Role of brain imaging in early parkinsonism
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d638 (Published 23 February 2011) Cite this as: BMJ 2011;342:d638
This article has a correction. Please see:
- David P Breen, clinical research fellow in neurology1,
- James B Rowe, consultant neurologist2,
- Roger A Barker, consultant neurologist1
- 1Cambridge Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY
- 2Department of Clinical Neurosciences, University of Cambridge
- Correspondence to: D P Breen davebreen{at}excite.co.uk
- Accepted 11 November 2010
Learning points
Routine brain imaging is unnecessary in patients with typical Parkinson’s disease
Dopamine transporter (DAT) imaging can help to differentiate patients with Parkinson’s disease from healthy individuals and patients with essential tremor or drug induced parkinsonism
Structural MRI may be performed to rule out alternative diagnoses (including other neurodegenerative syndromes and structural or vascular lesions)
The patient
A 67 year old man presents with an eight month history of tremor and “lagging behind” when walking with friends. He had labyrinthine symptoms in the past and has taken prochlorperazine for the past four years. Neurological examination confirms a rest and postural tremor affecting the left hand, as well as slight bradykinesia on repetitive fine finger and hand movements, worse on the left. No rigidity, gait disturbance, or postural instability are seen.
What is the differential diagnosis?
Parkinson’s disease is a clinical diagnosis, but even specialists are only 90% accurate.1 The first step is to decide whether the patient does in fact have parkinsonism. This relies on looking for four cardinal features: bradykinesia, rest tremor, rigidity, and postural instability. The diagnosis of parkinsonism requires the presence of at least two of these motor features. Our patient has evidence of bradykinesia and tremor, together with a degree of asymmetry, and therefore fulfils the criteria.
Prochlorperazine is one of several drugs that can induce parkinsonism; others are neuroleptics, metoclopramine, calcium channel blockers, methyldopa, sodium valproate, lithium, and certain antidepressants. Parkinsonism usually presents soon after the offending drug is started, with bilateral signs and no tremor, so our patient is atypical in this regard. In some patients the drug can be stopped and the response observed, but this is not always straightforward—for example, in those with severe mental health disorder who rely on neuroleptics—and the effect of the drug may take months to wear off.
Our patient has no clinical features pointing towards specific neurodegenerative syndromes that in their early stages can resemble Parkinson’s disease. These include multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Although sometimes called “Parkinson plus” syndromes, they are rather different in pathology, clinical features, prognosis, and response to drugs. Classic signs of progressive supranuclear palsy and multiple system atrophy include bilateral disease at onset and less rest tremor. Patients with progressive supranuclear palsy also develop a supranuclear gaze palsy, recurrent falls, apathy, and a frontal dementia. In contrast, patients with multiple system atrophy have early autonomic dysfunction or cerebellar signs, or both. Corticobasal degeneration is extremely variable, but common presentations include asymmetric rigidity and dystonia with apraxia (a “useless hand”), cognitive deficits, and a poor response to treatment with levodopa.
The diagnosis of Parkinson’s disease should be based primarily on clinical features. The UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria are commonly used in routine practice and research trials.2 These criteria do not incorporate brain imaging, which is unnecessary in patients with typical Parkinson’s disease. This approach is supported by the National Institute for Health and Clinical Excellence3 and Scottish Intercollegiate Guidelines Network.4 In this case, however, imaging is likely to be helpful because it remains unclear whether the patient’s symptoms are due to Parkinson’s disease or drug induced parkinsonism.
Clinical imaging modalities
Single photon emission computed tomography
The dopamine transporter (DAT) is an 80kDa protein located on the plasma membrane of axonal nerve terminals, where it regulates dopamine concentration in the synaptic cleft. Single photon emission computed tomography (SPECT) uses the density of a ligand radiolabelled with DAT as a marker of dopamine terminal innervation, thus helping to differentiate Parkinson’s disease from alternative diagnoses (in this case, drug induced parkinsonism).
In Parkinson’s disease, radiotracer uptake is markedly reduced in the putamen and to a lesser extent the caudate (often asymmetrically). Uptake is normal in controls and patients with essential tremor and drug induced parkinsonism (fig 1⇓). Striatal DAT imaging with SPECT differentiates between clinically probable Parkinson’s disease and essential tremor with a sensitivity of 79-100% and specificity of 80-100%.5
Fig 1 DAT scans in patients with drug induced parkinsonism (top) and Parkinson’s disease (bottom). Radiotracer uptake is reduced bilaterally in the patient with Parkinson’s disease (worse on the right side)
The diagnostic accuracy of DAT imaging depends on the patient population being tested—DAT imaging is more likely to be abnormal in patients with Parkinson’s disease with an akinetic-rigid presentation than in patients with tremor dominant disease.6 Reproducibility of scans is also contentious; one small study of 123I-β-SPECT showed that radiotracer uptake varied by up to 40% from one day to the next.7 A different tracer produced better reproducibility,8 and better measurement of radioligand binding may further reduce variability. Some drugs can affect the DAT scan; these include stimulants and some selective serotonin reuptake inhibitors but not levodopa (for a comprehensive list see Kagi et al9). DAT imaging cannot effectively differentiate between Parkinson’s disease, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration, so it should never be a substitute for careful clinical assessment. Given the exposure to radiation that is required and problems with interpretation, it should be requested only by a specialist.
Magnetic resonance imaging
When clinical features are not typical for Parkinson’s disease (young patients with acute or stepwise progression of symptoms, for example), structural brain imaging should be considered to rule out other conditions. Magnetic resonance imaging (MRI) is preferable to computed tomography because of superior resolution and diagnostic sensitivity (especially in the posterior fossa), unless there are contraindications such as severe claustrophobia or metal in the brain or eye. Our case study patient has no atypical parkinsonian features, so MRI is unnecessary.
Structural MRI is generally unremarkable in patients with Parkinson’s disease. In vascular parkinsonism (which typically presents in the lower body without tremor), MRI shows ischaemic lesions in the white matter. In elderly patients, however, it can be difficult to know if these lesions are sufficient to account for their parkinsonism. Space occupying lesions, normal pressure hydrocephalus, and lesions of the basal ganglia can also cause parkinsonism with characteristic MRI appearances.
MRI can be helpful in identifying other specific neurodegenerative syndromes. Although not pathognomonic, atrophy of the midbrain tegmentum is seen in virtually all patients with progressive supranuclear palsy (the “hummingbird sign” on saggital MRI or “Mickey Mouse” midbrain on axial slices; fig 2⇓).10 Putaminal abnormalities are more common in multiple system atrophy and progressive supranuclear palsy than in Parkinson’s disease,11 but they may be detected only by an experienced neuroradiologist (or not at all) and rarely change clinical management. In corticobasal degeneration, MRI shows asymmetric cortical atrophy in clinically affected areas, especially frontal and parietal association cortex.
Fig 2 Magnetic resonance brain scans in patient with progressive supranuclear palsy, showing characteristic “hummingbird sign” and “Mickey Mouse” midbrain
Outcome
The patient reported no improvement in symptoms after stopping prochlorperazine for three months. He was seen by a different neurologist in the follow-up clinic, and a DAT scan showed reduced uptake bilaterally (worse on the right side). He was diagnosed with idiopathic Parkinson’s disease and started taking ropinirole, and his motor symptoms improved considerably.
Research imaging modalities
Research into neuroimaging in Parkinson’s disease may lead to facilitation of early accurate diagnosis, prediction of complications such as dementia, a better understanding of the pathophysiology of the condition, and analysis of the mechanisms of cognitive and motor phenotypes in the disease.
Functional MRI
Patients with early Parkinson’s disease typically have difficulty in planning, organising, and regulating goal directed behaviours—so called frontal executive dysfunction. Functional MRI (fMRI) measures the blood oxygen level dependent (BOLD) signal, a function of the changes in cerebral blood flow and oxygenation after neural activity.
Previous fMRI studies have found abnormal frontostriatal activity in early Parkinson’s disease.12 Studies have also suggested that there is a U shaped relation between dopamine concentrations in the prefrontal cortex and neural function, with different optimal dopaminergic states for motor and cognitive functions.13
One of the limitations of this imaging technique (and others) is that we do not fully understand the pathological basis of Parkinson’s disease. Therefore, fMRI remains an indirect measure of pathology in Parkinson’s disease.
Positron emission tomography
Up to 80% of patients with Parkinson’s disease may develop a dementia.14 15 PET studies of resting brain function in such dementia show an Alzheimer-like pattern of reduced glucose utilisation; posterior parietal and temporal association areas are most affected.16 Up to a third of non-demented, but cognitively impaired, patients with Parkinson’s disease also show reduced metabolism in the parietal and temporal lobes17; longitudinal follow-up is needed to assess whether they too develop dementia. In an effort to elucidate the pathophysiology of Parkinson’s disease and its evolving dementia, PET ligands have also been used to study amyloid β plaque load (11C-PIB-PET; fig 3⇓)18 and binding to peripheral benzodiazepine receptors on activated microglial cells as a marker of cerebral inflammation (11C-PK11195; fig 4⇓).19
Fig 3 PET imaging with 11C-Pittsburgh Compound B, a thioflavin based marker of amyloid β plaque load: (A) elderly patient without Parkinson’s disease; (B) patient with Parkinson’s disease dementia with no significant plaque deposition in the brain; (C) patient with Alzheimer’s disease in whom amyloid β is extensive20
Fig 4 Assessment of microglial activation by use of 11C-PK11195 PET: (A) only mild microglial activation seen in the thalamus of healthy control; (B) raised activation in the midbrain and striata (arrows) of patient with Parkinson’s disease, with normal levels of thalamic activation20
Moreover, PET can differentiate between normal and abnormal nigrostriatal innervation. In a study of 167 patients with parkinsonism of unknown cause followed up for a mean of 2.6 years, FDG-PET was able to differentiate between Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy (positive predictive value >90% for each condition).21
Despite this, the future role of PET outside of research trials remains uncertain, given that this type of imaging is expensive, is not widely available, requires low dose exposure to radiation, and relies on specialist interpretation.
Prospective, longitudinal imaging studies are needed to identify patients with early Parkinson’s disease, who are at increased risk of cognitive impairment and dementia. The ICICLE-PD study (Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation—Parkinson’s Disease; http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=5643) is addressing this important research question using MRI (structural and functional) and PET alongside clinical markers.
Notes
Cite this as: BMJ 2011;342:d638
Footnotes
This series provides an update on the best use of different imaging methods for common or important clinical presentations. The series advisers are Fergus Gleeson, consultant radiologist, Churchill Hospital, Oxford, and Kamini Patel, consultant radiologist, Homerton University Hospital, London. To suggest a topic for this series, please email us at practice{at}bmj.com.
We thank David Brooks (MRC Cyclotron Unit, Hammersmith Hospital, London) and Nature Publishing Group for permission to use figures 4 and 5.
Contributors: DPB wrote the article and prepared the first draft, which was revised by JBR and RAB.
Funding: DPB is supported by a Raymond and Beverley Sackler studentship and the Big Lottery Fund/Parkinson’s UK. JBR is supported by Wellcome Trust. All authors work at the University of Cambridge/Addenbrooke’s Hospital which benefits from a National Institute for Health Research Biomedical Research Centre award.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. DPB, JBR, and RAB are sub-investigators for the ICICLE-PD study.
Provenance and peer review: Not commissioned; externally peer reviewed.
References
Log in
Log in using your username and password
Log in through your institution
Subscribe from £173 *
Subscribe and get access to all BMJ articles, and much more.
* For online subscription
Access this article for 1 day for:
£38 / $45 / €42 (excludes VAT)
You can download a PDF version for your personal record.