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Positron Emission Tomography in Pediatric Neurodegenerative Disorders

      Abstract

      Application of molecular neuroimaging using positron emission tomographic techniques to assess pediatric neurodegenerative disorders has been limited, unlike in adults where positron emission tomography has contributed to clinical diagnosis, monitoring of neurodegenerative disease progression, and assessment of novel therapeutic approaches. Yet, there is a huge unexplored potential of molecular imaging to improve our understanding of the pathophysiology of neurodegenerative disorders in children and provide radiological biomarkers that can be applied clinically. The obstacles in performing PET scans on children include sedation, radiation exposure, and access but, as will be illustrated, these barriers can be easily overcome. This review summarizes findings from PET studies that have been performed over the past three decades on children with various neurodegenerative disorders, including the neuronal ceroid lipofuscinoses, juvenile Huntington disease, Wilson disease, Niemann-Pick disease type C, Dravet syndrome, dystonia, mitochondrial disorders, inborn errors of metabolism, lysosomal storage diseases, dysmyelinating disorders, Rett syndrome, neurotransmitter disorders, glucose transporter Glut 1 deficiency, and Lesch-Nyhan disease. Because positron emission tomographic scans have often been clinically useful and have contributed to the management of these disorders, we suggest that the time has come for glucose metabolism positron emission tomographic scans to be reimbursed by insurance carriers for children with neurodegenerative disorders, and not restricted only to epilepsy surgery evaluation.

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      References

        • Kato T.
        • Inui Y.
        • Nakamura A.
        • Ito K.
        Brain fluorodeoxyglucose (FDG) PET in dementia.
        Ageing Res Rev. 2016; 30: 73-84
        • Valotassiou V.
        • Malamitsi J.
        • Papatriantafyllou J.
        • et al.
        SPECT and PET imaging in Alzheimer's disease.
        Ann Nucl Med. 2018; 32: 583-593
        • Chen M.K.
        • Mecca A.P.
        • Naganawa M.
        • et al.
        Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomography imaging.
        JAMA Neurol. 2018; 75: 1215-1224
        • Williams R.E.
        • Adams H.R.
        • Blohm M.
        • et al.
        Management strategies for CLN2 disease.
        Pediatr Neurol. 2017; 69: 102-112
        • Mole S.E.
        • Anderson G.
        • Band H.A.
        • et al.
        Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis.
        Lancet Neurol. 2019; 18: 107-116
        • De Volder A.G.
        • Cirelli S.
        • de Barsy T.
        • et al.
        Neuronal ceroid-lipofuscinosis: preferential metabolic alterations in thalamus and posterior association cortex demonstrated by PET.
        J Neurol Neurosurg Psychiatry. 1990; 53: 1063-1067
        • Philippart M.
        • Messa C.
        • Chugani H.T.
        Spielmeyer-Vogt (Batten, Spielmeyer-Sjogren) disease. Distinctive patterns of cerebral glucose utilization.
        Brain. 1994; 117: 1085-1092
        • Iannetti P.
        • Messa C.
        • Spalice A.
        • Lucignani G.
        • Fazio F.
        Positron emission tomography in neuronal ceroid lipofuscinosis (Jansky-Bielschowsky disease): a case report.
        Brain Dev. 1994; 16: 459-462
        • Philippart M.
        • da Silva E.
        • Chugani H.T.
        The value of positron emission tomography in the diagnosis and monitoring of late infantile and juvenile lipopigment storage disorders (so-called Batten or neuronal ceroid lipofuscinoses).
        Neuropediatrics. 1997; 28: 74-76
        • Rinne J.O.
        • Ruottinen H.M.
        • Nagren K.
        • Aberg L.E.
        • Santavuori P.
        Positron emission tomography shows reduced striatal D1 but not D2 receptors in juvenile neuronal ceroid lipofuscinosis.
        Neuropediatrics. 2002; 33: 138-141
        • Hayden M.R.
        • Martin W.R.
        • Stoessl A.J.
        • et al.
        Positron emission tomography in the early diagnosis of Huntington's disease.
        Neurology. 1986; 36: 888-894
        • Pagano G.
        • Niccolini F.
        • Politis M.
        Current status of PET imaging in Huntington's disease.
        Eur J Nucl Med Mol Imaging. 2016; 43: 1171-1182
        • Wilson H.
        • Niccolini F.
        • Haider S.
        • et al.
        Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington's disease gene carriers.
        J Neurol Sci. 2016; 368: 243-248
        • De Volder A.
        • Bol A.
        • Michel C.
        • et al.
        Brain glucose utilization in childhood Huntington's disease studied with positron emission tomography (PET).
        Brain Dev. 1988; 10: 47-50
        • Diggle C.P.
        • Rizzo S.J.S.
        • Popiolek M.
        • et al.
        Biallelic mutations in PDE10A lead to loss of striatal PDE10A and a hyperkinetic movement disorder with onset in infancy.
        Am J Hum Genet. 2016; 98: 735-743
        • Hawkins R.A.
        • Mazziotta J.C.
        • Phelps M.E.
        Wilson's disease studied with FDG and positron emission tomography.
        Neurology. 1987; 37: 1707-1711
        • Kuwert T.
        • Hefter H.
        • Scholz D.
        • et al.
        Regional cerebral glucose consumption measured by positron emission tomography in patients with Wilson's disease.
        Eur J Nucl Med. 1992; 19: 96-101
        • Westermark K.
        • Tedroff J.
        • Thuomas K.A.
        • et al.
        Neurological Wilson's disease studied with magnetic resonance imaging and with positron emission tomography using dopaminergic markers.
        Mov Disord. 1995; 10: 596-603
        • Bruehlmeier M.
        • Leenders K.L.
        • Vontobel P.
        • Calonder C.
        • Antonini A.
        • Weindl A.
        Increased cerebral iron uptake in Wilson's disease: a 52Fe-citrate PET study.
        J Nucl Med. 2000; 41: 781-787
        • Kumar A.
        • Chugani H.T.
        Niemann-Pick disease type C: unique 2-deoxy-2[18F] fluoro-D-glucose PET abnormality.
        Pediatr Neurol. 2011; 44: 57-60
        • Benussi A.
        • Alberici A.
        • Premi E.
        • et al.
        Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins.
        J Neurol. 2015; 262: 642-647
        • Huang J.Y.
        • Peng S.F.
        • Yang C.C.
        • Yen K.Y.
        • Tzen K.Y.
        • Yen R.F.
        Neuroimaging findings in a brain with Niemann-Pick type C disease.
        J Formos Med Assoc. 2011; 110: 537-542
        • Kumar A.
        • Chugani H.T.
        • Muzik O.
        • Chakraborty P.
        [C-11]PK-11195 as a positron emission tomography biomarker of brain inflammation in children with Niemann-Pick disease type-C.
        J Nucl Med. 2009; 50: 96P
        • Ferrie C.D.
        • Maisey M.
        • Cox T.
        • et al.
        Focal abnormalities detected by 18FDG PET in epileptic encephalopathies.
        Arch Dis Child. 1996; 75: 102-107
        • Kumar A.
        • Juhász C.
        • Luat A.
        • et al.
        Evolution of brain glucose metabolic abnormalities in children with epilepsy and SCN1A gene variants.
        J Child Neurol. 2018; 33: 832-836
        • Haginoya K.
        • Togashi N.
        • Kantea T.
        • et al.
        [18F]fluorodeoxyglucose-positron emission tomography study of genetically confirmed patients with Dravet syndrome.
        Epilepsy Res. 2018; 147: 9-14
        • Alongi P.
        • Iaccarino L.
        • Perani D.
        PET neuroimaging: insights on dystonia and Tourette syndrome and potential applications.
        Front Neurol. 2014; 5: 183-196
        • Szyszko T.A.
        • Dunn J.T.
        • O'Doherty M.J.
        • Reed L.
        • Lin J.P.
        Role of 18F-FDG PET imaging in paediatric primary dystonia and dystonia arising from neurodegeneration with brain iron accumulation.
        Nucl Med Commun. 2015; 36: 469-476
        • Rinne J.O.
        • Iivanainen M.
        • Metsähonkala L.
        • et al.
        Striatal dopaminergic system in dopa-responsive dystonia: a multi-tracer PET study shows increased D2 receptors.
        J Neural Transm (Vienna). 2004; 111: 59-67
        • Frackowiak R.S.
        • Herold S.
        • Petty R.K.
        • Morgan-Hughes J.A.
        The cerebral metabolism of glucose and oxygen measured with positron tomography in patients with mitochondrial diseases.
        Brain. 1988; 111: 1009-1024
        • Toyoda M.
        • Sakuragawa N.
        • Arai Y.
        • et al.
        Positron emission tomography using pyruvate-1-11C in two cases of mitochondrial encephalomyopathy.
        Ann Nucl Med. 1989; 3: 103-109
        • Yokoi F.
        • Hara T.
        • Iio M.
        • Nonaka I.
        • Satoyoshi E.
        1-[11C]pyruvate turnover in brain and muscle of patients with mitochondrial encephalomyopathy. A study with positron emission tomography (PET).
        J Neurol Sci. 1990; 99: 339-348
        • Shishido F.
        • Uemura K.
        • Inugami A.
        • et al.
        Cerebral oxygen and glucose metabolism and blood flow in mitochondrial encephalomyopathy: a PET study.
        Neuroradiology. 1996; 38: 102-107
        • Duncan D.B.
        • Herholz K.
        • Kugel H.
        • et al.
        Positron emission tomography and magnetic resonance spectroscopy of cerebral glycolysis in children with congenital lactic acidosis.
        Ann Neurol. 1995; 37: 351-358
        • Haginoya K.
        • Kaneta T.
        • Togashi N.
        • et al.
        FDG-PET study of patients with Leigh syndrome.
        J Neurol Sci. 2016; 362: 309-313
        • Mascalchi M.
        • Montomoli M.
        • Guerrini R.
        Neuroimaging in mitochondrial disorders.
        Essays Biochem. 2018; 62: 409-421
        • Al-Essa M.
        • Bakheet S.
        • Patay Z.
        • et al.
        Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in glutaric aciduria type 1: clinical and MRI correlations.
        Brain Dev. 1998; 20: 295-301
        • Al-Essa M.
        • Bakheet S.
        • Al-Shamsan L.
        • Patay Z.
        • Powe J.
        • Ozand P.T.
        18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in type IV 3-methylglutaconic aciduria: clinical and MRI correlations.
        Brain Dev. 1999; 21: 24-29
        • Al-Essa M.
        • Bakheet S.
        • Patay Z.
        • et al.
        18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in propionic acidemia: clinical and MRI correlations.
        Brain Dev. 1999; 21: 312-317
        • Al-Essa M.A.
        • al-Shamsan L.A.
        • Ozand P.T.
        Clinical and brain 18fluoro-2-deoxyglucose positron emission tomographic findings in ethylmalonic aciduria, a progressive neurometabolic disease.
        Eur J Paediatr Neurol. 1999; 3: 125-127
        • Al-Essa M.A.
        • Bakheet S.M.
        • Patay Z.J.
        • Powe J.E.
        • Ozand P.T.
        Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography (FDG PET), MRI of the brain and biochemical observations in a patient with 4-hydroxybutyric aciduria; a progressive neurometabolic disease.
        Brain Dev. 2000; 22: 127-131
        • Biffi A.
        Gene therapy for lysosomal storage disorders: a good start.
        Hum Mol Genet. 2016; 25: R65-R75
        • Al-Essa M.A.
        • Bakheet S.M.
        • Patay Z.J.
        • Nounou R.M.
        • Ozand P.T.
        Cerebral fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography (FDG PET), MRI, and clinical observations in a patient with infantile G(M1) gangliosidosis.
        Brain Dev. 1999; 21: 559-562
        • Lee S.M.
        • Lee M.J.
        • Lee J.S.
        • et al.
        Newly observed thalamic involvement and mutations of the HEXA gene in a Korean patient with juvenile GM2 gangliosidosis.
        Metab Brain Dis. 2008; 23: 235-242
        • Al-Essa M.A.
        • Bakheet S.M.
        • Patay Z.J.
        • Powe J.E.
        • Ozand P.T.
        Clinical and cerebral FDG PET scan in a patient with Krabbe's disease.
        Pediatr Neurol. 2000; 22: 44-47
        • Faria Dde P.
        • Copray S.
        • Buchpiguel C.
        • Dierckx R.
        • de Vries E.
        PET imaging in multiple sclerosis.
        J Neuroimmune Pharmacol. 2014; 4: 468-482
        • Singhal T.
        • Weiner H.L.
        • Bakshi R.
        TSPO-PET imaging to assess cerebral microglial activation in multiple sclerosis.
        Semin Neurol. 2017; 37: 546-557
        • Sawaishi Y.
        • Hatazawa J.
        • Ochi N.
        • et al.
        Positron emission tomography in juvenile Alexander disease.
        J Neurol Sci. 1999; 165: 116-120
        • Salsano E.
        • Marotta G.
        • Manfredi V.
        • et al.
        Brain fluorodeoxyglucose PET in adrenoleukodystrophy.
        Neurology. 2014; 83: 981-989
        • Kumar A.
        • Chugani H.T.
        • Chakraborty P.
        • Huq A.H.
        Evaluation of neuroinflammation in X-linked adrenoleukodystrophy.
        Pediatr Neurol. 2011; 44: 143-146
        • Naidu S.
        • Kaufmann W.E.
        • Abrams M.T.
        • et al.
        Neuroimaging studies in Rett syndrome.
        Brain Dev. 2001; 23: S62-S71
        • Dunn H.G.
        • Stoessl A.J.
        • Ho H.H.
        • et al.
        Rett syndrome: investigation of nine patients, including PET scan.
        Can J Neurol Sci. 2002; 29: 345-357
        • Wong D.F.
        • Blue M.E.
        • Brašić J.R.
        • et al.
        Are dopamine receptor and transporter changes in Rett syndrome reflected in Mecp2-deficient mice?.
        Exp Neurol. 2018; 307: 74-81
        • Pearl P.L.
        • Gibson K.M.
        • Quezado Z.
        • et al.
        Decreased GABA-A binding on FMZ-PET in succinic semialdehydedehydrogenase deficiency.
        Neurology. 2009; 73: 423-429
        • Pearl P.L.
        • Parviz M.
        • Vogel K.
        • Schreiber J.
        • Theodore W.H.
        • Gibson K.M.
        Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification.
        Dev Med Child Neurol. 2015; 57: 611-617
        • Pascual J.M.
        • Van Heertum R.L.
        • Wang D.
        • Engelstad K.
        • De Vivo D.C.
        Imaging the metabolic footprint of Glut1 deficiency on the brain.
        Ann Neurol. 2002; 52: 458-464
        • Ernst M.
        • Zametkin A.J.
        • Matochik J.A.
        • et al.
        Presynaptic dopaminergic deficits in Lesch-Nyhan disease.
        N Engl J Med. 1996; 334: 1568-1572
        • Wong D.F.
        • Harris J.C.
        • Naidu S.
        • et al.
        Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.
        Proc Natl Acad Sci U S A. 1996; 93: 5539-5543
        • Shandal V.
        • Veenstra A.L.
        • Behen M.
        • Sundaram S.
        • Chugani H.
        Long-term outcome in children with intractable epilepsy showing bilateral diffuse cortical glucose hypometabolism pattern on positron emission tomography.
        J Child Neurol. 2012; 27: 39-45