE4 carriers, but not in non‐carriers (interaction: standardized beta = 0.425[0.092–0.758], P = 0.013; Figure 5). Hypercholesterolemia, obesity, physical inactivity and smoking were not related to amyloid PET measures.ConclusionThe current findings suggest a contribution of diabetes and hypertension to the pathophysiology of AD. Since both conditions respond well to lifestyle modification and drug treatment, further research should be conducted to examine the preventative effect of early risk management on the development of AD neuropathology.
Longitudinal changes of automated speech markers in MCI and mild AD
Authors: Cho Sunghye , Shellikeri Sanjana , Ash Sharon , Agmon Galit , Cousins Katheryn A Q , Gonzalez‐Recober Carmen , Nevler Naomi , Liberman Mark Y , Grossman Murray 
Published: December 2022

AbstractBackgroundMild cognitive impairment (MCI) and mild Alzheimer’s disease (mAD) are characterized by decline in memory and other cognitive domains, including language. Previous studies have shown that MCI and mAD patients produce impaired speech. In this study, we investigated longitudinal changes in lexical and acoustic speech features from natural speech of MCI and mAD patients using highly reliable automated methods.MethodWe analyzed 116 digitized 1‐minute picture descriptions produced by 24 MCI (65.8±9.2y, 9 females, mean mini‐mental state exam (MMSE) score at the first recording (T1)=25.4±1.1) and 19 mAD patients (66.9±8.8y, 5 females, mean MMSE at T1=21.9±1.1). The groups did not differ in demographic characteristics, disease duration, and mean inter‐sample interval. Using automated pipelines, we tagged the part‐of‐speech categories of all words, rated words for word frequency, familiarity, concreteness, and semantic ambiguity, and counted partial words and total number of words. Speech samples were segmented into speech and silent pause segments to calculate mean speech segment duration, pause rate, percent of speech out of total time, and articulation rate. Linear mixed‐effects models examined changes over time for each measure, controlling for disease duration at T1. The difference between the first and the last recordings (mean=24±10.9 months) in each measure was related to changes in MMSE, covarying for disease duration at T1.ResultPatients’ adjectives (beta=‐0.04, p=0.006) and determiners (beta=‐0.06, p=0.01) decreased over time, whereas pronouns increased (beta=0.06, p=0.014). Patients produced more frequent (beta=0.004, p=0.043) and more familiar (beta=0.001, p=0.046) words over time. Patients articulated more slowly (beta=‐0.02, p=0.001) and produced more partial words (beta=0.04, p=0.004) and fewer total words (beta=‐0.9, p=0.018) over time. Patients produced shorter speech segments (beta=0.008, p=0.021), paused more frequently (beta=0.32, p=0.001), and produced less speech (beta=‐0.35, p<0.001) over time. All measures showed no group interaction. Patients whose MMSE scores decreased spoke more slowly (beta=2.25, p=0.04) and produced higher‐frequency words (beta=‐6.4, p=0.043) and more partial words (beta=‐0.72, p=0.028) compared with patients whose MMSE scores did not change.ConclusionMCI and mAD patients’ language changed over time, and this was significantly related to patients’ cognitive decline. These findings support the use of automated speech analyses in studying longitudinal changes in neurodegeneration.
Selecting appropriate meaningful change thresholds for trials of early (prodromal‐to‐mild) AD: A caregiver‐rated, anchor‐based analysis based on the Tauriel Study
Authors: Lansdall Claire J , Teng Edmond , McDougall Fiona , Delmar Paul , Smith Janice , Manser Paul T 
Published: December 2022

AbstractBackgroundClinically meaningful change thresholds for assessments used in Alzheimer’s disease (AD) trials, including the Clinical Dementia Rating Scale – Sum of Boxes (CDR‐SB), may differ by disease stage and are increasingly important to interpret efficacy. However, anchor‐based estimates for the CDR‐SB have largely used clinician‐ rather than caregiver‐rated anchors. We established meaningful change thresholds for the CDR‐SB using a caregiver‐rated anchor of global change in early (prodromal‐to‐mild) AD patients over an 18‐month clinical trial.MethodAnchor‐based analyses of the Tauriel data (NCT03289143) were conducted to establish CDR‐SB thresholds for biomarker confirmed early AD patients. The Caregiver Global Impression of Change – Alzheimer’s Disease (CaGI‐Alz), a 7‐point caregiver‐rated instrument, provided 2 independent anchors of meaningful decline in memory and activities of daily living (ADLs) (Figure 1). The anchor category of interest for establishing minimal meaningful change thresholds was the ‘Somewhat worse’ category. Average score changes were generated for the ‘No change’ category for comparison. Baseline CDR‐SB and Week 25, 49, and 73 CaGI‐Alz and CDR‐SB data were analyzed; correlations of >0.3 were deemed acceptable for anchor‐based analyses.ResultOur results focus on 49‐ and 73‐week time points based on strength of anchor‐measure correlation and group sample size (Table 1). At 49 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 1.54 (ADL anchor) and 1.08 (memory anchor), mild participants had changes of 2.22 (ADL) and 1.80 (memory), and the combined early AD population had changes of 1.97 (ADL) and 1.51 (memory). At 73 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 2.09 (ADL) and 1.52 (memory), mild participants had changes of 2.25 (ADL) and 2.32 (memory), and the combined early AD population had changes of 2.18 (ADL) and 2.01 (memory).ConclusionAlthough thresholds for meaningful change may differ across disease stages, AD is a continuum and the transition between prodromal to mild is often indistinct. In early (prodromal‐to‐mild) AD populations assessed over longer clinical trials, it may be appropriate to identify meaningful progression on the CDR‐SB using thresholds of 2–2.5 at the individual level.
Single‐Neuron Genome Sequencing in Alzheimer’s Disease Identifies Disease‐Specific Somatic Alterations and Insights into Pathogenesis
Authors: Miller Michael B. , Huang August Yue , Kim Junho , Zhou Zinan , Kirkham Samantha L , Maury Eduardo A , Ziegenfuss Jennifer S , Reed Hannah C , Rento Lariza , Ames Heather M , Oakley Derek , Frosch Matthew P. , Hyman Bradley T. , Lodato Michael , Lee Alice E. , Walsh Christopher A. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is characterized pathologically by deposition of misfolded amyloid‐b and tau proteins. However, protein‐directed therapeutic strategies have shown limited clinical benefit, pointing to the need to examine pathogenesis from a broader lens.Neurons each harbor somatic single nucleotide variants (sSNV) in their genomes, which increase with age, at a rate of ∼15 sSNV per year. In AD, DNA damage is increased, with potentially significant effects on the genome of each cell.MethodWe performed single‐cell whole‐genome sequencing on neurons from postmortem brain tissue from humans with AD and age‐matched controls, using two independent genome amplification methods (MDA and PTA), and analyzed the burden of somatic mutations. We also performed mutational signature analysis of the nucleotide changes and trinucleotide context to assess for mutagenic patterns.ResultWe found significantly increased sSNV in AD, with each neuron carrying hundreds of additional somatic mutations, with a distinct mutation pattern. AD neurons show an increase in Signature C, which contains distinct nucleotide changes including C>A variants. We found elevated 8‐Oxoguanine DNA lesions, evidence that these mutations may result from oxidative damage to DNA. Mutations also show a mechanistic role for gene transcription in the generation of sSNV. Somatic mutations are predicted to produce deleterious effects on the neuron, including gene inactivation and neoantigen‐stimulated immune attack.ConclusionSomatic mutations accumulate abundantly in Alzheimer’s disease, distributed across the genome. Our findings implicate multiple mutagenic forces in sSNV generation in AD, illuminating multiple upstream components of disease pathogenesis including DNA oxidation and transcription‐coupled DNA repair. Furthermore, elevated somatic mutation levels appear to produce a toxic cellular state, positioning neurons for dysfunction and death. These findings therefore identify somatic mutation accumulation as a novel process in neurodegeneration, through which we can dissect the cascade of events in Alzheimer’s disease pathogenesis.
Cognitive and Functional Trajectories in Prediagnostic Parkinson’s Disease
Authors: Bock Meredith A , Vittinghoff Eric , Bahorik Amber L , Leng Yue , Yaffe Kristine 
Published: December 2022

AbstractBackgroundCognitive and functional decline is typically considered a late manifestation of Parkinson’s Disease (PD). However, impactful non‐motor symptoms can occur prior to the typical motor symptoms due to prodromal neurodegeneration. Few studies have investigated prediagnostic trajectories of cognition and function.MethodWe studied 15,390 participants from two prospective cohort studies of community‐dwelling elders (one of men and one of women) followed up to 20 years. PD was repeatedly ascertained by self‐reported physician diagnosis over follow‐up. We excluded individuals with prevalent PD at baseline (n = 152). Global cognition (Modified Mini‐Mental State Examination or the Mini‐Mental Status Exam), executive function (Trails B), and functional status (interviewer administered IADL and physical function questionnaire) were repeatedly evaluated in both studies. Raw scores were z‐transformed to mean 0 and standard deviation 1. We estimated the associations of PD diagnosis with rates of change in cognition and function before and after PD diagnosis compared to healthy older adults using mixed‐effects models adjusted for age, education, race, body mass index, smoking, alcohol use, depression, and cardiovascular risk factors.ResultOver follow‐up, 297 individuals developed incident PD (168 men and 129 women). Interactions between the terms in our model and sex were statistically significant for all three outcomes (p<0.001 for all), so we stratified results by sex. Compared to older men without PD, men who developed PD exhibited faster decline in global cognition (0.04 SD difference in annual change, p<0.001), executive function (0.05 SD difference, p<0.001), and functional status (0.06 SD difference, p<0.001) in the prediagnostic period. Women who developed PD compared to women without PD displayed faster decline in executive function (0.02 SD difference, p = 0.006) and functional status in the prediagnostic period (0.07 SD difference, p<0.001).ConclusionIndividuals who develop PD exhibit decline in executive function and functional status during the prediagnostic phase that exceeds rates associated with normal aging. Men exhibit more cognitive decline prior to PD diagnosis compared to women. Better understanding the prodromal phase of PD may enable earlier diagnosis and open a window for the management of non‐motor symptoms to improve quality of life and facilitate the development of future neuroprotective treatments.
Sex differences in the association between hearing impairment and brain atrophy: findings from the UK Biobank
Authors: Fitzhugh Megan C , Pa Judy 
Published: December 2022

AbstractBackgroundHearing impairment is highly prevalent in older adults and was recently recognized as a modifiable risk factor for dementia. However, it is unknown if risk differs by sex and whether other issues associated with hearing, like social engagement or depression, impact these associations.MethodUK Biobank data was used to identify 165,471 participants (57±8 years, 55% female) without dementia who had a hearing assessment at baseline. Hearing was assessed using a speech reception threshold task, with scores grouped into good, insufficient, and poor severity levels based on previously derived cut‐offs (Dawes et al., 2014). Cox proportional‐hazard models were used to investigate sex differences in the association between hearing impairment and dementia risk. Sensitivity analyses were conducted to determine if social engagement or depressive symptoms mediated these associations. In a subset of participants with MRI data (n=2,322, 62±7 years, 52% female), linear mixed models stratified by sex were conducted to examine if development of impaired hearing from baseline was associated with gray matter atrophy in auditory and limbic regions.ResultInsufficient and poor hearing were associated with increased risk for dementia compared to good hearing (HR=1.76, 95%CI 1.43‐2.18 and HR=2.13, 95%CI 1.46‐3.11, respectively), but differed by sex. Women with insufficient (HR=1.73, 95% CI 1.25‐2.40) and poor (HR=3.08, 95%CI 1.80‐5.28) hearing had the greatest risk of dementia, whereas only men with insufficient hearing had increased risk (HR=1.78, 95%CI 1.34‐2.35; poor HR=1.60 95%CI 0.94‐2.73). These relationships were not mediated by social engagement or depression. In the MRI subset, women who developed or maintained impaired hearing had greater atrophy over 2.29 years in auditory pathway (e.g., primary auditory cortex, thalamus) and limbic (e.g., hippocampus, parahippocampus, amygdala) regions compared to women with good hearing. Men who developed impairment exhibited decreases over 2.30 years in a secondary auditory region only.ConclusionWomen with impaired hearing have greater risk of dementia compared to men. These sex differences are not mediated by social engagement or depression. Women with impaired hearing exhibit greater atrophy in auditory and limbic regions, while men do not. Sex differences in gray matter atrophy may explain why women with impaired hearing are at greater risk of dementia.