White matter hyperintensities and neuropsychiatric symptoms in mild cognitive impairment and Alzheimer's disease

Abstract

Neuropsychiatric symptoms (NPS), such as apathy, irritability and depression, are frequently encountered in patients with Alzheimer's disease (AD). Focal grey matter atrophy has been linked to NPS development. Cerebrovascular disease is common among AD patients and can be detected on MRI as white matter hyperintensities (WMH). In this longitudinal study, the relative contribution of WMH burden and GM atrophy to NPS was evaluated in a cohort of mild cognitive impairment (MCI), AD and normal controls. This study included 121 AD, 315 MCI and 225 normal control subjects from the Alzheimer's Disease Neuroimaging Initiative. NPS were assessed using the Neuropsychiatric Inventory and grouped into hyperactivity, psychosis, affective and apathy subsyndromes. WMH were measured using an automatic segmentation technique and mean deformation-based morphometry (DBM) was used to measure atrophy of grey matter regions. Linear mixed-effects models found focal grey matter atrophy and WMH volume both contributed significantly to NPS subsyndromes in MCI and AD subjects, however, WMH burden played a greater role. This study could provide a better understanding of the pathophysiology of NPS in AD and support the monitoring and control of vascular risk factors.

Keywords: Alzheimer’s disease; Cerebrovascular disease; Mild cognitive impairment; Neuropsychiatric symptoms; White matter hyperintensity.

Fig. 1

Flowchart of subject inclusion. WMH = white matter hyperintensity, NPI = neuropsychiatric inventory, AD = Alzheimer’s disease, MCI = mild cognitive impairment, NC = normal control, QC = quality control.

Fig. 2

Graphs examining age, NPI total scores and WMH load in AD, MCI and normal controls. Graphs showing age not associated with NPI total scores (left), age associated with white matter hyperintensity load (centre), and the relationship between NPI total scores and WMH load (right) across AD, MCI and normal control cohorts. Age is not significantly associated with NPI total scores in any cohort (left). All groups show a positive significant association of age with higher WMH load (middle), and AD and MCI cohorts show a positive significant association between higher WMH load and greater NPI total scores (right). Solid lines indicate the estimated effect and dotted lines represent the standard error. WMH = white matter hyperintensity, NPI = neuropsychiatric inventory, AD = Alzheimer’s disease, MCI = mild cognitive impairment, NC = normal control.

Fig. 3

Brain regions where GM DBM values were significantly associated with NPS subsyndrome scores. GM ROIs significantly associated with A) hyperactivity B) psychosis C) affective and D) apathy subsyndrome scores. Colors indicate AAL atlas brain regions associated with subsyndromes (please see Table 2 for ROIs, and Supplementary material Table I for complete list of AAL regions).

Fig. 4

Linear mixed-effects model results for the relationship between WMH load volume and NPS subsyndrome scores. Modelling of mean WMH load (log transformed) on NPS subsyndrome scores shows relationship between higher NPS scores associated with increased WMH load. Solid lines indicate the estimated effect and dotted lines represent the standard error. WMH = white matter hyperintensity, AD = Alzheimer’s disease, MCI = mild cognitive impairment, NC = normal control.