Clinical and genetic predictors of dementia in Parkinson's disease

ImportanceDementia is common in Parkinsons disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. ObjectiveTo investigate whether visual deficits and genetic factors predict PD dementia. DesignLarge prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. SettingCases were recruited between 2017-2020 at 35 UK PD clinics. ParticipantsPeople with PD without dementia at baseline were included. Main outcomes and measuresVisual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimers disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevancePoor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression. Key pointsO_ST_ABSQuestionC_ST_ABSDo clinical factors, measured by performance on visual tests, and genetic factors help predict which patients are more likely to develop cognitive involvement in Parkinsons disease? FindingsThis prospective longitudinal study of 450 Parkinsons patients, based in Parkinsons clinics, with mean follow-up 32.7 months, found that Parkinsons patients with poor vision are more likely to develop cognitive impairment; and that genetic factors in combination with poor vision further predict poor prognostic groups for Parkinsons dementia. MeaningThese data could enable selection of Parkinsons patients at highest risk of dementia for clinical trials aimed at slowing Parkinsons dementia.