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White matter hyperintensities: a marker for apathy in Parkinson's disease without dementia?

ABSTRACT: OBJECTIVE:The objective of this study was to assess the relationship between white matter hyperintensities (WMH) and the occurrence and progression of apathy in Parkinson's disease (PD). METHODS:We recruited patients with PD who underwent baseline evaluation, which included apathy assessment and magnetic resonance imaging (MRI) head scans. After 2.5 years of follow-up, we re-evaluated patient apathy symptoms. The severity and location of WMH were assessed with fluid-attenuated inversion recovery (FLAIR) sequences using the Fazekas visual rating scale. Logistic regression and linear regression analyses of baseline WMH characteristics were conducted to explore the potential association between apathy and WMH. RESULTS:A total of 141 PD patients were recruited. The apathy group had a higher proportion of male patients, advanced disease, and depression, which was coupled with a lower quality of life. Morever, higher WMH severity was significantly associated with apathy. Logistic regression analyses demonstrated that WMH severity was a risk factor for apathy. In addition, linear regression analysis also suggests that apathy severity is positively correlated with baseline WMH Fazekas scales (? = 0.959, P < 0.001). Baseline WMH severity was also a risk factor for apathy progression. INTERPRETATION:WMH is associated with apathy and could be a promising marker to predict apathy progression in PD.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7480903 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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White matter hyperintensities: a marker for apathy in Parkinson's disease without dementia?

Zhang Yu Y Zhang Guo Yong GY Zhang Zi En ZE He An Qi AQ Gan Jing J Liu Zhenguo Z

Annals of clinical and translational neurology 20200828 9

<h4>Objective</h4>The objective of this study was to assess the relationship between white matter hyperintensities (WMH) and the occurrence and progression of apathy in Parkinson's disease (PD).<h4>Methods</h4>We recruited patients with PD who underwent baseline evaluation, which included apathy assessment and magnetic resonance imaging (MRI) head scans. After 2.5 years of follow-up, we re-evaluated patient apathy symptoms. The severity and location of WMH were assessed with fluid-attenuated inv ...[more]

PMID: 32857484

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Project description:BackgroundPatients with Parkinson's disease (PD) present with a broad spectrum of nonmotor features including autonomic disorders. More severe autonomic dysfunction in PD is associated with increased cognitive deficits. The presence of cerebral small-vessel disease, measured by T2-weighted magnetic resonance imaging white matter hyperintensity (WMH) burden, is also observed in patients with PD with faster cognitive decline.ObjectiveTo investigate whether baseline orthostatic hypotension and autonomic dysfunction in early-stage PD affect later cognitive decline via mediation through cerebral small-vessel disease.MethodsDe novo PD patients (N = 365) and age-matched controls (N = 174) with baseline T2-weighted/ fluid-attenuated inversion recovery scans were selected from the Parkinson's Progression Markers Initiative. WMHs were automatically segmented. Mediation analysis was used to assess whether WMH load mediates the effect of orthostatic hypotension and autonomic dysfunction (measured by Scales for Outcomes in Parkinson's Disease-Autonomic) on future cognitive decline (measured by Montreal Cognitive Assessment) in an average of 4 years of follow-up.ResultsMediation analysis supported the existence of a full mediation of WMHs on the effect of diastolic orthostatic hypotension in patients with PD and future cognitive decline (average causal mediation effect: ab = -0.032, 95% confidence interval = -0.064 to -0.01, P = 0.01). There was also a partial mediation for overall autonomic dysfunction (ab = -0.027, 95% confidence interval = -0.054 to 0.00, P = 0.02).ConclusionsWMHs fully mediate the effect of diastolic orthostatic hypotension and partially mediate the effect of autonomic dysregulation on future cognitive decline in patients with PD. Our findings support the hypothesis that autonomic dysfunction in early clinical stages predisposes the brain to WMHs through dysregulation of the blood flow in the small vessels. This in turn increases the risk of future cognitive impairment in early PD.

Project description:Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.

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White matter hyperintensities: a marker for apathy in Parkinson's disease without dementia?

Publications

White matter hyperintensities: a marker for apathy in Parkinson's disease without dementia?

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