124 results on '"Alexander Klistorner"'
Search Results
2. Diffusivity in the core of chronic multiple sclerosis lesions.
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Alexander Klistorner, Chenyu Wang, Con Yiannikas, John Parratt, Joshua Barton, Yuyi You, Stuart L Graham, and Michael H Barnett
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Medicine ,Science - Abstract
Diffusion tensor imaging (DTI) has been suggested as a potential biomarker of disease progression, neurodegeneration and de/remyelination in MS. However, the pathological substrates that underpin alterations in brain diffusivity are not yet fully delineated. We propose that in highly cohesive fiber tracts: 1) a relative increase in parallel (axial) diffusivity (AD) may serve as a measure of increased extra-cellular space (ESC) within the core of chronic MS lesions and, as a result, may provide an estimate of the degree of tissue destruction, and 2) the contribution of the increased extra-cellular water to perpendicular (radial) diffusivity (RD) can be eliminated to provide a more accurate assessment of membranal (myelin) loss.The purpose of this study was to isolate the contribution of extra-cellular water and demyelination to observed DTI indices in the core of chronic MS lesions, using the OR as an anatomically cohesive tract.Pre- and post-gadolinium (Gd) enhanced T1, T2 and DTI images were acquired from 75 consecutive RRMS patients. In addition, 25 age and gender matched normal controls were imaged using an identical MRI protocol (excluding Gd). The optic radiation (OR) was identified in individual patients using probabilistic tractography. The T2 lesions were segmented and intersected with the OR. Average eigenvalues were calculated within the core of OR lesions mask. The proportion of extra-cellular space (ECS) within the lesional core was calculated based on relative increase of AD, which was then used to normalise the perpendicular eigenvalues to eliminate the effect of the expanded ECS. In addition, modelling was implemented to simulate potential effect of various factors on lesional anisotropy.Of 75 patients, 41 (55%) demonstrated sizable T2 lesion volume within the ORs. All lesional eigenvalues were significantly higher compared to NAWM and controls. There was a strong correlation between AD and RD within the core of OR lesions, which was, however, not seen in OR NAWM of MS patients or normal controls. In addition, lesional anisotropy (FA) was predominantly driven by the perpendicular diffusivity, while in NAWM and in OR of normal controls all eigenvectors contributed to variation in FA. Estimated volume of ECS component constituted significant proportion of OR lesional volume and correlated significantly with lesional T1 hypointensity. While perpendicular diffusivity dropped significantly following normalisation, it still remained higher compared with diffusivity in OR NAWM. The "residual" perpendicular diffusivity also showed a substantial reduction of inter-subject variability. Both observed and modelled diffusion data suggested anisotropic nature of water diffusion in ESC. In addition, the simulation procedure offered a possible explanation for the discrepancy in relationship between eigenvalues and anisotropy in lesional tissue and NAWM.This paper presents a potential technique for more reliably quantifying the effects of neurodegeneration (tissue loss) versus demyelination in OR MS lesions. This may provide a simple and effective way for applying single tract diffusion analysis in MS clinical trials, with particular relevance to pro-remyelinating and neuroprotective therapeutics.
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- 2018
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3. White matter tract-specific quantitative analysis in multiple sclerosis: Comparison of optic radiation reconstruction techniques.
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Chenyu Wang, Alexander Klistorner, Linda Ly, and Michael H Barnett
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Medicine ,Science - Abstract
The posterior visual pathway is commonly affected by multiple sclerosis (MS) pathology that results in measurable clinical and electrophysiological impairment. Due to its highly structured retinotopic mapping, the visual pathway represents an ideal substrate for investigating patho-mechanisms in MS. Therefore, a reliable and robust imaging segmentation method for in-vivo delineation of the optic radiations (OR) is needed. However, diffusion-based tractography approaches, which are typically used for OR segmentation are confounded by the presence of focal white matter lesions. Current solutions require complex acquisition paradigms and demand expert image analysis, limiting application in both clinical trials and clinical practice. In the current study, using data acquired in a clinical setting on a 3T scanner, we optimised and compared two approaches for optic radiation (OR) reconstruction: individual probabilistic tractography-based and template-based methods. OR segmentation results were applied to subjects with MS and volumetric and diffusivity parameters were compared between OR segmentation techniques. Despite differences in reconstructed OR volumes, both OR lesion volume and OR diffusivity measurements in MS subjects were highly comparable using optimised probabilistic tractography-based, and template-based, methods. The choice of OR reconstruction technique should be determined primarily by the research question and the nature of the available dataset. Template-based approaches are particularly suited to the semi-automated analysis of large image datasets and have utility even in the absence of dMRI acquisitions. Individual tractography methods, while more complex than template based OR reconstruction, permit measurement of diffusivity changes along fibre bundles that are affected by specific MS lesions or other focal pathologies.
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- 2018
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4. Progressive Injury in Chronic Multiple Sclerosis Lesions Is Gender-Specific: A DTI Study.
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Alexander Klistorner, Chenyu Wang, Con Yiannikas, Stuart L Graham, John Parratt, and Michael H Barnett
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Medicine ,Science - Abstract
OBJECTIVE:To evaluate the longitudinal integrity of white matter tracts in patients with relapsing remitting multiple sclerosis (RRMS) as determined by changes in diffusivity indices of lesional and non-lesional white matter in the optic radiation over 12 months. METHODS:The optic radiation (OR) was identified in sixty RRMS patients using probabilistic tractography. MS lesions were segmented on FLAIR T2 images and a lesion mask was intersected with the co-registered OR. Lesions within the OR were identified in 39 patients. Voxel-based analysis of axial diffusivity (AD) and radial diffusivity (RD) within OR lesions and non-lesional normal appearing white matter (NAWM) was performed at baseline and 12 months in 34 patients (five patients excluded due to new OR lesions). RESULTS:Both RD and AD demonstrated much higher values within the lesions compared with non-lesional NAWM. There was a significant (p
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- 2016
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5. Decoding diffusivity in multiple sclerosis: analysis of optic radiation lesional and non-lesional white matter.
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Alexander Klistorner, Nikitha Vootakuru, Chenyu Wang, Con Yiannikas, Stuart L Graham, John Parratt, Raymond Garrick, Netta Levin, Lynette Masters, Jim Lagopoulos, and Michael H Barnett
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Medicine ,Science - Abstract
ObjectivesDiffusion tensor imaging (DTI) has been suggested as a new promising tool in MS that may provide greater pathological specificity than conventional MRI, helping, therefore, to elucidate disease pathogenesis and monitor therapeutic efficacy. However, the pathological substrates that underpin alterations in brain tissue diffusivity are not yet fully delineated. Tract-specific DTI analysis has previously been proposed in an attempt to alleviate this problem. Here, we extended this approach by segmenting a single tract into areas bound by seemingly similar pathological processes, which may better delineate the potential association between DTI metrics and underlying tissue damage.MethodSeveral compartments were segmented in optic radiation (OR) of 50 relapsing-remitting MS patients including T2 lesions, proximal and distal parts of fibers transected by lesion and fibers with no discernable pathology throughout the entire length of the OR.ResultsAsymmetry analysis between lesional and non-lesional fibers demonstrated a marked increase in Radial Diffusivity (RD), which was topographically limited to focal T2 lesions and potentially relates to the lesional myelin loss. A relative elevation of Axial Diffusivity (AD) in the distal part of the lesional fibers was observed in a distribution consistent with Wallerian degeneration, while diffusivity in the proximal portion of transected axons remained normal. A moderate, but significant elevation of RD in OR non-lesional fibers was strongly associated with the global (but not local) T2 lesion burden and is probably related to microscopic demyelination undetected by conventional MRI.ConclusionThis study highlights the utility of the compartmentalization approach in elucidating the pathological substrates of diffusivity and demonstrates the presence of tissue-specific patterns of altered diffusivity in MS, providing further evidence that DTI is a sensitive marker of tissue damage in both lesions and NAWM. Our results suggest that, at least within the OR, parallel and perpendicular diffusivities are affected by tissue restructuring related to distinct pathological processes.
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- 2015
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6. Parallel changes in structural and functional measures of optic nerve myelination after optic neuritis.
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Anneke van der Walt, Scott Kolbe, Peter Mitchell, Yejun Wang, Helmut Butzkueven, Gary Egan, Con Yiannikas, Stuart Graham, Trevor Kilpatrick, and Alexander Klistorner
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Medicine ,Science - Abstract
Visual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON.Thirty acute ON patients were studied at 1, 3, 6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further.Both latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p =
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- 2015
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7. Relationship between optical coherence tomography and electrophysiology of the visual pathway in non-optic neuritis eyes of multiple sclerosis patients.
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Prema Sriram, Chenyu Wang, Con Yiannikas, Raymond Garrick, Michael Barnett, John Parratt, Stuart L Graham, Hemamalini Arvind, and Alexander Klistorner
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Medicine ,Science - Abstract
PURPOSE: Loss of retinal ganglion cells in in non-optic neuritis eyes of Multiple Sclerosis patients (MS-NON) has recently been demonstrated. However, the pathological basis of this loss at present is not clear. Therefore, the aim of the current study was to investigate associations of clinical (high and low contrast visual acuity) and electrophysiological (electroretinogram and multifocal Visual Evoked Potentials) measures of the visual pathway with neuronal and axonal loss of RGC in order to better understand the nature of this loss. METHODS: Sixty-two patients with relapsing remitting multiple sclerosis with no previous history of optic neuritis in at least one eye were enrolled. All patients underwent a detailed ophthalmological examination in addition to low contrast visual acuity, Optical Coherence Tomography, full field electroretinogram (ERG) and multifocal visual evoked potentials (mfVEP). RESULTS: There was significant reduction of ganglion cell layer thickness, and total and temporal retinal nerve fibre layer (RNFL) thickness (p
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- 2014
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8. Optic nerve diffusion tensor imaging after acute optic neuritis predicts axonal and visual outcomes.
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Anneke van der Walt, Scott C Kolbe, Yejun E Wang, Alexander Klistorner, Neil Shuey, Gelareh Ahmadi, Mark Paine, Mark Marriott, Peter Mitchell, Gary F Egan, Helmut Butzkueven, and Trevor J Kilpatrick
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Medicine ,Science - Abstract
BackgroundEarly markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS).ObjectivesTo assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months.MethodsThirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction.ResultsAffected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated.ConclusionsThese results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.
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- 2013
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9. Optic nerve magnetisation transfer ratio after acute optic neuritis predicts axonal and visual outcomes.
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Yejun Wang, Anneke van der Walt, Mark Paine, Alexander Klistorner, Helmut Butzkueven, Gary F Egan, Trevor J Kilpatrick, and Scott C Kolbe
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Medicine ,Science - Abstract
Magnetisation transfer ratio (MTR) can reveal the degree of proton exchange between free water and macromolecules and was suggested to be pathological informative. We aimed to investigate changes in optic nerve MTR over 12 months following acute optic neuritis (ON) and to determine whether MTR measurements can predict clinical and paraclinical outcomes at 6 and 12 months. Thirty-seven patients with acute ON were studied within 2 weeks of presentation and at 1, 3, 6 and 12 months. Assessments included optic nerve MTR, retinal nerve fibre layer (RNFL) thickness, multifocal visual evoked potential (mfVEP) amplitude and latency and high (100%) and low (2.5%) contrast letter acuity. Eleven healthy controls were scanned twice four weeks apart for comparison with patients. Patient unaffected optic nerve MTR did not significantly differ from controls at any time-point. Compared to the unaffected nerve, affected optic nerve MTR was significantly reduced at 3 months (mean percentage interocular difference = -9.24%, p = 0.01), 6 months (mean = -12.48%, p
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- 2012
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10. Correction: Optic Nerve Magnetisation Transfer Ratio after Acute Optic Neuritis Predicts Axonal and Visual Outcomes.
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Yejun Wang, Anneke van der Walt, Mark Paine, Alexander Klistorner, Helmut Butzkueven, Gary F. Egan, Trevor J. Kilpatrick, and Scott C. Kolbe
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Medicine ,Science - Published
- 2012
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11. Anterograde degeneration along the visual pathway after optic nerve injury.
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Yuyi You, Vivek K Gupta, Stuart L Graham, and Alexander Klistorner
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Medicine ,Science - Abstract
PURPOSE: To investigate anterograde degenerative changes along the visual pathway in a rat model of optic nerve axotomy. METHODS: Optic nerve transection was performed in adult Sprague-Dawley rats. Animals were sacrificed at regular time intervals and tissues harvested. Immunoblotting followed by densitometric analysis was used to determine the phosphorylation profile of Akt in the dorsal lateral geniculate nucleus (dLGN) and the primary visual cortex (V1). The neuronal cell size and cell density were measured in the dLGN and the V1 using Nissl staining. The prevalence of apoptosis was characterized by terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labelling (TUNEL) histochemistry. Caspase-3 antibodies were also used to identify apoptotic cells. Neurons and astrocytes were detected using NeuN and glial fibrillary acidic protein (GFAP), respectively. RESULTS: An early and sustained loss of Akt phosphorylation was observed after optic nerve transection in both dLGN and V1. At week one, a decrease in the neuronal cell size (50.5±4.9 vs 60.3±5.0 µm(2), P = 0.042) and an increase of TUNEL positive cells (7.9±0.6 vs 1.4±0.5 ×10(2) cells/mm(2), P
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- 2012
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12. Expansion of chronic MS lesions is associated with an increase of radial diffusivity in periplaque white matter
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Yuyi You, Alexander Klistorner, Stuart L. Graham, John De Parratt, Joshua Barton, Samuel Klistorner, Con Yiannikas, and Michael Barnett
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Pathology ,medicine.medical_specialty ,Multiple Sclerosis ,business.industry ,Multiple sclerosis ,Radial diffusivity ,Brain ,Inflammation ,medicine.disease ,White Matter ,Lesion ,White matter ,Diffusion Magnetic Resonance Imaging ,Multiple Sclerosis, Relapsing-Remitting ,medicine.anatomical_structure ,Neurology ,medicine ,Humans ,Neurology (clinical) ,medicine.symptom ,business ,Biomarkers - Abstract
Background: Expansion of chronic multiple sclerosis (MS) lesion is associated with slow-burning inflammation at lesion rim. However, the underlying mechanisms leading to expansion are not fully understood. Objective: To investigate the relationship between diffusivity markers of demyelination and axonal loss in perilesional white matter and lesion expansion in relapsing-remitting MS (RRMS). Methods: T1, FLAIR and diffusion tensor images were acquired from 30 patients. Novel single-streamline technique was used to estimate diffusivity in lesions, perilesional white matter and normal-appearing white matter (NAWM). Results: Significant association was found between baseline periplaque radial diffusivity (RD) and subsequent lesion expansion. Conversely, periplaque axial diffusivity (AD) did not correlate with lesion growth. Baseline RD (but not AD) in periplaque white matter of expanding lesions was significantly higher compared with non-expanding lesions. Correlation between increase of both RD and AD in the periplaque area during follow-up period and lesion expansion was noticeably stronger for RD. Increase of RD in periplaque area was also much higher compared to AD. There was significant increase of AD and RD in the periplaque area of expanding, but not in non-expanding, lesions. Conclusion: Periplaque demyelination is likely to be an initial step in a process of lesion expansion and, as such, potentially represents a suitable target for remyelinating therapies.
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- 2021
13. Impaired motion perception is associated with functional and structural visual pathway damage in multiple sclerosis and neuromyelitis optica spectrum disorders
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Alexander Klistorner, Hanna Zimmermann, Joseph Kuchling, Noah Ayadi, Susanna Asseyer, Rebekka Rust, Klemens Ruprecht, Frederike C. Oertel, Ankelien Duchow, Alexander U. Brandt, Friedemann Paul, and Judith Bellmann-Strobl
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Retina ,Multiple Sclerosis ,Optic Neuritis ,genetic structures ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Neuromyelitis Optica ,Motion Perception ,Visual evoked potentials ,medicine.disease ,medicine.anatomical_structure ,Neurology ,Optical coherence tomography ,Neuromyelitis Optica Spectrum Disorders ,medicine ,Humans ,Visual Pathways ,Optic neuritis ,Neurology (clinical) ,Motion perception ,Function and Dysfunction of the Nervous System ,business ,Neuroscience ,Tomography, Optical Coherence - Abstract
Background: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS). Objectives: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD). Methods: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS ( n = 38, confirmatory cohort n = 43), NMOSD ( n = 13) and healthy controls ( n = 33). Results: NFM was lower compared with controls in MS ( B = −12.37, p < 0.001) and NMOSD ( B = −34.5, p < 0.001). NFM was lower in ON than in non-ON eyes ( B = −30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity ( B = −139.4, p < 0.001/ B = −77.2, p < 0.001) and low contrast letter acuity ( B = 0.99, p = 0.002/ B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer ( B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer ( B = 64.8, p < 0.001/ B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer ( B = 1.351, p < 0.001) and increased mfVEP P100 latencies ( B = −1.159, p < 0.001). Conclusions: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD.
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- 2021
14. Expansion of chronic lesions is linked to disease progression in relapsing–remitting multiple sclerosis patients
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Alexander Klistorner, Joshua Barton, Stuart L. Graham, John De Parratt, Con Yiannikas, Samuel Klistorner, Yuyi You, and Michael Barnett
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Pathology ,medicine.medical_specialty ,Multiple Sclerosis ,Axonal loss ,Inflammation ,Lesion ,03 medical and health sciences ,Multiple Sclerosis, Relapsing-Remitting ,0302 clinical medicine ,medicine ,Humans ,030304 developmental biology ,0303 health sciences ,business.industry ,Incidence (epidemiology) ,Multiple sclerosis ,Disease progression ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Neurology ,Relapsing remitting ,Disease Progression ,T2 lesions ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background: Slow-burning inflammation is putatively associated with lesion expansion and leads to progressive loss of axons and disability worsening. Objective: To investigate the incidence and extent of chronic white matter lesion expansion in relapsing–remitting multiple sclerosis (RRMS) patients and to evaluate its relationship with biomarkers of disease progression. Methods: Pre- and post-gadolinium T1, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 33 patients. Lesional activity were analysed between baseline and 48 months using custom-designed software. Results: A total of 569 lesions were identified as chronic at baseline, of which 261 were expanding, 236 were stable and 72 were shrinking. In addition, 139 new lesions (both confluent and free-standing) were observed. Chronic lesion expansion was associated with patient’s age and accounted for the bulk (67.3%) of total brain lesion volume increase, while only 32.7% was attributable to new lesion formation. Change in chronic lesion volume correlated with the rate of brain atrophy ( r = −0.57, p = 0.001), change of Expanded Disability Status Scale (EDSS; r = 0.38, p = 0.03) and an increase of isotropic diffusivity inside the lesions ( r = 0.75, p Conclusion: Expansion of chronic lesions in RRMS patients is the primary determinant of increased T2 total lesion load. It significantly contributes to disease progression and partially driving axonal loss inside the lesions and brain damage outside of lesional tissue.
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- 2020
15. Latency of Multifocal Visual Evoked Potential in Multiple Sclerosis: A Visual Pathway Biomarker for Clinical Trials of Remyelinating Therapies
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Michael Barnett, Yuyi You, Stuart L. Graham, John De Parratt, James D. Triplett, Joshua Barton, Con Yiannikas, and Alexander Klistorner
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Optic Neuritis ,Physiology ,Neuritis ,Population ,050105 experimental psychology ,03 medical and health sciences ,Multiple Sclerosis, Relapsing-Remitting ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,0501 psychology and cognitive sciences ,Optic neuritis ,Latency (engineering) ,Remyelination ,Evoked potential ,education ,Clinical Trials as Topic ,education.field_of_study ,business.industry ,Multiple sclerosis ,05 social sciences ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Neurology ,Antirheumatic Agents ,Evoked Potentials, Visual ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Optic radiation - Abstract
PURPOSE Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing-remitting multiple sclerosis (RRMS) patients. The potential sample size required for a remyelination-based clinical trial using different treatment effect sizes and the mfVEP latency as an outcome measure was also estimated. METHODS A total of 50 RRMS consecutive patients with no previous history of optic neuritis in at least one eye and 15 normal controls of similar age and gender composition were prospectively enrolled. Fifteen patients had a history of unilateral ON more than 12 months earlier, whereas 41 patients demonstrated optic radiations lesions on MRI at baseline. Most patients were on disease modifying therapy. A mfVEP was recorded at baseline and 12 months later. RESULTS At baseline, the mfVEP latency in RRMS patients was delayed compared with normal controls in both optic neuritis and nonoptic neuritis eyes. Latency delay was significantly correlated to optic radiation lesion volume (R2 = 0.38, P < 0.001). There was no significant latency change in multiple sclerosis patients' eyes or optic neuritis and nonoptic neuritis eyes over the follow-up period with latency remaining remarkably constant. This was despite the fact that 46 of 50 patients were on disease-modifying therapies, implying current treatments do not affect myelination in chronic RRMS cases. Sample size calculations to evaluate an additional or alternative remyelinating agent, based on a 40% treatment effect, revealed that a relatively small sample size (78 patients) would be required to demonstrate efficacy in future trials of remyelination therapies. CONCLUSIONS Given its known sensitivity for latency changes and the stability found in this RRMS population, the mfVEP represents an ideal biomarker to assess the degree of latency recovery that may be achieved by remyelination in multiple sclerosis.
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- 2020
16. APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies
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Jennifer S. Graves, Robert P. Finger, Gema Rebolleda, Aykut Aytulun, Elliot Frohman, Ari J. Green, Peter A. Calabresi, Frank G. Holz, Bernardo Sanchez-Dalmau, Wolf A. Lagrèze, Sven G. Meuth, Lisanne J. Balk, Joachim Havla, Hanna Zimmermann, Laura J. Balcer, Patrick Yu-Wai-Man, Philipp Albrecht, Joel S. Schuman, Alexander U. Brandt, Piero Barboni, P. Villoslada, David Garway-Heath, Sven Schippling, Benjamin Knier, Friedemann Paul, Thomas Korn, Letizia Leocani, Scott Kolbe, Delia Cabrera DeBuc, Teresa Frohman, Jette Lautrup Frederiksen, Andrés Cruz-Herranz, Jaime Imitola, Robert C. Sergott, Oliver Maier, Augusto Azuara Blanco, Hans-Peter Hartung, Orhan Aktas, Julia Krämer, Marius Ringelstein, Elena H. Martinez-Lapiscina, Nicolas Feltgen, Rachel Kenney, Iñigo Gabilondo, Ahmed Toosy, E. Ann Yeh, Sebastian Wolf, Gorm Pihl-Jensen, Olivier Outteryck, Axel Petzold, Fiona Costello, Shiv Saidha, Jana Lizrova Preiningerova, Alexander Klistorner, Neurology, Ophthalmology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Aytulun, A., Cruz-Herranz, A., Aktas, O., Balcer, L. J., Balk, L., Barboni, P., Blanco, A. A., Calabresi, P. A., Costello, F., Sanchez-Dalmau, B., Debuc, D. C., Feltgen, N., Finger, R. P., Frederiksen, J. L., Frohman, E., Frohman, T., Garway-Heath, D., Gabilondo, I., Graves, J. S., Green, A. J., Hartung, H. -P., Havla, J., Holz, F. G., Imitola, J., Kenney, R., Klistorner, A., Knier, B., Korn, T., Kolbe, S., Kramer, J., Lagreze, W. A., Leocani, L., Maier, O., Martinez-Lapiscina, E. H., Meuth, S., Outteryck, O., Paul, F., Petzold, A., Pihl-Jensen, G., Preiningerova, J. L., Rebolleda, G., Ringelstein, M., Saidha, S., Schippling, S., Schuman, J. S., Sergott, R. C., Toosy, A., Villoslada, P., Wolf, S., Yeh, E. A., Yu-Wai-Man, P., Zimmermann, H. G., Brandt, A. U., and Albrecht, P.
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Research design ,medicine.medical_specialty ,Consensus ,Delphi Technique ,Computer science ,Delphi method ,MEDLINE ,610 Medicine & health ,Terminology ,03 medical and health sciences ,0302 clinical medicine ,Retinal Diseases ,medicine ,Humans ,Medical physics ,030212 general & internal medicine ,Research Methods in Neurology ,Grading (education) ,Protocol (science) ,Guideline ,Checklist ,ddc ,Ophthalmology ,Research Design ,Neurology (clinical) ,Function and Dysfunction of the Nervous System ,030217 neurology & neurosurgery ,Tomography, Optical Coherence - Abstract
ObjectiveTo update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.MethodsTo identify studies reporting quantitative OCT results, we performed a PubMed search for the terms “quantitative” and “optical coherence tomography” from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.ResultsA total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.ConclusionsThe modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.
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- 2021
17. Evidence of Müller Glial Dysfunction in Patients with Aquaporin-4 Immunoglobulin G–Positive Neuromyelitis Optica Spectrum Disorder
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John Parratt, Michael Barnett, Ling Zhu, Yuyi You, Angela Schulz, Ting Zhang, Ting Shen, Con Yiannikas, Clare L. Fraser, Vivek Gupta, Ariadna Fontes, Alexander Klistorner, Stuart L. Graham, Joshua Barton, and Mark C Gillies
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medicine.medical_specialty ,genetic structures ,Outer plexiform layer ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ophthalmology ,Medicine ,Outer nuclear layer ,030304 developmental biology ,0303 health sciences ,Retina ,Neuromyelitis optica ,medicine.diagnostic_test ,business.industry ,Retinal ,medicine.disease ,eye diseases ,medicine.anatomical_structure ,chemistry ,Inner nuclear layer ,030221 ophthalmology & optometry ,sense organs ,business ,Erg ,Electroretinography - Abstract
Purpose To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Design Cross-sectional study; biochemical study of human retinas. Participants A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis. Methods Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Muller glial distribution were analyzed using Western blotting and immunohistochemistry. Main Outcome Measures Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions. Results The b-wave amplitude was significantly reduced in patients with AQP4-IgG+ NMOSD in scotopic ERGs (compared with AQP4-IgG- subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Muller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgG+ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction (P = 0.005∼0.01, fixed-effects model). Western blotting demonstrated that Muller cell–specific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Muller glial distribution in the human macula. Conclusions This study provides in vivo structural and functional evidence of Muller glial dysfunction in eyes of patients with AQP4-IgG+ NMOSD. Topography of retinal structural change is supported by distribution of Muller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in NMOSD.
- Published
- 2019
18. Differing Structural and Functional Patterns of Optic Nerve Damage in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder
- Author
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Ariadna Fontes, Yuyi You, Sukanya Arunachalam, Michael Barnett, Ting Shen, Clare L. Fraser, John Parratt, Ling Zhu, Alexander Klistorner, Chenyu Wang, Joshua Barton, Vivek Gupta, Nitin Chitranshi, Sidong Liu, Stuart L. Graham, and Con Yiannikas
- Subjects
Adult ,Male ,Retinal Ganglion Cells ,medicine.medical_specialty ,Multiple Sclerosis ,Optic Neuritis ,Visual acuity ,genetic structures ,Anterior Visual Pathway ,Visual Acuity ,Axonal loss ,Nerve fiber layer ,03 medical and health sciences ,0302 clinical medicine ,Ophthalmology ,Humans ,Medicine ,Visual Pathways ,Optic neuritis ,030304 developmental biology ,0303 health sciences ,Neuromyelitis optica ,business.industry ,Multiple sclerosis ,Neuromyelitis Optica ,Optic Nerve ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Axons ,eye diseases ,Cross-Sectional Studies ,medicine.anatomical_structure ,030221 ophthalmology & optometry ,Optic nerve ,Evoked Potentials, Visual ,Female ,sense organs ,medicine.symptom ,business ,Tomography, Optical Coherence - Abstract
To assess differential patterns of axonal loss and demyelination in the optic nerve in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD).Cross-sectional study.One hundred ninety-two participants, including 136 MS patients (272 eyes), 19 NMOSD patients (38 eyes), and 37 healthy control participants (74 eyes).All participants underwent spectral-domain OCT scans and multifocal visual evoked potential (mfVEP) recordings. High-resolution magnetic resonance imaging (MRI) with the diffusion protocol also was performed in all patients.Ganglion cell-inner plexiform layer (GCIPL) thickness and mfVEP amplitude and latency at 5 eccentricities; global and temporal retinal nerve fiber layer thickness.In optic neuritis (ON) eyes, the NMOSD patients had more severe GCIPL loss (P0.001) and mfVEP amplitude reduction (P0.001) compared with MS patients, whereas in contrast, mfVEP latency delay was more evident in MS patients (P0.001). The NMOSD patients showed more morphologic and functional loss at the foveal to parafoveal region, whereas the MS patients showed evenly distributed damage at the macula. Correlation analysis demonstrated a strong structure-function (OCT-mfVEP) association in the NMOSD patients, which was only moderate in the MS patients. In non-ON (NON) eyes, the MS patients showed significantly thinner GCIPL than controls (P0.001), whereas no GCIPL loss was observed in NON eyes in NMOSD. In addition, a significant correlation was found between all OCT and mfVEP measures in MS patients, but not in NMOSD patients. MRI demonstrated significant lesional load in the optic radiation in MS compared to NMOSD eyes (P = 0.002), which was related to the above OCT and mfVEP changes in NON eyes.Our study demonstrated different patterns of ON damage in NMOSD and MS. In MS, the ON damage was less severe, with demyelination as the main pathologic component, whereas in NMOSD, axonal loss was more severe compared with myelin loss. The disproportional mfVEP amplitude and latency changes suggested predominant axonal damage within the anterior visual pathway as the main clinical feature of NMOSD, in contrast to MS, where demyelination spreads along the entire visual pathway.
- Published
- 2019
19. The electrophysiological assessment of visual function in Multiple Sclerosis
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Michael Barnett, Joshua L. Barton, Alexander Klistorner, and Justin Y. Garber
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genetic structures ,Multifocal visual evoked potentials ,Visual evoked potentials ,lcsh:RC321-571 ,Multiple sclerosis ,03 medical and health sciences ,0302 clinical medicine ,Reviews, Expert Opinions and Guideline ,Physiology (medical) ,Medicine ,In patient ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,medicine.diagnostic_test ,business.industry ,musculoskeletal, neural, and ocular physiology ,030208 emergency & critical care medicine ,Magnetic resonance imaging ,Clinical routine ,medicine.disease ,eye diseases ,Electrophysiology ,Neurology ,Visual function ,Neurology (clinical) ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Highlights • VEPs have largely been replaced by MRI in modern MS diagnosis and management. • Multifocal VEPs are superior to traditional VEPs in evaluating the integrity of the visual system. • Physiological asymmetry limits interpretation of small VEP differences., The assessment of vision is integral to the diagnosis and monitoring of patients with multiple sclerosis (MS). Visual electrophysiology, previously a critical investigation in patients with suspected MS, has in large part been supplanted by magnetic resonance imaging in clinical routine. However, the development of multi-focal visual evoked potentials and the advent of putative re-myelinating therapies that can be monitored with these techniques has led to a resurgence of interest in the field. Here, we review the clinical applications, technical considerations and limitations of visual evoked potentials in the management of patients with MS.
- Published
- 2019
20. Trans-synaptic degeneration in the visual pathway: Neural connectivity, pathophysiology, and clinical implications in neurodegenerative disorders
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Samridhi Sharma, Alexander Klistorner, Mehdi Mirzaei, Nitin Chitranshi, Stuart L. Graham, Roshana Vander Wall, Vivek Gupta, Devaraj Basavarajappa, and Yuyi You
- Subjects
Retinal Ganglion Cells ,endocrine system ,Retrograde Degeneration ,genetic structures ,Axonal loss ,Degeneration (medical) ,Biology ,Visual system ,Retinal ganglion ,Synapse ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Visual Pathways ,Retina ,Neurodegenerative Diseases ,eye diseases ,Ophthalmology ,Visual cortex ,medicine.anatomical_structure ,Synapses ,030221 ophthalmology & optometry ,sense organs ,Neuroscience ,030217 neurology & neurosurgery - Abstract
There is a strong interrelationship between eye and brain diseases. It has been shown that neurodegenerative changes can spread bidirectionally in the visual pathway along neuronal projections. For example, damage to retinal ganglion cells in the retina leads to degeneration of the visual cortex (anterograde degeneration) and vice versa (retrograde degeneration). The underlying mechanisms of this process, known as trans-synaptic degeneration (TSD), are unknown, but TSD contributes to the progression of numerous neurodegenerative disorders, leading to clinical and functional deterioration. The hierarchical structure of the visual system comprises of a strong topographic connectivity between the retina and the visual cortex and therefore serves as an ideal model to study the cellular effect, clinical manifestations, and deterioration extent of TSD. With this review we provide comprehensive information about the neural connectivity, synapse function, molecular changes, and pathophysiology of TSD in visual pathways. We then discuss its bidirectional nature and clinical implications in neurodegenerative diseases. A thorough understanding of TSD in the visual pathway can provide insights into progression of neurodegenerative disorders and its potential as a therapeutic target.
- Published
- 2021
21. Multiple sclerosis: structural and functional integrity of the visual system following alemtuzumab therapy
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Stephen W. Reddel, Chenyu Wang, Marinda Taha, Heidi N. Beadnall, Yael Barnett, Kain Kyle, Michael Barnett, Alexander Klistorner, Joshua Barton, Hans-Peter Hartung, and Linda Ly
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Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Context (language use) ,Lesion ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Fractional anisotropy ,medicine ,Clinical endpoint ,Humans ,Immunologic Factors ,Visual Pathways ,Remyelination ,Evoked potential ,Alemtuzumab ,030304 developmental biology ,Neurologic Examination ,0303 health sciences ,business.industry ,Multiple sclerosis ,Brain ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,medicine.anatomical_structure ,Cardiology ,Evoked Potentials, Visual ,Surgery ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
ObjectiveTo investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model.MethodsWe monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints.ResultsIn patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both pConclusionWe found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a ‘permissive’ local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.
- Published
- 2021
22. Pathophysiological basis of low contrast visual acuity loss in multiple sclerosis
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James D. Triplett, Stuart L. Graham, Yuyi You, John Parratt, Joshua Barton, Alexander Klistorner, Con Yiannikas, and Michael Barnett
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medicine.medical_specialty ,Visual acuity ,genetic structures ,media_common.quotation_subject ,Nerve fiber layer ,Axonal loss ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ophthalmology ,medicine ,Contrast (vision) ,Optic neuritis ,Latency (engineering) ,Research Articles ,media_common ,business.industry ,General Neuroscience ,Multiple sclerosis ,Retinal ,medicine.disease ,medicine.anatomical_structure ,chemistry ,030221 ophthalmology & optometry ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Research Article - Abstract
Objective There is currently an urgent need for reliable clinical biomarkers of remyelination to be used in Phase 2 and Phase 3 clinical trials. Low contrast visual acuity (LCVA) has been suggested as a functional measure of the integrity of the visual pathway. Therefore, the aim of this study was to elucidate the potential contribution of axonal loss and demyelination to LCVA loss in MS patients. Method In this study, 50 consecutive relapsing remitting MS patients with a previous history of unilateral optic neuritis were enrolled. Using the linear regression model, we assessed the relative contribution of multifocal Visual Evoked Potentials (mfVEP) latency and Retinal Nerve Fiber Layer (RNFL) thickness to LCVA deficit. Results Intereye asymmetry of mfVEP latency and RNFL thickness correlated significantly with intereye asymmetry of LCVA (P
- Published
- 2018
23. Multifocal visual evoked potentials in chronic inflammatory demyelinating polyneuropathy
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Lena Gemerzki, Jens Harmel, Marius Ringelstein, Rainer Guthoff, Robert Kolbe, John-Ih Lee, Jonas Graf, Alexander Klistorner, Jana Rybak, Laura Rhöse, Philipp Albrecht, Orhan Aktas, Hans-Peter Hartung, Jens Ingwersen, and Lea Jansen
- Subjects
medicine.medical_specialty ,Visual acuity ,genetic structures ,business.industry ,General Neuroscience ,Confounding ,Chronic inflammatory demyelinating polyneuropathy ,Visual evoked potentials ,medicine.disease ,Visual field ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Ophthalmology ,030221 ophthalmology & optometry ,Optic nerve ,Medicine ,Neurology (clinical) ,Latency (engineering) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Research Articles ,Research Article - Abstract
Objective Studies using conventional full‐field visual evoked potentials (ffVEP) have reported subtle abnormalities in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We hypothesize that these abnormalities can be detected in the majority of CIDP patients using enhanced methods. Methods We performed a cross‐sectional noninterventional study comparing 18 CIDP patients and 18 matched healthy controls using multifocal VEP (mfVEP) as a technique with enhanced sensitivity to detect conduction abnormalities across the spectrum of optic nerve fibers. Patients with confounding diseases (ophthalmologic, diabetes mellitus) were excluded. Results The mean amplitude and latency, as well as the low‐contrast visual acuity, did not differ between CIDP patients and controls. Subanalyses revealed latency differences concerning the superior sector of the visual field. Severity markers of CIDP (ODSS, motor nerve conduction velocity) were associated with mfVEP latency delay. Interpretation We could not adduce evidence for clinically or diagnostically relevant visual pathway involvement in CIDP. The latency differences identified were very subtle and restricted to the superior visual field which cannot be readily explained biologically, anatomically, or pathologically. In summary, we conclude that our study revealed no relevant differences in mfVEP parameters between CIDP patients and controls.
- Published
- 2018
24. Monitoring of optic nerve function in Neurofibromatosis 2 children with optic nerve sheath meningiomas using multifocal visual evoked potentials
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Clare L. Fraser, Frank A. Billson, V. Jayanetti, John R. Grigg, Stuart L. Graham, M. Dexter, Meredith Wilson, Maree Flaherty, Alexander Klistorner, Kathryn N. North, and Kristi J. Jones
- Subjects
Adult ,Male ,Neurofibromatosis 2 ,Optic nerve sheath ,medicine.medical_specialty ,Visual acuity ,genetic structures ,Vision Disorders ,Visual evoked potentials ,Optic nerve function ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Ophthalmology ,Optic Nerve Diseases ,Meningeal Neoplasms ,Humans ,Medicine ,Neurofibromatosis type 2 ,Neurofibromatosis ,Child ,General anaesthetic ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,eye diseases ,Neurology ,030221 ophthalmology & optometry ,Optic nerve ,Evoked Potentials, Visual ,Female ,Surgery ,Neurology (clinical) ,Visual Fields ,medicine.symptom ,Meningioma ,business ,030217 neurology & neurosurgery - Abstract
Monitoring optic nerve sheath meningiomas (ONSM) in Neurofibromatosis type 2 (NF2) patients remains difficult. Other ocular manifestations of NF2 may obscure ophthalmic assessment of optic nerve function in these patients. Serial magnetic resonance imaging (MRI) used to assess the optic nerve is not without limitations, being expensive and often requiring general anaesthetic in children, with associated risks. This study was undertaken to describe the use of multifocal visual evoked potentials (multifocal VEP, mfVEP) in the regular monitoring of NF2 patients with ONSM. This study involved three NF2 patients with ONSM who undertook mfVEP testing at an academic ophthalmic centre. Same day mfVEP and routine ophthalmic testing were undertaken. Topographical function of the optic nerve was assessed, utilising tools such as asymmetry deviation and accumap severity index. Results were assessed alongside MRI and visual acuity (VA). From the three patients, five eyes had ONSMs, of which two caused unilateral blindness. The remaining three affected eyes had initial VAs 6/6, 6/24, and 6/18. Over follow up, ranging from 5 to 12 years, all tumours progressed, and VA declined for all patients. Multifocal VEP detected optic nerve functional loss corresponding with visual decline. This case series suggests mfVEP is effective in the objective topographic monitoring of optic nerve function in NF2 patients with ONSM. Due also to its safety in a paediatric population, the test may be considered in the routine monitoring of these patients, to be used to assist regular ophthalmic review and MRI scans.
- Published
- 2018
25. Evidence of progressive tissue loss in the core of chronic MS lesions: A longitudinal DTI study
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Michael G. Dwyer, Michael Barnett, Alexander Klistorner, Con Yiannikas, John Parratt, Chenyu Wang, Joshua Barton, Stuart L. Graham, Sidong Liu, and Yuyi You
- Subjects
Adult ,Male ,0301 basic medicine ,Multiple Sclerosis ,Cognitive Neuroscience ,lcsh:Computer applications to medicine. Medical informatics ,Thermal diffusivity ,lcsh:RC346-429 ,Diffusion ,White matter ,Lesion ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Atrophy ,Lateral Ventricles ,Fractional anisotropy ,Image Processing, Computer-Assisted ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Longitudinal Studies ,lcsh:Neurology. Diseases of the nervous system ,Analysis of Variance ,Brain Mapping ,Core (anatomy) ,Chronic demyelination ,business.industry ,Multiple sclerosis ,Brain ,Regular Article ,Middle Aged ,medicine.disease ,Diffusion Tensor Imaging ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Disease Progression ,Lesions ,lcsh:R858-859.7 ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Nuclear medicine ,030217 neurology & neurosurgery ,Diffusion MRI - Abstract
Objective Using diffusion tensor imaging (DTI), we examined chronic stable MS lesions, peri-lesional white matter (PLWM) and normal appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (RRMS) for evidence of progressive tissue destruction and evaluated whether diffusivity change is associated with conventional MRI parameters and clinical findings. Method Pre- and post-gadolinium T1, T2 and DTI images were acquired from 55 consecutive RRMS patients at baseline and 42.3 ± 9.7 months later. Chronic stable T2 lesions of sufficient size were identified in 43 patients (total of 134 lesions). Diffusivity parameters such as axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) were compared at baseline and follow-up. MRI was also performed in 20 normal subjects of similar age and gender. Results Within the core of chronic MS lesions the diffusion of water molecules significantly increased over the follow-up period, while in NAWM all diffusivity indices remained stable. Since increase of AD and RD in lesional core was highly concordant, indicating isotropic nature of diffusivity change, and considering potential effect of crossing fibers on directionally-selective indices, only MD, a directionally-independent measure, was used for further analysis. The significant increase of MD in the lesion core during the follow-up period (1.29 ± 0.19 μm2/ms and 1.34 ± 0.20 μm2/ms at baseline and follow-up respectively, P, Highlights • Chronic stable MS lesions were examined by using diffusion tensor imaging for evidence of progressive tissue destruction; • Within the lesion core the diffusivity increased significantly over the follow-up period, while it remained stable in NAWM; • Change of mean diffusivity in the lesion core was associated with progressive brain atrophy; • This paper suggested progressive tissue destruction in demyelinated white matter.
- Published
- 2018
26. Performance of iPad-based threshold perimetry in glaucoma and controls
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Angela Schulz, Alexander Klistorner, Elizabeth C. Graham, Yuyi You, and Stuart L. Graham
- Subjects
Reproducibility ,Validation study ,genetic structures ,business.industry ,Glaucoma ,medicine.disease ,Visual field ,Correlation ,03 medical and health sciences ,Ophthalmology ,0302 clinical medicine ,Linear regression ,Statistics ,030221 ophthalmology & optometry ,medicine ,Visual field testing ,Bland–Altman plot ,business ,030217 neurology & neurosurgery - Abstract
IMPORTANCE Independent validation of iPad visual field testing software Melbourne Rapid Fields (MRF). BACKGROUND To examine the functionality of MRF and compare its performance with Humphrey SITA 24-2 (HVF). DESIGN Prospective, cross-sectional validation study. PARICIPANTS Sixty glaucomas mean deviation (MD:-5.08±5.22); 17 pre-perimetric, 43 HVF field defects and 25 controls. METHODS The MRF was compared with HVF for scotoma detection, global indices, regional mean threshold values and sensitivity/specificity. Long-term test-retest variability was assessed after 6 months. MAIN OUTCOME MEASURES Linear regression and Bland Altman analyses of global indices sensitivity/specificity using (ROC) curves, intraclass correlations. RESULTS Using a cluster definition of three points at
- Published
- 2017
27. Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations
- Author
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Yuyi You, Raymond Garrick, Michael Barnett, Elizabeth C. Graham, John Parratt, Con Yiannikas, Alexander Klistorner, Chenyu Wang, and Stuart L. Graham
- Subjects
Adult ,Male ,Retinal Ganglion Cells ,Pathology ,medicine.medical_specialty ,Multiple Sclerosis ,Nerve fiber layer ,Transneuronal degeneration ,Retina ,03 medical and health sciences ,chemistry.chemical_compound ,Nerve Fibers ,0302 clinical medicine ,Optical coherence tomography ,medicine ,Humans ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Brain ,Magnetic resonance imaging ,Retinal ,Anatomy ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Neurology ,chemistry ,Retinal ganglion cell ,Disease Progression ,030221 ophthalmology & optometry ,Female ,Neurology (clinical) ,business ,Tomography, Optical Coherence ,030217 neurology & neurosurgery - Abstract
Background and purpose The mechanism of retinal ganglion cell and retinal nerve fiber layer loss in multiple sclerosis (MS) remains unknown. This study aimed to investigate the association between temporal retinal nerve fiber layer (tRNFL) thinning and disease activity in the brain determined by T2 lesions on magnetic resonance imaging (MRI). Methods Fifty-five consecutive patients with relapsing–remitting MS and 25 controls were enrolled. All patients underwent annual optical coherence tomography and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively. Results Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 μm/year). Thinning of tRNFL fibers was more prominent in younger patients (P = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (ORs). There was significantly greater tRNFL thinning in patients with new lesional activity in the ORs compared with patients with new lesions outside the ORs (P = 0.009). Conclusions This study supports the notion that retrograde transneuronal degeneration caused by OR lesions might play a role in progressive retinal nerve fiber layer loss. In addition, the results of the study also indicate that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS.
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- 2017
28. DBA/2J mouse model for experimental glaucoma: pitfalls and problems
- Author
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Stuart L. Graham, Anita J. Turner, Roshana Vander Wall, Vivek Gupta, and Alexander Klistorner
- Subjects
0301 basic medicine ,medicine.medical_specialty ,genetic structures ,Glaucoma ,Fundus (eye) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Optical coherence tomography ,Ophthalmology ,Pupillary response ,Medicine ,Scotopic vision ,Pathological ,medicine.diagnostic_test ,business.industry ,Confounding ,Retinal ,medicine.disease ,eye diseases ,030104 developmental biology ,chemistry ,030221 ophthalmology & optometry ,sense organs ,business - Abstract
Purpose The DBA/2J mouse has been described as a model for congenital experimental glaucoma. It develops anterior segment anomalies with synechiae and pigment dispersion leading to raised intraocular pressure (IOP) and glaucomatous damage. However there are serious practical considerations when using this model in longitudinal studies. Methods We followed 118 mice from 12 - 48 weeks of age in a pharmaceutical trial. Here we report on the findings in control animals (n=37). IOP was measured weekly, electrophysiology and optical coherence tomography (OCT) every 6 weeks. A subset also had invasive IOP measurements performed prior to euthanasia. Results While IOP eventually rose by 9 months in most animals, tonometry was complicated by corneal calcification in the majority of animals rendering IOP measurement unreliable. Invasive IOP did not correlate with non-invasive measures. Loss of scotopic threshold response and thinning of inner retinal layers on OCT was observed over time, suggesting glaucomatous damage but this occurred in some animals without raised IOP. Poor pupil dilation significantly affected electrophysiology, OCT and fundus imaging. 22% of animals developed major systemic complications leading to high dropout rate. Conclusions The DBA/2J experimental glaucoma model shows variability in expression and its pathological changes cause major difficulties in assessing disease progression. From our experience the model presents significant challenges for drug studies in glaucoma, as there are many confounding factors; difficulty with accurate IOP measurement, in vivo imaging, and electrophysiology recording and a high drop-out rate. In addition there may be an underlying neurodegenerative process independent of IOP.
- Published
- 2017
29. Poster Abstracts
- Author
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Yuyi You, Brian Chua, Chenyu Wang, Stuart L. Graham, Alexander Klistorner, Sukanya Arunachalam, and Megha Kaushik
- Subjects
medicine.medical_specialty ,business.industry ,Glaucoma ,Degeneration (medical) ,medicine.disease ,03 medical and health sciences ,Ophthalmology ,0302 clinical medicine ,030221 ophthalmology & optometry ,Medicine ,business ,030217 neurology & neurosurgery ,Diffusion MRI - Published
- 2016
30. Association Between BDNF Val66Met Polymorphism and Optic Neuritis Damage in Neuromyelitis Optica Spectrum Disorder
- Author
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Alexander Klistorner, Ting Shen, Yuyi You, Stuart L. Graham, Vivek Gupta, and Con Yiannikas
- Subjects
0301 basic medicine ,medicine.medical_specialty ,genetic structures ,NMOSD ,Central nervous system ,Nerve fiber layer ,lcsh:RC321-571 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Val66Met ,Ophthalmology ,medicine ,Optic neuritis ,Evoked potential ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,optic neuritis ,Neuromyelitis optica ,business.industry ,optic nerve damage ,General Neuroscience ,Retinal ,Brief Research Report ,medicine.disease ,eye diseases ,Ganglion ,030104 developmental biology ,medicine.anatomical_structure ,BDNF ,chemistry ,Optic nerve ,sense organs ,business ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS). The purpose of the study was to examine the association between the brain-derived neurotrophic factor (BDNF) Val66Met genotype and structural and functional optic nerve damage in the eyes of NMOSD patients. A total of 17 NMOSD subjects (34 eyes) were included in the study and were divided into subgroups based on optic neuritis (ON) history and BDNF Val66Met polymorphisms. The mean (range) age was 47.8 (23–78) years, and the mean (SD) disease duration was 7.4 (2–39) years. All participants had undergone optical coherence tomography (OCT) scans for global retinal nerve fiber layer (gRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness and multifocal visual evoked potential (mfVEP) test for amplitude and latency. BDNF Val66Met polymorphisms were genotyped in all participants. OCT and mfVEP changes were compared between two genotype groups (Met carriers vs. Val homozygotes) by using the generalised estimating equation (GEE) models. The BDNF Val66Met polymorphism was significantly associated with more severe nerve fiber layer damage and axonal loss in ON eyes of NMOSD subjects. Met carriers had more significantly reduced GCIPL (P = 0.002) and gRNFL (P < 0.001) thickness as well as more delayed mfVEP latency (P = 0.008) in ON eyes. No association was found between Val66Met variants and non-ON (NON)-eye of the participants. These findings suggest that the BDNF Val66Met polymorphism may be associated with optic nerve damage caused by acute ON attacks in NMOSD patients.
- Published
- 2019
31. Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders
- Author
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I. Kleiter, Martin W. Hümmert, Tania Kümpfel, Joachim Havla, Ilya Ayzenberg, Hanna Zimmermann, Luisa Klotz, Kim Lea Young, Marius Ringelstein, Christian Geis, Philipp Albrecht, Michael Deppe, Hans-Peter Hartung, Luise Röpke, Nele Retzlaff, Matthias Kaste, Alexander Klistorner, Orhan Aktas, Corinna Trebst, Christoph Schroeder, Axel Haarmann, Paulus S. Rommer, Martin S. Weber, Mathias Buttmann, Friedemann Paul, Florian Lauda, Hannah L. Pellkofer, Alexander U. Brandt, Uwe K. Zettl, Kerstin Hellwig, Hayrettin Tumani, Jens Harmel, B. Wildemann, Sven Jarius, Wael Marouf, Jan-Patrick Stellmann, Jonas Graf, Pawel Kermer, Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Marseille] (CEMEREM), and Hôpital de la Timone [CHU - APHM] (TIMONE)
- Subjects
medicine.medical_specialty ,Neuromyelitis optica ,business.industry ,Multiple sclerosis ,Medizin ,Visual evoked potentials ,medicine.disease ,Observational period ,03 medical and health sciences ,0302 clinical medicine ,Ophthalmology ,030221 ophthalmology & optometry ,medicine ,Optic neuritis ,Neurology (clinical) ,Evoked potential ,NMO Spectrum Disorders ,business ,030217 neurology & neurosurgery ,ComputingMilieux_MISCELLANEOUS ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Subclinical infection - Abstract
ObjectiveTo investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks.MethodsA total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models.ResultsThe rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and −2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was −0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and −1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively.ConclusionThis first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.
- Published
- 2019
32. Interferon-β Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS
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Yuyi You, Stuart L. Graham, John De Parratt, Jim G Matthews, Alexander Klistorner, Michael Barnett, and Con Yiannikas
- Subjects
Adult ,Male ,Retinal Ganglion Cells ,medicine.medical_specialty ,Nerve fiber layer ,Nerve fiber ,Article ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,Multiple Sclerosis, Relapsing-Remitting ,0302 clinical medicine ,Natalizumab ,Ophthalmology ,medicine ,Humans ,030212 general & internal medicine ,Glatiramer acetate ,Fingolimod Hydrochloride ,business.industry ,Retinal ,Glatiramer Acetate ,Interferon-beta ,Middle Aged ,Fingolimod ,Ganglion ,medicine.anatomical_structure ,Neurology ,chemistry ,Retinal ganglion cell ,Disease Progression ,Female ,sense organs ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
ObjectiveTo investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS.MethodsOne hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration.ResultsThe annual rates of RNFL and GCIPL thinning were higher in patients treated with “platform” therapies (interferon-β and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = −0.22 μm/y, p = 0.02 for pRNFL; difference = −0.34 μm/y, p = 0.009 for tRNFL; and difference = −0.16 μm/y, p = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-β, glatiramer acetate, fingolimod, and natalizumab), interferon-β was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab.ConclusionsProgressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-β than other DMTs. This finding may have implications for DMT selection in MS.Classification of EvidenceThis study provides Class IV evidence that for patients with MS, treatment with interferon-β compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss.
- Published
- 2021
33. Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis
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Alexander Klistorner, Stuart L. Graham, Jakob Wasserthal, John De Parratt, Yuyi You, Michael Barnett, Samuel Klistorner, Joshua Barton, and Con Yiannikas
- Subjects
Central Nervous System ,Male ,Pathology ,Axonal loss ,Significant negative correlation ,Alzheimer's Disease ,Nervous System ,Nerve Fibers, Myelinated ,Diagnostic Radiology ,Medical Conditions ,Nerve Fibers ,Animal Cells ,Recurrence ,Medicine and Health Sciences ,Neurons ,Brain Mapping ,Multidisciplinary ,Radiology and Imaging ,Neurodegenerative Diseases ,Middle Aged ,Magnetic Resonance Imaging ,White Matter ,Diffusion Tensor Imaging ,Neurology ,Medicine ,Female ,Anatomy ,Cellular Types ,medicine.symptom ,Research Article ,Adult ,medicine.medical_specialty ,Multiple Sclerosis ,Imaging Techniques ,Science ,Brain Morphometry ,Immunology ,Neuroimaging ,Research and Analysis Methods ,Thermal diffusivity ,Neuroprotection ,Autoimmune Diseases ,Lesion ,Signs and Symptoms ,Diagnostic Medicine ,Mental Health and Psychiatry ,medicine ,Humans ,business.industry ,Multiple sclerosis ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,Demyelinating Disorders ,Axons ,Diffusion Magnetic Resonance Imaging ,Cellular Neuroscience ,Chronic Disease ,Lesions ,Cognitive Science ,Clinical Immunology ,Dementia ,Clinical Medicine ,business ,Neuroscience - Abstract
We describe a new single-streamline based approach to analyse diffusivity within chronic MS lesions. We used the proposed method to examine diffusivity profiles in 30 patients with relapsing multiple sclerosis and observed a significant increase of both RD and AD within the lesion core (0.38+/-0.09 μm2/ms and 0.30+/-0.12 μm2/ms respectively, p
- Published
- 2021
34. Exploring the methods of data analysis in multifocal visual evoked potentials
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L. de Santiago, Clare L. Fraser, Lasse Malmqvist, Alexander Klistorner, and Steffen Hamann
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Adult ,Male ,medicine.medical_specialty ,Computer science ,Coefficient of variation ,Vision Disorders ,Glaucoma ,Visual evoked potentials ,Signal-To-Noise Ratio ,Audiology ,Intra Subject Variability ,Root mean square ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,medicine ,Humans ,Evoked potential ,Aged ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Sensory Systems ,Ophthalmology ,Amplitude ,Signal-to-noise ratio (imaging) ,Data Interpretation, Statistical ,030221 ophthalmology & optometry ,Evoked Potentials, Visual ,Female ,Visual Fields ,030217 neurology & neurosurgery - Abstract
The multifocal visual evoked potential (mfVEP) provides a topographical assessment of visual function, which has already shown potential for use in patients with glaucoma and multiple sclerosis. However, the variability in mfVEP measurements has limited its broader application. The purpose of this study was to compare several methods of data analysis to decrease mfVEP variability. Twenty-three normal subjects underwent mfVEP testing. Monocular and interocular asymmetry data were analyzed. Coefficients of variability in amplitude were examined using peak-to-peak, root mean square (RMS), signal-to-noise ratio (SNR) and logSNR techniques. Coefficients of variability in latency were examined using second peak and cross-correlation methods. LogSNR and peak-to-peak methods had significantly lower intra-subject variability when compared with RMS and SNR methods. LogSNR had the lowest inter-subject amplitude variability when compared with peak-to-peak, RMS and SNR. Average latency asymmetry values for the cross-correlation analysis were 1.7 ms (CI 95 % 1.2–2.3 ms) and for the second peak analysis 2.5 ms (CI 95 % 1.7–3.3 ms). A significant difference was found between cross-correlation and second peak analysis for both intra-subject variability (p
- Published
- 2016
35. Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study
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Teresa C. Frohman, Lisanne J. Balk, Patrick Vermersch, Jennifer Resto, Clare L. Fraser, Shiv Saidha, Letizia Leocani, Elena H. Martinez-Lapiscina, Elena García-Martín, Friedemann Paul, P. Albrecht, Ines Gonzalez, Elliot M. Frohman, Bernardo Sanchez-Dalmau, Alexander Klistorner, Simone Guerrieri, Laura J. Balcer, Sam Arnow, Sven Schippling, Sebastian Lukas, Peter A. Calabresi, Giancarlo Comi, Wesley Chan, Luis E. Pablo, Ari J. Green, Celia Oreja-Guevara, Timm Oberwahrenbrock, Christian Cordano, James A. Wilson, Ann Kristin Mueller, Albert Saiz, Eva Havrdova, Orhan Aktas, Fiona Costello, Magi Andorra, Olivier Outteryck, Axel Petzold, Jana Lizrova Preiningerova, Jette L. Frederiksen, Irati Zubizarreta, Pablo Villoslada, Alexander U. Brandt, Robert A. Bermel, Martinez Lapiscina, Eh, Arnow, S, Wilson, Ja, Saidha, S, Preiningerova, Jl, Oberwahrenbrock, T, Brandt, Au, Pablo, Le, Guerrieri, S, Gonzalez, I, Outteryck, O, Mueller, Ak, Albrecht, P, Chan, W, Lukas, S, Balk, Lj, Fraser, C, Frederiksen, Jl, Resto, J, Frohman, T, Cordano, C, Zubizarreta, I, Andorra, M, Sanchez Dalmau, B, Saiz, A, Bermel, R, Klistorner, A, Petzold, A, Schippling, S, Costello, F, Aktas, O, Vermersch, P, Oreja Guevara, C, Comi, Giancarlo, Leocani, ANNUNZIATA MARIA LETIZIA, Garcia Martin, E, Paul, F, Havrdova, E, Frohman, E, Balcer, Lj, Green, Aj, Calabresi, Pa, Villoslada, P., Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, and Ophthalmology
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Multiple Sclerosis ,genetic structures ,Neuritis ,Severity of Illness Index ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Retinal Diseases ,Ophthalmology ,medicine ,Humans ,Macula Lutea ,Optic neuritis ,Expanded Disability Status Scale ,Clinically isolated syndrome ,business.industry ,Multiple sclerosis ,Hazard ratio ,Middle Aged ,Prognosis ,medicine.disease ,eye diseases ,Surgery ,030104 developmental biology ,Cohort ,Disease Progression ,Female ,sense organs ,Neurology (clinical) ,business ,Tomography, Optical Coherence ,030217 neurology & neurosurgery ,Follow-Up Studies ,Retinal Neurons ,Cohort study - Abstract
Summary Background Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. Methods In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. Findings 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5–5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36–3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63–8·91; p=0·002). We did not identify meaningful associations for macular volume. Interpretation Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. Funding Instituto de Salud Carlos III.
- Published
- 2016
36. Afferent visual pathways in multiple sclerosis: a review
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Stuart L. Graham and Alexander Klistorner
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,genetic structures ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Magnetic resonance imaging ,Visual system ,medicine.disease ,Retinal ganglion ,eye diseases ,03 medical and health sciences ,Ophthalmology ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Neuroimaging ,medicine ,Optic neuritis ,business ,030217 neurology & neurosurgery ,Diffusion MRI ,Optic radiation - Abstract
Multiple sclerosis (MS) is a disease of the central nervous system that involves inflammation and demyelination at multiple sites and causes a wide variety of clinical presentations with variable neurological deficits. The visual pathways are frequently involved with either visual or motor dysfunction. Optic neuritis (ON) is one the most common and best characterized presentations of the disease, but there are many other manifestations depending on the site of the lesion. Eyes that have never had ON show slow progressive loss of axons and retinal ganglion cells. Previously unrecognized optic radiation lesions may be associated with residual latency delays on visual evoked potentials. Both anterograde and retrograde degeneration may occur along the visual pathway. This review covers the features of MS in the anterior and posterior visual system and describes advances that have been made with newer techniques such as retinal optical coherence tomography (OCT), magnetic resonance imaging (MRI) with diffusion tensor imaging and probabilistic tractography (DTI) and multifocal visual evoked potentials (mfVEPs). We report on the inter-relationship between these measures of structure and function, and how they may be used as biomarkers for the disease.
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- 2016
37. Diffusivity in multiple sclerosis lesions: At the cutting edge?
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Alexander Klistorner, Stuart L. Graham, Vera Fofanova, Yuyi You, John Parratt, Chenyu Wang, Con Yiannikas, and Michael Barnett
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Multiple Sclerosis ,Cognitive Neuroscience ,lcsh:Computer applications to medicine. Medical informatics ,Thermal diffusivity ,lcsh:RC346-429 ,030218 nuclear medicine & medical imaging ,Lesion ,White matter ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Remyelination ,Myelin Sheath ,lcsh:Neurology. Diseases of the nervous system ,Chemistry ,Multiple sclerosis ,Myelin sheaths ,Radial diffusivity ,Brain ,Regular Article ,Middle Aged ,medicine.disease ,White Matter ,Diffusion Magnetic Resonance Imaging ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Neurology ,Anisotropy ,lcsh:R858-859.7 ,Female ,Neurology (clinical) ,medicine.symptom ,Biomarkers ,030217 neurology & neurosurgery ,Diffusion MRI - Abstract
Background Radial Diffusivity (RD) has been suggested as a promising biomarker associated with the level of myelination in MS lesions. However, the level of RD within the lesion is affected not only by loss of myelin sheaths, but also by the degree of tissue destruction. This may lead to exaggeration of diffusivity measures, potentially masking the effect of remyelination. Objective To test the hypothesis that the T2 hyperintense lesion edge that extends beyond the T1 hypointense lesion core is less affected by tissue loss, and therefore a more appropriate target for imaging biomarker development targeting de- and re-myelination. Method Pre- and post-gadolinium (Gd) enhanced T1, T2 and DTI images were acquired from 75 consecutive RRMS patients. The optic radiation (OR) was identified in individual patients using a template-based method. T2 lesions were segmented into T1-hypointense and T1-isointense areas and lesion masks intersected with the OR. Average Radial, Axial and Mean diffusivity (RD, AD and MD) and fractional anisotropy (FA) were calculated for lesions of the entire brain and the OR. In addition, Gd enhancing lesions were excluded from the analysis. Results 86% of chronic T2 lesions demonstrated hypointense areas on T1-weighted images, which typically occupied the central part of each T2 lesion, taking about 40% of lesional volume. The T1-isointense component of the T2 lesion was most commonly seen as a peripheral ring of relatively constant thickness (“T2-rim”). While changes of diffusivity between adjacent normal appearing white matter and the “T2-rim” demonstrated a disproportionally high elevation of RD compare to AD, the increase of water diffusion was largely isointense between the “T2-rim” and T1-hypointense parts of the lesion. Conclusion Distinct patterns of diffusivity within the central and peripheral components of MS lesions suggest that axonal loss dominates in the T1 hypointense core. The effects of de/remyelination may be more readily detected in the “T2-rim”, where there is relative preservation of structural integrity. Identifying and separating those patterns has an important implication for clinical trials of both neuroprotective and, in particular, remyelinating agents., Highlights • Distinct patterns of diffusivity within the central and peripheral components of MS lesions were identified. • Axonal loss is likely to dominate the T1 hypointense core. • The effects of de/remyelination may be more readily detected in the “T2-rim”.
- Published
- 2016
38. Physiological Correlates and Predictors of Functional Recovery After Chiasmal Decompression
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Sergey Spektor, Noa Raz, Netta Levin, Tamir Ben-Hur, Alexander Klistorner, Daniel S. Reich, and Atira S. Bick
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,genetic structures ,Optic tract ,Decompression ,Nerve fiber layer ,Optic chiasm ,Visual system ,Retina ,Article ,Young Adult ,chemistry.chemical_compound ,Nerve Fibers ,Ophthalmology ,Optic Nerve Diseases ,Meningeal Neoplasms ,medicine ,Humans ,Longitudinal Studies ,business.industry ,Retinal ,Recovery of Function ,Middle Aged ,Decompression, Surgical ,eye diseases ,Diffusion Magnetic Resonance Imaging ,Treatment Outcome ,medicine.anatomical_structure ,chemistry ,Receptive field ,Optic Chiasm ,Evoked Potentials, Visual ,Neurology (clinical) ,Visual Fields ,Meningioma ,business ,Tomography, Optical Coherence ,Diffusion MRI - Abstract
BACKGROUND The intrinsic abilities and limits of the nervous system to repair itself after damage may be assessed using a model of optic chiasmal compression, before and after a corrective surgical procedure. METHODS Visual fields (VFs), multifocal visual evoked potentials (mfVEP), retinal nerve fiber layer (RNFL) thickness, and diffusion tensor imaging were used to evaluate a patient before and after removal of a meningioma compressing the chiasm. Normally sighted individuals served as controls. The advantage of each modality to document visual function and predict postoperative outcome (2-year follow-up) was evaluated. RESULTS Postsurgery visual recovery was best explained by critical mass of normally conducting fibers and not associated with average conduction amplitudes. Recovered VF was observed in quadrants in which more than 50% of fibers were identified, characterized by intact mfVEP latencies, but severely reduced amplitudes. Recovery was evident despite additional reduction of RNFL thickness and abnormal optic tract diffusivity. The critical mass of normally conducting fibers was also the best prognostic indicator for functional outcome 2 years later. CONCLUSIONS Our results highlight the ability of the remaining normally conductive axons to predict visual recovery after decompression of the optic chiasm. The redundancy in anterior visual pathways may be explained, neuroanatomically, by overlapping receptive fields.
- Published
- 2015
39. Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis
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Alexander Klistorner, Yuyi You, Jim G Matthews, Stuart L. Graham, John De Parratt, Con Yiannikas, and Michael Barnett
- Subjects
Adult ,Male ,Retinal Ganglion Cells ,medicine.medical_specialty ,Optic Neuritis ,genetic structures ,Nerve fiber layer ,Axonal loss ,Article ,chemistry.chemical_compound ,Multiple Sclerosis, Relapsing-Remitting ,Ophthalmology ,medicine ,Humans ,Visual Pathways ,Optic neuritis ,Longitudinal Studies ,Evoked potential ,Myelin Sheath ,business.industry ,Optic Nerve ,Retinal ,Middle Aged ,medicine.disease ,Axons ,eye diseases ,medicine.anatomical_structure ,Neurology ,chemistry ,Retinal ganglion cell ,Disease Progression ,Optic nerve ,Evoked Potentials, Visual ,Female ,sense organs ,Neurology (clinical) ,business ,Tomography, Optical Coherence ,Optic disc - Abstract
ObjectiveTo examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons.MethodsProgressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve.ResultsAlthough both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination.ConclusionsAlthough the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS.
- Published
- 2020
40. Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease
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Michael Barnett, Con Yiannikas, Chenyu Wang, Ting Shen, Yogita Dheer, Chitra Joseph, Robert Borotkanics, Stuart L. Graham, Vivek Gupta, Alexander Klistorner, Alessandro Invernizzi, Nitin Chitranshi, Sidong Liu, Yuyi You, and Brian Chua
- Subjects
0301 basic medicine ,Adult ,Male ,genetic structures ,Axonal loss ,Cohort Studies ,03 medical and health sciences ,Myelin ,Mice ,0302 clinical medicine ,Demyelinating disease ,medicine ,Animals ,Humans ,Optic neuritis ,Aged ,Neurons ,business.industry ,Multiple sclerosis ,Neurodegenerative Diseases ,Human brain ,Middle Aged ,medicine.disease ,Axons ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Optic nerve ,Female ,Neurology (clinical) ,business ,Neuroscience ,030217 neurology & neurosurgery ,Optic radiation ,Demyelinating Diseases - Abstract
The spread of neurodegeneration through the human brain network is reported as underlying the progression of neurodegenerative disorders. However, the exact mechanisms remain unknown. The human visual pathway is characterized by its unique hierarchical architecture and, therefore, represents an ideal model to study trans-synaptic degeneration, in contrast to the complexity in neural connectivity of the whole brain. Here we show in two specifically selected patient cohorts, including (i) glaucoma patients with symmetrical bilateral hemifield defects respecting the horizontal meridian (n = 25, 14 females, 64.8 ± 10.1 years; versus 13 normal controls with similar age/sex distributions); and (ii) multiple sclerosis patients without optic radiation lesions (to avoid potential effects of lesions on diffusivity measures) (n = 30, 25 females, 37.9 ± 10.8 years; versus 20 controls), that there are measurable topographic changes in the posterior visual pathways corresponding to the primary optic nerve defects. A significant anisotropic increase of water diffusion was detected in both patient cohorts in the optic radiations, characterized by changes in perpendicular (radial) diffusivity (a measure of myelin integrity) that extended more posteriorly than those observed in parallel (axial) diffusivity (reflecting axonal integrity). In glaucoma, which is not considered a demyelinating disease, the observed increase in radial diffusivity within the optic radiations was validated by topographically linked delay of visual evoked potential latency, a functional measure of demyelination. Radial diffusivity change in the optic radiations was also associated with an asymmetrical reduction in the thickness of the calcarine cortex in glaucoma. In addition, 3 years longitudinal observation of the multiple sclerosis patient cohort revealed an anterograde increase of radial diffusivity in the anterior part of optic radiations which again was retinotopically associated with the primary damage caused by optic neuritis. Finally, in an animal model of optic nerve injury, we observed early glial activation and demyelination in the posterior visual projections, evidenced by the presence of myelin-laden macrophages. This occurred prior to the appearance of amyloid precursor protein accumulation, an indicator of disrupted fast axonal transport. This study demonstrated strong topographical spread of neurodegeneration along recognized neural projections and showed that myelin and glial pathology precedes axonal loss in the process, suggesting that the mechanism of trans-synaptic damage may be at least partially mediated by glial components at the cellular level. The findings may have broad biological and therapeutic implications for other neurodegenerative disorders.
- Published
- 2018
41. Correlation between inner retinal layer thickness and cognitive function in HIV: new insights from an exploratory study
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Sara Bochicchio, Alessandra Acquistapace, Agostino Riva, Chiara Resnati, Marta Ferrari, Giovanni Staurenghi, Valentina Leta, Peter McCluskey, Simone Pomati, Alexander Klistorner, Stefano Rusconi, and Alessandro Invernizzi
- Subjects
Adult ,Male ,medicine.medical_specialty ,AIDS Dementia Complex ,Cross-sectional study ,Immunology ,Nerve fiber layer ,HIV-associated neurocognitive disorder ,Retina ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cognition ,Ophthalmology ,medicine ,Immunology and Allergy ,Animals ,Humans ,Ganglion cell layer ,Aged ,business.industry ,virus diseases ,Montreal Cognitive Assessment ,Retinal ,Middle Aged ,medicine.disease ,Infectious Diseases ,medicine.anatomical_structure ,Cross-Sectional Studies ,chemistry ,Cohort ,030221 ophthalmology & optometry ,Female ,sense organs ,business ,030217 neurology & neurosurgery ,Tomography, Optical Coherence - Abstract
Objective To compare retinal layer thickness in HIV-infected subjects with (CI-HIV) and without (NCI-HIV) cognitive impairment, with a control population and to correlate this with the cognitive status of the patient and other clinical parameters. Design Single-center cross-sectional study. Methods Participants with controlled HIV infection aged between 40 and 70 years and sex-matched and age-matched controls were enrolled. Retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) and inner plexiform layer (IPL) thickness were assessed using optical coherence tomography. These measurements in HIV patients were compared with those in controls. Age-related and sex-related changes were compared in both groups. Other variables studied in HIV patients included: duration of HIV infection, CD4 cell count nadir, antiretroviral therapy regimen and cognitive status using the Montreal Cognitive Assessment (MoCA) test. Results Sixty-nine individuals, 34 with and 35 without cognitive impairment, and 70 controls were enrolled. GCL was significantly thinner in CI-HIV patients compared with NCI-HIV patients and controls (P = 0.01 and P = 0.02, respectively). GCL and IPL thickness significantly decreased with age in patients with HIV (P = 0.0003, P = 0.02, respectively, for the entire cohort). This change was not seen in controls. MoCA test score significantly decreased with age in HIV patients and controls. GCL thickness positively correlated with cognitive function across the entire HIV cohort (P = 0.02). Conclusion GCL was thinner in HIV patients with cognitive impairment. GCL thickness correlated positively with cognitive function and negatively with age in HIV patients. GCL thickness may reflect accelerated cognitive aging in HIV.
- Published
- 2018
42. Progressive inner nuclear layer dysfunction in non-optic neuritis eyes in MS
- Author
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Michael Barnett, Alexander Klistorner, Michael G. Dwyer, Ting Shen, Clare L. Fraser, Vivek Gupta, Elizabeth C. Graham, John Parratt, Stuart L. Graham, Yuyi You, Joshua Barton, and Con Yiannikas
- Subjects
0301 basic medicine ,medicine.medical_specialty ,genetic structures ,Neuritis ,Nerve fiber layer ,Article ,chemistry.chemical_compound ,03 medical and health sciences ,0302 clinical medicine ,Ophthalmology ,medicine ,Optic neuritis ,10. No inequality ,medicine.diagnostic_test ,business.industry ,Retinal ,medicine.disease ,eye diseases ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Retinal ganglion cell ,Neurology ,Inner nuclear layer ,030221 ophthalmology & optometry ,Neurology (clinical) ,sense organs ,Erratum ,business ,Erg ,Row ,030217 neurology & neurosurgery ,Electroretinography - Abstract
Objective:To investigate primary retinal functional changes in non-optic neuritis (ON) eyes of patients with MS by full-field electroretinography (ERG).Methods:Seventy-seven patients with relapsing-remitting MS with no history of clinical ON in at least 1 eye and 30 healthy controls were recruited in the cohort study. Full-field ERGs were recorded, and retinal optical coherence tomography scans were performed to assess the thicknesses of peripapillary retinal nerve fiber layer (RNFL) and retinal ganglion cell layer–inner plexiform layer (GCL-IPL). Annual MRI scans were also carried out to evaluate the disease activity in the brain. Patients were followed up for 3 years.Results:At baseline, a delayed b-wave peak time was observed in the cone response (p < 0.001), which was associated with the thicknesses of RNFL and GCL-IPL. The peak time of the delayed b-wave also correlated with the Expanded Disability Status Scale, T2 lesion volume, and disease duration. During the 3-year follow-up, progressive ERG amplitude reduction was observed (both a- and b-waves, p < 0.05). There was a correlation between the b-wave amplitude reduction and longitudinal RNFL loss (p = 0.001). However, no correlation was found between longitudinal ERG changes and disease activity in the brain.Conclusions:This study demonstrated progressive inner nuclear layer dysfunction in MS. The borderline a-wave changes suggested some outer retinal dysfunction as well. The correlation between full-field ERG changes and retinal ganglion cell loss suggested that there might be subclinical retinal pathology in MS affecting both outer and inner retinal layers.
- Published
- 2018
43. A Deep Learning-Based Algorithm Identifies Glaucomatous Discs Using Monoscopic Fundus Photographs
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Barbara Zangerl, Michael Kalloniatis, Alexander Klistorner, Hemamalini Arvind, Angela Schulz, Brian Chua, Yuyi You, Stuart L. Graham, Dewei Chu, Yang Gao, Sidong Liu, Weidong Cai, and John R. Grigg
- Subjects
Male ,Fundus Oculi ,Optic Disk ,Large population ,Glaucoma ,02 engineering and technology ,Fundus (eye) ,Diagnostic Techniques, Ophthalmological ,03 medical and health sciences ,0302 clinical medicine ,Deep Learning ,Artificial Intelligence ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,Humans ,Medical diagnosis ,Receiver operating characteristic ,business.industry ,Deep learning ,General Medicine ,Diabetic retinopathy ,Middle Aged ,medicine.disease ,Confidence interval ,ROC Curve ,030221 ophthalmology & optometry ,020201 artificial intelligence & image processing ,Female ,Artificial intelligence ,business ,Algorithm ,Algorithms - Abstract
Purpose To develop and test the performance of a deep learning-based algorithm for glaucomatous disc identification using monoscopic fundus photographs. Design Fundus photograph database study. Participants Four thousand three hundred ninety-four fundus photographs, including 3768 images from previous Sydney-based clinical studies and 626 images from publicly available online RIM-ONE and High-Resolution Fundus (HRF) databases with definitive diagnoses. Methods We merged all databases except the HRF database, and then partitioned the dataset into a training set (80% of all cases) and a testing set (20% of all cases). We used the HRF images as an additional testing set. We compared the performance of the artificial intelligence (AI) system against a panel of practicing ophthalmologists including glaucoma subspecialists from Australia, New Zealand, Canada, and the United Kingdom. Main Outcome Measures The sensitivity and specificity of the AI system in detecting glaucomatous optic discs. Results By using monoscopic fundus photographs, the AI system demonstrated a high accuracy rate in glaucomatous disc identification (92.7%; 95% confidence interval [CI], 91.2%–94.2%), achieving 89.3% sensitivity (95% CI, 86.8%–91.7%) and 97.1% specificity (95% CI, 96.1%–98.1%), with an area under the receiver operating characteristic curve of 0.97 (95% CI, 0.96–0.98). Using the independent online HRF database (30 images), the AI system again accomplished high accuracy, with 86.7% in both sensitivity and specificity (for ophthalmologists, 75.6% sensitivity and 77.8% specificity) and an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.76–1.00). Conclusions This study demonstrated that a deep learning-based algorithm can identify glaucomatous discs at high accuracy level using monoscopic fundus images. Given that it is far easier to obtain monoscopic disc images than high-quality stereoscopic images, this study highlights the algorithm's potential application in large population-based disease screening or telemedicine programs.
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- 2017
44. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis
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Axel Petzold, Laura J Balcer, Peter A Calabresi, Fiona Costello, Teresa C Frohman, Elliot M Frohman, Elena H Martinez-Lapiscina, Ari J Green, Randy Kardon, Olivier Outteryck, Friedemann Paul, Sven Schippling, Patrik Vermersch, Pablo Villoslada, Lisanne J Balk, Orhan Aktas, Philipp Albrecht, Jane Ashworth, Nasrin Asgari, Laura Balcer, Lisanne Balk, Graeme Black, Daniel Boehringer, Raed Behbehani, Leslie Benson, Robert Bermel, Jacqueline Bernard, Alexander Brandt, Jodie Burton, Peter Calabresi, Jonathan Calkwood, Christian Cordano, Ardith Courtney, Andrés Cruz-Herranz, Ricarda Diem, Avril Daly, Helene Dollfus, Christina Fasser, Carsten Finke, Jette Frederiksen, Elliot Frohman, Teresa Frohman, Elenaw Garcia-Martin, Inés González Suárez, Gorm Pihl-Jensen, Jennifer Graves, Ari Green, Joachim Havla, Bernhard Hemmer, Su-Chun Huang, Jaime Imitola, Hong Jiang, David Keegan, Eric Kildebeck, Alexander Klistorner, Benjamin Knier, Scott Kolbe, Thomas Korn, Bart LeRoy, Letizia Leocani, Dorothee Leroux, Netta Levin, Petra Liskova, Birgit Lorenz, Jana Lizrova Preiningerova, Elena Hernández Martínez-Lapiscina, Janine Mikolajczak, Xavier Montalban, Mark Morrow, Rachel Nolan, Timm Oberwahrenbrock, Frederike Cosima Oertel, Celia Oreja-Guevara, Benjamin Osborne, Athina Papadopoulou, Marius Ringelstein, Shiv Saidha, Bernardo Sanchez-Dalmau, Jaume Sastre-Garriga, Robert Shin, Neil Shuey, Kerstin Soelberg, Ahmed Toosy, Rubén Torres, Angela Vidal-Jordana, Amy Waldman, Owen White, Ann Yeh, Sui Wong, Hanna Zimmermann, Ophthalmology, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Mental Health, APH - Methodology, Neurology, Petzold, A, Balcer, Lj, Calabresi, Pa, Costello, F, Frohman, Tc, Frohman, Em, Martinez-Lapiscina, Eh, Green, Aj, Kardon, R, Outteryck, O, Paul, F, Schippling, S, Vermersch, P, Villoslada, P, Balk, Lj, on behalf of ERN-EYE, Imsvisual, and Leocani, L
- Subjects
Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Optic Neuritis ,genetic structures ,Nerve fiber layer ,Retina ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Atrophy ,Optical coherence tomography ,Ophthalmology ,Multiple Sclerosi ,medicine ,Humans ,Optic neuritis ,Aged ,Neuromyelitis optica ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Optic Neuriti ,Retinal ,Middle Aged ,medicine.disease ,eye diseases ,medicine.anatomical_structure ,chemistry ,030221 ophthalmology & optometry ,Optometry ,Female ,Neurology (clinical) ,sense organs ,business ,030217 neurology & neurosurgery ,Tomography, Optical Coherence ,Human - Abstract
Background Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. Methods In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. Findings Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference â20·10 μm, 95% CI â22·76 to â17·44; p
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- 2017
45. White matter tract-specific quantitative analysis in multiple sclerosis: Comparison of optic radiation reconstruction techniques
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Alexander Klistorner, Linda Ly, Chenyu Wang, and Michael Barnett
- Subjects
Male ,Central Nervous System ,Focal white matter lesions ,Computer science ,lcsh:Medicine ,Brain mapping ,Nervous System ,030218 nuclear medicine & medical imaging ,Diagnostic Radiology ,0302 clinical medicine ,Nerve Fibers ,Animal Cells ,Medicine and Health Sciences ,Segmentation ,lcsh:Science ,Neurons ,Brain Mapping ,Multidisciplinary ,Radiology and Imaging ,Neurodegenerative Diseases ,Human brain ,Middle Aged ,White Matter ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Diffusion Tensor Imaging ,Data Acquisition ,Neurology ,Female ,Anatomy ,Cellular Types ,Tractography ,Research Article ,Adult ,Computer and Information Sciences ,Multiple Sclerosis ,Histology ,Imaging Techniques ,Brain Morphometry ,Central nervous system ,Immunology ,Neuroimaging ,Research and Analysis Methods ,Temporal lobe ,Autoimmune Diseases ,White matter ,03 medical and health sciences ,Young Adult ,Diagnostic Medicine ,medicine ,Humans ,business.industry ,Multiple sclerosis ,lcsh:R ,Biology and Life Sciences ,Pattern recognition ,Cell Biology ,medicine.disease ,Demyelinating Disorders ,Diffusion Magnetic Resonance Imaging ,Cellular Neuroscience ,lcsh:Q ,Clinical Immunology ,Artificial intelligence ,Clinical Medicine ,business ,030217 neurology & neurosurgery ,Diffusion MRI ,Optic radiation ,Neuroscience - Abstract
The posterior visual pathway is commonly affected by multiple sclerosis (MS) pathology that results in measurable clinical and electrophysiological impairment. Due to its highly structured retinotopic mapping, the visual pathway represents an ideal substrate for investigating patho-mechanisms in MS. Therefore, a reliable and robust imaging segmentation method for in-vivo delineation of the optic radiations (OR) is needed. However, diffusion-based tractography approaches, which are typically used for OR segmentation are confounded by the presence of focal white matter lesions. Current solutions require complex acquisition paradigms and demand expert image analysis, limiting application in both clinical trials and clinical practice. In the current study, using data acquired in a clinical setting on a 3T scanner, we optimised and compared two approaches for optic radiation (OR) reconstruction: individual probabilistic tractography-based and template-based methods. OR segmentation results were applied to subjects with MS and volumetric and diffusivity parameters were compared between OR segmentation techniques. Despite differences in reconstructed OR volumes, both OR lesion volume and OR diffusivity measurements in MS subjects were highly comparable using optimised probabilistic tractography-based, and template-based, methods. The choice of OR reconstruction technique should be determined primarily by the research question and the nature of the available dataset. Template-based approaches are particularly suited to the semi-automated analysis of large image datasets and have utility even in the absence of dMRI acquisitions. Individual tractography methods, while more complex than template based OR reconstruction, permit measurement of diffusivity changes along fibre bundles that are affected by specific MS lesions or other focal pathologies.
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- 2017
46. Mechanism of delayed conduction of fellow eyes in patients with optic neuritis
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Clare L. Fraser, Con Yiannikas, Daniah Alshowaeir, and Alexander Klistorner
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medicine.medical_specialty ,genetic structures ,03 medical and health sciences ,fellow eyes ,0302 clinical medicine ,lcsh:Ophthalmology ,Ophthalmology ,Neuroplasticity ,Medicine ,Disseminated disease ,Optic neuritis ,In patient ,Evoked potential ,Latency (engineering) ,Pathological ,optic neuritis ,business.industry ,Multiple sclerosis ,Brief Report ,medicine.disease ,eye diseases ,latency delay ,lcsh:RE1-994 ,030221 ophthalmology & optometry ,multi-focal visual evoked potential ,sense organs ,business ,030217 neurology & neurosurgery - Abstract
To test the hypothesis that latency delay in the fellow eyes of optic neuritis (ON) patients and to compensate for delayed transmission of visual information, latency change of multi-focal visual evoked potential (mfVEP) traces in fellow eyes of 15 ON patients were analyzed. Patients with low risk (LR) for developing multiple sclerosis (MS) were examined separately from MS patients to isolate effect of cortical plasticity from potential pathological changes in disseminated disease. The small increase in latency in fellow eyes of LR group was statistically not significant. In MS patients, the latency was significantly delayed (P
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- 2017
47. Microstructural visual system changes in AQP4-antibody–seropositive NMOSD
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Alexander Klistorner, Joseph Kuchling, Klemens Ruprecht, Judith Bellmann-Strobl, Thomas Korn, Michael Scheel, Benjamin Knier, Frederike C. Oertel, Alexander U. Brandt, Felix Schmidt, Hanna Zimmermann, Claudia Chien, and Friedemann Paul
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Visual acuity ,genetic structures ,Nerve fiber layer ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ophthalmology ,Fractional anisotropy ,Medicine ,Optic neuritis ,business.industry ,Retinal ,medicine.disease ,eye diseases ,Ganglion ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,chemistry ,Neurology (clinical) ,sense organs ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Diffusion MRI ,Optic radiation - Abstract
Objective:To trace microstructural changes in patients with aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorders (NMOSDs) by investigating the afferent visual system in patients without clinically overt visual symptoms or visual pathway lesions.Methods:Of 51 screened patients with NMOSD from a longitudinal observational cohort study, we compared 6 AQP4-ab–seropositive NMOSD patients with longitudinally extensive transverse myelitis (LETM) but no history of optic neuritis (ON) or other bout (NMOSD-LETM) to 19 AQP4-ab–seropositive NMOSD patients with previous ON (NMOSD-ON) and 26 healthy controls (HCs). Foveal thickness (FT), peripapillary retinal nerve fiber layer (pRNFL) thickness, and ganglion cell and inner plexiform layer (GCIPL) thickness were measured with optical coherence tomography (OCT). Microstructural changes in the optic radiation (OR) were investigated using diffusion tensor imaging (DTI). Visual function was determined by high-contrast visual acuity (VA). OCT results were confirmed in a second independent cohort.Results:FT was reduced in both patients with NMOSD-LETM (p = 3.52e−14) and NMOSD-ON (p = 1.24e−16) in comparison with HC. Probabilistic tractography showed fractional anisotropy reduction in the OR in patients with NMOSD-LETM (p = 0.046) and NMOSD-ON (p = 1.50e−5) compared with HC. Only patients with NMOSD-ON but not NMOSD-LETM showed neuroaxonal damage in the form of pRNFL and GCIPL thinning. VA was normal in patients with NMOSD-LETM and was not associated with OCT or DTI parameters.Conclusions:Patients with AQP4-ab–seropositive NMOSD without a history of ON have microstructural changes in the afferent visual system. The localization of retinal changes around the Müller-cell rich fovea supports a retinal astrocytopathy.
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- 2017
48. Axonal loss of retinal neurons in multiple sclerosis associated with optic radiation lesions
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Prima Sriram, Alexander Klistorner, Nikitha Vootakuru, Netta Levin, Lynette Masters, Raymond Garrick, Con Yiannikas, Anneke van der Walt, John Parratt, Stuart L. Graham, Noa Raz, Michael Barnett, and Chenyu Wang
- Subjects
Adult ,Male ,Retinal Ganglion Cells ,medicine.medical_specialty ,Multiple Sclerosis ,Optic Neuritis ,Visual acuity ,genetic structures ,Optic tract ,Nerve fiber layer ,Article ,chemistry.chemical_compound ,Nerve Fibers ,Ophthalmology ,medicine ,Humans ,Optic neuritis ,business.industry ,Optic Nerve ,Retinal ,Anatomy ,Middle Aged ,medicine.disease ,Axons ,eye diseases ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Retinal ganglion cell ,chemistry ,Case-Control Studies ,Optic nerve ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Tomography, Optical Coherence ,Optic radiation - Abstract
Objective: To investigate the potential links between thinning of retinal ganglion cell axons in eyes of patients with multiple sclerosis (MS) without past optic neuritis (ON) and MS-related inflammatory damage of the posterior visual pathway. Methods: Temporal retinal nerve fiber layer (tRNFL) thickness was analyzed in eyes with no history of ON (NON) from 53 patients with relapsing-remitting MS. Fifty normal age- and sex-matched controls were examined with optical coherence tomography. Low-contrast visual acuity charts were used for functional assessment of vision. The optic tract (OT) and optic radiation (OR) were identified using probabilistic tractography, and volume of T2 fluid-attenuated inversion recovery lesions and diffusion tensor imaging (DTI) indices were measured within both structures. Cross-sectional diameter of the OT was also calculated. Results: tRNFL thickness was significantly reduced in NON eyes and was associated with reduced low-contrast visual acuity. Lesions within the OR were detected in the majority of patients. There was a significant correlation between thinning of the tRNFL and OR lesion volume (adjusted for non-OR lesion volume, age, sex, and disease duration). tRNFL thickness also correlated with OR DTI indices. No OT lesions were identified in any of the patients and no relationship between retinal nerve fiber layer loss and potential markers of OT lesions was found. Conclusion: The results demonstrate a strong tract-specific association between loss of tRNFL fibers and MS-related inflammation within OR.
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- 2014
49. Lesion activity and chronic demyelination are the major determinants of brain atrophy in MS
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Stuart L. Graham, Joshua L. Barton, John Parratt, Alexander Klistorner, Con Yiannikas, Chenyu Wang, Michael Barnett, and Yuyi You
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Article ,Cohort Studies ,White matter ,Lesion ,Lesion load ,03 medical and health sciences ,Multiple Sclerosis, Relapsing-Remitting ,0302 clinical medicine ,Atrophy ,Humans ,Medicine ,In patient ,030304 developmental biology ,0303 health sciences ,business.industry ,Multiple sclerosis ,Brain ,Middle Aged ,medicine.disease ,Diffusion Magnetic Resonance Imaging ,medicine.anatomical_structure ,Neurology ,Chronic Disease ,Brain size ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Demyelinating Diseases ,Diffusion MRI - Abstract
ObjectiveTo evaluate the combined effect of lesion activity and pathologic processes occurring in both chronically demyelinated lesions and normal-appearing white matter (NAWM) on brain atrophy in MS.MethodsPre- and post-gadolinium T1, fluid attenuation inversion recovery, and diffusion tensor imaging images were acquired from 50 consecutive patients with relapsing-remitting MS (all, but one, on disease-modifying therapy) at baseline and 5 years. Brain atrophy was measured using structural image evaluation, using normalization of atrophy percent brain volume change (PBVC) analysis.ResultsDuring follow-up, brain volume diminished by 2.0% ± 1.1%. PBVC was not associated with patient age, disease duration, sex, or type of treatment. PBVC moderately correlated with baseline lesion load (r = −0.38, p = 0.016), but demonstrated strong association with new lesion activity (r = −0.63, p < 0.001). Brain atrophy was also strongly linked to the increase of water diffusion within chronic MS lesions (r = −0.62, p < 0.001). In normal-appearing white matter (NAWM), PBVC demonstrated a significant correlation with both baseline and longitudinal increase of demyelination as measured by radial diffusivity (RD, r = −0.44, p = 0.005 and r = −0.35, p = 0.026, respectively). Linear regression analysis explained 62% of the variance in PBVC. It confirmed the major role of new lesion activity (p = 0.002, standardized beta-coefficient −0.42), whereas change in diffusivity inside chronic lesions and NAWM RD at baseline also contributed significantly (p = 0.04 and 0.02, standardized beta-coefficient −0.31 and −0.29, respectively), increasing predictive power of the model by 55%.ConclusionIn addition to new lesion activity, progressive loss of demyelinated axons in chronic lesions and the degree of demyelination in NAWM significantly contribute to accelerated loss of brain tissue in patients with MS receiving immunomodulatory therapy.
- Published
- 2019
50. Sex-Specific Effect of BDNF Val66Met Genotypes on the Progression of Open-Angle Glaucoma
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Nitin Chitranshi, Ting Shen, Yuyi You, Vivek Gupta, Alexander Klistorner, and Stuart L. Graham
- Subjects
Adult ,Male ,Retinal Ganglion Cells ,medicine.medical_specialty ,Genotype ,Genotyping Techniques ,genetic structures ,Glaucoma ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Nerve Fibers ,Sex Factors ,0302 clinical medicine ,Ophthalmology ,Humans ,Medicine ,Allele ,Generalized estimating equation ,Intraocular Pressure ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,Brain-derived neurotrophic factor ,business.industry ,Brain-Derived Neurotrophic Factor ,Retrospective cohort study ,Middle Aged ,medicine.disease ,eye diseases ,Visual field ,Sexual dimorphism ,Disease Progression ,030221 ophthalmology & optometry ,Visual Field Tests ,Female ,Visual Fields ,business ,Glaucoma, Open-Angle ,Tomography, Optical Coherence ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Purpose To investigate whether the brain-derived neurotrophic factor (BDNF) Val66Met genotype is associated with the rate of progression of open-angle glaucoma (OAG). Methods In this retrospective cohort study, 148 OAG patients (292 eyes) were enrolled with a median follow-up period of 5.3 (range, 1.1-8.6) years. All participants had undergone regular clinical examinations by using spectral-domain optical coherence tomography (SD-OCT) scans and Humphrey (SITA) visual field tests. BDNF Val66Met polymorphisms were genotyped in all participants. Longitudinal visual field and retinal nerve fiber layer (RNFL) changes were compared between Met carriers (n = 68, 135 eyes) and Val homozygotes (n = 80, 157 eyes) by using the generalized estimating equations (GEE) model and Kaplan-Meier survival analysis. Results There was no significant difference in mean rates of progression for the two genotypes. However, there was a significant association between the Val66Met genotypes and slower OAG progression, as suggested by a higher rate of global RNFL loss in Val/Val homozygotes (P = 0.008) in the long-term survival analysis. The effect demonstrated a degree of sex specificity, with the significant difference present only in females (P = 0.016) but not males. Similar sexual dimorphism was presented in superior (P = 0.005 in females, P = 0.38 in males) and inferior (P = 0.004 in females, P = 0.41 in males) RNFL loss. No significant difference was observed in visual field parameters. Conclusions Our results suggested that carriage of Met allele reduces the rate of long-term OAG progression. However, the fact that this effect is observed only in females indicates BDNF Val66Met influences the progression rate of OAG in a sex-specific manner.
- Published
- 2019
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