Testing the diagnostic accuracy of [18F]FDG-PET in discriminating spinal- and bulbar-onset amyotrophic lateral sclerosis
The role for [18F]FDG-PET in supporting amyotrophic lateral sclerosis (ALS) diagnosis is not fully established. In this study, we aim at evaluating [18F]FDG-PET hypo- and hyper-metabolism patterns in spinal- and bulbar-onset ALS cases, at the single-subject level, testing the diagnostic value in discriminating the two conditions, and the correlations with core clinical symptoms severity.
We included 95 probable-ALS patients with [18F]FDG-PET scan and clinical follow-up. [18F]FDG-PET images were analyzed with an optimized voxel-based-SPM method. The resulting single-subject SPM-t maps were used to: (a) assess brain regional hypo- and hyper-metabolism; (b) evaluate the accuracy of regional hypo- and hyper metabolism in discriminating spinal vs. bulbar-onset ALS; (c) perform correlation analysis with motor symptoms severity, as measured by ALS-FRS-R.
Primary motor cortex showed the most frequent hypo-metabolism in both spinal-onset (∼57%) and bulbar-onset (∼64%) ALS; hyper-metabolism was prevalent in the cerebellum in both spinal-onset (∼56.5%) and bulbar-onset (∼55.7%) ALS, and in the occipital cortex in bulbar-onset (∼62.5%) ALS. Regional hypo- and hyper-metabolism yielded a very low accuracy (AUC < 0.63) in discriminating spinal- vs. bulbar-onset ALS, as obtained from single-subject SPM-t-maps. Severity of motor symptoms correlated with hypo-metabolism in sensorimotor cortex in spinal-onset ALS, and with cerebellar hyper-metabolism in bulbar-onset ALS.
The high variability in regional hypo- and hyper-metabolism patterns, likely reflecting the heterogeneous pathology and clinical phenotypes, limits the diagnostic potential of [18F]FDG-PET in discriminating spinal and bulbar onset patients.
KeywordsAmyotrophic lateral sclerosis Biomarkers Diagnosis [18F]FDG-PET Brain metabolism
This study was funded by the Italian Ministry of Health (Ricerca Finalizzata Progetto Reti Nazionale AD NET-2011-02346784) (D.P), EU FP7 INMIND Project (FP7-HEALTH-2011-two-stage “Imaging of Neuroinflammation in Neurodegenerative Diseases”, grant agreement no. 278850)” (D.P.), “IVASCOMAR project “Identificazione, validazione e sviluppo commerciale di nuovi biomarcatori diagnostici prognostici per malattie complesse” (grant agreement no. CTN01_00177_165430)” (D.P.), CARIPLO Project “Evaluation of autonomic, genetic, imaging and biochemical markers for Parkinson-related dementia: longitudinal assessment of a PD cohort” 2016–2020 (grant agreement no. 2014–0832)” (D.P.), Fondazione Eli-Lilly (Eli-Lilly grant 2011 “Imaging of neuroinflammation and neurodegeneration in prodromal and presymptomatic Alzheimer’s disease phases”)(C.C.), Ministero dell’Istruzione, dell’Università e della Ricerca – MIUR project “Dipartimenti di Eccellenza 2018–2022″ to Department of Neuroscience “Rita Levi Montalcini”(Ad.C, And.C, Ant.C.). This work was in part supported by the Italian Ministry of Health (Ricerca Sanitaria Finalizzata 2010, grant RF-2010e2309849) (Ad.C), the European Community’s Health Seventh Framework Programme (FP7/2007–2013 under grant agreement 259867) (Ad.C), the Joint Programme - Neurodegenerative Disease Research (Italian Ministry of Education, University and Research) (Sophia) (Ad.C.), Fondazione Vialli e Mauro (And.C.); and Fondazione Magnetto (Ant.C.).
Compliance with ethical standards
Conflict of interest
A. Chiò reports grants from the Italian Ministry of Health (Ricerca Finalizzata), EU JPND through the Ministry of Education, University, and Research, and the Italy-Israel Scientific Collaboration through the Italian Foreign Ministry, as well as personal fees from Biogen Idec, Cytokinetics, Italfarmaco, Mitsubishi Tanabe, and Neuraltus. All other authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Ludolph A, Drory V, Hardiman O, Nakano I, Ravits J, Robberecht W, et al. A revision of the El Escorial criteria - 2015. Amyotroph Lateral Scler Front Degener. 2015;16:291–2.Google Scholar
- 12.McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s dement. Elsevier Ltd. 2011;7:263–9.Google Scholar
- 18.Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s dement. Elsevier Ltd. 2011;7:280–92.Google Scholar
- 20.Caminiti SP, Alongi P, Majno L, Volontè MA, Cerami C, Gianolli L, et al. Evaluation of an optimized [18F]fluoro-deoxy-glucose positron emission tomography voxel-wise method to early support differential diagnosis in atypical Parkinsonian disorders. Eur J Neurol. 2017;24:687–e26.CrossRefGoogle Scholar
- 22.Perani D, Della Rosa PA, Cerami C, Gallivanone F, Fallanca F, Vanoli EG, et al. Validation of an optimized SPM procedure for FDG-PET in dementia diagnosis in a clinical setting. NeuroImage. Clin. Elsevier BV. 2014;6:445–54.Google Scholar
- 27.Iaccarino L, Chiotis K, Alongi P, Almkvist O, Wall A, Cerami C, et al. A cross-validation of FDG- and amyloid-PET biomarkers in mild cognitive impairment for the risk prediction to dementia due to Alzheimer’s disease in a clinical setting. J Alzheimers Dis. 2017:1–12.Google Scholar
- 36.Gallivanone F, Della Rosa P, Perani D, Gilardi MC, Castiglioni I. The impact of different 18FDG PET healthy subject scans for comparison with single patient in SPM analysis. Q J Nucl Med Mol Imaging. 2017;6(1):115–32.Google Scholar
- 48.Endo H, Sekiguchi K, Ueda T, Kowa H, Kanda F, Toda T. Regional glucose hypometabolic spread within the primary motor cortex is associated with amyotrophic lateral sclerosis disease progression: a fluoro-deoxyglucose positron emission tomography study. eNeurologicalSci. 2017;6:74–9.CrossRefGoogle Scholar
- 50.Genç B, Jara JH, Lagrimas AKB, Pytel P, Roos RP, Mesulam MM, et al. Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS. Sci Rep Nature Publishing Group. 2017;7:41765.Google Scholar
- 51.Baker MR. ALS—dying forward, backward or outward? Nat Rev Neurol. 2014;10:660–0.Google Scholar
- 59.Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG. Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Neurobiology. 1998;95:316–21.Google Scholar
- 65.Willekens SMA, Van Weehaeghe D, Van Damme P, Van Laere K. Positron emission tomography in amyotrophic lateral sclerosis: towards targeting of molecular pathological hallmarks. Eur J Nucl Med Mol Imaging. 2016:1–15.Google Scholar