Magnetic resonance spectroscopy (MRS) and functional MRI (fMRI), related through common biophysical bases, provide complementary information about brain function. The link between MRS and fMRI measures is of interest, especially in the ultra-rare, metabolic disease late-onset GM2 gangliosidosis (LOGG). Imaging studies on LOGG have been few and far between, with cerebellar atrophy and neurochemical impairments being the most prominent findings. However, it remains unknown as to how these neurochemical aberrations relate to neurofunctional characteristics. The goal of this study (7 LOGG, 7 age/sex matched controls) was to assess the relationship between MRS concentrations and fMRI measures derived from the same MRS ROI (cerebellum, thalamus, precuneus) in LOGG. To quantify the communication between MRS regions and rest of the brain, we employed graph measures estimated from resting-state fMRI functional connectivity. We found that one such measure, local efficiency, which quantifies the aggregate relationship between a MRS region and rest of the brain, was significantly associated with N-acetylaspartate (NAA) in the cerebellum and thalamus (p<0.05, FDR corrected). Poorer neuronal health, neuronal loss (NAA), and neuroinflammation (myo-inositol) were related to poorer cerebellum-brain communication. Likewise, reduced thalamus-brain communication was also associated with poorer neuronal health and longer disease duration (p=0.002). These findings hint at a model of impaired neurochemical concentrations in these regions, leading to aberrant communication between them and rest of the brain, which may exacerbate disease progression. Future research must replicate these findings in larger cohorts, and further investigate such abnormalities in the cerebellum, thalamus and precuneus in this ultra-rare neurological disease.

Dr. Stephen has provided scientific advisory for Xenon Pharmaceuticals and received research funding from Sanofi-Genzyme for a study of video oculography in late-onset GM2 gangliosidosis. He has received financial support from Sanofi-Genzyme, Biogen and Biohaven for the conduct of clinical trials. Dr. Ratai serves on the advisory board of BrainSpec.

This study was supported by the Sanofi US Services Inc. and National Tay-Sachs & Allied Diseases Association Inc. Imaging was performed at the Athinoula A. Martinos Center for Biomedical Imaging using resources provided by the Center for Functional Neuroimaging Technologies (P41EB015896) and the Center for Mesoscale Mapping (P41EB030006), Biotechnology Resource Grants supported by the National Institute of Biomedical Imaging and Bioengineering, and the National Institutes of Health (NIH). The NIH also provided support through grants R01EB027779 and R00EB016689 (to R.L.B.). This research was also supported in part by the Athinoula A. Martinos Center for Biomedical Imaging.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The institutional review board (IRB) of Mass General Brigham (formerly Partners Healthcare) gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

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Since late-onset GM2 gangliosidosis (LOGG) is an extremely rare disease, the detailed protocol approved by the IRB states that all de-identifiable imaging and clinical data (and any other study data) can be shared externally only upon IRB approval and with a data usage agreement in place.