INTRODUCTION — Parkinson disease (PD) is the leading cause of parkinsonism, a syndrome manifested by rest tremor, rigidity, bradykinesia, and postural instability. PD is one of the most common neurodegenerative diseases of adulthood and a major cause of neurologic morbidity and mortality worldwide.
The clinical features of PD arise partly from progressive degeneration of dopamine-producing neurons in the basal ganglia, including the substantia nigra in the midbrain, but degeneration of nondopaminergic neurons is implicated in many motor and nonmotor symptoms. Thus, dopamine depletion and loss of other neurotransmitters account for the classic motor phenotype as well as a wide range of nonmotor and neuropsychiatric manifestations that affect function and quality of life.
The cause or etiologic trigger of neurodegeneration in PD is still unknown in the majority of cases. However, remarkable progress has been fueled by discoveries about the anatomy and function of the basal ganglia, improved characterization of neuropathologic and neurochemical abnormalities, and studies of genetic and experimental forms of parkinsonism [1].
This topic will review the epidemiology, pathology, pathogenesis, and genetics of PD. The clinical features, diagnosis, and treatment of PD are reviewed separately:
●(See "Clinical manifestations of Parkinson disease".)
●(See "Diagnosis and differential diagnosis of Parkinson disease".)
●(See "Cognitive impairment and dementia in Parkinson disease".)
●(See "Initial pharmacologic treatment of Parkinson disease".)
●(See "Management of nonmotor symptoms in Parkinson disease".)
●(See "Nonpharmacologic management of Parkinson disease".)
●(See "Palliative approach to Parkinson disease and parkinsonian disorders".)
HISTORICAL CONTEXT — PD was first described by James Parkinson in his 1817 Essay on the Shaking Palsy. However, there is some evidence that a disease known as "kampavata," consisting of shaking (kampa) and lack of muscular movement (vata), existed in the ancient Indian medical system, Ayurveda, as long as 4500 years ago [2]. The Mucuna pruriens plant was used in ancient times to treat the symptoms and was later discovered to contain levodopa [3].
The pathology of PD was not well understood until the early 20th century, when the German pathologist Frederick Lewy in 1912 reported neuronal cytoplasmic inclusions in a variety of brain regions. In 1919, Tretiakoff observed that the most critical abnormality in PD was the loss of neurons in the substantia nigra pars compacta (SNc) of the midbrain. In the 1950s, investigators discovered the importance of dopamine and its depletion from the basal ganglia as the key to understanding the pathophysiology and pathologic biochemistry of PD [4].
EPIDEMIOLOGY
Incidence and prevalence — PD is a growing source of disability and mortality among neurologic disorders. The estimated prevalence is 94 cases per 100,000 people, or approximately 0.3 percent in the general population 40 years of age and older [5,6]. The yearly incidence of new cases ranges from 8 to 18.6 per 100,000 person-years [7].
The incidence and prevalence of PD are rising. In the year 2016, the estimated global prevalence of PD was 6.1 million people, increased from 2.5 million in 1990 [6]. A similar trend has been observed in age-adjusted mortality from PD [8]. Although aging of the world population accounts for much of the increase in absolute numbers, the age-adjusted incidence is also rising, for reasons that are not fully understood.
Risk factors
●Age – Age is the most important risk factor for PD. The incidence and prevalence rise steadily in adults beginning in the fifth decade [5]. Nonetheless, PD is not solely a disease of older adults. Approximately 25 percent of people with PD are diagnosed before the age of 65 years.
●Sex – Males have a higher risk of PD than females by a ratio of approximately 1.4:1 [6]. However, a sex difference is not present in all studies, and in one meta-analysis, a significant difference in prevalence by sex was only present in the 50-to-59-year age group [5]. A protective effect of estrogen has been suggested by studies in females who have undergone premenopausal oophorectomy. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Cognitive function and neurologic disease'.)
●Genetics – A family history of PD in a first-degree relative is associated with a two- to threefold increase in the risk of PD [9]. Monogenic forms of PD account for less than 10 percent of PD cases and span autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Most have a younger age of onset compared with sporadic PD. (See 'Genetics' below.)
Aside from monogenic forms of PD, heterozygous pathogenic variants in the glucocerebrosidase 1 (GBA1) gene are another important genetic risk factor for PD. Other lysosomal enzyme-encoding genes have also been found to alter risk. (See 'Glucocerebrosidase gene' below and 'Other lysosomal genes' below.)
●Environmental exposures – A large number of environmental exposures have been identified as risk factors for PD in epidemiologic studies. Examples include the following:
•Exposure to pesticides [9-16]
•Exposure to nitrogen dioxide in air pollution [17]
•High consumption of dairy products [18,19]
•Living in urban or industrial areas with high release of copper, manganese, or lead [20]
•Exposure to hydrocarbon solvents, particularly trichloroethylene [21]
•Living in rural areas [9]
•Farming or agriculture work [9]
•The use of well water [9,22]
•High dietary intake of iron, especially in combination with high manganese intake [23]
•Reduced levels of dietary and sunlight-derived vitamin D [24-26]
Paradoxically, other data suggest that mortality from PD is increased among people with higher socioeconomic occupations (eg, education, computer and mathematical, legal, architecture and engineering) where exposure to toxins is unlikely, while PD mortality is decreased among people with lower socioeconomic occupations (eg, mining and drilling, transportation and material moving, construction) where exposure to toxins is more likely [27,28].
●Comorbidities – A variety of medical and psychiatric illnesses in early or mid-life have been associated with increased risk of PD in observational studies. Among the most consistently identified risk factors are:
•Excess body weight, type 2 diabetes, and metabolic syndrome [29-32]
•History of traumatic brain injury [33-35]
•History of melanoma or prostate cancer [36-40]
A number of reports, including several large population-based case-control studies, have found an association between depression and the subsequent development of PD [41-46]. These findings suggest that depression is either a risk factor for PD or a prodromal symptom of PD. Similarly, meta-analyses of observational studies suggest a preceding history of constipation is either an early manifestation of PD or a risk factor for PD [9,47].
Protective factors — The most consistently identified negative associations, or protective factors, for PD are cigarette smoking, caffeine consumption, and physical exercise. A variety of medications and classes of medications have been identified as potentially protective in observational studies, but none has yet borne out in prospective trials.
●Smoking – An inverse correlation between PD and smoking is supported by the findings of large cohort studies and meta-analyses [1,9,48-51]. In a meta-analysis of 26 observational studies, the risk of PD was more than twofold lower for current smokers compared with never smokers (relative risk [RR] 0.44, 95% CI 0.39-0.50) [9]. In addition, the risk of PD was lower for ever smokers compared with never smokers (RR 0.64, 95% CI 0.60-0.69). A neuroprotective effect of nicotine has been proposed as one possible explanation for these observations [52].
An alternative hypothesis is that patients who develop PD are less likely to smoke in the first place, or are more likely to quit smoking, than those who do not develop PD. This alternative explanation posits that since dopamine is an integral component of the brain's reward system, people who will later develop signs of PD do not engage in reward-seeking behaviors, such as smoking, because dopamine is significantly depleted in the basal ganglia years before symptoms of PD appear [53-55]. Others hypothesize that the tendency to smoke represents a risk-taking behavior, and that general risk tolerance as a genetically determined trait is causally related to PD [56].
●Caffeine – Coffee and caffeine intake have been associated with lower risk of PD in meta-analyses and large cohort studies [9,50,57,58].
●Exercise – Aerobic exercise and physical activity may be protective against development of PD [59-65]. In a meta-analysis of eight prospective studies in more than 500,000 individuals, moderate to vigorous physical activity was associated with an approximately 30 percent reduction in the RR of PD [66]. However, an alternative explanation for the association is reversed causality, given that reduced physical activity may be a preclinical sign of PD.
●Ibuprofen – There is evidence from several meta-analyses that ibuprofen may be associated with a reduced risk of PD [67-70]. The data regarding other nonsteroidal anti-inflammatory drugs (NSAIDs) are conflicting, with some meta-analyses finding that NSAIDs are associated with a reduced risk of PD [9,68] and others finding no significant association [67,69,70].
●Statins – The relationship among statin use, lipid levels, and PD is unsettled despite numerous observational studies. Some meta-analyses suggest that statins are associated with a lower risk of PD [71,72], while others conclude that the apparent protective effect of statin use is explained at least in part by failure to adjust for confounders [73]. Yet other observational studies have found that statin use is associated with a higher risk of PD incidence and progression [74,75].
The available prospective data, although limited, do not support use of statins for the purpose of neuroprotection in PD. In a randomized trial among 235 patients with moderate PD associated with motor complications, motor scores at 24 months were nonsignificantly worse in the simvastatin arm compared with the placebo arm (1.52 points more deterioration, 80% CI -0.77 to 3.80) [76]. By contrast, a smaller trial of lovastatin in patients with early-stage PD found a nonsignificant, approximately 3-point improvement in motor scores at 48 weeks compared with placebo, which lessened after a washout period, suggesting possible symptomatic rather than neuroprotective effects [77]. Larger studies are needed.
●Glycolysis-enhancing drugs – Terazosin, doxazosin, and alfuzosin are alpha-1-adrenergic receptor antagonists used to treat hypertension and benign prostatic hyperplasia that bind to phosphoglycerate kinase 1 (PGK1) and increase energy metabolism. In cellular and animal models, enhancing glycolysis reduces PD progression [78]. In several large database studies, use of terazosin, doxazosin, or alfuzosin has been associated with reduced risk of PD or PD progression compared with nonuse or use of tamsulosin, an alpha-1-adrenergic receptor antagonist that does not have PGK1 activity [78-80]. Further studies are needed to explore a possible protective effect prospectively.
●Inhibitors of the renin-angiotensin system – Preclinical studies suggest that activation of the renin-angiotensin system may promote neurodegeneration in PD via pro-oxidative and/or proinflammatory effects; there is corresponding interest in angiotensin receptor blockers as a neuroprotective strategy [81,82]. In several retrospective cohort studies, use of an angiotensin receptor blocker has been associated with lower risk of incident PD compared with nonuse [83-85]. Clinical trials are needed to further explore these associations.
PATHOPHYSIOLOGY — The central defect in PD is dopamine depletion from the basal ganglia. This results in major disruptions in the connections to the thalamus and motor cortex and results in the classic parkinsonian signs of bradykinesia and rigidity.
Basal ganglia circuits — The basal ganglia, sometimes referred to as the extrapyramidal system, include the substantia nigra, striatum (caudate and putamen), globus pallidus (GP), subthalamic nucleus (STN), and thalamus.
The cortical input to the basal ganglia from the prefrontal supplementary motor area, amygdala, and hippocampus is excitatory, mediated by the neurotransmitter glutamate. Neurons in the substantia nigra pars compacta (SNc) provide major dopaminergic input to the striatum and exert both excitatory and inhibitory influences on the striatal output neurons. The interaction between the afferent and efferent pathways is mediated by striatal interneurons, which utilize acetylcholine as the main neurotransmitter.
The striatal output system is mediated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The connection between the STN and the internal (medial) globus pallidus (GPi) and between STN and the external (lateral) globus pallidus (GPe) is excitatory, mediated by glutamate.
Five distinct dopamine receptors (D1 through D5) have been cloned and characterized; they are found throughout the basal ganglia and limbic system. The D1 and D2 receptors are highly concentrated in the dorsal (motor) striatum and are the most relevant to the pathophysiology of PD because they are activated by the dopaminergic pathway originating in the SNc and terminating in the caudate and putamen. Receptors designated as D3, D4, and D5 are more abundant in the mesolimbic or emotional part of the brain (D3, D4) and hippocampus/hypothalamus (D5) [86].
Dopamine deficiency in the nigrostriatal pathway, such as that seen in PD, causes denervation hypersensitivity of D1 and D2 receptors [87]. When compared with normal matched controls, D2 receptors in the dorsal putamen are increased by 15 percent in patients with PD, whereas D3 receptors in the mesolimbic system are decreased by 40 to 45 percent [88]. These results may explain the basis for the hypersensitivity of the nigrostriatal (D2) dopaminergic receptors that is observed in PD.
There are two output pathways from the striatum (figure 1):
●The indirect pathway is mediated chiefly via dopamine's inhibitory influence on striatal D2 dopamine receptors. In the indirect pathway, the striatum projects to the neurons in the GPe utilizing GABA, and the GPe in turn projects to the STN, which provides excitatory input via glutamate to the GPi and substantia nigra pars reticulata (SNr). GPi neurons are GABA-ergic and synapse in the ventrolateral nucleus of the thalamus. Thalamic input to the cortex is excitatory.
●The direct pathway is mediated via dopamine's excitatory influence on striatal D1 dopamine receptors. In the direct pathway, the striatum projects directly to the GPi and SNr.
In PD, a reduction of dopamine-producing neurons from the normal complement of approximately 550,000 to the critically low level of 100,000 leads to dopamine depletion in the substantia nigra and in the nigrostriatal pathway to the caudate and putamen. This, in turn, results in relative overactivity of the indirect pathway, functionally disinhibiting the STN. Decreased inhibition of the direct pathway causes additional disinhibition of the output nuclei (GPi and SNr). Increased output from GPi causes increased inhibition of the thalamus and reduced excitatory input to the motor cortex, which is ultimately expressed as bradykinesia and other parkinsonian signs.
In PD, synchronized oscillatory activity in the 10 to 50 Hz band (often termed the beta-band), prevalent in the basal ganglia thalamocortical circuit, may be important in mediating certain parkinsonian features, including bradykinesia and tremor, and can be reduced by dopaminergic treatments [89]. Therefore, surgical treatments for PD, such as lesion placement within or stimulation of GPi or STN, may act by desynchronizing the oscillatory basal ganglia-thalamo-cortical network activity.
Models of basal ganglia dysfunction (figure 1) are useful for conceptualizing how the motor symptoms of PD arise. However, the actual pathophysiology of the basal ganglia associated with PD is much more complex than indicated by these models [90]. Existing models should be constantly re-evaluated as new findings become available.
Compensatory mechanisms — The brain has a remarkable capacity to compensate for the presynaptic dopamine depletion by increasing the synthesis of dopamine in surviving neurons and by increasing the afferents to the dendrites of dopaminergic neurons. Dopaminergic denervation also results in a proliferation of D2 receptors, as well as a colocalization of D1 and D2 receptors [91]. Similarly, gap junctions, which allow rapid communications between striatal neurons, increase dramatically after dopaminergic denervation [92].
In the brains of patients with PD, the number of tyrosine hydroxylase-staining neurons in the striatum is markedly decreased [93]. Since tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine, is still present in surviving neurons, the synthesis of dopamine could be increased in these striatal neurons, thereby compensating for the presynaptic dopamine loss [94,95]. Another compensatory mechanism may be downregulation of the dopamine transporter, resulting in less dopamine reuptake and higher synaptic dopamine levels [96].
Three stages of compensation during the presymptomatic period of PD have been proposed [95]:
●An early period during which the dopamine homeostatic compensatory mechanisms discussed above are capable of "masking" the disease
●Increased activity of the basal ganglia output nuclei (eg, the GPi) as striatal dopamine homeostasis breaks down
●Increased intensity of compensation in structures outside of the basal ganglia (eg, supplementary motor area of the cortex) as parkinsonian motor abnormalities emerge
PATHOLOGY — The brains of patients with PD typically show depigmentation, neuronal loss, and gliosis, particularly in the substantia nigra pars compacta (SNc) and in the pontine locus ceruleus. Neuronal degeneration is also present in the dorsal nucleus of the vagus in the medulla and other brainstem nuclei.
Key sites of neuronal loss — The ventrolateral portion of the substantia nigra that projects to the dorsal putamen is preferentially affected early in the course of PD, resulting in the gradual loss of dopaminergic neurons in the SNc and a nearly complete depletion of dopamine, particularly in the putamen [97]. This contrasts with normal aging, which is usually associated with neuronal loss in the dorsal tier of the SNc, and depletion of dopamine, predominantly in the caudate nucleus [98].
In otherwise healthy adults, there are approximately 550,000 pigmented neurons and 260,000 nonpigmented neurons in the substantia nigra [99]. By the time the first symptoms of PD emerge, approximately 60 percent of the neurons in the SNc have been lost [4].
Because of the apparent discrepancy between loss of striatal dopamine (>80 percent) and the degree of loss of neurons in the substantia nigra (50 to 60 percent), some have suggested that the initial site of pathology is in the striatum and that retrograde degeneration may be responsible for the neuronal loss in the substantia nigra [4]. An alternative explanation is that each dopaminergic neuron has multiple projections that terminate in the striatum, so that death of the cell body has a multiplying effect on loss of terminals.
In addition to the degeneration of the SNc, other nuclei are affected by the pathology of PD, including the internal (medial) globus pallidus (GPi), the center median-parafascicular complex, the pedunculopontine tegmental nucleus, and the glutamatergic caudal intralaminar thalamic nuclei [100]. Moreover, volumetric magnetic resonance imaging (MRI) studies have found significant hippocampal atrophy in patients with PD, with or without cognitive impairment [101].
Lewy bodies and other intracellular inclusions — There is no consensus as to what pathologic criteria are necessary for the diagnosis of PD [1], but most investigators believe that Lewy bodies, named for Frederick Lewy, constitute the pathologic hallmark of PD.
Lewy bodies are round, eosinophilic, intracytoplasmic neuronal inclusions. They are 3 to 25 nm in diameter with a dense granular core (1 to 8 nm) and loosely arranged fibrillary elements extending towards a peripheral "halo." Immunohistochemical studies have demonstrated that Lewy bodies are made up mainly of alpha-synuclein and ubiquitin and also contain calbindin, synphilin-1, complement proteins, microfilament subunits, tubulin, microtubule-associated protein 1 and 2, and a parkin substrate protein called Pael-R [102,103].
In patients with PD, Lewy bodies are seen in the substantia nigra, the basal nucleus of Meynert, the locus ceruleus, the cerebral cortex, the sympathetic ganglia, the dorsal vagal nucleus, the myenteric plexus of the intestines, and even in the cardiac sympathetic plexus. Lewy bodies appear to arise from the peripheral portion of other inclusions known as pale bodies, which are found in the substantia nigra and locus ceruleus [104].
Lewy bodies are not specific for PD since they are found in as many as 10 percent of brains of otherwise healthy older adults, as well as in patients with other neurodegenerative diseases, such as neurodegeneration with brain iron accumulation (NBIA), ataxia-telangiectasia, progressive supranuclear palsy, corticobasal degeneration, Down syndrome, and Alzheimer disease. There is growing evidence that Lewy bodies occur not only in synucleinopathies such as PD or amyloidopathies such as Alzheimer disease, but also in tauopathies, such as frontotemporal dementia [105].
The lack of specificity of the pathologic findings raises the possibility that PD may not be a specific disease entity, but rather a clinically prototypical syndrome with different clinical subtypes and pathogenic causes (table 1) [106].
Inclusions such as Lewy bodies have traditionally been considered toxic. However, some studies suggest that they may actually be neuroprotective and that compounds that promote the formation of inclusions lessen the pathology of PD [104,107].
Braak staging — In the traditional view, the pathologic process of PD starts with degeneration of dopaminergic neurons in the substantia nigra. This view has been challenged by the neuropathologist Heiko Braak, who has proposed that the pathologic changes of PD start in the medulla of the brainstem and in the olfactory bulb, progressing rostrally over many years to the cerebral cortex in a predictable six-stage process (figure 2) [108,109].
According to Braak staging, the progression of pathologic changes occurs as follows [108]:
●During presymptomatic stages 1 and 2, the pathologic changes are found in the medulla oblongata and olfactory bulb.
●In stages 3 and 4, the pathology has migrated rostrally to the SNc and other neuronal clusters of the midbrain and basal forebrain, at which time the classic motor symptoms of PD first appear.
●In end-stages 5 and 6, the pathologic process encroaches upon the telencephalic cortex of the temporal and frontal lobes.
However, the validity and predictive utility of Braak staging has been questioned, as there are no cell counts to correlate with the described synuclein pathology and no observed asymmetry in the pathologic findings that correlate with the well-recognized asymmetry of clinical findings [110,111].
In addition, there is controversy as to the classification of dementia with Lewy bodies (DLB), considered by some to be a separate entity from PD. Braak did not include DLB in his observations on the progression of PD. (See "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies" and "Clinical features and diagnosis of dementia with Lewy bodies".)
PATHOGENESIS OF CELL DEGENERATION
Alpha-synuclein misfolding, aggregation, and toxicity — Alpha-synuclein is abundant in the central nervous system (CNS), accounting for 1 percent of total CNS protein. Its physiologic role is not fully understood, though it appears to be involved in synaptic function and plasticity [112].
An aggregated and insoluble form of alpha-synuclein is a major component of Lewy bodies, intracellular inclusions that are the pathologic hallmark of PD [113]. Alpha-synuclein aggregates are a prominent finding in PD and several other neurodegenerative disorders (eg, dementia with Lewy bodies [DLB], multiple system atrophy), together known as synucleinopathies [1,114].
The mechanisms by which alpha-synuclein aggregates cause toxicity in PD are not well understood. However, insights have been gained through study of a monogenic form of PD caused by pathogenic variants in the synuclein alpha (SNCA) gene. SNCA variants may cause the natively unfolded alpha-synuclein protein to alter its secondary structure and self-aggregate after being targeted for proteasomal degradation by ubiquitin [115]. Misfolding of proteins and subsequent formation of insoluble aggregates can occur due to genetic variants that result in abnormal structure of the gene product, or as a result of age-related phenomena [116].
The hydrophobic portion of alpha-synuclein can spontaneously form fibrillar protein aggregates, and SNCA variants may promote the development of these aggregates [117]. Furthermore, alpha-synuclein protoaggregates or oligomers can disrupt cell membranes, including dopamine vesicles and mitochondria, possibly by causing pores in the membranes [117]. A protofibrillar form of alpha-synuclein appears to be more toxic than the normal or fibrillar form.
Observations in transgenic and normal mice and in humans suggest that misfolded forms of alpha-synuclein can somehow be transmitted from diseased neurons to healthy ones [118]. In normal mice, a single injection of synthetic misfolded alpha-synuclein fibrils into the striatum leads to cell-to-cell transmission of pathologic alpha-synuclein and Lewy body-like pathology with progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and impaired motor coordination [119,120]. Pathologic alpha-synuclein appears to act as a template that corrupts normal alpha-synuclein, so it too becomes pathologic and thereby spreads the disease from an affected neuron to a normal one, which in turn becomes diseased.
Further suggestion of cell-to-cell spread is provided by long-term study of patients with PD who received human fetal nigral neuron transplantation. At autopsy, grafted nigral neurons have been found to contain Lewy bodies that stain positive for alpha-synuclein [121,122].
Several anti-synuclein strategies are being investigated in clinical trials as potential disease-modifying therapies [123]. Results have been disappointing thus far, however. Trials of two different monoclonal antibodies directed at alpha-synuclein, cinpanemab and prasinezumab, in patients with early-stage PD each showed similar clinical and radiographic outcomes in the active treatment and placebo groups at 52 weeks [124,125]. The cinpanemab trial also reported no clear differences at 104 weeks in a blinded extension phase, which was halted due to lack of efficacy [124]. Studies of active immunotherapy (vaccination) directed against alpha-synuclein in earlier stages of development are ongoing [126,127].
It should be noted that the Braak hypothesis and the notion of aggregated synuclein as the primary pathogenic mechanism of neurodegeneration have been increasingly challenged. Some investigators have proposed that abnormal soluble oligomers and fibrils of alpha-synuclein that aggregate into Lewy bodies are merely byproducts and may actually serve a protective rather than toxic function [128,129].
Defective proteolysis — Cellular protein homeostasis is normally maintained primarily by three coordinated pathways (molecular chaperones, the ubiquitin-proteasome system, and the autophagy-lysosomal pathway) that mediate the repair or removal of abnormal proteins [130-133]. While the data are not entirely consistent, it appears that all three pathways are involved in the processing of alpha-synuclein. When these systems are inhibited or impaired, abnormal proteins such as mutated alpha-synuclein can misfold, aggregate, and clog the normal molecular traffic of the cell, leading to cell death.
Of particular interest is the finding in mice that the proteins parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 bind to each other to form a complex that promotes degradation of unfolded or misfolded proteins via the ubiquitin-proteasome system [134]. This observation is notable because pathogenic variants of parkin (PRKN), PINK1, and DJ-1 (PARK7) are individually associated with autosomal recessive forms of PD. Furthermore, Atp13a2 deficiency can cause lysosomal dysfunction and enhance the accumulation and toxicity of alpha-synuclein in vitro [131,135]. This finding may reflect the pathogenesis of neurodegeneration associated with loss-of-function ATPase cation transporting 13A2 (ATP13A2) gene variants that cause an early-onset form of parkinsonism. (See 'Genetics' below.)
Mitochondrial dysfunction — The role of mitochondria in the pathogenesis of PD was first suggested by discovery of the association between the meperidine analog 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and parkinsonism [136,137]. The oxidation of MPTP produces 1-methyl-4-phenylpyridium (MPP+), which is taken up by dopaminergic terminals, selectively inhibits mitochondrial complex I activity, disrupts calcium homeostasis, and induces endoplasmic reticulum stress, resulting in cell damage [137,138].
Direct evidence of mitochondrial dysfunction is supported by the finding that complex I activity is decreased by 32 to 38 percent in the substantia nigra of patients with sporadic PD [139,140] and by the finding that mitochondrial membrane potential and intracellular adenosine triphosphate (ATP) levels are significantly decreased in skin fibroblasts of patients with PD who carry the leucine rich repeat kinase 2 (LRRK2) G2019S mutation [141].
The following cascade of intracellular events has been postulated to lead to neurodegeneration [142,143]:
●A cellular insult (eg, oxidative stress, excitotoxicity, deoxyribonucleic acid [DNA] damage) increases cytosolic calcium and oxidative radicals and activates nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), leading to the formation of poly(ADP-ribose) (PAR)
●This leads to decreased mitochondrial membrane potential, which in turn opens mitochondrial permeability transition pores (PTP)
●Release of nicotinamide adenine dinucleotide (NAD+) through the PTP leads to NAD+ depletion
●Release of mitochondrial apoptosis-initiating factors promotes release of cytochrome c, which leads to activation of the "executioner" enzyme caspase and to apoptosis
Mitochondrial toxicity in PD has been modeled in mice using the lipophilic pesticide, rotenone, which is a potent inhibitor of mitochondrial complex I [144]. The rotenone model provides support for the theory that neurodegeneration results from an interaction between environmental exposure and mitochondrial dysfunction.
Further evidence for the role of mitochondria in the pathogenesis of PD is provided by the increasing number of genes (such as PINK1) coding for mitochondrial proteins and implicated in cellular protection against oxidative damage, which have been associated with the PD phenotype [145,146]. (See 'PINK1-associated PD' below.)
Oxidative stress — The oxidative stress hypothesis postulates that inappropriate production of reactive oxygen species leads to neurodegeneration [140,147]. Dopamine is normally metabolized not only by monoamine oxidase-mediated enzymatic oxidation but also by auto-oxidation to neuromelanin.
Intraneuronal neuromelanin appears to have a dual role [148]. First, it may be neuroprotective, preventing toxic accumulation of metabolites of catechol amines and scavenging reactive metals, pesticides, and other oxidants. Second, dying neurons may release neuromelanin, leading to chronic inflammation.
These metabolic pathways generate byproducts, including hydrogen peroxide, superoxide anions, and hydroxyradicals. Free radicals, through interaction with membrane lipids, cause toxic lipid peroxidation, which has been found to be increased in the substantia nigra of PD brains. The oxidative products may cause neurotoxicity and, therefore, may play an important role in the development of PD.
It is possible that increased oxidative stress also contributes to misfolding of proteins. This notion is supported by the finding that nitric oxide, a free radical increased in the brains of patients with PD, attacks disulfide isomerase, an aggregation-preventing chaperone protein localized to the endoplasmic reticulum and normally responsible for unfolding and transport of proteins [149].
Iron metabolism — Elemental iron plays a critical role in oxidative metabolism, and it also serves as a cofactor in the synthesis of neurotransmitters [150]. It is increased by approximately 50 percent in the substantia nigra of PD brains relative to controls [151], suggesting that abnormal iron metabolism plays a pathologic role in the development of PD [152].
One study found that mice lacking the tau protein developed parkinsonism due to toxic iron accumulation and neuronal loss in the substantia nigra [153]. In addition, loss of tau in neuronal culture caused intracellular iron retention. Brain-permeable iron chelators prevent experimentally induced degeneration of nigrostriatal dopamine neurons [153,154]. However, in a randomized trial of 372 patients with newly diagnosed PD, deferiprone (an iron chelator) resulted in more rapid symptomatic progression and worsened functional scores compared with placebo despite decreasing nigrostriatal iron content by MRI [155].
Immunologic and inflammatory mechanisms — Immunologic mechanisms have been implicated in the pathogenesis of PD [156,157]. Supporting evidence comes from the finding of elevated levels of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin-1 beta, and interferon-gamma in patients with PD.
The role of inflammatory processes in the pathogenesis of PD is further supported by the following observations:
●Cyclooxygenase-2, the rate-limiting enzyme in prostaglandin E2 synthesis, appears to be upregulated in patients with PD and in the MPTP mouse model of PD; cyclooxygenase-2 inhibition prevents the formation of potentially toxic dopamine-quinones in MPTP mice and presumably in patients with PD [158].
●In a positron emission tomography (PET) study that used markers for activated microglia and for dopamine transporter, microglial activity in patients with PD correlated with decreased density of dopamine transporter [159].
●Infiltration of CD4+ T lymphocytes contributed to neuronal cell death in a mouse model of PD [160].
Mechanisms of cell death — Irrespective of the initial trigger (etiology) of neuronal degeneration in PD, the pathogenesis of neurodegeneration probably involves either programmed cell death (apoptosis) or necrosis [1,161-163].
Apoptosis is characterized by condensation of cytoplasm and chromatin, DNA fragmentation, and cell fragmentation into apoptotic bodies, followed by lysosome-mediated phagocytosis. The other mechanism of cell death, called autophagy, is characterized by accumulation of autophagic vesicles (autophagosomes and autophagolysosomes) and also plays an important role in neurodegeneration in PD [164].
It has been suggested that only 0.5 percent of substantia nigra neurons in otherwise healthy brains are undergoing apoptosis, but this number is increased fourfold to 2 percent in those with PD. Some experimental models of PD suggest that apoptosis is the primary mechanism of substantia nigra neuronal degeneration in PD, but convincing evidence from careful neuropathologic studies is lacking [165,166].
Although the precise mechanisms of neurodegeneration in PD are not yet understood, they most likely involve a cascade of events that include interaction between genetic and environmental factors and abnormalities in protein processing, oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammation, immune regulation, glial-specific factors, lack of trophic factors, and other, as-yet unknown, mechanisms (figure 3 and figure 4).
One of the hypotheses is that neurodegeneration in PD is due to disruption of intracellular vesicular transport as a result of destabilizing of microtubules [167]. Another area of interest is the role of astrocytes in various neurodegenerative disorders [168].
Another hypothesis is that PD arises from an early environmental exposure that increases vulnerability to dopaminergic cell loss later in life. As an example, it is possible that prenatal or early postnatal exposure to certain dopaminergic neuronal toxins, such as the MPTP-like herbicide paraquat and the manganese-containing fungicide maneb, may reduce the number of dopamine neurons in the substantia nigra in early development and enhance vulnerability to these toxins when individuals are subsequently exposed in adulthood [169]. This is consistent with the so-called "multiple-hit hypothesis."
GENETICS — Although the majority of cases of PD appear to be sporadic, there is increasing evidence that genetic factors play a role in the pathogenesis of PD, particularly when the age at symptom onset is younger than 50 years [170-172].
Monogenic forms of PD — Familial forms of parkinsonism have historically been designated numerically (eg, PARK1 through PARK23) based on their order of phenotypic description and chromosomal localization. Autosomal dominant, autosomal recessive, and possible X-linked forms of PD have been identified. As the number of monogenic causes of parkinsonism has rapidly expanded, a classification based on clinical phenotype and the causative gene variant (eg, PARK-SNCA) is replacing the older numeric PARK designations [173,174].
The reported frequency of monogenic forms of PD varies considerably across studies, depending on the genes tested, the racial and ethnic background of the cohort, and age at disease onset. In a population-based cohort in the United Kingdom that included analysis of four genes (PRKN, PINK1, LRRK2, and SNCA) in over 2000 patients with PD, monogenic forms of PD accounted for 1.4 percent of all PD cases and approximately 3 percent of young-onset PD (≤50 years old at onset) [175]. In a multicenter cross-sectional study of 953 patients with young-onset PD that included analysis of six relevant genes (including glucocerebrosidase), the mutation carrier frequency was 17 percent [176].
Several of the most important monogenic forms of PD are discussed in greater detail in the following sections.
SNCA-associated PD — SNCA gene missense mutations (PARK1) or multiplications (PARK4) are rare causes of autosomal dominant parkinsonism [177]. The phenotype varies from classic PD to dementia with Lewy bodies (DLB) [178-180].
The mechanism of SNCA-associated neurodegeneration is not yet fully understood but is probably due to a toxic gain-of-function effect [178]. As discussed above, there is evidence that impaired processing of alpha-synuclein leads to abnormal protein aggregation and misfolding, Lewy body formation, cellular oxidative stress, and energy depletion. (See 'Alpha-synuclein misfolding, aggregation, and toxicity' above.)
The SNCA gene was the first to be associated with parkinsonism when a genome scan in the Greek-Italian Contursi kindred identified a genetic marker on chromosome 4q21-q23 linked to the PD phenotype [181]. This finding led to the discovery of a mutation in the single base pair (Ala53Thr) of the SNCA gene, designated PARK1 in the hierarchy of genetic forms of PD [181,182].
In the Contursi kindred, the clinical features of the disease are similar to otherwise typical PD, except for younger age at onset (mean 46 years), greater cognitive decline, and more rapid progression, with a mean time from onset to death of nine years [183-185]. The pattern of nigrostriatal degeneration with preservation of D2 receptors, as demonstrated by positron emission tomography (PET), is similar to that seen in sporadic PD.
Subsequently, a second pathogenic variant in the SNCA gene involving an alanine-for-proline substitution at amino acid 30 (Ala30Pro) was found in a German family [179], and a third variant involving a glutamic acid-to-lysine substitution at position 46 (E46K) was identified in a Spanish family [180].
With reports of additional families, the phenotype of PARK1 has expanded to include not only typical PD features but also dementia, hallucinations, central hypoventilation, orthostatic hypotension, myoclonus, and urinary incontinence, with pathologic involvement of the brainstem pigmented nuclei, hippocampus, and temporal neocortex. Thus, the clinical and pathologic features of families with SNCA pathogenic variants and parkinsonism overlap the features of multiple system atrophy and DLB.
Similarly, overexpression of SNCA may lead to neurodegenerative disease with features that overlap those of PD, DLB, and multiple system atrophy, as observed in families with parkinsonism and whole-gene duplication or triplication of SNCA [186]. Duplication of SNCA appears to be associated with late-onset parkinsonism and dysautonomia, while triplication (designated PARK4) leads to early-onset PD and dementia [187]. SNCA triplication was found in one large family with autosomal dominant, young-onset parkinsonism, dysautonomia, cardiac denervation, DLB, and glial cytoplasmic inclusions at autopsy, features typical of multiple system atrophy [188].
Mounting evidence supports the role of common SNCA polymorphisms in sporadic PD [189-192]. In particular, several large genome-wide association studies (GWAS) in PD found that SNCA was a risk locus for PD [191-194].
LRRK2-associated PD — The most common form of monogenic PD is PARK8, caused by variants in the LRRK2 gene on chromosome 12p11.2-q13.1 [195,196].
The LRRK2 gene product is a protein called dardarin (from the Basque word "dardara," meaning tremor) that probably functions as a cytoplasmic kinase involved in phosphorylation of proteins, such as alpha-synuclein and microtubule-associated protein tau [197-199]. Dardarin is a large molecule, encoded by 51 exons and containing 2527 amino acids. This contrasts with the much smaller alpha-synuclein protein, which contains 140 amino acids.
Dardarin is closely associated with a variety of membrane and vesicular structures, membrane-bound organelles, and microtubules, suggesting its role in vesicular transport and in membrane and protein turnover, including lysosomal degradation pathway.
LRRK2-associated PD may account for a significant proportion of familial PD cases and a smaller proportion of sporadic PD cases. It is estimated to cause up to 8 percent of autosomal dominant PD in the Basque population and up to 50 percent of familial PD in people of North African and Middle Eastern origin [198,200-203]. In addition, LRRK2 variants have been found in 0.4 to 1.9 percent of patients with idiopathic PD [204-208], although such cases could also be explained by reduced penetrance in familial disease [201].
Genetic screening studies suggest that the G2019S mutation, the most common of the LRRK2 pathogenic variants, accounts for 3 to 13 percent of autosomal dominant PD in Europe [177,202,209-211] and 10 to 18 percent of autosomal dominant PD in Ashkenazi Jews [203,212]. The G2019S variant has also been identified in asymptomatic carriers, suggesting reduced or age-dependent penetrance [201,210]. Evidence of age-dependent penetrance was found in a study of 19 families with the G2019S variant, in whom the cumulative incidence of PD at ages 60, 70, and 80 years was 15, 21, and 32 percent, respectively [213].
The LRRK2-associated PD phenotype is often, but not always, associated with late-onset (mean age 65 years) disease [199,210,214-216]. However, the typical features of PD associated with LRRK2 G2019S variants are indistinguishable from idiopathic PD [185,208]. The course of the disease is relatively benign, usually presenting with unilateral hand or leg tremor without cognitive deficit. Patients respond well to levodopa and have a slower decline in motor function compared with patients without an LRRK2 mutation [217]. Several studies have suggested that patients with LRRK2-associated PD may have an increased risk of certain types of cancer compared with idiopathic PD and healthy controls, such as leukemia, colon cancer, and possibly breast cancer [218-221].
Other clinical phenotypes associated with LRRK2 variants have included parkinsonism with dementia or amyotrophy or both, typical essential tremor, dysautonomia, familial progressive supranuclear palsy, familial multiple system atrophy, corticobasal degeneration, and primary progressive aphasia [222,223].
Autopsy findings in patients with LRRK2-associated PD are heterogeneous and range from pure nigral degeneration without Lewy bodies to pathology consistent with typical PD, diffuse Lewy body disease, and neurofibrillary tangle and other tau pathology [222,224,225].
PRKN-associated PD — Patients with PD due to biallelic parkin (PRKN) pathogenic variants (PARK2) usually have a family history consistent with autosomal recessive inheritance. The disease is characterized by early onset of symptoms (before age 50), a slowly progressive course, a symmetric presentation at onset of parkinsonian signs and symptoms (unlike classic PD, which is asymmetric), and early dystonia and postural instability. Additional features include leg tremor, freezing, festination, retropulsion, hyperreflexia, sensory axonal neuropathy, and autonomic involvement [226-229]. Dementia is uncommon [230]. However, on an individual basis, patients with early-onset PD who have PRKN variants are clinically indistinguishable from those with early-onset PD who lack PRKN variants [231].
There is typically a good response to levodopa with early development of motor fluctuations and dyskinesia. Fluorodopa PET shows a marked reduction in the fluorodopa uptake, similar to idiopathic PD, but asymptomatic carriers may also have abnormal PET studies [232].
Parkin, the protein product of the PRKN gene, is expressed in the substantia nigra and other brain regions, as well as in Lewy bodies. Normal parkin strongly binds to microtubules and is involved in ubiquitination and subsequent degradation of certain proteins by proteasomes [167,233]. However, mutated parkin protein loses this proteasome-enhancing activity, and the result is a hastening of neuronal cell death because the disabled proteasome cannot clear the cell of accumulating aggregated protein. Neurodegeneration associated with the parkin mutation is not usually accompanied by formation of Lewy bodies, although there are exceptions [234].
Over 180 variants and polymorphisms have been identified in the PRKN gene [230]. However, it is not clear which of these changes leads to functional deficits. Several studies have demonstrated that heterozygous PRKN variants in the general population are not associated with increased risk of PD [235-238].
The incomplete penetrance and variability of clinical and pathologic expression of PRKN-associated PD may be due to an interaction between the PRKN gene and other genes, including SNCA [239].
PINK1-associated PD — Biallelic variants in the mitochondrial PINK1 gene (PARK6) are associated with autosomal recessive familial PD. Most patients are younger than 50 years of age at onset, have a slowly progressive course, and have an excellent response to levodopa [240-242], similar to patients with PRKN and DJ-1 variants. PINK1 variants have been found worldwide with a frequency that ranges from 1 to 8 percent of patients, most of whom had early-onset and/or familial PD [178,241,243-245].
Postmortem brain examinations of patients with PINK1-associated PD are limited to a few cases. One showed Lewy body pathology in the brainstem and Meynert nucleus, while the locus ceruleus and the amygdala were spared [246]; another case revealed nigral degeneration without Lewy bodies [247].
PINK1 variants may cause disease through a loss-of-function effect resulting in mitochondrial dysfunction [248,249].
DJ-1-associated PD — Biallelic variants in the mitochondrial DJ-1 gene (PARK7) are associated with autosomal recessive inheritance, age younger than 40 at onset, slow progression, and good response to levodopa [250,251]. Wildtype DJ-1 is thought to be neuroprotective against oxidative stress.
Others — Additional monogenic forms of parkinsonism are classified by the predominant phenotype and the specific gene variant [173,174]. An updated list of genetically determined movement disorders is available on the International Parkinson and Movement Disorder Society (MDS) website.
Risk alleles — Numerous candidate risk alleles associated with increased risk of PD have been identified through GWAS and other population screening efforts. In addition to the gene discussed below, common variants in the SNCA gene may also function as risk alleles, distinct from rare, disease-causing variants. (See 'SNCA-associated PD' above.)
Glucocerebrosidase gene — Heterozygous pathogenic variants in the glucocerebrosidase 1 (GBA1) gene, which when homozygous are the cause of Gaucher disease, are an important genetic risk factor for PD [1,252-255].
Across various populations, the risk of PD among GBA1 variant carriers is increased two- to sevenfold over noncarriers [252,256-259]. The estimated penetrance of heterozygous GBA1 variants for PD over a lifetime varies fairly widely, from approximately 10 to 30 percent depending on the population studied [260-264]. Genotype-phenotype relationships have not been well established, but GBA1 variant carriers as a group appear to have more cognitive decline compared with patients with idiopathic PD.
Alterations in GBA1 were initially linked with PD and other movement disorders in people of Ashkenazi Jewish decent, who have an increased prevalence of GBA1 pathogenic variants [265]. One of the largest studies analyzed data from 16 centers around the world, including 5691 patients with PD and 4898 controls [252]. All centers screened for two relatively frequent GBA1 pathogenic variants (N370S and L444P). Compared with controls, either GBA1 variant was more common in patients with PD, both among Ashkenazi Jewish subjects (15 percent, versus 3 percent of controls) and among non-Ashkenazi Jewish subjects (3 percent, versus <1 percent of controls). Overall, the likelihood of finding any GBA1 pathogenic variant was significantly higher in patients with PD than in controls (odds ratio 5.43, 95% CI 3.89-7.57).
Among all patients with PD, the clinical profile was generally similar. However, when compared with patients who had PD but lacked a GBA1 pathogenic variant, those with PD who carried a GBA1 variant were significantly more likely to have the following features [252]:
●Younger age at onset
●Less prominent tremor, bradykinesia, and rigidity
●Lower frequency of asymmetric onset
●Higher frequency of a family history of PD
●Greater likelihood of cognitive impairment
Other reports have also found that patients with PD who are GBA1 pathogenic variant carriers have a younger age at onset, faster motor progression, and an increased prevalence of cognitive dysfunction compared with noncarriers [265-271].
Other lysosomal genes — There is emerging evidence that variants in other lysosomal enzyme-encoding genes also affect PD risk through effects on alpha-synuclein [272-275]. For example, several genetic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, the gene associated with Niemann-Pick type A, have been identified with increased prevalence in patients of Ashkenazi Jewish ancestry (and other populations) with PD compared with controls [276-279]. Furthermore, experimentally, SMPD1 knockdown results in alpha-synuclein accumulation [276].
Genetic testing — The role of clinical genetic testing in patients with PD is discussed separately. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Role of genetic testing'.)
BIOMARKERS — In the absence of a confirmatory diagnostic test, the clinical diagnosis of PD is made by history and neurologic examination, supplemented by striatal dopamine transporter imaging (DaTscan) in some cases. Structural MRI is used primarily to rule out rare, unexpected mimics of PD. (See "Diagnosis and differential diagnosis of Parkinson disease".)
There are a variety of biomarker techniques that are emerging as potential diagnostic tests for PD and other synucleinopathies. The two most investigated techniques are skin biopsy (using immunofluorescence to detect phosphorylated alpha-synuclein in skin nerve fibers) and real-time quaking-induced conversion assay (RT-QuIC, also known as protein misfolding cyclic amplification [PMCA]) to identify abnormal clusters of alpha-synuclein in blood, cerebrospinal fluid (CSF), and/or skin. These tests have been found to have a high sensitivity and specificity for the diagnosis of alpha-synuclein neurodegenerative disease [280-282]. For the most part, however, they do not distinguish between PD and other synucleinopathies and are not yet used for clinical diagnostic purposes.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Parkinson disease (The Basics)")
●Beyond the Basics topics (see "Patient education: Parkinson disease symptoms and diagnosis (Beyond the Basics)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Parkinson disease".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Parkinson disease (PD) is one of the most common neurodegenerative diseases of adulthood and a major cause of neurologic morbidity and mortality worldwide. It is estimated to affect 0.3 percent of the adult population 40 years of age and older. (See 'Incidence and prevalence' above.)
The incidence of PD rises steadily with age starting in the fifth decade and is higher in males, particularly between the ages of 50 and 60 years. Caffeine intake, physical activity, and cigarette smoking are consistently associated with lower risk of PD. Evidence linking PD with a variety of environmental exposures (eg, air pollution, pesticides, metals) is inconclusive. (See 'Risk factors' above and 'Protective factors' above.)
●Pathophysiology – The clinical features of PD (ie, bradykinesia, rigidity, and tremor) arise due to progressive degeneration of dopamine-producing neurons in the basal ganglia, including the substantia nigra in the midbrain (figure 1). Dopamine depletion accounts for the emergence of the classic motor phenotype as well as a wide range of nonmotor and neuropsychiatric manifestations that affect function and quality of life. (See 'Basal ganglia circuits' above.)
●Pathologic hallmarks – The brains of patients with PD show depigmentation (from loss of neuromelanin), neuronal loss, and gliosis, particularly in the substantia nigra pars compacta (SNc) and in the pontine locus ceruleus. These same areas are populated by Lewy bodies, which are round, eosinophilic, intracytoplasmic inclusions in the nuclei of neurons that stain positive for alpha-synuclein protein. (See 'Pathology' above.)
●Pathogenesis – The precise mechanisms of neurodegeneration in PD are not yet understood, but they most likely involve a cascade of events that include interaction between genetic and environmental factors and abnormalities in protein processing, oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammation, immune regulation, and other mechanisms (figure 3 and figure 4). (See 'Pathogenesis of cell degeneration' above.)
●Genetics – Although the majority of cases of PD appear to be sporadic, there are monogenic forms of parkinsonism (designated PARK1 through PARK23) related to nuclear and mitochondrial genes. (See 'Monogenic forms of PD' above.)
Heterozygous pathogenic variants in the GBA1 gene, which when homozygous are the cause of Gaucher disease, are the best characterized risk allele among patients with apparently sporadic PD. Other lysosomal genes have also been implicated as risk alleles. (See 'Risk alleles' above.)
