7T MR spectroscopy reflects disease severity in a large animal model of neurologic disease and the effects of gene therapy
Heather Gray-Edwards1, Nouha Salibi2, Anne Maguire1, Taylor Voss1, Lauren Ellis1, Ashley Randle1, Ronald Beyers1, Miguel Sena-Esteves3, Thomas Denney1, and Douglas Martin1

1Auburn University, Auburn, AL, United States, 2Siemens Healthcare, Malvern, PA, United States, 3University of Massachusetts, Worcester, MA, United States


GM1 gangliosidosis is a fatal neurodegenerative disorder of children and currently only palliative care is available to patients. Preclinical gene therapy experiments in the GM1 cat resulted in >5 fold increased lifespan, prompting human clinical trials, however objective markers are lacking. 7T MR spectroscopy reliably predicts feline GM1 neurodegeneration with several alterations occurring presymptomatically and worsening with disease progression. Gene therapy results in partial correction of several parameters and changes correlate with clinical assessment scores. Post-mortem analyses included assessment of microgliosis and demyelination, and these findings also correlated with MRS.


GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of the enzyme β-galactosidase (β-gal). Feline GM1 recapitulates human GM1 and is a powerful tool to study disease pathology as well as evaluate AAV gene therapy. Preclinical gene therapy studies in cats have resulted in a >5 fold increase in lifespan1. These results have prompted initiation of human clinical trials, but objective measures to track disease are lacking. In this study we evaluate the ability of ultra-high field MR spectroscopy to reflect neurodegeneration.


GM1 cats were treated with AAVrh8 encoding feline β-galactosidase by intracranial injections bilaterally in the thalami + one lateral ventricle at 2-3 months of age. MR spectroscopy was performed at 4 months, 8 months and at neurologic endpoint (12-20 months). Single voxel spectroscopy (SVS) was acquired using a PRESS (Point Resolved Spectroscopy) sequence optimized for 7T with TE/TR = 30/5000 ms , 64 averages and a Variable Pulse power and Optimized Relaxation Delays (VAPOR) water suppression. Using high resolution MRI images, voxels were positioned in the thalamus, corona radiata, parietal cortex, temporal lobe, occipital cortex and cerebellum. MRS data were processed with LC model and internal water scaling (http://www.s-provencher.com/pages/lcmodel.shtml).


MR spectroscopy showed reduction in N-acetyl aspartate (NAA) levels, elevated glycerophospho-choline (GPC) + phosphocholine (PCh), increased myoinositol (Ins), and reduced glutamate + glutamine (GLX) levels with severity dependent upon pathologic change in individual brain areas. NAA, GPC+PCh and Ins correlated with clinical assessment and histopathology.

Figure 1

In the untreated GM1 cat cerebellum (A), the earliest detectable change was a reduction of NAA by 4 months (p<0.01). At 8 months, GPC+PCh and Ins were elevated (p<0.01) and GLX (GLU+GLN) was reduced in the GM1cat (p<0.05). After gene therapy, Ins was normalized at 8 months, but trended toward an increase at endpoint (p=0.08). NAA and GLX were reduced by 8 months in the GM1+AAV cohort and reduction was more prominent with age (p<0.01 and p<0.05, respectively). NAA (B), GPC+PCH (C) and Ins (D) concentrations correlated with clinical disease in both untreated and AAV treated GM1 cats (R2 = 0.63, 0.46, 0.59 respectively). Histopathology in the GM1 cat revealed increased microglial activation/ proliferation (E), reduced myelination (F) in the GM1 cat and partial amelioration of both demyelination and microgliosis after gene therapy (E&F).


Ultra-high field single voxel spectroscopy reliably quantifies neurodegeneration in GM1 gangliosidosis and correlates with both clinical scoring and histopathology. Gene therapy partially ameliorates metabolite changes, and NAA and GPC+PCh alterations are detectable presymptomatically. MRS is a viable outcome measure for AAV-gene therapy human clinical trials.




[1] McCurdy VJ, Johnson AK, Gray-Edwards HL, Randle AN, Brunson BL, Morrison NE, Salibi N, Johnson JA, Hwang M, Beyers RJ, Leroy SG, Maitland S, Denney TS, Cox NR, Baker HJ, Sena-Esteves M, Martin DR: Sustained normalization of neurological disease after intracranial gene therapy in a feline model. Science translational medicine 2014, 6:231ra48.


7T MRS in the cerebellum of the GM1 cat, the effect of AAV gene therapy and correlation with clinical assessment and histopathology.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)