Measures of deep gray matter and cerebellar structural involvement served as useful markers of genetic frontotemporal lobar degeneration (FTLD), particularly in regard to disorders related to C9orf72 mutations, according to study findings published in Neurology.
Neuroimaging has been a helpful tool when it comes to vivo, non-invasive measures of neurodegeneration in FTLD. However, the role of pathological burden within gray matter structures (aside from the brain cortex) has only been recently investigated. The current study authors believe there’s distinctive neurodegeneration of deep gray matter and cerebellar structures in patients with genetic FTLD, including motor neuron disease. Prior studies have only focused on pure cognitive phenotypes. A deeper overview of subcortical and cerebellar damage in genetic forms of frontotemporal dementia (FTD) and motor neuron disease spectrum is still unclear.
The objective of the current study was to explore cortical, subcortical, and cerebellar gray matter atrophy in patients with FTLD disorders with known genetic mutations.
The study included 66 patients with FTLD-related mutations, including those with pure motor neuron disease (MND; n=44) and FTD (n=22). Another 61 patients with sporadic FTLD (sFTLD) were matched for age, sex, disease severity, and magnetic resonance type with patients with genetic FTLD (gFTLD). In addition, a total of 52 healthy controls were also included in the study. Researchers conducted a whole-brain voxel-based morphometry (VBM) analysis and obtained gray matter volumes of subcortical and cerebellar structures of all participants.
Gray matter atrophy on VBM analysis was greater and more diffuse in patients with genetic FTD compared with controls, while patients with sporadic MND had greater focal motor cortical atrophy. In addition, those who carried C9orf72 and GRN mutations demonstrated greater widespread cortical volume loss, while gray matter sparing was observed in SOD1 and TARDBP. Patients with gFTLD had greater atrophy of parietal cortices and thalami vs those with sFTLD.
Volumetric analysis showed that patients with gFTLD had volume loss in the caudate nuclei and thalami. Patients with gFTLD also had greater atrophy of the right lobule VIIb in the cerebellum compared with those with sFTLD. The thalamic volumes of patients with gFTLD with a C9orf72 mutation featured an inverse correlation with Frontal Behavioral Inventory scores (left: P =.031; right: P =.002). In a subanalysis according to only C9orf72 status, this inverse correlation remained significant for only C9-FTLD (left: P =.024; right: P =.025).
Study limitations included its small sample size as well as the lack of neuropathological post-mortem diagnosis of the sporadic FTLD cases.
The researchers concluded that their findings “strongly suggest that neuroimaging can provide useful volumetric measures applicable to future clinical trials targeting these genetic mutations.”
Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.
Spinelli EG, Ghirelli A, Basaia S, et al. Structural MRI signatures in genetic presentations of the frontotemporal dementia-motor neuron disease spectrum. Neurology. Published online September 20, 2021. doi:10.1212/WNL.0000000000012702