bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of Changes in the Clinical Dementia Rating Scale: Reversion and Conversion
Authors: Wilks Hannah M , Cruchaga Carlos , Fagan Anne M. , Schindler Suzanne E. , Morris John C , Hassenstab Jason J. 
Published: December 2023

AbstractBackgroundAt the Knight Alzheimer Disease Research Center (ADRC), clinicians are blinded to cognitive data and prior assessments to ensure that ratings are free of circularity and examiner bias. It is common for cognitive status to fluctuate between normal and abnormal in longitudinal studies of aging and dementia, even when using the gold standard Clinical Dementia Rating (CDRâ) scale. CDR fluctuation is common when clinical symptoms are mild. It was hypothesized reverters, defined as individuals who change from CDR 0.5 to CDR 0, would have worse cognition, more abnormal biomarkers, and more likely to progress to CDR>0 compared to participants who remain unimpaired (“CN").MethodCognitively normal participants with at least three annual visits were included (n = 924, Table 1). Participants were classified as CN, reverters, and converters to stable dementia (“converters”). The Knight PACC was used to compare cognition between groups. Participants (n = 187) with cerebrospinal fluid or positron imaging tomography biomarkers were classified as amyloid “positive” or “negative”. The visit of first CDR>0 was defined as the “index visit” and the visit prior was defined as the “pre‐index visit.” Linear models evaluated relationships between biomarker status, APOE ε4 status, and cognition at the pre‐index and index visit. Logistic regression evaluated predictors of converting to a dementia status (“conversion”) and reverting from CDR 0.5 back to CDR 0 (“reversion”).ResultOf 924 participants, 127 (14%) were reverters and 142 (15%) were converters. Converters had the lowest PACC scores of the three groups at the pre‐index and index visit, with reverters having slightly better PACC scores than converters but significantly worse scores than CN (Figure 1). Predictors of conversion and reversion included older age, male gender, APOE ε4 carriage, and worse PACC scores. Amyloid positivity did not predict conversion or reversion. Reverters exhibited more longitudinal cognitive decline compared to CN but the magnitude of decline was less than converters (Figure 2).ConclusionCDR reversion is a risk factor for future conversion to CDR>0 and is associated with older age, APOE ε4 carriage, and poor cognitive performance. CDR reversion appears to occupy a transitional phase in disease progression between cognitive stability and consistent progression to stable dementia.
GM‐CSF Treatment Increases the Number of Purkinje Cells in a Mouse Model of Down Syndrome
Authors: Ahmed Md. Mahiuddin , Aghili Leila , Wang Athena Ching‐Jung , Elos Mihret , Boyd Timothy D. , Chial Heidi J , Potter Huntington 
Published: December 2023

AbstractBackgroundDown syndrome (DS), the most common chromosomal disorder that is a genetic cause of intellectual disability (ID), is characterized by mild‐to‐severe cognitive deficits and several neurological and brain anatomical abnormalities in people with DS and in animal models of DS. Among them, a marked reduction in the volume of the cerebellum has been reported in fetuses, newborns, and adults with DS, and in mouse models of DS. It has been well documented that children and adults with DS display motor deficits consistent with cerebellar abnormalities. Growing evidence suggests that the cerebellum is involved in the processing of cognitive functions. Reduced size of the cerebellum may be one of the underlying causes of cognitive deficits in DS. However, the cellular functions of the cerebellum remain poorly understood in people with DS. The beneficial effects of treatment with the hematopoietic growth factor granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in animal models of DS, Alzheimer’s disease (AD), normal aging, and clinical trials of AD subjects suggest that it may serve as a potential therapeutic for these disorders. Our recent published data showed that treatment with GM‐CSF rescues the cognitive impairments and improves hippocampal pathology in Dp16 mice. To elucidate cerebellum‐associated cellular functions, we investigated purkinje cell pathology in aged male Dp16 mice after treatment with GM‐CSF compared to saline‐injected mice.MethodWe injected 12‐ to 14‐month‐old male Dp16 male mice subcutaneously with GM‐CSF (5 mg/day; 5 days/week) or with saline (200 ml) for 24 injections total over 29 days. On day 29, the brains were fixed, and tissues were processed for immunohistochemistry.ResultWe observed a reduced number of parvalbumin‐positive purkinje cells and loss of arborization in the cerebellum of male Dp16 mice compared to wild‐type littermates. Treatment with GM‐CSF significantly increased the number of parvalbumin‐positive purkinje cells and partially restored dendritic arborization in the cerebellum of Dp16 mice compared to saline‐injected mice.ConclusionOur results suggest that treatment with GM‐CSF improves cellular abnormalities by increasing the number of purkinje cells in the cerebellum of Dp16 mice. Taken together with our previous results, these findings provide further evidence that GM‐CSF/sargramostim may have therapeutic benefits in people with DS.
Associations between aerobic fitness and subsequent memory performance in non‐demented Presenilin‐1 E280A mutation carriers: A preliminary report from the Colombia‐Boston longitudinal biomarker study
Authors: Guzman‐Velez Edmarie , Fabrega‐Ching Sofia , Oliveira Gabriel , Baena Ana Y. , Martinez Jairo E. , Vila‐Castelar Clara , Noriega Daisy , Munera Diana , Lopera Francisco , Quiroz Yakeel T. 
Published: December 2023

AbstractBackgroundGreater aerobic fitness, objectively measured by VO2‐max, is considered a critical component of overall health and a strong predictor of cognitive functioning. It has been associated with less neurodegeneration in Alzheimer’s disease (AD) and greater functional brain connectivity and plasticity in healthy older adults. Yet, less is known about how it relates to AD progression in people at increased risk for dementia. In this study, we examined whether VO2‐max predicted memory decline in non‐demented mutation carriers and non‐carriers from a Colombian kindred with autosomal dominant AD (ADAD), and hypothesized that those with greater VO2‐max levels would exhibit slower cognitive decline.Methods12 Presenilin‐1 E280A mutation carriers (ages: μ = 39.61 years, SD:4.18) and 14 non‐carriers (ages: μ = 37.11 years, SD:6.59) underwent a standard graded maximal exercise test performed on a treadmill to assess their VO2‐max, which is the maximal rate of oxygen consumption during exercise, measured in milliliters of oxygen per minute per kilogram body mass. Participants also completed the CERAD word list learning and delayed recall, a measure of episodic memory, at baseline and again 18‐24 months later. Group differences were tested using the Mann‐Whitney U test. Linear mixed models were used to examine associations among baseline VO2 max and changes in CERAD word list test scores.ResultsVO2‐max levels did not differ between groups (p = .16). Compared to mutation non‐carriers, mutation carriers performed worse in word list learning (p = .008) and recall (p<.001) at baseline. VO2‐max levels were not associated with baseline word list learning (non‐carriers: p = .93; carriers: p = .76) or recall scores (non‐carriers: p = .82; carriers: p = .63). Baseline VO2‐max levels did not predict change in word list learning (non‐carriers: p = .47; carriers: p = .85) or recall scores (non‐carriers: p = .70; carriers: p = .87).ConclusionPreliminary findings suggest that aerobic fitness, which can be increased with exercise and is associated with greater health, does not relate to memory decline in preclinical ADAD. This is an ongoing longitudinal study, and we will continue to collect more physical activity data in this kindred to characterize these associations better. More research with larger samples is needed to elucidate whether physical activity could help delay AD progression regardless of aerobic fitness levels.
Fatigue Interacts with Amyloid Status To Predict Daily Working Memory Performance in Preclinical Alzheimer’s Disease
Authors: De Vito Alyssa N. , Kunicki Zachary J. , Emrani Sheina , Strenger Jennifer , Harrington Karra D , Roque Nelson A , Sliwinski Martin J. , Salloway Stephen , Correia Stephen , Thompson Louisa I 
Published: December 2023

AbstractBackgroundSmartphone‐based cognitive assessment has the potential to reduce barriers to cognitive screening and increase sensitivity to detect preclinical Alzheimer’s disease (AD). Ecological momentary assessment of cognition is novel, and it is not yet well understood how psychological factors (i.e., mood, stress, and fatigue) may impact cognitive performance in remote, real‐world settings. We aimed to evaluate whether psychological factors influence daily cognitive performance differently between older adults with and without AD‐related pathologic change.MethodParticipants (N = 73) were cognitively unimpaired adults aged 60‐80 years (71% female, 89% White, 16.5 mean years of education) recruited for a digital cognitive assessment study. Participants had amyloid (Aβ) PET imaging results available from prior research participation [(n = 25 Aβ positive (Aβ+) and n = 48 Aβ negative (Aβ‐)]. A modified Telephone Interview for Cognitive Status (TICSm) score of ≥34 was used to indicate normal cognition. Participants completed 8 consecutive days of cognitive assessment using Mobile Monitoring of Cognitive Change (M2C2), a smartphone‐based testing platform developed as part of the National Institute of Aging’s Mobile Toolbox. Brief (i.e., 3‐4 minute) M2C2 sessions were assigned three times daily (morning, afternoon, and evening). Tasks included measures of visual working memory (WM, “Color shapes”), processing speed (PS, “Symbol search”), and episodic memory (EM, “Prices”). Multilevel modeling was used to examine the impact of self‐reported mood, stress, fatigue, and Aβ status on daily cognitive performance while controlling for age, sex, education, and time of day.ResultDaily fatigue was found to interact with amyloid status such that Aβ+ individuals performed worse on the WM task when experiencing higher levels of fatigue (Est. = .004, p = .01) Higher levels of daily stress were associated with poorer performance on the PS task (Est. = ‐.0005, p = .03) but no interaction with Aβ status was observed. There were no significant relationships between mood and cognitive performance.ConclusionWe demonstrated that psychological factors including fatigue and stress may impact performance on remote cognitive assessments. Results also suggested that fatigue may impact daily cognitive performance more among those with AD pathological change. These preliminary results suggest that psychological factors should be considered when determining optimal windows for remote cognitive screening.
Time of day cognitive performance differences in remote, self‐administered assessments and its association with cerebral amyloidosis
Authors: Strenger Jennifer , Emrani Sheina , Kunicki Zachary J. , Harrington Karra D , Roque Nelson A , Sliwinski Martin J. , Salloway Stephen , Correia Stephen , Thompson Louisa I 
Published: December 2023

AbstractBackgroundTime of day (TOD) is known to potentially influence cognition in healthy older adults. Smartphone‐based ‘burst’ testing approaches are increasingly used in AD clinical research to assess cognition across multiple timepoints. This repeated assessment approach can therefore potentially help us understand how TOD may affect different domains of cognitive functioning in normal aging and AD. This study examined the effect of TOD, and its potential interactions with cerebral amyloidosis (Aß), on remote, smartphone‐based cognitive assessment performance.MethodWe recruited 73 cognitively normal adults with elevated (Aß+, n = 25) and non‐elevated (Aß‐, n = 48) Aß positron emission tomography (PET) status from the Butler Hospital Alzheimer’s Prevention Registry (mean age = 69.29, education = 16.45, 71.2% female, 89.0% White). Participants completed brief cognitive testing sessions 3x per day for 8 days using a mobile app. We used ANOVA to examine potential differences in performance on multiple cognitive tasks by TOD (see Table 1), and linear mixed models (adjusted for age, education, and session number) to determine how TOD, Aß status, and their interaction may predict episodic memory (EM) and processing speed (PS) performance.ResultThere were main effects of both Aß status and TOD on EM, with worse performance in the Aß+ group in the afternoon (p < .10 level; Est. = ‐0.05, SE = .02, p = .07), and in the evening (Est = ‐0.02, SE = .01, p = .02) relative to morning. A main effect of TOD on PS was also observed (Est. = ‐92.72, SE = 22.10, p < .001). Additionally, we found an interaction between Aß status and afternoon TOD on PS (Est. = 131.05, SE = 37.76, p < .001).ConclusionThese findings suggest older adults may perform worse on episodic memory tasks in the evening, regardless of Aß status. Effect of TOD on PS varied by Aß status, with Aß+ individuals performing worse in the afternoon, and Aß‐ individuals performing better in the afternoon, relative to morning. While further validation is needed, these results suggest time of day is a significant factor in remote cognitive test performance and may be moderated by AD‐related pathology.
Validation of high resolution subcortical MRI signal using voxel to voxel histology to neuroimaging correlation in AD continuum: advancing neuroimaging biomarker tools for early AD staging
Authors: LaMore Tia , Huang Shuo , Chen Yuheng , Li Song Hua , Lee Wing Hung , Carreira Luzia Lima , Heinsen Helmut , Otaduy Maria Concepción Gracía , Shi Yonggang , Grinberg Lea T. 
Published: December 2023

AbstractBackgroundStudies suggest a decrease in LC volume by 8% each Braak stage, starting at Braak 0‐1, while in normal aging the LC volume remains intact. Thus, LC volumetry is an attractive potential biomarker to monitor AD progression from precognitive stages. However, precise LC volumetry neuroimaging is challenging due to the LC’s small size and location in the brainstem that’s prone to artifacts. To validate the precision/utility of neuroimaging sequences designed for LC volumetry, we developed a pipeline allowing voxel‐to‐voxel histology to neuroimaging comparisons. We tested this pipeline to analyze the neuro‐histological counterpart of an LC volume obtained from manual segmentation from a MRI neuromelanin(NM)sensitive GRE image.MethodWhole brain high resolution(0.7mm)3D‐T1 images and 2D‐2mm thick NM‐sensitive axial GRE images of the brainstem were obtained postmortem in situ before brain removal from a single subject using a 7T MRI(Siemens Magnetom). We combined celloidin‐based histological processing and 3D reconstructions of the histology volume at microscopic resolution which was then aligned to T1. We used structures visible in structural MRI(T1)(brainstem surface, red nucleus, and 4th ventricle) to calculate Dice coefficient to measure registration accuracy. Next, we performed an overlap percentage analysis to investigate how well GRE sequence detected LC borders compared to histology.ResultWe ran Dice coefficient analysis for brainstem structures to measure histology to MRI registration accuracy(Table1). The LC GRE to histology masks overlap percentage was 35.29% and 10.77% compared to the MRI and histology mask total voxels(voxel size = 0.34mm3). The overlap percentage obtained for the rostral and middle LC thirds ranged from 9.43% to 75%when compared to total voxels in MRI/histology masks, while the caudal third had zero overlap(Table2,Fig.1).ConclusionOur pipeline enables voxel‐to‐voxel correlation analysis between histology and high resolution LC MRIs for neuroimaging validation. The caudal third of the LC in our case has shown a clear lack of overlap potentially due to lack of signal specificity in MRI when compared to the gold standard that is histology. Current analysis of another five other cases is ongoing. Validation of LC MRI signal will inform interpretations of signal results in living patients with the potential to act as a diagnostic tool for ADRD.
Play It Again: Differential pupillometry responses to familiar and unfamiliar music: Findings from typical and atypical Alzheimer’s disease
Authors: Brotherhood Emilie V , Macdougall Amy , Firth Nicholas C. , Pavisic Ivanna M , Mengoudi Kyriaki , Yong Keir X X , Levett Benjamin , Warren Jason D , Camic Paul , Crutch Sebastian J 
Published: December 2023

AbstractBackgroundMusic has gained more attention than other art forms as a potent tool in supporting cognitive, emotional and social functioning in dementia populations. Methods for measuring moment‐to‐moment responses ‐ rather than comparing pre‐ and post‐stimulus effects ‐ may enable tailoring of musical experiences for the individual. The current study investigated whether differential pupillometry responses could be established for familiar/unfamiliar music in people living with early‐mid stages of typical, memory‐led Alzheimer’s disease (tAD), atypical ‘visual variant’ of Alzheimer’s disease (posterior cortical atrophy; PCA), and healthy age‐matched controls.MethodPatient groups [tAD = 18; PCA = 21] were recruited via the Specialist Cognitive Disorders clinic at the National Hospital for Neurology and Neurosurgery, London, UK. Healthy older adults [N = 90] were recruited opportunistically via departmental research databases/Join Dementia Research.Pupillometry responses were recorded while participants listened to 30 musical excerpts [classical (N = 5); 1960s (N = 10), 1970s (N = 10), reversed ‘de novo’ tracks (N = 5)], each rated for familiarity: (a) a priori (known/unknown); (b) self‐rated by participants (not familiar‐extremely familiar); and (c) whether the excerpt evoked a memory (yes/no). Background, basic clinical and music experience information was collected, alongside additional neuropsychological assessment in the patient groups.Separate linear regression models obtaining cluster robust standard errors were run to predict pupil response from a priori predicted‐ and subjective‐ratings of music familiarity in each participant group, controlling for demographic factors including disease severity.ResultResults indicate significant within‐group effects of familiarity on pupil response in controls and the tAD group. No effects were observed within the PCA group. Preliminary between‐group analyses including diagnosis as a predictor revealed that, for each music‐pupillometry model, tAD overall pupil dilation responses did not differ significantly compared to controls, however a significant difference was observed between PCA and control pupil dilation responses.ConclusionThe results are discussed in relation to the preliminary finding of preserved differential pupillometry responses to familiar/unfamiliar music in the tAD group. Although the PCA results question the utility of pupillometry in individuals with significant oculomotor dysfunction, pupillometry may serve as a useful non‐invasive ‘biosignal’ for establishing in‐the‐moment response to music, including in post‐verbal individuals in the later stages of dementia.
Sense of Purpose in Life Predicts Reduced Risk for and Delayed Onset of Mild Cognitive Impairment: A Multistate Survival Model
Authors: Lewis Nathan A , Hofer Scott M , Bennett David A. A , Hill Patrick L 
Published: December 2023

AbstractBackgroundWith no known cure for Alzheimer’s disease and related dementias, delaying the onset of cognitive decline represents a key target for future dementia research. Sense of purpose has been shown to be associated with high cognitive functioning, more supportive social ties, and greater intellectual activity, and may be valuable for mitigating cognitive impairment both before and following its onset.MethodLongitudinal data from the Health and Retirement Study (HRS, n = 10,542) and the Rush Memory and Aging Project (MAP, n = 10.48) were used to examine associations between sense of purpose and prospective transitions across normal cognition, mild cognitive impairment (MCI), dementia, and death over up to 12 and 19 years, respectively. Multistate survival modeling examined the impact of sense of purpose on risk for each transition, adjusting for age, sex, education, apolipoprotein‐E allele, and depressive symptoms. Multinomial regression was used to estimate life expectancy in each cognitive state.ResultMore purposeful older adults were found to have lower prospective risk of developing MCI in the HRS (HR = 0.93, 95% CI: 0.90, 0.97) and MAP (HR = 0.82, 95% CI: 0.69, 0.98) and had increased likelihood of improvement in cognitive functioning following MCI classification. In both samples, those higher in sense of purpose were found to have significantly longer overall life expectancy and life expectancy free of cognitive impairment (without MCI or dementia).ConclusionOlder adults higher in sense of purpose appear to live longer lives, with these differences in life expectancy attributable to increases in years lived without cognitive impairment. Replication of findings across longitudinal studies with disparate samples and measurement procedures provides robust support that having a strong sense of purpose in life contributes to cognitive reserve and resilience. Interventions aiming to promote older adult sense of purpose could extend the cognitive healthspan—the period in which individuals live in a cognitively healthy state free of impairment.