Mild cognitive dysfunction in hereditary spastic paraplegia 4 disease related to fluorodesoxyglucose cerebral positron emission tomography

Autosomal dominant spastic paraplegia type 4 (SPG4, SPAST gene) is commonly described as a pure phenotype, with progressive spastic weakness of the lower limbs. Some cognitive disorders have been reported but remain difficult to characterize. Brain flurodesoxyglucose (18F-FDG) PET is a sensitive biomarker of glycolytic metabolism and shows loss of neuronal activity. Our objective was to describe the cognitive impairment of patients carrying the SPG4 variant, supported by brain 18F-FDG PET, to characterize the cognitive pattern and its localization. Twenty subjects from the Grand Est region, with a pathogenic variant in the SPAST gene, were included. Each patient had to undergo a neuropsychological assessment, a brain 18F-FDG PET scan, and a SPATAX-EuroSpa clinical assessment, including the Spastic Paraplegia Rating Scale (SPRS). Brain 18F-FDG PET was analyzed semiquantitatively after comparison with age and sex-matched control subjects. The study population was 65% (13/20) female, with an average age of 50 years (19−75 years). The median SPRS was 15/52 (12−45). Forty-four percent (7/16) of patients had a deficient Montreal Cognitive Assessment (MoCa) score (score <26) without any severe impairment (score <10). Assessments with a pathological score of <1.65 standard deviations or at the 5th percentile included verbal episodic memory in 16-item Free and Cued Recall (FCRT; 63%, 10/16), facial emotion recognition (56%, 9/16), and executive functions (Trail Making Test A and B; 47%, 7/15; the Stroop; 47%, 7/15; digit spans of Weschler Adult Intelligence Scale 4; 38%, 6/16). Compared with those of control subjects, 18-FDG PET images of the brains of SPG4 subjects revealed frontotemporal and precuneus hypometabolism, principally in the prefrontal cortex, which was mainly mesial (p voxel value <0.001, corrected for the size of the familywise error (FWE) cluster, k=1464). Frontal hypometabolism was correlated with age at onset (k=-0.475, p=0.046) and the time to perform the Trail Making Test B test (k=-0.597, p =0.019). Here, we describe a mild cognitive disorder clinically in SPG4 patients, associated with an hypometabolism on 18F-FDG PET imaging, which mainly corresponded to frontotemporal localization. Mild cognitive dysfunction should be screened in SPG4, as it can have a significant impact on socioprofessional life. Brain 18F-FDG PET, combined with neuropsychological assessment. appears to be a good screening and follow-up examination for cognitive disorders.