7 research outputs found

    The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome

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    The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post‐mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = −0.58, p = 0.009) and age of death (Spearman r = −0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS

    Visualizing Cholesterol in the Brain by On-Tissue Derivatization and Quantitative Mass Spectrometry Imaging.

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    Despite being a critical molecule in the brain, mass spectrometry imaging (MSI) of cholesterol has been under-reported compared to other lipids due to the difficulty in ionizing the sterol molecule. In the present work, we have employed an on-tissue enzyme-assisted derivatization strategy to improve detection of cholesterol in brain tissue sections. We report distribution and levels of cholesterol across specific structures of the mouse brain, in a model of Niemann-Pick type C1 disease, and during brain development. MSI revealed that in the adult mouse, cholesterol is the highest in the pons and medulla and how its distribution changes during development. Cholesterol was significantly reduced in the corpus callosum and other brain regions in the Npc1 null mouse, confirming hypomyelination at the molecular level. Our study demonstrates the potential of MSI to the study of sterols in neuroscience

    Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

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    Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp3 )-acids with labelled CO2. Substrates that are not compatible with transition metal catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabelling of drug molecules and precursors with [11C]CO2 is demonstrated

    Comparing the pathology, clinical and demographic characteristics of younger and older‐onset multiple sclerosis

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    Objective: Older people with multiple sclerosis have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group?Methods: We used data from the UK MS Register to characterise demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≄50 years), compared to adult-onset MS (AOMS; onset 18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n=18, mean age of onset 54 years) versus AOMS (n=23, age of onset 30 years).Results: In the Register cohort there were 1608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of females, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 v 28.3, p<0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease modifying treatment and attained substantial disability sooner.Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whilst actively demyelinating lesions and compartmentalised inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalised inflammation, correlated with disability outcomes in older-onset MS.Interpretation: The more progressive nature of older-onset MS is associated with significant neurodegeneration but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people

    Aldehyde-Catalyzed Carboxylate Exchange in a-Amino Acids with Isotopically Labeled CO2

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    a-Amino acids are among the essential chemical building blocks of life. These structures are embedded in many small molecule pharmaceuticals and are the primary components of peptide-based therapeutics and biologics. Isotopically labeled a-amino acids and their derivatives have widespread use in structural and mechanistic biochemistry, quantitative proteomics, absorption distribution metabolism and excretion (ADME) profiling, and as imaging agents in positron emission tomography (PET) techniques. The preparation of carbon-labeled a-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labeled products and presents a major challenge in 11C applications (11C t1/2 = 20 min). Here we report that simple aldehydes catalyze the isotopic carboxylate exchange of native a-amino acids with *CO2 (* = 14, 13, 11). Proteinogenic a-amino acids and many non-natural variants containing diverse functional groups undergo labeling. The reaction likely proceeds via the trapping of *CO2 by imine-carboxylate intermediates to generate aminomalonates that are prone to monodecarboxylation. Tempering catalyst electrophilicity was key to preventing irreversible aldehyde consumption. The pre-generation of the imine carboxylate intermediate allows for the rapid and late-stage 11C-radiolabeling of a-amino acids in the presence of 11CO2

    The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome

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    The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post-mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10&nbsp;matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r&nbsp;=&nbsp;0.79, p&nbsp;&lt;&nbsp;0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r&nbsp;=&nbsp;-0.58, p&nbsp;=&nbsp;0.009) and age of death (Spearman r&nbsp;=&nbsp;-0.47, p&nbsp;=&nbsp;0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS

    Comparing the pathology, clinical and demographic characteristics of younger and older-onset multiple sclerosis

    No full text
    Objective: Older people with multiple sclerosis have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group? Methods: We used data from the UK MS Register to characterise demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≄50 years), compared to adult-onset MS (AOMS; onset18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n=18, mean age of onset 54 years) versus AOMS (n=23, age of onset 30 years). Results: In the Register cohort there were 1608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of females, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 v 28.3, p&lt;0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whilst actively demyelinating lesions and compartmentalised inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalised inflammation, correlated with disability outcomes in older-onset MS. Interpretation: The more progressive nature of older-onset MS is associated with significant neurodegeneration but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. This article is protected by copyright. All rights reserved
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