By Rivka Sachdev, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Both higher levels of cerebral white matter hyperintensities and cerebrovascular disease pathologies may be associated with a more rapid progression of parkinsonism in older adults.
SOURCE: Oveisgharan S, Yu L, Poole VN, et al. Association of white matter hyperintensities with pathology and progression of parkinsonism in aging. JAMA Neurol 2021;78:1494-1502.
Parkinsonism is a term that often is used to describe a constellation of neurological signs consisting of tremor, rigidity, bradykinesia, impaired gait (characterized by small, shuffling steps), and postural instability. Parkinsonism commonly is observed in older adults and can lead to significant problems with mobility and falls. Although it generally is agreed that having parkinsonism can lead to adverse health outcomes, the pathological basis of parkinsonism remains controversial.
The researchers of this community-based cohort study sought to determine whether the burden of white matter hyperintensities (WMH) in older adults without a clinical diagnosis of Parkinson’s disease is associated with the rate of progression of parkinsonism. The primary objective in this study was “to examine the association between WMH and progressive parkinsonism, controlling for postmortem brain pathologies.” Therefore, only decedents with completed brain autopsies, with two or more valid clinical assessments of parkinsonism, and without a clinical diagnosis of PD were included.
Participants were enrolled in one of three ongoing longitudinal clinical-pathological studies of aging conducted at the Rush Alzheimer’s Disease Center of Rush University Medical Center with enrollments beginning in 1994, 1997, and 2004. Participants were 65 years of age or older without a known dementia diagnosis. A total of 4,227 participants were recruited, and patients were observed for a mean of 7.5 years before death. Of the enrolled participants, 2,134 died. Postmortem autopsy was performed in 1,725 of the decedents and 598 of these also had ex vivo brain magnetic resonance imaging (MRI). Twenty-two participants were excluded because they lacked any of the nine postmortem pathology indices (five cerebrovascular indices and four neurodegenerative indices, including PD). Forty-one participants were excluded because of missed repeat parkinsonism assessments, and 19 participants were excluded because they received a clinical diagnosis of PD before or during the study.
For the assessment of parkinsonism, trained nurse practitioners examined patients annually for four parkinsonism signs (rigidity, tremor, bradykinesia, and parkinsonian gait) using the 26-item motor section of a modified Unified Parkinson’s Disease Rating Scale. Parkinsonism was considered present if at least two of the four signs were present.
For the assessment of ex vivo WMH, after brain removal at autopsy, one hemisphere of the brain was fixed in a formaldehyde solution and MRI was conducted while the sample was immersed in the solution. To assess WMH burden, a trained rater examined fluid-attenuated inversion recovery (FLAIR) and T2-weighted images to separately rate WMH burden in periventricular and deep white matter brain regions according to the four-level Fazekas scale. Because of uncertainty in separating the “none” from “mild” level of WMH (owing to incomplete cancellation of formalin solution signals), the researchers combined these two levels, resulting in a three-level scale that then was used for a brain WMH rating system of “none to mild,” “moderate,” and “severe.”
Researchers then assessed and quantified nine indices of pathology. The five cerebrovascular pathology indices included macroinfarcts, microinfarcts, atherosclerosis, arteriosclerosis, and cerebral amyloid angiography. The four neurodegenerative pathology indices were categorized as PD, Alzheimer’s disease, TDP-43 in the hippocampus and/or neocortex, and hippocampal sclerosis (details of pathological assessment were provided in supplementary reading and the researchers’ prior publications, so are not specified further in the current paper).
Researchers found that of the 516 decedents, 47.3% had severe WMH burden, 35.1% had moderate WMH burden, and 17.6% had mild or no WMH burden. Older adults, women, and those with a history of stroke were more likely to have severe WMH burden. In terms of WMH and progression of parkinsonism, their analysis revealed that more severe WMH was associated with a more rapid progression of parkinsonism. A higher level of WMH was associated with more rapid progression of bradykinesia (estimate, 0.036; standard error [SE], 0.012; P = 0.004) and parkinsonian gait (estimate, 0.036; SE, 0.012; P = 0.003). Because rigidity and tremor did not meet the linear mixed effects model assumptions, the researchers noted these as present or absent before death and examined their associations with postmortem WMH, finding that a higher level of WMH was associated with higher odds of rigidity but not of tremor.
COMMENTARY
The authors’ prior studies already had suggested that a more rapid progression of parkinsonism is associated with a higher burden of both PD and cerebrovascular disease pathologies. This current work showed that WMH is associated with postmortem brain pathologies. In an attempt to understand if there was an independent association between WMH and progressive parkinsonism when controlling for other brain pathologies, they found that WMH has an association with progressive parkinsonism apart from markers of both cerebrovascular and neurodegenerative disease pathologies (which was significant despite partial attenuation in a model that included postmortem indices of cerebrovascular disease brain pathologies).
The authors concluded that, in this cohort study, higher levels of WMH were associated with a more rapid progression of parkinsonism and that both WMH and cerebrovascular disease pathologies may be independent contributors to progressive parkinsonism. This research adds important information to the ongoing dialogue regarding the controversial topic of brain WMH and parkinsonism. As the authors stated, further studies to help determine if in vivo brain MRI for WMH assessment and aggressive treatment of vascular risk factors reduce the occurrence or severity of parkinsonism in older adults.
