Trans-synaptic degeneration as a mechanism of neurodegeneration in multiple sclerosis.
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ABSTRACT:
SUBMITTER: Murphy OC
PROVIDER: S-EPMC10358689 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
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Trans-synaptic degeneration as a mechanism of neurodegeneration in multiple sclerosis.
Murphy Olwen C OC Calabresi Peter A PA Saidha Shiv S
Neural regeneration research 20231201 12
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Project description:BackgroundTrans-synaptic degeneration (TSD) describes the propagation of neuronal injury through synaptic pathways in the human nervous system and may be linked to the accelerated retinal atrophy seen in multiple sclerosis (MS).ResultsWe report six cases where homonymous, hemi-macular ganglion cell + inner plexiform (GCIP) thickness reduction was seen in conjunction with posterior visual pathway lesions. Macular microcystoid changes of the inner nuclear layer (INL) were seen in a subset of three subjects.ConclusionOur findings highlight the utility of assessing regional GCIP changes to identify potential retrograde TSD in MS and demonstrate that INL changes may be an accompaniment in such instances.
| S-EPMC5451303 | biostudies-literature
Project description:ObjectiveIncreasing evidence suggest that neuronal damage is an early and diffuse feature of Multiple Sclerosis (MS) pathology. Analysis of the optic pathway may help to clarify the mechanisms involved in grey matter damage in MS. Purpose of our study was to investigate the relationship between inflammation and neurodegeneration and to achieve evidence of trans-synaptic degeneration in the optic pathway in MS at clinical onset.Methods50 clinically isolated syndromes/early relapse-onset MS (CIS/eRRMS) with mean disease duration of 4.0±3.5 months, 28 MRI healthy controls (HC) and 31 OCT-HC were studied. Ten patients had optic neuritis at presentation (MSON+), 40 presented with other symptoms (MSON-). MRI examination included 3D-T1, 3D-FLAIR and 3D-DIR sequences. Global cortical thickness (gCTh), pericalcarin CTh (pCTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 scans. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Jülich's Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV = WMLV% and OR-WMLV/ORV = ORWMLV%) were obtained by 3D-FLAIR image segmentation. 3D-DIR sequences were applied to identify inflammatory lesions of the optic nerve. Optic coherence tomography (OCT) protocol included the analysis of global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi's sectors (temporal, T-RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+).ResultsNo difference in CTh was found between CIS/eRRMS and HC, and between MSON+ and MSON-. Moreover, MSON+ and MSON- did not differ for any WM lesion load parameter. The most significant correlations between RNFL thickness and optic radiation WM pathology were found in MSON+. In these patients, the temporal RNFL inversely correlated to ipsilateral optic radiation WM lesion load (T-RNFL: r -0.7, p<0.05; TS-RNFL: r -0.7, p<0.05), while nasal RNFL inversely correlated to contralateral optic radiation WM lesion load (NI: r -0.8, p<0.01; NS-RNFL: r -0.8, p<0.01).ConclusionsOur findings suggest that in MSON+ the optic pathway is site of a diffuse pathological process that involves both directly and via trans-synaptic degeneration the RNFL.
| S-EPMC5574611 | biostudies-literature
Project description:Imaging Neurodegeneration in Multiple Sclerosis
| PRJNA827227 | ENA
Project description:Increasing evidence suggests that pathological hallmarks of chronic degenerative syndromes progressively spread among interconnected brain areas in a disease-specific stereotyped pattern. Functional brain imaging from patients affected by various neurological syndromes such as traumatic brain injury and stroke indicates that the progression of such diseases follows functional connections, rather than simply spreading to structurally adjacent areas. Indeed, initial damage to a given brain area was shown to disrupt the communication in related brain networks. Using cortico-striatal neuronal networks reconstructed in a microfluidic environment, we investigated the role of glutamate signaling in activity-dependent neuronal survival and trans-synaptic degeneration processes. Using a variety of neuronal insults applied on cortical neurons, we demonstrate that acute injuries such as axonal trauma, focal ischemia, or alteration of neuronal rhythms, lead to glutamate-dependent striatal neuron dysfunction. Interestingly, focal pro-oxidant insults or chronic alteration of spontaneous cortical rhythms provoked dysfunction of distant striatal neurons through abnormal glutamate GluN2B-NMDAR-mediated signaling at cortico-striatal synapses. These results indicate that focal alteration of cortical functions can initiate spreading of dysfunction along neuronal pathways in the brain, reminiscent of diaschisis-like processes.
| S-EPMC6072786 | biostudies-literature
Project description:In multiple sclerosis, microstructural damage of normal-appearing brain tissue is an important feature of its pathology. Understanding these mechanisms is vital to help develop neuroprotective strategies. The visual pathway is a key model to study mechanisms of damage and recovery in demyelination. Anterograde trans-synaptic degeneration across the lateral geniculate nuclei has been suggested as a mechanism of tissue damage to explain optic radiation abnormalities seen in association with demyelinating disease and optic neuritis, although evidence for this has relied solely on cross-sectional studies. We therefore aimed to assess: (i) longitudinal changes in the diffusion properties of optic radiations after optic neuritis suggesting trans-synaptic degeneration; (ii) the predictive value of early optic nerve magnetic resonance imaging measures for late optic radiations changes; and (iii) the impact on visual outcome of both optic nerve and brain post-optic neuritis changes. Twenty-eight consecutive patients with acute optic neuritis and eight healthy controls were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by magnetic resonance imaging, at baseline, 3, 6, and 12 months. Magnetic resonance imaging sequences performed (and metrics obtained) were: (i) optic nerve fluid-attenuated inversion-recovery (optic nerve cross-sectional area); (ii) optic nerve proton density fast spin-echo (optic nerve proton density-lesion length); (iii) optic nerve post-gadolinium T1-weighted (Gd-enhanced lesion length); and (iv) brain diffusion-weighted imaging (to derive optic radiation fractional anisotropy, radial diffusivity, and axial diffusivity). Mixed-effects and multivariate regression models were performed, adjusting for age, gender, and optic radiation lesion load. These identified changes over time and associations between early optic nerve measures and 1-year global optic radiation/clinical measures. The fractional anisotropy in patients' optic radiations decreased (P = 0.018) and radial diffusivity increased (P = 0.002) over 1 year following optic neuritis, whereas optic radiation measures were unchanged in controls. Also, smaller cross-sectional areas of affected optic nerves at 3 months post-optic neuritis predicted lower fractional anisotropy and higher radial diffusivity at 1 year (P = 0.007) in the optic radiations, whereas none of the inflammatory measures of the optic nerve predicted changes in optic radiations. Finally, greater Gd-enhanced lesion length at baseline and greater optic nerve proton density-lesion length at 1 year were associated with worse visual function at 1 year (P = 0.034 for both). Neither the cross-sectional area of the affected optic nerve after optic neuritis nor the damage in optic radiations was associated with 1-year visual outcome. Our longitudinal study shows that, after optic neuritis, there is progressive damage to the optic radiations, greater in patients with early residual optic nerve atrophy, even after adjusting for optic radiation lesions. These findings provide evidence for trans-synaptic degeneration.
| S-EPMC5839599 | biostudies-literature
Project description:During the course of multiple sclerosis (MS), inflammatory insults drive neuro-axonal loss and disability progression. However, pathways that guide neurons toward survival or death during central nervous system (CNS) inflammation are largely unexplored. Here we show that somatic deposition of the presynaptic protein bassoon (Bsn) in inflamed neurons directly contributes to neurodegeneration in MS. By comparing neuron-specific RNA-seq of healthy mice to mice undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identified key components of neurodegenerative pathways, including reduced mitochondrial ATP synthesis and increased protein catabolism. These changes were accompanied by neuronal induction and deposition of the intrinsically disordered protein Bsn in both EAE and in patients with MS. Somatic Bsn also accumulated in Bsn-overexpressing Neuro-2a (N2a) cells and single cell RNA-seq revealed dose-dependent repression of energy metabolism and induction of the unfolded protein response, reminiscent of our in vivo findings. Furthermore, Bsn overexpression in N2a cells or in Drosophila melanogaster neurons led to decreased survival and shortened lifespan, respectively. Conversely, genetic disruption of Bsn in mice was neuroprotective, with reduced neuro-axonal injury and clinical disability during EAE, establishing a toxic gain-of-function of Bsn during CNS inflammation. Our study provides systemic insights into neuronal responses to inflammation and identifies protein accumulation as a generic pathomechanism uniting primary and inflammatory neurodegeneration. Moreover, it offers a new explanation and possible treatment strategy to halt disability progression in MS, irrespective of immunotherapies.
2019-04-03 | GSE104899 | GEO
Project description:ObjectiveCerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.MethodsNinety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.ResultsThe density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level. Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.InterpretationThese findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.
| S-EPMC3580047 | biostudies-literature
Project description:ObjectiveIron may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age. Our study focused on nonheme iron distribution and the expression of the iron-related proteins ferritin, hephaestin, and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases.MethodsWe performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism, and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation.ResultsWe found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration. In chronic MS, however, there was a significant decrease of iron in the normal-appearing white matter (NAWM) corresponding with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an upregulation of iron-exporting ferroxidases. In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages. Iron-containing microglia showed signs of cell degeneration. At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons.InterpretationIron decreases in the NAWM of MS patients with increasing disease duration. Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst.
| S-EPMC4223935 | biostudies-literature
Project description:Atrophy related to multiple sclerosis (MS) has been found at the early stages of the disease. However, the archetype dynamic trajectories of the neurodegenerative process, even prior to clinical diagnosis, remain unknown. We modeled the volumetric trajectories of brain structures across the entire lifespan using 40,944 subjects (38,295 healthy controls and 2649 MS patients). Then, we estimated the chronological progression of MS by assessing the divergence of lifespan trajectories between normal brain charts and MS brain charts. Chronologically, the first affected structure was the thalamus, then the putamen and the pallidum (around 4 years later), followed by the ventral diencephalon (around 7 years after thalamus) and finally the brainstem (around 9 years after thalamus). To a lesser extent, the anterior cingulate gyrus, insular cortex, occipital pole, caudate and hippocampus were impacted. Finally, the precuneus and accumbens nuclei exhibited a limited atrophy pattern. Subcortical atrophy was more pronounced than cortical atrophy. The thalamus was the most impacted structure with a very early divergence in life. Our experiments showed that lifespan models of most impacted structures could be an important tool for future preclinical/prodromal prognosis and monitoring of MS.
| S-EPMC10619394 | biostudies-literature
Project description:Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.
| S-EPMC2677799 | biostudies-literature