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Neurodegeneration of brain networks in the amyotrophic lateral sclerosis–frontotemporal lobar degeneration (ALS–FTLD) continuum: evidence from MRI and MEG studies

  • Francesca Trojsi (a1), Pierpaolo Sorrentino (a2), Giuseppe Sorrentino (a3) and Gioacchino Tedeschi (a1)

Abstract

Brain imaging techniques, especially those based on magnetic resonance imaging (MRI) and magnetoencephalography (MEG), have been increasingly applied to study multiple large-scale distributed brain networks in healthy people and neurological patients. With regard to neurodegenerative disorders, amyotrophic lateral sclerosis (ALS), clinically characterized by the predominant loss of motor neurons and progressive weakness of voluntary muscles, and frontotemporal lobar degeneration (FTLD), the second most common early-onset dementia, have been proven to share several clinical, neuropathological, genetic, and neuroimaging features. Specifically, overlapping or mildly diverging brain structural and functional connectivity patterns, mostly evaluated by advanced MRI techniques—such as diffusion tensor and resting-state functional MRI (DT–MRI, RS–fMRI)—have been described comparing several ALS and FTLD populations. Moreover, though only pioneering, promising clues on connectivity patterns in the ALS–FTLD continuum may derive from MEG investigations. We will herein overview the current state of knowledge concerning the most advanced neuroimaging findings associated with clinical and genetic patterns of neurodegeneration across the ALS–FTLD continuum, underlying the possibility that network-based approaches may be useful to develop novel biomarkers of disease for adequately designing and monitoring more appropriate treatment strategies.

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Corresponding author

*Address for correspondence: Francesca Trojsi, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, MRI Research Center SUN–FISM, University of Campania “Luigi Vanvitelli,” Piazza Miraglia 2, 80138 Naples, Italy. (Email: francesca.trojsi@unicampania.it)

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*

These authors have contributed equally.

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References

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1. Burrell, JR, Halliday, GM, Kril, JJ, et al. The frontotemporal dementia–motor neuron disease continuum. Lancet. 2016; 388(10047): 919931.
2. Bennion Callister, J, Pickering-Brown, SM. Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Exp Neurol. 2014; 262(Pt B): 8490.
3. Ling, SC, Polymenidou, M, Cleveland, DV. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013; 79(3): 416438.
4. De Jesus-Hernandez, M, Mackenzie, IR, Boeve, BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011; 72(2): 245256.
5. Renton, AE, Majounie, E, Waite, A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS–FTD. Neuron. 2011; 72(2): 257268.
6. Deng, HX, Chen, W, Hong, ST, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011; 477(7363): 211215.
7. Cirulli, ET, Lasseigne, BN, Petrovski, S, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015; 347(6229): 14361441.
8. Smith, BN, Ticozzi, N, Fallini, C, et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron. 2014; 84(2): 324331.
9. Benajiba, L, Le Ber, I, Camuzat, A, et al. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol. 2009; 65(4): 470473.
10. Blair, IP, Williams, KL, Warraich, ST, et al. FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry. 2010; 81(6): 639645.
11. Johnson, JO, Pioro, EP, Boehringer, A, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014; 17(5): 664666.
12. Brenner, D, Müller, K, Wieland, T, et al. NEK1 mutations in familial amyotrophic lateral sclerosis. Brain. 2016; 139(Pt 5): e28.
13. Arai, T, Hasegawa, M, Akiyama, H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006; 351(3): 602611.
14. Neumann, M, Sampathu, DM, Kwong, LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 314(5796): 130133.
15. Van Hoecke, A, Schoonaert, L, Lemmens, R, et al. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med. 2012; 18(9): 14181422.
16. Xie, T, Deng, L, Mei, P, et al. Genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations. Neurobiol Aging. 2014; 35(7): 1778.e9--1778.e23.
17. Van Battum, EY, Brignani, S, Pasterkamp, RJ. Axon guidance proteins in neurological disorders. Lancet Neurol. 2015; 14(5): 532546.
18. Phukan, J, Pender, NP, Hardiman, O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007; 6(11): 9941003.
19. Ringholz, GM, Appel, SH, Bradshaw, M, Cooke, NA, Mosnik, DM, Schulz, PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005; 65(4): 586590.
20. Abrahams, S, Goldstein, LH, Suckling, J, et al. Frontotemporal white matter changes in amyotrophic lateral sclerosis. J Neurol. 2005; 252(3): 321331.
21. Agosta, F, Pagani, E, Rocca, MA, et al. Voxel-based morphometry study of brain volumetry and diffusivity in amyotrophic lateral sclerosis patients with mild disability. Hum Brain Mapp. 2007; 28(12): 14301438.
22. Agosta, F, Pagani, E, Petrolini, M, et al. Assessment of white matter tract damage in patients with amyotrophic lateral sclerosis: a diffusion tensor MR imaging tractography study. AJNR Am J Neuroradiol. 2010; 31(8): 14571461.
23. Agosta, F, Canu, E, Valsasina, P, et al. Divergent brain network connectivity in amyotrophic lateral sclerosis. Neurobiol Aging. 2013; 34(2): 419427.
24. Mohammadi, B, Kollewe, K, Samii, A, Krampfl, K, Dengler, R, Münte, TF. Changes of resting state brain networks in amyotrophic lateral sclerosis. Exp Neurol. 2009; 217(1): 147153.
25. Filippini, N, Douaud, G, Mackay, CE, Knight, S, Talbot, K, Turner, MR. Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology. 2010; 75(18): 16451652.
26. Teismann, IK, Warnecke, T, Suntrup, S, et al. Cortical processing of swallowing in ALS patients with progressive dysphagia: a magnetoencephalographic study. PLoS One. 2011; 6(5): E19987.
27. Douaud, G, Filippini, N, Knight, S, Talbot, K, Turner, MR. Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain. 2011; 134(Pt 12): 34703479.
28. Tedeschi, G, Trojsi, F, Tessitore, A, et al. Interaction between aging and neurodegeneration in amyotrophic lateral sclerosis. Neurobiol Aging. 2012; 33(5): 886898.
29. 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(8): e43993.
30. Trojsi, F, Esposito, F, de Stefano, M, et al. Functional overlap and divergence between ALS and bvFTD. Neurobiol Aging. 2015; 36(1): 413423.
31. Proudfoot, M, Rohenkohl, G, Quinn, A, et al. Altered cortical beta-band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis. Hum Brain Mapp. 2017; 38(1): 237254.
32. Whitwell, JL, Josephs, KA, Avula, R, et al. Altered functional connectivity in asymptomatic MAPT subjects: a comparison to bvFTD. Neurology. 2011; 77(9): 866874.
33. Zhou, J, Greicius, MD, Gennatas, ED, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease. Brain. 2010; 133(Pt 5): 13521367.
34. Whitwell, JL, Avula, R, Senjem, ML, et al. Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia. Neurology. 2010; 74(16): 12791287.
35. Farb, NAS, Grady, CL, Strother, S, et al. Abnormal network connectivity in frontotemporal dementia: evidence for prefrontal isolation. Cortex. 2013; 49(7): 18561873.
36. Filippi, M, Agosta, F, Scola, E, et al. Functional network connectivity in the behavioral variant of frontotemporal dementia. Cortex. 2013; 49(9): 23892401.
37. Lee, SE, Khazenzon, AM, Trujillo, AJ, et al. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain. 2014; 137(11): 30473060.
38. Kasper, E, Schuster, C, Machts, J, et al. Microstructural white matter changes underlying cognitive and behavioural impairment in ALS: an in vivo study using DTI. PLoS One. 2014; 9(12): e114543.
39. Agosta, F, Ferraro, PM, Riva, N, et al. Structural brain correlates of cognitive and behavioral impairment in MND. Hum Brain Mapp. 2016; 37(4): 16141626.
40. Christidi, F, Karavasilis, E, Riederer, F, et al. Gray matter and white matter changes in non-demented amyotrophic lateral sclerosis patients with or without cognitive impairment: a combined voxel-based morphometry and tract-based spatial statistics whole-brain analysis. Brain Imaging Behav. 2017. doi: 10.1007/s11682-017-9722-y.
41. Van den Heuvel, MP, Stam, CJ, Kahn, RS, Hulshoff Pol, HE. Efficiency of functional brain networks and intellectual performance. J Neurosci. 2009; 29(23): 76197624.
42. Strong, MJ, Abrahams, S, Goldstein, LH, et al. Amyotrophic lateral sclerosis–frontotemporal spectrum disorder (ALS–FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017; 18(3–4): 153174.
43. Feiler, MS, Strobel, B, Freischmidt, A, et al. TDP-43 is intercellularly transmitted across axon terminals. J Cell Biol. 2015; 211(4): 897911.
44. Friston, KJ, Worsley, KJ, Frackowiak, RS, Mazziotta, JC, Evans, AC. Assessing the significance of focal activations using their spatial extent. Hum Brain Mapp. 1994; 1(3): 210220.
45. Bullmore, E, Sporns, O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci. 2009; 10(3): 186198.
46. Thivard, L, Pradat, PF, Lehéricy, S, et al. Diffusion tensor imaging and voxel based morphometry study in amyotrophic lateral sclerosis: relationships with motor disability. J Neurol Neurosurg Psychiatry. 2007; 78(8): 889892.
47. Sach, M, Winkler, G, Glauche, V, et al. Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis. Brain. 2004; 127(Pt 2): 340350.
48. Sage, CA, Van Hecke, W, Peeters, R, et al. Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis: revisited. Hum Brain Mapp. 2009; 30(11): 36573675.
49. Cirillo, M, Esposito, F, Tedeschi, G, et al. Widespread microstructural white matter involvement in amyotrophic lateral sclerosis: a whole brain DTI study. AJNR Am J Neuroradiol. 2012; 33(6): 11021108.
50. Müller, HP, Turner, MR, Grosskreutz, J, et al. A large-scale multicentre cerebral diffusion tensor imaging study in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2016; 87(6): 570579.
51. Ayers, JI, Fromholt, SE, O’Neal, VM, et al. Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways. Acta Neuropathol. 2016; 131(1): 103114.
52. Brettschneider, J, Del Tredici, K, Toledo, JB, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2014; 74(1): 2038.
53. Schmidt, R, de Reus, MA, Scholtens, LH, van den Berg, LH, van den Heuvel, MP. Simulating disease propagation across white matter connectome reveals anatomical substrate for neuropathology staging in amyotrophic lateral sclerosis. NeuroImage. 2016; 124(Pt A): 762769.
54. Verstraete, E, Veldink, JH, Mandl, RCW, van den Berg, LH, van den Heuvel, MP. Impaired structural motor connectome in amyotrophic lateral sclerosis. PLoS One. 2011; 6: e24239.
55. 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. 2015; 41(5): 13421352.
56. 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(4): 13511361.
57. Seeley, WW, Menon, V, Schatzberg, AF, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 2007; 27(9): 23492356.
58. Mahoney, CJ, Simpson, IJ, Nicholas, JM, et al. Longitudinal diffusion tensor imaging in frontotemporal dementia. Ann Neurol. 2015; 77(1): 3346.
59. Mahoney, CJ, Beck, J, Rohrer, JD, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain. 2012; 135(Pt 3): 736750.
60. Galantucci, S, Tartaglia, MC, Wilson, SM, et al. White matter damage in primary progressive aphasias: a diffusion tensor tractography study. Brain. 2011; 134(Pt 10): 30113029.
61. Grossman, M, Powers, J, Ash, S, et al. Disruption of large-scale neural networks in non-fluent/agrammatic variant primary progressive aphasia associated with frontotemporal degeneration pathology. Brain Lang. 2013; 127(2): 106120.
62. McMillan, CT, Irwin, DJ, Avants, BB, et al. White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. 2013; 84(9): 949955.
63. Mantini, D, Perrucci, MG, Del Gratta, C, Romani, GL, Corbetta, M. Electrophysiological signatures of resting state networks in the human brain. Proc Natl Acad Sci U S A. 2007; 104(32): 1317013175.
64. Hall, EL, Robson, SE, Morris, PG, Brookes, MJ. The relationship between MEG and fMRI. NeuroImage. 2014; 102(1): 8091.
65. Hämäläinen, MS. Magnetoencephalography: a tool for functional brain imaging. Brain Topogr. 1992; 5(2): 95102.
66. Kew, JJ, Goldstein, LG, Leigh, PN, et al. The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis: a neuropsychological and positron emission study. Brain. 1993; 116(Pt 6): 13991423.
67. Abrahams, S, Leigh, PN, Kew, JJ, Goldstein, LH, Lloyd, CM, Brooks, DJ. A positron emission tomography study of frontal lobe function (verbal fluency) in amyotrophic lateral sclerosis. J Neurol Sci. 1995; 129(Suppl): 4446.
68. Vercelletto, M, Belliard, S, Wiertlewski, S, et al. Neuropsychological and scintigraphic aspects of frontotemporal dementia preceding amyotrophic lateral sclerosis. Rev Neurol (Paris). 2003; 159(5 Pt 1): 529542.
69. Jacova, C, Hsiung, GYR, Tawankanjanachot, I, et al. Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers. Neurology. 2013; 81(15): 13221331.
70. Lant, SB, Robinson, AC, Thompson, JC, et al. Patterns of microglial cell activation in frontotemporal lobar degeneration. Neuropathol Appl Neurobiol. 2013; 40(6): 686696.
71. 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. 2014; 41(5): 844852.
72. Agosta, F, Canu, E, Inuggi, A, et al. Resting state functional connectivity alterations in primary lateral sclerosis. Neurobiol Aging. 2014; 35(4): 916925.
73. Rytty, R, Nikkinen, J, Paavola, L, et al. Group ICA dual regression analysis of resting state networks in a behavioral variant of frontotemporal dementia. Front Hum Neurosci. 2013; 7: 461.
74. Do-Ha, D, Buskila, Y, Ooi, L. Impairments in motor neurons, interneurons and astrocytes contribute to hyperexcitability in ALS: underlying mechanisms and paths to therapy. Mol Neurobiol. 2017. doi: 10.1007/s12035-017-0392-y.
75. Teismann, IK, Warnecke, T, Suntrup, S, et al. Cortical processing of swallowing in ALS patients with progressive dysphagia: a magnetoencephalographic study. PLoS One. 2011; 6(5): e19987.
76. Fraschini, M, Demuru, M, Hillebrand, A, et al. EEG functional network topology is associated with disability in patients with amyotrophic lateral sclerosis. Sci Rep. 2016; 6: 38653.
77. Agosta, F, Sala, S, Valsasina, P, et al. Brain network connectivity assessed using graph theory in frontotemporal dementia. Neurology. 2013; 81(2): 134143.
78. Agosta, F, Galantucci, S, Valsasina, P, et al. Disrupted brain connectome in semantic variant of primary progressive aphasia. Neurobiol Aging. 2014; 35(11): 26462655.
79. 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(9): 43864395.

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