This study found that the annual incidence rate of cognitive impairment in the DATATOP study was 12.7 cases/1,000 person-years; Kaplan-Meier estimates were 2.4% at 2 years and 5.8% at 5 years. This incidence estimate of cognitive impairment is lower than reported dementia incidences from hospital5,8
cohorts of subjects with existing PD, as well as a community-based incident PD cohort.2
However, informal comparisons suggest that the annual incidence rate of cognitive impairment in the DATATOP study is higher than the observed incidence of dementia in comparable age brackets in several general population cohorts.25
For example, an Olmsted County, MN, cohort with similar demographic characteristics followed during approximately the same period as the DATATOP study showed lower incidences of dementia for the age groups of 65–69 (1.7 cases/1,000 person-years) and 70–74 (5.2 cases/1,000 person-years).26
Factors that may account for the relatively low incidence of cognitive impairment in the DATATOP cohort include recruitment bias inherent to clinical trial volunteers (e.g., younger age, higher education, better general health),14
shorter follow-up in the early endpointers (15.8% of the original analysis cohort, worse parkinsonism at baseline), the retrospective nature of our study, and potentially low sensitivity of the MMSE-based cognitive impairment criterion.27
The mean age at baseline in the DATATOP cohort was 61.0, similar to the mean baseline age in other clinical trials in patients with early PD (range 59–64),12,28–32
whereas the peak incidence of PD in the general population is between ages 70 and 79 years.33
In the only study of PDD in incident PD, the mean age at baseline was 69.6, with an annual incidence rate of PDD of 30.0 cases/1,000 person-years.2
While the generalizability of our incidence results may be limited, our study provides knowledge on the cognitive prognosis of patients with early PD who participate in clinical trials, which may have implications for future clinical trial design.
Choosing an outcome measure for this study was a challenge as DATATOP was not designed primarily as a study on the cognitive course of PD. Although cognitive impairment was significantly associated with functional decline, our ad hoc functional criteria were not suitable for dementia diagnosis as recent studies have shown that the intellectual impairment item of the UPDRS has low sensitivity34,35
and is not appropriate for screening or diagnostic purposes.34
Furthermore, the responses on the occupational capacity and handling finances questions on the DATATOP disability progression form16
can be confounded by motor dysfunction. The truncation of the DATATOP neuropsychological battery after the initial phase limited our options for the objective assessment of cognitive impairment. As we only had one reliable cognitive test that was longitudinally available (SRT–verbal learning and memory), we used an MMSE-based criterion for global cognitive impairment. The limitations of this approach included potential practice effects due to repeated administration of the MMSE despite using alternate versions of 3-word list during different visits, and heavy reliance of the MMSE on verbal abilities and low sensitivity to detect dementia, especially when the frequently used cutoff score for dementia (24/30) is applied to highly educated individuals.27,36
However, using age- and education-specific MMSE criterion21,22
for cognitive impairment, our MMSE cutoff score was ≤26 for the most common demographic group in DATATOP (ages 61–65, >12 years of education). This cutoff is consistent with the recommendations of a recent study which found that the ≤26 cutoff had a high sensitivity (0.89) and specificity (0.91) for detecting dementia in highly educated individuals with cognitive complaints screened with the MMSE and followed up with neuropsychological testing.36
Furthermore, our cognitive impairment criterion was able to discriminate well between subjects who showed progressive decline and those who remained stable on all longitudinally available neuropsychological tests (). Those who developed cognitive impairment started at a lower baseline level on average and showed progressive decline in performance on the SRT–total recall (verbal learning), SRT–delayed recall (verbal memory), SDMT (visuomotor speed and attention), and NDT (visuospatial working memory), while those who did not develop cognitive impairment displayed stable performance during follow-up.
We have confirmed a number of previously identified risk factors for PDD such as older age, male gender, poorer performance on neuropsychological tests, hallucinations, worse motor function, PIGD, and increased symmetry of motor severity. We found that the risk of cognitive impairment in early PD did not appear to be associated with the use of medications to treat PD. We also identified potentially novel risk factors such as bulbar dysfunction, early difficulties in dexterity, and gastrointestinal and genitourinary disorders at baseline, suggestive of early autonomic dysfunction. Alternatively, one could interpret the genitourinary disturbances as related to common disorders in this age population such as hypertrophy of the prostate or prolapse, and the gastrointestinal disturbances, specifically constipation, as an early prodromal symptom in PD.
Bulbar dysfunction appeared to be more strongly associated with cognitive impairment than PIGD, the most commonly reported motor risk factor for cognitive impairment.2,4,6
Both PIGD and bulbar impairment reflect axial dysfunction.6
Bulbar dysfunction has not been investigated as a separate entity because previous factor analyses of the UPDRS37,38
and UPDRS item groupings6
have combined items from the bulbar dysfunction and PIGD factors into a single axial dysfunction factor. The large sample size of DATATOP is a major strength of our factor analysis and might have enabled us to better separate the axial functions into 2 factors.
Gastrointestinal and genitourinary (and, to a lesser extent, cardiac) disorders at baseline were risk factors for cognitive impairment. We cannot say with certainty whether they represent specific diseases or just symptom complexes referable to these systems. Presence of these disorders as severe specific diseases is unlikely, however, as unstable medical comorbidity was among the exclusion criteria in the DATATOP study.16
Considering that symptoms such as constipation, difficulty with gastric emptying, urinary urgency, and erectile dysfunction are common nonmotor manifestations of PD,39
it is conceivable that these disorders might have represented autonomic symptoms. An association between autonomic dysfunction and time to cognitive impairment is compatible with results of cross-sectional studies showing increased frequency of autonomic dysfunction in patients with DLB or PDD compared to patients with PD without dementia.40