bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐wide association study of brain MRI and other phenotypes in the Tohoku Medical Megabank Organization
Authors: Taira Makiko , Saykin Andrew J. , Fuse Nobuo 
Published: December 2023

AbstractBackgroundThe Tohoku Medical Megabank Organization (ToMMo) is a large cohort study and biobank established in 2013 in the Miyagi Prefecture of Northern Japan following the Great East Japan Earthquake and Tsunami. ToMMo enrolled 150K individuals in a planned longitudinal study aiming to reveal numerous and diverse biological, psychological, and lifestyle characteristics associated with important diseases, and it collects and analyzes a rich set of biological data, including genomics, from participants to support innovative research on these diseases. Importantly, aging and Alzheimer’s disease are key areas of our research agenda, but little is known about common genetic variants that affect quantitative traits related to AD in Japanese people. MRI brain scans and cognitive screening on 12,164 cohort participants were collected at baseline (the TMM Brain‐MRI Study) since 2014 to 2019.MethodThe TMM Brain‐MRI study acquired multiple MRI sequences, including T1‐weighted imaging (T1WI). The ADNI Phantom was used, and each scan’s quality was checked. Following pre‐processing steps, Freesurfer (v7.2.0) was used with the Destrieux or Desikan‐Killiany atlas to parcellate multiple anatomical brain regions and derive cortical thickness data. We conducted a Genome‐Wide Association Study (GWAS) on all Brain‐MRI Study participants who were also genetically profiled with a Japanese‐oriented microarray (Japonica‐Array® v1, v2 and NEO) and WGS.ResultAlong with the other data types, the genotyping data for the TMM Brain‐MRI study participants represented etiological characteristics. The attached Figure shows the age distribution by decile for 7,630 male and female participants who were profiled with the Japonica‐Array® v2. The usable archived volumetric T1WI data demonstrated inverse correlations between brain volume and age, as well as very good agreement with correlations observed in previous clinical studies. We identified nominally genome‐wide significant loci (P < 5×10‐8) associated with imaging phenotypes in this sample consisted of Japanese adults as the discovery stage of the study.ConclusionThe ToMMo MRI and genetic data provide insights into the genetic architecture of the brain that are relevant to understanding brain aging and AD. Our results require some replication stages and meta‐analyses using samples of Japanese individuals in other studies.
Neurodegenerative biomarkers of A‐T+ compared to A+T+ and A‐T‐ older adults
Authors: Jung Joon Hyung , Yi Dahyun , Byun Min Soo , Kong Nayeong , Chang Yoon Young , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Kyoung Mi , Sohn Chul‐Ho , Lee Dong Young 
Published: December 2023

AbstractBackgroundPrimary age‐related tauopathy (PART) is a neuropathological entity with neurofibrillary tangles in the absence of beta‐amyloid plaques in the brain. Recent advances in neuroimaging made it possible to identify amyloid PET‐negative (A‐) tau PET‐positive (T+) condition as a possible candidate for PART in living human brains. We tried to investigate neurodegenerative biomarkers of A‐T+ older adults compared to those of A+T+ and A‐T‐ [corresponding to Alzheimer’s disease (AD) and no AD pathology, respectively] individuals.MethodA total of 156 older participants (64 cognitively normal, 43 mild cognitive impairment (MCI), and 49 dementia), were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). All participants underwent comprehensive clinical evaluation and multimodal brain imaging including amyloid and tau PET, and MRI. Global PiB retention measured by 11C‐PiB‐PET and tau deposition in the regions corresponding to Braak stages measured by 18F‐AV‐1451 PET were used in this study. A+ was defined as global mean Aß deposition standardized uptake value ratio (SUVR) > 1.4 and T+ was defined as tau burden corresponding to Braak stages I/II, III/IV, or V/VI. Hippocampal volume, AD‐signature cortical thickness (AD‐CT), AD‐signature cerebral glucose metabolism (AD‐CM) and white matter hyperintensity (WMH) volume were also measured as neurodegenerative biomarkers. Multiple linear regression analysis controlling for age, gender, and APOE e4 positivity was used to investigate the group differences of neurodegenerative biomarkers.ResultOf the 156 participants, 31 were defined as A‐T‐, 53 as A+T‐, and 72 as A+T+. A‐T+ group had higher levels of hippocampal volume (B = 683.448, p<0.001), AD‐CT (B = 0.267, p<0.001) and AD‐CM (B = 0.174, p<0.001), but not WMH volume (B = ‐1.188, p = 0.651), compared to A+T+ group. When compared to A‐T‐ group, A‐T+ group did not show significant difference in any of the neurodegenerative biomarkers.ConclusionOur findings suggest that, in regard of neurodegeneration, older adults with A‐T+ condition, close to pathological PART, are less severe than those with A+T+, while they appear similar to those with A‐T‐.
A Centiloid cut‐off to help predict true amyloid accumulation
Authors: Bollack Ariane , Collij Lyduine E. , García David Vállez , Shekari Mahnaz , Altomare Daniele , Payoux Pierre , Dubois Bruno , Grau‐Rivera Oriol , Rovira Mercè Boada , Nordberg Agneta K , Walker Zuzana , Scheltens Philip , Schöll Michael , Wolz Robin , Schmidt Mark E , Gismondi Rossella , Stephens Andrew W. , Buckley Christopher , Frisoni Giovanni B , Hanseeuw Bernard J , Visser Pieter Jelle , Vandenberghe Rik , Drzezga Alexander , Yaqub Maqsood , Boellaard Ronald , Markiewicz Pawel J , Cash David M , Farrar Gill , Gispert Juan Domingo , Barkhof Frederik 
Published: December 2023

AbstractBackgroundLongitudinal amyloid‐PET‐based imaging endpoints are often included in clinical trials, where they provide critical evidence of treatment efficacy. We assessed the longitudinal variability of the Centiloid (CL) scale and its ability to predict early amyloid accumulation.MethodLongitudinal amyloid‐PET with 18F‐flutemetamol and 18F‐florbetaben (N = 711 at follow‐up 1, time interval: 3.0±1.3years; N = 98 at follow‐up 2, 5.1±0.7years) was conducted in predominantly cognitively unimpaired participants of the AMYPAD Prognostic and Natural History Study (PNHS). Quantification of scans was performed using the MR‐based CL pipeline and visually read (VR) by local certified assessors. Longitudinal change in CL was modelled using linear mixed effects models corrected for age, sex, and education. Subjects were classified based on VR status over time (i.e., Stable VR‐, VR‐Converters or Stable VR+) and based on amyloid accumulation over time (i.e., Accumulator or Non‐accumulator; Accumulator if annualised rate of change [ARC]>95th percentile of a subset of 110 subjects for whom no amyloid accumulation was expected, selection criteria in Table‐1). Finally, a baseline CL cut‐off to identify future Accumulators was derived from a receiver operating characteristic (ROC) curve analysis.ResultParticipants had a median age of 65 years, 57% were females, 41% were APOE‐e4 carriers, and 18% had baseline VR+ scan (Table‐1). The 95th percentile of ARC in the stable 110 subjects was 2.7 CL/year. Baseline CL was higher in Accumulators compared to Non‐accumulators (24.8 versus 8.7 CL, p<.001). Based on the ROC analysis, the optimal baseline CL threshold to predict Accumulators was 12.1 CL (sensitivity = 67% and specificity = 74%, Figure B‐C‐D), in line with the baseline CL threshold that best predicts VR conversion (11.6 CL). Baseline CL values and ARC were also higher in Stable VR+ and VR‐Converters compared to Stable VR‐ (p<.001), but no significant difference in ARC was found between VR‐Converters and Stable VR+ (Table‐1, Figure A). Results were robust across tracers.ConclusionIncreases over 2.7 CL/year can be indicative of reliable amyloid accumulation. A CL cut‐off of ∼12CL can help identify subjects more likely to accumulate amyloid in the short future. Annualised rates of change in amyloid deposition where highly comparable across tracers.
Age in Place, Move in VR: Investigating the Feasibility and Usability of a Custom‐made Virtual Reality Exergame to Promote the Well‐being of Community‐Dwelling Older Adults
Authors: Mehrabi Samira , Basharat Aysha , Mazen Sarah , Cao Shi , Boger Jennifer , Barnett‐Cowan Michael , Muñoz John , Middleton Laura E 
Published: December 2023

AbstractBackgroundInteractive virtual reality (VR) games combined with exercise (exergames) are a plausible strategy to encourage physical activity (PA) among older adults. However, there is little systematic evaluation of the feasibility, usability, and potential benefits of deploying at‐home VR exergames among this population.MethodFifteen community‐dwelling older adults (M = 67.33 ± 5.3, age range 60‐77) (Table1) were recruited to play 18 sessions (each 15‐20 min) of a custom‐made VR exergame at home over six weeks. Recruitment, retention, and adherence rates were calculated to determine feasibility. The usability of the exergame was assessed through i) a game user experience questionnaire, ii) a self‐reported physical/emotional discomfort questionnaire, and iii) a perceived enjoyment scale. The exploratory outcome measures included changes in i) PA, ii) exercise self‐efficacy, iii) affect, iv) various cognitive and perceptual tasks and were assessed i) before and after acute data, and ii) before and after the intervention.ResultThirteen participants completed the study (13% attrition rate) without missing any exergaming session (100% adherence rate). The completion rate of cognitive assessments, perceptual tasks, and self‐reported questionnaires was = 97%. Low levels of cybersickness were reported (M = 0.9 ±1.0 out of 10). The average perceived enjoyment and perceived rate of exertion were 3.2. ±1.1 (out of 5) and 2.4±1.9 (out of 10), respectively. Most of the participants (92.3%) found the exergame’s instructions easy to follow and had an overall positive experience (84.6%). Whereas the exergame was perceived as useful for increasing PA levels (61.6%), mood enhancement was reported among less than half of participants (46.2%) and only 38% indicated that they would choose VR exergaming for at‐home PA. The likelihood of playing VR exergames in the future was also low (38.5%). The exploratory outcome measures are presented in Table 2.ConclusionOur study provides insights into the feasibility and usability of a custom‐made VR exergaming intervention to promote PA in community‐dwelling older adults which may potentially benefit their well‐being. Our findings inform the future adoption of VR at home. Our results can also be used to inform large‐scale trials and support the design and deployment of other remote exergames and assessments.
DETECT‐AD (Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease): A simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures
Authors: Kaye Jeffrey A , Marcoe Jennifer , Mar Amanda B , Hanna Elise J , Pierce Aimee , Silbert Lisa C , Shang Yanan , Schwartz Daniel , Gothard Sarah , Mattek Nora , Au‐Yeung Wan‐Tai M. , Steele Joel S. , Beattie Zachary T 
Published: December 2023

AbstractBackgroundEarly detection and precise monitoring of cognitive and functional decline in persons with Alzheimer’s Disease (AD) in clinical trials is a high priority. Unfortunately, early detection and monitoring of the subtle and slow changes of disease with conventional cognitive testing and self‐report questionnaires has been fraught with poor sensitivity and lack ecological validity. Digital biomarkers using ambient sensing technologies may afford a more effective approach to conducting trials. Remaining to be established is the ability of this approach to fundamentally improve early AD treatment response readout in a formal clinical trial setting. A simulated clinical trial (DETECT‐AD: ClinicalTrials.gov, NCT05385913) is being conducted to determine how well continuously assessed, home‐based digital biomarkers may detect clinically meaningful changes in individuals with changing amyloid (Aß) burdens in pre‐symptomatic AD.MethodClinically prodromal AD patients with estimable rates of AD progression based on Aß Florbetapir‐PET status are enrolled divided n = 50:n = 50 into Aß “positive” (higher amyloid burden) patients who predictably progress (as if they were receiving placebo) and Aß “negative” patients progressing more slowly (representing the treatment group). A study‐provided multivitamin mimics RCT conditions and study drug adherence behavior. Baseline standard clinical and biomarker measures are obtained along with digital biomarkers (DB) captured with passive and active sensors (actigraphy, bed mats, IR sensing, e‐pillbox, computing/phone device use, weekly online reporting/cognitive assessment). Primary outcome is the change in a composite DB composed of measures in 4 domains: mobility, cognition, sleep, and socialization. Secondary measures are the relationship of DB to fluid biomarkers (plasma ptau181/217, amyloid, NfL) and MRI/PET measures.ResultTo date (01/16/2023), 46/100 have been enrolled with mean(SD): follow‐up = 27.0(7.9) weeks (no dropout); age = 78(6.6); 63% women; MoCA = 25.5(2.3); PET SUVR = 1.09(0.20), range: 0.850‐2.07. Exemplary baseline digital biomarker metrics are presented in the Table. Preliminary data shows an inverse Aß‐SUVR correlation with mean steps/day (r = ‐.41, p = .012) and a positive correlation of MoCA with computer use (r = .61; p = .036).ConclusionHome‐based continuous capture of multi‐domain DBs is feasible in a clinical trial setting and may yield early meaningful indicators of clinically relevant changes in older adults with pre‐AD dementia. Further evidence will evolve as sample sizes and longitudinal follow‐up increases.
Diagnostic Performance of MRI‐based Alzheimer’s Disease Resemblance Atrophy Index and Plasma‐Based Biomarkers on Alzheimer’s Disease
Authors: Fu Siu Ting , Cai Yuan , Huang Junzhe , Liu Wanting , Shi Lin , Au Lisa Wing Chi , Ko Ho , Mok Vincent Chung Tong 
Published: December 2023

AbstractBackgroundAlthough positron emission tomography (PET) or cerebrospinal fluid measurements of amyloid and tau burden are available for the detection of Alzheimer’s disease pathology, such methods are invasive and not easily accessible. Recent studies show that Alzheimer’s Disease‐resemblance atrophy index (AD‐RAI), an MRI‐based machine learning‐derived biomarker, and plasma‐based biomarkers can be used as accurate biomarkers for Alzheimer’s disease pathology. We aim to evaluate the diagnostic metrics of AD‐RAI and plasma‐based biomarkers for detecting Alzheimer’s disease.MethodWe recruited 69 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had different degrees of cognitive impairment: 8 cognitive unimpaired [CU], 26 with subjective cognitive decline [SCD], 21 with mild cognitive impairment [MCI] and 14 with dementia. All subjects underwent 11C‐ PIB and 18F‐T807 PET to measure pathological Aß deposition (A+) and tau burden (T+). Subjects received structural MRI for deriving AD‐RAI. Plasma levels of Aß40, Aß42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181), and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays.ResultAmong 69 subjects (mean [SD] age, 67.7 [6.8] years; 28 men [40.6%]), 25 (36.23%) subjects were confirmed to be A+ and T+. AD‐RAI, plasma p‐tau 181, and plasma Aß42 were associated with A+T+ after adjusting for age, gender, and education (p<0.01). AD‐RAI individually outperformed all plasma‐based biomarkers (AUC = 0.911; Sensitivity = 0.826; Specificity = 0.905). The combination of AD‐RAI, p‐tau181 and Aß42 yielded the best diagnostic metrics for detecting A+T+ subjects (AUC = 0.957; Sensitivity = 0.870; Specificity = 0.929).ConclusionA panel of AD‐RAI, plasma p‐tau, and plasma Aß42 might help with screening and diagnosis of Alzheimer’s disease.
Longitudinal changes in driving behaviours among older adults with different A/T/N biomarker profiles
Authors: Long Kelly , Bayat Sayeh , Babulal Ganesh M. 
Published: December 2023

AbstractBackgroundThe pathophysiological process of Alzheimer’s disease (AD) spans approximately 10‐15 years. To define AD by its pathologic processes, the A/T/N classification framework was proposed constituting ß‐amyloid (A), tau (T), and neurodegeneration (N) biomarkers derived from cerebrospinal fluid (CSF) or imaging. With these biomarkers, individuals can be divided into four categories: normal (A‐T‐N‐), AD pathologic change (A+T‐N‐), AD (A+T+N‐, A+T‐N+, A+T+N+), and suspected non‐AD pathology (SNAP) (A‐T+N‐, A‐T‐N+, A‐T+N+). Recent evidence indicates that daily driving behaviours can identify preclinical AD, solely based on CSF ß‐amyloid (A), with high accuracy. This study aims to determine the extent to which longitudinal changes in driving behaviour vary between individuals with different A/T/N profile categories.MethodParticipants were enrolled in a longitudinal study on driving and preclinical AD biomarkers from Washington University School of Medicine. Temporospatial driving behaviours were collected with a data logger installed in participant vehicles over a period between January 2015 and March 2020. CSF collected within three years of each driving event was used to assign A/T/N categories. The cohort included 132 cognitively normal (Clinical Dementia Rating of 0) older adults (>65). Changes in driving behaviours over time were modelled for each group using linear mixed‐effects models. A Z‐test was used to determine if the slopes significantly differed between individuals with normal biomarkers and the remaining groups.ResultParticipants were classified as 59 individuals with normal biomarkers, 9 with AD pathologic change biomarkers, 45 with AD biomarkers, and 19 with SNAP biomarkers. Compared to normal aging, the AD pathology group had a statistically significantly higher increase in average occurrences of under‐speeding (p = 0.001), a significant decrease in average trip duration (p = 0.021), and a significant decrease in the average standard deviation of vehicle speed (p = 0.029). The AD group had no significant differences from the normally aging group. The SNAP group showed a significantly higher increase in the average occurrences of over‐speeding (p<0.001) than normal aging.ConclusionDriving behaviours and their rate of change over time vary between individuals with different A/T/N profile categories. These differences provide an opportunity to strengthen our understanding of the disease trajectory.
Long‐term results of Alzheimers’ dementia treated with transcranial pulse stimulation
Authors: Lohse‐Busch Henning 
Published: December 2023

AbstractBackgroundThe treatment of the brain with focused extracorporal shock waves (ESW) in patients with unresponsive wakefulness syndrome dates back to 2006 (1). This was followed by preliminary investigations for the treatment of Alzheimer’s dementia and Parkinson’s disease in the years up to 2014. The introduction of a shock wave generator with a navigation system in 2016 (Neurolith, Storz Medical) was a breakthrough for the precise treatment of brain structures. This method of brain treatment was then called TPS. After a 3 month study with people living with Alzheimer’s dementia in 2019 (2), we now present patients with long‐term follow‐up over 3 years during continous monthly TPS treatment as a critical undertaking for future treatments.Method6 persons living with mild Alzheimer’s dementia (Mini Mental Status >18) were treated initially 6 times during 2 weeks with TPS. Subsequently, they received one TPS session monthly over 3 years. The results were assessed with the CERAD Plus score and compared with the data of the expected natural development with standard medication according to the ALSOVA study of Hallikainen.ResultWhile cognitive skills improved by 12% over 12 months, outcomes returned to the baseline in the second year. A two‐week booster of 6 sessions with TPS improved outcomes again by 4.5% compared to the baseline. After 3 years, the results were at the level of the expected natural development with standard medication.ConclusionA symptomatic improvement of Alzheimer’s symptoms with low‐energy TPS over several years seems to be possible. It was a methodological mistake not to examine the patients more frequently neuropsychologically. It is conceivable that this would achieve a better long‐term result. (1.) H. Lohse‐Busch, U. Reime and R. Falland, (2014) Symptomatic treatment of unresponsive wakefulness syndrome with transcranially focused extracorporeal shock waves. NeuroRehabilitation 35 (2014) 235‐244 (2.) Beisteiner R, Matt E, …… Lohse‐Busch H (2019) Transcranial pulse stimulation with ultrasound in Alzheimer’s disease—A new navigated focal brain therapy. Adv Sci (Weinh) 23;7(3):1902583.
Developing an occupational telerehabilitation program for caregivers of people with dementia to increase their ability to care and reduce burden
Authors: Giovanni Orientina Miriam Di , Chinaglia Cinzia Negri , Petrucci Bianca Maria , Fritzsching Daniela Matilde , Fabbo Andrea 
Published: December 2023

AbstractBackground People with dementia (PwD) require high levels of care, most of which is provided by either family or informal caregivers. Psychosocial interventions have been demonstrated to reduce caregiver burden and delay nursing home admission. Telemedicine could provide caregivers access to such interventions, increasing their sense of competence and resilience. Method Through a co‐design process involving geriatricians, psychologists, neurologists, nurses, occupational therapists and 25 dyads, a telerehabilitation program has been developed and tested through a 12‐months Beta Test protocol. The program comprises a multidimensional clinical assessment and a telerehabilitation plan. Whilst occupational therapists act as care manager interface towards caregivers through a telemedicine platform, a multidisciplinary team including nurses, psychologists and geriatricians, regularly oversees each plan and delivers interventions whenever required. Results Almost all caregivers were spouses or children (22 out of 25). 79% were female and 59% lived with the care recipient in the same household. The average age of caregivers was 63,72 and Zarit index 36,88. On average PwD’s age was 83,75, Barthel Index 61,27, IADL 0,97, NPI Index 24,86 with 4,8 BPSD. The program has required on average 18,8 sessions per caregiver: which comprised of 4,5 sessions for multidimensional evaluation of both PwD and caregiver, 9,1 sessions for the execution of the telerehabilitation plan and 5,2 sessions for follow up. Sessions could range from 45 minutes (clinical scales‐based assessment) to 10 minutes (follow up). 48% of telerehabilitation sessions addressed BPSD, 17% provided emotional support, 14% supported caregivers in ADL activities, 11% addressed comorbidities and 10% addressed other issues (communication and cognition). A self‐developed caregivers' reported outcome questionnaire (24 responders out of 25) reported that 88% of caregivers improved their health literacy, 87% their sense of competence and 97% felt emotionally supported. After at least 6 months, a follow up analysis on 13 PwD and 10 family caregivers, NPI Index has improved on average by 41% while Zarit Index by 16%. Average yearly cost of the program reached 2 euro per day per dyad. Conclusions The beta test showed encouraging outcomes in terms of caregivers’ satisfaction that require further investigation in terms of clinical outcomes and cost‐effectiveness.