2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Multiple-Sclerosis

In multiple sclerosis, spontaneous remyelination is generally incomplete and heterogeneous across patients. A high heterogeneity in remyelination may also exist across lesions within the same individual, suggesting the presence of local factors interfering with myelin regeneration. In this study we explored in vivo the regional distribution of myelin repair and investigated its relationship with neurodegeneration. We first took advantage of the myelin binding property of the amyloid radiotracer 11C-PiB to conduct a longitudinal 11C-PiB PET study in an original cohort of 19 participants with a relapsing-remitting form of multiple sclerosis, followed-up over a period of 1-4 months. We then replicated our results on an independent cohort of 40 people with multiple sclerosis followed-up over 1 year with magnetization transfer imaging, an MRI metrics sensitive to myelin content. For each imaging method, voxel-wise maps of myelin content changes were generated according to modality-specific thresholds. We demonstrated a selective failure of remyelination in periventricular white matter lesions of people with multiple sclerosis in both cohorts. In both the original and the replication cohort, we estimated that the probability of demyelinated voxels to remyelinate over the follow-up increased significantly as a function of the distance from ventricular CSF. Enlarged choroid plexus, a recently discovered biomarker linked to neuroinflammation, was found to be associated with the periventricular failure of remyelination in the two cohorts (r = -0.79, P = 0.0018; r = -0.40, P = 0.045, respectively), suggesting a role of the brain-CSF barrier in affecting myelin repair in surrounding tissues. In both cohorts, the failure of remyelination in periventricular white matter lesions was associated with lower thalamic volume (r = 0.86, P < 0.0001; r = 0.33; P = 0.069, respectively), an imaging marker of neurodegeneration. Interestingly, we also showed an association between the periventricular failure of remyelination and regional cortical atrophy that was mediated by the number of cortex-derived tracts passing through periventricular white matter lesions, especially in patients at the relapsing-remitting stage. Our findings demonstrate that lesion proximity to ventricles is associated with a failure of myelin repair and support the hypothesis that a selective periventricular remyelination failure in combination with the large number of tracts connecting periventricular lesi

Topics: Aniline Compounds; Brain; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Myelin Sheath; Remyelination; Thiazoles; White Matter

PET imaging with β-amyloid ligands is emerging as a molecular imaging technique targeting white matter integrity and demyelination. β-amyloid PET ligands such as

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Humans; Middle Aged; Multiple Sclerosis; Positron-Emission Tomography; Thiazoles; White Matter

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, leading to motor dysfunctions, psychical disability, and cognitive impairment during MS progression. Positron emission tomography (PET) is an imaging technique able to quantify in vivo cellular and molecular alterations. Radiotracers with affinity to intact myelin can be used for in vivo imaging of myelin content changes over time. It is possible to detect either an increase or decrease in myelin content, what means this imaging technique can detect demyelination and remyelination processes of the central nervous system. In this protocol we demonstrate how to use PET imaging to detect myelin changes in the lysolecithin rat model, which is a model of focal demyelination lesion (induced by stereotactic injection) (i.e., a model of multiple sclerosis disease).

Topics: Aniline Compounds; Animals; Disease Models, Animal; Image Processing, Computer-Assisted; Lysophosphatidylcholines; Magnetic Resonance Imaging; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Positron-Emission Tomography; Rats; Stereotaxic Techniques; Thiazoles

To investigate β-amyloid and tau depositions using Pittsburgh compound B (PiB) positron emission tomography (PET) and AV1451 tau PET imaging in aging multiple sclerosis (MS) patients.. Patients with MS (n = 16) and controls (n = 80) matched for age, sex, and APOE ε4 status from the population-based Mayo Clinic Study of Aging who underwent PiB PET imaging were studied. Of these individuals, 12 patients with MS and 60 matching controls also underwent AV1451 tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVrs) from the entire cortex and previously determined Alzheimer disease (AD) signature regions in the same population were calculated for group comparisons and testing for associations with age.. AD signature PiB SUVr (odds ratio [OR] [95% confidence interval (CI)] = 0.52 [0.27-0.98], p = 0.044), total cortical PiB SUVr (OR [95% CI] = 0.52 [0.28-0.99], p = 0.048), and the frequency of abnormal PiB SUVrs (OR [95% CI] = 0.10 [0.01-0.90], p = 0.040) were lower in MS than controls. Although AD-signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (OR [95% CI] = 10.65 [1.10-103.35], p = 0.041) in MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.14 [-0.023 to -0.006], p = 0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.13 [-0.021 to -0.005], p = 0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls.. Although both β-amyloid and tau are biomarkers of cognitive aging and AD, cortical β-amyloid deposition was lower in MS than age-matched controls, suggesting that some aspect of MS pathobiology retards the accumulation of β-amyloid but not the accumulation of tau. ANN NEUROL 2020;87:556-567.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Carbolines; Case-Control Studies; Cerebral Cortex; Contrast Media; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Odds Ratio; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Thiazoles

Cerebrospinal fluid (CSF) plays an important role in solute clearance and maintenance of brain homeostasis.

Topics: Adult; Aged; Algorithms; Alzheimer Disease; Aniline Compounds; Area Under Curve; Brain; Case-Control Studies; Cerebrospinal Fluid; Cognitive Dysfunction; Databases, Factual; Female; Homeostasis; Humans; Kinetics; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Thiazoles

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [

Topics: Aniline Compounds; Animals; Autoradiography; Brain Edema; Carbon Radioisotopes; Cerebral Ventricles; Corpus Callosum; Corpus Striatum; Demyelinating Diseases; Dilatation, Pathologic; Disease Models, Animal; Ethylene Glycols; False Positive Reactions; Fluorine Radioisotopes; Image Processing, Computer-Assisted; Injections; Lysophosphatidylcholines; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Myelin Sheath; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Thiazoles

There is growing interest in white matter (WM) imaging with positron emission tomography (PET).. We studied the association of cognitive function in late multiple sclerosis (MS) with cortical and WM Pittsburgh compound-B PET (PiB-PET) binding.. In the population-based Mayo Clinic Study of Aging, 24 of 4869 participants had MS (12 underwent PiB-PET). Controls were age and sex matched (5:1). We used automated or semi-automated processing for quantitative image analyses and conditional logistic regression for group differences.. MS patients had lower memory ( p = 0.03) and language ( p = 0.02) performance; smaller thalamic volumes ( p = 0.003); and thinner temporal ( p = 0.001) and frontal ( p = 0.045) cortices on magnetic resonance imaging (MRI) than controls. There was no difference in global cortical PiB standardized uptake value ratios between MS and controls ( p = 0.35). PiB uptake was lower in areas of WM hyperintensities compared to normal-appearing white matter (NAWM) in MS ( p = 0.0002). Reduced PiB uptake in both the areas of WM hyperintensities ( r = 0.65; p = 0.02) and NAWM ( r = 0.69; p = 0.01) was associated with decreased visuospatial performance in MS.. PiB uptake in the cortex in late MS is not different from normal age-matched controls. PiB uptake in the WM in late MS may be a marker of the large network structures' integrity such as those involved in visuospatial performance.

Topics: Aged; Aging; Aniline Compounds; Brain; Cognition; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles; White Matter

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Humans; Multiple Sclerosis; Positron-Emission Tomography; Thiazoles; White Matter

In this study, we compared the ability of [(11)C]CIC, [(11)C]MeDAS and [(11)C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake.. Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group).. The kinetics of [(11)C]CIC, [(11)C]MeDAS and [(11)C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [(11)C]CIC make this tracer less suitable for in vivo PET imaging. [(11)C]PIB showed good uptake in the white matter in the cerebrum, but [(11)C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [(11)C]MeDAS distribution correlated well with myelin density in different brain regions.. This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [(11)C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [(11)C]CIC and [(11)C]PIB.

Topics: Aniline Compounds; Animals; Benzothiazoles; Encephalomyelitis, Autoimmune, Experimental; Male; Multiple Sclerosis; Myelin Sheath; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Stilbenes; Thiazoles

Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine-T derivative 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker.. PIB fixation to myelin was studied by fluorescence in the normal and dysmyelinating mouse brain, as well as in the postmortem brain of MS patients. Positron emission tomography (PET) experiments were conducted using [¹¹C]PIB in baboons and in a proof of concept clinical study in 2 MS patients.. Applied directly on tissue sections or after intraperitoneal injection, PIB stained CNS myelin, and the decrease in the level of fixation paralleled the amount of myelin loss in a dysmyelinating mutant. In normally myelinated areas of postmortem MS brain, demyelinated and remyelinated lesions were clearly distinguishable by the differential intensity of labeling observed with PIB. PET using intravenously injected radiolabeled [¹¹C]PIB imaged CNS myelin in baboons and humans. In MS patients, the dynamic analysis of PET acquisitions allowed quantitative assessment of demyelination.. PIB could be used as an imaging marker to quantify myelin loss and repair in demyelinating diseases.

Topics: Aniline Compounds; Animals; Benzothiazoles; Brain; Cadaver; Carbon Radioisotopes; Demyelinating Diseases; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Multiple Sclerosis; Nerve Regeneration; Papio anubis; Positron-Emission Tomography; Thiazoles