Specificity & Sensitivity of Transcranial Ultrasound as Biomarker in Parkinson's Disease
In recent years transcranial sonography (TCS) has become a widely used method to visualize the brain by applying an ultrasound probe to the temporal bone window of the intact skull. Routinely used structural neuroimaging methods, such as cranial computer tomography (CCT) and magnet resonance imaging (MRI) do not show specific alterations that help to establish the diagnosis of Parkinson's disease (PD). Only more sophisticated not ubiquitously applicable methods can be used to substantiate the diagnosis. Our team has shown that TCS allows the depiction of a typical marker for PD: In about 90 percent of PD patients it reveals an increased echogenicity of the substantia nigra, the brain region where loss of dopaminergic neurons accounts for many of the motor symptoms of the disease.
Initial studies indicate that this marker may help to distinguish patients with idiopathic PD from patients with atypical Parkinsonian syndromes. However, although a number of independent groups have confirmed our findings, the predictive value of this method requires further validation.
Our teams will now undertake two studies toward conclusive validation of this promising method. In the first study, a neurologist totally blinded to the diagnosis of the person investigated will have to decide solely through application of TCS whether a person suffers from PD or not. In the second study, patients with clinical symptoms that could point to either idiopathic PD or atypical PD will be prospectively investigated by TCS. Clinical and functional neuroimaging follow-up examinations will help to decide which diagnosis will be favored in the course of the disease, and whether TCS would have enabled the diagnosis already at a stage where clinical examination alone would not have been sufficient.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Validating this method has become even more important since the discovery that a small percentage of healthy subjects display the same echofeature as PD patients. Functional neuroimaging such as PET examinations, as well as clinical follow-up of these subjects, has indicated that increased echogenicity of the substantia nigra might be a marker for a vulnerability to an impairment of the neurotransmitter systems involved in PD and even eventually to PD in some affected subjects. If the value of TCS for diagnosis (including differential diagnosis) of PD were proven, it could serve as a broadly available, easily applicable, side-effect free and inexpensive technique to improve diagnostic accuracy of PD. A high positive predictive value would also indicate that increased echogenicity of the substantia nigra in healthy controls may indicate a vulnerability marker with high sensitivity, which could have a major impact on the development of neuroprotective strategies in the future.
Based on our initial findings, we anticipate confirming the potential of TCS as a non-invasive, side-effect free and inexpensive method suitable for differential diagnosis of Parkinsonian syndromes.
Dr. Berg tested and validated transcranial ultrasonography as a potential imaging biomarker for PD. She found that individuals with PD have a 'hyperechogenicity' of the substantia nigra not seen in healthy individuals. She has completed and published an initial confirmation study and is continuing to examine patients as part of a longitudinal study to determine how well TCS compares to current 'gold standard' clinical diagnoses of PD. Based on the work in this project, Dr. Berg was awarded a Biomarkers 2007 grant to look for early markers of Parkinson's disease. Additionally, the team's successful and promising outcomes have increased interest in the diagnostic use of TCS. Neurologists, radiologists and technicians have visited the Berg lab for training in the method. Follow-on funding for new collaborations focused on TCS has been provided by Janssen Pharmaceutica NV, Teva Pharmaceuticals and the Center for Integrative Neuroscience at the University of Tuebingen.
Results of this work were published in the journals Movement Disorders and Lancet Neurology.
Professor, Department for Neurodegenerative Diseases at Centre of Neurology and Hertie-Institute for Clinical Brain Research, University Hospital Tuebingen
Location: Tuebingen, Germany