Value of¹⁸Fluorodeoxyglucose–Positron-Emission Tomography in Amyotrophic Lateral Sclerosis

Abstract

IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting the motor system, with extramotor involvement to a variable extent. Biomarkers for early differential diagnosis and prognosis are needed. An autosomal dominant hexanucleotide (GGGGCC) expansion in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent genetic cause of ALS, but its metabolic pattern has not been studied systematically.OBJECTIVES To evaluate the use of 18 fluorodeoxyglucose-positron-emission tomography as a marker of ALS pathology and investigate whether a specific metabolic signature is present in patients with C9orf72 mutations. DESIGN, SETTING, AND PARTICIPANTSIn total, 81 patients with a suspected diagnosis of ALS at University Hospital Leuven were prospectively investigated. All underwent detailed neurological examination and electrodiagnostic and genetic testing for the major known genetic causes of ALS (C9orf72, SOD1, TARDBP, and FUS). A diagnosis of ALS was made in 70 of 81 patients. Of these, 11 were C9orf72 positive and 59 were C9orf72 negative. In 7 patients, the diagnosis of primary lateral sclerosis was made; 4 patients had progressive muscular atrophy. A screened healthy control population was used for comparison. MAIN OUTCOMES AND MEASURESPositron-emission tomographic data were spatially normalized and analyzed using a predefined volume of interest and a voxel-based analysis (SPM8). Discriminant analysis was done both volume of interest based and voxel based using a support vector machine approach.RESULTS Compared with control participants, 18 fluorodeoxyglucose-positron-emission tomography showed perirolandic and variable prefrontal hypometabolism in most patients. Patients with primary lateral sclerosis showed a similar pattern. Patients with C9orf72-positive ALS had discrete relative hypometabolism in the thalamus and posterior cingulate compared with those with C9orf72-negative ALS. A posteriori-corrected discriminant analysis was able to correctly classify 95% of ALS cases and 71% of primary lateral sclerosis cases. Prefrontal hypometabolism was associated with reduced clinical functioning (ALS Functional Rating Scale). Extensive hypometabolism in the prefrontal or anterior temporal areas was present in 10% of patients and associated with significantly shorter survival as an independent factor (n = 63, P < .001). Patients who were C9orf72 positive did not differ in survival compared with those who were C9orf72 negative. 18 Fluorodeoxyglucose-positron-emission tomography is a useful early diagnostic and prognostic marker for ALS. Amyotrophic lateral sclerosis that is positive for C9orf72 is characterized by only mild cerebral metabolic differences that show no prognostic difference. CONCLUSIONS AND RELEVANCE

Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

“…ALS, with both upper and lower motor neuron involvement, is part of the spectrum of motor neuron diseases consisting also of primary lateral sclerosis (PLS), with exclusively upper motor neuron disease, and progressive muscular atrophy (PMA), with only lower motor neuron disease. Both PMA and PLS can progress to ALS (1)(2)(3)(4).…”

“…In patients with ALS, a pattern of relative hypometabolism in the primary motor cortex, premotor cortices, and supplementary motor cortex but extending to extramotor areas such as the frontal and parietal lobes as well has been observed (2,4,(7)(8)(9)(10)(11). Relative hypermetabolism is observed in the mesotemporal cortex, cerebellum, and upper brain stem (2,4,7,10,(12)(13)(14). Within-center retrospective discriminant analysis methods to differentiate subjects with early ALS from controls have resulted in an overall classification accuracy of 90%-95% (2,4,10).…”

Neuroimaging as a New Diagnostic Modality in Amyotrophic Lateral Sclerosis

“…Additionally, decreased metabolism was seen in the frontal brain regions. However, only the larger study reported decreased metabolism in the motor cortex [68]. A more recent study reported reduced metabolism in the frontal, motor, and occipital regions, and increased metabolism in the midbrain, temporal pole, and hippocampus in patients with ALS [69].…”

“…Two [ 18 F]FDG studies of patients with ALS reported increased metabolic activity in extramotor regions, including the upper brain stem, mesial temporal region, and cerebellum [67,68]. Additionally, decreased metabolism was seen in the frontal brain regions.…”

“…A more recent study reported reduced metabolism in the frontal, motor, and occipital regions, and increased metabolism in the midbrain, temporal pole, and hippocampus in patients with ALS [69]. In 2 studies, patients with ALS could be differentiated from healthy controls with a high degree of diagnostic accuracy using [ 18 F]FDG [68,69]. Undoubtedly, continued development of new PET agents will provide more potential biomarkers for ALS.…”