Differentiation between PD, DLB and MSA continues to be a problematic diagnostic dilemma. This study compared these groups based upon their neuropsychological and neuropsychiatric profiles. Overall, on test of cognitive ability, the PD subjects demonstrated the least impairment and the DLB subjects exhibited the most impairment. Despite the perception that MSA tends to spare cognition, the MSA group consistently performed in an intermediate level between the PD and DLB group.
Significant differences between groups were found in tests of executive function. In particular, the DLB and MSA subjects performed worse than PD subjects on tasks that rely heavily on visuospatial processing functions (modified Trails and design fluency). DLB subjects also demonstrated slower processing speed, decreased generation and increased errors relative to both MSA and PD, consistent with previous research suggesting that DLB subjects show significant impairment in frontal-subcortical executive abilities 32, 33
. Tests of executive function on which there were no significant differences between PD, MSA and DLB (backward digit span and letter fluency) tended to involve language, rather than visuospatial frontal cortical and subcortical systems.
Results from language testing were notable for relative sparing of sentence repetition and object naming across all groups. However, both DLB and MSA subjects showed decreased semantic fluency relative to PD subjects. Consistent with previous research suggesting that DLB is associated with specific impairment in visuospatial skills 34
, we found that DLB subjects had more difficulty copying a complex figure and on a spatial location task. Again, the MSA group tended to show scores between PD and DLB groups on visuospatial tasks.
Interestingly, some of the most significant cognitive discrepancies were found on tasks of memory. Although all groups demonstrated reductions in visuospatial memory, DLB tended to have the worst performance. Additionally, on a verbal learning task, the DLB group had greater impairment both encoding and retrieving information and made more false positive responses on a recognition task. These findings are not unexpected given that Lewy bodies and neurites have been found in the hippocampus at pathology in DLB 35, 36
. Furthermore, Alzheimer's Disease (AD) and DLB pathology frequently occur together and memory is further impaired in individuals with combined pathology 34
. Not surprisingly, the degree of functional impairment was most severe in DLB and least severe in PD, which is consistent with the higher observed rates of cognitive impairment and of some neuropsychiatric symptoms in DLB.
DLB is known to manifest with neuropsychiatric symptoms, particularly hallucinations and delusions 4
. Depression is associated with PD and DLB 12
. In our study, caregivers reported high rates of depression on the GDS in all three groups (PD = 87.5%, MSA = 50% and DLB = 91.7%). Prominent anxiety was also notable across all groups. Anxiety is known to be found in PD 12, 37
; we show that it is also seen in MSA and DLB. Although less frequent, other neuropsychiatric symptoms, including apathy, irritability, sleep disturbance, and eating problems were also present across all three groups. Although limited by low numbers of subjects, the GDS and NPI results suggest that these α-synuclein disorders share similar neuropsychiatric features, most notably depression and anxiety, which suggests that these symptoms should be monitored and targeted interventions applied when clinically warranted. Future studies are needed to understand whether similar underlying α-synuclein pathology is responsible for the depression and anxiety observed in all three groups and how differential pathology may contribute to the hallucinations and delusions of DLB.
Unfortunately, we did not collect UPDRS data for the DLB or MSA patients in our study at the time of enrollment. However, subjects were excluded if the examiner felt the neuropsychological data collected was unreliable because of motor slowing. The PD patients would be most likely to have lower test scores due to motor impairment. However, on the Trails, Design Fluency and Rey copy tests, which require relatively more motor coordination, they scored the best compared to other groups. This is consistent with the findings on many of the other tests in which inter-group differences were noted.
Lack of pathological confirmation of the clinical diagnosis represents a potential limitation of this study. However, we employed the most recent clinical consensus criteria available at the time of the study for each disorder which, in autopsy series, are estimated to have an accuracy of seventy to ninety-five percent 38, 39
. New consensus criteria have since been published for MSA 14
. A review of the MSA patients using the new criteria did not result in any change of classification. The most likely confounding factor is the presence of two neurodegenerative conditions, such as DLB and AD, occurring simultaneously in the same subject. Since concurrent AD would tend to lower MMSE scores, we have tried to minimize this possibility by selecting DLB subjects with relatively high MMSE scores compared to the general population of DLB patients. Nonetheless, pathological verification of the clinical diagnosis is important for definitive classification of disease characteristics, thus the participants of this study will be followed to autopsy. Additional confounds that could drive inter-group differences include medication treatment (differential use of dopaminergic agents, cholinesterase inhibitors, anti-psychotics), gender, disease duration, and differences in numbers of patients meeting criteria for dementia based on the DSM-IV. An inability to detect differences between MSA-P and MSA-C subgroups may be due to low numbers of test subjects. Although group differences remained significant after corrections for multiple comparisons, we acknowledge that our sample is small and use of FDR correction can result in Type I error. Thus, our findings deserve additional study and replication.
Despite sharing α-synuclein immunoreactivity in the brain, PD, MSA and DLB exhibit distinctive profiles of cognitive impairment that are may be related to differential regional sensitivity to the toxic effects of α-synuclein or some other factor. Some scientists now believe that formation of pathological inclusions such as Lewy Bodies represents a protective mechanism that cells use to sequester away toxic proteins 40
. Thus, it may be soluble forms of α-synuclein, that are not easily visualized on autopsy samples, are responsible for the differences found in this study. Mutations in α-synuclein are responsible for some forms of familial PD 41
; whether changes in α-synuclein will be found to causal for sporadic PD, DLB and MSA remains to be seen. However, their distinctive clinical signs and cognitive profiles in the setting of common α-synuclein immunoreactivity suggests further avenues in which to study the intriguing problem of selective neuronal vulnerability.