FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations

Abstract

C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.

Impact of long- and short-range fibre depletion on the cognitive deficits of fronto-temporal dementia

“…Our structural connectivity results were in agreement with the fixel-based results suggesting that both techniques were able to detect WM impairments in FTD. In addition, we found that one of the largest reductions in structural connectivity was between thalamo-frontal regions, supporting the finding that thalamic atrophy is a prominent feature of FTD ( Diehl-Schmid et al, 2019 ) and that it is common across episodic and genetic mutation ( Bocchetta et al, 2018 ).…”

Frontotemporal Dementia and Glucose Metabolism

“…Nevertheless, one study found that ∼80% of PGRN mutation carrying patients had glucose hypometabolism in the temporal regions of the brain, which extended beyond the boundaries of the frontotemporal region ( Licata et al, 2020 ). C9 carriers were found to have glucose hypometabolism extending into the cerebellar cortex, occipital cortex, cingulate cortex, rolandic operculum, and caudate nuclei ( Castelnovo et al, 2019 ; Diehl-Schmid et al, 2019 ). Furthermore, C9 carriers also showed a characteristic thalami glucose hypometabolism ( Diehl-Schmid et al, 2019 ).…”

“…C9 carriers were found to have glucose hypometabolism extending into the cerebellar cortex, occipital cortex, cingulate cortex, rolandic operculum, and caudate nuclei ( Castelnovo et al, 2019 ; Diehl-Schmid et al, 2019 ). Furthermore, C9 carriers also showed a characteristic thalami glucose hypometabolism ( Diehl-Schmid et al, 2019 ). With over 70 FTD causal MAPT pathogenic mutations known to date, glucose hypometabolic patterns have been harder to establish across MAPT mutation carriers ( Clarke et al, 2021 ).…”

Voxel-based analysis of the metabolic asymmetrical and network patterns in hypermetabolism-associated crossed cerebellar diaschisis

“…The neighboring internal capsule with compact fiber bundle may also be involved, inducing the inhibition of the cortico-ponto-cerebellar pathway. Moreover, striatum and thalamus were also considered to be involved in the process of cognitive function ( Diehl-Schmid et al, 2019 , Hirata et al, 2015 , Leisman and Melillo, 2013 ). These findings may provide a new insight into not only the hemiataxia, but also the cognitive and behavior comorbidities of CCD ( Devita et al, 2021 , Leisman and Melillo, 2013 ).…”