Following the impressive progress in the treatment of relapsing-remitting multiple sclerosis (MS), the major challenge ahead is the development of treatments to prevent or delay the irreversible ...accumulation of clinical disability in progressive forms of the disease. The substrate of clinical progression is neuro-axonal degeneration, and a deep understanding of the mechanisms that underlie this process is a precondition for the development of therapies for progressive MS. PET imaging involves the use of radiolabelled compounds that bind to specific cellular and metabolic targets, thereby enabling direct in vivo measurement of several pathological processes. This approach can provide key insights into the clinical relevance of these processes and their chronological sequence during the disease course. In this Review, we focus on the contribution that PET is making to our understanding of extraneuronal and intraneuronal mechanisms that are involved in the pathogenesis of irreversible neuro-axonal damage in MS. We consider the major challenges with the use of PET in MS and the steps necessary to realize clinical benefits of the technique. In addition, we discuss the potential of emerging PET tracers and future applications of existing compounds to facilitate the identification of effective neuroprotective treatments for patients with MS.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Summary The mechanisms underlying the pathogenesis of multiple sclerosis induce the changes that underpin relapse-associated and progressive disability. Disease mechanisms can be investigated in ...preclinical models and patients with multiple sclerosis by molecular and metabolic imaging techniques. Many insights have been gained from such imaging studies: persisting inflammation in the absence of a damaged blood–brain barrier, activated microglia within and beyond lesions, increased mitochondrial activity after acute lesions, raised sodium concentrations in the brain, increased glutamate in acute lesions and normal-appearing white matter, different degrees of demyelination in different patients and lesions, early neuronal damage in grey matter, and early astrocytic proliferation and activation in lesions and white matter. Clinical translation of molecular and metabolic imaging and extension of these techniques will enable the assessment of novel drugs targeted at these disease mechanisms, and have the potential to improve health outcomes through the stratification of patients for treatments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose
Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a ...quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative
11
C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as
11
C-MeDAS, have also been shown to bind to myelin in animals and are considered a promising radiopharmaceutical class for myelin imaging. Fluorinated compounds from both classes are now commercially available and thus should constitute clinically useful myelin radiotracers. The aim of this study is to provide a head-to-head comparison of
18
F-florbetaben,
18
F-florbetapir,
18
F-flutemetamol,
11
C-MeDAS, and
11
C-PiB with regard to brain kinetics and binding in white matter (WM).
Methods
Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for
18
F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90 min (SUVR
75–90
), binding potential (BP) estimated with Logan method with input function, and distribution volume ratio (DVR) estimated with Logan reference method (using cerebellar gray matter as reference region) were calculated in WM and compared between tracers using mixed effect models.
Results
In WM,
18
F-florbetapir had the highest SUVR
75–90
(1.38 ± 0.03), followed by
18
F-flutemetamol (1.34 ± 0.02),
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F-florbetaben (1.32 ± 0.07),
11
C-MeDAS (1.27 ± 0.04), and
11
C-PiB (1.25 ± 0.07). With regard to BP,
18
F-florbetaben had the highest value (0.32 ± 0.06) compared with
18
F-flutemetamol (0.20 ± 0.03),
11
C-MeDAS (0.17 ± 0.03), and
11
C-PiB (0.16 ± 0.03). No difference in DVR was detected between
18
F-florbetaben (1.26 ± 0.06) and
18
F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than
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F-flutemetamol (1.17 ± 0.02),
11
C-MeDAS (1.16 ± 0.03), and
11
C-PiB (1.14 ± 0.02).
Conclusions
Given their higher binding and longer half-life, our study indicates that
18
F-florbetapir and
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F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
5.
Smouldering multiple sclerosis: the ‘real MS’ Giovannoni, Gavin; Popescu, Veronica; Wuerfel, Jens ...
Therapeutic Advances in Neurological Disorders,
01/2022, Volume:
15
Book Review, Journal Article
Peer reviewed
Open access
Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central ...nervous system (CNS). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of ‘no evident inflammatory disease activity’ (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.
Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system (CNS). The demyelination process can be repaired by the generation of a new sheath of myelin around ...the axon, a process termed remyelination. In MS patients, the demyelination–remyelination cycles are highly dynamic. Over the years, magnetic resonance imaging (MRI) has been increasingly used in the diagnosis of MS and it is currently the most useful paraclinical tool to assess this diagnosis. However, conventional MRI pulse sequences are not specific for pathological mechanisms such as demyelination and remyelination. Recently, positron emission tomography (PET) with radiotracer 11CPIB has become a promising tool to measure in-vivo myelin content changes which is essential to push forward our understanding of mechanisms involved in the pathology of MS, and to monitor individual patients in the context of clinical trials focused on repair therapies. However, PET imaging is invasive due to the injection of a radioactive tracer. Moreover, it is an expensive imaging test and not offered in the majority of medical centers in the world. In this work, by using multisequence MRI, we thus propose a method to predict the parametric map of 11CPIB PET, from which we derived the myelin content changes in a longitudinal analysis of patients with MS. The method is based on the proposed conditional flexible self-attention GAN (CF-SAGAN) which is specifically adjusted for high-dimensional medical images and able to capture the relationships between the spatially separated lesional regions during the image synthesis process. Jointly applying the sketch-refinement process and the proposed attention regularization that focuses on the MS lesions, our approach is shown to outperform the state-of-the-art methods qualitatively and quantitatively. Specifically, our method demonstrated a superior performance for the prediction of myelin content at voxel-wise level. More important, our method for the prediction of myelin content changes in patients with MS shows similar clinical correlations to the PET-derived gold standard indicating the potential for clinical management of patients with MS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
Respiratory disorders remain incompletely described in multiple sclerosis (MS), even though they are a frequent cause of death.
Methods:
The objective was to describe respiratory ...disorders in MS patients with Expanded Disability Status Score (EDSS) ⩾ 6.5. Diaphragm dysfunction was defined by at least two of the seven criteria: clinical signs, inspiratory recruitment of neck muscles during wakefulness, reduced upright vital capacity (VC) < 80%, upright-to-supine VC ⩾ 15% of upright VC, decrease in Maximal Inspiratory Pressure < 60%, phasic activation of inspiratory neck muscles during sleep, and opposition of thoracic and abdominal movements during sleep. Cough weakness was defined by a peak cough flow < 270 L/min and/or need for cough assist. Sleep apnea syndrome was defined by an apnea–hypopnea index ⩾ 15.
Results:
Notably, 71 MS patients were included: median age 54 48, 61 years; median disease duration 21.4 16.0, 31.4 years. Of these, 52 patients had one or more respiratory disorders; diaphragm dysfunction was the most frequent (n = 34). Patients with diaphragm dysfunction and cough weakness were more disabled. The fatigue score and the cognitive evaluations did not differ between the groups. Five patients required non-invasive ventilation.
Conclusion:
Respiratory disorders are frequent in severe MS, mostly diaphragm dysfunction. Of interest, instrumental interventions are available to address these disorders.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The 11CPIB PET tracer, originally developed for amyloid imaging, has been recently repurposed to quantify demyelination and remyelination in multiple sclerosis (MS). Myelin PET imaging, however, is ...limited by its low resolution that deteriorates the quantification accuracy of white matter (WM) lesions. Here, we introduce a novel partial volume correction (PVC) method called Multiresolution–Multimodal Resolution-Recovery (MM-RR), which uses the wavelet transform and a synergistic statistical model to exploit MRI structural images to improve the resolution of 11CPIB PET myelin imaging. MM-RR performance was tested on a phantom acquisition and in a dataset comprising 11CPIB PET and MR T1- and T2-weighted images of 8 healthy controls and 20 MS patients. For the control group, the MM-RR PET images showed an average increase of 5.7% in WM uptake while the grey-matter (GM) uptake remained constant, resulting in +31% WM/GM contrast. Furthermore, MM-RR PET binding maps correlated significantly with the mRNA expressions of the most represented proteins in the myelin sheath (R2 = 0.57 ± 0.09). In the patient group, MM-RR PET images showed sharper lesion contours and significant improvement in normal-appearing tissue/WM-lesion contrast compared to standard PET (contrast improvement > +40%). These results were consistent with MM-RR performances in phantom experiments.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Objective:
To investigate the clinical relevance of individual profiles of cortical and white matter lesion myelin content changes combining magnetisation transfer imaging (MTI) and 11C-PiB-positron ...emission tomography (PET) in patients with multiple sclerosis (MS).
Methods:
MTI and 11CPiB-PET acquired in 19 patients with MS followed up over 2–4 months and in seven healthy controls (HCs), were employed to generate individual maps of cortical and white matter (WM) lesion myelin content changes, respectively. These maps were used to calculate individual indices of demyelination and remyelination, and to investigate their association with clinical scores.
Results:
Cortical remyelination ranged between 1% and 5% of the total cortical volume (17%–45% of the cortical volume demyelinated at baseline). WM lesion remyelination ranged between 8% and 22% of the lesional volume. An extensive cortical remyelination was associated with a shorter disease duration (rho = −0.63, p = 0.01) and, in combination with WM lesion remyelination, explained 68%–70% of the variance of clinical scores (p < 0.01).
Conclusion:
Our multimodal and multicompartment approach allows us to explore single-patient cortical and WM lesion demyelination and remyelination, and to generate clinically relevant indices of myelin repair. These indices may be used as outcome measures in clinical trials, thus increasing the chance to identify successful promyelinating treatments in patients with MS.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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