Parkinsonism

Epidemiology

Parkinson disease, which is the second most common neurodegenerative disorder after Alzheimer disease ( Chapter 371 ), occurs in approximately 1 in 1000 in the general population and in at least 1% of persons older than 65 years. Men are affected slightly more often than women (3 : 2). The prevalence of Parkinson disease is thought to be increasing greatly as the world’s population ages. For example, the age-adjusted mortality from Parkinson disease increased by 2.4% per year between 1999 and 2019.

Pathobiology

The cause of Parkinson disease is believed to be a variable combination of poorly understood genetic and environmental factors. The increased risk among former U.S. marines stations at Camp Lejeune has been linked to trichloroethylene. Environmental exposures such as pesticides or heavy metals and traumatic brain injury severe enough to cause an emergency department visit are associated with increased risk of developing Parkinson disease. Both autosomal dominant and recessive genes can cause syndromes that appear like classic Parkinson disease. The protein α-synuclein, which is the chief constituent of the hallmark cytoplasmic inclusion, the Lewy body ( Chapter 371 ), is critical in the pathogenesis of Parkinson disease. Abnormal aggregation of the protein, either from mutations in the α-synuclein gene or as a result of excessive production of the normal protein because of gene duplications or triplications, is associated with varying disease phenotypes. Other defined genetic abnormalities may be associated with classic later-onset Parkinson disease, including LRRK2 , which is currently the most common cause of autosomal dominantly inherited Parkinson disease. Early-onset parkinsonism is typically found in the autosomal recessive forms associated with parkin, DJ1 , and PINK1 . The PARK10 haplotype on chromosome 1 also is strongly associated with Parkinson disease. Other genes in which mutations may increase the risk for developing of Parkinson disease include the glucocerebrosidase gene, which appears to be associated with higher rates of dementia and faster progression of motor symptoms.

Since known genetic causes account for only about 10% of cases, environmental triggers are also likely. Strong support for the environmental hypothesis of sporadic Parkinson disease relates to the observation that the selective neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes acute parkinsonism due to loss of dopamine neurons in the substantia nigra pars compacta. MPTP is oxidized to the active toxin MPP ⁺ , which is a selective inhibitor of complex I of the mitochondrial electron transport chain. This observation, combined with recognition of the importance of dopamine (see later), has implicated the role of oxidative stress in the pathogenesis of Parkinson disease. Other proposed pathogenetic factors include mitochondrial dysfunction, protein misfolding and aggregation, excitotoxicity, inflammation, apoptotic cell death, and loss of trophic support.

Clinical Manifestations

Patients typically receive a diagnosis of Parkinson disease after parkinsonism symptoms become notable. However, the disease begins years earlier in what is now termed the premotor or prodromal phase of the disease, when patients have minimal motor signs or symptoms but early evidence of neurodegeneration. In this phase of the disease, common signs or symptoms include disorders in rapid eye movement (REM) sleep, loss of olfaction, autonomic dysfunction, and depression.