In this clinical-autopsy study of more than 400 community-dwelling older persons, we found that cerebrovascular pathologies including macroscopic and microinfarcts as well as small-vessel disease based on the severity of arteriolosclerosis were present in almost 2/3 of cases. Furthermore, almost 30% of cases without macroscopic infarcts, showed pathologies not likely to be directly detected by conventional brain imaging including microinfarcts or arteriolosclerosis or both . Each of the 3 cerebrovascular pathologies were separately associated with the severity of parkinsonian signs, especially parkinsonian gait. Subcortical macroscopic infarcts, subcortical microinfarcts, and arteriolosclerosis appear to be particularly important in the parkinsonian gait impairment. 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 prior to death and suggests that cerebrovascular disease may be an even larger public health challenge than currently estimated. Furthermore, cerebrovascular pathologies in older persons may contribute to the development of what is currently considered “normal” age-related motor symptoms such as parkinsonian signs.
There are currently about 40 million persons over age 65 in the US and by 2030, more than 70 million persons, about one in five Americans, will be over age 65.19
Loss of motor function is a familiar consequence of aging but the specific motor abilities impaired in old age vary and encompass a wide spectrum including reduced gait speed and loss of muscle strength and bulk, balance, and dexterity. Mild parkinsonian signs is one of the constructs which has been used to assess mild motor symptoms in older persons and these signs have been shown to be related to adverse health consequences including death, disability and dementia.1–4, 20
While parkinsonian signs in old age are common and may affect up to 50% or more of community-dwelling older persons by age 85,4
little is known about their underlying neuropathology. Since the combination of both Lewy bodies and nigral degeneration, the pathognomic feature of PD are relatively uncommon in the aging brain, they cannot account for the common occurrence of parkinsonian signs reported in older persons. To investigate the possible role of extranigral factors, after accounting for PD pathology, the current study focused on cerebrovascular pathologies which are common in the aging brain and have been studied in vascular parkinsonism21–23
The term arteriosclerotic parkinsonism was first used by Critchley24
and no clear consensus has been developed which allows clinical differentiation of the neurodegenerative disorder PD from cases caused by severe vascular disease.21–23
In contrast to the mild parkinsonian signs studied in the current study, the clinical parkinsonian signs in vascular parkinsonism are much more severe which underscores why these individuals may receive a clinical diagnosis of PD.25, 26
Both post-mortem and brain imaging studies have been employed in vascular parkinsonism to demonstrate the presence of underlying cerebrovascular pathologies as well as the absence of post-mortem evidence of PD.21–23
In contrast, we are not aware of any autopsy studies and there are few brain imaging studies which have explored the role of cerebrovascular pathologies and mild parkinsonian signs in old age.9, 10
Similar to cognition, structural brain imaging may provide a window to both direct and surrogate markers of currently undetectable vascular pathologies which may contribute to mild parkinsonian signs in old age. For instance, in a recent imaging-pathology study, microscopic infarcts were not only related to macroscopic infarcts but also to leukoencephalopathy.27
Indeed, 2 recent brain imaging studies showed that there was a robust association between the size of white matter hyperintensities, a presumed marker of vascular disease, and lacunar brain infarcts with mild parkinsonian signs in older persons, suggesting that cerebrovascular pathologies may play an important role in the development of parkinsonian signs.10
The current clinical-pathologic study supports and extends prior imaging studies by providing direct and compelling evidence that cerebrovascular pathologies including macroscopic and microscopic infarcts as well as the severity of small-vessel arteriolosclerosis contribute to the development of mild parkinsonian signs in old age.8, 28, 29
Cerebrovascular pathology appears to be particularly important in the severity of parkinsonian gait impairment and subcortical cerebrovascular pathology, including macroscopic infarct, microinfarcts, and arteriolosclerosis, appears to be the main culprit. We are not aware of previous studies demonstrating independent roles for microinfarcts and the severity of arteriolosclerosis in the development of parkinsonian gait. Given that microinfarcts and severity of arteriolosclerosis are not discernable during life, these pathologies likely represent unrecognized common etiologies for parkinsonian gait in older persons,30
and support clinical – imaging studies that suggest subclinical cerebrovascular disease abnormalities are associated with gait dysfunction in older persons.8, 31
These data have important translational implications. First, they raise the question as to whether improved public health strategies for the increased prevention and more aggressive treatment of vascular risk factors and diseases prior to death might decrease the burden of mild age-related parkinsonian signs. Second, because microinfarcts and arteriolosclerosis are not directly detected with conventional brain imaging and were observed in almost 30% of cases in this study, these data suggest that the contribution of cerebrovascular disease to loss of motor function in older age is likely underestimated. Indeed, the current study is among the first to show the clinical relevance of specifically subcortical microinfarcts, as well as a deleterious effect of arteriolosclerosis separate from either macro or microinfarcts. Third, because small vessel disease has a separate relationship with parkinsonian gait after accounting for both macroscopic and microscopic infarcts, one may hypothesize that there are either structural or functional brain tissue changes other than infarcts that are also contributing to parkinsonian signs. Indeed, the small vessel changes observed in the current study may be related to the white matter hyperintensities previously recognized with brain imaging studies and which correlated with parkinsonian signs.10
Further clinical-pathologic-imaging studies will be needed to delineate ante-mortem imaging markers, as well as the pathophysiology of both microinfarcts and small vessel disease in the development of motor impairment in old age.
This study has some limitations. Microinfarcts were measured in many regions classically related to cognitive function and arteriolosclerosis severity was estimated only in the anterior basal ganglia; which may underestimate the association with parkinsonian signs. Further study of microvascular pathology in additional brains regions is warranted. Brain imaging data was not obtained in this study and might provide a way to link post-mortem findings to ante-mortem brain imaging. Finally, our findings are cross-sectional so causal inferences are limited. It is possible that the cerebrovascular pathologies do not play a causal role in the development of parkinsonian signs, but rather both cerebrovascular pathologies and parkinsonian signs might be caused by a third factor. There are also several strengths to the study, including the community-based cohort with large numbers of women and men with high rates of clinical follow-up and autopsy. Uniform structured clinical procedures were used that included a detailed assessment of parkinsonian signs used in other studies. Uniform structured post-mortem procedures were employed that assessed several cerebrovascular pathologies which cannot be directly detected with current imaging techniques.