We measured parkinsonian signs in more than 2,500 older persons participating in 2 longitudinal clinical-pathologic studies, of whom 744 persons without PD died and underwent brain autopsy and a complete neuropathologic examination. Almost 40% had either mild or more severe nigral neuronal loss or Lewy bodies or both. When considered separately, both neuronal loss and Lewy bodies were related to parkinsonian signs proximate to death. Further analyses suggested that the association of Lewy bodies to global parkinsonism and rigidity was mediated through nigral neuronal loss. Thus, nigral pathology is common in older persons without PD and may contribute to motor impairment in old age.
The results of the current study have important public health consequences. There are currently about 40 million persons over age 65 in the US and by 2030, there will be more than 70 million persons over 65.21
Prior work in these and other cohorts has shown that parkinsonian signs may occur in up to half of older persons without PD over age of 85.Further, these signs are not benign, but are associated with a wide range of adverse health outcomes.3, 5–7
With a public health problem of this magnitude, it is essential to understand the neuropathology which underlies parkinsonism so as to facilitate the development of treatments to decrease the growing burden of motor impairment in old age.
In the current study, nearly 20% of cases showed evidence of Lewy bodies, which is similar to other post-mortem studies.22
However, few of these studies have investigated the association of nigral Lewy bodies and neuronal loss with parkinsonian signs in older persons without PD.11, 12
An earlier study reported that neuronal loss occurs in older persons with incidental Lewy bodies and controls without PD, but did not assess signs of parkinsonism. A second study reported that nigral neuronal loss was associated with parkinsonian signs in 50 cases without a history of PD or post-mortem evidence of Lewy bodies.11, 12
Nigral pathology was common in the current study, being observed in almost 40% of cases without PD. Furthermore, the presence of Lewy bodies and the degree of neuronal loss were related to severity of global parkinsonism and individual parkinsonian signs including parkinsonian gait, bradykinesia and rigidity. These associations were robust and persisted even after controlling for demographic variables, body composition and several chronic conditions. Together these findings suggest that nigral pathology is common and related to what is often considered “normal” age-related motor signs. Thus, subclinical nigral pathology may not be “incidental” but may be an unrecognized contributor to the development of motor impairment in older persons without overt PD.13, 23, 24
The basis for the association between nigral pathology and parkinsonian signs in the current study is uncertain. Lewy bodies and neuronal loss are the histopathologic hallmarks of PD, which is reported to occur in upto5% of older persons by age 85.25
In the current study, we excluded a dozen cases in which there was both clinical and post-mortem evidence of PD. Nonetheless, there were still more than 50additional cases without a clinical history of PD but with the classic post-mortem characteristics of PD(, Group 4B).25
Furthermore, we found that cases with nigral neuronal loss showed a reduction in neuron density which extended beyond the ventral tier, (Supplemental Table 3
).However, the most significant reductions in neuron density were observed in the ventral lateral and medial quadrants which is similar to the pattern previously reported for PD. 11, 12, 26
Together, these data support the notion of “preclinical PD” during which nigral pathology accumulates but clinical symptoms may not warrant a clinical diagnosis of PD,13
analogous to the pathology of AD in persons without dementia.27
Recent brain imaging studies have reported that older persons with “preclinical PD” not only have nigral pathology, but have reductions in striatal dopaminergic nerve terminals at levels intermediate between brains from subjects with known PD and controls without neuropathology.13
Since nigral pathology in the current study was related to the severity of parkinsonian signs, this suggests that individuals with a clinical diagnosis of PD may represent the “tip of the iceberg” and that nigral degeneration and Lewy bodies may also account for a substantial proportion of motor dysfunction currently considered “normal aging”. This has important public health implications, since it suggests that there may be a much larger number of older persons who may benefit from treatments developed for PD. This approach has not been adequately studied since prior studies which have employed levedopa to ameliorate motor symptoms in older persons without PD have been very small.28
It is likely that more sensitive clinical measures may help to identify at risk individuals prior to the development of clinical PD.29
The precise role of Lewy bodies and nigral neuronal loss in producing clinical signs in PD has not been resolved.22, 30
Some have suggested that there is a causal sequence such that Lewy bodies contribute to neuronal loss which determines the level of parkinsonism, while others have suggested a protective role.8, 19, 31
In the current study, mediation analyses was to used to examine the extent to which nigral neuronal loss represents a key step in the causal chain linking Lewy bodies with parkinsonism.32
The results from the current analysis (, Model C) are consistent with a causal sequence in which Lewy bodies may lead to neuronal loss which in turn may lead to more severe parkinsonism.8, 19
Sensitivity analyses which were done complement the mediation analyses since when we excluded the group with more severe neuronal loss (group 4B) our findings were attenuated and no longer significant. Our results might also be consistent with models in which smaller alpha-synuclein aggregates or soluble synuclein are toxic to nigral neurons, in which case Lewy bodies are a proxy for these toxic species.33
These analyses do not preclude the possibility that Lewy bodies and neuronal loss may be linked to parkinsonism through other mechanisms. In fact, in this study, many cases showed evidence of either Lewy bodies alone or neuronal loss alone (, groups 2 & 3).It is unclear whether cases with only Lewy bodies represent an early stage prior to nigral neuronal loss or might be linked with parkinsonian signs through other pathways. Similarly, our mediation analyses do not preclude the possibility that neuronal loss may occur alone due to other mechanisms.
While there were only a small number of cases, our sensitivity analyses also lend support for the speculation that more severe neuronal loss may contribute to parkinsonism even without the presence of Lewy bodies(group 3B)as has been previously suggested.12
Our results also suggest that nigral pathology is not the only cause of parkinsonism in old age, since AD and cerebrovascular pathologies measured in other brain regions were also associated with the severity of parkinsonism ()and may contribute to neuronal loss without Lewy bodies.34, 35
While these findings were statistically significant, together nigral, AD and cerebrovascular pathologies explain only a modest amount of the variance of parkinsonism. There are several reasons why our study may have underestimated the contributions of these pathologies to mild parkinsonian signs in old age, the postmortem indices for AD pathology were preferentially collected from traditional cognitive-related brain regions, while other motor-related regions rostral and caudal to the substantia nigra were not examined and are likely to make separate contributions to the severity of parkinsonism. Furthermore other known traditional pathologies such as white matter loss were not measured. Further studies are needed to replicate these findings and to determine the other neuropathologies and mechanisms which contribute to parkinsonian signs in old age.
There are several strengths to the study, including the community-based cohort with large numbers of women and men coming to autopsy following high rates of clinical follow-up and high autopsy rates. Uniform structured clinical procedures were used that included a detailed assessment of parkinsonian signs that has been widely used in other studies. Uniform post-mortem procedures assessed several post-mortem indices of PD. There are a number of limitations too. The current study only evaluated nigral pathology in one region in a hemisection of the substantia nigra so that it may underestimate the presence of both neuronal loss and Lewy bodies in this structure. The study did not assess other brainstem and extranigral structures regions to allow comparison with other studies with more complete Braak staging of PD pathology 9, 10
It will be important for future studies to fully assess non-dopaminergic neurons i.e., noradrenergic neurons known to be sensitive to α-synuclein pathology. The cohort is selected and replication of these findings in a more general population is needed. This study was large since on an individual level the effect sizes are small. Nonetheless, from a public policy perspective given the extent of motor impairments in old age, even the modest effect sizes observed in the current study are likely to be important. Further studies are needed to more fully explicate the types and locations of pathologies which underlie mild parkinsonian signs in old age.