Kantarci, Orhun H.

AbstractBeing a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P < 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48–52) and controls (median, interquartile range: 51 years, 49–53) (P = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) (P = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1–3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) (P = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (R2 = 0.359, P < 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) (P = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1–3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R2 = 0.229, P < 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.

AbstractBackgroundWhile β‐amyloid and tau PET imaging are widely studied in cognitive aging and Alzheimer’s disease (AD), little is known about findings in aging multiple sclerosis (MS) patients. As aging is an essential factor in developing neurodegeneration in MS, β‐amyloid and tau biomarkers may be utilized to understand the influence of AD pathophysiology on cognitive aging in MS.MethodWe studied 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 Pittsburgh compound‐B (PiB) PET imaging. Twelve of the 16 patients with MS and 60 matching controls also underwent flortaucipir (AV1451) tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVr) from previously determined AD signature regions and from the entire cortex were calculated for group comparisons and testing for associations with age.ResultAD signature PiB SUVr (p=0.044), total cortical PiB SUVr (p=0.048) and the frequency of abnormal PiB SUVrs (p=0.040) were lower in patients with 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 (p=0.041) in patients with MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls (Figure 1). The AD signature PiB SUVr increased more with increasing AD signature AV1451 SUVr in controls than in patients with MS (p=0.03) (Figure 2).ConclusionIn patients with MS, cortical β‐amyloid deposition was lower than age‐matched controls, while cortical tau deposition was not different between the groups. This suggests that some aspect of MS pathobiology retards the accumulation of β‐amyloid, but not the accumulation of tau.

The recent expansion of the radiological criteria and the use of a highly specific biomarker, anti-aquaporin 4-IgG (AQP4 IgG), has significantly improved the ability of clinicians to provide a timely and accurate diagnosis for neuromyelitis optica spectrum disorder (NMOSD), especially when faced with an abnormal disease presentation. Here, we report on the 5-year clinical experience of a 69-year-old right-handed African American woman who initially presented following symptoms suggestive of transient global amnesia. Her clinical history was only remarkable for a single episode of visual decline with poor recovery experienced 35 years prior, with prior unrevealing serological investigations. Brain MRI features were significant for diffuse, bilateral white matter abnormalities throughout the supratentorial, deep gray matter, and infratentorial regions. Spinal cord imaging studies were within normal limits with no intramedullary high-signal abnormalities identified. Serological studies were significant for the presence of anti-aquaporin 4-IgG. The clinical features were supportive of the diagnosis of NMOSD. The data provided here highlight both the clinical and radiological heterogeneity of NMOSD.

Background: New inflammatory activity is of unclear frequency and clinical significance in progressive multiple sclerosis (MS); it is uncertain in patient cohorts with motor progression due to critical demyelinating lesions. Objectives: The aim of this study is to determine the likelihood of central nervous system (CNS) inflammatory activity, assessed by new clinical relapses or active magnetic resonance imaging (MRI) lesions, following onset of motor progression due to critical demyelinating lesions. Methods: Patients with progressive upper motor neuron impairment for ⩾1 year attributable to critical demyelinating lesions with single CNS lesion (progressive solitary sclerosis (PSS)), 2 to 5 total CNS demyelinating lesions (progressive “pauci-sclerosis” (PPS)), or >5 CNS demyelinating lesions and progressive exclusively unilateral monoparesis or hemiparesis (PUHMS) were identified. Clinical data were reviewed for acute MS relapses, and subsequent MRI was reviewed for active T1-gadolinium-enhancing or T2-demyelinating lesions. Results: None of the 91 patients (22 PSS, 40 PPS, 29 PUHMS) identified experienced clinical relapses over a median clinical follow-up of 93 months (range: 12–518 months). Nine patients (10%) developed active lesions over median 84 months radiologic follow-up (range: 12–518 months). Active lesions occurred in 24% PUHMS, 5% PSS, and 3% PPS cohorts. Conclusion: New inflammatory activity, defined by active lesions and clinical relapses following motor progression in patients with critical demyelinating lesions, is low. Disease-modifying therapies that reduce demyelinating relapses and active MRI lesions are of uncertain benefit in these cohorts.

Objective: To compare progressive motor impairment onset attributable to a “critical” central nervous system (CNS) demyelinating lesion in patients with highly restricted versus unlimited magnetic resonance imaging (MRI) lesion burden. Methods: We identified 135 patients with progressive motor impairment for ⩾1 year attributable to a “critical” demyelinating lesion with: MRI burden of 1 lesion (“progressive solitary sclerosis”), 2–5 lesions (“progressive paucisclerosis”), or unrestricted (>5) lesions and “progressive unilateral hemiparesis.” Neuroradiology review of brain and spinal cord MRI documented unequivocally demyelinating lesions. Results: A total of 33 (24.4%) patients had progressive solitary sclerosis; 56 (41.5%) patients had progressive paucisclerosis; and 46 (34.1%) patients had progressive unilateral hemiparesis. Median age at onset of progressive motor impairment was younger in progressive solitary sclerosis (49 years; range 24–73) and progressive paucisclerosis (50 years; range 30–64) than in progressive unilateral hemiparesis (54 years; range 39–77; p = 0.02 and p = 0.003, respectively). Within progressive unilateral hemiparesis, motor-progression onset was similar between those with 4–10, 11–20, or >20 brain lesions (55, 54, 53 years of age, respectively; p = 0.44). Conclusion: Motor-progression age is similar, but paradoxically earlier, in cohorts with highly restricted CNS lesion burden than in those with unrestricted lesion burden with progressive unilateral hemiparetic MS. The “critical” demyelinating lesion rather than total brain MRI lesion burden is the major contributor to motor-progression onset in these cohorts.

Background: Progressive motor impairment anatomically attributable to prominent, focally atrophic lateral column spinal cord lesions (“critical lesions”) can be seen in multiple sclerosis (MS), for example, progressive hemiparetic MS. Objective: The aim of this study was to investigate whether similar spinal cord lesions are more frequent in long-standing MS patients with secondary progressive motor impairment (secondary progressive MS (SPMS)) versus those maintaining a relapsing-remitting course (relapsing-remitting MS (RRMS)). Methods: We retrospectively identified Olmsted County (MN, USA) residents on 31 December 2011 with (1) RRMS or SPMS for ⩾25 years, and (2) available brain and spine magnetic resonance imaging (MRI). A blinded neuroradiologist determined demyelinating lesion burden and presence of potential critical lesions (prominent focally atrophic spinal cord lateral column lesions). Results: In total, 32 patients were included: RRMS, 18; SPMS, 14. Median (range) disease duration (34 (27–53) vs. 39 (29–47) years) and relapse number (4 (1–10) vs. 3 (1–15)) were similar. In comparison to RRMS, SPMS patients more commonly showed potential critical spinal cord lesions (8/18 (44%) vs. 14/14 (100%)), higher spinal cord (median (range) 4 (1–7) vs. 7.5 (3–12)), and brain infratentorial (median (range) 1 (0–12) vs. 2.5 (1–13)) lesion number; p < 0.05. By multivariate analysis, only the presence of potential critical lesions independently associated with motor progression ( p = 0.02). Conclusion: Critical spinal cord lesions may be important contributors to motor progression in MS.

Objective We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5‐year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. Here, we investigate risk factors for the development of a clinical event using a 10‐year, multinational, retrospectively identified RIS dataset. Methods RIS subjects were identified according to 2009 RIS criteria and followed longitudinally as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and magnetic resonance imaging (MRI) characteristics and the risk of developing a first clinical event were determined using multivariate Cox regression models. Results Additional follow‐up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11–74 years), with a median clinical follow‐up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium‐enhanced lesions during follow‐up was also associated with the risk of a seminal event. The reason for MRI and gadolinium‐enhancing lesions at baseline did not influence the risk of a subsequent clinical event. Interpretation Approximately half of all individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS. ANN NEUROL 2020;88:407–417.

ObjectiveTo 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.MethodsPatients with MS (n = 16) and controls (n = 80) matched for age, sex, andAPOEε4 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.ResultsAD 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.InterpretationAlthough 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