We found that side and type of PD symptom onset were not associated with impairment in any of the neurocognitive domains that we studied. Specifically, in contrast to the findings of Katzen et al,12
our RSO-T group did not perform better than the other groups. It is important, first, to show that the largely negative results that we found for our cognitive measures were not simply a function of sample size. In fact, our sample was nearly twice as large as Katzen’s. For simplicity, the power analysis consisted of 2 groups of equal size, a power of 0.8, and an alpha level of 0.05. The smallest sample size per group under these conditions would have been 559 obtained with the Controlled Oral Word Association Test-TS, and the largest sample size per group would have been 110,432 obtained with the Trail Making Test Part B T-score. Clearly, our results cannot be attributed to lack of power.
There are several possible explanations for our discordant findings with Katzen et al.12
First, because we excluded patients with dementia from our analysis, we studied a higher-functioning cohort. Second, Katzen’s 4 groups were of roughly equal size, but our larger study had many more patients in the tremor groups than in the bradykinesia/rigidity groups. Third, we gave different neuropsychological tests for the domains that we evaluated, and we did not evaluate the visuospatial domain, an area in which Katzen’s RSO-T group outperformed the LSO-T group.
Despite these methodological differences, our study was sufficiently powered to have detected a difference in neurocognitive domains between groups had one existed. Our finding that side and type of symptom onset do not directly influence the later development of cognitive impairment fits well with the Braak hypothesis of PD,25
which maintains that cortical pathways important for cognition become involved by Lewy pathology only comparatively late in the disease course.
In contrast to our negative findings for cognition, those participants with right-side onset tremor had significantly milder depressive symptoms than those in the other groups. Although this observation is statistically robust, our study population overall had quite mild depressive symptoms. Only 6 participants met research diagnostic criteria for major depressive disorder, and none of them had right-side onset tremor. These findings are unlikely to have been confounded by antidepressant use, given that most of the users exhibited some depressive symptoms on the QIDS-SR16.
Our observation favors the endogenous over the reactive model of depression in PD because patients with dominant hand tremor (which would be expected to be more disabling than nondominant tremor) had the fewest depressive symptoms. That patients who have alpha-synuclein pathology beginning on the left side, with relatively healthy right brain function, are less prone to depression is concordant with previous reports that depression is associated with decreased activity in the right dorsolateral prefrontal cortex,26
but is discordant with studies of depression and lateralized onset of PD symptoms.16, 17
Limitations of our study include the retrospective collection of information about side and symptom of onset, the unequal numbers of patients in the 4 groups, few newly diagnosed patients in the cohort (only 4 participants had disease onset within 2 years of enrolling in the study), the lack of a measure of visuospatial function, and the lack of an analysis of our participants’ handedness because too few were left-handed. Although our results cannot be generalized to apply to newly diagnosed patients, in light of our power calculations we think it is quite unlikely that our failure to find a link between side and symptom of onset and cognitive impairment represents a type II error.
Further study will be needed to sort out this complex and conflicting picture of the relationship among motor symptoms at onset, cognition, and depression. Given that we did not find a relationship between side and type of initial symptom and cognitive impairment, we think that all patients with PD should be carefully observed for cognitive impairment as a routine part of clinical care. At our center, we give patients the AD827–29
at each follow-up visit to detect the start of dementia. When found, cognitive impairment prompts further evaluation and treatment. Although we believe that all patients with PD should also be carefully monitored for depression during routine follow-up, our results suggest that those with right-side onset tremor may be at lower risk for this disabling complication.