The landscape of functional brain network impairments in late-onset GM2 gangliosidosis

Abstract

Late-onset GM2 gangliosidosis (LOGG) is an ultra-rare neurological disease with motor, cognitive and psychiatric manifestations. It is caused by mutations in the HEXA or HEXB genes. Although cerebellar structural and metabolic impairments have been established, global brain functional impairments in this disease remain unknown. In this first functional MRI (fMRI) report on LOGG (N=14), we took an exploratory, multi-pronged approach by assessing impairments in several resting-state fMRI signal characteristics: fMRI signal strength, neurovascular coupling, static and time-varying functional connectivity, and network topology. Contrary to the predominance of cerebellar aberrations in prior non-functional studies, we found more widespread cortical aberrations (p<0.05, FDR-corrected) mainly in cognitive control networks but also in the default mode and somatomotor networks. There was reduced fMRI signal strength, enhanced neurovascular coupling, pathological hyper-connectivity, and altered temporal variability of connectivity in the LOGG cohort. We also observed an imbalance between functional segregation and integration as seen in other psychiatric/neurological disorders, with heightened segregation and suppressed integration (i.e., inefficient brain-wide communication). Some of these imaging markers were significantly associated with clinical measures, as well as with HEXA and HEXB gene expression. These aberrations might contribute to psychiatric symptoms (psychosis, mood disturbances), cognitive impairments (memory, attention, executive function), and oculomotor disturbances commonly seen in LOGG. Future LOGG imaging studies should probe brain function in addition to structure/metabolism while looking for mechanistic insights beyond the cerebellum.

Competing Interest Statement

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.

Funding Statement

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

Author Declarations

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

Yes

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

Mass General Brigham (formerly Partners HealthCare) Institutional Review Board (IRB) 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.

Yes

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).

Yes

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.

Yes

Data Availability

Late-onset GM2 gangliosidosis (LOGG) is an extremely rare disease. Hence, the detailed protocol (approved by the Mass General Brigham IRB) states that all de-identifiable imaging and clinical data and any other study data can be shared externally only with both IRB approval and a data usage agreement.

留言 (0)

沒有登入
gif