Synaptic Loss in Multiple Sclerosis: A Systematic Review of Human Post-mortem Studies

Background: Gray matter pathology plays a central role in the progression of multiple sclerosis (MS). The occurrence of synaptic loss appears to be important but, to date, still poorly investigated aspect of MS pathology. In this systematic review, we drew from the recent knowledge about synaptic loss in human post-mortem studies.Methods: We conducted a systematic search with PubMed to identify relevant publications. Publications available from15 June 2021 were taken into account. We selected human post-mortem studies that quantitatively assessed the synapse number in MS tissue.Results: We identified 14 relevant publications out of which 9 reported synaptic loss in at least one investigated subregion. The most commonly used synaptic marker was synaptophysin; non-etheless, we found substantial differences in the methodology and the selection of reference tissue. Investigated regions included the cortex, the hippocampus, the cerebellum, the thalamus, and the spinal cord.Conclusion: Synaptic loss seems to take place throughout the entire central nervous system. However, the results are inconsistent, probably due to differences in the methodology. Moreover, synaptic loss appears to be a dynamic process, and thus the nature of this pathology might be captured using in vivo synaptic density measurements.

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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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High-resolution myelin water imaging in post-mortem multiple sclerosis spinal cord: A case report

Multiple Sclerosis Journal ◽

10.1177/1352458515624559 ◽

2016 ◽

Vol 22 (11) ◽

pp. 1485-1489 ◽

Cited By ~ 19

Author(s):

Cornelia Laule ◽

Andrew Yung ◽

Vlady Pavolva ◽

Barry Bohnet ◽

Piotr Kozlowski ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Cross Sections ◽

Anatomical Variation ◽

Conus Medullaris ◽

Entire Length ◽

Post Mortem ◽

Water Fraction ◽

Formalin Fixed

Background: Loss of myelin in the spinal cord in multiple sclerosis (MS) is likely an important, and early, contributor to atrophy and associated disability. In vivo measurement of myelin is possible using myelin water fraction (MWF) imaging, but MWF has never been assessed in MS along the entire length of the spinal cord in vivo or in post-mortem tissue. Objective: To assess the feasibility of measuring the distribution of MWF along the entire length of the spinal cord in post-mortem MS tissue using high-field MRI. Methods: One formalin-fixed spinal cord from a female with secondary progressive MS (age: 78 years, disease duration: 25 years) was cut into 104 5-mm-thick cross sections along the entire length of the spinal cord from the cervico-medullary junction to the conus medullaris and imaged using a 64 echo T2 relaxation experiment at 7T. Results: Myelin water maps showed cord anatomy in superb detail, white matter demonstrating a higher MWF than the grey matter. Anatomical variation in myelin distribution along cervical, thoracic and lumbar regions was observed. Lesions demonstrated myelin loss. Conclusion: Post-mortem myelin water imaging of formalin-fixed MS spinal cord is feasible.

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Exploring In-Vivo and Post-Mortem Multiple Sclerosis Lesions at 7T MRI with R2* and Phase Images

NeuroImage ◽

10.1016/s1053-8119(09)70122-3 ◽

2009 ◽

Vol 47 ◽

pp. S50

Author(s):

B Yao ◽

F Bagnato ◽

H Merkle ◽

P van Gelderen ◽

FK Cantor ◽

...

Keyword(s):

Multiple Sclerosis ◽

Post Mortem ◽

Phase Images

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Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

10.1101/2020.09.03.281543 ◽

2020 ◽

Author(s):

Lynn van Olst ◽

Carla Rodriguez-Mogeda ◽

Carmen Picon-Munoz ◽

Svenja Kiljan ◽

Rachel E. James ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neuronal Loss ◽

Post Mortem ◽

Protective Properties ◽

Phenotypic Changes ◽

Extensive Analysis ◽

Meningeal Inflammation ◽

Cortical Pathology ◽

Over Time

AbstractMeningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, contributing to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. Using extensive analysis of human post-mortem tissue, we identified two distinct microglial phenotypes, termed MS1 and MS2, in the cortex of progressive MS patients. These phenotypes differed in morphology and protein expression, but both associated with inflammation of the overlying meninges. We could replicate the MS-specific microglial phenotypes in a novel in vivo rat model for progressive MS-like meningeal inflammation, with microglia present at 1 month post-induction resembling MS1 microglia whereas those at 2 months acquired an MS2-like phenotype. Interestingly, MS1 microglia were involved in presynaptic displacement and phagocytosis and associated with a relative sparing of neurons in the MS and animal cortex. In contrast, the presence of MS2 microglia coincided with substantial neuronal loss. Taken together, we uncovered that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Our data suggests that these phenotypes occur sequentially and that microglia may lose their protective properties over time, contributing to neuronal loss.

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Analysis of the Ocular Refractive State in Fighting Bulls: Astigmatism Prevalence

BioMed Research International ◽

10.1155/2017/8203269 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7

Author(s):

Juan M. Bueno ◽

Matteo Lo Sapio ◽

J. Manuel Sanes ◽

Juan Seva

Keyword(s):

Post Mortem ◽

Horizontal Meridian ◽

Vertical Meridian ◽

Refractive State ◽

Starting Point ◽

Left And Right ◽

Highly Correlated ◽

First Time ◽

Selection Of

The purpose of this study was to describe the ocular refractive state (ORS) of fighting bulls. The study consisted of 90 ophthalmological healthy animals (85 in post-mortem and 5 in living conditions, resp.). The ORS of the eyes (2 per animal) was determined using streak retinoscopy. In vivo animals were assessed at a fighting bull farm facility. Post-mortem measurements were carried out at a local arena. The ORS along the horizontal meridian ranged between −1.00 and +2.50 diopters (D), with a mean of +0.66±0.85 D in post-mortem animals. Values for in vivo conditions were similar (+0.75±0.46 D). Left and right eyes were highly correlated in both sets (p<0.001). A fairly good correlation was also observed when comparing living and post-mortem eyes in the same animals. Anisometropia ≥ 1.00 D was diagnosed in 3 animals. Astigmatism (≥+0.5 D) was detected in 93% of the eyes. To our knowledge, the ORS of the fighting bull has been reported for the first time. Although values vary among individuals, all eyes presented a marked astigmatism. Whereas the horizontal meridian was slightly hyperopic, the vertical meridian was always closer to emmetropia. These results represent a starting point to understand the ocular optics of this kind of animals, which might benefit the selection of animals at the farm before being sent to the bullfighting arena.

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A Systematic Review on the Role of Arachidonic Acid Pathway in Multiple Sclerosis

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200825164123 ◽

2020 ◽

Vol 19 ◽

Author(s):

Malvina Hoxha ◽

Erila Spahiu ◽

Emanuela Prendi ◽

Bruno Zappacosta

Keyword(s):

Multiple Sclerosis ◽

Systematic Review ◽

Arachidonic Acid ◽

Immune Cell ◽

Inflammatory Responses ◽

Lox Inhibitors ◽

Acid Pathway ◽

Arachidonic Acid Pathway

Background & Objective: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease characterized by destruction of oligodendrocytes, immune cell infiltration and demyelination. Inflammation plays a significant role in MS, and the inflammatory mediators such as eicosanoids, leukotrienes, superoxide radicals are involved in pro-inflammatory responses in MS. In this systematic review we tried to define and discuss all the findings of in vivo animal studies and human clinical trials on the potential association between arachidonic acid (AA) pathway and multiple sclerosis. Methods: A systematic literature search across Pubmed, Scopus, Embase and Cochrane database was conducted. This systematic review was performed according to PRISMA guidelines. Results: A total of 146 studies were included, of which 34 were conducted in animals, 58 in humans, and 60 studies reported the role of different compounds that target AA mediators or their corresponding enzymes/ receptors, and can have a therapeutic effect in MS. These results suggest that eicosanoids have significant roles in experimental autoimmune encephalomyelitis (EAE) and MS. The data from animal and human studies elucidated that PGI2, PGF2α, PGD2, isoprostanes, PGE2, PLA2, LTs are increased in MS. PLA2 inhibition modulates the progression of the disease. PGE1 analogues can be a useful option in the treatment of MS. Conclusions: All studies reported the beneficial effects of COX and LOX inhibitors in MS. The hybrid compounds, such as COX-2 inhibitors/TP antagonists and 5-LOX inhibitors can be an innovative approach for multiple sclerosis treatment. Future work in MS should shed light in synthesizing new compounds targeting arachidonic acid pathway.

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The Rise of Synaptic Density PET Imaging

Molecules ◽

10.3390/molecules25102303 ◽

2020 ◽

Vol 25 (10) ◽

pp. 2303

Author(s):

Guillaume Becker ◽

Sylvestre Dammicco ◽

Mohamed Ali Bahri ◽

Eric Salmon

Keyword(s):

Pet Imaging ◽

Kinetic Modelling ◽

Synaptic Proteins ◽

Preclinical Development ◽

Synaptic Loss ◽

Synaptic Density ◽

Pet Radiotracers ◽

Modelling Methods

Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and immunohistochemical labelling of synaptic proteins were the gold-standard methods for such analyses. Over the last decade, several PET radiotracers for the synaptic vesicle 2A protein have been developed to achieve in vivo synapses visualization and quantification. Different strategies were used, namely radiolabelling with either 11C or 18F, preclinical development in rodent and non-human primates, and binding quantification with different kinetic modelling methods. This review provides an overview of these PET tracers and underlines their perspectives and limitations by focusing on radiochemical aspects, as well as preclinical proof-of-concept and the main clinical outcomes described so far.

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Effects of Cannabis Use on Human Brain Structure in Psychosis: A Systematic Review Combining In Vivo Structural Neuroimaging and Post Mortem Studies

Current Pharmaceutical Design ◽

10.2174/138161212802884861 ◽

2012 ◽

Vol 18 (32) ◽

pp. 5070-5080 ◽

Cited By ~ 36

Author(s):

Charlotte Rapp ◽

Hilal Bugra ◽

Anita Riecher-Rossler ◽

Corinne Tamagni ◽

Stefan Borgwardt

Keyword(s):

Systematic Review ◽

Human Brain ◽

Brain Structure ◽

Cannabis Use ◽

Post Mortem ◽

Structural Neuroimaging

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Molecular pathology and synaptic loss in primary tauopathies: [18F]AV-1451 and [11C]UCB-J PET study

10.1101/2021.03.03.21252808 ◽

2021 ◽

Author(s):

Negin Holland ◽

Maura Malpetti ◽

Timothy Rittman ◽

Elijah E Mak ◽

Luca Passamonti ◽

...

Keyword(s):

Disease Severity ◽

Pet Imaging ◽

Molecular Pathology ◽

Brain Regions ◽

Synaptic Function ◽

Amyloid Pet ◽

Synaptic Loss ◽

Synaptic Density ◽

The Relationship

AbstractThe relationship betweenin vivosynaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine thein vivorelationship between synaptic density and molecular pathology, in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity.Twenty three patients with PSP, and twelve patients with Corticobasal Syndrome (CBS) were recruited from a tertiary referral centre. Nineteen education, sex and gender-matched control participants were recruited from the National Institute for Health Research ‘Join Dementia Research’ platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands [11C]UCB-J and [18F]AV-1451, respectively. Patients with CBS also underwent amyloid PET imaging with [11C]PiB to exclude those with likely Alzheimer’s pathology – we refer to the amyloid negative cohort as having CBD although acknowledge other pathologies exist. Disease severity was assessed with the PSP rating scale; regional non-displaceable binding potentials (BPND) of [11C]UCB-J and [18F]AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for [18F]AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions, and synaptic density in connected subcortical areas.Across brain regions, there was apositivecorrelation between [11C]UCB-J and [18F]AV-1451 BPND(β=0.4, t=4.7, p<0.0001). However, the direction of this correlation became less positive as a function of disease severity in patients(β = -0.03, T = -4.0, p = 0.002). Between brain regions, cortical [18F]AV-1451 binding wasnegativelycorrelated with synaptic density in subcortical areas (caudate nucleus, putamen, and substantia nigra).Brain regions with higher synaptic density are associated with a higher [18F]AV-1451 binding in PSP/CBD, but this association diminishes with disease severity. Moreover, higher cortical [18F]AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and tauopathy, with synapse rich regions vulnerable to accrual of pathology, followed by a loss of synapses in response to pathology. Given the importance of synaptic function for cognition, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.

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Automation of citation screening in pre-clinical systematic reviews

10.1101/280131 ◽

2018 ◽

Cited By ~ 2

Author(s):

J. Liao ◽

S. Ananiadou ◽

L. G. Currie ◽

B. E. Howard ◽

A. Rice ◽

...

Keyword(s):

Machine Learning ◽

Multiple Sclerosis ◽

Systematic Review ◽

Vitamin D ◽

Neuropathic Pain ◽

Meta Analysis ◽

In Vivo Studies ◽

Citation Screening ◽

Field Systematic

AbstractBackgroundThe amount of published in vivo studies and the speed researchers are publishing them make it virtually impossible to follow the recent development in the field. Systematic review emerged as a method to summarise and analyse the studies quantitatively and critically but it is often out-of-date due to its lengthy process.MethodWe invited five machine learning and text-mining groups to build classifiers for identifying publications relevant to neuropathic pain (33814 training publications). We kept 1188 publications for the assessment of the performance of different classifiers. Two groups participated in the next stage: testing their algorithm on datasets labeled for psychosis (11777/2944) and datasets labeled for Vitamin D in multiple sclerosis (train/text: 2038/510).ResultThe performances (sensitive/specificity) of the most promising classifier built for neuropathic pain are: 95%/84%. The performance for psychosis and Vitamin D in multiple sclerosis datasets are 95%/73% and 100%/45%.ConclusionsMachine learning can significantly reduce the irrelevant publications in a systematic review, and save the scientists’ time and money. Classifier algorithms built for one dataset can be reapplied on another dataset in different field. We are building a machine learning service at the back of Systematic Review & Meta-analysis Facility (SyRF).

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