Dataset Information

Early diffusion evidence of retrograde transsynaptic degeneration in the human visual system.

ABSTRACT:

Objective

We investigated whether diffusion tensor imaging (DTI) indices of white matter integrity would offer early markers of retrograde transsynaptic degeneration (RTD) in the visual system after stroke.

Methods

We performed a prospective longitudinal analysis of the sensitivity of DTI markers of optic tract health in 12 patients with postsynaptic visual pathway stroke, 12 stroke controls, and 28 healthy controls. We examined group differences in (1) optic tract fractional anisotropy (FA-asymmetry), (2) perimetric measures of visual impairment, and (3) the relationship between FA-asymmetry and perimetric assessment.

Results

FA-asymmetry was higher in patients with visual pathway lesions than in control groups. These differences were evident 3 months from the time of injury and did not change significantly at 12 months. Perimetric measures showed evidence of impairment in participants with visual pathway stroke but not in control groups. A significant association was observed between FA-asymmetry and perimetric measures at 3 months, which persisted at 12 months.

Conclusions

DTI markers of RTD are apparent 3 months from the time of injury. This represents the earliest noninvasive evidence of RTD in any species. Furthermore, these measures associate with measures of visual impairment. DTI measures offer a reproducible, noninvasive, and sensitive method of investigating RTD and its role in visual impairment.

SUBMITTER: Patel KR

PROVIDER: S-EPMC4940065 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

Early diffusion evidence of retrograde transsynaptic degeneration in the human visual system.

Patel Kevin R KR Ramsey Lenny E LE Metcalf Nicholas V NV Shulman Gordon L GL Corbetta Maurizio M

Neurology 20160615 2

<h4>Objective</h4>We investigated whether diffusion tensor imaging (DTI) indices of white matter integrity would offer early markers of retrograde transsynaptic degeneration (RTD) in the visual system after stroke.<h4>Methods</h4>We performed a prospective longitudinal analysis of the sensitivity of DTI markers of optic tract health in 12 patients with postsynaptic visual pathway stroke, 12 stroke controls, and 28 healthy controls. We examined group differences in (1) optic tract fractional anis ...[more]

PMID: 27306632

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Project description:Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.

Project description:BackgroundAccurate diagnosis in patients presenting with lesions at various locations within the visual pathway is challenging. This study investigated functional and structural changes secondary to such lesions to identify patterns useful to guide early and effective management.MethodsOver 10,000 records from patients referred for optic nerve head assessment were reviewed and 31 patients with a final diagnosis of likely neuropathic lesions posterior to the eye were included in the current study. Fundus photographs, optic coherence tomography images and visual field tests were evaluated for changes with respect to retinal nerve fibre layer topography and prediction of structure-function paradigms. Emerging clinical patterns were examined for their consistency with the likely anatomical origin of the underlying insult in the presence of varying diagnoses.ResultsData from patients with lesions along the visual system allowed identification of retinal nerve fibre layer asymmetry correlated with visual field defects and ganglion cell analysis. Bilateral discordance in retinal nerve fibre loss easily discernible from an altered pattern of the temporal-superior-nasal-inferior-temporal curve was characteristic for post-chiasmal lesions. These sometimes-subtle changes supported diagnosis in cases with multiple aetiologies or with ambiguous visual field analysis and/or ganglion cell loss.ConclusionIntricate knowledge of the retinal architecture and projections allows coherent predictions of functional and structural deficits following various lesions affecting the visual pathway. The integration of adjunct imaging and retinal nerve fibre layer thinning will assist clinicians to guide clinical investigations toward a likely diagnosis in the light of significant individual variations. The case series presented in this study aids in differential diagnosis of retrograde optic neuropathies by using retinal nerve fibre layer asymmetric patterns as an important clinical marker.

Dataset Information

Early diffusion evidence of retrograde transsynaptic degeneration in the human visual system.

Objective

Methods

Results

Conclusions

Publications

Early diffusion evidence of retrograde transsynaptic degeneration in the human visual system.

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