Family History and Genetic Risk Shape Parkinson Disease Progression

Patients with Parkinson disease (PD) and a family history of the condition may experience slower disease progression and a reduced risk of developing freezing of gait (FOG), according to a study published in Neurology Genetics.

Researchers analyzed data from 395 newly diagnosed patients in the Parkinson’s Progression Markers Initiative (PPMI). “We examined the independent effects of positive family history and PRS on the longitudinal prognosis of PD, including cognition, nigrostriatal degeneration, and motor complication,” authors explained. “We hypothesized that the information on family history could be a proxy for the clinical heterogeneity of PD.”

The researchers found that family history and polygenic risk scores (PRS), calculated from genetic variants associated with PD, independently impact cognitive decline, motor symptoms, and disease progression.

Patients with a family history of PD exhibited a slower decline in dopamine transporter (DAT) uptake in the caudate region of the brain, a key marker of dopaminergic degeneration. Linear mixed models showed that the rate of DAT decline was 0.02 units slower annually (95% CI, 0.002–0.036; P =.027) compared with patients without a family history. This association remained significant even after adjusting for PRS (β = 0.02; 95% CI, 0.001–0.035; P =.042).

Cognitive decline, measured using the Montreal Cognitive Assessment (MoCA), was slower among those with a family history of PD. MoCA scores in this group declined by 0.12 points less per year (95% CI, 0.02–0.22; P =.017). Higher PRS also contributed to a reduced cognitive decline rate of 0.09 points annually (95% CI, 0.03–0.16; P =.006). When both factors were analyzed together, family history and PRS independently contributed to slower cognitive deterioration (P =.024 and P =.014, respectively).

Motor symptoms, assessed via the Unified Parkinson's Disease Rating Scale (UPDRS-III), worsened over time in all participants. However, neither family history nor PRS significantly altered the rate of motor symptom progression.

Additionally, patients with a family history of PD were less likely to develop FOG, a common and debilitating motor complication. Kaplan-Meier analysis showed a lower risk of FOG in patients with a family history, even after adjusting for PRS and other variables.

“Having a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS,” concluded the study authors. “Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD.”

Reference

Park M, Lee YG. Association of family history and polygenic risk score with longitudinal prognosis in Parkinson Disease. Neurol Genet. 2023;10(1):e200115. doi:10.1212/NXG.0000000000200115