Approach Considerations
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic resonance imaging (MRI) and computed tomography (CT) scan are unremarkable. Positron emission tomography (PET) and single-photon emission CT (SPECT) may show findings consistent with Parkinson disease, and olfactory testing may provide evidence pointing toward Parkinson disease, but these studies are not routinely needed. (Olfactory testing can reveal hyposmia, which may precede the motor signs of Parkinson disease by several years. [37] However, olfactory loss is not specific and can also occur in Alzheimer disease.)
No laboratory or imaging study is required in patients with a typical presentation. Such patients are aged 55 years or older and have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity. Patients who do not have tremor should generally be considered for MRI evaluation to exclude brain lesions such as stroke, tumor, or demyelination.
In patients with an unusual presentation, diagnostic testing may be indicated to exclude other disorders in the differential diagnosis. Such tests may include serum ceruloplasmin, sphincter electromyography, or lumbar puncture.
Serum ceruloplasmin concentration is obtained as a screening test for Wilson disease in patients younger than 40 years who present with parkinsonian signs. If the ceruloplasmin level is low, measurement of 24-hour urinary copper excretion and slit-lamp examination for Kayser-Fleischer rings must be performed. Abnormal results on urinary sphincter electromyography have been noted in patients with multiple system atrophy (MSA).
A substantial and sustained response to dopamine medications (dopamine agonists or levodopa) helps confirm a diagnosis of Parkinson disease. It is unclear whether acute levodopa or apomorphine challenge has any advantage over clinical diagnostic criteria. [22] Over time, diagnostic accuracy improves as the progression of signs and symptoms and response to medications unfolds.
In the general community, there is a high diagnosis error rate between Parkinson disease and essential tremor. For movement disorder neurologists, when an erroneous diagnosis of Parkinson disease is made, the most likely correct diagnoses are the atypical parkinsonisms (MSA, progressive supranuclear palsy [PSP], corticobasal ganglionic degeneration [CBD]). Early in the disease course, it may be very difficult to distinguish between Parkinson disease and the atypical parkinsonisms. These disorders also do not have laboratory biomarkers, and, therefore, distinguishing among them is based on clinical criteria. Olfactory testing may help differentiate Parkinson disease from PSP and CBD, but olfaction is also reduced in MSA.
Radiologic Studies
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is useful to exclude strokes, tumors, multi-infarct state, hydrocephalus, and the lesions of Wilson disease. MRI should be obtained in patients whose clinical presentation does not allow a high degree of diagnostic certainty, including those who lack tremor, have an acute or stepwise progression, or are younger than 55 years.
The following MRI indicates where a thalamic stimulator is typically placed.
Axial, fast spin-echo inversion recovery magnetic resonance image at the level of the posterior commissure. The typical target for placing a thalamic stimulator is demonstrated (cross-hairs).
Below is a coronal MRI following bilateral subthalamic nuclei deep brain stimulation.
Postoperative coronal magnetic resonance image (MRI) demonstrating desired placement of bilateral subthalamic nuclei-deep brain stimulation (STN-DBS) leads.
PET and SPECT scanning
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scanning are useful diagnostic imaging studies, but these are not routinely required. Different radioligands permit imaging of different components or abnormalities within the brain.
At the onset of motor signs, patients with Parkinson disease show an approximately 30% decrease in 18F-dopa (Fluorodopa F18) uptake on PET imaging in the contralateral putamen.18F-Dopa is taken up by the terminals of dopamine neurons and converted to 18F-dopamine. The rate of striatal 18F accumulation reflects transport of 18F-dopa into dopamine neurons and its decarboxylation to 18F-dopamine, which is stored in dopamine nerve terminals in the striatum. Thus,18F-dopa PET imaging provides an index of remaining dopamine neurons. Fluorodopa F18 (fluorodeoxyphenylalanine 18F-DOPA) was approved by the FDA in October 2019 and is indicated with PET to visualize dopaminergic nerve terminals in the striatum to evaluate adults with suspected Parkinsonian syndromes. [38]
Carbon-11 (11C)-nomifensine and cocaine analogues such as 123I-beta-CIT (iodine-123-labeled carboxymethoxy-3beta-4-iodophenyl-nortropane) and 123I-FP-CIT (fluoropropyl-CIT) bind to dopamine reuptake sites on nigrostriatal terminals and provide an index of the remaining dopamine neurons. Ioflupane (12 I) (DaTscan) is a radiopharmaceutical agent that is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adults with suspected Parkinsonian syndromes (PSs). This agent may be used to help differentiate essential tremor from tremor due to PSs (idiopathic Parkinson disease [IPD] and Parkinson-plus syndromes [PPS]). [1] Analysis of data from 2 clinical trials demonstrated that the use of ioflupane with iodine-123 and single-photon emission computed tomography (SPECT) scanning to diagnose early-stage Parkinson's disease performed as well as clinical assessment at 1-year follow-up. [39, 40]
Deficits on 123I SPECT scans indicate a dopamine deficiency syndrome but do not differentiate Parkinson disease from atypical parkinsonisms, including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Ioflupane SPECT imaging reveals a dopamine deficiency in Parkinson disease, MSA, PSP, corticobasal ganglionic degeneration, and Lewy body disease. This study is normal in essential tremor, dystonic tremor, medication-induced parkinsonism or tremor, psychogenic disorders, and in normal individuals.
Histologic Findings
Classic pathologic findings in Parkinson disease include degeneration of the neurons containing neuromelanin, especially in the substantia nigra and the locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic inclusions called Lewy bodies (see the following image). The primary biochemical defects are loss of striatal dopamine, which results from degeneration of dopamine-producing cells in the substantia nigra, as well as hyperactivity of the cholinergic neurons in the caudate nucleus.
Lewy bodies are intracytoplasmic eosinophilic inclusions, often with halos, that are easily seen in pigmented neurons, as shown in this histologic slide. They contain polymerized alpha-synuclein; therefore, Parkinson disease is a synucleinopathy.
Alpha-synuclein is a major structural component of Lewy bodies; all Lewy bodies stain for alpha-synuclein, and most also stain for ubiquitin. Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and dense cores. The presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic, but not pathognomonic, of Parkinson disease. Lewy bodies are also found in the cortex, nucleus basalis, locus ceruleus, intermediolateral column of the spinal cord, and other areas.
According to the Braak hypothesis, Lewy body pathology in the brain begins in the olfactory bulb and lower brainstem and slowly ascends to affect dopamine neurons in the substantia nigra and, ultimately, the cerebral cortex. [41] Lewy body pathology is also observed in autonomic nerves of the gut and heart.
Lumbar Puncture
Lumbar puncture should be considered if signs of normal-pressure hydrocephalus (NPH) are observed (eg, incontinence, ataxia, dementia). In NPH, clinical signs characteristically improve after removal of about 20 mL of cerebrospinal fluid.
Dopa-responsive dystonia should be considered in patients with juvenile-onset dystonia and parkinsonism, particularly with diurnal fluctuations in symptoms. In such patients, a trial of levodopa is critical. Additional tests for this condition include measurement of CSF concentrations of biopterin, neopterin, and the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). In both forms of dopa-responsive dystonia, an altered pattern of decreases in these compounds is observed.
In the "Parkinson's Progression Markers Initiative" cross-sectional study of 63 drug-naive patients with early-stage PD and 39 healthy controls, CSF levels of the Alzheimer's biomarkers β-amyloid 1-42 (Aβ1-42), total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and α-synuclein were lower in the PD patients than in the controls. Aβ1-42 and P-tau181 were significant predictors of Parkinson's disease, and T-tau and α-synuclein were associated with the severity of motor dysfunction. In particular, lower Aβ1-42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant PD phenotype, but were not associated with the tremor-dominant or intermediate phenotypes. [42, 43]
See Lumbar Puncture for detailed information on indications for the procedure, contraindications, and a step-by-step discussion containing images and video on how to perform the procedure.
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Schematic representation of the basal ganglia - thalamocortical motor circuit and its neurotransmitters in the normal state. From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson disease and movement disorders. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:240. Copyright, McGraw-Hill Companies, Inc. Used with permission.
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Schematic representation of the basal ganglia - thalamocortical motor circuit and the relative change in neuronal activity in Parkinson disease. From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson disease and movement disorders. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:241. Used with kind permission. Copyright, McGraw-Hill Companies, Inc.
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Parkinson disease diary. The patient or caregiver should place 1 check mark in each half-hour time slot to indicate the patient's predominant response during most of that period. The goal of therapeutic management is to minimize off time and on time with troublesome dyskinesia. Copyright Robert Hauser, 1996. Used with permission.
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Stages in the development of Parkinson disease (PD)-related pathology (path.). Adapted from Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004 Oct;318(1):121-34.
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Schematic diagram of the basal ganglia circuitry. Represented are the following: inhibitory (red arrows) and excitatory (green arrows) projections between the motor cortex, the putamen, the globus pallidus pars externa (GPe) and globus pallidus pars interna (GPi), the subthalamic nucleus (STN), the substantia nigra pars reticulata (SNr) and substantia nigra pars compacta (SNc), and the ventrolateral thalamus (VL). D1 and D2 indicate the direct (regulated by dopamine D1 receptors) and indirect (regulated by dopamine D2 receptors) pathways, respectively.
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Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN) (lavender). The STN is one of the preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease.
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The deep brain stimulating lead is equipped with 4 electrode contacts, each of which may be used, alone or in combination, for therapeutic stimulation.
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Axial, fast spin-echo inversion recovery magnetic resonance image at the level of the posterior commissure. The typical target for placing a thalamic stimulator is demonstrated (cross-hairs).
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Implantation of the deep brain stimulation (DBS) lead.
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Insertion of an electrode during deep brain stimulation for Parkinson disease.
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Postoperative coronal magnetic resonance image (MRI) demonstrating desired placement of bilateral subthalamic nuclei-deep brain stimulation (STN-DBS) leads.
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Radiograph of the skull depicting a deep brain stimulator and leads in a patient with Parkinson disease.
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Lewy bodies in the locus coeruleus from a patient with Parkinson disease.
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A: Schematic initial progression of Lewy body deposits in the first stages of Parkinson disease (PD), as proposed by Braak and colleagues. B: Localization of the cluster of significant volume reduction in PD compared with health control subjects. The significant cluster located in the medulla oblongata/pons is superimposed as a red blob on the mean normalized anatomic scan of all participants. The axial and sagittal sections are centered on the peak of significance (–1; –36; –49). This image using voxel-based morphometry (VBM), which searched for regional atrophy in idiopathic PD by comparing a group of subjects with the disease and a group of healthy controls. Jubault T, Brambati SM, Degroot C, et al. Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI. PLoS ONE. 2009;4(12):e8247.
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Gross comparison of the appearance of the substantia nigra between a normal brain and a brain affected by Parkinson disease. Note the well-pigmented substantia nigra in the normal brain specimen on the left. In the brain of a Parkinson disease patient on the right, loss of pigmented substantia nigra due to depopulation of pigmented neurons is observed.
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Lewy bodies are intracytoplasmic eosinophilic inclusions, often with halos, that are easily seen in pigmented neurons, as shown in this histologic slide. They contain polymerized alpha-synuclein; therefore, Parkinson disease is a synucleinopathy.
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- Symptomatic Therapy, Early Disease
- Symptomatic Therapy, Advanced Disease
- Putative Neuroprotective Therapy
- Deep Brain Stimulation
- Neuroablative Lesion Surgeries
- Preoperative Evaluation
- Neural Transplantation
- Gene Therapy
- Management of Psychiatric Comorbidities
- Exercise and Physical Therapy
- Speech Therapy
- Dietary Considerations
- Consultations
- Long-Term Monitoring
- Future Treatments for Parkinson Disease
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