Grey Matter Atrophy and its Relationship with White Matter Lesions in Patients with Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease, Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis.

OBJECTIVE: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease. METHODS: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported. RESULTS: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation. INTERPRETATION: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024.

Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

Pushing MP2RAGE boundaries: Ultimate time-efficient parameterization combined with exhaustive T1 synthetic contrasts.

PURPOSE: MP2RAGE parameter optimization is redefined to allow more time-efficient MR acquisitions, whereas the T1 -based synthetic imaging framework is used to obtain on-demand T1 -weighted contrasts. Our aim was to validate this concept on healthy volunteers and patients with multiple sclerosis, using plug-and-play parallel-transmission brain imaging at 7 T. METHODS: A "time-efficient" MP2RAGE sequence was designed with optimized parameters including TI and TR set as small as possible. Extended phase graph formalism was used to set flip-angle values to maximize the gray-to-white-matter contrast-to-noise ratio (CNR). Several synthetic contrasts (UNI, EDGE, FGATIR, FLAWSMIN , FLAWSHCO ) were generated online based on the acquired T1 maps. Experimental validation was performed on 4 healthy volunteers at various spatial resolutions. Clinical applicability was evaluated on 6 patients with multiple sclerosis, scanned with both time-efficient and conventional MP2RAGE parameterizations. RESULTS: The proposed time-efficient MP2RAGE protocols reduced acquisition time by 40%, 30%, and 19% for brain imaging at (1 mm)3 , (0.80 mm)3 and (0.65 mm)3 , respectively, when compared with conventional parameterizations. They also provided all synthetic contrasts and comparable contrast-to-noise ratio on UNI images. The flexibility in parameter selection allowed us to obtain a whole-brain (0.45 mm)3 acquisition in 19 min 56 s. On patients with multiple sclerosis, a (0.67 mm)3 time-efficient acquisition enhanced cortical lesion visualization compared with a conventional (0.80 mm)3 protocol, while decreasing the scan time by 15%. CONCLUSION: The proposed optimization, associated with T1 -based synthetic contrasts, enabled substantial decrease of the acquisition time or higher spatial resolution scans for a given time budget, while generating all typical brain contrasts derived from MP2RAGE.

Positron Emission Tomography with [18 F]-DPA-714 Unveils a Smoldering Component in Most Multiple Sclerosis Lesions which Drives Disease Progression.

OBJECTIVE: To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa-translocator-protein-positron emission tomography (PET) -based classification of each lesion according to innate immune cell content and localization. We assessed the respective predictive value of lesion phenotype and diffuse inflammation on atrophy and disability progression over 2 years. METHODS: Thirty-six people with MS (disease duration 9 ± 6 years; 12 with relapsing-remitting, 13 with secondary-progressive, and 11 with primary-progressive) and 19 healthy controls (HCs) underwent a dynamic [18 F]-DPA-714-PET. At baseline and after 2 years, the patients also underwent a magnetic resonance imaging (MRI) and neurological examination. Based on a threshold of significant inflammation defined by a comparison of [18 F]-DPA-714 binding between patients with MS and HCs, white matter lesions were classified as homogeneously active (active center), rim-active (inactive center and active periphery), or nonactive. Longitudinal cortical atrophy was measured using Jacobian integration. RESULTS: Patients with MS had higher innate inflammation in normal-appearing white matter (NAWM) and cortex than HCs (respective standardized effect size = 1.15, 0.89, p = 0.003 and < 0.001). Out of 1,335 non-gadolinium-enhancing lesions, 53% were classified as homogeneously-active (median = 17 per patient with MS), 6% rim-active (median = 1 per patient with MS), and 41% non-active (median = 14 per patient with MS). The number of homogenously-active lesions was the strongest predictor of longitudinal changes, associating with cortical atrophy (ß = 0.49, p = 0.023) and Expanded Disability Status Scale (EDSS) changes (ß = 0.35, p = 0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes. INTERPRETATION: The [18 F]-DPA-714-PET revealed that an unexpectedly high proportion of MS lesions have a smoldering component, which predicts atrophy and clinical progression. This suggests that following the acute phase, most lesions develop a chronic inflammatory component, promoting neurodegeneration and clinical progression. ANN NEUROL 2023;94:366-383.

Clinical correlates of respiratory disorders in patients with severe multiple sclerosis: A cross-sectional cohort.

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.

The COVID-19 pandemic and neurology: A survey on previous and continued restrictions for clinical practice, curricular training, and health economics.

BACKGROUND AND PURPOSE: The COVID-19 pandemic has significantly impacted health systems worldwide. Here, we assessed the pandemic's impact on clinical service, curricular training, and financial burden from a neurological viewpoint during the enforced lockdown periods and the assumed recovery by 2023. METHODS: An online 18-item survey was conducted by the European Academy of Neurology (EAN) NeuroCOVID-19 Task Force among the EAN community. The survey was online between February and March 2023. Questions related to general, demographic, clinical, work, education, and economic aspects. RESULTS: We collected 430 responses from 79 countries. Most health care professionals were aged 35-44 years, with >15 years of work experience. The key findings of their observations were as follows. (i) Clinical services were cut back in all neurological subspecialties during the most restrictive COVID-19 lockdown period. The most affected neurological subspecialties were services for patients with dementia, and neuromuscular and movement disorders. The levels of reduction and the pace of recovery were distinct for acute emergencies and in- and outpatient care. Recovery was slow for sleep medicine, autonomic nervous system disorders, neurorehabilitation, and dementia care. (ii) Student and residency rotations and grand rounds were reorganized, and congresses were converted into a virtual format. Conferences are partly maintained in a hybrid format. (iii) Affordability of neurological care and medication shortage are emerging issues. CONCLUSIONS: Recovery of neurological services up to spring 2023 has been incomplete following substantial disruption of neurological care, medical education, and health economics in the wake of the COVID-19 pandemic. The continued limitations for the delivery of neurological care threaten brain health and call for action on a global scale.

Periventricular remyelination failure in multiple sclerosis: a substrate for neurodegeneration.

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 lesions with cortical areas is a key mechanism contributing to cortical damage in multiple sclerosis.

Clinical and MRI measures to identify non-acute MOG-antibody disease in adults.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice.

Clinically relevant profiles of myelin content changes in patients with multiple sclerosis: A multimodal and multicompartment imaging study.

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 [11C]PiB-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.

Lessons learned from people with neurological diseases at the time of COVID-19: The EFNA-EAN survey.

BACKGROUND AND PURPOSE: The European Federation of Neurological Associations (EFNA), in partnership with the NeuroCOVID-19 taskforce of the European Academy of Neurology (EAN), has investigated the impact of the first wave of the COVID-19 pandemic on individuals with neurological diseases, as well as the hopes and fears of these patients about the post-pandemic phase. METHODS: An EFNA-EAN survey was available online to any person living with a neurological disorder in Europe. It consisted of 18 items concerning the impact of the first wave of the COVID-19 pandemic on the medical care of people with neurological disorders, and the hopes and fears of these individuals regarding the post-pandemic phase. RESULTS: For 44.4% of the 443 survey participants, the overall care of their neurological disease during the pandemic was inappropriate. This perception was mainly due to significant delays in accessing medical care (25.7%), insufficiently reliable information received about the potential impact of COVID-19 on their neurological disease (49.6%), and a substantial lack of involvement in their disease management decisions (54.3%). Participants indicated that their major concerns for the post-pandemic phase were experiencing longer waiting times to see a specialist (24.1%), suffering from social isolation and deteriorating mental well-being (23.1%), and facing delays in clinical trials with disinvestment in neuroscience research (13.1%). CONCLUSIONS: Despite the great efforts of health services to cope with the first wave of the COVID-19 pandemic, individuals with neurological conditions feel they have been left behind. These findings provide invaluable insights for improving the care of patients with neurological disorders in the further course of the COVID-19 pandemic.

Spontaneous remyelination in lesions protects the integrity of surrounding tissues over time in multiple sclerosis.

BACKGROUND AND PURPOSE: Lesion remyelination preserves axonal integrity in animal models of multiple sclerosis (MS), but an in vivo demonstration of its protective effect on surrounding tissues in humans is lacking. METHODS: Nineteen persons with MS were enrolled in a cohort study and underwent two positron emission tomography (PET)/magnetic resonance imaging (MRI) scans 1-4 months apart. Voxelwise maps of Pittsburgh compound B distribution volume ratio, reflecting myelin content, were used to calculate an index of baseline demyelination, and of dynamic demyelination and remyelination over the follow-up in 549 single white matter lesions. Changes in fractional anisotropy and mean diffusivity, reflecting microstructural damage, were calculated in the proximal and distal 3-mm-thick rings surrounding each lesion, and used to classify perilesional microstructure as "preserved" or "worsening" over the follow-up. Mixed-effect linear models and logistic regressions were employed to investigate whether PET-derived lesional indices were associated with changes in MRI metrics in perilesions, and to identify which of them best predicted the microstructural evolution of perilesions over time. RESULTS: A higher index of remyelination, and a lower index of baseline and dynamic demyelination in lesions were associated with a less severe microstructural deterioration of the corresponding proximal and distal perilesions over time (p-value range: <0.001-0.012), but the index of remyelination was the best predicting variable of perilesional fate. For every extra 1% of remyelination within each lesion, the probability of the corresponding perilesional microstructure remaining preserved over time increased by 39% (odds ratio = 6.62, 95% confidence interval = 2.16-20.32, p < 0.001). CONCLUSIONS: Intralesional remyelination is associated with the microstructural preservation of surrounding tissues, possibly preventing neuroaxonal damage resulting from Wallerian degeneration.

COVID-19 vaccination hesitancy among people with chronic neurological disorders: A position paper.

BACKGROUND AND PURPOSE: Health risks associated with SARS-CoV-2 infection are undisputed. Moreover, the capability of vaccination to prevent symptomatic, severe, and fatal COVID-19 is recognized. There is also early evidence that vaccination can reduce the chance for long COVID-19. Nonetheless, the willingness to get vaccinated and receive booster shots remains subpar among people with neurologic disorders. Vaccine scepticism not only jeopardizes collective efforts to end the COVID-19 pandemic but puts individual lives at risk, as some chronic neurologic diseases are associated with a higher risk for an unfavorable COVID-19 course. METHODS: In this position paper, the NeuroCOVID-19 Task Force of the European Academy of Neurology (EAN) summarizes the current knowledge on the prognosis of COVID-19 among patients with neurologic disease, elucidates potential barriers to vaccination coverage, and formulates strategies to overcome vaccination hesitancy. A survey among the Task Force members on the phenomenon of vaccination hesitancy among people with neurologic disease supports the lines of argumentation. RESULTS: The study revealed that people with multiple sclerosis and other nervous system autoimmune disorders are most skeptical of SARS-CoV-2 vaccination. The prevailing concerns included the chance of worsening the pre-existing neurological condition, vaccination-related adverse events, and drug interaction. CONCLUSIONS: The EAN NeuroCOVID-19 Task Force reinforces the key role of neurologists as advocates of COVID-19 vaccination. Neurologists need to argue in the interest of their patients about the overwhelming individual and global benefits of COVID-19 vaccination. Moreover, they need to keep on eye on this vulnerable patient group, its concerns, and the emergence of potential safety signals.

Choroid Plexus Enlargement in Inflammatory Multiple Sclerosis: 3.0-T MRI and Translocator Protein PET Evaluation.

Background Choroid plexuses (CPs) have been suggested as a key gateway for inflammation in experimental autoimmune encephalitis, but in vivo evidence of their involvement in multiple sclerosis (MS) is lacking. Purpose To assess CP volumetric and inflammatory changes in patients with MS versus healthy control participants. Materials and Methods This was a secondary analysis of 97 patients (61 with relapsing-remitting MS [RRMS] and 36 with progressive MS) and 44 healthy control participants who participated in three prospective 3.0-T brain MRI studies between May 2009 and September 2017. A subgroup of 37 patients and 19 healthy control participants also underwent translocator protein fluorine 18 (18F)-DPA-714 PET for neuroinflammation. Relapses and disability scores were collected at baseline and over 2 years. CPs were manually segmented on three-dimensional T1-weighted images; other brain volumes were additionally segmented. Volumes were expressed as a ratio of intracranial volume. The 18F-DPA-714 distribution volume ratio was quantified in parenchymal regions, whereas standardized uptake value was used for CP inflammation. Multivariable linear regression analyses were performed to assess CP volumetric and inflammatory differences between patients with MS and healthy control participants and correlations between CP volume and lesion load, brain volumes, 18F-DPA-714 uptake, and annualized relapse rate. Results Ninety-seven patients with MS (mean age, 42 years ± 12 [standard deviation]; 49 women) and 44 healthy control participants (mean age, 39 years ± 14; 23 women) underwent MRI. Thirty-seven patients with MS and 19 healthy control participants underwent PET. CPs were 35% larger in patients with MS (mean value, 15.9 × 10-4 ± 4.5) than in healthy control participants (mean value, 11.8 × 10-4 ± 3.8; P = .004). Subgroup analysis confirmed greater CP volume in patients with RRMS (mean value, 15.5 × 10-4 ± 4.6; P = .008) than in healthy control participants. CP enlargement was greater in patients with active lesions at MRI (mean volume, 18.2 × 10-4 ± 4.9 in patients with lesions that enhanced with gadolinium vs 14.9 × 10-4 ± 4 in patients with lesions that did not enhance with gadolinium; P < .001) and correlated with white matter lesion load (r = 0.39; 95% CI: 0.20, 0.55; P < .001) and 18F-DPA-714 binding in the thalami (r = 0.44; 95% CI: 0.22, 0.72; P = .04) and normal-appearing white matter (r = 0.5; 95% CI: 0.20, 0.71; P = .005). Moreover, it correlated with annualized relapse rate in patients with RRMS (r = 0.37; 95% CI: 0.1, 0.55; P = .005). Finally, patients with MS showed 18.5% higher CP 18F-DPA-714 uptake than control participants (mean value, 0.778 ± 0.23 vs 0.635 ± 0.15, respectively; P = .01). CP volume in patients with RRMS (r = 0.57; 95% CI: 0.37, 0.73; P = .009) correlated with higher 18F-DPA-714 uptake. Conclusion Choroid plexuses (CPs) are enlarged and inflamed in patients with multiple sclerosis (MS), particularly in those with relapsing-remitting MS with inflammatory profiles; CP volumetric analysis could represent an MS imaging marker. © RSNA, 2021 EudraCT no. 2008-004174-40; clinical trial registration nos. NCT02305264 and NCT01651520 Online supplemental material is available for this article.

Thalamic energy dysfunction is associated with thalamo-cortical tract damage in multiple sclerosis: A diffusion spectroscopy study.

BACKGROUND: Diffusion-weighted 1H magnetic resonance spectroscopy (DW-MRS) allows to quantify creatine-phosphocreatine brain diffusivity (ADC(tCr)), whose reduction in multiple sclerosis (MS) has been proposed as a proxy of energy dysfunction. OBJECTIVE: To investigate whether thalamic ADC(tCr) changes are associated with thalamo-cortical tract damage in MS. METHODS: Twenty patients with MS and 13 healthy controls (HC) were enrolled in a DW-MRS and DW imaging (DWI) study. From DW-MRS, ADC(tCr) and total N-acetyl-aspartate diffusivity (ADC(tNAA)) were extracted in the thalami. Three thalamo-cortical tracts and one non-thalamic control tract were reconstructed from DWI. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD), reflecting microstructural integrity, were extracted for each tract. Associations between thalamic ADC(tCr) and tract metrics were assessed using linear regression models adjusting for age, sex, thalamic volume, thalamic ADC(tNAA), and tract-specific lesion load. RESULTS: Lower thalamic ADC(tCr) was associated with higher MD and RD of thalamo-cortical projections in MS (MD: p = 0.029; RD: p = 0.017), but not in HC (MD: p = 0.625, interaction term between thalamic ADC(tCr) and group = 0.019; RD: p = 0.320, interaction term = 0.05). Thalamic ADC(tCr) was not associated with microstructural changes of the control tract. CONCLUSION: Reduced thalamic ADC(tCr) correlates with thalamo-cortical tract damage in MS, showing that pathologic changes in thalamic energy metabolism are associated with structural degeneration of connected fibers.

Human papillomavirus lesions in 16 MS patients treated with fingolimod: Outcomes and vaccination.

Few cases of human papillomavirus (HPV) diseases have been reported in multiple sclerosis (MS) patients treated with fingolimod. We describe a case series of 16 MS patients (11 women, 5 men) developing HPV lesions after the onset of fingolimod, without previous HPV history. Fingolimod had to be discontinued in six patients. Six patients received vaccination for HPV, with good tolerance. Our report highlights that systematic HPV screening and discussion about HPV vaccination before fingolimod onset are crucial. In case of occurrence of HPV lesions during fingolimod treatment, a comprehensive workup of HPV disease is necessary, with discussion of HPV vaccination to prevent secondary lesions. Prevalence studies of HPV lesions are needed in MS patients with the different disease-modifying therapies.

A plea for equitable global access to COVID-19 diagnostics, vaccination and therapy: The NeuroCOVID-19 Task Force of the European Academy of Neurology.

Coronavirus disease 2019 (COVID-19), a multi-organ disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to challenge health and care systems around the globe. The pandemic has disrupted acute neurology services and routine patient care and has impacted the clinical course in patients with chronic neurological disease. COVID-19 appears to have exposed inequalities of societies and healthcare systems and had a disproportionate impact on already vulnerable communities. The next challenge will be to set up initiatives to stop disparities in all aspects related to COVID-19. From the medical perspective, there is a need to consider inequalities in prevention, treatment and long-term consequences. Some of the issues of direct relevance to neurologists are summarised. With this appraisal, the European Academy of Neurology NeuroCOVID-19 Task Force intends to raise awareness of the potential impact of COVID-19 on inequalities in healthcare and calls for action to prevent disparity at individual, national and supranational levels.

Predicting PET-derived myelin content from multisequence MRI for individual longitudinal analysis in multiple sclerosis.

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 [11C]PIB 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 [11C]PIB 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.

Repurposing radiotracers for myelin imaging: a study comparing 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol,11C-MeDAS, and 11C-PiB.

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 11C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as 11C-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 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol, 11C-MeDAS, and 11C-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 18F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90 min (SUVR75-90), 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, 18F-florbetapir had the highest SUVR75-90 (1.38 ± 0.03), followed by 18F-flutemetamol (1.34 ± 0.02), 18F-florbetaben (1.32 ± 0.07), 11C-MeDAS (1.27 ± 0.04), and 11C-PiB (1.25 ± 0.07). With regard to BP, 18F-florbetaben had the highest value (0.32 ± 0.06) compared with 18F-flutemetamol (0.20 ± 0.03), 11C-MeDAS (0.17 ± 0.03), and 11C-PiB (0.16 ± 0.03). No difference in DVR was detected between 18F-florbetaben (1.26 ± 0.06) and 18F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than 18F-flutemetamol (1.17 ± 0.02), 11C-MeDAS (1.16 ± 0.03), and 11C-PiB (1.14 ± 0.02). CONCLUSIONS: Given their higher binding and longer half-life, our study indicates that 18F-florbetapir and 18F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.

Dysregulation of energy metabolism in multiple sclerosis measured in vivo with diffusion-weighted spectroscopy.

OBJECTIVE: We employed diffusion-weighted magnetic resonance spectroscopy (DW-MRS), which allows to measure in vivo the diffusion properties of metabolites, to explore the functional neuro-axonal damage and the ongoing energetic dysregulation in multiple sclerosis (MS). METHODS: Twenty-five patients with MS and 18 healthy controls (HC) underwent conventional magnetic resonance imaging (MRI) and DW-MRS. The apparent diffusion coefficient (ADC) of total N-acetyl-aspartate (tNAA) and creatine-phosphocreatine (tCr) were measured in the parietal normal-appearing white matter (NAWM) and in the thalamic grey matter (TGM). Multiple regressions were used to compare metabolite ADCs between groups and to explore clinical correlations. RESULTS: In patients compared with HCs, we found a reduction in ADC(tNAA) in the TGM, reflecting functional and structural neuro-axonal damage, and in ADC(tCr) in both NAWM and TGM, possibly reflecting a reduction in energy supply in neurons and glial cells. Metabolite ADCs did not correlate with tissue atrophy, lesional volume or metabolite concentrations, while in TGM metabolite ADCs correlated with clinical scores. CONCLUSION: DW-MRS showed a reduction in tCr diffusivity in the normal-appearing brain of patients with MS, which might reflect a state of ongoing energy dysregulation affecting neurons and/or glial cells. Reversing this energy dysregulation before neuro-axonal degeneration arises may become a key objective in future neuroprotective strategies.

Imaging markers of multiple sclerosis prognosis.

PURPOSE OF REVIEW: Studies of large longitudinal cohorts of patients with multiple sclerosis (MS) have emphasized the prognostic value of conventional MRI markers, at least during early stages. Advanced imaging metrics derived from quantitative MRI and PET provide relevant information about microstructural damage within and outside visible lesions that may be more sensitive to predict long-term disability. Here, we summarize the most recent findings regarding the prognostic value of imaging markers throughout MS stages. RECENT FINDINGS: In clinically isolated syndrome, the presence of at least one brain or spinal cord T2 lesion strongly increases the risk of conversion to clinically definite MS (hazard ratio ranging from 5 to 11). Similarly, the occurrence of new white matter lesions is strongly predictive of subsequent relapse rate and response to current disease modifying therapies. Beyond white matter lesions, volumetric changes in the grey matter and normal-appearing tissue damage are more sensitive prognostic markers for physical and cognitive disability, especially in progressive MS. SUMMARY: Although white matter lesion number and volume still remains the imaging metric used in daily clinical practice, further development of advanced imaging predictors of long-term disability should allow a better stratification of patients in future clinical trials aimed at promoting repair or neuroprotection.