Abstract
Although motor neuron degeneration is the predominant feature in ALS, recent data point to a more widespread pathology also comprising non-motor symptoms. Retinal thinning has been reported in a variety of neurodegenerative conditions. Yet, studies of retinal involvement in ALS are sparse and results are heterogeneous. We studied retinal alterations in ALS using a systematic approach combining Optical Coherence Tomography (OCT), Diffusion Tensor Imaging (DTI) and clinical phenotyping. We hypothesized that selective changes of specific retinal layers may be a reflection of overall neurodegeneration as measured by DTI. Spectral domain OCT images were analyzed to calculate the average thickness of retinal layers in 71 ALS patients and 20 controls. In 30 patients, the region of interest (ROI) based fractional anisotrophy (FA) was measured in the corticospinal tract (CST), as this region is preferentially affected by motor neuron degeneration. Clinical data were collected for correlation analysis. Patients showed a significant thinning of the inner nuclear layer (INL; p = 0.04) and the retinal nerve fibre layer (RNFL; p = 0.004) compared to controls. We saw significant correlations between retinal thickness and FA values of the CST in patients (p = 0.005). No significant correlation between clinical parameters and retinal involvement was observed. Our study provides evidence for a retinal involvement in ALS. Interestingly, ALS patients show a reduction in FA of the CST, which is correlated to retinal thinning. We conclude that retinal involvement is in fact associated to overall neurodegeneration and may be regarded as a potential technical biomarker in ALS.
Similar content being viewed by others
References
Agosta F, Chio A, Cosottini M et al (2010a) The present and the future of neuroimaging in amyotrophic lateral sclerosis. Am J Neuroradiol 31:1769–1777. doi:10.3174/ajnr.A2043
Agosta F, Pagani E, Petrolini M et al (2010b) Assessment of white matter tract damage in patients with amyotrophic lateral sclerosis: a diffusion tensor MR imaging tractography study. Am J Neuroradiol 31:1457–1461. doi:10.3174/ajnr.A2105
Agosta F, Weiler M, Filippi M (2015) Propagation of pathology through brain networks in neurodegenerative diseases: from molecules to clinical phenotypes. CNS Neurosci Ther n/a–n/a. doi:10.1111/cns.12410
Boycott B, Wassle H (1999) Parallel processing in the mammalian retina: the Proctor Lecture. Invest Ophthalmol Vis Sci 40:1313–1327
Brett M, Johnsrude IS, Owen AM (2002) The problem of functional localization in the human brain. Nat Rev Neurosci 3(3):243–249
Brettschneider J, Del Tredici K, Toledo JB et al (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74:20–38. doi:10.1002/ana.23937
Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299
Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169(1–2):13–21
Chio A, Pagani M, Agosta F et al (2014) Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes. Lancet Neurol 13:1228–1240. doi:10.1016/S1474-4422(14)70167-X
Eisen A, Weber M (2000) Neurophysiological evaluation of cortical function in the early diagnosis of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 1(Suppl 1):S47–S51
Fawzi AA, Simonett JM, Purta P et al (2014) Clinicopathologic report of ocular involvement in ALS patients with C9orf72 mutation. Amyotroph Lateral Scler Frontotemporal Degener. doi:10.3109/21678421.2014.951941
Foerster BR, Callaghan BC, Petrou M et al (2012) Decreased motor cortex gamma-aminobutyric acid in amyotrophic lateral sclerosis. Neurology 78:1596–1600. doi:10.1212/WNL.0b013e3182563b57
Foerster BR, Dwamena BA, Petrou M et al (2013a) Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: a systematic review and individual patient data meta-analysis. Acad Radiol 20:1099–1106. doi:10.1016/j.acra.2013.03.017
Foerster BR, Pomper MG, Callaghan BC et al (2013b) An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy. JAMA neurology 70:1009–1016. doi:10.1001/jamaneurol.2013.234
Geevasinga N, Menon P, Howells J et al (2015) Axonal ion channel dysfunction in c9orf72 familial amyotrophic lateral sclerosis. JAMA Neurol 72:49–57. doi:10.1001/jamaneurol.2014.2940
Genovese CR, Lazar NA, Nichols T (2002) Thresholding of statistical maps in functional neuroimaging using the false discovery rate. NeuroImage 15:870–878. doi:10.1006/nimg.2001.1037
Kassubek J, Müller H-P, Del Tredici K et al (2014) Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain J Neurol 137:1733–1740. doi:10.1093/brain/awu090
Kesler A, Vakhapova V, Korczyn AD et al (2011) Retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Clin Neurol Neurosurg 113:523–526. doi:10.1016/j.clineuro.2011.02.014
Kiernan MC, Vucic S, Cheah BC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955. doi:10.1016/S0140-6736(10)61156-7
Kunimatsu A, Aoki S, Masutani Y et al (2004) The optimal trackability threshold of fractional anisotropy for diffusion tensor tractography of the corticospinal tract. Magn Reson Med Sci 3:11–17
London A, Benhar I, Schwartz M (2013) The retina as a window to the brain-from eye research to CNS disorders. Nature Rev Neurol 9:44–53. doi:10.1038/nrneurol.2012.227
Lulé D, Burkhardt C, Abdulla S et al (2014) The Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen: a cross-sectional comparison of established screening tools in a German-Swiss population. Amyotroph Lateral Scler Frontotemporal Degener. doi:10.3109/21678421.2014.959451
MacNeil MA, Masland RH (1998) Extreme diversity among amacrine cells: implications for function. Neuron 20:971–982
Moss HE, McCluskey L, Elman L et al (2012) Cross-sectional evaluation of clinical neuro-ophthalmic abnormalities in an amyotrophic lateral sclerosis population. J Neurol Sci 314:97–101. doi:10.1016/j.jns.2011.10.016
Müller H-P, Kassubek J (2013) Diffusion tensor magnetic resonance imaging in the analysis of neurodegenerative diseases. J Vis Exp. doi:10.3791/50427
Muller HP, Unrath A, Ludolph AC, Kassubek J (2007) Preservation of diffusion tensor properties during spatial normalization by use of tensor imaging and fibre tracking on a normal brain database. Phys Med Biol 52:N99–N109. doi:10.1088/0031-9155/52/6/N01
Müller A-K, Blasberg C, Südmeyer M et al (2014) Photoreceptor layer thinning in parkinsonian syndromes. Mov Disord 29:1222–1223. doi:10.1002/mds.25939
Nubling GS, Mie E, Bauer RM et al (2014) Increased prevalence of bladder and intestinal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 15:174–179. doi:10.3109/21678421.2013.868001
Phukan J, Elamin M, Bede P et al (2012) The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 83:102–108. doi:10.1136/jnnp-2011-300188
Ringelstein M, Albrecht P, Südmeyer M et al (2014) Subtle retinal pathology in amyotrophic lateral sclerosis. Ann Clin Trans Neurol 1:290–297. doi:10.1002/acn3.46
Roth NM, Saidha S, Zimmermann H et al (2013) Optical coherence tomography does not support optic nerve involvement in amyotrophic lateral sclerosis. Euro J Neurol Off J Euro Federat Neurol Societ 20:1170–1176. doi:10.1111/ene.12146
Schneider M, Müller H-P, Lauda F et al (2014) Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study. Journal of neural transmission (Vienna, Austria: 1996) 121:41–47. doi:10.1007/s00702-013-1072-3
Sharma R, Hicks S, Berna CM et al (2011) Oculomotor dysfunction in amyotrophic lateral sclerosis: a comprehensive review. Arch Neurol 68:857–861. doi:10.1001/archneurol.2011.130
Tewarie P, Balk L, Costello F et al (2012) The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS One 7:e34823–e34827. doi:10.1371/journal.pone.0034823
Turner MR, Kiernan MC (2012) Does interneuronal dysfunction contribute to neurodegeneration in amyotrophic lateral sclerosis? Amyotroph Lateral Scler 13:245–250. doi:10.3109/17482968.2011.636050
Turner MR, Modo M (2010) Advances in the application of MRI to amyotrophic lateral sclerosis. Expert Opin Med Diagn 4:483–496. doi:10.1517/17530059.2010.536836
Vucic S, Cheah BC, Kiernan MC (2009) Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis. Exp Neurol 220:177–182. doi:10.1016/j.expneurol.2009.08.017
Wassle H (2004) Parallel processing in the mammalian retina. Nat Rev Neurosci 5:747–757. doi:10.1038/nrn1497
Weis J, Katona I, Muller-Newen G et al (2011) Small-fiber neuropathy in patients with ALS. Neurology 76:2024–2029. doi:10.1212/WNL.0b013e31821e553a
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Funding
This study was not funded.
Rights and permissions
About this article
Cite this article
Hübers, A., Müller, H.P., Dreyhaupt, J. et al. Retinal involvement in amyotrophic lateral sclerosis: a study with optical coherence tomography and diffusion tensor imaging. J Neural Transm 123, 281–287 (2016). https://doi.org/10.1007/s00702-015-1483-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-015-1483-4