Objectives
To compare the trajectories of motor and cognitive decline in older adults who progress to dementia with the trajectories of those who do not. To evaluate the added value of measuring ...motor and cognitive decline longitudinally versus cross‐sectionally for predicting dementia.
Design
Prospective cohort study with 5 years of follow‐up.
Setting
Clinic based at a university hospital in London, Ontario, Canada.
Participants
Community‐dwelling participants aged 65 and older free of dementia at baseline (N=154).
Measurements
We evaluated trajectories in participants' motor performance using gait velocity and cognitive performance using the MoCA test twice a year for 5 years. We ascertained incident dementia risk using Cox regression models and attributable risk analyses. Analyses were adjusted using a time‐dependent covariate.
Results
Overall, 14.3% progressed to dementia. The risk of dementia was almost 7 times as great for those whose gait velocity declined (hazard ratio (HR)=6.89, 95% confidence interval (CI)=2.18–21.75, p=.001), more than 3 times as great for those with cognitive decline (HR=3.61, 95% CI=1.28–10.13, p=.01), and almost 8 times as great in those with combined gait velocity and cognitive decline (HR=7.83, 95% CI=2.10–29.24, p=.002), with an attributable risk of 105 per 1,000 person years. Slow gait at baseline alone failed to predict dementia (HR=1.16, 95% CI=0.39–3.46, p=.79).
Conclusion
Motor decline, assessed according to serial measures of gait velocity, had a higher attributable risk for incident dementia than did cognitive decline. A decline over time of both gait velocity and cognition had the highest attributable risk. A single time‐point assessment was not sufficient to detect individuals at high risk of dementia.
See related editorial by Snitz.
The influence of binge-like feeding schedules on subsequent food-related behavior is not well understood. We investigated the effect of repeated cycles of restriction and refeeding on two ...food-related behaviors; goal-directed responding for a palatable food reward and sensory-specific satiety. Hungry rats were trained to perform two instrumental actions for two distinct food outcomes and were then subjected to repeated cycles of restricted and unrestricted access to their maintenance chow for 30-days or were maintained on food restriction. Goal-directed control was then assessed using specific satiety-induced outcome devaluation. Rats were given 1 h access to one of theoutcomes and were then immediately given a choice between the two actions. Rats maintained on restriction responded more for the valued than the devalued reward but rats with a history of restriction and refeeding failed to show this effect. Importantly, all rats showed sensory-specific satiety when offered a choice between the two foods, indicating that pre-feeding selectively reduced the value of the pre-fed food. By contrast, sensory-specific satiety was not observed in rats with a history of intermittent feeding when the foods were offered sequentially. These results indicate that, similar to calorically dense diets, intermittent feeding patterns can impair the performance of goal-directed actions as well as the ability to reject a pre-fed food when it is offered alone.
Introduction
Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.
Methods
This multi‐site, ...longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.
Results
We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.
Discussion
Data will be shared with the global scientific community. Within‐disease and disease‐agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.
Background and purpose
The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and ...motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years.
Methods
Ninety‐eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3–8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2‐year follow‐up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial–temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale.
Results
Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline.
Conclusion
White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid‐stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.
Background
Acute change in gait speed while performing a mental task dual-task gait cost (DTC), and hyperintensity magnetic resonance imaging signals in white matter are both important disability ...predictors in older individuals with history of stroke (poststroke). It is still unclear, however, whether DTC is associated with overall hyperintensity volume from specific major brain regions in poststroke.
Methods
This is a cohort study with a total of 123 older (69 ± 7 years of age) participants with history of stroke were included from the Ontario Neurodegenerative Disease Research Initiative. Participants were clinically assessed and had gait performance assessed under single- and dual-task conditions. Structural neuroimaging data were analyzed to measure both, white matter hyperintensity (WMH) and normal appearing volumes. Percentage of WMH volume in frontal, parietal, occipital, and temporal lobes as well as subcortical hyperintensities in basal ganglia + thalamus were the main outcomes. Multivariate models investigated associations between DTC and hyperintensity volumes, adjusted for age, sex, years of education, global cognition, vascular risk factors, APOE4 genotype, residual sensorimotor symptoms from previous stroke and brain volume.
Results
There was a significant positive global linear association between DTC and hyperintensity burden (adjusted Wilks’ λ = .87, P = .01). Amongst all WMH volumes, hyperintensity burden from basal ganglia + thalamus provided the most significant contribution to the global association (adjusted β = .008, η2 = .03; P = .04), independently of brain atrophy.
Conclusions
In poststroke, increased DTC may be an indicator of larger white matter damages, specifically in subcortical regions, which can potentially affect the overall cognitive processing and decrease gait automaticity by increasing the cortical control over patients’ locomotion.
Recent studies suggest that interindividual genetic differences in glial-dependent CSF flow through the brain parenchyma, known as glymphatic flow, may trigger compensatory changes in human sleep ...physiology. In animal models, brain perivascular spaces are a critical conduit for glymphatic flow. We tested the hypothesis that MRI-visible PVS volumes, a putative marker of perivascular dysfunction, are associated with compensatory differences in real-world human sleep behavior.
We analyzed data from 152 cerebrovascular disease patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). PVS volumes were measured using 3T-MRI. Self-reported total sleep time, time in bed, and daytime dysfunction were extracted from the Pittsburgh Sleep Quality Index.
Individuals with greater PVS volumes reported longer time in bed (+0.85 h per log10 proportion of intracranial volume (ICV) occupied by PVS, SE = 0.30, p = 0.006) and longer total sleep times (+0.70 h per log10 proportion of ICV occupied by PVS volume, SE = 0.33, p = 0.04), independent of vascular risk factors, sleep apnea, nocturnal sleep disturbance, depression, and global cognitive status. Further analyses suggested that the positive association between PVS volumes and total sleep time was mediated by greater time in bed. Moreover, despite having on average greater total sleep times, individuals with greater basal ganglia PVS volumes were more likely to report daytime dysfunction (OR 5.63 per log10 proportion of ICV occupied by PVS, 95% CI: 1.38–22.26, p = 0.018).
Individuals with greater PVS volumes spend more time in bed, resulting in greater total sleep time, which may represent a behavioral compensatory response to perivascular space dysfunction.
•Normal perivascular spaces (PVS) play an important role in sleep function.•Perivascular abnormalities may be an important determinant of sleep behavior.•Interventions targeting PVS biology may modify sleep need and daytime dysfunction.
Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid DiHOME and 9,10-DiHOME) to their ...parent epoxides (12(13)-epoxyoctadecenoic acid EpOME and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251,
=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266,
=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364,
<0.001; β=0.362,
<0.001) and white matter MRI-visible perivascular spaces (β=0.302,
=0.011; β=0.314,
=0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (β=0.439,
=0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (β=-0.277,
=0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.
The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural ...MRI, from neurodegenerative patients with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online.
Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to ...investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases.
Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss.
Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities.
In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.
Abstract
Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and ...severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer’s disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and cerebrovascular disease; n = 391, age 40–87) and healthy controls (n = 149, age 42–87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer’s disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.
Riek et al. report that oculomotor parameters derived from prosaccade/antisaccade assessment in a large cohort (n = 391) of neurodegenerative disease patients load on four factors corresponding to distinct brain processes and correlate differentially to cognitive domains. Additionally, cognitively impaired patients were differentiated from cognitively normal patients and controls on individual parameters.
Graphical Abstract
Graphical Abstract
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