Skip to main content

Advertisement

SpringerLink
Log in

The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Recently, a GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene, located on chromosome 9p21 has been demonstrated to be the commonest cause of familial amyotrophic lateral sclerosis (ALS) and to account for 5 to 10 % of apparently sporadic ALS. Relatively little is known about the brain metabolism profile of patients carrying the expansion. Our aim was to identify the [18F]FDG PET profile in ALS patients with the C9ORF72 expansion (C9ORF72-ALS).

Methods

Fifteen C9ORF72-ALS patients were compared with 12 patients with ALS and comorbid frontotemporal dementia (FTD) without the C9ORF72 expansion (ALS-FTD) and 30 cognitively normal patients with ALS without mutations of ALS-related genes (sALS). The three groups were then cross-matched to 40 neurologically normal controls. All patients underwent FDG PET within 4 months of diagnosis.

Results

The C9ORF72-ALS patients compared with the sALS patients showed significant hypometabolism in the anterior and posterior cingulate cortex, insula, caudate and thalamus, the left frontal and superior temporal cortex, and hypermetabolism in the midbrain, bilateral occipital cortex, globus pallidus and left inferior temporal cortex. The ALS-FTD patients compared with the sALS patients showed more limited hypometabolic areas, including the orbitofrontal, prefrontal, anterior cingulate and insular cortex, and hypermetabolic areas, including the bilateral occipital cortex, the left precentral and postcentral cortex and superior temporal gyrus. The C9ORF72-ALS patients compared with the ALS-FTD patients showed hypometabolism in the left temporal cortex.

Conclusion

ALS patients with the C9ORF72 hexanucleotide repeat expansion had a more widespread central nervous system involvement than ALS patients without genetic mutations, with or without comorbid FTD, consistent with their more severe clinical picture.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377:942–55.

    Article  CAS  PubMed  Google Scholar 

  2. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9ORF72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012;11:232–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, et al. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012;135:784–93.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Dejesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of the C9ORF72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11:323–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Sabatelli M, Conforti FL, Zollino M, Mora G, Monsurrò MR, Volanti P, et al. C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population. Neurobiol Aging. 1848;2012(33):e15–20.

    Google Scholar 

  8. Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R, et al. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry. 2011;82:196–203.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain. 2012;135:765–83.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:293–9.

    Article  CAS  PubMed  Google Scholar 

  11. Brown JA, Min J, Staropoli JF, Collin E, Bi S, Feng X, et al. SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: a United States clinical testing lab experience. Amyotroph Lateral Scler. 2012;13:217–22.

    Article  CAS  PubMed  Google Scholar 

  12. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546–54.

    Article  CAS  PubMed  Google Scholar 

  13. Strong MJ, Grace GM, Freedman M, Lomen-Hoerth C, Woolley S, Goldstein LH, et al. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioral syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2009;10:131–46.

    Article  Google Scholar 

  14. Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosci Psychiatry. 2011;83:102–8.

    Article  Google Scholar 

  15. Grace J, Malloy P. Frontal Systems Behavior Scale (FrSBe): professional manual. Lutz, Fla, Psychological Assessment Resources, 2001.

  16. Varrone A, Asenbaum S, Vander Borght T, Booij J, Nobili F, Någren K, et al. EANM procedure guidelines for PET brain imaging using [18F]FDG, version 2. Eur J Nucl Med Mol Imaging. 2009;36:2103–10.

    Article  PubMed  Google Scholar 

  17. Oishi N, Udaka F, Kameyama M, Sawamoto N, Hashikawa K, Fukuyama H. Regional cerebral blood flow in Parkinson disease with nonpsychotic visual hallucinations. Neurology. 2005;65:1708–15.

    Article  CAS  PubMed  Google Scholar 

  18. Bloudek LM, Spackman DE, Blankenburg M, Sullivan SD. Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer’s disease. J Alzheimers Dis. 2011;26:627–45.

    Article  CAS  PubMed  Google Scholar 

  19. Caroli A, Prestia A, Chen K, Ayutyanont N, Landau SM, Madison CM, et al. Summary metrics to assess Alzheimer disease-related hypometabolic pattern with 18F-FDG PET: head-to-head comparison. J Nucl Med. 2012;53:592–600.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Cistaro A, Valentini MC, Chiò A, Nobili F, Calvo A, Moglia C, et al. Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset. Eur J Nucl Med Mol Imaging. 2012;39:251–9.

    Article  CAS  PubMed  Google Scholar 

  21. Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranuline and sporadics. Brain. 2012;135:794–806.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain. 2012;135:736–50.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Bede P, Bokde ALW, Byrne S, Elamin M, McLaughlin RL, Kenna K, et al. A multiparametric MRI study of ALS stratified for the C9ORF72 genotype. Neurology. 2013;81:361–9.

    Article  PubMed  Google Scholar 

  24. Murray ME, DeJesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 2011;122:673–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S, et al. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain. 2012;135:751–64.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Allman JM, Hakeem A, Erwin JM, Nimchinsky E, Hof P. The anterior cingulate cortex. The evolution of an interface between emotion and cognition. Ann N Y Acad Sci. 2001;935:107–17.

    Article  CAS  PubMed  Google Scholar 

  27. Fujimoto T, Takeuch K, Matsumoto T, Kamimura K, Hamada R, Nakamura K, et al. Abnormal glucose metabolism in the anterior cingulate cortex in patients with schizophrenia. Psych Res Neuroimaging. 2007;154:49–58.

    Article  CAS  Google Scholar 

  28. Patel NH, Vyas NS, Puri BK, Nijran KS, Al Nahhas A. Positron emission tomography in schizophrenia: a new perspective. J Nucl Med. 2010;51:511–20.

    Article  CAS  PubMed  Google Scholar 

  29. Simpson EH, Kellendonk C, Kandel E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron. 2010;65:585–96.

    Article  CAS  PubMed  Google Scholar 

  30. Grahn JA, Parkinson JA, Owen AM. The role of the basal ganglia in learning and memory: neuropsychological studies. Behav Brain Res. 2009;199:53–60.

    Article  PubMed  Google Scholar 

  31. Majounie E, Abramzon Y, Renton AE, Perry R, Bassett SS, Pletnikova O, et al. Repeat expansion in C9ORF72 in Alzheimer’s disease. N Engl J Med. 2012;366:283–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S, et al. C9ORF72 repeat expansions are a rare genetic cause of parkinsonism. Brain. 2013;136:385–91.

    Article  PubMed  Google Scholar 

  33. Turner MR, Cagnin A, Turkheimer FE, Turkheimer F, Miller CCJ, Shaw CE. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15:601–9.

    Article  CAS  PubMed  Google Scholar 

  34. Johansson A, Engler H, Blomquist G, Scott B, Wall A, Aquilonius SM, et al. Evidence for astrocytosis in ALS demonstrated by [11C]-(L)-deprenyl-D2-PET. J Neurol Sci. 2007;255:17–22.

    Article  CAS  PubMed  Google Scholar 

  35. Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A. 1994;91:10625–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab. 2012;32:1152–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Pioro EP, Majors AW, Mitsumoto H, Nelson DR, Ng TC. 1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology. 1999;53:71–9.

    Article  CAS  PubMed  Google Scholar 

  38. Ibáñez V, Pietrini P, Alexander GE, Furey ML, Teichberg D, Rajapakse JC, et al. Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer’s disease. Neurology. 1998;50:1585–93.

    Article  PubMed  Google Scholar 

  39. Pagani M, Dessi B, Morbelli S, Brugnolo A, Salmaso D, Piccini A, et al. MCI patients declining and not-declining at mid-term follow-up: FDG-PET findings. Curr Alzheimer Res. 2010;7:287–94.

    Article  CAS  PubMed  Google Scholar 

  40. Alessandrini M, Pagani M, Napolitano B, Micarelli A, Bruno E, Chiaravalloti A, et al. Early and phasic cortical metabolic changes in vestibular neuritis onset. PLoS One. 2013;8(3):e57596.

    Google Scholar 

  41. Nobili F, Mazzei D, Dessi B, Morbelli S, Brugnolo A, Barbieri P, et al. Unawareness of memory deficit in amnestic MCI: FDG-PET findings. J Alzheimers Dis. 2010;22:993–1003.

    Google Scholar 

Download references

Acknowledgments

We thank the patients and the neurologically normal controls for their collaboration in this study. This work was supported in part by Compagnia di San Paolo, Programma Neuroscienze 2008-2009 (to M. Consuelo Valentini and A. Calvo), Ministero della Salute (Ricerca Sanitaria Finalizzata, 2010, grant RF-2010-2309849) (to A. Chiò) European Community’s Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867) (to A. Chiò); The Intramural Research Programmes of the National Institutes of Health (NIH); National Institute on Aging (Z01-AG000949-02) (to Bryan J. Traynor).

Disclosures

Angelina Cistaro reports no disclosures.

Marco Pagani reports no disclosures.

Anna Montuschi reports no disclosures.

Andrea Calvo has received research support from the Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata) and Compagnia di San Paolo.

Cristina Moglia reports no disclosures.

Antonio Canosa reports no disclosures.

Gabriella Restagno has received research support from the Ministry of Health (Ricerca Finalizzata), and Regione Piemonte (Ricerca Finalizzata).

Maura Brunetti reports no disclosures.

Bryan J. Traynor has a patent pending on the diagnostic and therapeutic uses of the C9ORF72 hexanucleotide repeat expansion.

Flavio Nobili reports no disclosures.

Giovanna Carrara reports no disclosures.

Piercarlo Fania reports no disclosures.

Leonardo Lopiano has received research support from the Ministry of Health (Ricerca Finalizzata), and Regione Piemonte (Ricerca Finalizzata).

M. Consuelo Valentini reports no disclosures.

Adriano Chiò has received research support from the Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata), and European Commission (7th Framework Program); he serves on the editorial advisory board of Amyotrophic Lateral Sclerosis; he serves on a scientific advisory board for Biogen Idec and Cytokinetics.

Author Contributions

Study concept and design: Cistaro, Pagani, Chiò. Acquisition of data: Montuschi, Calvo, Moglia, Canosa, Restagno, Brunetti, Traynor, Nobili, Carrara, Fania. Analysis and interpretation of data: Cistaro, Pagani, Traynor, Nobili, Chiò. Drafting of the manuscript: Pagani, Chiò. Critical revision of the manuscript for important intellectual content: Cistaro, Pagani, Montuschi, Calvo, Restagno, Traynor, Valentini, Chiò. Obtained funding: Chiò. Administrative, technical, and material support: Cistaro, Pagani, Montuschi, Calvo, Moglia, Canosa, Brunetti, Restagno, Brunetti, Traynor, Nobili, Carrara, Fania, Lopiano, Valentini, Chiò. Study supervision: Cistaro, Pagani, Restagno, Valentini, Lopiano, Chiò.

Adriano Chiò had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors have approved the submitted version of the paper.

Author information

Authors and Affiliations

  1. Positron Emission Tomography Center IRMET S.p.A, Torino, Italy

    Angelina Cistaro & Piercarlo Fania

  2. Institute of Cognitive Sciences and Technologies, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy

    Marco Pagani

  3. Department of Nuclear Medicine, Karolinska Hospital, Stockholm, Sweden

    Marco Pagani

  4. ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Torino, Italy

    Anna Montuschi, Andrea Calvo, Cristina Moglia, Antonio Canosa, Leonardo Lopiano & Adriano Chiò

  5. Neuroscience Institute of Turin, Turin, Italy

    Andrea Calvo, Leonardo Lopiano & Adriano Chiò

  6. Molecular Genetics Unit, Department of Clinical Pathology, Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy

    Gabriella Restagno & Maura Brunetti

  7. Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Ageing, National Institutes of Health, Bethesda, MD, USA

    Bryan J. Traynor

  8. Clinical Neurophysiology Unit, Department of Neurosciences, Ophthalmology and Genetics, University of Genova, Genova, Italy

    Flavio Nobili

  9. Department of Neuroradiology, Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy

    Giovanna Carrara & M. Consuelo Valentini

  10. ALS Center, ‘Rita Levi Montalcini’ Department of Neuroscience, Via Cherasco 15, 10126, Torino, Italy

    Adriano Chiò

Authors
  1. Angelina Cistaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Pagani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Montuschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cristina Moglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Canosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabriella Restagno
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maura Brunetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bryan J. Traynor
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Flavio Nobili
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giovanna Carrara
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Piercarlo Fania
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Leonardo Lopiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M. Consuelo Valentini
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Adriano Chiò
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adriano Chiò.

Additional information

Angelina Cistaro and Marco Pagani contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure E-1

(DOCX 104 kb)

Figure E-2

(DOCX 104 kb)

Figure E-3

(DOCX 101 kb)

Figure E-4

(DOCX 102 kb)

Figure E-5

(DOCX 100 kb)

Figure E-6

(DOCX 103 kb)

Figure E-7

(DOCX 102 kb)

Figure E-8

(DOCX 102 kb)

Figure E-9

(DOCX 100 kb)

Figure E-10

(DOCX 103 kb)

Figure E-11

(DOCX 96.4 kb)

Table E-1

(DOC 45.5 kb)

Table E-2

(DOC 55.5 kb)

Table E-3

(DOC 79.5 kb)

Table E-4

(DOC 56 kb)

Table E-5

(DOC 30.5 kb)

Table E-6

(DOC 124 kb)

Table E-7

(DOC 167 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cistaro, A., Pagani, M., Montuschi, A. et al. The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. Eur J Nucl Med Mol Imaging 41, 844–852 (2014). https://doi.org/10.1007/s00259-013-2667-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-013-2667-5

Keywords

Search

Navigation