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Small Vessel Disease in Parkinson's Can Lead to Worsening Motor Impairment

Lehmann, Christine

doi: 10.1097/01.NT.0000550491.03694.9a
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Researchers found that small vessel disease was associated with worsening motor impairment in Parkinson's disease. An additional association between vascular risk factors, particularly hypertension, and dementia in PD underscores the need to manage vascular comorbidities, the study authors said.

Small vessel disease (SVD) was correlated with greater motor impairment in autopsy-determined Parkinson's disease (PD), according to a paper published in the October 13 online edition of the Journal of Clinical Neuroscience.

“Our study suggests that neurologists treating patients with PD should proactively manage their patient's vascular risk factors, which may reduce gait and cognitive impairment, two of the main clinical features that undermine well-being and independence in patients with PD,” lead investigator Jillian Kril, PhD, professor of neuropathology at the University of Sydney Medical School in Australia, told Neurology Today in an email. She also suggested obtaining magnetic resonance imaging of the brain to determine the presence of SVD.

“Parkinsonism can be caused by either PD, which is a synucleinopathy (abnormal protein accumulation) or vascular pathology — either infarcts or SVD, although vascular parkinsonism is rarer than PD. We hypothesized that small vessel cerebrovascular disease could be a contributor to PD,” said Dr. Kril.

However, she noted that previous studies of the association between vascular disease and PD have produced conflicting results. For example, Dr. Kril and her colleagues in Australia conducted an earlier study with the same PD population as the current study but with a control group. They found that both SVD and vascular risk factor were greater in the controls than the patients with PD.

But other studies pertaining to Alzheimer's disease and Parkinson's disease have shown that cognition is worse in patients with SVD and vascular pathology. And so Dr. Kril and her colleagues conducted the current study to determine whether SVD makes the motor or cognitive functions worse in PD patients.

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The retrospective study included 77 autopsy-confirmed PD patients that were recruited by the Sydney Brain Bank from 1995 to 2006. The researchers at several Australian universities conducted a neuropathological assessment using the Braak neuritic stage, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) plaque score, and Braak PD stage. They also recorded the size, number, and age of infarcts.

The researchers assessed the extent and severity of SVD pathologically and the severity of motor impairment and disease progression using the Hoehn and Yahr scale. They used the Clinical Dementia Rating to assess the severity of cognitive dysfunction and progression.

“Because the study used PD cases with both a clinical diagnosis of PD and autopsy-proven PD, rather than cases with only a clinical diagnosis in whom the pathology may be variable, we relied on the clinical records from a number of different clinicians collected by the brain bank,” Dr. Kril explained.

Most of the PD patients (50/77) had a mean age of 78, were men, and had a diagnosis of dementia based on the DSM-IV criteria. The mean duration of PD was 12 years for patients with and without dementia. Patients with dementia had more vascular risk factors than those without dementia, including stroke, heart disease, hypertension and diabetes, and a longer history of cigarette smoking.

“Notably, we showed that greater small vessel disease pathology in the globus pallidus internus (GPi) that is involved in motor function correlated with more marked motor impairment,” said Dr. Kril. Specifically, the severity of SVD pathology characterized by GPi pallor correlated with the Hoehn and Yahr stage and the presence of hypertension correlated with dementia in PD, she said. The severity of SVD pathology was not significantly correlated with a diagnosis of dementia.

The main study limitations were its retrospective design, albeit using detailed case records, and the relatively small sample size, said Dr. Kril.

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“This is one of the few studies in which we have pathologically confirmed diagnoses of PD, which provides a level of certainty that can't be obtained from clinical studies alone,” said Rodolfo Savica MD, PhD, associate professor of neurology at Mayo Clinic in Rochester, MN, who was not involved in the study.



Another study suggests that “despite dementia and the progression of PD, there are other factors, including vascular risk factors, that play a role in cognitive impairment and PD,” Dr. Savica said.

“The message for clinicians is that we have to ensure that our patients with PD who tend to be older, have their vascular risk factors under control.”

The results of this study support other recent studies “that show a relatively high occurrence of cardiovascular risk factors, including hypertension and diabetes in PD,” said Joseph Jankovic, MD, FAAN, professor of neurology and distinguished chair in movement disorders at Baylor College of Medicine in Houston, Texas.

Dr. Jankovic said two aspects of vascular pathology “need to be considered in relationship to Parkinson's: vascular parkinsonism characterized by the phenotype of ‘lower-body parkinsonism’ because it predominantly affects the lower extremities, and the form presented in the study involving patients with pathologically proven PD who exhibit co-existent vascular pathology.”

The existence of vascular parkinsonism is controversial, Dr. Jankovic said. But, he added, “there is clearly a subset of parkinsonian patients who are found at autopsy to have only microinfarcts or other evidence of vascular disease without the pathological features of idiopathic PD. This is in contrast to this study which examined evidence of vascular pathology and SVD, in patients with pathologically proven PD.”

Besides the limitations noted by the authors, Dr. Jankovic mentioned the lack of rigorous clinical assessments and the use of a questionnaire to gather clinical information about patients which was completed by neurologists or geriatricians, general practitioners, and family members.

“I would have preferred prospective annual exams by neurologists experienced in PD or at least the use of the Unified Parkinson's Disease Rating Scale (UPDRS) considered the ‘gold standard’ assessment tool for characterizing impairments in persons with PD. Instead, the authors used the Hoehn and Yahr stage, which is a relatively crude assessment tool of motor impairment in PD,” said Dr. Jankovic.



Dr. Jankovic said he would have also liked to see some evidence that the SVD changes described in the article including pallor, thickening, enlarged of vascular spaces, actually correlate with vascular or microvascular pathology.

Dr. Jankovic also noted the authors didn't report the overall frequency of these SVD changes and whether they were associated with microinfarcts or previous hemorrhages.

“The study did not assess small vessel infarction or microbleeds, but rather the microvascular pathology. Large vessel (cortical) infarction was seen in 21 percent (16/77) of PD cases,” responded Dr. Kril.

Dr. Jankovic also questioned how these vascular or microvascular changes correlate with clinical phenotypes and subtypes of PD. “This is another important area of research. We previously proposed two major subtypes of PD: tremor-dominant PD and postural instability gait difficulty (PIGD). I suggest that those patients with PD and vascular comorbidity are more likely to have the PIGD subtype based on the fact that most of SVD changes were noted in the GPi, a subcortical region of the brain that is very involved with gait and balance.”

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Drs. Kril, Jankovic, and Savica had no disclosures related to the study.

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•. Mehanna R, Jankovic J. Movement disorders in cerebrovascular disease Lancet Neurol 2013;12(6):597–608.
    •. Schwartz RS, Halliday GM, Soh D, et al Impact of small vessel disease on severity of motor and cognitive impairment in Parkinson's disease J Clin Neurosci 2018; Epub 2018 Oct 13.
      •. Schwartz RS, Halliday GM, Cordato DJ, et al Small-vessel disease in patients with Parkinson's disease: a clinicopathological study Mov Disord 2012;27:1506–12.
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