Transcranial Ultrasound: A Promising Biomarker for Early Parkinson's Disease
Abstract & Commentary
By Melissa J. Nirenberg, MD, PhD Assistant Professor, Neurology and Neuroscience, Weill Cornell Medical College Dr. Nirenberg reports that she receives grant/research support from Boehringer-Ingelheim.
Synopsis: Transcranial ultrasound is an inexpensive, non-invasive technique that can be used in early parkinsonism to support clinical diagnosis of Parkinson's disease.
Source: Gaenslen A, et al. The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study. Lancet Neurol 2008;7:417-424.
Despite major breakthroughs in the pathophysiology and treatment of Parkinson's disease (PD), the diagnosis is still primarily a clinical one; it also has a relatively high rate of diagnostic error, particularly early in the disease course. As such, there is a compelling need for biomarkers to distinguish PD from other neurological disorders. One promising approach has been transcranial ultrasound, which in retrospective studies of patients with well-established disease has demonstrated hyperechogenicity of the substantia nigra in PD and of the basal ganglia in certain types of atypical parkinsonism.
In this study, the authors use a prospective, blinded study design to evaluate the sensitivity and specificity of transcranial B-mode sonography (TCS) in the diagnosis of early parkinsonism. Subjects (n=60) with early, mild, mainly akinetic-rigid parkinsonism were recruited at the time of their initial visit to a university outpatient PD clinic in Germany. Patients with prominent rest tremor were excluded from entry in the study (to avoid potential bias from this readily observable sign), as were those whose temporal acoustic bone windows did not allow for TCS of the substantia nigra.
All subjects underwent baseline TCS of the substantia nigra by an investigator blinded to the clinical data; TCS of the basal ganglia also was performed in those subjects (n=54) for whom it was anatomically feasible. A movement disorders specialist who was blinded to the TCS results performed detailed neurological examinations at baseline and periodically thereafter. At the final (12-month) time point, a third, blinded investigator reviewed the clinical data and applied standard diagnostic criteria to classify subjects as having PD or atypical parkinsonism. In cases in which the clinical diagnosis remained unclear, functional neuroimaging was used to confirm the diagnosis. In a subset of subjects (n=7), the above criteria failed to produce a clear clinical diagnosis and a "forced clinical diagnosis" was designated by 2-3 additional, independent examiners.
After 12 months of follow-up, 88% of subjects (n=53) were given a clinical diagnosis of either idiopathic PD (n=39), multiple system atrophy (n=4), progressive supranuclear palsy (n=4), corticobasal ganglionic degeneration (n=2), or non-parkinsonian disorder (n=4). A forced clinical diagnosis was used in the remaining subjects (n=7), after which an additional 4 were diagnosed with PD, 2 with multiple system atrophy, and 1 with corticobasal ganglionic degeneration. Compared with the clinical diagnosis at 12 months, baseline hyperechogenicity of the substantia nigra had an overall 90.7% sensitivity and 82.4% specificity for idiopathic PD, and a classification accuracy of 88.3%. Exclusion of subjects with a forced clinical diagnosis improved the sensitivity to 94.9%, specificity to 85.7%, and classification accuracy to 92.4%.
For assessment of baseline TCS in discriminating between early PD and atypical parkinsonism, subjects with a forced clinical diagnosis or non-parkinsonian syndrome were excluded from statistical analysis. In the remaining subjects (n=49), SN hyperechogenicity had a sensitivity of 94.8%, specificity of 90%, and classification accuracy of 93.9% for discriminating PD from atypical parkinsonism. In the subset of these subjects for whom basal ganglia TCS was technically feasable, baseline basal ganglia hyperechogenicity had a sensitivity of 66.7% and specificity of 68.6% for atypical parkinsonism, with a classification accuracy of 68.2%.
Commentary
As the search for neuroprotective treatments for PD intensifies, there is an increasing need for biomarkers to facilitate the early and accurate diagnosis of PD. Such biomarkers will not only help to determine the prognosis and likelihood of medication responsiveness within individual patients, but also allow for the initiation of future neuroprotective treatments before significant motor disability occurs. TCS is a safe, inexpensive, widely available, and non-invasive technique that has the potential to meet this need.
In this study, the authors confirm and expand prior retrospective findings showing the promise of TCS in the diagnosis of PD. Advantages of this study include the prospective, blinded study design, as well as its focus on early parkinsonism when this technique is of particular clinical relevance. Study limitations include the relatively small sample size, single-center design, exclusion of patients with prominent tremor, short follow-up time, and lack of neuropathological correlation. Given that substantia nigra hyperechogenicity is sometimes absent in PD, and may be present in other conditions such as Lewy body dementia and corticobasal ganglionic degeneration, clinical correlation is necessary.
TCS is a promising biomarker for the diagnosis of PD and differentiation of PD from atypical parkinsonism. This technique has important limitations, however, and should be regarded as a complement to, rather than a substitute for, clinical diagnosis. Further investigation is warranted to determine whether TCS can be used to diagnose PD in its presymptomatic or premotor stages to facilitate early implementation of future neuroprotective therapies.
Additional Reading
Stern MB. Transcranial ultrasound in Parkinson's disease. Lancet Neurol 2008;7:376-378.
Transcranial ultrasound is an inexpensive, non-invasive technique that can be used in early parkinsonism to support clinical diagnosis of Parkinson's disease.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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