Parkinson's disease

The aetiology of PD is unknown, although several factors have been implicated. There is probably a genetic predisposition, with subsequent environmental factors/exposures contributing to the evolution of clinical disease. Within this multifactorial model, age is the only undisputed risk factor. The rate of progression of PD varies, and is associated with a patient's symptoms and response to medications. For example, early cognitive impairment, orthostatic hypotension at presentation, and a poor response to levodopa tend to be associated with more rapid disease progression.[15]

Generally, PD is considered a sporadic disorder. However, rare autosomal dominant and recessive familial forms have been identified. Approximately 20 different causative genes have been identified from studies of familial PD; these include SNCA, LRRK2, PRKN, PINK-1, GBA, DJ-1, TREM2, VPS35, and MHFTR.[16][17][18][19][20][21][22] These genes code for proteins including alpha-synuclein, LRRK2 (leucine-rich repeat kinase 2), PINK-1 (a mitochondrial protein kinase), and components of the ubiquitin-protease system. Mutations in the gene encoding glucocerebrosidase (GBA), the enzyme that is deficient in Gaucher's disease, have been shown to confer an increased risk of PD.[23][24][25] One meta-analysis identified 90 independent genome-wide significant risk signals for PD across 78 genomic regions.[16] Some gene variants may confer different levels of risk on different populations.[26][27] Furthermore, certain gene variants may affect cognitive outcomes in people with PD or may predict response to surgical therapies such as deep brain stimulation (DBS).[28][29]

Environmental factors are likely to be involved in the pathogenesis of PD. Neurotoxic mechanisms have been proposed based on findings that substances such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause selective damage to dopaminergic neurons in the nigrostriatal pathway, by means of mitochondrial poisoning of complex I.[30] Chronic heavy metal exposure has also been implicated as a cause.[31]

Oxidative stress probably has a role in neuronal loss. The conversion of dopamine into free radicals by numerous mechanisms may contribute to selective substantia nigral damage. Mitochondrial defects, deficiency of neurotrophic factors, programmed cell death (apoptosis), immune system activation, impaired protein clearance, and infection have all also been implicated.[17]

The underlying pathophysiology of PD is unknown. Selective loss of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) occurs with findings of intracytoplasmic eosinophilic inclusions (Lewy bodies) and neurites, both of which are composed of the protein synuclein. One theory suggests that misfolded alpha-synuclein can recruit endogenous alpha-synuclein to seed further protein aggregation in new neurons in a prion-like fashion.[32] Loss of striatal dopaminergic output within the circuitry of the basal ganglia accounts for the constellation of motor symptoms. It is believed that decreased activity of the direct pathway and increased activity of the indirect pathway cause increased inhibitory activity from the globus pallidus internus (GPi)/substantia nigra zona reticulata to the thalamus, and therefore reduced output to the cortex.[33]

Bradykinesia, the most characteristic symptom of basal ganglia dysfunction, correlates with dopamine deficiency, as evidenced by reduced striatal fluorodopa uptake measure by positron emission tomography scans.[34][35] It is the result of excessive stimulation of the subthalamic nucleus (STN) and the GPi.[36] The resulting slowness and delay in initiating movement leads to symptoms including loss of dexterity, drooling, hypophonia (decreased speech volume), loss of facial expression, and reduced arm swing.

The pathophysiology of rigidity is not well understood, but enhancement of long latency stretch reflexes is a generally accepted hypothesis.[37] Postural instability is due to loss and/or dysfunction of postural righting reflexes.[38]

No definitive cause of the resting tremor (4-6 Hz) is known. It is hypothesised that nigrostriatal degeneration leads to disinhibition of either STN or GPi, or possibly disrupts thalamo-cortical-cerebellar circuits, leading to clinical manifestation of thalamic pacemaker cells.[39][40][41] Research suggests that synuclein pathology may actually begin in the lower brainstem (dorsal motor nucleus of the vagus in the medulla oblongata) and progress in a predictable caudal to rostral pattern.[42] There is also evidence that pathology may begin distally in the enteric and peripheral autonomic nervous systems.[43][44]

Age of onset

If PD is described according to age of onset, the following applies:

Juvenile parkinsonism: under age 21 years
Young-onset parkinsonism: ages 21-40 years.

Pathophysiology

Classification

Age of onset