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Journal of Neurology

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01-06-2019 | Original Communication

Brain white matter changes in asymptomatic carriers of Leber’s hereditary optic neuropathy

Authors: Miaomiao Long, Ling Wang, Qin Tian, Hao Ding, Wen Qin, Dapeng Shi, Chunshui Yu

Published in: Journal of Neurology | Issue 6/2019

Abstract

Objective

Subclinical abnormalities, including microangiopathy, swelling of nerve fibers, visual field abnormalities and visual functional impairments had been reported in Leber’s hereditary optic neuropathy (LHON) carriers. The purpose of this study was to investigate microstructural changes of brain white matter in asymptomatic LHON carriers using DTI and tract-based spatial statistics (TBSS).

Methods

DTI and neuro-ophthalmologic measurements were acquired in 14 LHON carriers and 15 gender- and age-matched healthy controls, and diffusion metrics, including fractional anisotropy (FA), axial (AD), radial diffusion (RD) and mean diffusion (MD) were calculated. Intergroup differences in diffusion metrics were compared regressing out potential nuisance covariates of age and gender. A correlation analysis was performed to test associations between abnormal neuro-ophthalmologic measures and diffusion metrics while controlling the effects of age and gender.

Results

Compared to healthy controls, LHON carriers showed a weak increase of thickness of the retinal nerve fiber layer (RNFL) of the right inferior quadrant (F = 5.22, p = 0.032, before multiple comparison correction). LHON carriers exhibited widespread decreased FA value (bilateral anterior thalamic radiations, bilateral corticospinal tracts, major and minor forceps, bilateral inferior fronto-occipital fasciculi and left superior longitudinal fasciculus), increased RD value (bilateral anterior thalamic radiations, bilateral corticospinal tracts, major and minor forceps, bilateral inferior fronto-occipital fasciculi, bilateral inferior longitudinal fasciculi, bilateral superior longitudinal fasciculi and bilateral uncinate fasciculi) and increased MD value (bilateral anterior thalamic radiations, bilateral corticospinal tracts, minor forceps, bilateral inferior fronto-occipital fasciculi, bilateral inferior longitudinal fasciculi, left superior longitudinal fasciculus and bilateral uncinate fasciculi). Moreover, these changed diffusion metrics were not correlated with age, gender, LHON mutations and retinal measures in LHON carriers.

Conclusion

Our results show microstructural alterations in brain white matter in asymptomatic LHON carriers, indicating that LHON-related genetic mutations themselves might result in occult white matter alterations in the brain.

Alexander AL, Lee JE, Lazar M, Field AS (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4:316–329CrossRefPubMedPubMedCentral

Balducci N, Savini G, Cascavilla ML, La Morgia C, Triolo G, Giglio R, Carbonelli M, Parisi V, Sadun AA, Bandello F, Carelli V, Barboni P (2016) Macular nerve fibre and ganglion cell layer changes in acute Leber’s hereditary optic neuropathy. Br J Ophthalmol 100:1232–1237CrossRefPubMed

Barboni P, Carbonelli M, Savini G, Ramos Cdo V, Carta A, Berezovsky A, Salomao SR, Carelli V, Sadun AA (2010) Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology 117:623–627CrossRefPubMed

Barcella V, Rocca MA, Bianchi-Marzoli S, Milesi J, Melzi L, Falini A, Pierro L, Filippi M (2010) Evidence for retrochiasmatic tissue loss in Leber’s hereditary optic neuropathy. Hum Brain Mapp 31:1900–1906CrossRefPubMedPubMedCentral

Basser PJ, Mattiello J, LeBihan D (1994) Estimation of the effective self-diffusion tensor from the NMR spin echo. J Magn Reson Ser B 103:247–254CrossRef

Bianco A, Bisceglia L, De Caro MF, Galeandro V, De Bonis P, Tullo A, Zoccolella S, Guerriero S, Petruzzella V (2018) Leber’s hereditary optic neuropathy, intellectual disability and epilepsy presenting with variable penetrance associated to the m.3460G> A mutation and a heteroplasmic expansion of the microsatellite in MTRNR1 gene—case report. BMC Med Genet 19:129CrossRefPubMedPubMedCentral

Bianco A, Valletti A, Longo G, Bisceglia L, Montoya J, Emperador S, Guerriero S, Petruzzella V (2018) Mitochondrial DNA copy number in affected and unaffected LHON mutation carriers. BMC Res Notes 11:911CrossRefPubMedPubMedCentral

Carelli V, Valentino ML, Liguori R, Meletti S, Vetrugno R, Provini F, Mancardi GL, Bandini F, Baruzzi A, Montagna P (2001) Leber’s hereditary optic neuropathy (LHON/11778) with myoclonus: report of two cases. J Neurol Neurosurg Psychiatry 71:813–816CrossRefPubMedPubMedCentral

d’Almeida OC, Mateus C, Reis A, Grazina MM, Castelo-Branco M (2013) Long term cortical plasticity in visual retinotopic areas in humans with silent retinal ganglion cell loss. NeuroImage 81:222–230CrossRefPubMed

10.

De Vries DD, Went LN, Bruyn GW, Scholte HR, Hofstra RM, Bolhuis PA, van Oost BA (1996) Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am J Hum Genet 58:703–711PubMedPubMedCentral

11.

Flanigan KM, Johns DR (1993) Association of the 11778 mitochondrial DNA mutation and demyelinating disease. Neurology 43:2720–2722CrossRefPubMed

12.

Funakawa I, Kato H, Terao A, Ichihashi K, Kawashima S, Hayashi T, Mitani K, Miyazaki S (1995) Cerebellar ataxia in patients with Leber’s hereditary optic neuropathy. J Neurol 242:75–77CrossRefPubMed

13.

Grazina MM, Diogo LM, Garcia PC, Silva ED, Garcia TD, Robalo CB, Oliveira CR (2007) Atypical presentation of Leber’s hereditary optic neuropathy associated to mtDNA 11778G> A point mutation—a case report. Eur J Paediatr Neurol 11:115–118CrossRefPubMed

14.

Guy J, Feuer WJ, Porciatti V, Schiffman J, Abukhalil F, Vandenbroucke R, Rosa PR, Lam BL (2014) Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci 55:841–848CrossRefPubMedPubMedCentral

15.

Harding AE, Riordan-Eva P, Govan GG (1995) Mitochondrial DNA diseases: genotype and phenotype in Leber’s hereditary optic neuropathy. Muscle Nerve Suppl 3:S82–S84CrossRefPubMed

16.

Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, McDonald WI, Compston DA (1992) Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain J Neurol 115(Pt 4):979–989CrossRef

17.

Haselgrove JC, Moore JR (1996) Correction for distortion of echo-planar images used to calculate the apparent diffusion coefficient. Magn Reson Med 36:960–964CrossRefPubMed

18.

Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML (1991) A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 48:1147–1153PubMedPubMedCentral

19.

Jancic J, Dejanovic I, Radovanovic S, Ostojic J, Kozic D, Duric-Jovicic M, Samardzic J, Cetkovic M, Kostic V (2016) White matter changes in two Leber’s hereditary optic neuropathy pedigrees: 12-year follow-up. Ophthalmologica 235:49–56CrossRefPubMed

20.

Jansen PH, van der Knaap MS, de Coo IF (1996) Leber’s hereditary optic neuropathy with the 11 778 mtDNA mutation and white matter disease resembling multiple sclerosis: clinical, MRI and MRS findings. J Neurol Sci 135:176–180CrossRefPubMed

21.

Johns DR, Smith KH, Miller NR (1992) Leber’s hereditary optic neuropathy. Clinical manifestations of the 3460 mutation. Arch Ophthalmol (Chicago, Ill: 1960) 110:1577–1581CrossRef

22.

Johnsson P, Lundqvist C, Lindgren A, Ferencz I, Alling C, Stahl E (1995) Cerebral complications after cardiac surgery assessed by S-100 and NSE levels in blood. J Cardiothorac Vasc Anesth 9:694–699CrossRefPubMed

23.

Kermode AG, Moseley IF, Kendall BE, Miller DH, MacManus DG, McDonald WI (1989) Magnetic resonance imaging in Leber’s optic neuropathy. J Neurol Neurosurg Psychiatry 52:671–674CrossRefPubMedPubMedCentral

24.

Klivenyi P, Karg E, Rozsa C, Horvath R, Komoly S, Nemeth I, Turi S, Vecsei L (2001) alpha-Tocopherol/lipid ratio in blood is decreased in patients with Leber’s hereditary optic neuropathy and asymptomatic carriers of the 11778 mtDNA mutation. J Neurol Neurosurg Psychiatry 70:359–362CrossRefPubMedPubMedCentral

25.

La Morgia C, Achilli A, Iommarini L, Barboni P, Pala M, Olivieri A, Zanna C, Vidoni S, Tonon C, Lodi R, Vetrugno R, Mostacci B, Liguori R, Carroccia R, Montagna P, Rugolo M, Torroni A, Carelli V (2008) Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. Neurology 70:762–770CrossRefPubMed

26.

Le Bihan D (2003) Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 4:469–480CrossRefPubMed

27.

Le Bihan D, Johansen-Berg H (2012) Diffusion MRI at 25: exploring brain tissue structure and function. NeuroImage 61:324–341CrossRefPubMed

28.

Li Y, Li J, Jia X, Xiao X, Li S, Guo X (2017) Genetic and clinical analyses of DOA and LHON in 304 chinese patients with suspected childhood-onset hereditary optic neuropathy. PloS One 12:e0170090CrossRefPubMedPubMedCentral

29.

Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, Ross-Cisneros FN, Baciu P, Sung E, McManus MJ, Pan BX, Gil DW, Macgregor GR, Wallace DC (2012) Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc Natl Acad Sci USA 109:20065–20070CrossRefPubMedPubMedCentral

30.

Lodi R, Montagna P, Cortelli P, Iotti S, Cevoli S, Carelli V, Barbiroli B (2000) ‘Secondary’ 4216/ND1 and 13708/ND5 Leber’s hereditary optic neuropathy mitochondrial DNA mutations do not further impair in vivo mitochondrial oxidative metabolism when associated with the 11778/ND4 mitochondrial DNA mutation. Brain J Neurol 123(Pt 9):1896–1902CrossRef

31.

Lodi R, Taylor DJ, Tabrizi SJ, Kumar S, Sweeney M, Wood NW, Styles P, Radda GK, Schapira AH (1997) In vivo skeletal muscle mitochondrial function in Leber’s hereditary optic neuropathy assessed by 31P magnetic resonance spectroscopy. Ann Neurol 42:573–579CrossRefPubMed

32.

Mackey D, Howell N (1992) A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Am J Hum Genet 51:1218–1228PubMedPubMedCentral

33.

Manners DN, Rizzo G, La Morgia C, Tonon C, Testa C, Barboni P, Malucelli E, Valentino ML, Caporali L, Strobbe D, Carelli V, Lodi R (2015) Diffusion tensor imaging mapping of brain white matter pathology in mitochondrial optic neuropathies. Am J Neuroradiol 36:1259–1265CrossRefPubMedPubMedCentral

34.

Meire FM, Van Coster R, Cochaux P, Obermaier-Kusser B, Candaele C, Martin JJ (1995) Neurological disorders in members of families with Leber’s hereditary optic neuropathy (LHON) caused by different mitochondrial mutations. Ophthalmic Genet 16:119–126CrossRefPubMed

35.

Milesi J, Rocca MA, Bianchi-Marzoli S, Petrolini M, Pagani E, Falini A, Comi G, Filippi M (2012) Patterns of white matter diffusivity abnormalities in Leber’s hereditary optic neuropathy: a tract-based spatial statistics study. J Neurol 259:1801–1807CrossRefPubMed

36.

Nakaso K, Adachi Y, Fusayasu E, Doi K, Imamura K, Yasui K, Nakashima K (2012) Leber’s hereditary optic neuropathy with olivocerebellar degeneration due to G11778A and T3394C mutations in the mitochondrial DNA. J Clin Neurol (Seoul Korea) 8:230–234CrossRef

37.

Newman NJ, Lott MT, Wallace DC (1991) The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 111:750–762CrossRefPubMed

38.

Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15:1–25CrossRefPubMed

39.

Nikoskelainen EK, Marttila RJ, Huoponen K, Juvonen V, Lamminen T, Sonninen P, Savontaus ML (1995) Leber’s “plus”: neurological abnormalities in patients with Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 59:160–164CrossRefPubMedPubMedCentral

40.

Nishioka T, Soemantri A, Ishida T (2004) mtDNA/nDNA ratio in 14484 LHON mitochondrial mutation carriers. J Hum Genet 49:701–705CrossRefPubMed

41.

Olsen NK, Hansen AW, Norby S, Edal AL, Jorgensen JR, Rosenberg T (1995) Leber’s hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand 91:326–329CrossRefPubMed

42.

Ostojic J, Jancic J, Kozic D, Semnic R, Koprivsek K, Prvulovic M, Kostic V (2009) Brain white matter 1 H MRS in Leber optic neuropathy mutation carriers. Acta Neurol Belg 109:305–309PubMed

43.

Popescu BF, Pirko I, Lucchinetti CF (2013) Pathology of multiple sclerosis: where do we stand? Continuum (Minneap Minn) 19:901–921

44.

Qin W, Zhang M, Piao Y, Guo D, Zhu Z, Tian X, Li K, Yu C (2012) Wallerian degeneration in central nervous system: dynamic associations between diffusion indices and their underlying pathology. PloS One 7:e41441CrossRefPubMedPubMedCentral

45.

Rance G, Kearns LS, Tan J, Gravina A, Rosenfeld L, Henley L, Carew P, Graydon K, O’Hare F, Mackey DA (2012) Auditory function in individuals within Leber’s hereditary optic neuropathy pedigrees. J Neurol 259:542–550CrossRefPubMed

46.

Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE (1995) The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain J Neurol 118(Pt 2):319–337CrossRef

47.

Rocca MA, Valsasina P, Pagani E, Bianchi-Marzoli S, Milesi J, Falini A, Comi G, Filippi M (2011) Extra-visual functional and structural connection abnormalities in Leber’s hereditary optic neuropathy. PloS One 6:e17081CrossRefPubMedPubMedCentral

48.

Sadun AA, Win PH, Ross-Cisneros FN, Walker SO, Carelli V (2000) Leber’s hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc 98:223–232 (discussion 232–225)PubMedPubMedCentral

49.

Salomao SR, Berezovsky A, Andrade RE, Belfort R Jr, Carelli V, Sadun AA (2004) Visual electrophysiologic findings in patients from an extensive Brazilian family with Leber’s hereditary optic neuropathy. Doc Ophthalmol Adv Ophthalmol 108:147–155CrossRef

50.

Savini G, Barboni P, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L, Zanini M, Carelli V (2005) Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber’s hereditary optic neuropathy mutations. Ophthalmology 112:127–131CrossRefPubMed

51.

Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31:1487–1505CrossRefPubMed

52.

Smith SM, Nichols TE (2009) Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. NeuroImage 44:83–98CrossRefPubMed

53.

Ventura DF, Quiros P, Carelli V, Salomao SR, Gualtieri M, Oliveira AG, Costa MF, Berezovsky A, Sadun F, de Negri AM, Sadun AA (2005) Chromatic and luminance contrast sensitivities in asymptomatic carriers from a large Brazilian pedigree of 11778 Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci 46:4809–4814CrossRefPubMed

54.

Vergani L, Martinuzzi A, Carelli V, Cortelli P, Montagna P, Schievano G, Carrozzo R, Angelini C, Lugaresi E (1995) MtDNA mutations associated with Leber’s hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells. Biochem Biophys Res Commun 210:880–888CrossRefPubMed

55.

Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242:1427–1430CrossRefPubMed

56.

Wheeler-Kingshott CA, Cercignani M (2009) About “axial” and “radial” diffusivities. Magn Reson Med 61:1255–1260CrossRefPubMed

57.

Yardan T, Cevik Y, Donderici O, Kavalci C, Yilmaz FM, Yilmaz G, Vural K, Yuzbasioglu Y, Gunaydin YK, Sezer AA (2009) Elevated serum S100B protein and neuron-specific enolase levels in carbon monoxide poisoning. Am J Emerg Med 27:838–842CrossRefPubMed

58.

Yee KM, Ross-Cisneros FN, Lee JG, Da Rosa AB, Salomao SR, Berezovsky A, Belfort R Jr, Chicani F, Moraes-Filho M, Sebag J, Carelli V, Sadun AA (2012) Neuron-specific enolase is elevated in asymptomatic carriers of Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 53:6389–6392CrossRefPubMedPubMedCentral

Title: Brain white matter changes in asymptomatic carriers of Leber’s hereditary optic neuropathy
Authors: Miaomiao Long
Ling Wang
Qin Tian
Hao Ding
Wen Qin
Dapeng Shi
Chunshui Yu
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 6/2019
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-019-09284-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Brain white matter changes in asymptomatic carriers of Leber’s hereditary optic neuropathy

Abstract

Objective

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objective

Methods

Results

Conclusion

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