Brain tissue loss in early-stage multiple sclerosis predicts future cognitive decline

Introduction: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which factor contributes most to the development of brain atrophy: extent and severity of lesions or damage of whole brain tissue (WBT). Methods: Eighty-six patients with MS [32 primary progressive (PP), 32 secondary progressive (SP)] and 22 relapsing-remitting (RR) were studied. MRI included T1- and T2-weighted imaging to obtain hypointense T1 lesion volume (T1LV) and two brain volume measurements: 1) the parenchymal fraction (PF; whole brain parenchymal volume/intracranial volume) as a marker of overall brain volume, and 2) the ventricular fraction (VF; ventricular volume/intracranial volume) as a marker of central atrophy. From magnetization transfer ratio (MTR) histograms, the relative peak height (rHp) was derived as an index of damage of WBT (a lower peak height reflects damage of WBT). Results: Multiple linear regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coefficient b=0.59, p <0.001 for WBT and b= −0.19, p <0.05 for T1LV). These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall brain volume. By contrast, the variance in VF is explained by both T1LV and damage of WBT (standardized coefficient b =0.43, p<0.001 for T1LV and b = −0.38, p <0.001 for WBT). Conclusion: This study shows that overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss. Central atrophy (VF) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.

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Whole Brain Tract Disruption Better Explains Cognitive Decline in Multiple Sclerosis than Total Lesion Volume

10.26226/morressier.59a3e8b7d462b8028d895711 ◽

2017 ◽

Author(s):

Tom Fuchs

Keyword(s):

Multiple Sclerosis ◽

Cognitive Decline ◽

Lesion Volume ◽

Whole Brain

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Faculty Opinions recommendation of Cortical atrophy accelerates as cognitive decline worsens in multiple sclerosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736558681.793568404 ◽

2019 ◽

Author(s):

Peter Stys

Keyword(s):

Multiple Sclerosis ◽

Cognitive Decline ◽

Cortical Atrophy

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Cognitive Issues in Pediatric Multiple Sclerosis

Brain Sciences ◽

10.3390/brainsci11040442 ◽

2021 ◽

Vol 11 (4) ◽

pp. 442

Author(s):

Emilio Portaccio ◽

Ermelinda De Meo ◽

Angelo Bellinvia ◽

Maria Pia Amato

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Pediatric Patients ◽

Leisure Activities ◽

Disease Onset ◽

Cognitive Profiles ◽

Brain Growth ◽

Network Activation ◽

Definition Of

Multiple sclerosis (MS) is one of the leading causes of disability in young adults. The onset of MS during developmental age makes pediatric patients particularly susceptible to cognitive impairment, resulting from both disease-related damage and failure of age-expected brain growth. Despite different test batteries and definitions, cognitive impairment has been consistently reported in approximately one-third of pediatric patients with MS. However, the lack of a uniform definition of cognitive impairment and the adoption of different test batteries have led to divergent results in terms of cognitive domains more frequently affected across the cohorts explored. This heterogeneity has hampered large international collaborative studies. Moreover, research aimed at the identification of risk factors (e.g., demographic, clinical, and radiological features) or protective factors (e.g., cognitive reserve, leisure activities) for cognitive decline is still scanty. Mood disorders, such as depression and anxiety, can be detected in these patients alongside cognitive decline or in isolation, and can negatively affect quality of life scores as well as academic performances. By using MRI, cognitive impairment was attributed to damage to specific brain compartments as well as to abnormal network activation patterns. However, multimodal MRI studies are still needed in order to assess the contribution of each MRI metric to cognitive impairment. Importantly, longitudinal studies have recently demonstrated failure of age-expected brain growth and of white matter (WM) and gray matter (GM) maturation plays a relevant role in determining cognitive dysfunction, in addition to MS-related direct damage. Whether these growth retardations might result in specific cognitive profiles according to the age at disease onset has not been studied, yet. A better characterization of cognitive profiles in pediatric MS patients, as well as the definition of neuroanatomical substrates of cognitive impairment and their longitudinal evolution are needed to develop efficient therapeutic strategies against cognitive impairment in this patient population.

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Acute and chronic synaptic pathology in multiple sclerosis gray matter

Multiple Sclerosis Journal ◽

10.1177/13524585211022174 ◽

2021 ◽

pp. 135245852110221

Author(s):

Marco Vercellino ◽

Stella Marasciulo ◽

Silvia Grifoni ◽

Elena Vallino-Costassa ◽

Chiara Bosa ◽

...

Keyword(s):

Multiple Sclerosis ◽

Brain Tissue ◽

Gray Matter ◽

Axonal Loss ◽

Strong Indication ◽

Synaptic Loss ◽

Synaptic Density ◽

Synaptic Pathology ◽

Gabaergic Synapses ◽

And Control

Objectives: To investigate the extent of synaptic loss, and the contribution of gray matter (GM) inflammation and demyelination to synaptic loss, in multiple sclerosis (MS) brain tissue. Methods: This study was performed on two different post-mortem series of MS and control brains, including deep GM and cortical GM. MS brain samples had been specifically selected for the presence of active demyelinating GM lesions. Over 1,000,000 individual synapses were identified and counted using confocal microscopy, and further characterized as glutamatergic/GABAergic. Synaptic counts were also correlated with neuronal/axonal loss. Results: Important synaptic loss was observed in active demyelinating GM lesions (−58.9%), while in chronic inactive GM lesions, synaptic density was only mildly reduced compared to adjacent non-lesional gray matter (NLGM) (−12.6%). Synaptic loss equally affected glutamatergic and GABAergic synapses. Diffuse synaptic loss was observed in MS NLGM compared to control GM (−21.2% overall). Conclusion: This study provides evidence, in MS brain tissue, of acute synaptic damage/loss during active GM inflammatory demyelination and of synaptic reorganization in chronically demyelinated GM, affecting equally glutamatergic and GABAergic synapses. Furthermore, this study provides a strong indication of widespread synaptic loss in MS NLGM also independently from focal GM demyelination.

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Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis

Scientific Reports ◽

10.1038/s41598-021-82388-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ellen F. Mosleth ◽

Christian Alexander Vedeler ◽

Kristian Hovde Liland ◽

Anette McLeod ◽

Gerd Haga Bringeland ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Neural Development ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Early Stage ◽

Retinol Binding Protein ◽

Proteomics Data ◽

Disease Heterogeneity ◽

Low Levels

AbstractDespite intensive research, the aetiology of multiple sclerosis (MS) remains unknown. Cerebrospinal fluid proteomics has the potential to reveal mechanisms of MS pathogenesis, but analyses must account for disease heterogeneity. We previously reported explorative multivariate analysis by hierarchical clustering of proteomics data of MS patients and controls, which resulted in two groups of individuals. Grouping reflected increased levels of intrathecal inflammatory response proteins and decreased levels of proteins involved in neural development in one group relative to the other group. MS patients and controls were present in both groups. Here we reanalysed these data and we also reanalysed data from an independent cohort of patients diagnosed with clinically isolated syndrome (CIS), who have symptoms of MS without evidence of dissemination in space and/or time. Some, but not all, CIS patients had intrathecal inflammation. The analyses reported here identified a common protein signature of MS/CIS that was not linked to elevated intrathecal inflammation. The signature included low levels of complement proteins, semaphorin-7A, reelin, neural cell adhesion molecules, inter-alpha-trypsin inhibitor heavy chain H2, transforming growth factor beta 1, follistatin-related protein 1, malate dehydrogenase 1 cytoplasmic, plasma retinol-binding protein, biotinidase, and transferrin, all known to play roles in neural development. Low levels of these proteins suggest that MS/CIS patients suffer from abnormally low oxidative capacity that results in disrupted neural development from an early stage of the disease.

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