Parkinsonian signs such as motor slowing, gait disturbance, and tremor in old age may be caused by underlying cerebrovascular pathologies that cannot be detected by conventional brain imaging, according to findings from a clinical-autopsy study involving 418 cases.
"Together these data suggest that a substantial portion of older people have brain tissue damage and small vessel disease that are unlikely to be detected before death and suggest that cerebrovascular disease may be an even larger public health challenge than currently estimated," Dr. Aron S. Buchman and his colleagues wrote in a report published Sept. 1 in Stroke: Journal of the American Heart Association.
Macroscopic infarcts were found in 150 (36%) of the 418 brains that were autopsied for the study, and 110 of those also had evidence of pathologies that can’t be detected by conventional imaging, including microinfarcts, arteriolosclerosis, or both.
Furthermore, those pathologies were detected in almost 30% of cases without macroscopic infarcts, according to Dr. Buchman, associate professor of neurological sciences at Rush University Medical Center, Chicago, and his coauthors.
Of the 268 patients without macroinfarcts, 33 (7.9%) had microinfarcts, 62 (14.8%) had arteriolosclerosis, and 24 (5.7%) had both microinfarcts and arteriolosclerosis.
All three cerebrovascular pathologies were related to global parkinsonian scores in unadjusted analyses, and in linear regression analyses, significant associations were found between higher global parkinsonian scores before death and macroscopic infarcts, particularly for multiple (three or more) macroscopic infarcts. This was true for both cortical and subcortical macroscopic infarcts (Stroke 2011 Sept. 1 [doi:10.1161/STROKEAHA.111.623462]).
On further analysis, multiple cortical infarcts, or a single subcortical macroscopic infarct, were related to a higher global parkinsonian score, the investigators said.
"Microinfarcts showed a trend for an association with global parkinsonian [score], but the effect was attenuated and no longer significant when controlling for macroscopic infarcts," they wrote.
After the researchers controlled for macroscopic infarcts, an association between multiple microscopic infarcts and higher global parkinsonism was found, particularly for three or more microscopic infarcts.
Cortical microinfarcts, but not subcortical microinfarcts, also were associated with a higher global parkinsonian score. The association was particularly pronounced for those with multiple cortical microinfarcts.
An association between global parkinsonian score and arteriolosclerosis was no longer statistically significant after accounting for infarcts, the investigators noted.
However, analyses of the relationships between individual parkinsonian signs and each of the three pathologies (arteriolosclerosis, microinfarcts, and macroinfarcts – particularly subcortical microinfarcts and macroinfarcts) was found to be independently and significantly associated with gait disturbance, they found.
This association was present for both single and multiple subcortical macroscopic infarcts, and for multiple subcortical microinfarcts.
The brain autopsies used for this study were from deceased participants from the Religious Order Study, a longitudinal clinical-pathological study of aging in community-dwelling nuns and priests who had no known dementia at enrollment, and who were evaluated for parkinsonian signs with the 26-item modified version of the motor portion of the United Parkinson’s Disease Rating Scale prior to death. The study involved more women (61%) than men, and participants had a mean global parkinsonian score of 18.6 and a mean age of 88.5 years at death.
The findings are important because mild parkinsonian signs are common in community-dwelling older adults, affecting up to 50% of those aged 85 and older without known neurological disease, and are the source of significant morbidity and mortality in many of those affected, the investigators said.
They also noted that the findings could have important translational implications: They raise the question of whether improved public health strategies to increase prevention and more aggressively treat vascular risk factors and disease before death could decrease the burden of mild age-related parkinsonian signs; they suggest that the contribution of cerebrovascular disease to loss of motor function in older age is likely underestimated; and they suggest – given that small vessel disease was shown to have a separate relationship with parkinsonian gait – that there are either structural or functional brain tissue changes other than infarcts that might also be contributing to parkinsonian signs.
"Further clinical-pathological-imaging studies will be needed to delineate antemortem imaging markers as well as the pathophysiology of both microinfarcts and small vessel disease in the development of motor impairment in old age," they wrote.
The study was funded by National Institutes of Health grants and the Illinois Department of Public Health. The authors had no disclosures.