Cognitive phenotypes predict response to restorative cognitive rehabilitation in multiple sclerosis.

BACKGROUND: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis. OBJECTIVE: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR). METHODS: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation. RESULTS: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory. CONCLUSIONS: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall.

Cognitive progression independent of relapse in multiple sclerosis.

BACKGROUND: Substantial physical-disability worsening in relapsing-remitting multiple sclerosis (RRMS) occurs outside of clinically recorded relapse. This phenomenon, termed progression independent of relapse activity (PIRA), is yet to be established for cognitive decline. METHODS: Retrospective analysis of RRMS patients. Cognitive decline was defined using reliable-change-index cut-offs for each test (Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test-II). Decline was classified as PIRA if the following conditions were met: no relapse observed between assessments nor within 9 months of cognitive decline. RESULTS: The study sample (n = 336) was 80.7% female with a mean (standard deviation (SD)) age, disease duration, and observation period of 43.1 (9.5), 10.8 (8.4), and 8.1 (3.1) years, respectively. A total of 169 (50.3%) subjects were cognitively impaired at baseline relative to age-, sex-, and education-matched HCs. Within subjects who experienced cognitive decline (n = 167), 89% experienced cognitive PIRA. A total of 141 (68.1%) cognitive decline events were observed independent of EDSS worsening. Cognitive PIRA was more likely to be observed with increased assessments (p < 0.001) and lower assessment density (p < 0.001), accounting for baseline clinical factors. CONCLUSION: These results establish the concept of cognitive PIRA and further our understanding of progressive cognitive decline in RRMS.

Paramagnetic rim lesions predict greater long-term relapse rates and clinical progression over 10 years.

BACKGROUND: Paramagnetic rim lesions (PRLs) have been linked to higher clinical disease severity and relapse frequency. However, it remains unclear whether PRLs predict future, long-term disease progression. OBJECTIVES: The study aimed to assess whether baseline PRLs were associated with subsequent long-term (10 years) Expanded Disability Status Scale (EDSS) increase and relapse frequency and, if so, whether PRL-associated EDSS increase was mediated by relapse. METHODS: This retrospective analysis included 172 people with multiple sclerosis (pwMS) with 1868 yearly clinical visits over a mean follow-up time of 10.2 years. 3T magnetic resonance imaging (MRI) was acquired at baseline and PRLs were assessed on quantitative susceptibility mapping (QSM) images. The associations between PRLs, relapse, and rate of EDSS change were assessed using linear models. RESULTS: PRL+ pwMS had greater overall annual relapse rate (ß = 0.068; p = 0.010), three times greater overall odds of relapse (exp(ß) = 3.472; p = 0.009), and greater rate of yearly EDSS change (ß = 0.045; p = 0.010) than PRL- pwMS. Greater PRL number was associated with greater odds of at least one progression independent of relapse activity (PIRA) episode over follow-up (exp(ß) = 1.171, p = 0.009). Mediation analysis showed that the association between PRL presence (yes/no) and EDSS increase was 96.7% independent of relapse number. CONCLUSION: PRLs are a marker of aggressive ongoing disease inflammatory activity, including more frequent future clinical relapses and greater long-term, relapse-independent disability progression.

Functional alteration due to structural damage is network dependent: insight from multiple sclerosis.

Little is known about how the brain's functional organization changes over time with respect to structural damage. Using multiple sclerosis as a model of structural damage, we assessed how much functional connectivity (FC) changed within and between preselected resting-state networks (RSNs) in 122 subjects (72 with multiple sclerosis and 50 healthy controls). We acquired the structural, diffusion, and functional MRI to compute functional connectomes and structural disconnectivity profiles. Change in FC was calculated by comparing each multiple sclerosis participant's pairwise FC to controls, while structural disruption (SD) was computed from abnormalities in diffusion MRI via the Network Modification tool. We used an ordinary least squares regression to predict the change in FC from SD for 9 common RSNs. We found clear differences in how RSNs functionally respond to structural damage, namely that higher-order networks were more likely to experience changes in FC in response to structural damage (default mode R2 = 0.160-0.207, P < 0.001) than lower-order sensory networks (visual network 1 R2 = 0.001-0.007, P = 0.157-0.387). Our findings suggest that functional adaptability to structural damage depends on how involved the affected network is in higher-order processing.

Evolution of atrophied T2 lesion volume in primary-progressive multiple sclerosis: results from the phase 3 ORATORIO study.

BACKGROUND: Atrophied T2-lesion volume (aT2-LV) is an exploratory imaging marker in multiple sclerosis (MS) reflecting the volume of lesions subsumed into cerebrospinal fluid (CSF). OBJECTIVE: To investigate the effect of ocrelizumab (OCR) versus placebo (PBO) over 120 weeks on the accumulation of aT2-LV in a double-blind placebo-controlled (DBP) phase 3, primary-progressive (PP) MS study (ORATORIO; NCT01194570). METHODS: This post-hoc, MRI-blinded analysis evaluated 732 PPMS randomised to OCR (488) or PBO (244). Atrophied T2-LV was calculated by overlaying baseline T2-lesion masks on follow-up CSF maps. Clinical data from DBP and open-label extension (OLE) periods were available. Treatment effect was evaluated by a mixed-effect model with repeated measures, while logistic regression explored the association of aT2-LV at week 120 and clinical outcomes in the OLE period. RESULTS: OCR treatment significantly reduced accumulation of aT2-LV compared with PBO (319.4 mm3 vs 366.1 mm3, p=0.015) at 120 weeks. OCR showed superiority over PBO in reducing aT2-LV in patients who developed confirmed disability progression (CDP) during the DBP period at 12 (CDP12) and 24 (CDP24) weeks for the composite of Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test and Timed 25-Foot Walk test. Accumulation of aT2-LV at week 120 was related to CDP12-EDSS (p=0.018) and CDP24-EDSS (p=0.022) in the OLE for the patients who were treated by PBO in the DBP only. CONCLUSIONS: OCR showed a significant effect of reducing the accumulation of aT2-LV in PPMS in the DBP period and was related to CDP-EDSS in OLE only in the PBO arm.

Paramagnetic rim lesions are associated with greater incidence of relapse and worse cognitive recovery following relapse.

BACKGROUND: Paramagnetic rim lesions (PRL) may be linked to relapse risk of people with relapsing-remitting multiple sclerosis (pwRRMS). OBJECTIVE: To determine the relationship between presence of PRL lesions and cognitive recovery after relapse. METHODS: PRL load was compared between acutely relapsing pwRRMS and matched stable pwRRMS controls (each group n = 21). In addition, cognitive recovery was compared between acutely relapsing pwRRMS with at least one PRL (PRL+) and those without any PRL (PRL-). RESULTS: Acutely relapsing pwRRMS had significantly greater prevalence and number of PRL (p = 0.004 and p = 0.003) compared with stable controls. These findings remained significant after adjusting for global neuroinflammatory burden (enhancing and non-enhancing lesions). In addition, acutely relapsing PRL + pwRRMS (n = 10) had worse recovery of verbal memory following relapse compared with acutely relapsing PRL - pwRRMS (n = 7; p = 0.027). CONCLUSION: These findings may partially explain previously suggested associations between presence of PRL with more severe disease course.

Detecting isolated cognitive relapses in persons with MS.

BACKGROUND: The existence of isolated cognitive relapses (ICRs) in persons with MS (PwMS) has been debated. OBJECTIVE: To examine relapses with decline on Symbol Digit Modalities Test (SDMT) but no change on Expanded Disability Status Scale (EDSS). METHODS: This 3-year prospective cohort study identified PwMS experiencing a relapse with decrease on SDMT. Participants with SDMT decline/stable EDSS were labeled "ICR," while those with a corresponding decrease on EDSS were classified "Relapse with Cognitive Decline (RCD)." Two definitions of SDMT decline were explored: (1) ⩾ 8 points, and (2) ⩾ 4 points. Logistic regression was used to analyze the relationship between ICR and RCD. RESULTS: The full cohort had 592 participants: 83 experienced relapses; 22 (26.5%) had an SDMT decrease of ⩾ 8 points; 14 (63.6%) met ICR criteria. Logistic regression (X2(1) = 5.112, p = 0.024) using demographics and disease characteristics explained 28.4% of the variance in ICR versus RCD. Only the MS Neuropsychological Questionnaire was associated with ICR (odds ratio (OR): 8.6; 95% confidence interval (CI): 1.1-16.4) 40 relapsing participants with SDMT decrease of ⩾ 4 points were identified: 26 (65%) had a stable EDSS (ICR). Logistic regression did not find any variable predictive of ICR. CONCLUSION: This prospective study demonstrates evidence of ICR in PwMS.

Auditory Test of Processing Speed: Preliminary validation of a smartphone-based test of mental speed.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is a gold-standard measure of cognitive efficiency and processing speed for people with multiple sclerosis (PwMS) but relies on vision and oculomotor function. OBJECTIVES: To develop and validate a new processing speed test with minimal memory involvement and no eye function requirements. METHODS: We created an Auditory Test of Processing Speed (ATOPS). A total of 122 PwMS, of whom 33 were severely disabled (median Expanded Disability Status Scale 8.0) and 37 healthy volunteers (HVs), were enrolled. We assessed sensitivity to discriminate MS participants from HVs, convergent validity between ATOPS and SDMT, sensitivity to discriminate between cognitively impaired (CI) and cognitively preserved (CP) MS participants, and correlations with MS pathology (overall brain lesion burden). Acceptability was examined with completion rates and participant ratings of ATOPS. RESULTS: ATOPS discriminated PwMS from HVs (d = 0.739-0.856), correlated with SDMT (|r| = 0.528-0.587), discriminated between CI and CP PwMS (d = 0.623-0.776), and correlated with lesion burden (r = 0.332-0.436). All groups indicated high favorability of ATOPS and severely disabled MS patients could be assessed by ATOPS more frequently than by SDMT (100% vs. 72.4% completion). CONCLUSIONS: ATOPS is a novel, accessible, and acceptable cognitive processing speed test that may be useful in clinical and/or research settings.

Susceptibility networks reveal independent patterns of brain iron abnormalities in multiple sclerosis.

Brain iron homeostasis is necessary for healthy brain function. MRI and histological studies have shown altered brain iron levels in the brains of patients with multiple sclerosis (MS), particularly in the deep gray matter (DGM). Previous studies were able to only partially separate iron-modifying effects because of incomplete knowledge of iron-modifying processes and influencing factors. It is therefore unclear to what extent and at which stages of the disease different processes contribute to brain iron changes. We postulate that spatially covarying magnetic susceptibility networks determined with Independent Component Analysis (ICA) reflect, and allow for the study of, independent processes regulating iron levels. We applied ICA to quantitative susceptibility maps for 170 individuals aged 9-81 years without neurological disease ("Healthy Aging" (HA) cohort), and for a cohort of 120 patients with MS and 120 age- and sex-matched healthy controls (HC; together the "MS/HC" cohort). Two DGM-associated "susceptibility networks" identified in the HA cohort (the Dorsal Striatum and Globus Pallidus Interna Networks) were highly internally reproducible (i.e. "robust") across multiple ICA repetitions on cohort subsets. DGM areas overlapping both robust networks had higher susceptibility levels than DGM areas overlapping only a single robust network, suggesting that these networks were caused by independent processes of increasing iron concentration. Because MS is thought to accelerate brain aging, we hypothesized that associations between age and the two robust DGM-associated networks would be enhanced in patients with MS. However, only one of these networks was altered in patients with MS, and it had a null age association in patients with MS rather than a stronger association. Further analysis of the MS/HC cohort revealed three additional disease-related networks (the Pulvinar, Mesencephalon, and Caudate Networks) that were differentially altered between patients with MS and HCs and between MS subtypes. Exploratory regression analyses of the disease-related networks revealed differential associations with disease duration and T2 lesion volume. Finally, analysis of ROI-based disease effects in the MS/HC cohort revealed an effect of disease status only in the putamen ROI and exploratory regression analysis did not show associations between the caudate and pulvinar ROIs and disease duration or T2 lesion volume, showing the ICA-based approach was more sensitive to disease effects. These results suggest that the ICA network framework increases sensitivity for studying patterns of brain iron change, opening a new avenue for understanding brain iron physiology under normal and disease conditions.

Thalamic atrophy measured by artificial intelligence in a multicentre clinical routine real-word study is associated with disability progression.

BACKGROUND: The thalamus is a key grey matter structure, and sensitive marker of neurodegeneration in multiple sclerosis (MS). Previous reports indicated that thalamic volumetry using artificial intelligence (AI) on clinical-quality T2-fluid-attenuated inversion recovery (FLAIR) images alone is fast and reliable. OBJECTIVE: To investigate whether thalamic volume (TV) loss, measured longitudinally by AI, is associated with disability progression (DP) in patients with MS, participating in a large multicentre study. METHODS: The DeepGRAI (Deep Grey Rating via Artificial Intelligence) Registry is a multicentre (30 USA sites), longitudinal, observational, retrospective, real-word study of relapsing-remitting (RR) MS patients. Each centre enrolled between 30 and 35 patients. Brain MRI exams acquired at baseline and follow-up on 1.5T or 3T scanners with no prior standardisation were collected. TV measurement was performed on T2-FLAIR using DeepGRAI, and on two dimensional (D)-weighted and 3D T1-weighted images (WI) by using FMRIB's Integrated Registration and Segmentation Tool software where possible. RESULTS: 1002 RRMS patients were followed for an average of 2.6 years. Longitudinal TV analysis was more readily available on T2-FLAIR (96.1%), compared with 2D-T1-WI (61.8%) or 3D-T1-WI (33.2%). Over the follow-up, DeepGRAI TV loss was significantly higher in patients with DP, compared with those with disability improvement (DI) or disease stability (-1.35% in DP, -0.87% in DI and -0.57% in Stable, p=0.045, Bonferroni-adjusted, age-adjusted and follow-up time-adjusted analysis of covariance). In a regression model including MRI scanner change, age, sex, disease duration and follow-up time, DP was associated with DeepGRAI TV loss (p=0.022). CONCLUSIONS: Thalamic atrophy measured by AI in a multicentre clinical routine real-word setting is associated with DP over mid-term follow-up.