How does the heterogeneity of Parkinson’s disease affect patient management?

The many different genetic causes of PD

Professor Clemens Scherzer, Boston, MA, highlighted 21 Mendelian genes already identified as causing Parkinson’s disease (PD), and their different themes and phenotypes:¹

At least 21 genes cause PD

• mitochondrial dysfunction associated with rare recessive loss of function of PINK1, PRKN, and PARK7 genes
• lysosomal and trafficking dysfunction associated with LRRK2, GBA, and VPS35 gene variants
• PD without Lewy bodies associated with LRRK2, PRKN, and PINK1 variants
• pyramidal and other atypical features associated with several gene variants including ATP13A2

LRRK2 mutations are associated with a slower UPDRS decline

LRRK2 mutations are associated with a slower decline in motor Unified Parkinson’s Disease Rating Scale (UPDRS) scores.²

GBA mutations are detected in 10.3% of patients with PD and linked to accelerated cognitive decline.³

Furthermore, genome-wide association studies have identified 90 independent PD risk signals suggesting that many other PD-associated genes remain to be identified.⁴

PD is a heterogeneous disease clinically, neuropathologically and prognostically

The many different nongenetic factors associated with PD heterogeneity

The etiological heterogeneity for PD is reflected in its clinical, neuropathologic, and prognostic heterogeneity,⁵ said Professor Connie Marras, Toronto, Canada.

Nongenetic factors influencing clinical manifestations and prognosis include:

• organophosphate pesticide exposure, which is associated with worsening of UPDRS and Mini-Mental State Exam scores⁶
• diet—a Mediterranean-style non-dairy diet is associated with slower worsening of patient-reported outcomes of PD (PRO-PD) whereas a processed food dairy-based diet is associated with faster worsening of PRO-PD⁷
• exercise and physical activity, which lower risk of cognitive decline and progression to Hoehn & Yahr stage 3⁸
• comorbidities, for example diabetes mellitus, cerebrovascular disease, and cardiac disease, which increase the risk of PD with cognitive impairment⁹

Lifestyle factors influence PD progression and mortality

Large longitudinal cohort studies will help physicians answer their patients’ questions

Professor Rodolfo Savica, Rochester, MN, highlighted the multifactorial longitudinal changes for patients with PD and the lack of markers for monitoring effectiveness of treatment.

Physicians are therefore unable to answer their patients’ basic questions such as “What is going to happen next?” and What will be the next symptom?” he said.

Large longitudinal cohort studies from countries worldwide are therefore needed to provide answers to these questions and enable more effective management and therapies.¹⁰