A proposed new taxonomy of cognitive phenotypes in multiple sclerosis: The International Classification of Cognitive Disorders in MS (IC-CoDiMS).

BACKGROUND: Characterization of cognitive impairment (CI) in multiple sclerosis into distinct phenotypes holds promise for individualized treatments and biomarker exploration. OBJECTIVE: Apply a previously validated, neuropsychologically driven diagnostic algorithm to identify a taxonomy of the type of cognitive phenotypes in multiple sclerosis. METHODS: An algorithm developed and validated in other neurological diseases was applied to a cohort of 1281 people with multiple sclerosis who underwent clinical neuropsychological evaluation across three multiple sclerosis centers. A domain was marked impaired if scores on two tests within the domain fell below one of the two thresholds of interest (compared to controls; -1.0 SD and -1.5 SD below the mean). Results were then tabulated for each participant to determine the type of impairments across the sample. RESULTS: At -1 SD threshold, 48.7% were intact, 21.6% had single-domain, 14.3% bi-domain, and 15.4% multi-domain impairment. At -1.5 SD threshold, 72.9% were intact, 14.0% had single-domain, 8.2% bi-domain, and 5.0% multi-domain impairment. Processing speed was the most frequent single-domain impairment, followed by executive function and memory. CONCLUSIONS: These findings advance the taxonomy of cognitive phenotypes in multiple sclerosis and clarify the type and distribution of possible cognitive diagnoses, pave the way for further investigation of associated biomarkers, and provide clinically meaningful information to guide individualized treatment and rehabilitation.

Cognitive outcomes in anti-LGI-1 encephalitis.

OBJECTIVE: Cognitive impairment is one of the most common symptoms of anti-leucine rich glioma inactivated 1 (anti-LGI-1) encephalitis, but little is known about the cognitive profile of these patients. This study characterized the cognitive profile of patients with anti-LGI-1 encephalitis and compared patterns of impairment to healthy controls and other patient groups with known temporal lobe/limbic involvement. METHODS: A retrospective analysis of adult patients with anti-LGI-1 encephalitis who underwent neuropsychological assessment was conducted. Performance patterns of anti-LGI-1 patients were compared to patients deemed cognitively healthy (HC), as well as patients with amnestic mild cognitive impairment (aMCI) and temporal lobe epilepsy (TLE). RESULTS: Among 10 anti-LGI encephalitis patients (60% male, median age 67.5 years) who underwent neuropsychological testing (median = 38.5 months from symptom onset), cognitive deficits were common, with 100% of patients showing impairment (≤1.5 SD below mean) on 1+ measures and 80% on 2+ measures. Patients with anti-LGI-1 encephalitis performed worse than controls on measures of basic attention, vigilance, psychomotor speed, complex figure copy, and aspects of learning/memory. Of measures which differed from controls, there were no differences between the anti-LGI-1 and TLE patients, while the anti-LGI-1 patients exhibited higher rates of impairment in basic attention and lower rates of delayed verbal memory impairment compared to the aMCI patients. CONCLUSIONS: Long-term cognitive deficits are common in patients with anti-LGI-1 encephalitis and involve multiple domains. Future research in larger samples is needed to confirm these findings.

Performance Validity Testing in Multiple Sclerosis.

OBJECTIVE: Performance validity tests (PVTs) are designed to detect nonvalid responding on neuropsychological testing, but their associations with disease-specific and other factors are not well understood in multiple sclerosis (MS). We examined PVT performance among MS patients and associations with clinical characteristics, cognition, mood, and disability status. METHOD: Retrospective data analysis was conducted on a sample of patients with definite MS (n = 102) who were seen for a clinical neuropsychological evaluation. Comparison samples included patients with intractable epilepsy seen for presurgical workup (n = 102) and patients with nonacute mild traumatic brain injury (mTBI; n = 50). Patients completed the Victoria Symptom Validity Test (VSVT) and validity cutoffs were defined as <16/24 and <18/24 on the hard items. RESULTS: In this MS cohort, 14.4% of patients scored <16 on the VSVT hard items and 21.2% scored <18. VSVT hard item scores were associated with disability status and depression, but not with neuropsychological scores, T2 lesion burden, atrophy, disease duration, or MS subtype. Patients applying for disability benefits were 6.75 times more likely to score <18 relative to those who were not seeking disability. Rates of nonvalid scores were similar to the mTBI group and greater than the epilepsy group. CONCLUSIONS: This study demonstrates that nonvalid VSVT scores are relatively common among MS patients seen for clinical neuropsychological evaluation. VSVT performance in this group relates primarily to disability status and psychological symptoms and does not reflect factors specific to MS (i.e., cognitive impairment, disease severity). Recommendations for future clinical and research practices are provided.

The role of migraine headache severity, associated features and interactions with overweight/obesity in inhibitory control.

AIM OF THE STUDY: While migraine and obesity are related and both conditions are associated with reduced executive functioning, no study has examined whether obesity exacerbates executive dysfunction in migraine. This cross-sectional study examined whether overweight/obesity moderated associations of migraine severity and associated features with inhibitory control, one aspect of executive function. MATERIALS AND METHODS: Women (n = 124) aged 18-50 years old with overweight/obesity body mass index (BMI) = 35.1 ± 6.4 kg/m2 and migraine completed a 28-day smartphone-based headache diary assessing migraine headache severity (attack frequency, pain intensity) and frequency of associated features (aura, photophobia, phonophobia, nausea). They then completed computerized measures of inhibitory control during an interictal (headache-free) period. RESULTS: Participants with higher migraine attack frequency performed worse on the Flanker test (accuracy and reaction time; p < .05). Migraine attack frequency and pain intensity interacted with BMI to predict slower Stroop and/or Flanker Reaction Time (RT; p < .05). More frequent photophobia, phonophobia and aura were independently related to slower RT on the Stroop and/or Flanker tests (p < .05), and BMI moderated the relationship between the occurrence of aura and Stroop RT (p = .03). CONCLUSIONS: Associations of migraine severity and presence of associated features with inhibitory control varied by BMI in overweight/obese women with migraine. These findings warrant consideration of weight status in clarifying the role of migraine in executive functioning.

Depressive Symptoms Contribute to Executive Deficits in Temporal Lobe Epilepsy.

This study examined the contribution of depression to reduced executive functioning in temporal lobe epilepsy (TLE) using three groups: TLE only (TLE; N=29), TLE+depression (TLE+DEP) (N=22), and nonneurologic participants with depression (DEP; N=31). Participants completed the Delis-Kaplan Executive Function System. Individuals with TLE performed worse than the DEP group on many tests of executive functions. Among the TLE participants, those with depression demonstrated poorer executive functioning. These findings support the notion that depression may further contribute to executive difficulties in individuals with TLE. Depression treatment in this population could lead to improvements in cognition.

Lower inhibitory control interacts with greater pain catastrophizing to predict greater pain intensity in women with migraine and overweight/obesity.

BACKGROUND: Pain catastrophizing (PC) is associated with more severe and disabling migraine attacks. However, factors that moderate this relationship are unknown. Failure of inhibitory control (IC), or the ability to suppress automatic or inappropriate responses, may be one such factor given previous research showing a relationship between higher PC and lower IC in non-migraine samples, and research showing reduced IC in migraine. Therefore, we examined whether lower IC interacts with increased PC to predict greater migraine severity as measured by pain intensity, attack frequency, and duration. METHODS: Women (n = 105) aged 18-50 years old (M = 38.0 ± 1.2) with overweight/obesity and migraine who were seeking behavioral treatment for weight loss and migraine reduction completed a 28-day smartphone-based headache diary assessing migraine headache severity. Participants then completed a modified computerized Stroop task as a measure of IC and self-report measures of PC (Pain Catastrophizing Scale [PCS]), anxiety, and depression. Linear regression was used to examine independent and joint associations of PC and IC with indices of migraine severity after controlling for age, body mass index (BMI) depression, and anxiety. RESULTS: Participants on average had BMI of 35.1 ± 6.5 kg/m2and reported 5.3 ± 2.6 migraine attacks (8.3 ± 4.4 migraine days) over 28 days that produced moderate pain intensity (5.9 ± 1.4 out of 10) with duration of 20.0 ± 14.2 h. After adjusting for covariates, higher PCS total (ß = .241, SE = .14, p = .03) and magnification subscale (ß = .311, SE = .51, p < .01) scores were significant independent correlates of longer attack duration. IC interacted with total PCS (ß = 1.106, SE = .001, p = .03) rumination (ß = 1.098, SE = .001, p = .04), and helplessness (ß = 1.026, SE = .001, p = .04) subscale scores to predict headache pain intensity, such that the association between PC and pain intensity became more positive at lower levels of IC. CONCLUSIONS: Results showed that lower IC interacted with higher PC, both overall and specific subcomponents, to predict higher pain intensity during migraine attacks. Future studies are needed to determine whether interventions to improve IC could lead to less painful migraine attacks via improvements in PC.

Cognitive impairment in older adults with epilepsy: Characterization and risk factor analysis.

OBJECTIVE: Cognitive deficits are common in epilepsy, though the impact of epilepsy on cognition in older adults is understudied. This study aimed to characterize cognition in older adults with epilepsy compared with healthy older adults and identify potential risk factors for impairment. METHODS: Thirty-eight older adults with epilepsy and 29 healthy controls completed a comprehensive neuropsychological battery, as well as measures of depression and anxiety. Chart review for current medications, seizure history, and neuroimaging was also completed. To compare cognitive performance between groups, ANOVA was used, and linear regression identified predictors of impairment among the group with epilepsy. RESULTS: Patients with epilepsy performed worse across nearly all cognitive domains, and were clinically impaired (i.e., ≥ 1.5 SD below mean) on more individual tests when compared with controls, including a subset of patients with epilepsy with normal MRIs. For all patients with epilepsy, taking a greater number of antiepileptic drugs was associated with poorer language and visuospatial abilities, and higher anxiety was associated with poorer visual memory. CONCLUSIONS: Older adults with epilepsy demonstrated greater cognitive deficits than matched controls. Polytherapy and anxiety heightened the risk for cognitive impairment in some cognitive domains, but not in others. Understanding the nature of cognitive decline in this population, as well as associated risk factors, may assist in the differential diagnosis of cognitive complaints and improve the design of treatment studies for older patients with epilepsy. Replication in larger, longitudinal studies is warranted to generalize these findings.

Subjective cognitive complaints versus objective neuropsychological performance in older adults with epilepsy.

Memory complaints are common among older adults with epilepsy (OAE), though discrepancy between subjective complaints and objective performance often exists. This study examined how accurately OAE and their informants reported on the participant's cognitive difficulties by comparing ratings of everyday cognition to objective performance. Thirty-seven OAE and 27 older adult controls completed a brief battery of neuropsychological tests, the Beck Depression Inventory, and the Cognitive Difficulties Scale (CDS). Each participant had an informant who completed the CDS. Older adults with epilepsy performed worse than controls on cognitive testing and reported more subjective cognitive complaints. Neither participant- nor informant-reported cognitive complaints were related to performance on any of the neuropsychological tests for either the group with epilepsy or control group, but both were related to greater depressive symptoms. Results suggest that subjective report of cognitive problems by both OAE and their informants may not reliably reflect the extent to which these problems exist.

Neurocognitive Effects of Obesity and Bariatric Surgery.

This review paper will discuss the recent literature examining the relationship between obesity and neurocognitive outcomes, with a particular focus on cognitive changes after bariatric surgery. Obesity is now recognized as an independent risk factor for adverse neurocognitive outcomes, and severely obese persons appear to be at even greater risk. Bariatric surgery is associated with rapid improvements in cognitive function that persist for at least several years, although the mechanisms underlying these improvements are incompletely understood. Assessment of cognitive impairment in bariatric surgery patients is challenging, and improved methods are needed, as poorer performance on neuropsychological tests of memory and executive function leads to poorer clinical weight outcomes. In addition to its clinical importance, further study in this area will provide key insight into obesity-related cognitive dysfunction and clarify the possibility of an obesity paradox for neurological outcomes.

Physical activity and cognitive function in bariatric surgery candidates.

Cognitive impairment is common in severe obesity. Lack of physical activity is a likely contributor to impairment in this population, as many obese persons are inactive and physical activity has been positively and independently associated with cognitive function in healthy and medically-ill samples. This study investigated whether physical activity, measured by self-report of aerobic physical activity in 85 bariatric surgery candidates, was associated with cognitive function. A subset of 31 participants also completed objective activity monitoring. Steps/d and high-cadence min/week, representative of ambulatory moderate to vigorous physical activity (MVPA), were calculated. Approximately one quarter of participants self-reported at least 30 min/d of aerobic MVPA, at least 5 d/week. Median steps/d was 7949 (IQR = 4572) and median MVPA min/week was 105 (IQR = 123). Cognitive deficits were found in 32% of participants (29% memory, 10% executive function, 13% language, 10% attention). Controlling for demographic and medical factors, self-reported aerobic physical activity was weakly correlated with lower attention (r = -0.21, p = 0.04) and executive function (r = -0.27, p < 0.01) and both self-reported aerobic physical activity and objectively-determined MVPA min/week were negatively correlated with memory (r = -0.20, p = 0.04; r = -0.46; p = 0.02, respectively). No other correlations between physical activity measures and cognitive function were significant. Contrary to expectations, greater levels of physical activity were not associated with better cognitive functioning. Such findings encourage future studies to clarify the association among cognitive function and physical activity in obese persons.

Body mass index and brain structure in healthy children and adolescents.

Obesity is associated with cognitive dysfunction in children and adolescents, although the mechanisms underlying these deficits remain unclear. This study examined the associations between body mass index (BMI) and regional gray matter volume and white matter integrity in 120 healthy children and adolescents (6-18 years of age) who underwent magnetic resonance and diffusion tensor imaging. Bonferroni-corrected partial correlation analyses controlling for demographic and clinical characteristics revealed significant inverse associations between demographically standardized BMI values and gray matter volume of frontal (r = -0.31) and limbic (r = -0.35) brain regions. No such pattern emerged for fractional anisotropy of white matter tracts. Subsequent hierarchical regression analyses indicated that the relationship between standardized BMI and structural gray and white matter brain indices did not vary with age. These findings suggest that obesity in children and adolescents is associated with decreased volume of frontal and limbic cerebral gray matter regions. Further research is much needed to better elucidate possible brain-based mechanisms for cognitive dysfunction associated with obesity.

Standalone Performance Validity Tests May Be Differentially Related to Measures of Working Memory, Processing Speed, and Verbal Memory in Patients With Multiple Sclerosis.

Cognitive functioning may account for minimal levels (i.e., 5%-14%) of variance of performance validity test (PVT) scores in clinical examinees. The present study extended this research twofold: (a) by determining the variance cognitive functioning explains within three distinct PVTs (b) in a sample of patients with multiple sclerosis (pwMS). Seventy-five pwMS (Mage = 48.50, 70.6% female, 80.9% White) completed the Victoria Symptom Validity Test (VSVT), Word Choice Test (WCT), Dot Counting Test (DCT), and three objective measures of working memory, processing speed, and verbal memory as part of clinical neuropsychological assessment. Regression analyses in credible groups (ns ranged from 54 to 63) indicated that cognitive functioning explained 24% to 38% of the variance in logarithmically transformed PVT variables. Variance from cognitive testing differed across PVTs: verbal memory significantly influenced both VSVT and WCT scores; working memory influenced VSVT and DCT scores; and processing speed influenced DCT scores. The WCT appeared least related to cognitive functioning of the included PVTs. Alternative plausible explanations, including the apparent domain/modality specificity hypothesis of PVTs versus the potential sensitivity of these PVTs to neurocognitive dysfunction in pwMS were discussed. Continued psychometric investigations into factors affecting performance validity, especially in multiple sclerosis, are warranted.

Neuropsychological Manifestations of Multiple Sclerosis.

This review article summarizes the literature on the cognitive impairment seen amongst people with multiple sclerosis (MS) and how that impairment can impact not only their lives but also how their care needs to be managed. Recommendations regarding screening and monitoring of cognitive issues are reviewed, as well as how common comorbidities can further impact cognition. The current literature with respect to treatment options is also summarized. Finally, the article reviews the literature on some special populations living with MS.

Disparities in DMT treatment: Demographic and neurocognitive differences between MS patients currently treated versus not treated with disease-modifying therapies.

BACKGROUND: Current treatment guidelines recommend consideration of disease-modifying therapy (DMT) for all multiple sclerosis (MS) patients, but barriers to access have begun to be identified. In particular, prior studies have found that people with higher education have better access to DMTs, perhaps explained by the association of higher education with higher income. And while the majority of people with MS are women, being male is also associated with higher income. These factors argue for the need to better understand whether there are differences in DMT uptake based on sex and education. Finally, in addition to well-documented benefits of DMTs for slowing disease progression, there is growing evidence to suggest benefits of DMTs for cognitive functioning. OBJECTIVE: Determine whether rates of DMT treatment differ based on education and sex. Secondarily, we investigate whether neurocognitive test performance differs in treated versus not treated groups. METHODS: In cross-sectional data, mixed effects linear regression evaluated differences in education and sex of those treated versus not treated with DMTs. Models included the following predictors: age, disease duration, MS subtype, sex/education, disability, atrophy, and T2 lesion volume. Propensity score weights were extracted to obtain unbiased estimates of the relationship between DMT status and each outcome of interest. The same models evaluated performance differences between groups on an iPad-based processing speed test (PST) and manual dexterity test (MDT). RESULTS: Controlling for covariates, individuals with less education (OR=1.09, 95 % CI=[1.03, 1.14], p = 0.003) and women (OR=0.80, 95 % CI=[0.72, 0.90], p < 0.001) were less likely to be currently treated with DMTs. Small effect size association was shown for DMT treatment with better performance on PST (beta=0.09, CI=[0.06, 0.13], p < 0.001) and MDT (beta=0.05, CI=[0.01,0.08], p = 0.011). CONCLUSIONS: Women and people with lower education had a lower likelihood of being currently treated with DMTs. After controlling for all relevant variables, an independent (small) association of DMT treatment to better performance on tests of processing speed and fine motor dexterity was found. Reasons for disparities remain to be investigated in future work, and may include employment status, health insurance coverage, or sex differences in risk tolerance.

Associations Between Cognitive Impairment and Neuroimaging in Patients with Multiple Sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a debilitating inflammatory and neurodegenerative disease which commonly involves cognitive dysfunction. Magnetic resonance imaging (MRI) studies have shown that patients with MS (pwMS) have diffuse patterns of brain atrophy, however, the relationship between the presentation of cognitive dysfunction and brain tissue loss remains understudied. Given the integral function of thalamus as a central nervous system relay center and its involvement in various brain circuits, thalamic atrophy may play a key role in the development and progression of cognitive dysfunction. The purpose of this study is to examine the relationship between cognitive impairment in pwMS and thalamic atrophy. METHODS: A total of 121 pwMS who had neuropsychological testing and quantitative MRI within 1 year of each were retrospectively identified. Grouped LASSO linear regression with 10-fold cross validation was used to estimate each neuropsychological test score with thalamic volume as the focal predictor and all other demographic and MRI metrics as covariates. RESULTS: Rates of impairment ranged from 19% to 44%. Results showed notable associations between thalamic volume and Symbol Digit Modalities Test (ß = 0.11), Brief Visuospatial Memory Test, delayed (ß = 0.12), California Verbal Learning Test, delayed and total (ß = 0.24 and ß = 0.15 respectively), and Trail Making Test Part A (ß = -0.01), after adjusting for covariates. CONCLUSIONS: These findings demonstrate an independent association between thalamic volumes and processing speed and memory performance, after accounting for demographic, clinical, and other MRI variables, among pwMS.

Review of the Longitudinal Management of Autoimmune Encephalitis, Potential Biomarkers, and Novel Therapeutics.

Purpose of Review: Increasing awareness and earlier diagnosis of autoimmune encephalitis (AE) have led to a greater number of patients being cared for longitudinally by neurologists. Although many neurologists are now familiar with the general approach to diagnosis and acute immunosuppression, this review aims to provide neurologists with guidance related to management beyond the acute phase of disease, including long-term immunosuppression, monitoring, potential biomarkers of disease activity, outcome measures, and symptom management. Recent Findings: Observational studies in AE have demonstrated that early diagnosis and treatment is associated with improved neurologic outcomes, particularly in AE with antibodies targeting neuronal cell surface/synaptic proteins. The literature regarding long-term management is evolving. In addition to traditional immunosuppressive approaches, there is emerging use of novel immunosuppressive therapies (ISTs) in case series, and several randomized controlled trials are planned. Novel biomarkers of disease activity and methods to measure outcomes and response to treatment are being explored. Furthermore, it is increasingly recognized that many individuals have chronic symptoms affecting quality of life including seizures, cognitive impairment, fatigue, sleep disorders, and mood disorders, and there are emerging data supporting the use of patient centered outcome measures and multidisciplinary symptom-based care. Summary: This review aims to summarize recent literature and offer a practical approach to long-term management of adult patients with AE through a multidisciplinary approach. We summarize current knowledge on ISTs, potential biomarkers of disease activity, outcome measures, and long-term sequelae. Further research is needed to answer questions regarding optimal IST, biomarker validity, and sequelae of disease.

Neuropsychological Testing in Autoimmune Encephalitis: A Scoping Review.

BACKGROUND AND OBJECTIVES: Identifying optimal methods for evaluation and monitoring of cognitive outcomes in AE is important for clinical care and research. This scoping review aimed to evaluate neuropsychological tests (NPT) that are most frequently impaired in AE cohorts to provide recommendations for a standardized NPT battery for AE outcome. METHODS: PubMed search for studies examining NPT in patients with AE was conducted on June 9, 2023. Studies were screened for inclusion/exclusion criteria as follows: at least 1 NPT, individual NPT test scores with comparison with healthy controls or normative data and neural-IgG status, total sample size ≥5, and English manuscript available. RESULTS: The search yielded 5,393 studies, of which 3,359 were screened, 107 were full text reviewed, and 32 met inclusion/exclusion criteria, anti-NMDA-R (k = 18), anti-LGI1 (k = 10), anti-GABAB-R (k = 2), anti-GAD-65 (k = 4), and anti-CASPR2 (k = 3). The cognitive domains most frequently impaired were visual and verbal episodic memory, attention/working memory, processing speed, and aspects of executive functions. DISCUSSION: Given the dearth of literature examining NPT in AE in combination with small sample sizes and methodological differences, more research in this area is needed. However, we provide recommendations for a test battery to be used in future studies, with the aim of standardizing research in this area. Based on the available literature, we recommend the use of comprehensive NPT batteries, spanning all cognitive domains. The highest yield measures may include the tests of (1) visual and verbal learning/memory, (2) basic and sustained attention, (3) processing speed, and (4) executive functions.

Utility of the Brief Assessment of Cognitive Health (BACH) computerized screening tool in identifying MS-related cognitive impairment.

BACKGROUND: Current guidelines recommend that individuals with MS are screened annually for processing speed deficits, often using the Symbol Digit Modalities Test (SDMT). However, given the heterogeneity of cognitive deficits in individuals with MS, other screening measures that assess a range of cognitive domains are necessary. The current cross-sectional study aimed to examine the ability of the computerized, self-administered Brief Assessment of Cognitive Health (BACH) screening measure to detect the presence of cognitive impairment in adults with MS as determined by performance on a standard neuropsychological test battery. METHODS: Seventy-two individuals with MS completed the BACH and a comprehensive neuropsychological test battery. Receiver operating characteristic (ROC) analyses were conducted to investigate the ability of the BACH to identify cognitively impaired and cognitively intact individuals. ROC analyses were also conducted to compare the ability of the SDMT to discriminate between cognitively intact and cognitively impaired groups as a comparison with the BACH. RESULTS: Cognitive impairment was observed in 56 % of the sample. The BACH showed acceptable ability to discriminate between cognitively intact and cognitively impaired groups (AUC = 0.78). Additionally, the BACH was able to adequately predict cognitive impairment in domains other than processing speed (AUC = 0.71). The SDMT also demonstrated adequate utility in identifying individuals with cognitive impairment (AUC = 0.73); however, the SDMT was not able to adequately predict cognitive impairment in domains other than processing speed (AUC = 0.56). CONCLUSION: The BACH showed adequate ability to detect cognitive impairment in individuals with MS. The BACH was able to identify impairments across various assessed cognitive domains, including individuals with and without processing speed deficits.

Comparing Cognitive Profiles in Older Adults With Multiple Sclerosis and Alzheimer Disease: More Similarities Than Differences.

Background and Objectives: Up to 65% of people with multiple sclerosis (MS) experience disease-related cognitive impairment, but even after decades of research, still very little is known about the cognitive issues among older adults with MS (EwMS; individuals aged 60+). To date, few studies have attempted to characterize cognitive impairment in this group or compare EwMS with those with other neurodegenerative diseases. Our goal was to address this knowledge gap by comparing EwMS with individuals experiencing cognitive impairment due to probable Alzheimer disease (AD) with biomarker confirmation. Methods: We conducted an observational study of individuals seen for routine clinical care at the Cleveland Clinic. After excluding for potential confounding factors, 6 groups were assembled based on the results of their clinical workup and neuropsychological examination: cognitively normal, cognitively normal with MS, mild neurocognitive disorder (due to MS or AD), and major neurocognitive disorder (due to MS or AD). These groups were compared in terms of cognitive test performance, percentage of the group impaired on specific cognitive skills, and rates of cognitive impairment. Results: The sample comprised 140 individuals (64 EwMS and 76 demographically matched individuals from a memory clinic). Among those with mild neurocognitive disorder, differences between MS and AD were marked. However, in those with major neurocognitive disorder, these differences largely disappeared, except persistent performance differences on a measure of rote verbal memory. EwMS outperformed those with AD on memory tests at each level of cognitive impairment. EwMS also exhibited both subcortical and cortical deficits, rather than solely subcortical deficits. Discussion: The overall characterization of the cognitive profile of MS may be different than once described, involving both classically cortical and subcortical functions. Clinically, our results suggest that distinguishing between the cognitive effects of MS and AD at more severe levels of cognitive impairment may be less reliable than once thought. Future work to replicate these findings in other samples and deepen the understanding of cognition in older individuals with MS is needed.