Communicating the relevance of neurodegeneration and brain atrophy to multiple sclerosis patients: patient, provider and researcher perspectives.

Central nervous system (CNS) atrophy provides valuable additional evidence of an ongoing neurodegeneration independent of lesion accrual in persons with multiple sclerosis (PwMS). However, there are limitations for interpretation of CNS volume changes at individual patient-level. Patients are receiving information on the topic of atrophy through various sources, including media, patient support groups and conferences, and discussions with their providers. Whether or not the topic of CNS atrophy should be proactively discussed with PwMS during office appointments is currently controversial. This commentary/perspective article represents perspectives of PwMS, providers and researchers with recommendations for minimizing confusion and anxiety, and facilitating proactive discussion about brain atrophy, as an upcoming routine measure in evaluating disease progression and treatment response monitoring. The following recommendations were created based on application of patient's and provider's surveys, and various workshops held over a period of 2 years: (1) PwMS should receive basic information on understanding of brain functional anatomy, and explanation of inflammation and neurodegeneration; (2) the expertise for atrophy measurements should be characterized as evolving; (3) quality patient education materials on these topics should be provided; (4) the need for standardization of MRI exams has to be explained and communicated; (5) providers should discuss background on volumetric changes, including references to normal aging; (6) the limitations of brain volume assessments at an individual-level should be explained; (7) the timing and language used to convey this information should be individualized based on the patient's background and disease status; (8) a discussion guide may be a very helpful resource for use by providers/staff to support these discussions; (9) understanding the role of brain atrophy and other MRI metrics may elicit greater patient satisfaction and acceptance of the value of therapies that have proven efficacy around these outcomes; (10) the areas that represent possibilities for positive self-management of MS symptoms that foster hope for improvement should be emphasized, and in particular regarding use of physical and mental exercise that build or maintain brain reserve through increased network efficiency, and (11) an additional time during clinical visits should be allotted to discuss these topics, including creation of specific educational programs.

A prospective study to validate the expanded timed get-up-and-go in a population with multiple sclerosis.

Background: Timed 25-foot walk (T25FW) test serves as gold standard in care of persons with multiple sclerosis (PwMS) and as walking measure of regulatory trials. Objective: To validate and determine the clinical utility of Expanded Timed Get-Up and Go (ETGUG) as a disability measure in MS. Methods: ETGUG intra-rater and inter-rater reproducibility was determined in 65 PwMS that were examined twice in two centres over 1-week. Values below the 5th and above the 95th percentile were considered minimally detectable change. A longitudinal cohort (32.4 months) of 145 PwMS from New York State MS Consortium (NYSMSC) was used for clinical validation as a predictor of disability worsening measured by Expanded Disability Status Scale (EDSS). Results: ETGUG and T25FW had noteworthy intra-rater and inter-rater reproducibility (Cronbach coefficient>0.949). One-week ETGUG difference ranged from 15.07% to -14.84% (5th and 95th percentile). Over the NYSMSC follow-up, PwMS had significant slowing in walking as measured by ETGUG (20.8 to 25.9s, p = 0.009) but not by T25FW. 15% ETGUG worsening had similar ability to predict EDSS worsening when compared to 20% T25FW worsening (AUC 0.596 vs. 0.552). Conclusion: Over 32-month follow-up, PwMS experience slowing in ETGUG walking time but not in T25FW. Although the scoring may be more challenging, ETGUG could be more sensitive to change and provide more comprehensive measure of lower extremity performance and ambulation in PwMS.

COVID-19 Vaccination in Multiple Sclerosis and Inflammatory Diseases: Effects from Disease-Modifying Therapy, Long-Term Seroprevalence and Breakthrough Infections.

Background: To determine the effect of disease-modifying therapies (DMT) on humoral postvaccine seroconversion, long-term humoral response, and breakthrough COVID-19 infections in persons with multiple sclerosis (PwMS) and other neuroinflammatory disorders. Methods: A total of 757 PwMS and other neuroinflammatory disorders were recruited in two MS centers and vaccinated with one of the FDA-approved vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S). The primary outcomes are the rate of humoral postvaccine seroconversion and anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immunoglobulin G (IgG) differences between patients on different DMTs. Secondary measures include breakthrough infections and humoral response after six months. Other outcomes include differences in vaccine response between SARS-CoV-2 vaccines and the effects of age and comorbidities on the vaccine response. Results: A total of 465 (68.4%) PwMS and 55 (74.3%) patients with neuroinflammatory diseases were seropositive at 4−12 weeks after vaccination. A significant difference in seroconversion based on the DMT used at the time of vaccination (p < 0.001) was observed, with the lowest rates seen in patients treated with anti-CD20 antibodies (23.2%) and sphingosine-1-phosphate modulators (S1P) (30.8%). In seropositive patients, there was a significant decrease in anti-SARS IgG from mean 20.0 to 4.7 at six months (p = 0.004). Thirty-nine patients had breakthrough infection, but only two seronegative patients required hospitalization. mRNA vaccines resulted in significantly greater seroconversion compared to Ad26.COV2.S (p < 0.001). Older age and presence of cardiovascular comorbidities were associated with lower anti-SARS IgG (p = 0.021 and p = 0.003, respectively) Conclusions: PwMS and neuroinflammatory disorders treated with anti-CD20 and S1P medications have lower humoral response after anti-SARS-CoV-2 vaccination, even after booster dose. Waning of the humoral response puts vaccinated PwMS at a greater risk of COVID-19 breakthrough.

Elevated spermidine serum levels in mild cognitive impairment, a potential biomarker of progression to Alzheimer dementia, a pilot study.

BACKGROUND/AIMS: There is a close link between iron and polyamine biosynthesis and metabolism. In a recent study, we reported alterations in the serum levels of hepcidin and other iron-related proteins in Alzheimer's disease (AD) patients (Sternberg et al., 2017). Based on these findings, this pilot study compared serum levels of one of the polyamines, Spermidine, between AD, mild cognitive impairment (MCI), and control subjects, correlating the levels with the existing clinical and neuroimaging data. METHODS: This cross-sectional study measured Spermidine levels in frozen serum samples of 43 AD patients, 12 MCI patients, and 21 age-matched controls, provided by the Oregon Alzheimer's Disease Center Bio-repository, using enzyme-linked immunosorbent assay. RESULTS: MCI patients showed significantly higher mean Spermidine serum levels compared to controls (P = 0.01), with a non-significant trend for higher Spermidine serum levels in pure AD (P = 0.08) participants compared to controls. Spermidine serum levels correlated with the values of cognitive assessment tests including MMSE (r = -0.705, P = 0.003), CDR (r = 0.751, P = 0.002), and CDR-SOB (r = 0.704, P = 0.007), in "pure" AD subgroup, suggesting that higher Spermidine serum levels in MCI can be a potential biomarker of conversion to dementia in subjects with AD underlying pathology. Furthermore, Spermidine serum levels correlated with serum levels of the chief iron regulatory protein, hepcidin in AD participants with a more advanced disease stage, indicated by MMSE (strata of 8-19, P = 0.02), and CDR-SOB (strata of 6-12, P = 0.03). CONCLUSION: Studies with larger cohort are warranted for defining the role of Spermidine in AD pathophysiology, and the utility of polyamines as biomarkers of progression of MCI to AD.

Leptomeningeal, dura mater and meningeal vessel wall enhancements in multiple sclerosis.

BACKGROUND: Leptomeningeal contrast enhancement (LMCE) has previously shown potential to be an indirect marker for leptomeningeal inflammation in multiple sclerosis (MS). Dura mater (DME), inclusive falx cerebri (FCE) enhancement and meningeal vessel wall enhancement (VWE) represent two other meningeal enhancement patterns in MS that have not been extensively studied. OBJECTIVES: To investigate the frequency of LMCE, DME/FCE and VWE in patients with MS and their associations with demographic, clinical and MRI characteristics in a longitudinal retrospective study. METHODS: 217 MS patients (193 relapsing-remitting MS, 24 progressive MS) were assessed at baseline and over 18 months follow-up using 3T 3D FLAIR pre- and post-contrast and subtraction images. Lesion and brain volume outcomes were additionally calculated. Analyses were adjusted for age, and corrected for multiple comparisons. RESULTS: LMCE and VWE frequency was associated with higher age (p<0.02), but the presence of DME/FCE was not (p=0.402). 24% of MS patients revealed LMCE and VWE, respectively, and 47% showed DME/FCE. Presence of LMCE, VWE and DME/FCE was not significantly associated with clinical or imaging markers of disease severity. All three patterns of meningeal enhancement showed a high persistence in shape and size at follow-up. CONCLUSIONS: LMCE, DME/FCE and VWE can be identified by gadolinium-enhanced 3D FLAIR MR imaging. Meningeal enhancement is associated with higher age. DME/FCE is the most frequent meningeal enhancement pattern in MS, however further case-control studies should determine whether this represents abnormal lymphatic drainage in these patients or is an age-dependent physiologic phenomenon.

Recovery of cognitive function after relapse in multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS) but its manifestation as acute disease activity is underappreciated. OBJECTIVE: The aim of this study is to examine recovery after MS relapse on multiple tests of cognitive and motor function and explore correlates of change with Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI), and cognitive reserve. METHODS: Fifty relapsing group (RG) and matched stable participants were examined at baseline, during relapse, and at 3-month follow-up. Tests of cognitive processing speed (Symbol Digit Modalities Test (SDMT)) and consensus opinion measures of memory, ambulation, and manual dexterity were administered. All RG patients were treated with a 5-day course of Acthar Gel (5 mL/80 IU). RESULTS: In RG patients, SDMT declined from 55.2 to 44.6 at relapse and recovered to 51.7, a slope differing from stable controls (p = 0.001). A statistical trend (p = 0.07) for the same effect was observed for verbal memory and was significant for ambulation (p = 0.03). The Cerebral Function Score from the EDSS also changed in the RG and recovered incompletely relative to controls (p = 0.006). CONCLUSION: These results replicate earlier reports of cognitive worsening during relapse in MS. Clinically meaningful improvements followed relapse on SDMT and ambulation. Cognitive decline during relapse can be appreciated on neurological exam but not patient-reported outcomes.

Late onset multiple sclerosis is associated with more severe ventricle expansion.

BACKGROUND: Late-onset multiple sclerosis (LOMS) is associated with faster disability progression than persons with adult-onset MS (PwAOMS). The differences in brain atrophy are currently unknown. OBJECTIVES: To determine MRI-derived atrophy rates in persons with late-onset MS (PwLOMS) and compare them to an age-matched and disease duration-matched sample of PwAOMS. METHODS: 870 persons with MS (290 PwLOMS, 290 age-matched PwAOMS, and 290 disease duration-matched PwAOMS), and 150 healthy controls (HCs), were followed for 5 years and 3 years, respectively. Cross-sectional and longitudinal measures of T2-lesion volume (LV), lateral ventricular volume (LVV) and whole brain volume (WBV) were derived. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) were calculated. Both analyses were corrected for false discovery rate. RESULTS: Persons with MS exhibited significantly greater annualized WBV loss (-0.88% vs. -0.38%, p<0.001) and annualized LVV expansion (3.1% vs. 1.7%, p=0.002) when compared to HCs. PwLOMS had significantly higher baseline and follow-up median MSSS when compared to both age-matched and disease duration-matched PwAOMS (p<0.026). PwLOMS showed significantly greater percent LVV change (14.3% vs. 9.3% p=0.001) and greater annualized percent LVV change (4.1% vs. 1.6%, p<0.001) compared to age-matched PwAOMS. CONCLUSION: PwLOMS had higher MSSS and greater ventricle expansion when compared to PwAOMS.

Functional Connectivity and Structural Disruption in the Default-Mode Network Predicts Cognitive Rehabilitation Outcomes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Efficacy of restorative cognitive rehabilitation can be predicted from baseline patient factors. In addition, patient profiles of functional connectivity are associated with cognitive reserve and moderate the structure-cognition relationship in people with multiple sclerosis (PwMS). Such interactions may help predict which PwMS will benefit most from cognitive rehabilitation. Our objective was to determine whether patient response to restorative cognitive rehabilitation is predictable from baseline structural network disruption and whether this relationship is moderated by functional connectivity. METHODS: For this single-arm repeated measures study, we recruited 25 PwMS for a 12-week program. Following magnetic resonance imaging, participants were tested using the Symbol Digit Modalities Test (SDMT) pre- and postrehabilitation. Baseline patterns of structural and functional connectivity were characterized relative to healthy controls. RESULTS: Lower white matter tract disruption in a network of region-pairs centered on the precuneus and posterior cingulate (default-mode network regions) predicted greater postrehabilitation SDMT improvement (P = .048). This relationship was moderated by profiles of functional connectivity within the network (R2 = .385, P = .017, Interaction ß = -.415). CONCLUSION: Patient response to restorative cognitive rehabilitation is predictable from the interaction between structural network disruption and functional connectivity in the default-mode network. This effect may be related to cognitive reserve.

Sex-Specific Differences in Life Span Brain Volumes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Numerous sex-specific differences in multiple sclerosis (MS) susceptibility, disease manifestation, disability progression, inflammation, and neurodegeneration have been previously reported. Previous magnetic resonance imaging (MRI) studies have shown structural differences between female and male MS brain volumes. To determine sex-specific global and tissue-specific brain volume throughout the MS life span in a real-world large MRI database. METHODS: A total of 2,199 MS patients (female/male ratio of 1,651/548) underwent structural MRI imaging on either a 1.5-T or 3-T scanner. Global and tissue-specific volumes of whole brain (WBV), white matter, and gray matter (GMV) were determined by utilizing Structural Image Evaluation using Normalisation of Atrophy Cross-sectional (SIENAX). Lateral ventricular volume (LVV) was determined with the Neurological Software Tool for REliable Atrophy Measurement (NeuroSTREAM). General linear models investigated sex and age interactions, and post hoc comparative sex analyses were performed. RESULTS: Despite being age-matched with female MS patents, a greater proportion of male MS patients were diagnosed with progressive MS and had lower normalized WBV (P < .001), GMV (P < .001), and greater LVV (P < .001). In addition to significant stand-alone main effects, an interaction between sex and age had an additional effect on the LVV (F-statistics = 4.53, P = .033) and GMV (F-statistics = 4.59, P = .032). The sex and age interaction was retained in both models of LVV (F-statistics = 3.31, P = .069) and GMV (F-statistics = 6.1, P = .003) when disease subtype and disease-modifying treatment (DMT) were also included. Although male MS patients presented with significantly greater LVV and lower GMV during the early and midlife period when compared to their female counterparts (P < .001 for LVV and P < .019 for GMV), these differences were nullified in 60+ years old patients. Similar findings were seen within a subanalysis of MS patients that were not on any DMT at the time of enrollment. CONCLUSION: There are sex-specific differences in the LVV and GMV over the MS life span.

Dalfampridine benefits ambulation but not cognition in multiple sclerosis.

BACKGROUND: Impaired cognition and ambulation are common in multiple sclerosis (MS). Dalfampridine is the first Food and Drug Administration (FDA)-approved medication to treat impaired ambulation in MS. Dalfampridine may benefit patients with cognitive impairment, given its effects on saltatory conduction and the association between cognitive and motor function. OBJECTIVE: To examine the effects of dalfampridine on cognition in MS. To determine if the anticipated improved cognition is grounded in dalfampridine's effects on ambulation. METHODS: Adults with MS were randomized to dalfampridine (n = 45) or placebo (n = 16) for 12 weeks. Cognition and motor function were assessed at baseline and end-point. RESULTS: T25FW and 6-minute walk (6MW) performance improved at end-point in the treatment group but not in the placebo group (p < 0.05). Our primary outcome, performance on the Symbol Digit Modalities Test, did not improve. About 30% (n = 12) of the dalfampridine group demonstrated ⩾20% improved ambulation and were categorized "responders." Among "responders", Symbol Digit Modalities test performance did not improve. However, performance on the Paced Auditory Serial Addition Test improved among "responders" (p < 0.05). CONCLUSION: Dalfampridine benefits timed ambulation but not cognition. Some improvement among ambulation "responders" is consistent with prior reports of cognition-motor coupling in MS ( ClinicalTrials.gov #: NCT02006160).

Atrophied Brain T2 Lesion Volume at MRI Is Associated with Disability Progression and Conversion to Secondary Progressive Multiple Sclerosis.

Background Atrophied T2 lesion volume at MRI is an imaging measure that reflects the replacement of T2 lesions by cerebrospinal fluid spaces in patients with multiple sclerosis (MS). Purpose To investigate the association of atrophied T2 lesion volume and development of disability progression (DP) and conversion to secondary progressive MS (SPMS). Materials and Methods This retrospective study included 1612 participants recruited from 2006 to 2016 and followed up for 5 years with clinical and MRI examinations. Accumulation of T2 lesion volume, atrophied T2 lesion volume, percentage brain volume change (PBVC), and percentage ventricular volume change (PVVC) were measured. Disability progression and secondary progressive conversion were defined by using standardized guidelines. Analysis of covariance (ANCOVA) adjusted for age and Cox regression adjusted for age and sex were used to compare study groups and explore associations between MRI and clinical outcomes. Results A total of 1314 patients with MS (1006 women; mean age, 46 years ± 11 [standard deviation]) and 124 patients with clinically isolated syndrome (100 women; mean age, 39 years ± 11) along with 147 healthy control subjects (97 women; mean age, 42 years ± 13) were evaluated. A total of 336 of 1314 (23%) patients developed DP, and in 67 of 1213 (5.5%) the disease converted from clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS) to SPMS. Patients with conversion to DP had higher atrophied T2 lesion volume (+34.4 mm3; 95% confidence interval [CI]: 17.2 mm3, 51.5 mm3; d = 0.27; P < .001) and PBVC (-0.21%; 95% CI: -0.36%, -0.05%; d = 0.19; P = .042) but not PVVC (0.36%; 95% CI: -0.93%, 1.65%; d = 0.04; P = .89) or T2 lesion volume change (-64.5 mm3; 95% CI: -315.2 mm3, 186.3 mm3; d = 0.03; P = .67) when compared with DP nonconverters. ANCOVA showed that atrophied T2 lesion volume was associated with conversion from CIS or RRMS to SPMS (+26.4 mm3; 95% CI: 4.2 mm3, 56.9 mm3; d = 0.23; P = .002) but not PBVC (-0.14%; 95% CI: -0.46%, 0.18%; d = 0.11; P = .66), PVVC (+0.18%; 95% CI: -2.49%, 2.72%; d = 0.01; P = .75), or T2 lesion volume change (-46.4 mm3; 95% CI: -460.8 mm3, 367.9 mm3; d = 0.03; P = .93). At Cox regression analysis, only atrophied T2 lesion volume was associated with the DP (hazard ratio, 1.23; P < .001) and conversion to SPMS (hazard ratio, 1.16; P = .008). Conclusion Atrophied brain T2 lesion volume is a robust MRI marker of MS disability progression and conversion into a secondary progressive disease course. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chiang in this issue.

Teriflunomide's effect on humoral response to Epstein-Barr virus and development of cortical gray matter pathology in multiple sclerosis.

BACKGROUND: Teriflunomide has been shown to slow cortical gray matter (GM) atrophy in patients with multiple sclerosis (MS). Previous work showed that higher levels of Epstein-Barr virus (EBV) are associated with greater development of cortical pathology in MS. OBJECTIVES: To investigate whether the effect of teriflunomide on cortical volume loss in relapsing MS patients may be associated with the change in humoral response to EBV. METHODS: This was a prospective, observational, single-blinded, longitudinal study of 30 relapsing MS patients, who started treatment with teriflunomide, and 20 age- and sex-matched healthy controls (HCs). Subjects were assessed at baseline, 6 and 12 months with clinical, MRI and EBV examinations. MRI outcomes included percent changes in cortical, GM, deep GM and whole brain volumes. Serum samples were analyzed for IgG antibodies titers against EBV viral capsid antigen (VCA) and nuclear antigen-1 (EBNA-1). RESULTS: There were no significant differences in anti-VCA and anti-EBNA-1 IgG titers between MS patients and HC at baseline. However, over the 12-month follow-up, MS patients experienced a greater decrease in anti-EBNA-1 (-35.1, p = .003) and anti-VCA (-15.9, p = .05) IgG titers, whereas no significant changes were observed in HCs (-3.7 and -1.6, respectively). MS patients who showed the highest decrease in anti-EBV VCA and EBNA-1 IgG titers from baseline to follow-up, developed less cortical (p < .001 and p = .02) and GM volume loss (p = .004 for both), respectively. CONCLUSIONS: Teriflunomide's effect on slowing cortical and GM volume loss may be mediated by its effect on altering humoral response to EBV.

Cumulative gadodiamide administration leads to brain gadolinium deposition in early MS.

OBJECTIVE: Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS. METHODS: A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration <2 years at baseline and received exclusively gadodiamide at all MRI time points. SI ratio (SIR) to pons and CSF of lateral ventricle volume (CSF-LVV) were assessed. Analysis of covariance and correlation analyses, adjusted for age, sex, and region of interest volume, were used. RESULTS: The mean follow-up time was 55.4 months, and the mean number of gadolinium-based contrast agents administrations was 9.2. At follow-up, 49.3% of patients with MS and no controls showed DN T1 hyperintensity (p < 0.001). The mean SIR of DN (p < 0.001) and of GP (p = 0.005) to pons and the mean SIR of DN, GP, and thalamus to CSF-LVV were higher in patients with MS compared to controls (p < 0.001). SIR of DN to pons was associated with number of gadodiamide doses (p < 0.001). No associations between SIR of DN, GP, and thalamus and clinical and MRI outcomes of disease severity were detected over the follow-up. CONCLUSIONS: DN, GP, and thalamus gadolinium deposition in early MS is associated with lifetime cumulative gadodiamide administration without clinical or radiologic correlates of more aggressive disease.

No association between variations in extracranial venous anatomy and clinical outcomes in multiple sclerosis patients over 5 years.

BACKGROUND: No longitudinal, long-term, follow-up studies have explored the association between presence and severity of variations in extracranial venous anatomy, and clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVE: This prospective 5-year follow-up study assessed the relationship of variations in extracranial venous anatomy, indicative of chronic cerebrospinal venous insufficiency (CCSVI) on Doppler sonography, according to the International Society for Neurovascular Disease (ISNVD) proposed consensus criteria, with clinical outcomes and disease progression in MS patients. METHODS: 90 MS patients (52 relapsing-remitting, RRMS and 38 secondary-progressive, SPMS) and 38 age- and sex-matched HIs were prospectively followed for 5.5 years. Extracranial and transcranial Doppler-based venous hemodynamic assessment was conducted at baseline and follow-up to determine the extent of variations in extracranial venous anatomy. Change in Expanded Disability Status Scale (∆EDSS), development of disability progression (DP) and annualized relapse rate (ARR) were assessed. RESULTS: No significant differences were observed in MS patients, based on their presence of variations in extracranial venous anatomy at baseline or at the follow-up, in ∆EDSS, development of DP or ARR. While more MS patients had ISNVD CCSVI criteria fulfilled at baseline compared to HIs (58% vs. 37%, p = 0.03), no differences were found at the 5-year follow-up (61% vs. 56%, p = 0.486). DISCUSSION: This is the longest follow-up study assessing the longitudinal relationship between the presence of variations in extracranial venous anatomy and clinical outcomes in MS patients. CONCLUSION: The presence of variations in extracranial venous anatomy does not influence clinical outcomes over the 5-year follow-up in MS patients.

Aging and Brain Atrophy in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Brain atrophy accelerates at the age of 60 in healthy individuals (HI) and at disease onset in multiple sclerosis (MS) patients. Whether there is an exacerbating effect of aging superimposed on MS-related brain atrophy is unknown. We estimated the aging effect on lateral ventricular volume (LVV) and whole brain volume (WBV) changes in MS patients. METHODS: 1,982 MS patients (mean follow-up: 4.8 years) and 351 HI (mean follow-up: of 3.1 years), aged from 20 to 79 years old (yo), were collected retrospectively. Percent LVV change (PLVVC) and percent brain volume change (PBVC) on 1.5T and 3T MRI scanners (median of 3.9 scans per subject) were calculated. These were determined between all-time points and subjects were divided in six-decade age groups. MRI differences between age groups were calculated using analysis of covariance (ANCOVA). RESULTS: Compared to HI, at first MRI, MS patients had significantly increased LVV in the age groups: 30-39 yo, 40-49 yo, 50-59 yo, 60-69 yo (all P < .0001), and 70-79 yo (P = .029), and decreased WBV in the age groups: 20-29 yo (P = .024), 30-39 yo (P = .031), 40-49 yo, and 50-59 yo (all P < .0001). Annualized PLVVC was significantly different between the age groups 20-59 and 60-79 yo in MS patients (P = .005) and HI (P < .0001), as was for PBVC in MS patients (P = .001), but not for HI (P = .521). There was a significant aging interaction effect in the annualized PLVVC (P = .001) between HI and MS patients, which was not observed for the annualized PBVC (P = .380). CONCLUSIONS: Development of brain atrophy manifests progressively in MS patients, and occurs with a different pattern, as compared to aging HI. PLVVC increased across age in HI as compared to MS, while PBVC decreased across ages in both HI and MS.

Increased free prostate specific antigen serum levels in Alzheimer's disease, correlation with Cognitive Decline.

BACKGROUND/AIMS: Prostate specific antigen (PSA) is regulated by steroid hormones, such as testosterone, the serum levels of which are altered in patients with Alzheimer's disease (AD).This pilot study compared serum levels of the free (f) PSA between AD, mild cognitive impairment (MCI), and control subjects, and evaluated the relationship between fPSA serum levels and cognitive assessment tests and neuroimaging data. In addition, in a subgroup of AD patients, we correlated fPSA serum levels with the existing data on serum levels of amyloid-beta (Aß), and iron-related proteins, including hepcidin and ferritin. METHODS: Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of fPSA using enzyme-linked immunosorbent assay. RESULTS: fPSA serum levels calculated as median ±â€¯SD were higher in AD males (663.6 ±â€¯821.0 pg/ml) compared to control males (152.0 ±â€¯207.0 pg/ml), p = 0.003. A similar Pattern emerged when comparing MCI males (310.7 ±â€¯367.0 pg/ml) to control males (P = 0.02). Correlation studies showed a significant association between fPSA and CDR (r = 0.56, P = 0.006) and CDR-SOB (r = 0.54, P = 0.009) in AD males. CONCLUSION: Additional studies in a larger cohort are required for determining whether fPSA can be used as biomarker of AD disease progression and whether it has the potential to identify male subjects at risk of AD dementia.

Effect of Teriflunomide and Dimethyl Fumarate on Cortical Atrophy and Leptomeningeal Inflammation in Multiple Sclerosis: A Retrospective, Observational, Case-Control Pilot Study.

Background: Pathologic changes in cortical gray matter (GM) and leptomeninges contribute to disability worsening in patients with multiple sclerosis (MS), but there is little evidence whether disease-modifying treatments can slow down cortical pathology in MS. Objectives: To investigate the effect of teriflunomide (TFM) and dimethyl fumarate (DMF) in reducing cortical pathology, as determined by percentage cortical volume change (PCVC) and leptomeningeal contrast enhancement (LMCE) on MRI. Methods: This was a retrospective, single-center, observational study that selected 60 TFM- and 60 DMF-treated MS patients over 24 months. Results: TFM had a lower rate of PCVC compared to DMF over 24 months (-0.2% vs. -2.94%, p = 0.004). Similar results were observed for percentage GM volume change over 0⁻12 (p = 0.044) and 0⁻24 (-0.44% vs. -3.12%, p = 0.015) months. No significant differences were found between the TFM and DMF groups in the frequency and number of LMCE foci over the follow-up. TFM showed a numerically lower rate of whole brain atrophy over 24 months (p = 0.077), compared to DMF. No significant clinical or MRI lesion differences between TFM and DMF were detected over follow-up. Conclusions: These findings suggest that TFM has a superior effect on the preservation of cortical GM volume, compared to DMF.

Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis.

Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (ß = -0.42; P = .002), higher degree of disability (ß = -0.64; P = .03), and secondary-progressive course (ß = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (ß = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy. © RSNA, 2018 Online supplemental material is available for this article.

The Effect of Glatiramer Acetate on Retinal Nerve Fiber Layer Thickness in Patients with Relapsing-Remitting Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study.

BACKGROUND: Optical coherence tomography (OCT) is a technique that allows for the assessment of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV), which reflect neuroaxonal integrity within the retina. As such it has been used in multiple sclerosis (MS) to study neurodegeneration. Glatiramer acetate (GA) is a widely used treatment for MS, which is suggested to have a possible neuroprotective role. OBJECTIVE: The aim of this study was to assess RFNLT and TMV changes in relapsing-remitting MS (RRMS) patients who started treatment with GA and were followed for a 24-month period. METHODS: A cohort of 60 RRMS patients and 40 healthy controls (HCs) were imaged with OCT at baseline and follow-up. All subjects also underwent clinical and neurological examination. Measurements were compared between the RRMS patients and HCs as well as between optic neuritis (ON)-affected and ON-unaffected eyes. RESULTS: At baseline, MS patients showed lower average RNFLT (p = 0.046) and TMV (p = 0.013) when compared with HCs. No significant differences in the evolution of OCT measures were detected over the follow-up between MS patients and HCs. MS patients with both affected and unaffected eyes showed significantly lower average RNFLT, temporal inferior RNFLT, and TMV at baseline, compared with HCs. No significant differences between ON-affected and ON-unaffected eyes in MS patients were detected over the follow-up, except for the nasal superior RNFLT (p = 0.019). CONCLUSIONS: This study suggests a beneficial role of GA on retinal axonal degeneration in MS, and further confirms the utility of OCT to monitor the neuroprotective effect of disease-modifying treatment.