title: Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  To evaluate the use of 18fluorodeoxyglucose-positron-emission tomography as a marker of ALS pathology and investigate whether a specific metabolic signature is present in patients with C9orf72 mutations.
  
  
  METHODS
  In 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.
  
  
  METHODS
  Positron-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, 18fluorodeoxyglucose-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.
  
  
  CONCLUSIONS
  18Fluorodeoxyglucose-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.
authors.affiliation: KU Leuven, Nuclear Medicine and Molecular Imaging, University Hospital Leuven, Leuven, Belgium3KU Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium4VIB, Vesalius.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: KU Leuven, Department of Neurology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Vanhee
authors.affiliation: KU Leuven, Nuclear Medicine and Molecular Imaging, University Hospital Leuven, Leuven, Belgium.
authors.forename: Jolien
authors.initials: J
authors.lastname: Verschueren
authors.affiliation: KU Leuven, Nuclear Medicine and Molecular Imaging, University Hospital Leuven, Leuven, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: De Coster
authors.affiliation: KU Leuven, Department of Neurology, University Hospital Leuven, Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Driesen
authors.affiliation: KU Leuven, Department of Neurology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dupont
authors.affiliation: KU Leuven, Department of Neurology, University Hospital Leuven, Leuven, Belgium3KU Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium4VIB, Vesalius Research Cente.
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: KU Leuven, Department of Neurology, University Hospital Leuven, Leuven, Belgium3KU Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium4VIB, Vesalius Research Cente.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000378:metabolism; D000073885:C9orf72 Protein; D015331:Cohort Studies; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000592:standards*; D011379:Prognosis; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D019788:Fluorodeoxyglucose F18