Remyelination Trials

Klistorner, Alexander; Barnett, Michael

doi:10.1212/nxi.0000000000001066

Cited by 12 publications

(7 citation statements)

References 46 publications

(76 reference statements)

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“…However, although there was a significant reduction of LCVA in both ON and fellow eyes, no correlation was observed between progressive LCVA change in ON eyes and mfVEP latency asymmetry at baseline or the rate of RNFL thinning, implying lower sensitivity of this functional measure in monitoring subtle axonal damage caused by chronic loss of myelin. 41 There are several limitations in this study. First, there is potentially an alternative explanation for accelerated axonal loss observed in ON eyes, namely, that slow-burning inflammation at the rim of chronic active MS lesions can potentially cause axonal degeneration and accompanying lesion expansion.…”

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis

Klistorner

You

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesTo investigate the long-term effect of permanent demyelination on axonal attrition by examining an association between intereye asymmetry of the multifocal visual evoked potential (mfVEP) latency delay and subsequent thinning of retinal ganglion cell axons in patients with a long-standing history of unilateral optic neuritis (ON).MethodsOnly patients with a significant degree of chronic demyelination (intereye latency asymmetry >5 ms) were included in this study. The level of optic nerve demyelination was estimated at baseline by the latency delay of mfVEP, while the degree of axonal loss was assessed by thinning of the retinal nerve fiber layer (RNFL) thickness between baseline and follow-up visits. Low-contrast visual acuity (LCVA) was also evaluated at baseline and follow-up. Patients were examined twice with an average interval of 6.1 ± 1.4 years.ResultsFrom 85 examined patients with multiple sclerosis, 28 satisfied inclusion criteria. Latency of the mfVEP was delayed, and RNFL thickness was reduced in ON eyes compared with fellow eyes at both visits. There was significant correlation between latency asymmetry and baseline or follow-up intereye RNFL thickness asymmetry. Intereye asymmetry of LCVA at baseline correlated with baseline latency asymmetry of mfVEP and baseline asymmetry of RNFL thickness. Latency of the mfVEP in ON eyes improved slightly during the follow-up period, whereas latency of the fellow eye remained stable. By contrast, RNFL thickness significantly declined in both ON and fellow eyes during the follow-up period. The rate of RNFL thinning in ON eyes, however, was more than 2 times faster compared with the fellow eyes (p < 0.001). Furthermore, baseline latency asymmetry significantly correlated with the rate of RNFL thinning in ON eyes during the follow-up (p < 0.001), explaining almost half of the variability of temporal RNFL progression. For each millisecond of latency delay (i.e., ∼0.5 mm of demyelination along the optic nerve), temporal RNFL thickness was annually reduced by 0.05%.DiscussionOur study provides clear in vivo evidence that chronic demyelination significantly accelerates axonal loss. However, because this process is slow and its effect is mild, long-term monitoring is required to establish and confidently measure the neurodegenerative consequences of demyelination.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis

Klistorner

You

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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“…Although it is likely that the pathology of both axon fibers and the surrounding myelin sheaths is involved, further studies will be of critical importance for the development of specific therapeutic strategies supporting myelin and axonal regeneration simultaneously or independently. Indeed, remyelination, through lifestyle changes or drug interventions, is considered a putative neuroprotective strategy in neurodegenerative diseases, including MS. 61 Similarly, axonal regeneration is emerging as a necessary disease-modifying therapeutic strategy against AD and dementias. 62 Although our work examined a relatively large cohort and used advanced methodology, it had certain limitations.…”

Section: Discussionmentioning

confidence: 99%

Lower myelin content is associated with more rapid cognitive decline among cognitively unimpaired individuals

Gong

Bilgel

Kiely

et al. 2023

Alzheimer's & Dementia

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Introduction The influence of myelination on longitudinal changes in cognitive performance remains unclear. Methods For each participant (N = 123), longitudinal cognitive scores were calculated. Myelin content was probed using myelin water fraction (MWF) or longitudinal relaxation rate (R1); both are MRI measures sensitive to myelin, with MWF being specific. Results Lower MWF was associated with steeper declines in executive function (p < .02 in all regions) and lower R1 was associated with steeper declines in verbal fluency (p < .03 in all regions). Additionally, lower R1 was associated with steeper declines in executive function (p < .02 in all regions) and memory (p < .04 in occipital and cerebral white matter) but did not survive Bonferroni correction. Discussion We demonstrate significant relationships between myelin content and the rates of change in cognitive performance among cognitively normal individuals. These findings highlight the importance of myelin in cognitive functioning and suggest MWF and R1 as imaging biomarkers to predict cognitive changes.

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“…Understanding these different dynamics can affect therapeutic decision-making and help with the design of clinical trials that will use measures of neurodegeneration as their outcomes. 10 Data from limited autopsy pathology suggest some correlation between axonal loss and the concurrent magnitude of inflammation (quantification of T and B cells, plasma cells, HLA-DR+ cells) in both relapsing and progressive MS. 11 However, investigators who have studied this pathologic tissue recognize that-unlike for studying axons where spheroids and axon bulbs can show evidence of degeneration of nerve fibers-pathologic assessment of neuronal cell body loss is difficult in MS, and evaluation of longitudinal change is impossible based on tissue. There has been neuronal cell body loss documented in a limited number of cases within cortical lesions.…”

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confidence: 98%

“…Understanding these different dynamics can affect therapeutic decision-making and help with the design of clinical trials that will use measures of neurodegeneration as their outcomes. 10…”

mentioning

confidence: 99%

Differences in Age-related Retinal and Cortical Atrophy Rates in Multiple Sclerosis

et al. 2022

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Background and Objectives:The timing of neurodegeneration in MS remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course.Methods:We analyzed 597 MS patients who underwent longitudinal OCT imaging annually for 4.5±2.4 years and 432 patients who underwent longitudinal MRI scans for 10±3.4 yrs, quantifying macular ganglion-cell–inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. To evaluate the rate of loss, linear mixed-effects modeling with subject-specific intercepts and slopes were fitted using restricted maximum likelihood estimation. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort’s age quartiles) was assessed by linear regression models.Results:The rate of CGM volume loss declined with increasing age of study entry (1.3%/year atrophy for the age of entry in the cohort <35 years; 1.1% for age >35 years and <41; 0.97% for age >41 years and <49; 0.9% for age >49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7%/year thinning for the age of entry in the cohort <35 years; 0.29% for age >35 years and <41; 0.34% for age >41 years and <49; 0.33% for age >49 years).Conclusions:An age-dependent reduction in retinal and cortical volume loss rates during RRMS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive-immune-mediated inflammatory activity is also the period with the greatest neuroaxonal loss.

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Remyelination Trials

Cited by 12 publications

References 46 publications

Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis

Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis

Lower myelin content is associated with more rapid cognitive decline among cognitively unimpaired individuals

Differences in Age-related Retinal and Cortical Atrophy Rates in Multiple Sclerosis

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