Parkinson’s disease (PD) is characterized by the progressive degeneration of dopamine (DA) neurons in the substantia nigra (SN) and the development of Lewy bodies within affected dopaminergic cells in the SN, cerebral cortex, and brainstem. PD occurs in about 1% of older adults over age 55 years (Cowen, 2012) and the age of onset is typically between 55-75 years (Jankovic, 2008). The etiology is thought to be idiopathic, although “sporadic PD” is a term used to describe PD associated with genetic polymorphisms and autosomal inheritance. It is also worth noting that an adverse reaction of antipsychotic medications include extrapyramidal side effects, which mimic parkinsonian symptoms secondary to the blockade of DA neurons.
The cardinal clinical features of PD are the movement symptoms. This is due to impaired SN projections to the striatum of the basal ganglia, which is the pathway responsible for voluntary movement. These symptoms can be categorized under the acronym “TRAP,” which include Tremors at rest, Rigidity, Akinesia (bradykinesia), and Postural instability (Jankovic, 2008). Other clinical features are secondary motor symptoms, (i.e. shuffling gait, dystonia, and dysphagia) and non-motor symptoms (i.e. autonomic dysfunction, neurobehavioral and sensory abnormalities, and pain). These symptoms manifest when “50-70% of nigrostriatal DA neurons have been lost,” (Lesage, 2009), indicating a significant period of pre-symptomatic PD between onset and the physical appearance of symptoms. However, no definitive diagnostics tests are available to test for PD before noticeable impairment.
One common early feature of PD that can predate noticeable motor symptoms by at least 4 years is olfactory deficits (Ross, 2008). The pathogenesis is unknown, but thought to be due to Lewy body formation in the olfactory structures, as well as impaired olfactory neurogenesis. Precursor olfactory cells originate in the subventricular zone between the striatum and lateral ventricle and are downregulated by the nigrostriatal lesions of PD. REM sleep behavior disorder also precedes motor symptoms and is considered a “risk factor for the development of PD” (Jankovic, 2008). It occurs in 1/3 of PD patients and is characterized by violent dream content and “potentially injurious motor activity, such as kicking and punching (Jankovic, 2008). Studies have linked the sleep abnormalities observed in PD to a 50% loss of orexin neurons, which also occurs in narcolepsy (Thannickal, 2007).
Contributing risk factors for idiopathic PD include age, environmental toxins, and oxidative stress that cause genetic mutations. Exogenous toxins was first linked to PD in the early 1980s, when substance abusers using a synthetic narcotic succumbed to a disabling parkinsinism due to the dangerous compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This discovery led to the experimental use of MPTP in animal models to produce nigrostriatal degeneration and has since enhanced our understanding the gene-toxin interactions in PD. The effects of MPTP are age-dependent, which suggests the incidence of PD may increases over time due to synergistic effects of toxins (Di Monte, 2002). Further research shows that toxins such as specific pesticides and bacteriotoxins cause an inflammatory response that may be involved in the progression of PD. More specifically, one study found that rats exposed to lipopolysaccharide, a bacteriotoxin, in utero, had increased concentrations of cytokine tumor necrosis factor alpha, a pro-inflammatory marker, and decreased DA concentrations in the striatum secondary to a 25% decrease in tyrosine, the precursor of DA (Di Monte, 2003). Another study showed that mice exposed to herbicides had an upregulation of the protein alpha-synuclein, a component of Lewy bodies (Di Monte, 2003). These studies illustrate the effects of exogenous factors on pathology.
PD is also marked by neuropsychiatric sequela that include cognitive impairment, depression, psychosis, and impulse control disorders.
Patients diagnosed with PD are twice as likely to develop mild cognitive impairment (MCI) and between 20-57% of people with PD experience MCI symptoms in the first 5 years of diagnosis (Kehagia, 2010). Moreover, studies show that the severity of the deficits may predict the progression of cognitive dysfunction and dementia in people with PD (Kehagia, 2010). Cognitive impairments early in PD include symptoms of dysexecutive syndrome, which involves difficulties with the executive functioning tasks of planning, working memory, organization, and behavioral regulation (Kehagia, 2010). These cognitive symptoms are associated with pathological changes in the fronto-striatal and mesocortical dopaminergic pathways. This latter pathway connects to the prefrontal cortex and is involved in attention and cognition (Higgins, 2013). Dementia in PD is diagnosed if the dementia begins “more than 12 months after the onset of Parkinsonism” (Cowen, 2012) and occurs in up to 40% of people with PD (Cowen, 2012). As PD is considered to be “part of the spectrum of Lewy body disease” (Cowen, 2012), dementia in PD is similar to Lewy Body dementia in that alpha-synuclein proteins found in the nigral, limbic, brainstem, and neocortical regions may lead to a fluctuating course of dementia with recurrent perceptual disturbances and hallucinations (Cowen, 2012).
Depression symptoms are common in early and advanced PD and appear in 30-40% of the PD population. The diagnosis of co-morbid depression is complicated due to overlapping symptoms with PD, such as loss of energy, reduced memory, psychomotor retardation, and altered sleep (Arsland, 2009). It is understood that the pathogenesis of depression in PD is due to decreased norepinephrine and DA release from brain stem regions that innervate limbic circuits involved in emotional processing. Depression has also been linked to changes in the amygdala, a key structure in emotional regulation. One postmortem study identified Lewy bodies in the amygdala of patients with PD and the authors concluded that up to 20% of PD patients may have a reduced amygdala volume (Remy, 2005).
Psychosis, particularly visual hallucinations, occurs in up to 37% of people with PD and are associated with dopamine agonist medications, older age, severity of disease, depression, cognitive impairment, dementia, and reduced visual acuity (Cowen, 2012). Often the visual hallucinations are marked by the perception of “seeing a figure in a shadow or mistaking one object or person for another” (Friedman, 2010). Pathologically, psychotic symptoms in PD appear to be due to impairments in cholinergic projections that modify sensory input to the visual cortex and the presence of Lewy bodies in the temporal lobe, which is the site of visual memory processing (Manganelli, 2009; Friedman, 2010). It has also been hypothesized that visual hallucinations can be attributed to REM phenomena and sleep disturbance in PD (Friedman, 2010).
Lastly, impulse control disorder in PD is found to be a function of an overdose of dopaminergic medications. When this occurs, patients experience a marked increase in impulsivity, characterized by behaviors such as, “cravings, binge eating, compulsive foraging, hypersexuality, pathological gambling, and compulsive shopping” (Jankovic, 2008). These behaviors are maintained by over-stimulation of the dopamine receptors concentrated in the mesolimbic regions, the structures involved in underlying motivation and reward anticipation. This adverse effect is compounded by reduced negative feedback inhibition secondary to the impairment of the prefrontal cortex-ventral striatal circuitry in PD and subsequent reduced executive functioning.
Aarsland D, Marsh L, and Schrag A (2009). Neuropsychiatric symptoms in Parkinson’s disease. Movement Disorders, 24, 2175-86.
Cowen, P., Harrison, P., Burns, T. (2012). Shorter Oxford Textbook of Psychiatry. Oxford: Oxford University Press.
Di Monte DA, Lavasani M, Manning-Bog AB (2002). Environmental factors in Parkinson’s disease. Neurotoxicology, 23: 487–502
Di Monte DA (2003). The environment and Parkinson’s disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurology, 2, 531-8.
Friedman JH (2010) Parkinson’s disease psychosis 2010: a review article. Parkinsonism and Related Disorders, 16, 553-60.
Jankovic, J. (2008). Parkinson’s disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery, and Psychiatry, 79, 368-76.
Higgins, E.S., George, M.S. (2013). The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness. Philadelphia: Lippincott Williams & Wilkins.
Kehagia AA, Barker RA, and Robbins TW (2010). Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson’s disease. Lancet Neurology, 9, 1200-13.
Lesage, S., & Brice, A. (2009). Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Human Molecular Genetics, 18, R48-R59.
Manganelli F, Vitale C, Santangelo G, Pisciotta C, Iodice R, Cozzolino A, et al. Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson’s disease. Brain 2009; 132:2350-5.
Remy, P., Doder, M., Lees, A., Turjanski, N., & Brooks, D. (2005). Depression in parkinson’s disease: Loss of dopamine and noradrenaline innervation in the limbic system. Brain : A Journal of Neurology, 128, 1314-1322.
Ross GW et al. (2008). Association of olfactory dysfunction with risk for future Parkinson’s disease. Annals of Neurology, 63, 167-73.
Thannickal, T. C., Lai, Y., & Siegel, J. M. (2007). Hypocretin (orexin) cell loss in parkinson’s disease. Brain, 130, 1586-1595.