Pediatric acquired demyelinating syndromes (PADS) include a heterogeneous group of diagnoses, including acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders (NMOSD), optic neuritis (ON) and transverse myelitis (TM). Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is often associated with demyelinating conditions, but may also present with encephalopathy without demyelinating lesions. Approximately 30% of patients diagnosed with MOGAD experience a relapse. Neurocognitive outcomes in PADS have reduced performance on tasks related to attention, processing speed, visual motor, and fine motor functioning. Psychosocial problems include anxiety, depression, and fatigue. Neurocognitive and psychosocial impacts of MOGAD events for the pediatric population are sparse. The current study sought to characterize neurocognitive sequelae from MOGAD (MAGAD+) compared to patients diagnosed withPADS without MOGAD (MOGAD-).

Twenty children and adolescents (6–18 years) diagnosed with PADS were recruited using a clinic convenience sample of patients. Study participants completed a neurocognitive battery and parents completed questionnaires of behavioral and emotional functioning. Demographic and medical variables were collected via retrospective chart review. Chi square and t-test analyses were used to compare MOGAD+ and MOGAD- groups. Performance on neuropsychological and behavioral questionnaires were compared to established sex and age norms to assess the degree to which group means deviate from normative expectations.

MOGAD+ and MOGAD- groups did not significantly differ based on demographic, neurocognitive, or parent reported social and behavioral functioning. Neurocognitive testing documented mean scores that were in the average range between groups. Notable variability in performance was observed within both MOGAD+ and MOGAD- groups. Bilateral fine motor deficits, visual motor, visual perception attention, and executive functioning deficits were notable for the combined PADS group, with 30-50% performing >1.5 SD below the mean. The number of white matter lesions or hospital duration were not significantly associated with performance on neurocognitive measures. However, older age of onset of PADS was significantly correlated with lower performance on visual motor integration and visual perception tasks (r(18) = -.50 p = .026; r(18) = -.53 p = .016). Findings also revealed associations of shorter hospitalization stays with higher behavioral symptoms on a parent measure of social/behavioral functioning (r(18) = -.47 p = .037).

Consistent with the PADS literature, relative to control norms, lower performance on tasks related to attention, executive functioning, visual motor, and fine motor skills, irrespective of MOGAD status, are observed in the current study. The variability of functioning and heterogeneity observed across PADS diagnoses warrants further study to better understand the impact of clinical course, treatment outcomes, and neuropsychological sequelae over time in this population. Higher behavioral distress with shorter hospital stays may indicate a potential opportunity for patient and family education preparing for return to home/community. The current study was limited by small sample size, variable time since hospitalization, and heterogeneous diagnoses within PADS that make it difficult to generalize findings. Future studies could prospectively follow patients over time to better understand the trajectory of recovery, identify predictors for relapse, and those at greatest risk of neurocognitive and behavioral deficits.

Social support is an emerging protective factor against cognitive decline. However, the relationship between social support and cognitive functioning in the multiple sclerosis (MS) population is not well understood. The present study aimed to investigate the associations between different aspects of social support and cognitive performance among persons with MS.

A volunteer sample of 63 persons with MS (% female = 88.9, mean age = 48.16) completed measures assessing perceived levels of social support measured by the Medical Outcomes Study Support Social Survey 5-item short form (MSSS-5), and social network (social network diversity and total size of social network) measured by the Social Network Index (SNI). Cognitive functioning was assessed by a brief virtual examiner-administered neuropsychological test battery (using a teleconferencing platform), including the Rey Auditory Verbal Learning Test, Controlled Oral Word Association Test, animal naming, and the Symbol Digit Modalities Test. Participants also completed brief, self-paced, virtual cognitive tests through the testmybrain.org platform, which consisted of digit span and the Trail-Making Test. A principal component analysis (PCA) was carried out to reduce the number of neuropsychological outcomes into fewer dimensions. Multiple linear regressions were conducted to examine the associations between social support measures and cognitive performance. Regression models were adjusted by the levels of depressive symptoms (operationalized by the Chicago Multiscale Depression Inventory or the Hospital Anxiety and Depression Scale) and premorbid functioning (measured by the Test of Premorbid Functioning).

A PCA reduced neuropsychological outcomes into 3 components representing cognitive domains of 1) processing speed/executive functioning, 2) verbal memory, and 3) verbal fluency / simple attention. In the unadjusted models, both perceived social support (i.e., to what extent one receives assistance from their social network) as well as total size of social network (i.e., total number of people one regularly talks to) were significant predictors of the processing speed/executive functioning component score of moderate strength, where F(1, 59) = 11.93, p = .001, β = 0.41 and F(1, 59) = 11.57, p = .001, β = 0.41, respectively. These associations were maintained after adjusting for depressive symptoms and level of premorbid functioning (F(4, 55) = 3.31, p = .003 and F(4, 55) = 3.31, p = .006, respectively). On the other hand, social network diversity (i.e., number of different types of close social relationships one has) was not a significant predictor of the processing speed/executive functioning component score (p > 0.05). None of the social support measures were significantly associated with the verbal memory and verbal fluency/simple attention component scores.

Greater social support (specifically, perceived levels of assistance and total size of social network) is associated with better performance on processing speed/executive functioning measures among persons with MS, independent of effects from depressive symptoms and premorbid functioning. Maintaining a strong social support network may be an important factor in optimizing cognitive health in MS.

Multiple Sclerosis (MS) affects up to 500,000 adults in the United States, with cognitive impairment present in 45%-65% of people. Studies showed hippocampal atrophy in MS, but the underlying mechanisms remain unknown. Inflammation has been proposed to play a significant role, and associations between systemic inflammatory biomarkers and hippocampal atrophy have been shown in other neurological conditions. However, research exploring serum biomarker and volumetric associations in MS are lacking. Given that conventional imaging methods lack resolution for hippocampal internal architecture (HIA), new protocols were developed. We used the High-Resolution Multiple Image Co-Registration and Averaging (HR-MICRA) method to visualize the HIA subfields. We investigated the relationship between subfield volumes generated from HR-MICRA scans and systemic serum biomarkers in MS.

Patients with MS were recruited (N= 34, mean age= 54.6, 35.3% Black) underwent Magnetic Resonance Imaging (MRI), and serum biomarkers were obtained, specifically chosen for their potential role in MS. Inflammatory biomarkers included; granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor- a (TNF- a), and growth factors; vascular endothelial growth factor (VEGF); insulin-like growth factor-1 (IGF-1), and brain derived growth factor (BDNF). Imaging was performed in a Siemens Prisma 3T scanner with a 64-channel head coil using the HR-MICRA method. Hippocampal subfields were calculated using the Automated Segmentation of Hippocampal Subfields (ASHS) package. We used the Magdeburg Young Adult 7T Atlas for sub-hippocampal structures and Penn Temporal Lobe Epilepsy T1-MRI Whole Hippocampus ASHS Atlas for general hippocampal structure and segmentation. Pearson's product-moment analyses provided correlations between biomarkers and hippocampal subfield volumes for each cerebral hemisphere. A statistical significance level of p < 0.05 was used for all analyses.

Correlations emerged between left hemisphere Cornu Ammonis (CA) 2 and G-CSF (r = -.384; p = .025); IL-10 (r = -.342; p = .048); VEGF (r = -.371; p= .031); and CA3 with IL-10 (r = -.488, p = .003); G-CSF (r = -.386; p= .024); VEGF (r = -.352; p= .041). Dentate gyrus correlated with MMP-9 (r =.416; p=.014); IL-10 (r = -.365; p =.034). BDNF was correlated with right hemisphere CA1 (r = -.417, p = .014), CA2 (r = -.497; p= .003) and CA3 (r = -.451; p=.007).

In our sample of persons with MS, left hemisphere hippocampal subfield volumes were negatively correlated with inflammatory biomarkers, supporting previous reports linking inflammation to reduced brain volumes in other neurological conditions. In the right hemisphere, we found negative correlations between HIA and BDNF, suggesting a neuroprotective function for BDNF in this neurodegenerative disease. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between HIA and systemic serum biomarkers in MS.

To investigate the relationship between systematic inflammatory biomarkers and cognition in patients with Multiple Sclerosis (MS).

We recruited 36 patients diagnosed with MS (31 with relapsing-remitting and 5 with progressive) who presented for treatment at the University of Alabama at Birmingham (UAB). Patients underwent a comprehensive neuropsychological battery, and serum blood samples were collected. Cognitive data was divided into an overall Cognitive Composite score and seven cognitive domains (i.e., Attention, Verbal Memory, Visual Memory, Visuospatial Ability, Language, Processing Speed, and Executive Function) using z-score averages. Pearson's product-moment correlations were conducted to determine the relationship between cognitive performance and 14 inflammatory biomarkers specifically chosen for their potential role in MS.

Granulocyte Colony Stimulating Factor (G-CSF) was significantly correlated with Executive Function (r= -.355; p=.039) and Processing Speed (r= -.528; p= .001) scores. Additionally, Interleukin-10 (IL-10) was significantly correlated with Visual Memory (r= -.346; p= .041) scores. Finally, Tumor Necrosis Factor (TNF-a) was significantly correlated with Visual Memory (r= -.347; p= .041).

Studies investigating associations between inflammation and cognition in MS are lacking. In our sample of persons with Multiple Sclerosis, G-CSF biomarkers were negatively correlated with Executive Function as well as Processing Speed. In addition, IL-10 and TNF-a biomarkers were negatively correlated with Visual Memory scores. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between systematic inflammatory biomarkers and cognition in MS.

Multiple sclerosis (MS), an inflammatory autoimmune disease of the central nervous system, is characterized by damage to white matter via myelin degeneration with resulting sclerotic plaques and lesions. Upwards of 70% of people with MS show cognitive changes in multiple domains including verbal memory. Advances in disease-modifying therapies have increased the expected lifespan of people with MS, making aging with MS a critical emerging area of study. Memory declines during normal aging, yet the specific impact of MS on verbal memory in aging is inconclusive and understudied. To address this gap in knowledge, we examined whether MS was associated with verbal learning slope, total learning, delayed recall, and recognition performance in older adults. We further explored whether MS disease severity influenced these memory operations.

Participants included two cohorts: older adults with MS recruited from MS centers and patient registries, and healthy controls recruited from the community. A total of 164 adults age 60 and older without dementia were included in the current study, 79 in the MS group (mean age = 65.05 + 4.72; %female = 62) and 85 in the control group (mean age = 69.53 + 6.65; %female = 65.9). All participants were administered a neuropsychological battery including the Hopkins Verbal Learning Test-Revised (HVLT-R). The Patient Determined Disease Steps (PDDS), a patient-rated score of disability severity in MS comprised of eight steps related to walking ability, was used to operationalize MS severity. Using a median split, the PDDS was dichotomized into low (PDDS = 0-2) versus high (PDDS = 3-5) MS severity groups. Linear regression models were run to examine the effect of group (MS vs. control) and disease severity (PDDS) on four operations from the HVLT-R: learning slope, total learning, delayed recall, and recognition. Statistical analyses adjusted for age, years of education, and sex.

Linear regression models revealed that older adults with MS showed lower total learning compared to healthy controls (β = -.18, p = .03). Learning slope, delayed recall, and recognition did not differ by group (p > .05). Compared to healthy controls, older adults with high MS severity performed worse on total learning (β = -.21; p = .01) and delayed recall (β = -.18; p = .03). Group differences on learning slope and recognition were not significant (p > .05).

The presence of MS was associated with worse total learning. Moreover, high severity of MS was associated with worse total learning and delayed recall in older adults. These results delineate the influence of MS on specific memory operations and emphasize the potential utility of disease severity on cognitive performance in aging.

The relationship between frontotemporal dementias (FTDs) and amyotrophic lateral sclerosis (ALS) is well established and is believed to be more pronounced in those with bulbar onset ALS (B-ALS). This study compared cognitive and behavioral symptoms among persons with B-ALS to those of individuals with nonbulbar phenotypes (NB-ALS).

Outpatient clinic data collected during an initial neuropsychology consultation at an ALS interdisciplinary clinic in an academic medical center was retroactively analyzed. All individuals were diagnosed with ALS by neurologists specializing in movement and neuromuscular disorders based on results of neurological/motor examination, electromyographies, and (when available) genotypic data. Total scores on the short form of the Montreal Cognitive Assessment (MoCA-SF) and scores on the ALS Cognitive Behavioral Screen (ALS-CBS) and ALS CBS Caregiver questionnaire were of focus. 22 B-ALS and 44 NB-ALS individuals were compared on said measures using univariate analyses while controlling for ALS symptoms duration.

B-ALS individuals scored significantly lower on the MoCA-SF (F(2)=3.15, p=0.05, n2=0.13) and the tracking subscale of the ALS-CBS (F(2)=3.50, p=0.04, n2=0.17). The groups were not significantly different on other ALS-CBS measures, including caregiver-rated behavior questionnaire.

Consistent with previous research, this study found lower total scores on a brief screener of global cognition and tasks of tracking requiring cognitive control in those with B-ALS relative to NB-ALS individuals. Interestingly, despite behavioral variant being the most prevalent FTD phenotype, the groups did not differ significantly in terms of caregiver-rated behavioral changes. It is hypothesized that the absence of these differences could reflect effects of gradual loss of speech and functionality that secondarily limit caregivers' abilities to observe behavioral changes concerning for possible behavioral variant FTD. That said this could reflect limitations of the sample and/or study design, and further exploration is therefore needed. Recommendations for future studies of neuropsychological/behavioral variables in B-ALS as well as development of more targeted instruments for use in this population are discussed.

Verbal memory deficits are present in multiple sclerosis (MS), but neither inflammatory T2 lesion volume nor cerebral atrophy (generalized or localized hippocampal atrophy) fully explain disease-related verbal memory changes. Importantly, the hippocampus does not function in a vacuum; memory encoding and retrieval requires interactions between the hippocampus and cortical areas where information is processed and represented. Indeed, we have previously shown that lexical access speed (a language function assessed by rapid automatized naming) independently predicted delayed recall of verbal information (word list) for persons with MS, even when controlling for total learning. Informed by this work and recent ultra high field (7.0 Tesla) MRI research reporting high cortical lesion count in regions associated with phonological processing (e.g., plenum temporale, superior temporal gyrus), we assessed whether phonological processing independently explains verbal memory deficits in persons with MS.

Analyses were performed on a clinical sample of persons withMS aged 18 to 59 years (n=60: 49 relapsing, 11 progressive). Word-list memory was assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R), which yielded scores for Total Learning (TL) and Delayed Recall (DR). Phonological processing was assessed with WIAT-4 Phonemic Proficiency. WIAT-4 Sentence Repetition was utilized as a non-phonological language control task, and WIAT-4 Word Reading was administered to control for premorbid verbal ability. CANTAB Paired Associate Learning served as a nonverbal memory comparison. Performance on tasks was standardized using published age-adjusted norms. Primary analyses used partial correlations to assess relationships between Phonemic Proficiency and (a) HVLT-R TL and DR controlling for WIAT-4 Word Reading, and (b) HVLT-R DR controlling for WIAT-4 Word Reading and HVLT-R TL. To assess specificity to phonological processing, the same partial correlations assessed relationships between Sentence Repetition and HVLT-R variables, and between Phonemic Proficiency and nonverbal memory (CANTAB PAL).

When controlling for premorbid verbal ability, Phonemic Proficiency performance accounted for 7.8% of the variance in HVLT-R TL (rpartial=0.28, p=0.031) and 16% of the variance in HVLT-R DR (rpartial=0.40, p=0.002). Moreover, when additionally controlling for HVLT-R TL, Phonemic Proficiency still accounted for 10% of the variance in HVLT-R DR (r partial— 0.32, p=0.016). Showing specificity to phonological processing ability, performance on Sentence Repetition was not significantly related to HVLT-R DR when controlling for premorbid verbal ability (WIAT-4 Word Reading) and HVLT-R TL (rpartial=0.09, p=0.510). Showing specificity to verbal memory, neither Phonemic Proficiency nor Sentence Repetition performance were reliably related to CANTAB PAL for any variance in performance in nonverbal memory (Ps>0.9).

Results suggest that language ability, specifically phonological processing, contributes to delayed recall of word lists independent of premorbid verbal ability and initial total learning scores in persons with MS. These findings demonstrate contributions of language ability to verbal memory and highlight the need for further research into language ability changes in persons with MS. This may have implications for verbal memory rehabilitation in MS.

Research has shown that social support has protective effects against cognitive decline in older adults. No study to date has examined the relationship between social support and cognition in older adults with Multiple Sclerosis (MS). Advances in treatments for MS have resulted in a growing number of aging individuals with MS, making it imperative to identify modifiable risk factors that affect cognition, such as social support. Therefore, this study was designed to examine the association between social support and cognition in older adults with MS and healthy controls.

Participants were older adults with MS (N = 70; M age = 64.71, SD + 3.86 years; 62.9% female) and community-residing older adults (N = 74; M age = 68.42, SD + 5.96 years; 58.1% female). Perceived social support was assessed using the Medical Outcomes Study Modified Social Support Survey (MSSS), which measures emotional/informational support, tangible support, affectionate support, and positive social interaction. Cognition was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which measures immediate and delayed memory, attention, language, and visuospatial abilities. Linear regressions stratified by group status (MS vs. control) assessed the association between perceived social support and cognition.

Linear regressions controlling for age, gender, education, and medical comorbidities showed that higher total MSSS scores were related to higher RBANS scores in the MS group (β = 0.243, p = .046) and marginally in the control group (β = 0.239, p = .053). Examination of MSSS domains showed that emotional/informational support (β = 0.246, p = .044) and positive social interaction (β = 0.279, p = .023) were significant predictors of RBANS performance in the MS group. Positive social interaction (β = 0.262, p = .011) was a significant predictor of RBANS performance in the control group. Analyses that further adjusted for depression scores showed that positive social interaction remained a significant predictor of RBANS performance in the control group (β = 0.361, p = .005). In contrast, depression scores attenuated associations between all aspects of social support and RBANS performance in the MS group (p > .05).

Among older adults, the association between social support and cognition varied as a function of MS status. Overall perceived social support, emotional/informational support, and positive social interaction were significantly associated with cognition in the MS group. However, depressive symptoms attenuated these associations. In contrast, positive social interaction was the key driver of the association between social support and cognition among the healthy controls, and notably, this association remained significant even after adjusting for depressive symptoms.

Prospective memory (PM) is the ability to remember to produce an action at a specific moment in the future signaled by the occurrence of a specific event (EB condition), a time or a time interval (TB condition). Detection of the appropriate moment corresponds to the prospective component (PC), while production of the appropriate action corresponds to the retrospective (RC) component. Although PM difficulties have been reported in healthy aging and in association with Multiple Sclerosis (MS), PM has not been examined in elderly people with MS (PwMS), which is particularly relevant since their life expectancy has improved significantly in recent years due to available treatments, and PM is essential to daily functioning. The main objective of this study was to investigate whether the decline in PM performance with advancing age is influenced by the presence of multiple sclerosis (MS). This study also aimed to clarify the type of PM impairment (PC vs RC in TB and EB conditions) in MS as a function of age.

A total of 80 participants were recruited and separated into four groups: elderly PwMS (n = 20), young PwMS (n = 20), elderly healthy controls (HC) (n = 20) and young HC (n = 20). PM and its components were measured using the TEMP, an experimental ecological tool developed by our laboratory that has been validated in previous studies. In addition, all participants underwent a series of neuropsychological tests specific to MS (MACIFMS) and aging (Boston Naming Test, Clock Drawing Test, Towers of London, Trail making Test, Stroop, MoCA).

On the TEMP total score, a two-way ANOVA showed a main effect of age (F[1,75]=47.4, p<0.001, n2 = .40), a main effect of the presence of MS (F[1,75]=19.51, p<0.001, n2 = .21) as well as a significant Age X Disease interaction (F[2,74] =5.40, p=0.023, n2 = .07). Direct comparison between EB and TB conditions revealed that for the PC, only elderly PwMS had more difficulty in the TB than in the EB condition (Z = -2.51, p = 0.012), whereas RC score was significantly lower in the TB than in the EB condition in all groups except in younger controls (younger PwMS : Z = -2.56, p = 0.01; elderly HC : Z = -3.31, p < 0.001; elderly PwMS :Z = -3.04, p = 0.002).

The TEMP revealed a marked impairment in PM in elderly PwMS compared to elderly HC and young PwMS. This impairment was particularly evident on the PC component in the TB condition. RC difficulties noted in the TB condition in all but younger controls reflect the arbitrary nature of the cue-action link that is particularly sensitive to episodic memory difficulties often observed in aging and MS.

To test whether adherence to treatment in patients with MS is influenced by cognitive variables (executive functions), personality, and social support.

This is a pilot observational, descriptive, cross-sectional study. 60 patients with Relapsing remitting MS ( 73.33% female; age: 41.41 ±14.00) undergoing medical treatment ( 28 dymethilfumarate, 7 ocrelizumab/ rituximab, 6 fingolimod, 5 interferon, 5 natalizumab, 4 cladribine, 3 teriflunomide, 1 alemtuzumab, 1 glatiramer acetate) underwent a comprehensive multi-component evaluation including : cognition, social support (using the self-reported record of social support scale), personality (using the NEO-FFI questionnaire) and evaluation of treatment adherence using the Morisky Green Levine Medication Adherence Scale Participants were divided into two groups according to their adherence to medical treatment, low vs. high adherence was defined using a cutoff score of 4. Differences between groups were evaluated using Student's t-test with a significance level of p<0.05, the effect size was calculated with Cohen's d test.

Groups did not differ significantly in age, sex, type of treatment, Montreal Cognitive Assesments (MoCA) or neuropsychiatric scales of depression and anxiety. Regardless of treatment type, 63.33% of the patients had high treatment adherence. Significant differences between groups were found in the Global Index of Social Support (p=0.016, Cohen's d= 0.73) and the responsibility factor of the NEO-FFI (p=0.048, Cohen's d= 0.20). Conversely, no significant differences were found in executive functions (p=0.8), Openness (p=0.062), Extraversion (p=0.5), Neuroticism (p=0.4) and Agreeableness (p=0.8).

Social support and the responsibility factor of personality are significantly different between MS patients with high and low adherence to medical treatment. The study of social support and personality may be a key component in improving adherence strategies.

Theory of mind (ToM) deficits have been reported in patients with multiple sclerosis (pwMS). However, most studies have used pictures or written scenarios as stimuli without distinguishing between cognitive and affective ToM, and no studies have investigated older pwMS. The aims of this study were to determine the impact of MS and age on cognitive and affective ToM using a more ecological video-based task. We also aimed to investigate the relationships between ToM, cognition and emotion reading to understand the nature of ToM deficits in pwMS.

We recruited 13 young healthy controls (HC), 14 young pwMS, 14 elderly HC and 15 elderly pwMS. ToM was measured using an adaptation of the Conversations and Insinuations task (Ouellet et al. 2010). In this task, participants watch four 2-minutes videos of social interactions, which are interrupted by multiple choice questions about either the emotional state (affective ToM; 14 questions) or the intention (cognitive ToM; 14 questions) of the characters. They also underwent a short neuropsychological battery including cognitive tasks (Montreal Cognitive Assessment (MoCA), DKEFS Color-Word Interference Test) and an experimental multimodal emotion recognition task.

We found significant effects of group (pwMS < HC), age (older < younger) and condition (cognitive ToM < affective ToM) on the ToM task. Although no interaction effect was found, the elderly pwMS group showed the largest discrepancy between their cognitive and affective ToM, the cognitive subtask being significantly more affected. ToM significantly correlated with general cognition (MoCA) in all participants, while cognitive inhibition (DKEFS Color-Word Interference Test) correlated with ToM only in elderly pwMS. No significant correlation was observed between ToM and emotion reading.

This study highlights both cognitive and affective ToM deficits in pwMS, and particularly in cognitive ToM in elderly pwMS. These impairments could be underlied by cognitive and executive difficulties, but not by core social cognitive impairments, as observed in the correlation analyses. Future studies should investigate the relationships between ToM impairments and impairments in real-life empathy and social behavior in pwMS.

Research examining co-occurring anxiety and depression in persons with multiple sclerosis (PwMS) is scarce, though an estimated 20% of PwMS experience clinically significant anxiety and depression (Gascoyne et al., 2019). Recent work by Hanna & Strober (2020) found that PwMS with comorbid anxiety and depression reported worse outcomes in all constructs of symptomatology, disease management, psychological well-being, and quality of life. However, it is unclear how co-occurring anxiety and depression symptoms may influence or exacerbate cognitive difficulties in PwMS. Further, considering there are high levels of comorbidity between depression, anxiety, and fatigue in PwMS, this study aims to examine the unique variances of depression, anxiety, co-occurring depression and anxiety, and fatigue on cognitive functioning.

86 PwMS (F=65,M=21) completed a comprehensive neuropsychological battery that included self-report measures of anxiety, depression, and fatigue. An intraindividual variability (IIV) composite score was calculated by combining standardized intraindividual standard deviation and maximum discrepancy scores on measures of attention/processing speed and memory for each participant. Lower scores indicate worse performance (i.e., greater variability). A hierarchical regression was conducted with IIV as the outcome variable and with depression, anxiety, cognitive fatigue, physical fatigue, and the interaction between depression and anxiety as predictors. Expanded Disability Status Scale (EDSS) scores were included as a covariate.

The only model that included a statistically significant predictor of IIV was the final model, which included EDSS, depression, anxiety, cognitive fatigue, physical fatigue, and the interaction between depression and anxiety, F(6,77)=2.97, p=.01, AR2=.08. While the main effects of depression and anxiety were not significant, the interaction between depression and anxiety was significant, F(6,77)=7.20, p=.01, n2=.09. Simple effects tests revealed that the relationship between IIV and anxiety was marginally significant for those at the cutoff for clinical depression (square root BDI-FS=2; BDI-FS=4), F(6,77)=3.52, p=.07, n2=.04. However, the effect of anxiety on IIV increased as depression increased. For example, in those with high levels of depression (1.5 SD above the mean), there was a significant relationship between anxiety and IIV, F(6,77)=4.16, p=.04, n2=.05, though this was not the case for those with low levels of depression (1.5 SD below the mean), F(6,77)=0.01, p=.92, n2=.00.

The interaction between depression and anxiety predicted variability in performance such that those with high levels of depression and anxiety demonstrated significantly greater IIV. Since dispersion is considered a marker for neurocognitive integrity, this may suggest that co-occurring psychological disturbances are associated with poorer cognitive integrity, an important consideration for interventions and outcomes. While interventions aimed at treating co-occurring depression and anxiety have been largely overlooked within the MS literature (Butler et al., 2016), transdiagnostic interventions have been beneficial for general adult populations with co-occurring anxiety and depression (McEvoy et al., 2009). Future work should examine the efficacy of interventions aimed at addressing co-occurring depression and anxiety in PwMS, as this may help to improve cognitive functioning, as well as perception of functioning, which will likely further improve quality of life and overall well-being.

Lower levels of social support in persons with Multiple Sclerosis (PwMS) are associated with myriad poor outcomes including worse mental health, lower quality of life, and reduced motor function (Kever et al., 2021). Social support has also been associated with physical pain (Alphonsus et al., 2021) and sleep disturbance (Harris et al., 2020) in PwMS. Pain is one of the most common symptoms of MS (Valentine et al., 2022) and is also known to be related to sleep disturbance (Neau et al., 2012). With these considerations in mind, the goal of the current study was to examine social support as a possible moderator in the relationship between pain and sleep quality in PwMS.

This cross-sectional study included 91 PwMS (females = 76). A neuropsychological battery and psychosocial questionnaires were administered. For sleep quality a composite was created from the sleep and rest scale of the Sickness Impact Profile (SIP), sleep-related items on the Multiple Sclerosis-Symptom Severity Scale (MS-SSS) (i.e., sleeping too much or sleep disturbance, fatigue or tiredness, and not sleeping enough), and an item from the Sleep Habits Questionnaire (SHQ) ("How many nights on average are you troubled by disturbed sleep?"). This composite (a = .76) has been used in prior research. Lower scores were indicative of worse sleep quality. Pain intensity and pain interference were measured using the Brief Pain Inventory (BPI). Pain intensity was calculated from four pain indices (i.e., pain at its worst in the last 24 hours, at its least in the last 24 hours, on average, and current pain at the time of the assessment) and pain interference was calculated from seven indices (i.e., general activity, mood, walking ability, normal work, relationships with others, sleep, and enjoyment of life). The Social Support Questionnaire (SSQ) measured average satisfaction with supports. A series of hierarchical linear regressions were conducted with the sleep quality index as the outcome variable and satisfaction with social supports, both indices of pain (intensity and interference), and their interactions as predictors. Then, simple effects tests were used to clarify the pattern of any significant interactions.

Regression analysis revealed that the interaction between pain interference and satisfaction with social support was significant (p = .034). Simple effects tests revealed that when satisfaction with social support was high, pain interference was associated with better sleep quality (p < .001). The interaction between pain intensity and satisfaction with social supports was also significant (p = .014). Simple effects test revealed that at high levels of satisfaction with social supports, pain intensity was associated with better sleep quality (p < .001).

Satisfaction with social support moderated the relationship between pain interference and pain intensity on sleep quality in PwMS. Specifically, high satisfaction with social support buffers against the negative effects of pain interference and pain intensity on sleep quality in PwMS. This provides evidence that interventions aimed at increasing social supports in PwMS may lead improvements in sleep quality and reduce the impact of pain on sleep quality.

Depression is highly prevalent in persons with multiple sclerosis (pwMS). A reformulated version of the learned helplessness theory posits that individuals who attribute the cause of negative events to personal factors (internal), perceive that the cause persists for a long period of time (stable), and believe it is present in all situations (global) are at an increased risk for depression. As such, it is critical to examine possible modifiable factors that buffer against the deleterious effects of negative attributional style. Therefore, the current study investigated whether stress moderates the relationship between negative attributional style and depression symptoms in an MS sample.

Thirty-six pwMS (30 Female, 6 Male) completed a comprehensive neuropsychological test battery and psychosocial questionnaires that assessed cognitive attributional style, daily stressors, and depression symptoms. The Attributional Style Questionnaire (ASQ) was used to create internal, stable, and global attribution dimension scores, as well as an overall attributional style score combining the three dimensions. Stress was quantified as the total score of perceived hassles from the Hassles and Uplifts Scale (HUS). Depression symptoms were measured using the Beck Depression Inventory-Fast Screen (BDI-FS). Hierarchical linear regressions were conducted with depression symptoms as the outcome variable. Each dimension of attributional style (internal, stable, global, or overall ASQ), stress, and their interactions were included as predictors. Simple effects tests were used to clarify the pattern of any significant interaction.

Regression analyses revealed that the interaction between overall attributional style and stress was significant (p = .025). Simple effects tests revealed that overall attributional style was associated with depression symptoms only in pwMS with high levels of stress (p = .015). For the individual dimensions of the ASQ, several interactions were also significant. The interaction between the internal dimension and stress was significant (p= .009), such that internal attributions were associated with depression symptoms only in pwMS with high levels of stress (p = .002). The interaction between the stable dimension and stress was also significant (p = .01); stable attributional style was associated with depression symptoms only in pwMS with high levels of stress (p = .009). The interaction between the global dimension and stress was not significant.

Stress moderated the relationship between negative attributional style and depression symptoms in pwMS. Specifically, the internal and stable dimensions and overall attributional style were associated with increased depression symptoms only in pwMS who reported high levels of stress, but not in those with low levels of stress. Interventions aimed at reducing and managing stress may help protect against the effects of negative cognitive schemas on depression symptoms in MS. Additionally, previous research demonstrates that attributional style may be a malleable target of evidence-based psychotherapy (Seligman et al., 1988; Proudfoot et al., 2009). Our findings suggest that cognitive therapy specifically targeting the internal and stable dimensions of attributional style may be effective in modifying attributional style, perceptions of stress and, subsequently, improve depression outcomes in MS.

The current study aimed to examine real-time associations between non-cognitive symptoms and cognitive dysfunction (latter measured both objectively and subjectively in real-time) using ecological momentary assessment (EMA).

Forty-five persons with MS completed EMA four times per day for three weeks. For each EMA, participants completed mobile versions of the Trail-Making Test part B (mTMT-B) and a finger tapping task, as well as surveys about symptom severity. Trait (usual levels of a symptom) and state (when symptom level was higher or lower than the individual's usual levels) aspects of each symptom's severity were calculated. Multilevel models were conducted to account for within-person clustering, with performance on the mTMT-B and self-reported rating of cognitive dysfunction as primary outcomes.

A total of 3,174 EMA sessions were collected; compliance rate was 84%. There was significant intra-day variability in mTMT-B performance, anxiety, fatigue, and pain. More severe state depressive symptoms predicted lower performance on the mTMT-B in real-time. Self-reported difficulties with sleeping the night before predicted mTMT-B performance the following day. In contrast, state (but not trait) fatigue, depression, anxiety, and pain all predicted self-reported cognitive dysfunction in real time. Further, state self-reported cognitive dysfunction (but not mTMT-B performance) was associated with a higher perceived sense of accomplishment.

Self-reported cognitive dysfunction was more susceptible to influences of other MS symptoms (especially when the symptom is more severe than the individual's usual levels) and better predicted perceived sense of accomplishment than objectively measured executive functioning in real-time. Objective executive functioning performance was sensitive to effects of depressive symptoms and sleep difficulties. The current study demonstrated the feasibility of assessing real-time associations among MS symptoms using smartphone-administered EMA.

Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease of the central nervous system. Apathy is significantly higher in adults with MS compared to healthy populations. Apathy is a lack of motivation that can cause dysfunctions in each step of goal-directed behaviors. Apathy is associated with diminished ability to perform activities of daily living, tasks requiring normal executive function, and quality of life. Across various neurodegenerative disorders, apathy has been regarded as a predictor of poor cognition and functional outcomes. However, the severity of apathy and its association with cognitive function in older adults with MS have not been reported. This study's objective was to address this gap of knowledge. Hence, we evaluated: 1) the severity of apathy symptoms in older adults with MS compared to healthy older adults and, 2) the association of apathy symptoms and global cognitive functioning in older adults with MS compared to controls.

Participants were community-residing older adults (age >60ys) enrolled in a cohort study, “Brain Predictors of Mobility and Falls in Older Adults with Multiple Sclerosis.” Healthy controls (n=59; mean age=66.25± 3.37; %female=47.5) and persons with MS (n=69; mean age=64.58± 3.88; %female=62.3) were included in the analysis. Using McDonald criteria, MS diagnosis was physician-confirmed by medical record review, apathy symptoms were assessed through 4 apathy symptom questions on the 30-item Geriatric Depression Scale (GDS), and global cognitive functioning was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Covariates included age, gender, years of education, global health score (GHS), and depression (GDS w/out apathy questions). For the first objective, a linear regression model was used with a bi-level group status variable (MS vs controls) serving as a predictor of apathy symptoms. For the second objective, two linear regression models stratified by group status were run with apathy symptoms as a predictor of global cognitive functioning.

The presence of MS was significantly associated with worse apathy (β=.34, p < .001) and it remained significant after adjusting for covariates (β=.19, p=.03). Additionally, apathy was negatively associated with global cognition in persons with MS (β=-.32, p =.01) and this association remained significant after adjusting for covariates (β=-.33, p =.01) except depression (β=-.27, p =.08). The association of apathy and global cognitive functioning was not significant in healthy controls (β=.01, p=.95).

This study is the first to report worse apathy symptoms in older persons with MS compared to healthy controls. Additionally, worse apathy symptoms were associated lower global cognitive functioning in older adults with MS but not in healthy controls.

Word finding difficulty is a prevalent cognitive symptom in multiple sclerosis (MS). Word finding relies on retrieving concepts and word forms from the long-term store. Neuropsychological assessment of word finding difficulty in persons with MS (pwMS) is typically characterized by semantic errors and decreased speed in naming tests, along with decreased semantic verbal fluency scores. Despite this, there is significant heterogeneity in the detection of verbal fluency deficits across studies in the MS literature. This may be partially due to disease-related heterogeneity and/or low sensitivity of commonly used scoring approaches. We investigate the latter in the present study. Semantic network analysis, derived from graph theory, provides a fine-grained approach to understanding semantic retrieval by utilizing information about the co-occurrence of words produced on semantic verbal fluency tasks. Analysis results in a graphical quantification of the conceptual-lexical store. A preliminary study found that semantic networks from Spanish-speaking pwMS had fewer associative connections and more central connective pathways, which if affected, may lead parts of the network to become inaccessible for retrieval. However, their investigation was limited in the generalizability of their findings, as they excluded pwMS who have cognitive impairment (CI), which represents a significant proportion of pwMS. We sought to investigate network differences in an English-speaking MS sample, without exclusion based on CI, using widely-used metrics of micro-, meso-, and macroscopic structure. We hypothesize the MS network will be less efficiently organized, thus characterized by higher average shortest path length (ASPL), lower clustering coefficient (CC) and lower modularity (Q).

53 persons with MS and 44 neurologically healthy controls (HC) were recruited as a part of an ongoing study (NMSS RG-1907-34364 & RG-1901-33304). As a part of a larger battery, participants were administered the semantic verbal fluency subtest of the Controlled Oral Word Association Test. Responses were analyzed using a network-analysis R suite.

The MS and HC networks were characterized by having similar average shortest path lengths (ASPL MS =2.466, ASPL HC=2.463, F(1,1997)=0.281, p=0.596), indicating they require similar numbers of edges to be traversed to reach other nodes in the network. This suggests similar efficiency of information transfer. Clustering coefficient was not significantly different between the MS and HC networks (CC MS = 0.742, CC HC =0.742, F(1,1997)=0.10, p=0.919), suggesting similar local interconnectivity. The MS network had significantly lower modularity compared to the HC network (Q MS =0.497, Q HC = 0.502, F(1,1997)=16.678, p<0.001). This means that sub-communities of the network were less segregated into densely connected sub-graphs.

Contrary to expectation, ASPL and CC were not significantly different between groups. The absence of finding lower CC was consistent with prior findings. Consistent with our hypothesis, the MS network had lower modularity. This may suggest that pwMS were unable to use categorical clustering to aid in retrieval from the lexicon. Specifically, low modularity coupled with similar CC may suggest the structure of the MS lexicon is characterized by intact clustering on a microscopic scale but less strong organization into distinct clusters on a larger scale.

Fatigue is common in pediatric-onset multiple sclerosis (POMS), yet causal factors and correlates of fatigue are poorly understood in this population. A 2016 review suggested an association between fatigue and emotional difficulties, sleep disturbance, and reduced quality of life in POMS. Information regarding the potential association between fatigue and cognitive challenges is limited and mixed. Through this systematic review, we searched for relationships between fatigue, cognition, and mental health.

Systematic review methodology and PRISMA guidelines were followed. Five electronic databases were searched: Ovid: Medline, Ovid: EMBASE, Ovid: PsycInfo, Web of Science and CINAHL. Search terms were specific to each database. Reference lists of included studies were also hand-searched. We included empirical studies that were published in English after 2001, included a sample with confirmed diagnoses of POMS using McDonald criteria, and measured fatigue, cognition and clinical factors including mental health outcomes. Cognition had to be assessed using a standardized assessment tool and studies must have examined associations between outcomes of interest either descriptively or by assessing bivariate or multivariate relationships. Covidence was used to complete the screening, extraction, and quality assessment. Two independent researchers (i.e., T.L.F, and/or S.D, and/or M.G) reviewed each paper included in the title and abstract screen and full text review. S.D and M.G completed the extraction and quality assessments. Conflicts at all stages were resolved by the lead author (T.L.F). The University of Adelaide JBI critical appraisal checklist for analytical cross-sectional studies was used to ensure the scientific rigor of each included study. Sample characteristics and measures of fatigue, clinical and cognitive variables were extracted. A narrative synthesis was conducted.

We identified 1025 abstracts through our initial search and retained 119 articles for full text review. One hundred and six of these studies were excluded during the full text review including six studies which did not examine the relationship between the outcomes of interest. Fifty-one additional studies were identified from hand-searching reference lists of included studies, of which 24 were retained for full text review. A total of 15 studies were extracted and analyzed. Overall, a positive relationship was found between fatigue and mental health outcomes (i.e., anxiety and depression), whereas results were mixed regarding the association between fatigue and performance-based measures of cognition as well as fatigue and other clinical characteristics (e.g., disease duration, EDSS, treatment with DMDs, relapse rate, age at disease onset). In some studies, fatigue and executive functioning performance were negatively related; the relationship was less clear in others (e.g., both fatigued and non-fatigued MS patients demonstrated cognitive challenges, an association between fatigue and executive functioning was identified at follow-up but not baseline). Eleven of the 15 included studies (73%) did not identify associations between fatigue and cognition.

While studies are mixed, fatigue in children has been associated with aspects of cognition. Understanding the relationship between fatigue, cognition, and mental health and identifying gaps in the existing literature, have implications for informing interventions for this clinical population.

Depression is common in persons with MS (PwMS), substantially contributing to morbidity and mortality. Depression can dually impact PwMS as both a psychosocial reaction to living with the disease and a neurological effect of it. Cardinal features of depression include reduced ability to seek and experience pleasure, often attributed to dysregulation of the brain's reward system. People with depression exhibit atypical reward processing, as do fatigued PwMS. However, it is unclear whether MS itself affects reward processing, and whether it interacts with depression. The current study explored the associations of depression, MS, and their interaction on reward responsiveness. We hypothesized that depression and MS would independently be associated with poorer reward responsiveness and that they would interact synergistically to impair reward responsiveness.

Forty PwMS and 40 healthy age- and education-matched healthy controls (HC) participated in a computerized switching task with high- and low-reward manipulations. The Chicago Multiscale Depression Inventory (CMDI) Mood subscale measured depressive symptoms. The Behavioral Inhibition/Activation Scales (BIS/BAS) measured self-reported reward responsiveness and behavioral inhibition. Switching task performance was measured as response time (RT) and accuracy. Performance differences between the high- and low-reward conditions represented performance-based reward responsiveness. Linear mixed effects models were used to estimate the associations of MS and depression with reward responsiveness, behavioral inhibition, and task performance.

Depression, but not MS, was associated with higher BIS scores (p=.007). Neither depression nor MS was associated with BAS subscales. On the switching task, participants who reported lower depression responded to reward such that they were slightly faster in the high-reward condition compared to the low-reward condition (p=.07). By contrast, in participants who reported higher depression, there was no effect of reward on response time. Additionally, MS (p=.009) and depression (p=.018) were each associated with slower response times. Regarding accuracy, no effects of reward were observed; however, there was an interaction between MS and depression. Among HC participants, depression was not related to accuracy. In comparison, PwMS who reported higher depression were more accurate than PwMS who reported less depression (p=.043).

Consistent with hypotheses, higher depressive symptoms were associated with increased behavioral inhibition. Depression was not associated with self-reported reward responsiveness, but it was associated with reduced reward responsiveness on a cognitive task. Contrary to hypotheses, MS was not associated with reduced reward responsiveness. Additionally, higher depression and an MS diagnosis were related to slower response time, consistent with prior findings that psychomotor slowing is a hallmark feature of both disorders. Interestingly, we observed a unique behavioral trend in PwMS, such that PwMS with higher depressive symptoms were more accurate than PwMS with lower depressive symptoms, whereas this relationship was not present among HCs. Altogether, depression in both PwMS and cognitively healthy individuals may be associated with blunted reward responsiveness, but MS does not exacerbate this relationship. In fact, PwMS with depression may be more conscientious in their functioning and therefore perform better on cognitive task accuracy. Continued work should examine how reward processing and its underlying mechanisms may differ in depressed PwMS.

Parkinson’s disease (PD) affects the person’s quality of life, but the comorbidity of PD and impulsive control disorder (ICD), which has an average prevalence of 23%, can enhance the disruption of quality of life for the patients and their caregivers. The effects of ICD in PD on brain morphology and cognition have been little studied. Thus, this study proposes to investigate the differences in the evolution of cognitive performance and brain structures between PD patients with ICD (PD-ICD) vs. without ICD (PD-no-ICD).

Parkinson’s Progression Markers Initiative (PPMI) data of 58 patients with idiopathic PD, including their MRI data at baseline and three years later, were analyzed. The MRIs were processed with FreeSurfer (7.1.1) to extract cortical volumes, areas, thicknesses, curvatures and folding index as well as volumes of subcortical segmentations. All participants underwent cognitive evaluations. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease was used to differentiate those with at least one ICD from those without any ICD. 12 of the 58 patients had an ICD at their first visit and 19 had an ICD at their visit three years later. There was no significant difference between PD-ICD and PD-no-ICD with respect to sex, use of overall medication, age, age of onset, age at diagnosis, years of education and the Montreal cognitive assessment score. Two-way mixed ANOVAs were performed for each neuropsychological test and brain structure extracted from MRIs with the time of the visit as the repeated independent variable (within participants) and the presence or absence of an ICD as the other independent variable (between participants).

The mixed ANOVA revealed that PD-ICD had their performance decline after three years, for the Hopkins Verbal Learning Test delayed recall and the Symbol Digit Modalities Test while PD-no-ICD saw their performance increase. A whole brain analysis showed that PD-ICD had a significant decrease after three years of the right cortex area total brain volume in comparison to PD-no-ICD. Specific brain structures also underwent significant changes over three years. Cortical changes in PD-ICD were: (1) increased surface area in the left temporal parahippocampus and (2) decreased surface areas of the right insula, right middle and superior temporal regions, left occipital lingual as well as left cingulate isthmus. Furthermore, in the subcortical nuclei, PD-ICD showed (1) increased volumes of the paratenial thalamic nucleus and whole right amygdala and (2) decreased volumes of the right amygdalian basal nucleus and thalamic ventromedial nucleus.

This study suggests that PD patients who also have ICD might be prone to develop over three years: (1) significant changes in cognitive performance (memory, attention), (2) morphological changes in the amygdala and thalamic nuclei and (3) significant atrophy and area shrinkage in the temporal and insula regions.