Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

BACKGROUND: Progressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP. OBJECTIVES: To determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS. METHODS: Multicenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity. RESULTS: The earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity. CONCLUSION: The PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials

Identifying healthy individuals with Alzheimer’s disease neuroimaging phenotypes in the UK Biobank

Background: Identifying prediagnostic neurodegenerative disease is a critical issue in neurodegenerative disease research, and Alzheimer’s disease (AD) in particular, to identify populations suitable for preventive and early disease-modifying trials. Evidence from genetic and other studies suggests the neurodegeneration of Alzheimer’s disease measured by brain atrophy starts many years before diagnosis, but it is unclear whether these changes can be used to reliably detect prediagnostic sporadic disease. Methods: We trained a Bayesian machine learning neural network model to generate a neuroimaging phenotype and AD score representing the probability of AD using structural MRI data in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Cohort (cut-off 0.5, AUC 0.92, PPV 0.90, NPV 0.93). We go on to validate the model in an independent real-world dataset of the National Alzheimer’s Coordinating Centre (AUC 0.74, PPV 0.65, NPV 0.80) and demonstrate the correlation of the AD-score with cognitive scores in those with an AD-score above 0.5. We then apply the model to a healthy population in the UK Biobank study to identify a cohort at risk for Alzheimer’s disease. Results: We show that the cohort with a neuroimaging Alzheimer’s phenotype has a cognitive profile in keeping with Alzheimer’s disease, with strong evidence for poorer fluid intelligence, and some evidence of poorer numeric memory, reaction time, working memory, and prospective memory. We found some evidence in the AD-score positive cohort for modifiable risk factors of hypertension and smoking. Conclusions: This approach demonstrates the feasibility of using AI methods to identify a potentially prediagnostic population at high risk for developing sporadic Alzheimer’s disease

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The association between cognition and dual-tasking among older adults: the effect of motor function type and cognition task difficulty

Hossein Ehsani,1,2 Martha Jane Mohler,1–3 Kathy O’Connor,4 Edward Zamrini,4,5 Coco Tirambulo,2 Nima Toosizadeh1–3 1Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA; 2Arizona Center on Aging, Department of Medicine, University of Arizona, Tucson, AZ, USA; 3Division of Geriatrics, General Internal Medicine and Palliative Medicine, Department of Medicine, University of Arizona, Tucson, AZ, USA; 4Neurology Department, Banner Sun Health Research Institute, Sun City, AZ, USA; 5Department of Neurology, University of Utah, Salt Lake City, UT, USA Background: Dual-task actions challenge cognitive processing. The usefulness of objective methods based on dual-task actions to identify the cognitive status of older adults has been previously demonstrated. However, the properties of select motor and cognitive tasks are still debatable. We investigated the effect of cognitive task difficulty and motor task type (walking versus an upper-extremity function [UEF]) in identifying cognitive impairment in older adults. Methods: Older adults (≥65 years) were recruited, and cognitive ability was measured using the Montreal Cognitive Assessment (MoCA). Participants performed repetitive elbow flexion under three conditions: 1) at maximum pace alone (Single-task); and 2) while counting backward by ones (Dual-task 1); and 3) threes (Dual-task 2). Similar single- and dual-task gait were performed at normal speed. Three-dimensional kinematics were measured for both motor functions using wearable sensors. Results: One-hundred older adults participated in this study. Based on MoCA score <20, 21 (21%) of the participants were considered cognitively impaired (mean age =86±10 and 85±5 for cognitively impaired and intact participants, respectively). Within ANOVA models adjusted with demographic information, UEF dual-task parameters, including speed and range-of-motion variability were significantly higher by 52% on average, among cognitively impaired participant (p<0.01). Logistic models with these UEF parameters plus age predicted cognitive status with sensitivity, specificity, and area under curve (AUC) of 71%, 81% and 0.77 for Dual-task 1. The corresponding values for UEF Dual-task 2 were 91%, 73% and 0.81, respectively. ANOVA results were non-significant for gait parameters within both dual-task conditions (p>0.26). Conclusion: This study demonstrated that counting backward by threes within a UEF dual-task experiment was a pertinent and challenging enough task to detect cognitive impairment in older adults. Additionally, UEF was superior to gait as the motor task component of the dual-task. The UEF dual-task could be applied as a quick memory screen in a clinical setting. Keywords: wearable motion sensor, gait, upper-extremity function, biomechanics, MCI, Alzheimer’s diseas

Impaired financial abilities in mild cognitive impairment

Objectives: To assess financial capacity in patients with mild cognitive impairment (MCI) using a standardized psychometric capacity measure.Methods: Participants were 21 cognitively normal older controls, 21 patients with amnestic MCI, and 22 patients with mild AD. The Financial Capacity Instrument (FCI), a psychometric capacity measure consisting of 18 financial ability tests (tasks), 9 domains (activities), and 2 total scores, was administered to participants along with a battery of neuropsychological tests sensitive to dementia. Group differences were examined on the neuropsychological and financial capacity variables.Results: Relative to controls, the MCI group demonstrated impairments in episodic memory, and also semantic knowledge, executive function, written arithmetic, and spatial attention. MCI participants demonstrated impairments in FCI domains of conceptual knowledge, cash transactions, bank statement management, and bill payment, and in overall financial capacity. The control and MCI groups performed significantly better than patients with AD on most financial capacity and cognitive measures.Conclusions: On direct assessment, patients with amnestic MCI as a group demonstrate impairments across a range of financial abilities. These impairments are mild and may only apply to a subset of patients with MCI. However, existing diagnostic criteria for MCI should be applied flexibly to include mild impairments in higher order activities of daily life such as financial capacity.</jats:p