purpose

Huntington disease (HD) is an incurable inherited neurodegenerative disease, characterized by the expansion of glutamine-repeat sequence. One of the challenges in investigating disease progression is the heterogeneous neuropathology and symptomatology in patients despite the single gene etiology. Previous structural imaging studies reported cortical thinning in HD[1]. Here we aim to further investigate cross-sectional and longitudinal changes in brain white matte and microglial activation profile in vivo in HD, using diffusion magnetic resonance imaging (dMRI) and positron emission tomography with radioligand 11C-(R)-PK11195 (PK), respectively.

Methods

13 manifest HD patients (Figure 1) were recruited from the University Health Center (UHC) Neurology Movement Disorders Clinic by their treating neurologist. 7 age-matched healthy controls (HC) were also recruited. Diffusion and structural images were acquired for all participants on a 3 T Siemens scanner. Microglial activation data were collected for 2 patients on GE discovery PET scanner. Multi-shell dMRI data was acquired with b-values 0 and 1000 s/mm2 with 2 and 40 directions, respectively with isotropic voxels (2 mm3). T1‐weighted images were acquired in the axial plane with isotropic voxels (1 mm3) using the magnetization prepared gradient‐echo sequence. Cortical thickness differences between HD and HC were assessed using FreeSurfer MRI_GLMFIT. Post-processing of DTI data was performed using FSL[2] and Fractional anisotropy (FA) and mean diffusivity (MD) maps were generated using the FDT module. Tract based spatial statistics (TBSS, [3]) was used to analyze diffusion tensor imaging (DTI) data and investigate brain white matter in HD patients compared to HC and upon follow up (at 6 months visit). Parametric images of PK binding potential (BP) were generated using a simplified reference tissue model. We performed a voxel-based analysis of PK BP images using SPM12 to compare the PK binding over the entire brain in HD and controls applying no a priori hypothesis. The normalized PK BP images were smoothed using an isotropic kernel of 12 mm. Between- and within-group comparisons were made with a voxel threshold of P < 0.01 after family-wise error correction. Patients’ motor disability was assessed with the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor score and Symbol Digit Modality Test (SDMT) was used to assess processing speed (Figure 1). Montreal Cognitive Assessment (MoCA) was used to screen for mild cognitive dysfunction (a score of 26 or above is considered normal)

RESULTS

69.18% of HD patients scored 1 standard deviation (SD) lower than HC, indicating executive dysfunction at level of processing speed (Figure 2). Evidence of neuronal loss in HD patients compared to HC, was reflected by reduced average cortical thickness (Figure 3). Areas of cortical thinning included pericalcarine, precuneus, paracentral, superior frontal, inferior parietal and cingulate gyri (p<0.05). TBSS analysis revealed significant reductions in FA (p<0.05) in HD patients compared to HC in widespread regions of cerebral white matte (Figure 4). Longitudinal TBSS analysis of HD group did not yield any significant changes. Voxel based analysis of PET data, revealed no significant changes in PK binding in HD patients (n=2) compared to HC (n=2). However, there as a significant increase in PK uptake in HD patients upon follow up in globus pallidus and brodmann area 47 (Figure 5).

Conclusion:

There is a need to characterize cortical and white matter abnormalities in PD in an attempt to understand their contribution to disease progression. Microglial activation could be one mechanism driving neurodegeneration, and thus our longitudinal study will provide more insight in this regard. In addition, specific regions of interest will be delineated to study FA and other DTI metrics based on TBSS results. More HD subjects are being recruited and follow up will extend to one year after baseline.

Acknowledgements

This work was supported by the Sastry Foundation Advance Imaging Laboratory and Biogen