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Neuroimaging Carriers of the Alpha-synuclein E46K Mutation as a Model of Idiopathic Lewy Body Disease

Study Rationale:
In 2004 our group described, for the first time in literature, the E46K mutation of the alpha-synuclein gene in a family from the Basque region of Spain. The rare E46K mutation is associated with early onset Parkinson disease (PD) with prominent cognitive, cardiac and visuospatial abnormalities that resemble severe forms of non-familial PD. Characterization of E46K mutation carriers with imaging techniques such as brain magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) has not been performed to date.

We hypothesize that E46K carriers have a specific pattern of pathology in the brain (as measured by MRI) and in the retina (by OCT) similar to that observed in severe cases of non-familial PD. We also believe the presence of this pattern is related to the progression of cognitive impairment in E46K carriers and in non-familial or idiopathic PD.

Study Design:
We will evaluate 49 subjects including seven E46K mutation carriers and a control group of 28 patients with idiopathic Lewy body disease and 14 healthy controls. We will characterize E46K carriers using brain MRI and retinal OCT and compare those findings with results from matched participants from the control group. Lastly, we will look for imaging biomarkers associated with cognitive impairment in E46K carriers and in patients with Lewy body disease.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Alpha-synuclein is the main component of Lewy bodies, protein aggregates that are the pathological hallmark of PD. Thus, the study of E46K carriers is a unique opportunity to improve our understanding of Parkinson’s. This work may lead to identification of imaging biomarkers for early identification of aggressive cases of PD and the development of neuroprotective therapies for PD.                

Next Steps for Development:
Next steps are toward clinical validation of identified imaging biomarkers. We will test them longitudinally in E46K mutation carriers and in different cohorts of patients with non-familial PD.


  • Juan Carlos Gomez-Esteban, MD, PhD

    Baracaldo, Vizcaya Spain

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