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Parkinson Disease Workup

Updated: Apr 10, 2017
Author: Robert A Hauser, MD, MBA; Chief Editor: Selim R Benbadis, MD more...

WORKUP

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. [33] 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. [18] 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.

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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).

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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.
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PET and SPECT scanning

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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 in18 F-dopa (fluorodopa) uptake on PET imaging in the contralateral putamen. 18
F-Dopa is taken up by the terminals of dopamine neurons and converted to 18 F-dopamine. The
rate of striatal18 F accumulation reflects transport of18 F-dopa into dopamine neurons and its
decarboxylation to18 F-dopamine, which is stored in dopamine nerve terminals in the striatum.
Thus,18 F-dopa PET imaging provides an index of remaining dopamine neurons. However, this
study is not widely available, is usually not covered by insurance, and is currently generally
considered a research tool.

Carbon-11 (11 C)-nomifensine and cocaine analogues such as123 I-beta-CIT (iodine-123-labeled
carboxymethoxy-3beta-4-iodophenyl-nortropane) and123 I-FP-CIT (fluoropropyl-CIT) bind to
dopamine reuptake sites on nigrostriatal terminals and provide an index of the remaining
dopamine neurons. Ioflupane (123 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. [34, 35]

Deficits on123 I 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.

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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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Lewy bodies in the locus coeruleus from a patient with Parkinson disease.
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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. [36] 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

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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
-amyloid 1-42 (A1-42), total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and
-synuclein were lower in the PD patients than in the controls. A1-42 and P-tau181 were
significant predictors of Parkinson's disease, and T-tau and -synuclein were associated with
the severity of motor dysfunction. In particular, lower A1-42 and P-tau181 concentrations were
associated with the postural instabilitygait disturbancedominant PD phenotype, but were not
associated with the tremor-dominant or intermediate phenotypes. [37, 38]

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.

Treatment & Management

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