Parkinson's Disease: Understanding the key risk factors

Parkinson's disease (PD) is a neurodegenerative movement disorder comprising cardinal symptoms of bradykinesia, rigidity, rest tremor and gait impairment; due to loss of dopaminergic neurons in substantia nigra. It is a complex disorder resulting from genetic alterations, environmental exposures, and interactions among these factors.

Risk factors for PD can be divided into two categories:

Endogenous biological risk factors:

• Age: Age is the single most important risk factor. The mean age at onset is approximately 60 years.
• Sex: Males are affected more than females; due to possible hormonal contribution, however mechanism still unknown
• Genetic: The majority of cases are sporadic, however variety of genetic factors have been identified as pathogenic or contributory, especially in PD with onset < 50 years.

SNCA (PARK1, PARK4) – AD, incomplete penetrance; early onset PD with rapid progression, possible early dementia

PRKN Parkin (PARK2) – AR, early-onset PD with slow progression, atypical features, less cognitive impairment than idiopathic PD

PINK1 (PARK6) – AR, rare, features similar to Parkin mutation

PARK7 (DJ1) – AR, rare, early onset PD with good levodopa response

LRRK2 (PARK8) – AD, incomplete penetrance, Similar motor phenotype as idiopathic PD with slower progression fewer non motor symptoms

VPS35 (PARK17) – AD, rare (case reports only)

GBA (glucocerebrosidase) – AD, markedly reduce penetrance, rapid progression with more severe non motor features

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Pathogenic variants in these seven genes contribute to about 10-15% of PD patients. Most of the commercial laboratories include these 7 genes in their PD panels.

• Single-nucleotide polymorphisms (SNPs) – Around 80 risk loci for PD have been identified, associated with increased risk
• Family history – higher risk in first degree relatives

Exogenous (behavioural and environmental) risk factors:

• Head trauma
• Pesticides and organic solvents
• Rural living, farming, consumption of dairy products and well water drinking

• Metabolic factors – Diabetes, physical inactivity, low plasma urate levels
• Toxin exposure – MPTP, manganese (welding)

These risk factors have been postulated based on epidemiological studies and have been shown to confer either an increased risk or an earlier onset of disease.

Certain factors including use of caffeine, antioxidants and nicotine are associated with a reduced risk of PD.

Thus PD is a heterogenous movement disorder whose presence and phenotype is influenced by varied risk factors and etiologies, which give us an insight onto the mechanism underplay for PD and further prospects for research in treatment and management.

(Author: Dr. Charulata Sankhla, Consultant Neurophysician, P. D. Hinduja Hospital & MRC, Mahim)