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

Current Neurology and Neuroscience Reports

Volumn 15, Issue 7, 2015, Pages

  Turner, Martin R ^a,c   Verstraete, Esther ^b,d  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UTRECHT UNIVERSITY   (Netherlands)

^c JOHN RADCLIFFE HOSPITAL   (United Kingdom)

^d UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

Cortical thickness; Diffusion tensor imaging; Functional imaging; Magnetic resonance imaging; Motor neurone disease; Positron emission tomography

Indexed keywords

COPPER ZINC SUPEROXIDE DISMUTASE; LIGAND;

AMYOTROPHIC LATERAL SCLEROSIS; BRAIN FUNCTION; FUNCTIONAL MAGNETIC RESONANCE IMAGING; FUNCTIONAL NEUROIMAGING; GENE MUTATION; GRAY MATTER; HUMAN; MULTIMODAL IMAGING; NERVOUS SYSTEM INFLAMMATION; NEUROIMAGING; NEUROPATHOLOGY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; POSITRON EMISSION TOMOGRAPHY; RESTING STATE FUNCTIONAL MAGNETIC RESONANCE IMAGING; REVIEW; SEROTONINERGIC SYSTEM; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; SOD1 GENE; SPINAL CORD; STANDARDIZATION; STRUCTURAL MAGNETIC RESONANCE IMAGING; TASK BASED FUNCTIONAL MAGNETIC RESONANCE IMAGING; WHITE MATTER; ANIMAL; BRAIN; PATHOLOGY; PROCEDURES;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMALS; BRAIN; HUMANS; LIGANDS; MAGNETIC RESONANCE IMAGING; NEUROIMAGING; POSITRON-EMISSION TOMOGRAPHY;

EID: 84930197944     PISSN: 15284042     EISSN: 15346293     Source Type: Journal    
DOI: 10.1007/s11910-015-0569-6     Document Type: Review

References (128)

1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377:942–55.
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.
3. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009;73:805–11.
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.
5. Smith MC. Nerve fibre degeneration in the brain in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1960;23:269–82.
6. Brownell B, Oppenheimer DR, Hughes JT. The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry. 1970;33:338–57.
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 ofpost mortemALS brains, looking at the regional burden of the signature cellular pathology, which was categorised by its extent into discrete histopathological stages.
8. 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.
9. 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.
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.
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.
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.
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.
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.
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.
18. Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 2009;8:94–109.
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.
20. Dalakas MC, Hatazawa J, Brooks RA, Di Chiro G. Lowered cerebral glucose utilization in amyotrophic lateral sclerosis. Ann Neurol. 1987;22:580–6.
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.
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.
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.
26. Evans MC, Couch Y, Sibson N, Turner MR. Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol Cell Neurosci. 2012;53:34–41.
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.
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.
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.
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.
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.
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.
34. Yokota T, Yoshino A, Inaba A, Saito Y. Double cortical stimulation in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1996;61:596–600.
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.
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.
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.
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.
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.
48. Goodin DS, Rowley HA, Olney RK. Magnetic resonance imaging in amyotrophic lateral sclerosis. Ann Neurol. 1988;23:418–20.
49. Turner MR. Reversible diffusion MRI abnormalities and transient mutism after liver transplantation. Neurology. 2005;64:177. author reply.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
62. Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol. 2014;10:661–70.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
82. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011;7:603–15.
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.
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 thepost mortemhistopathological 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.
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.
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.
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.
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.
92. Sporns O, Zwi JD. The small world of the cerebral cortex. Neuroinformatics. 2004;2:145–62.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
106. Proudfoot M, Woolrich MW, Nobre AC, Turner MR. Magnetoencephalography. Pract Neurol. 2014;14:336–43.
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.
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.
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.
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.
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.
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.
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.
117. Benatar M, Wuu J. Presymptomatic studies in ALS: rationale, challenges, and approach. Neurology. 2012;79:1732–9.
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.
119. Vucic S, Winhammar JM, Rowe DB, Kiernan MC. Corticomotoneuronal function in asymptomatic SOD-1 mutation carriers. Clin Neurophysiol. 2010;121:1781–5.
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.
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.
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.
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.
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.
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.
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.