In a recent study in JAMA Neurology, a Leuven research team led by Prof. Philip Van Damme, reveals that FDG-PET imaging is an early and sensitive biomarker to detect cerebral metabolic changes in presymptomatic carriers of a C9orf72 mutation. Their findings suggest that FDG-PET captures early cerebral changes years before disease onset.

C9orf72 mutations cause FTD and ALS

C9orf72 mutations are the most common cause of familial frontotemporal dementia and amyotrophic lateral sclerosis, better known as ALS.

ALS is characterized by a progressive loss of motor neurons in the brain and spinal cord, resulting in progressive muscle weakness and wasting. The majority of patients will die within two to five years after symptom onset. About half of all patients also show non-motor symptoms.

Frontotemporal dementia or FTD is the second most common form of early onset dementia, after Alzheimer’s disease, and is characterized by neuronal loss in the frontal and anterior temporal lobes of the brain. Symptoms include changes in cognition (e.g. language, executive functions…) as well as behavior (e.g. apathy, disinhibition …).

The discovery of the hexanucleotide repeat expansion in C9orf72 as the major cause of both ALS and FTD proves that both disorders can represent two extremes of the same continuum.

A C9orf72 gene mutation is the most common cause of both familial ALS and FTD. The presence of this mutation is associated with an extremely variable clinical phenotype and does not appear to always cause disease. This suggests that multiple disease modifiers are at work, which could be potential therapeutic targets.

“People who carry this particular mutation most likely represent the largest reservoir of future patients with a neurodegenerative disorder caused by a single genetic mutation,” explains Philip Vandamme. The study of such presymptomatic individuals offers tremendous opportunities to understand how age-dependent neurodegenerative diseases develop and progress.

FDG-PET as an early marker for cerebral changes

In this study, Joke De Vocht from the team of Van Damme in Leuven (Neurology Department UZ Leuven, Laboratory of Neurobiology at the VIB Center for Brain & Disease Research) studied the presymptomatic disease phase in carriers of a C9orf72 gene mutation, using state-of-the-art time-of-flight 18F FDG-PET MR imaging. 18F FDG-PET imaging appears to identify changes at the individual level, prior to significant changes in neurofilament levels, previously reported to rise in the year preceding disease onset.

“In an exciting era with potential for novel treatment strategies (e.g. antisense oligonucleotides), that can slow down or even prevent symptom onset, we believe that a test that can detect early changes in individual patients is extremely relevant,” says De Vocht. “Our findings suggest that FDG-PET appears to be an early and sensitive biomarker, which may ultimately contribute to identifying the optimal window for preventive treatments.”


Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion

De Vocht et al., JAMA Neurology 2020

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