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Longitudinal measurement of synaptic density to monitor progression of Parkinson's disease and Huntington's disease

Parkinson’s disease (PD) and Huntington’s disease (HD) are disabling neurodegenerative disorders that affect the basal ganglia and multiple other brain regions. Current therapies for both disorders are purely symptomatic. There are no biomarkers yet that objectively quantify the progression of PD and HD in their motor and non-motor domains, and this hampers the development of disease-modifying therapies that slow down PD or HD progression.

PD is the second most common neurodegenerative disorder and characterized by nigrostriatal dopaminergic loss but also affects many non-dopaminergic brain regions. Clinically, PD is characterized by variable combinations of motor and non-motor symptoms. Mounting evidence indicates that the pathological process of PD is likely initiated at presynaptic terminals. The traditional ‘gold standard’ for measuring PD progression consists of longitudinal clinical assessment of motor signs, using part III of the (MDS-)UPDRS in the medication OFF state. Limitations of this approach are that these scores are subjective and semi-quantitative,  influenced by effects of symptomatic drugs, stress and fatigue. In addition, these scores only reflect the motor side of PD. The scales to rate non-motor symptoms are subjective and semi-quantitative and most of them are poorly validated as measures of PD progression. Imaging techniques to visualize the nigrostrial tract, using ligands that bind to dopaminergic terminals, detect nigrostriatal cell loss in early PD and are more objective. However, longitudinal decline in nigrostriatal imaging indices generally does not correlate well with clinical motor progression.

HD is an autosomal dominant disease caused by a CAG repeat expansion in the HTT gene which leads to aggregation of mutant huntingtin protein and primarily affects the medium spiny neurons of the striatum, but also in many other brain regions neurons degenerate. HD manifests with a progressive movement disorder, cognitive impairment and a wide range of behavioral and psychiatric symptoms. Previous research suggested that synaptic pathology and dysfunction are a prominent component of HD. Scales have been developed to rate the clinical manifestations of HD, but they are subjective and lack sensitivity. Two imaging techniques of the striatum, volumetric magnetic resonance (MR) imaging and phosphodiesterase 10A (PDE10A) PET imaging are promising biomarkers. However, both techniques mainly detect degeneration of the striatum and are less sensitive to extrastriatal changes.

Recently, in vivo imaging of synaptic density in the human brain is possible with 11C-UCB-J, a PET radioligand for the synaptic vesicle protein SV2A. SV2A is ubiquitously and homogeneously present in presynaptic terminals throughout the brain. Given the evidence for synaptic loss as an early pathogenic event in PD and HD, SV2A PET could potentially provide a long-awaited biomarker to track PD and HD progression across the multiple affected brain regions.

The general aim of this project is to assess global and regional synaptic density in the human brain in vivo in patients with PD and in HD mutation carriers, as well as investigate the potential relationship of regional synaptic loss with motor and non-motor symptoms and with disease progression.

For the PD part of the study, we will recruit 30 early PD patients and 20 controls, for the HD part, we will recruit 20 HD mutation carriers (10 premanifest, 10 manifest) and 15 controls. The healthy controls will be age- and gender-matched. All subjects will undergo the same clinical and imaging evaluation at baseline and after 2 years. For the clinical evaluation, we will comprehensively assess a wide range of motor and non-motor symptoms with a panel of rating scales that have been validated for PD and HD. For the PD study the clinical motor assessment will be in medication OFF state. To investigate the added value of SV2A PET as an imaging biomarker, we will compare SV2A PET/CT with the most promising current imaging biomarkers, namely 18F-PE2I PET/MR (dopamine transporter (DAT) levels) for PD patients, and volumetric MRI (striatal volumes) and PDE10A PET/MR (striatal PDE10A) for HD patients.  

For the baseline study, global and regional synaptic density will be compared between PD or HD patients and controls. In the PD and HD groups, we will also look for correlations between the clinical motor and non-motor scores and regional synaptic density and the currently available imaging parameters (DAT levels, striatal volumes and PDE10A levels). After completion of the 2-year follow-up, we will compare the rate of decline of global and regional synaptic density between patients and controls. In the PD and HD group, we will look for correlations between progression of the clinical motor and non-motor scores and decline of regional synaptic density and current imaging biomarkers (decline in DAT levels, striatal volumes and striatal PDE10A levels).

Our project is innovative, because in vivo imaging of synaptic density has not been reported before in PD or HD. Our study will, for the first time, reveal the extent of synaptic loss in PD and HD in vivo and may provide novel insights into the anatomic origin of the various non-motor symptoms of PD and HD. In contrast to dopaminergic imaging, SV2A PET will provide information on all affected brain regions in PD, not just the nigrostriatal tract. It could also possibly monitor the progression of synaptic pathology in HD in both striatal and extrastriatal brain regions. If SV2A PET is found to provide a biomarker for progression of PD or HD, this would greatly facilitate clinical trials with novel potential disease-modifying treatments.

Date:1 Oct 2018 →  Today
Keywords:Parkinson's disease, Huntington's disease, PET, PD, HD
Disciplines:Cognitive neuroscience
Project type:PhD project