Top

Current Neurology and Neuroscience Reports

Published in:

Open Access 01-07-2015 | Neuroimaging (DJ Brooks, Section Editor)

What Does Imaging Reveal About the Pathology of Amyotrophic Lateral Sclerosis?

Authors: Martin R. Turner, Esther Verstraete

Published in: Current Neurology and Neuroscience Reports | Issue 7/2015

Abstract

Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre-symptomatic landscape.

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

2.•

Turner MR, Swash M. The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey. J Neurol Neurosurg Psychiatry. 2015. This review explores the increasing genetic and cellular biological complexity of ALS in relation to the core clinical syndrome described by the pioneers of clinical neurology and its overlap with FTD.

Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009;73:805–11.PubMedCentralPubMed

4.•

Verstraete E, Veldink JH, van den Berg LH, van den Heuvel MP. Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis. Hum Brain Mapp. 2014;35:1351–61. Pioneering network-based analysis of structural MRI data at two time points, showing an expanding network of impaired sub-connections, and supporting an emerging concept of pathological spread occuring along neuronal connections.PubMed

Smith MC. Nerve fibre degeneration in the brain in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1960;23:269–82.PubMedCentralPubMed

Brownell B, Oppenheimer DR, Hughes JT. The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry. 1970;33:338–57.PubMedCentralPubMed

7.•

Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013;74:20–38. A ground-breaking study of post mortem ALS brains, looking at the regional burden of the signature cellular pathology, which was categorised by its extent into discrete histopathological stages.

Gallassi R, Montagna P, Ciardulli C, Lorusso S, Mussuto V, Stracciari A. Cognitive impairment in motor neuron disease. Acta Neurol Scand. 1985;71:480–4.PubMed

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 Neurosurg Psychiatry. 2012;83:102–8.PubMed

10.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science (New York, NY). 2006;314:130–3.

11.

Renton AE, Majounie E, Waite A, Simon-Sanchez 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.PubMedCentralPubMed

12.

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.PubMedCentralPubMed

13.

Alzheimer A. Űber einen Fall von spinaler progressiver Muskelatrophie mit hinzutretender Erkrankung bulbärer Kerne in der Rinde. Archiv Psychiatrie. 1891;23:459–85.

14.

Elamin M, Phukan J, Bede P, Jordan N, Byrne S, Pender N, et al. Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology. 2011;76:1263–9.PubMed

15.

Eisen A, Turner MR, Lemon R. Tools and talk: an evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis. Muscle Nerve. 2014;49:469–77.PubMed

16.

Douglass CP, Kandler RH, Shaw PJ, McDermott CJ. An evaluation of neurophysiological criteria used in the diagnosis of motor neuron disease. J Neurol Neurosurg Psychiatry. 2010;81:646–9.PubMed

17.•

Turner MR, Agosta F, Bede P, Govind V, Lule D, Verstraete E. Neuroimaging in amyotrophic lateral sclerosis. Biomark Med. 2012;6:319–37. A comprehensive review of all neuroimaging (SPECT, PET and MRI) in ALS, including online tables listing the main findings of every study.PubMed

18.

Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 2009;8:94–109.PubMed

19.

Neary D, Snowden JS, Mann DM, Northen B, Goulding PJ, Macdermott N. Frontal lobe dementia and motor neuron disease. J Neurol Neurosurg Psychiatry. 1990;53:23–32.PubMedCentralPubMed

20.

Dalakas MC, Hatazawa J, Brooks RA, Di Chiro G. Lowered cerebral glucose utilization in amyotrophic lateral sclerosis. Ann Neurol. 1987;22:580–6.PubMed

21.

Ludolph AC, Langen KJ, Regard M, Herzog H, Kemper B, Kuwert T, et al. Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study. Acta Neurol Scand. 1992;85:81–9.PubMed

22.

Kew JJ, Goldstein LH, Leigh PN, Abrahams S, Cosgrave N, Passingham RE, et al. The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. A neuropsychological and positron emission tomography study. Brain J Neurol. 1993;116(Pt 6):1399–423.

23.

Kew JJ, Leigh PN, Playford ED, Passingham RE, Goldstein LH, Frackowiak RS, et al. Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study. Brain J Neurol. 1993;116(Pt 3):655–80.

24.

Pagani M, Chio A, Valentini MC, Oberg J, Nobili F, Calvo A, et al. Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis. Neurology. 2014;83:1067–74.PubMed

25.

Van Laere K, Vanhee A, Verschueren J, De Coster L, Driesen A, Dupont P, et al. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurol. 2014;71:553–61.PubMed

26.

Evans MC, Couch Y, Sibson N, Turner MR. Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol Cell Neurosci. 2012;53:34–41.PubMed

27.

Murdock BJ, Bender DE, Segal BM, Feldman EL. The dual roles of immunity in ALS: injury overrides protection. Neurobiol Dis. 2015.

28.

Troost D, Van den Oord JJ, Vianney de Jong JM. Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 1990;16:401–10.PubMed

29.

Troost D, Claessen N, Van den Oord JJ, Swaab DF, de Jong JM. Neuronophagia in the motor cortex in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 1993;19:390–7.PubMed

30.

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

31.

Zurcher NR, Loggia ML, Lawson R, Chonde DB, Izquierdo-Garcia D, Yasek JE, et al. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: Assessed with [(11)C]-PBR28. NeuroImage Clin. 2015;7:409–14.PubMedCentralPubMed

32.

Turner MR, Gerhard A, Al-Chalabi A, Shaw CE, Hughes RAC, Banati RB, et al. Mills' and other isolated upper motor neuron syndromes: in vivo study with [11C]-PK11195 PET. J Neurol Neurosurg Psychiatry. 2005;76:871–4.PubMedCentralPubMed

33.

Baumer D, Butterworth R, Menke RA, Talbot K, Hofer M, Turner MR. Progressive hemiparesis (Mills syndrome) with aphasia in amyotrophic lateral sclerosis. Neurology. 2014;82:457–8.PubMedCentralPubMed

34.

Yokota T, Yoshino A, Inaba A, Saito Y. Double cortical stimulation in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1996;61:596–600.PubMedCentralPubMed

35.

Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W. Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology. 1997;49:1292–8.PubMed

36.

Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg Psychiatry. 2013;84:1161–70.PubMedCentralPubMed

37.

Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain J Neurol. 2008;131:1540–50.

38.

Turner MR, Kiernan MC. Does interneuronal dysfunction contribute to neurodegeneration in amyotrophic lateral sclerosis? Amyotroph Lateral Scler Off Publ World Fed Neurol Res Group Motor Neuron Dis. 2012;13:245–50.

39.

Lloyd CM, Richardson MP, Brooks DJ, Al Chalabi A, Leigh PN. Extramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenil. Brain J Neurol. 2000;123(Pt 11):2289–96.

40.

Maekawa S, Al-Sarraj S, Kibble M, Landau S, Parnavelas J, Cotter D, et al. Cortical selective vulnerability in motor neuron disease: a morphometric study. Brain J Neurol. 2004;127:1237–51.

41.

Petri S, Kollewe K, Grothe C, Hori A, Dengler R, Bufler J, et al. GABA(A)-receptor mRNA expression in the prefrontal and temporal cortex of ALS patients. J Neurol Sci. 2006;250:124–32.PubMed

42.

Turner MR, Hammers A, Al-Chalabi A, Shaw CE, Andersen PM, Brooks DJ, et al. Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C]flumazenil PET. Brain J Neurol. 2005;128:1323–9.

43.

Turner MR, Rabiner EA, Hammers A, Al-Chalabi A, Grasby PM, Shaw CE, et al. [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain J Neurol. 2005;128:896–905.

44.

Lanctot KL, Herrmann N, Ganjavi H, Black SE, Rusjan PM, Houle S, et al. Serotonin-1A receptors in frontotemporal dementia compared with controls. Psychiatry Res. 2007;156:247–50.PubMed

45.

Bowen DM, Procter AW, Mann DM, Snowden JS, Esiri MM, Neary D, et al. Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy. Psychopharmacology (Berl). 2008;196:603–10.

46.

Filippi M, Agosta F, Abrahams S, Fazekas F, Grosskreutz J, Kalra S, et al. EFNS guidelines on the use of neuroimaging in the management of motor neuron diseases. Eur J Neurol Off J Eur Fed Neurol Soc. 2010;17:526–33.

47.

Turner MR. MRI as a frontrunner in the search for amyotrophic lateral sclerosis biomarkers? Biomark Med. 2011;5:79–81.PubMedCentralPubMed

48.

Goodin DS, Rowley HA, Olney RK. Magnetic resonance imaging in amyotrophic lateral sclerosis. Ann Neurol. 1988;23:418–20.PubMed

49.

Turner MR. Reversible diffusion MRI abnormalities and transient mutism after liver transplantation. Neurology. 2005;64:177. author reply.PubMed

50.

Agosta F, Pagani E, Rocca MA, Caputo D, Perini M, Salvi F, et al. Voxel-based morphometry study of brain volumetry and diffusivity in amyotrophic lateral sclerosis patients with mild disability. Hum Brain Mapp. 2007;28:1430–8.PubMed

51.

Mezzapesa DM, Ceccarelli A, Dicuonzo F, Carella A, De Caro MF, Lopez M, et al. Whole-brain and regional brain atrophy in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol. 2007;28:255–9.PubMed

52.

Rajagopalan V, Yue GH, Pioro EP. Do preprocessing algorithms and statistical models influence voxel-based morphometry (VBM) results in amyotrophic lateral sclerosis patients? A systematic comparison of popular VBM analytical methods. J Magn Reson Imaging. 2014;40:662–7.PubMed

53.•

Bede P, Bokde A, Elamin M, Byrne S, McLaughlin RL, Jordan N, et al. Grey matter correlates of clinical variables in amyotrophic lateral sclerosis (ALS): a neuroimaging study of ALS motor phenotype heterogeneity and cortical focality. J Neurol Neurosurg Psychiatry. 2013;84:766–73. Analysis of the motor homunclus topography using structual MRI changes in relation to clinical features in ALS.PubMed

54.•

Menke RA, Korner S, Filippini N, Douaud G, Knight S, Talbot K, et al. Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis. Brain J Neurol. 2014;137:2546–55. A large longitudinal MRI study in ALS, revealing extensive white matter damage cross-sectionally, and widespread greay matter involvement with time.

55.

Lillo P, Mioshi E, Burrell JR, Kiernan MC, Hodges JR, Hornberger M. Grey and white matter changes across the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS One. 2012;7:e43993.PubMedCentralPubMed

56.

Rajagopalan V, Pioro EP. Distinct patterns of cortical atrophy in ALS patients with or without dementia: an MRI VBM study. Amyotroph Lateral Scler Frontotemporal Degen. 2014;15:216–25.

57.

Verstraete E, Veldink JH, Hendrikse J, Schelhaas HJ, van den Heuvel MP, van den Berg LH. Structural MRI reveals cortical thinning in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:383–8.PubMed

58.

Schuster C, Kasper E, Machts J, Bittner D, Kaufmann J, Benecke R, et al. Focal thinning of the motor cortex mirrors clinical features of amyotrophic lateral sclerosis and their phenotypes: a neuroimaging study. J Neurol. 2013;260:2856–64.PubMed

59.•

Walhout R, Westeneng HJ, Verstraete E, Hendrikse J, Veldink JH, van den Heuvel MP, et al. Cortical thickness in ALS: towards a marker for upper motor neuron involvement. J Neurol Neurosurg Psychiatry. 2015;86:288–94. First application of cortical thickness measurement to patients from the MND spectrum, uniquely also involving a disease control group, demonstrating specificity of cortical thinning for clinical UMN involvement.PubMed

60.

Schuster C, Kasper E, Dyrba M, Machts J, Bittner D, Kaufmann J, et al. Cortical thinning and its relation to cognition in amyotrophic lateral sclerosis. Neurobiol Aging. 2014;35:240–6.PubMed

61.

Geser F, Brandmeir NJ, Kwong LK, Martinez-Lage M, Elman L, McCluskey L, et al. Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol. 2008;65:636–41.PubMed

62.

Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol. 2014;10:661–70.PubMed

63.

Bede P, Elamin M, Byrne S, McLaughlin RL, Kenna K, Vajda A, et al. Basal ganglia involvement in amyotrophic lateral sclerosis. Neurology. 2013;81:2107–15.PubMed

64.

Westeneng HJ, Verstraete E, Walhout R, Schmidt R, Hendrikse J, Veldink JH, et al. Subcortical structures in amyotrophic lateral sclerosis. Neurobiol Aging. 2015;36:1075–82.PubMed

65.

Takeda T, Uchihara T, Arai N, Mizutani T, Iwata M. Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease. Acta Neuropathol. 2009;117:35–44.PubMed

66.

Prell T, Grosskreutz J. The involvement of the cerebellum in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degen. 2013;14:507–15.

67.

Tan RH, Devenney E, Dobson-Stone C, Kwok JB, Hodges JR, Kiernan MC, et al. Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS One. 2014;9:e105632.PubMedCentralPubMed

68.

King A, Maekawa S, Bodi I, Troakes C, Al-Sarraj S. Ubiquitinated, p62 immunopositive cerebellar cortical neuronal inclusions are evident across the spectrum of TDP-43 proteinopathies but are only rarely additionally immunopositive for phosphorylation-dependent TDP-43. Neuropathology. 2011;31:239–49.PubMed

69.

Ciccarelli O, Catani M, Johansen-Berg H, Clark C, Thompson A. Diffusion-based tractography in neurological disorders: concepts, applications, and future developments. Lancet Neurol. 2008;7:715–27.PubMed

70.

Blain CR, Brunton S, Williams VC, Leemans A, Turner MR, Andersen PM, et al. Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS. J Neurol Neurosurg Psychiatry. 2011;82:843–9.PubMedCentralPubMed

71.

Verstraete E, Polders DL, Mandl RC, Van Den Heuvel MP, Veldink JH, Luijten P, et al. Multimodal tract-based analysis in ALS patients at 7T: a specific white matter profile? Amyotroph Lateral Scler Frontotemporal Degen. 2014;15:84–92.

72.

Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS One. 2012;7:e39216.PubMedCentralPubMed

73.

Miller KL, Stagg CJ, Douaud G, Jbabdi S, Smith SM, Behrens TE, et al. Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner. NeuroImage. 2011;57:167–81.PubMedCentralPubMed

74.

Kwan JY, Jeong SY, Van Gelderen P, Deng HX, Quezado MM, Danielian LE, et al. Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology. PLoS One. 2012;7:e35241.PubMedCentralPubMed

75.

Foerster BR, Dwamena BA, Petrou M, Carlos RC, Callaghan BC, Pomper MG. Diagnostic accuracy using diffusion tensor imaging in the diagnosis of ALS: a meta-analysis. Acad Radiol. 2012;19:1075–86.PubMedCentralPubMed

76.

Ince PG, Evans J, Knopp M, Forster G, Hamdalla HH, Wharton SB, et al. Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology. 2003;60:1252–8.PubMed

77.

Senda J, Kato S, Kaga T, Ito M, Atsuta N, Nakamura T, et al. Progressive and widespread brain damage in ALS: MRI voxel-based morphometry and diffusion tensor imaging study. Amyotroph Lateral Scler Off Publ World Fed Neurol Res Group Motor Neuron Dis. 2011;12:59–69.

78.

Trojsi F, Corbo D, Caiazzo G, Piccirillo G, Monsurro MR, Cirillo S, et al. Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: a 3T high angular resolution diffusion imaging (HARDI) study. Amyotroph Lateral Scler Frontotemporal Degen. 2013;14:553–61.

79.

Verstraete E, Veldink JH, Mandl RC, van den Berg LH, van den Heuvel MP. Impaired structural motor connectome in amyotrophic lateral sclerosis. PLoS One. 2011;6:e24239.PubMedCentralPubMed

80.

Buchanan CR, Pettit LD, Storkey AJ, Abrahams S, Bastin ME. Reduced structural connectivity within a prefrontal-motor-subcortical network in amyotrophic lateral sclerosis. J Magn Reson Imaging. 2014.

81.

Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011;122:691–702.PubMed

82.

Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011;7:603–15.PubMed

83.

Chio A, Mora G, Sabatelli M, Caponnetto C, Traynor BJ, Johnson JO, et al. CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging. 2015;36:1767. e3-6.PubMed

84.•

Kassubek J, Muller HP, Del Tredici K, Brettschneider J, Pinkhardt EH, Lule D, et al. Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain J Neurol. 2014;137:1733–40. An innovative attempt to explore in vivo white matter tract involvement in ALS patients in relation to the post mortem histopathological stages previously demonstrated by members of the same group, showing indications of conformity.

85.

Roche JC, Rojas-Garcia R, Scott KM, Scotton W, Ellis CE, Burman R, et al. A proposed staging system for amyotrophic lateral sclerosis. Brain J Neurol. 2012;135:847–52.

86.

Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, et al. Correspondence of the brain's functional architecture during activation and rest. Proc Natl Acad Sci U S A. 2009;106:13040–5.PubMedCentralPubMed

87.

Schoenfeld MA, Tempelmann C, Gaul C, Kuhnel GR, Duzel E, Hopf JM, et al. Functional motor compensation in amyotrophic lateral sclerosis. J Neurol. 2005;252:944–52.PubMed

88.

Mohammadi B, Kollewe K, Samii A, Dengler R, Munte TF. Functional neuroimaging at different disease stages reveals distinct phases of neuroplastic changes in amyotrophic lateral sclerosis. Hum Brain Mapp. 2011;32:750–8.PubMed

89.

Witiuk K, Fernandez-Ruiz J, McKee R, Alahyane N, Coe BC, Melanson M, et al. Cognitive deterioration and functional compensation in ALS measured with fMRI using an inhibitory task. J Neurosci Off J Soc Neurosci. 2014;34:14260–71.

90.

Raaphorst J, van Tol MJ, Groot PF, Altena E, van der Werf YD, Majoie CB, et al. Prefrontal involvement related to cognitive impairment in progressive muscular atrophy. Neurology. 2014;83:818–25.PubMed

91.

Lowe MJ, Dzemidzic M, Lurito JT, Mathews VP, Phillips MD. Correlations in low-frequency BOLD fluctuations reflect cortico-cortical connections. NeuroImage. 2000;12:582–7.PubMed

92.

Sporns O, Zwi JD. The small world of the cerebral cortex. Neuroinformatics. 2004;2:145–62.PubMed

93.

Mohammadi B, Kollewe K, Samii A, Krampfl K, Dengler R, Munte TF. Changes of resting state brain networks in amyotrophic lateral sclerosis. Exp Neurol. 2009;217:147–53.PubMed

94.

Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A. 2003;100:253–8.PubMedCentralPubMed

95.

van den Heuvel MP, Mandl RC, Kahn RS, Hulshoff Pol HE. Functionally linked resting-state networks reflect the underlying structural connectivity architecture of the human brain. Hum Brain Mapp. 2009;30:3127–41.PubMed

96.

De Luca M, Smith S, De Stefano N, Federico A, Matthews PM. Blood oxygenation level dependent contrast resting state networks are relevant to functional activity in the neocortical sensorimotor system. Exp Brain Res. 2005;167:587–94.PubMed

97.

Lowe MJ, Phillips MD, Lurito JT, Mattson D, Dzemidzic M, Mathews VP. Multiple sclerosis: low-frequency temporal blood oxygen level-dependent fluctuations indicate reduced functional connectivity initial results. Radiology. 2002;224:184–92.PubMed

98.

Jelsone-Swain LM, Fling BW, Seidler RD, Hovatter R, Gruis K, Welsh RC. Reduced interhemispheric functional connectivity in the motor cortex during rest in limb-onset amyotrophic lateral sclerosis. Front Syst Neurosci. 2010;4:158.PubMedCentralPubMed

99.

Tedeschi G, Trojsi F, Tessitore A, Corbo D, Sagnelli A, Paccone A, et al. Interaction between aging and neurodegeneration in amyotrophic lateral sclerosis. Neurobiol Aging. 2012;33:886–98.PubMed

100.

Douaud G, Filippini N, Knight S, Talbot K, Turner MR. Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain J Neurol. 2011;134:3470–9.

101.

Agosta F, Valsasina P, Absinta M, Riva N, Sala S, Prelle A, et al. Sensorimotor functional connectivity changes in amyotrophic lateral sclerosis. Cereb Cortex (New York 1991). 2011;21:2291–8.

102.

Zhou F, Xu R, Dowd E, Zang Y, Gong H, Wang Z. Alterations in regional functional coherence within the sensory-motor network in amyotrophic lateral sclerosis. Neurosci Lett. 2014;558:192–6.PubMed

103.

Agosta F, Canu E, Valsasina P, Riva N, Prelle A, Comi G, et al. Divergent brain network connectivity in amyotrophic lateral sclerosis. Neurobiol Aging. 2013;34:419–27.PubMed

104.

Schmidt R, Verstraete E, de Reus MA, Veldink JH, van den Berg LH, van den Heuvel MP. Correlation between structural and functional connectivity impairment in amyotrophic lateral sclerosis. Hum Brain Mapp. 2014;35:4386–95.PubMedCentralPubMed

105.

Trojsi F, Esposito F, de Stefano M, Buonanno D, Conforti FL, Corbo D, et al. Functional overlap and divergence between ALS and bvFTD. Neurobiol Aging. 2015;36:413–23.PubMed

106.

Proudfoot M, Woolrich MW, Nobre AC, Turner MR. Magnetoencephalography. Pract Neurol. 2014;14:336–43.PubMedCentralPubMed

107.

Pioro EP, Antel JP, Cashman NR, Arnold DL. Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology. 1994;44:1933–8.PubMed

108.

Stagg CJ, Knight S, Talbot K, Jenkinson M, Maudsley AA, Turner MR. Whole-brain magnetic resonance spectroscopic imaging measures are related to disability in ALS. Neurology. 2013;80:610–5.PubMedCentralPubMed

109.

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.PubMed

110.

Foerster BR, Callaghan BC, Petrou M, Edden RA, Chenevert TL, Feldman EL. Decreased motor cortex gamma-aminobutyric acid in amyotrophic lateral sclerosis. Neurology. 2012;78:1596–600.PubMedCentralPubMed

111.

Bede P, Bokde AL, Byrne S, Elamin M, Fagan AJ, Hardiman O. Spinal cord markers in ALS: diagnostic and biomarker considerations. Amyotroph Lateral Scler Off Publ World Fed Neurol Res Group Motor Neuron Dis. 2012;13:407–15.

112.•

Cohen-Adad J, El Mendili MM, Morizot-Koutlidis R, Lehericy S, Meininger V, Blancho S, et al. Involvement of spinal sensory pathway in ALS and specificity of cord atrophy to lower motor neuron degeneration. Amyotroph Lateral Scler Frontotemporal Degen. 2012;14:30–8. Important early demonstration of the great potential of advanced spinal cord MRI in furthering understanding of the evolution of in vivo pathology in ALS.

113.

Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 2012;124:339–52.PubMed

114.

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 J Neurol. 2012;135:736–50.

115.

Bede P, Bokde AL, Byrne S, Elamin M, McLaughlin RL, Kenna K, et al. Multiparametric MRI study of ALS stratified for the C9orf72 genotype. Neurology. 2013;81:361–9.PubMedCentralPubMed

116.

Cistaro A, Pagani M, Montuschi A, Calvo A, Moglia C, Canosa A, et al. The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. Eur J Nucl Med Mol Imaging. 2014;41:844–52.PubMed

117.

Benatar M, Wuu J. Presymptomatic studies in ALS: rationale, challenges, and approach. Neurology. 2012;79:1732–9.PubMedCentralPubMed

118.

Ng MC, Ho JT, Ho SL, Lee R, Li G, Cheng TS, et al. Abnormal diffusion tensor in nonsymptomatic familial amyotrophic lateral sclerosis with a causative superoxide dismutase 1 mutation. J Magn Reson Imaging. 2008;27:8–13.PubMed

119.

Vucic S, Winhammar JM, Rowe DB, Kiernan MC. Corticomotoneuronal function in asymptomatic SOD-1 mutation carriers. Clin Neurophysiol. 2010;121:1781–5.PubMed

120.

Carew JD, Nair G, Andersen PM, Wuu J, Gronka S, Hu X, et al. Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS. Neurology. 2011;77:1370–5.PubMedCentralPubMed

121.

Dopper EG, Rombouts SA, Jiskoot LC, Heijer TD, Graaf JR, Koning ID, et al. Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia. Neurology. 2013;80:814–23.PubMedCentralPubMed

122.•

Evans MC, Serres S, Khrapitchev AA, Stolp HB, Anthony DC, Talbot K, et al. T(2)-weighted MRI detects presymptomatic pathology in the SOD1 mouse model of ALS. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2014;34:785–93. Demonstration of the applicability of advanced MRI to mouse models of ALS, with insights into the neuroinflammatory landscape prior to motor symptoms through a combined histological analysis.

123.

Evans MC, Gaillard PJ, de Boer M, Appeldoorn C, Dorland R, Sibson NR, et al. CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2014;2:66.PubMedCentralPubMed

124.

Foerster BR, Carlos RC, Dwamena BA, Callaghan BC, Petrou M, Edden RAE, et al. Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2014;1:107–14.PubMedCentralPubMed

125.

Cervo A, Cocozza S, Sacca F, Giorgio SM, Morra VB, Tedeschi E, et al. The combined use of conventional MRI and MR spectroscopic imaging increases the diagnostic accuracy in amyotrophic lateral sclerosis. Eur J Radiol. 2015;84:151–7.PubMed

126.

Menke RAL, Gray E, Lu CH, Kuhle J, Talbot K, Malaspina A, et al. CSF neurofilament light chain reflects corticospinal tract degeneration in ALS. Ann Clin Transl Neurol. 2015; in press.

127.

Turner MR, Grosskreutz J, Kassubek J, Abrahams S, Agosta F, Benatar M, et al. Towards a neuroimaging biomarker for amyotrophic lateral sclerosis. Lancet Neurol. 2011;10:400–3.PubMed

128.

Wood H. Alzheimer disease: [(11)C]PBB3-a new PET ligand that identifies tau pathology in the brains of patients with AD. Nat Rev Neurol. 2013;9:599.PubMed

Title: What Does Imaging Reveal About the Pathology of Amyotrophic Lateral Sclerosis?
Authors: Martin R. Turner
Esther Verstraete
Publication date: 01-07-2015
Publisher: Springer US
Published in: Current Neurology and Neuroscience Reports / Issue 7/2015
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-015-0569-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

What Does Imaging Reveal About the Pathology of Amyotrophic Lateral Sclerosis?

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2015

Psychotic Symptoms in Frontotemporal Dementia

Developments in the Role of Transcranial Sonography for the Differential Diagnosis of Parkinsonism

The Relationship Between Atrophy and Hypometabolism: Is It Regionally Dependent in Dementias?

Neuroscience of Aphasia Recovery: the Concept of Neural Multifunctionality

The Genetics of the Epilepsies

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy