Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease

You, Yuyi; Joseph, Chitra; Wang, Chenyu; Gupta, Vivek; Liu, Sidong; Yiannikas, Con; Chua, Beng Huat; Chitranshi, Nitin; Shen, Ting; Dheer, Yogita; Invernizzi, Alessandro; Borotkanics, Robert; Barnett, Michael; Graham, Stuart L.; Klistorner, Alexander

doi:10.1093/brain/awy338

Cited by 89 publications

(80 citation statements)

References 72 publications

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“…MS. 9,13,[28][29][30][31] RGC and its axon are thought to be analogous to brain gray and white matter. Therefore, studying mechanisms of its damage in MS may provide crucial insights into pathogenesis of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…current study, therefore, strongly supports the need for development of new pro-remyelination therapies, a rapidly emerging research area in MS. 38,39 In addition, given the fact that demyelination has also been observed as a pathologic component in other neurodegenerative disorders 7,8 as well as being implicated in transneuronal degeneration, 9 the revealed association between chronic demyelination and axonal loss may have broader implications for human neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…4,6 Although numerous animal and in vitro studies have demonstrated negative effects of demyelination on axonal survival, the clinical significance of chronic demyelination as a precursor of axonal damage in humans has never been ascertained. Myelin pathology has also been identified in many neurodegenerative diseases other than MS [7][8][9] and may play an important role in their pathogenesis. Moreover, transneuronal spread of degeneration along human neuronal projections could also be partially mediated by demyelination.…”

mentioning

confidence: 99%

“…Moreover, transneuronal spread of degeneration along human neuronal projections could also be partially mediated by demyelination. 9 Therefore, an understanding of whether chronic demyelination can cause neuroaxonal loss in humans is of paramount importance.…”

mentioning

confidence: 99%

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Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

You¹,

Barnett²,

Yiannikas

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

You¹,

Barnett²,

Yiannikas

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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View full text Add to dashboard Cite

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“…Further, we assessed whether the protective effects observed in RN22 (Schwann) cells might contribute to myelin recovery, a key process in MS and more recently shown in glaucoma [40]. We evaluated the effects of BN201 on the differentiation of OPCs (Olig+ cells) to mature OLs (MBP + ) in vitro and on promoting the myelin ensheathing of axons [17].…”

Section: Screening For Small Chemicals With Neuroprotective Activity mentioning

confidence: 99%

Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

et al. 2019

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The development of neuroprotective therapies is a sought-after goal. By screening combinatorial chemical libraries using in vitro assays, we identified the small molecule BN201 that promotes the survival of cultured neural cells when subjected to oxidative stress or when deprived of trophic factors. Moreover, BN201 promotes neuronal differentiation, the differentiation of precursor cells to mature oligodendrocytes in vitro, and the myelination of new axons. BN201 modulates several kinases participating in the insulin growth factor 1 pathway including serum-glucocorticoid kinase and midkine, inducing the phosphorylation of NDRG1 and the translocation of the transcription factor Foxo3 to the cytoplasm. In vivo, BN201 prevents axonal and neuronal loss, and it promotes remyelination in models of multiple sclerosis, chemically induced demyelination, and glaucoma. In summary, we provide a new promising strategy to promote neuroaxonal survival and remyelination, potentially preventing disability in brain diseases.

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Gradient of microstructural damage along the dentato‐thalamo‐cortical tract in Friedreich ataxia

Cocozza,

Bosticardo,

Battocchio

et al. 2024

Ann Clin Transl Neurol

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ObjectiveThe dentato‐thalamo‐cortical tract (DTT) is the main cerebellar efferent pathway. Degeneration of the DTT is a core feature of Friedreich ataxia (FRDA). However, it remains unclear whether DTT disruption is spatially specific, with some segments being more impacted than others. This study aimed to investigate microstructural integrity along the DTT in FRDA using a profilometry diffusion MRI (dMRI) approach.MethodsMRI data from 45 individuals with FRDA (mean age: 33.2 ± 13.2, Male/Female: 26/19) and 37 healthy controls (mean age: 36.5 ± 12.7, Male/Female:18/19) were included in this cross‐sectional multicenter study. A profilometry analysis was performed on dMRI data by first using tractography to define the DTT as the white matter pathway connecting the dentate nucleus to the contralateral motor cortex. The tract was then divided into 100 segments, and dMRI metrics of microstructural integrity (fractional anisotropy, mean diffusivity and radial diffusivity) at each segment were compared between groups. The process was replicated on the arcuate fasciculus for comparison.ResultsAcross all diffusion metrics, the region of the DTT connecting the dentate nucleus and thalamus was more impacted in FRDA than downstream cerebral sections from the thalamus to the cortex. The arcuate fasciculus was minimally impacted.InterpretationOur study further expands the current knowledge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex.

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Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease

Cited by 89 publications

References 72 publications

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

Gradient of microstructural damage along the dentato‐thalamo‐cortical tract in Friedreich ataxia

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