Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients

Zivadinov, Robert; Bergsland, Niels; Cappellani, Roberto; Hagemeier, Jesper; Melia, Rebecca; Carl, Ellen; Dwyer, Michael G.; Lincoff, Norah S.; Weinstock‐Guttman, B.; Ramanathan, Murali

doi:10.1111/ene.12449

Cited by 23 publications

(7 citation statements)

References 38 publications

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“…More recently, Mühlau et al (Muhlau et al, 2013) found that WM lesions and PUL atrophy are spatially related in MS, with axonal transection within WM lesions and subsequent degeneration along the axonal projections being the most plausible explanation. Gabilondo et al (Gabilondo et al, 2014) showed retro- and anterograde trans-synaptic neuronal degeneration in the visual pathway and Zivadinov et al (Zivadinov et al, 2014) reported a trend toward associations between retinal nerve fiber layer thickness in RRMS patients and microstructural damage in the thalamus, in particular, volume changes in the GT and PUL.…”

Section: Discussionmentioning

confidence: 99%

Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: A proposed mechanistic relationship between inflammation and oligodendrocyte vitality

et al. 2018

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Recent advances in susceptibility MRI have dramatically improved the visualization of deep gray matter brain regions and the quantification of their magnetic properties in vivo, providing a novel tool to study the poorly understood iron homeostasis in the human brain. In this study, we used an advanced combination of the recent quantitative susceptibility mapping technique with dedicated analysis methods to study intra-thalamic tissue alterations in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). Thalamic pathology is one of the earliest hallmarks of MS and has been shown to correlate with cognitive dysfunction and fatigue, but the mechanisms underlying the thalamic pathology are poorly understood. We enrolled a total of 120 patients, 40 with CIS, 40 with Relapsing Remitting MS (RRMS), and 40 with Secondary Progressive MS (SPMS). For each of the three patient groups, we recruited 40 controls, group matched for age- and sex (120 total). We acquired quantitative susceptibility maps using a single-echo gradient echo MRI pulse sequence at 3 T. Group differences were studied by voxel-based analysis as well as with a custom thalamus atlas. We used threshold-free cluster enhancement (TFCE) and multiple regression analyses, respectively. We found significantly reduced magnetic susceptibility compared to controls in focal thalamic subregions of patients with RRMS (whole thalamus excluding the pulvinar nucleus) and SPMS (primarily pulvinar nucleus), but not in patients with CIS. Susceptibility reduction was significantly associated with disease duration in the pulvinar, the left lateral nuclear region, and the global thalamus. Susceptibility reduction indicates a decrease in tissue iron concentration suggesting an involvement of chronic microglia activation in the depletion of iron from oligodendrocytes in this central and integrative brain region. Not necessarily specific to MS, inflammation-mediated iron release may lead to a vicious circle that reduces the protection of axons and neuronal repair.

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Section: Discussionmentioning

confidence: 99%

Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: A proposed mechanistic relationship between inflammation and oligodendrocyte vitality

et al. 2018

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“…Instead, the volume of the entire thalamus was associated with retinal damage in 2 previous studies: one of them used voxel-based morphometry (VBM) and showed that retinal axonal loss (measured as thinning of the retinal nerve fiber layer [RNFL]) was associated with a decrease in the volume of thalamus and the visual cortex. 2 The other study showed a cross-sectional correlation between RNFL and thalamic volume in MS. 30 However, the thalamus has multiple nuclei with many different functions and shows structural changes early in the course of MS. 31 Moreover, neuroaxonal loss in the retina correlates with brain atrophy 32 and is thought to generally reflect neurodegenerative processes in MS. 33 Thus, a specific assessment of the LGN is crucial to investigate neurodegeneration occurring specifically in the visual pathway.…”

Section: Discussionmentioning

confidence: 99%

Damage of the lateral geniculate nucleus in MS

et al. 2019

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ObjectiveTo study if the thalamic lateral geniculate nucleus (LGN) is affected in multiple sclerosis (MS) due to anterograde degeneration from optic neuritis (ON) or retrograde degeneration from optic radiation (OR) pathology, and if this is relevant for visual function.MethodsIn this cross-sectional study, LGN volume of 34 patients with relapsing-remitting MS and 33 matched healthy controls (HC) was assessed on MRI using atlas-based automated segmentation (MAGeT). ON history, thickness of the ganglion cell–inner plexiform layer (GC-IPL), OR lesion volume, and fractional anisotropy (FA) of normal-appearing OR (NAOR-FA) were assessed as measures of afferent visual pathway damage. Visual function was tested, including low-contrast letter acuity (LCLA) and Hardy-Rand-Rittler (HRR) plates for color vision.ResultsLGN volume was reduced in patients vs HC (165.5 ± 45.5 vs 191.4 ± 47.7 mm3, B = −25.89, SE = 5.83, p < 0.001). It was associated with GC-IPL thickness (B = 0.95, SE = 0.33, p = 0.006) and correlated with OR lesion volume (Spearman ρ = −0.53, p = 0.001), and these relationships remained after adjustment for normalized brain volume. There was no association between NAOR-FA and LGN volume (B = −133.28, SE = 88.47, p = 0.137). LGN volume was not associated with LCLA (B = 5.5 × 10−5, SE = 0.03, p = 0.998), but it correlated with HRR color vision (ρ = 0.39, p = 0.032).ConclusionsLGN volume loss in MS indicates structural damage with potential functional relevance. Our results suggest both anterograde degeneration from the retina and retrograde degeneration from the OR lesions as underlying causes. LGN volume is a promising marker reflecting damage of the visual pathway in MS, with the advantage of individual measurement per patient on conventional MRI.

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“…The effect of retrograde transsynaptic neurodegeneration on retinal atrophy was shown in previous studies in established MS. 27,28 Our findings indicate that such a mechanism also occurs in the earliest stages of demyelination. This finding is also supported by two previous studies showing the association of pRNFL with nTBV 6,29 and nWMV 29 in early MS. Several cross-sectional studies in established MS showed that both mGCL/GCIPL 27,30,31 and pRNFL 27,30–32 of non-ON eyes are associated with volumetric brain measurements. However, a longitudinal study showed that rate of atrophy in mGCIPL, but not pRNFL, was related to the rate of nTBV, nGMV, nTV loss, and also the lesion accumulation rate.…”

Section: Discussionmentioning

confidence: 99%

Retinal degeneration is associated with brain volume reduction and prognosis in radiologically isolated syndrome

et al. 2018

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Background: The extent of neurodegeneration in the earliest stages of central nervous system (CNS) demyelination is not known. Optical coherence tomography (OCT) is a powerful tool to study neurodegeneration in demyelinating disorders. Objectives: To study neuroaxonal loss in the retina of individuals with radiologically isolated syndrome (RIS) and investigate whether OCT measurements are associated with brain volumetrics and clinical conversion to multiple sclerosis (MS). Methods: Subjects fulfilling the Okuda criteria for RIS ( n = 15 patients, 30 eyes) and age- and sex-matched healthy controls (HC) underwent spectral-domain OCT and magnetic resonance imaging for volumetric measurement of brain structures. Results: Macular ganglion cell-inner plexiform layer (mGCIPL), macular retinal nerve fiber layer (mRNFL), and temporal peripapillary RNFL (pRNFL) thickness; normalized total brain volume (nTBV); and normalized thalamic volume (nTV) were reduced in RIS compared to HC. mGCIPL, mRNFL, and pRNFL measurements were associated with nTBV, nTV, and normalized gray and white matter volumes in the RIS group. pRNFL was thinner in individuals with RIS who converted to MS in 5 years. Conclusions: Retinal neurodegeneration can be detected in the papillomacular region in the earliest stages of CNS demyelination and reflects global disease processes in the brain. OCT can be potentially useful for predicting prognosis in RIS.

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Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients

Abstract: Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR-MS.

Cited by 23 publications

References 38 publications

Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: A proposed mechanistic relationship between inflammation and oligodendrocyte vitality

Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: A proposed mechanistic relationship between inflammation and oligodendrocyte vitality

Damage of the lateral geniculate nucleus in MS

Retinal degeneration is associated with brain volume reduction and prognosis in radiologically isolated syndrome

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