Oral Symbol Digit Modalities Test Research Articles

Impact of Acute Dopamine Replacement on Cognitive Function in Parkinson's Disease.

PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico-striato-pallido-thalamic loops differentially susceptible to hyperdopaminergic effects with treatment. As the choice and titration of symptomatic PD medications are guided primarily by motor symptoms, it is important to understand their cognitive implications. To investigate the effects of acute dopaminergic medication administration on executive function in Parkinson's disease (PD). Participants with idiopathic PD were administered the oral Symbol Digit Modalities Test (SDMT; n = 181) and the Stroop test (n = 172) in the off-medication and "best on" medication states. ANCOVA was used to test for differences between off-medication and on-medication scores corrected for age and years of education. After administration of symptomatic medications, scores worsened on the SDMT (F = 11.70, P < 0.001, d = -0.13), improved on the Stroop color (F = 26.89, P < 0.001, d = 0.184), word (F = 6.25, P = 0.013, d = 0.09), and color-word (F = 13.22, P < 0.001, d = 0.16) test components, and the Stroop difference and ratio-based interference scores did not significantly change. Longer disease duration correlated with lower scores on the SDMT, Stroop color, word, and color-word scores; however, longer disease duration and higher levodopa-equivalents correlated with higher Stroop difference-based interference scores. Symptomatic medication differentially affects performance on two cognitive tests in PD. After acute treatment, core Stroop measures improved, Stroop interference was unchanged, and SDMT performance worsened, likely reflecting complex changes in processing speed and executive function related to acute treatment. When considering motor symptom therapies in PD, an individual's cognitive demands and expectations, especially regarding executive function, should be considered.

Internet-delivered lifestyle physical activity intervention for cognitive processing speed in multiple sclerosis

BackgroundWe propose a randomized controlled trial(RCT) of a Social Cognitive Theory-based(SCT), Internet-delivered behavioral intervention targeting lifestyle physical activity(LPA) for yielding improvements in cognitive processing speed(CPS), learning and memory(L/M), symptoms, and quality of life(QOL) among persons with mild multiple sclerosis(MS)-related ambulatory impairment who have impaired CPS. Methods/designThe study involves a Phase-II, parallel group, RCT design. Participants with MS(N = 300) will be randomly assigned on an equal basis(1:1) into behavioral intervention(n = 150) or attention and social contact control(n = 150) conditions. The conditions will be administered over 6-months by trained behavior coaches who will be uninvolved in screening, recruitment, random assignment, and outcome assessment. We will collect outcome data remotely every 6-months over the 12-month period(baseline, immediate follow-up, and 6-month follow-up) using a treatment blinded assessor. The primary outcome is the raw, oral Symbol Digit Modalities Test as a neuropsychological measure of CPS. The secondary outcomes include the California Verbal Learning Test-II as an objective measure of L/M, and patient-reported outcomes of fatigue, depressive symptoms, anxiety, pain, and QOL. The tertiary outcome is accelerometry as an objective, device-based measure of steps/day for generating a minimal clinically important difference(MCID) value that guides the prescription of LPA for improving CPS in clinical practice. The primary data analyses will involve intent-to-treat principles, and mixed-effects models and logistic regression. DiscussionIf successful, the proposed study will provide Class I evidence for the efficacy of a theory-based, Internet-delivered behavioral intervention focusing on LPA for improving CPS and mitigating its negative impact on other outcomes in persons with MS.Clinicaltrials.gov: NCT04518657

50 Remote Assessment has Minimal Effect on Test-Retest Reliability Among Older Adults with Essential Tremor

Objective:The COVID-19 pandemic increased utilization of remote assessment to allow clinicians and researchers to continue valuable work while maintaining quarantine guidelines. With guidelines relaxing, researchers have returned to in-person assessment. Information is needed regarding the effect of remote assessments on test-retest reliability. COGNET, a longitudinal study of cognition in participants with essential tremor, transitioned from in-person to remote assessments during the pandemic, and has now returned to in-person assessment. The current study investigates the extent to which remote assessment affected test-retest reliability across a range of neuropsychological assessments administered in COGNET.Participants and Methods:Participants included 27 older adults enrolled in COGNET (mean age=75.0 (9.1), education=16.2 (2.6), 67% female, and 100% white). Memory tests included: California Verbal Learning Test II, Logical Memory subtest of the Wechsler Memory Scales - Revised, and Verbal Paired? Associates. Executive function tests included: Digit Span Backwards and the Delis-Kaplan Executive Function System subtests of Verbal Fluency, Sorting, and Color-Word. Attention tests included Oral Symbol Digit Modalities Test and Digit Span Forward. Language was assessed with the Boston Naming Test. Intraclass correlation coefficients (ICCs) were calculated to examine test-retest reliability of InPerson to In-Person visits (P-P), and combination visits (e.g., In-Person to Remote (PR), and Remote to In-Person (R-P)). Following Koo &amp; Li (2016), ICCs were interpreted as: &gt;.90 excellent, .75-.90 good, .50-.74 moderate, and &lt;.50 poor reliability. The Feldt approach was used to compare ICCs from P-P visits against ICCs calculated for combination visits (P-R or R-P), with the test statistic compared to an F distribution.Results:ICCs for person-to-person assessment ranged from .51 to .89. Memory test ICCs ranged from moderate to good (.51 to .80). Executive function test ICCs ranged from moderate to good (.55 to .89). The attention domain had moderate ICCs (.67 - .68). Language ICC was moderate (.70). ICCs for person-to-remote assessment ranged from .42 to .89. Memory tests ranged from moderate to good ICCs (.59 to .83). Executive function tests ranged from poor to good ICCs (.42 to .89). Attention ICCs were moderate to good (.55 to .79). The Language ICC was moderate (.72). ICCs for remote-to-person ranged from .48 to 86. Memory ICCs ranged from moderate to good (.59 to .86). Executive function ICCs ranged from poor to good (.48 to .83). Attention ICCs were moderate to good (.56 to .79). The Language ICC was good (.78). The only test for which an ICC from a combination visit was significantly lower than a person to person visit was Digit Span Backwards.Conclusions:Test-retest reliability was moderate or better for all P-P assessments, consistent with the known psychometrics of these tests. Only one test of executive function showed lower reliability when remote assessment was introduced. From a broad standpoint, current results suggest that remote administration of neuropsychological tests can be used as a reliable substitute for in-person assessment for many measures, and suggest that caution be used when interpreting any change in Digit Span Backwards across person and remote assessments.

18 Language Predicts Verbal Learning in Parkinson's Disease

Objective:Cognitive impairment in Parkinson's disease (CIPD) is present in approximately 40% of patients. Language deficits, evidenced by poor word- retrieval, have historically characterized memory weaknesses in PD. That is, the "retrieval deficit hypothesis," suggests successful memory encoding, but poor retrieval subsequent to language and executive dysfunction, another prominent area of CIPD. However, recent studies suggest that memory impairments in PD are instead at the level of learning. At present, several suggested etiologies to explain learning impairments in PD exist that are not related to language, for example that processing speed deficits (another characteristic of CIPD) impact learning; however, other studies present evidence against this theory. Therefore, we hypothesize that deficits in language continue to be a primary component of memory impairment in PD, but at the level of learning rather than retrievalParticipants and Methods:85 adults (age M = 61.54, SD = 10.00; %female = 26.7; Dementia Rating Scale M = 137.77, SD = 5.63) diagnosed with Parkinson's disease according to the UK Brain Bank criteria for idiopathic PD, completed a neuropsychological test battery when "off" levodopa medication. The battery included the Boston Naming Test (BNT), verbal fluency tests (Controlled Oral Word Association [COWA] and category fluency), the California Verbal Learning Test, 2nd Edition (CVLT-II), and the Oral Symbol Digit Modalities Test (SDMT). Separate linear regression models were used to examine BNT, COWA, category fluency, and SDMT performance as predictors of total learning (sum of trials 1-5), short-delay free recall, long-delay free recall, and recognition discriminability on the CVLT-II. Analyses were adjusted for age, sex, education, and disease severity (MDS-Unified Parkinson's Disease Rating Scale, part 3 score). Follow up analyses adjusted for processing speed (oral SDMT).Results:Adjusted linear regression models revealed that both verbal fluencies predicted verbal learning (letter: ß = .37, p &lt; .01; category: ß = .45, p &lt; .01), long-delay free recall (letter: ß = .25, p = .05; category: ß = .34, p = .01), and recognition discriminability (letter: ß = .36, p = .02; category: ß =.33, p = .03) on the CVLT-II. Confrontation naming significantly predicted only long-delay free recall (ß =.31, p = .01). Processing speed predicted verbal learning (ß = .51, p &lt; .01), short-delay free recall (ß = .35, p = .03), and long-delay free recall (ß = .44, p &lt; .01). After adjusting for processing speed, letter fluency significantly predicted learning (ß = .23, p = .05) and discriminability (ß = .33, p = .04). Category fluency significantly predicted learning only (ß = .28, p = .04). Finally, confrontation naming significantly predicted only long-delay free recall (ß= .28, p = .01).Conclusions:While processing speed was associated with verbal learning and recall, components of language predicted variance in verbal learning in PD that was not accounted for by speed. Additionally, discriminability was related to aspects of language that are more reliant on executive functioning. It is therefore suggested that verbal memory in PD is interpreted within the context of one's language ability. Other potential mechanisms and clinical implications are discussed.

98 Cognitive Outcomes Following Bilateral Focused Ultrasound Thalamotomy for Tremor

Objective:Essential tremor (ET) is the most common movement disorder, characterized by bilateral action tremors of the upper extremities. Surgical interventions can be considered for severe cases that are refractory to medication. Magnetic resonance-guided focused ultrasound (MRgFUS) of the ventral intermediate nucleus of the thalamus (Vim) is a recently approved, minimally invasive treatment for unilateral tremor. While patients are generally pleased with unilateral treatment, many patients are bothered by tremor on the untreated side. Historically, bilateral thalamotomy has been associated with a higher rate of adverse events, including cognitive impairment. MRgFUS Vim thalamotomy for bilateral tremor is currently being investigated. The goal of the present study was to evaluate the effect of bilateral MRgFUS Vim thalamotomy on cognition.Participants and Methods:Twelve patients with medication-refractory essential tremor (mean age = 68.77 +/- 11.78 years, mean education = 14.34 +/- 2.71 years, 8 male) were included in the present study. Three of the 12 patients met criteria for mild cognitive impairment (MCI). All patients successfully underwent unilateral MRgFUS thalamotomy at least 48 weeks before the second thalamotomy. A battery of neuropsychological tests was administered to patients before (considered baseline in the present study) and three months following the second thalamotomy. Baseline evaluations occurred on average 144.64 +/- 91.53 weeks (range: 55.00 - 346.58) after the first thalamotomy. The neuropsychological battery assessed domains of processing speed (Oral Symbol Digit Modalities Test, D-KEFS Color-Word Naming and Reading), attention (WAIS-IV Digit Span Forward), executive function (D-KEFS Color-Word Inhibition and Inhibition/Switching), working memory (WAIS-IV Digit Span Backward and Sequencing), verbal fluency (D-KEFS Letter Fluency and Animal Fluency), confrontation naming (Boston Naming Test), verbal memory (Hopkins Verbal Learning Test-Revised), and visuospatial perception (Judgment of Line Orientation). Alternate versions of tests were used when possible. Cognitive changes were analyzed at the group and individual level. Group level changes were assessed with paired sample t-tests (corrected for multiple comparisons). At the individual level, postoperative declines &gt; 1.5 SD from baseline were considered clinically significant.Results:Participants’ baseline intellectual functioning ranged from low average to superior (as measured by the WTAR). The mean baseline score on the Montreal Cognitive Assessment was 24.58 (range: 17 - 30). At the group level, there were no significant changes in cognitive scores from baseline to follow-up (all p values &gt; 0.635). At the individual level, one patient with MCI declined &gt; 1.5 SD on the verbal memory composite. No other patients showed declines &gt; 1.5 SD.Conclusions:Our preliminary findings suggest that bilateral MRgFUS Vim thalamotomy is relatively safe from a cognitive perspective. However, a single patient with MCI exhibited clinically significant postoperative decline in verbal memory. Future studies with larger sample sizes are needed to investigate the factors that increase the risk of postoperative cognitive decline, including pre-existing cognitive impairment, older age, and lesion size.

A - 82 Perceived Social Support Is Associated with Cognition but Not Physical Functioning in Older Adults with and without Multiple Sclerosis.

To examine the association between perceived social support, cognition, and physical functioning in older adults with and without Multiple Sclerosis (MS). Participants were dementia-free older adults with MS (N = 89; M age = 64.75, SD + 4.25years; 66.3% female) and community-residing older adults (N = 102; M age = 68.74, SD + 7.12years; 62.7% female). The medical outcomes study modified social support survey (MSSS), oral symbol digit modalities test (SDMT) and timed-25-foot-walk-test (T25FW) served as outcome measures. Linear regressions stratified by group status assessed the associations between PSS, cognition, and physical functioning. Higher total MSSS scores were associated with higher SDMT scores in the MS group (β= 0.24, p = 0.02) and in the control group (β= 0.26, p = 0.005). Positive social interaction (β= 0.27, p = 0.011) was associated with SDMT performance in the MS group. Emotional/informational support (β= 0.27, p = 0.003) and positive social interaction (β= 0.25, p = 0.007) were associated with SDMT performance in the control group. Depression scores attenuated associations between perceived social support and SDMT performance in the MS group (p > 0.05) but not the control group. In contrast, higher MSSS scores were not associated with higher T25FW scores in either group. Among older adults with and without MS, perceived social support was associated with cognition but not physical functioning. Depressive symptoms attenuated associations between perceived social support and cognition in the MS group only.

Diet-induced changes in functional disability are mediated by fatigue in relapsing-remitting multiple sclerosis: A secondary analysis of the WAVES randomized parallel-arm trial.

People with multiple sclerosis (MS) often report dietary modifications; however, evidence on functional outcomes remains sparse. Evaluate the impact of the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets on functional disability among people with relapsing-remitting MS. Baseline-referenced MS functional composite (MSFC) scores were calculated from nine-hole peg-test (NHPT), timed 25-foot walk, and oral symbol digit modalities test (SDMT-O) collected at four study visits: (a) run-in, (b) baseline, (c) 12 weeks, and (d) 24 weeks. Participants were observed at run-in and then randomized at baseline to either the Swank (n = 44) or Wahls (n = 43) diets. Among the Swank group, MSFC scores significantly increased from -0.13 ± 0.14 at baseline to 0.10 ± 0.11 at 12 weeks (p = 0.04) and 0.14 ± 0.11 at 24 weeks (p = 0.02). Among the Wahls group, no change in MSFC scores was observed at 12 weeks from 0.10 ± 0.11 at baseline but increased to 0.28 ± 0.13 at 24 weeks (p = 0.002). In both groups, NHPT and SDMT-O z-scores increased at 24 weeks. Changes in MSFC and NHPT were mediated by fatigue. Both diets reduced functional disability as mediated by fatigue. Clinicaltrials.gov Identifier: NCT02914964.

Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy

BackgroundWe analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability...

Traumatic Brain Injury, Cognition and Structural Racism in Persons Newly Diagnosed with Multiple Sclerosis (P4-9.007)

<h3>Objective:</h3> To determine if traumatic brain injury (TBI) contributes to the oral lower Symbol Digit Modalities Test (SDMT) scores we previously reported in Black and Hispanic patients with newly diagnosed multiple sclerosis (MS) compared to white patients. <h3>Background:</h3> The MS Sunshine Study found that Black and Hispanic participants with newly diagnosed MS had lower oral SDMT scores than white participants but that this difference was best explained by underlying population differences rather than disease severity. TBI has been correlated with lower SDMT scores. Rates of TBI are higher and rehabilitative care for TBI is provided less often in Black and Hispanic people residing in the US. <h3>Design/Methods:</h3> We studied 1,172 adults (553 incident MS, 619 controls) who enrolled in the MS Sunshine Study. Detailed TBI histories were obtained during the structured in-person interview. TBI was classified as Mild A (no loss of consciousness, LOC, but with concussive/post-concussive symptoms), Mild B (LOC for &lt;30 minutes), Moderate (LOC &gt;30min and &lt;24 hours) or Severe (LOC &gt;24 hours). Multivariable regression was used to examine correlates of SDMT scores. <h3>Results:</h3> 103 (9%) participants reported a history of at least one TBI with maximum severity of Mild A, 190 (16%) Mild B, 29 (2%) Moderate and 8 (0.7%) Severe. There was no significant difference in frequency or severity of TBIs across racial or ethnic groups or by case/control status. There was no significant correlation between any category of TBI and SDMT scores, nor did accounting for TBI modify the correlation between having MS, being Black or Hispanic and lower SDMT scores. <h3>Conclusions:</h3> TBI did not explain the lower SDMT scores observed in Black or Hispanic participants. The pervasive effects of systemic racism in the US remain the best explanation for the lower SDMT scores observed in Black and Hispanic participants, both those with newly diagnosed MS patients and matched controls. <b>Disclosure:</b> Dr. Akinsanya has nothing to disclose. Ms. Smith has nothing to disclose. Ms. Gonzales has nothing to disclose. An immediate family member of Dr. Langer-Gould has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of American Thoracic Society. The institution of Dr. Langer-Gould has received research support from PCORI. The institution of an immediate family member of Dr. Langer-Gould has received research support from PCORI, ARQ, NIH. Dr. Langer-Gould has a non-compensated relationship as a Voting Member with ICER CTAF Panel that is relevant to AAN interests or activities.

Individual reserve in aging and neurological disease.

Cognitive and physical functions correlate and delineate aging and disease trajectories. Whereas cognitive reserve (CR) is well-established, physical reserve (PR) is poorly understood. We, therefore, developed and evaluated a novel and more comprehensive construct, individual reserve (IR), comprised of residual-derived CR and PR in older adults with and without multiple sclerosis (MS). We hypothesized that: (a) CR and PR would be positively correlated; (b) low CR, PR, and IR would be associated with worse study outcomes; (c) associations of brain atrophy with study outcomes would be stronger in lower compared to higher IR due to compensatory mechanisms conferred by the latter. Older adults with MS (n = 66, mean age = 64.48 ± 3.84years) and controls (n = 66, mean age = 68.20 ± 6.09years), underwent brain MRI, cognitive assessment, and motoric testing. We regressed the repeatable battery for the assessment of neuropsychological status and short physical performance battery on brain pathology and socio-demographic confounders to derive independent residual CR and PR measures, respectively. We combined CR and PR to define a 4-level IR variable. The oral symbol digit modalities test (SDMT) and timed-25-foot-walk-test (T25FW) served as outcome measures. CR and PR were positively correlated. Low CR, PR and IR were associated with worse SDMT and T25FW performances. Reduced left thalamic volume, a marker of brain atrophy, was associated with poor SDMT and T25FW performances only in individuals with low IR. The presence of MS moderated associations between IR and T25FW performance. IR is a novel construct comprised of cognitive and physical dimensions representing collective within-person reserve capacities.

Sensory-Motor and Affective-Fatigue Factors are Associated with Symbol Digit Performance in Multiple Sclerosis.

The oral Symbol Digit Modalities Test (SDMT) has become the standard for the brief screening of cognitive impairment in persons with multiple sclerosis (PwMS). It has been shown to be sensitive to sensory-motor factors involving rudimentary oral motor speed and visual acuity, as well as multiple sclerosis (MS) affective-fatigue factors including depression, fatigue, and anxiety. The present study was designed to provide a greater understanding of these noncognitive factors that might contribute to the oral SDMT by examining all these variables in the same sample. We examined 50 PwMS and 49 healthy controls (HCs). All participants were administered the oral SDMT, two sensory-motor tasks (visual acuity and oral motor speed), and three affective-fatigue measures (depression, fatigue, and anxiety). Partially consistent with hypotheses, we found that sensory-motor skills, but not affective-fatigue factors, accounted for some of the group differences between the MS and HC groups on the oral SDMT, reducing the MS/HC group variance predicted from 10% to 4%. Also, PwMS with below average sensory-motor abilities had oral SDMT scores that were lower than PwMS with intact sensory-motor skills (p<.05). Finally, 71% of PwMS in the below-average sensory-motor group were impaired on the oral SDMT compared with 14% of the intact group (p=.006). When the oral SDMT is used as the sole screening tool for cognitive impairment in MS, clinicians should know that limitations in visual acuity and rudimentary oral motor speed should be considered as possibly being associated with performance on it in MS.

A New Score Unveils a High Prevalence of Mild Cognitive Impairment in Patients with Nonalcoholic Fatty Liver Disease.

Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The neurological functions affected remain unclear. The aims were to: (1) Characterize the neuropsychological alterations in NAFLD patients; (2) assess the prevalence of impairment of neurological functions evaluated; (3) develop a new score for sensitive and rapid MCI detection in NAFLD; (4) assess differences in MCI features between patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH); and (5) compare neuropsychological alterations in NAFLD patients with cirrhotic patients with MCI. Fifty-nine NAFLD patients and 53 controls performed psychometric tests assessing different neurological functions: PHES (Psychometric Hepatic Encephalopathy Score) battery, d2, Stroop, Oral SDMT (Symbol Digit Modalities Test), Digit Span, number-letter test, and bimanual and visual-motor coordination tests. NAFLD patients show impairment in attention, mental concentration, psychomotor speed, cognitive flexibility, inhibitory mental control, and working memory. We developed a new, rapid, and sensitive score based on the most affected parameters in NAFLD patients, unveiling that 32% of NAFLD show MCI. Prevalence was similar in NAFL (36%) or NASH (27%) patients, but lower in NAFLD than in cirrhosis (65%). MCI prevalence is significant in NAFLD patients. Psychometric testing is warranted in these patients to unveil MCI and take appropriate measures to reverse and prevent its progression.

Exercise training and cognition in multiple sclerosis: The GET Smart trial protocol

Background and objectivesMultiple sclerosis (MS) causes cognitive impairment in approximately 50% of cases. Disease modifying medications and cognitive rehabilitation produce only small positive effects on cognition in MS. Converging animal and human research suggests that aerobic exercise may improve cognition in people with MS, but definitive trials are lacking. We describe the design of the GET Smart study, a randomized controlled trial comparing the effects of aerobic exercise versus stretching and toning on cognition in MS. MethodsThe study is a single-blind, parallel group randomized (1:1) controlled trial that compares aerobic exercise training with an active control group consisting of stretching and toning exercises for improving cognition. Participants are nondepressed, ambulatory, non-exercising adults with MS aged 18–54 years who have below average cognitive processing speed. Both treatments were designed to generate equivalent outcome expectancies and entailed supervised, progressive exercise programs, 3 times per week for up to 40 min over a 6 month period. Projected patient outcomesThe primary hypothesis is that the aerobic training group will demonstrate significantly greater cognitive processing speed compared with the control group at the end of the treatment phase (6 months) as measured by a composite of the Paced Auditory Serial Additon Test and the oral Symbol-Digit Modalities Test using intent-to treat analyses. Secondary outcomes are neuropsychological functioning and cardiorespiratory fitness as well as participant reported outcomes such as depression, sleep, and fatigue. Study findings will inform future research, patient education, clinical care and policymaking. Trial RegistrationClinicalTrials.gov Identifier NCT02106052

Performance of Regression-Based Norms for Cognitive Functioning of Persons With Multiple Sclerosis in an Independent Sample.

Background: Cognitive impairment is common in multiple sclerosis (MS). Interpretation of neuropsychological tests requires the use of normative data. Traditionally, normative data have been reported for discrete categories such as age. More recently continuous norms have been developed using multivariable regression equations that account for multiple demographic factors. Regression-based norms have been developed for use in the Canadian population for tests included in the MACFIMS and BICAMS test batteries. Establishing the generalizability of these norms is essential for application in clinical and research settings.Objectives: We aimed to (i) test the performance of previously published Canadian regression-based norms in an independently collected sample of Canadian healthy controls; (ii) compare the ability of Canadian and non-Canadian regression-based norms to discriminate between healthy controls and persons with MS; and (iii) develop regression-based norms for several cognitive tests drawn from batteries commonly used in MS that incorporated race/ethnicity in addition to age, education, and sex.Methods: We included 93 adults with MS and 96 healthy adults in this study, with a replication sample of 104 (MS) and 39 (healthy adults). Participants reported their sociodemographic characteristics, and each was administered the oral Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R). From the healthy control data, we developed regression-based norms incorporating race, age, education and sex. We then applied existing discrete norms and regression-based norms for the cognitive tests to the healthy controls, and generated z-scores which were compared using Spearman rank and concordance coefficients. We also used receiver operating characteristic (ROC) curves to compare the ability of each set of norms to discriminate between participants with and without MS. Within the MS samples we compared the ability of each set of norms to discriminate between differing levels of disability and employment status using relative efficiency.Results: When we applied the published regression norms to our healthy sample, impairment classification rates often differed substantially from expectations (7%), even when the norms were derived from a Canadian (Ontario) population. Most, but not all of the Spearman correlations between z-scores based on different existing published norms for the same cognitive test exceeded 0.90. However, concordance coefficients were often lower. All of the norms for the SDMT reliably discriminated between the MS and healthy control groups. In contrast, none of the norms for the CVLT-II or BVMT-R discriminated between the MS and healthy control groups. Within the MS population, the norms varied in their ability to discriminate between disability levels or employment status; locally developed norms for the SDMT and CVLT-II had the highest relative efficiency.Conclusion: Our findings emphasize the value of local norms when interpreting the results of cognitive tests and demonstrate the need to consider and assess the performance of regression-based norms developed in other populations when applying them to local populations, even when they are from the same country. Our findings also strongly suggest that the development of regression-based norms should involve larger, more diverse samples to ensure broad generalizability.

Switching to fingolimod in PREFERMS: Effect of treatment history and naïvety on clinical, MRI and treatment satisfaction outcomes✰

BackgroundInjectable disease-modifying therapies (iDMTs) are often used as first-line treatments for relapsing multiple sclerosis. Fingolimod is frequently used following treatment with iDMTs. Whether prior iDMT treatment impacts the effectiveness of subsequent fingolimod therapy is unclear. Here, we assessed switching from iDMTs to fingolimod, and the impact of treatment history on fingolimod escalation using data from the 12-month ‘Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease-modifying thErapies in adults with Relapsing–remitting Multiple Sclerosis’ (PREFERMS). The study design and results at the end of randomized treatment (EoRT) in PREFERMS have been published. MethodsBoth treatment-naïve patients and those who had previously received an iDMT were eligible for enrolment in PREFERMS, and one treatment switch was permitted on study. Pre-specified exploratory analyses compared outcomes in those randomized to fingolimod or to an iDMT at end of study (EoS), which included time spent on randomized and on switch treatment. Post hoc exploratory analyses (unadjusted for multiplicity owing to the large number of comparisons) among patients randomized to an iDMT who switched to fingolimod, compared outcomes longitudinally before (EoRT) and after (EoS) switching, and compared outcomes at EoRT and EoS among subgroups stratified by iDMT-treatment history. Outcomes included brain volume, various measures of gadolinium-enhancing [Gd+] lesion counts, annualized relapse rate (ARR), Symbol Digit Modalities Test (SDMT) score, patient-reported treatment satisfaction using the Medication Satisfaction Questionnaire (MSQ) and adverse event (AE) rates. ResultsAt EoS, 255 of 439 patients randomized to an iDMT had switched to fingolimod and 27 of 436 patients randomized to fingolimod had switched to an iDMT. By EoS, 44.2% of total treatment exposure in the iDMT group was to fingolimod and the mean time spent on fingolimod in this group was 220 days (approximately 7 months). Outcomes in the fingolimod group at EoS (brain volume, changes in Gd+ lesion counts, ARR, oral SDMT score and MSQ score) were similar to those seen at EoRT, but in the iDMT group these outcomes were more favorable at EoS than at EoRT and were similar to rates seen in the fingolimod group. Among patients who switched from iDMT to fingolimod, there were longitudinal improvements in ARR (EoRT, 0.3 [95% confidence interval (CI), 0.2–0.4]; EoS, 0.2 [0.1–0.3]; odds ratio, 0.5 [0.3–0.9]) and in treatment satisfaction (proportion of patients with MSQ > 5; EoRT, 67.4%; EoS, 90.4%; odds ratio, 5.7 [95% CI, 3.4–9.4]) after fingolimod treatment, and changes in brain volume, Gd+ lesion count, and AEs or AEs causing discontinuation were also more favorable at EoS than at EoRT. In all patient groups stratified by iDMT-treatment history, differences in outcomes narrowed or disappeared after fingolimod treatment. ConclusionThese analyses indicate that patients in PREFERMS had improved outcomes within months of switching to fingolimod from an iDMT and that improvements occurred irrespective of the number of iDMTs previously administered. These data provide a unique opportunity to explore clinical, radiological and safety outcomes associated with a range of clinically relevant treatment pathways.

Device-Measured Physical Activity and Cognitive Processing Speed Impairment in a Large Sample of Persons with Multiple Sclerosis.

There is accumulating evidence regarding the beneficial effects of physical activity (PA) on cognitive processing speed in persons with multiple sclerosis (MS). However, one overarching limitation of this research is that researchers have not recruited samples who have the actual problem of being studied (i.e., cognitive processing speed impairment). This study examined associations between device-measured PA and cognitive processing speed in a large sample of persons with MS overall and between those with and without cognitive processing speed impairment. Three hundred eighty-five persons with MS underwent the oral Symbol Digit Modalities Test (SDMT) and wore an accelerometer for 7 days for PA measurement. We divided the overall sample into subsamples with (n = 140) and without (n = 245) cognitive processing speed impairment based on age, sex, and education-adjusted SDMT Z-scores. After controlling for age and disability status, higher levels of device-measured PA were significantly associated with faster cognitive processing speed overall, and the association was significantly stronger among persons with MS who presented with cognitive processing speed impairment. This examination provides initial cross-sectional support for informing the development of PA interventions as a possible approach for managing MS-related cognitive processing speed impairment. This highlights the importance of developing purposefully designed trials involving PA interventions for targeting cognitive processing speed as a primary end point among persons with MS with impaired cognitive processing speed.

Race, ethnicity, and cognition in persons newly diagnosed with multiple sclerosis.

To determine whether black or Hispanic patients with newly diagnosed multiple sclerosis (MS) are more likely to have cognitive impairment than white patients when compared to controls matched on age, sex, and race/ethnicity. Whether black or Hispanic patients have a more aggressive MS disease course than white patients remains unclear. No prior studies have examined differences in early cognitive impairment. The oral Symbol Digit Modalities Test (SDMT) is sensitive to early cognitive impairment in MS but normative data in nonwhite patients are limited. We studied 1,174 adults who enrolled in the MS Sunshine Study. SDMT and verbal fluency were measured in 554 incident cases of MS or clinically isolated syndrome (CIS) and 620 matched controls. Multivariable regression was used to examine correlates of abnormal SDMT in the entire cohort. The strongest independent predictors of lower oral SDMT scores in rank order were having MS/CIS, lower educational attainment, and being black or Hispanic. Black and Hispanic patients and controls had lower SDMT scores than white participants even after controlling for age, sex, and education. However, no interaction between race/ethnicity and MS case status on SDMT scores was detected. Easy-to-use reference scores stratified by age and educational attainment for black and Hispanic patients are provided. Persons with newly diagnosed MS/CIS are more likely to have subtly impaired cognitive function than controls regardless of race/ethnicity. Lower absolute SDMT scores among black and Hispanic patients compared to white patients highlight underlying US population differences rather than differences in MS disease severity.

Cognitive mediated eye movements during the SDMT reveal the challenges with processing speed faced by people with MS

BackgroundThe Symbol Digit Modalities Test (SDMT) is regarded as the cognitive test of choice for people with MS (pwMS). While deficits are linked to impaired processing speed, the mechanisms by which they arise are unclear. Cognitive-mediated eye movements offer one putative explanation. The objective of this study was to determine the association between eye movements and performance on the SDMT.MethodsThirty-three people with confirmed MS and 25 matched healthy control subjects (HC) were administered the oral SDMT while eye movements were recorded.ResultsMean SDMT scores were significantly lower in pwMS (p < 0.038). Shorter mean saccade distance in the key area (p = 0.007), more visits to the key area per response (p = 0.014), and more total number of fixations in the test area (p = 0.045) differentiated pwMS from HCs. A hierarchical regression analysis revealed that the number of visits to the key area per response (p < 0.001; ΔR2 = 0.549) and total number of fixations in the test area (p < 0.001; ΔR2 = 0.782) were the most robust predictors of SDMT scores.ConclusionCognitive-mediated eye movements help elucidate the processing speed challenges confronted by people with MS. Mechanistic insights such as these can potentially help inform new cognitive rehabilitation strategies.

The Effects of Radiation and Sex Differences on Adaptive Functioning in Adult Survivors of Pediatric Posterior Fossa Brain Tumors.

Radiation therapy (RT) improves rates of survival of patients with childhood brain tumors but increases deficits in cognition and independent living skills. Previous literature has studied difficulties in basic cognitive processes, but few explore impairment in higher-order skills such as adaptive functioning. Some studies identify females as at risk for cognitive deficits due to RT, but few investigate sex differences in adaptive functioning. It was hypothesized that females would exhibit poorer long-term independent living skills and core cognitive skills relative to males following RT. Forty-five adult survivors of posterior fossa childhood brain tumors (24 females) completed the Wechsler Abbreviated Scale of Intelligence (WASI-II), Wechsler Memory Scale, Third Edition (WMS-III) Digit Span Forward (DSF) and Backward (DSB), and Oral Symbol Digit Modalities Test (OSDMT). Informants completed the Scales of Independent Behavior-Revised (SIB-R). DSF and OSDMT were positively correlated with all five SIB-R domains, full-scale IQ (FSIQ) was positively correlated with four SIB-R domains, and DSB was positively correlated with three SIB-R domains. There was an interaction between sex and RT for OSDMT and community living skills with trend level interactions for personal living skills and broad independent living skills, where females without RT had higher scores than females with RT. Female survivors were more affected by RT than males across the community living skills domain of adaptive functioning as well as processing speed. Processing speed deficits may have a cascading impact on daily living skills. Future studies should investigate how clinical and biological factors may contribute to personalized treatment plans between sexes. (JINS, 2019, 25, 729-739).

Motor-free composites from the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) for people with disabilities.

The National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) includes a group of brief measures (i.e., 30 min) designed to assess language, processing speed, working memory, episodic memory, and executive functioning. These subtests can be combined to create composite scores that reflect fluid and crystallized cognition, as well as overall cognition. The battery is of limited utility with individuals who have impaired upper extremity motor functioning. This manuscript examines the accuracy of the Oral Symbol Digit Modalities Test as a substitute for the Pattern Comparison Processing Speed Test for computing motor-free composite scores. Research Method/Design: Individuals with spinal cord injury (SCI; n = 188), traumatic brain injury (TBI; n = 159), or stroke (n = 180) completed the NIHTB-CB. We used the Oral Symbol Digit Modalities Test to create a Motor-Free Pattern Comparison score; this was used to create revised, Motor-Free Composite scores for Fluid Cognition and Overall Cognition. Although there were statistically significant overall differences between the two Fluid and Overall Cognition composite scores for some of the clinical groups (scores based on the motor-free approach were significantly higher than the original score), these differences were small and partly because of overclassification of impaired processing speed in participants with motor impairment. There was good to substantial agreement with regard to "impairment" classification between the two sets of Original and Motor-Free composite scores. Although the Motor-Free scores are not a perfect match for the Original Composite scores, they provide a reliable and valid way to examine overall and fluid cognition in individuals with upper extremity motor impairments. (PsycINFO Database Record