High-resolution diffusion tensor imaging of the fornix predicts memory function in multiple sclerosis.

Background: Cognitive dysfunction is a known symptom of multiple sclerosis (MS), with memory recognized as a frequently impacted domain. Here, we used high-resolution MRI at 7 tesla to build on cross-sectional work by evaluating the longitudinal relationship of diffusion tensor imaging (DTI) measures of the fornix to episodic memory performance. Methods: A sample of 80 people with multiple sclerosis (mean age 51.9 ± 8.1 years; 24% male) underwent baseline clinical evaluation, neuropsychological assessment, and MRI. Sixty-four participants had follow-up neuropsychological testing after 1-2 years. Linear regression was used to assess the relationship of baseline imaging measures to follow-up episodic memory performance, measured using the Selective Reminding Test and Brief Visuospatial Memory Test. A reduced prediction model included cognitive function at baseline, age, sex, and disease course. Results: Radial (ß = -0.222, p < 0.026; likelihood ratio test (LRT) p < 0.018), axial (ß = -0.270, p < 0.005; LRT p < 0.003), and mean (ß = -0.242, p < 0.0139; LRT p < 0.009) diffusivity of the fornix significantly added to the model, with follow-up analysis indicating that a longer prediction interval may increase accuracy. Conclusion: These results suggest that fornix DTI has predictive value specific to memory function in MS and warrants additional investigation in the drive to develop predictors of disease progression.

Processing speed test: Results from a Japanese normative sample of healthy participants compared with a US normative sample.

BACKGROUND: The Processing Speed Test (PST), a validated iPad®-based cognitive screening test for MS, has been applied to the cognitive assessment of Japanese MS patients using US normative data. METHODS: To develop PST normative data from Japanese healthy volunteers and compare the PST score distribution between Japanese and US healthy volunteers, 254 healthy Japanese-speaking volunteers were enrolled and stratified by age (20-65 years). Potential participants with a Mini-Mental State Examination score < 27 were excluded. PST raw scores (total correct) were from the Japan cohort and compared with age-restricted US normative data and propensity score-matched data created by matching sex, age, and educational level from a published study of 428 healthy participants. PST score distributions and standardized z-scores were compared using t-test and Kolmogorov-Smirnov test statistics. RESULTS: The mean age of the Japan cohort was 44.1 years. The PST scores of Japanese volunteers were significantly different from those of the age-restricted (mean ± SD 61.8 ± 10.1 vs 53.7 ± 10.8; p < 0.001) and the propensity score-matched US cohort (62.1 ± 10.1 vs 53.3 ± 10.6; p < 0.001). CONCLUSION: Regression analyses centered on US normative data could underestimate disease severity in Japanese MS patients, suggesting that separate normative data should be considered for each population sample.

Cooling vest improves surgeons' thermal comfort without affecting cognitive performance: a randomised cross-over trial.

OBJECTIVES: Surgeons become uncomfortable while performing surgery because heat transfer and evaporative cooling are restricted by insulating surgical gowns. Consequently, perceptions of thermal discomfort during surgery may impair cognitive performance. We, therefore, aimed to evaluate surgeons' thermal comfort, cognitive performance, core and mean skin temperatures, perceptions of sweat-soaked clothing, fatigue and exertion with and without a CoolSource cooling vest (Cardinal Health, Dublin, Ohio, USA). METHODS: Thirty orthopaedic surgeons participated in a randomised cross-over trial, each performing four total-joint arthroplasties with randomisation to one of four treatment sequences. The effects of cooling versus no cooling were measured using a repeated-measures linear model accounting for within-subject correlations. RESULTS: The cooling vest improved thermal comfort by a mean (95% CI) of -2.1 (-2.7 to -1.6) points on a 0-10 scale, p<0.001, with no evidence of treatment-by-period interaction (p=0.94). In contrast, cooling had no perceptible effect on cognition, with an estimated mean difference (95% CI) in Cleveland Clinic Cognitive Battery (C3B) Processing Speed Test score of 0.03 (95% CI -2.44 to 2.51), p=0.98, or in C3B Visual Memory Test score with difference of 0.88 (95% CI -2.25 to 4.01), p=0.57. Core temperature was not lower with the cooling vest, with mean difference (95% CI) of -0.13 (-0.33°C to 0.07°C), p=0.19, while mean skin temperature was lower, with mean difference of -0.23 (95% CI -0.40°C to -0.06°C) lower, p=0.011. The cooling vest significantly reduced surgeons' perceptions of sweat-soaked clothing, fatigue and exertion. CONCLUSIONS: A cooling vest worn during surgery lowered core and skin temperatures, improved thermal comfort, and decreased perceptions of sweating and fatigue, but did not improve cognition. Thermal discomfort during major orthopaedic surgery is thus largely preventable, but cooling does not affect cognition. TRIAL REGISTRATION NUMBER: NCT04511208.

Neural correlates of inhibitory control in severe class III compared with class I/II obesity using a sample of endometrial cancer survivors seeking weight loss.

OBJECTIVE: No prior studies have evaluated inhibitory control in people with severe class III compared with class I/II obesity. Thus, the study aim was to evaluate inhibitory control and neural correlates of response inhibition by obesity class using a sample of endometrial cancer (EC) survivors with obesity, who have a higher risk of overall but not cancer-specific mortality. METHODS: Forty-eight stage I EC survivors with obesity (class I/II: n = 21; class III: n = 27) seeking weight loss in a lifestyle intervention at baseline completed a stop signal task during functional magnetic resonance imaging. RESULTS: It was found that participants with class III obesity had a longer stop signal reaction time (mean [SD], 278.8 [51.3] vs. 251.5 [34.0] milliseconds, p < 0.01) compared with those with class I/II obesity, indicating that patients with EC with severe obesity had greater impulsivity and poorer inhibitory control. Results also showed increased activation in the thalamus and superior frontal gyrus for the incorrect versus correct inhibition contrast in class III but not class I/II obesity (whole brain cluster corrected, p < 0.05). CONCLUSIONS: These results provide novel insights into inhibitory control and corresponding neural correlates in severe versus less severe classes of obesity and highlight the importance of targeting inhibitory control processes in weight-loss interventions, particularly for people with severe obesity and greater impulsivity.

Cleveland Clinic Cognitive Battery (C3B): Normative, Reliability, and Validation Studies of a Self-Administered Computerized Tool for Screening Cognitive Dysfunction in Primary Care.

BACKGROUND: The self-administered iPad-based Cleveland Clinic Cognitive Battery (C3B) was designed specifically for the efficient screening of cognitive functioning of older adults in a primary care setting. OBJECTIVE: 1) Generate regression-based norms from healthy participants to enable demographic corrections to facilitate clinical interpretation; 2) estimate test-retest reliability and practice effects; 3) examine ability to discriminate mild cognitive impairment (MCI) from healthy aging; 4) d etermine validity of screening in a distracting clinical environment; and 5) determine completion rates and patient satisfaction in a primary care setting. METHODS: Study 1 (S1) recruited a stratified sample of 428 healthy adults, ages 18-89, to generate regression-based equations. S2 assessed 2-week test-retest reliability and practice effects in 30 healthy elders. S3 recruited 30 MCI patients and 30 demographically-matched healthy controls. In S4, 30 healthy elders self-administered the C3B in a distracting environment and in a quiet private room in counterbalanced order. In a demonstration project, 470 consecutive primary care patients were administered the C3B as part of routine clinical care (S5). RESULTS: C3B performance was primarily influenced by age, education, and race (S1), had acceptably high test-retest reliability and minimal practice effects (S2), discriminated MCI from healthy controls (S3), was not negatively impacted by a distracting clinical environment (S4), had high completion rates (>92%) and positive ratings from primary care patients (S5). CONCLUSION: The C3B is a computerized cognitive screening tool that is reliable, validated, self-administered, and is conducive to integration into a busy primary care clinical workflow for detecting MCI, early Alzheimer's disease, and other related dementias.

Multiple Sclerosis Performance Test (MSPT): Normative study of 428 healthy participants ages 18 to 89.

BACKGROUND: The Multiple Sclerosis Performance Test (MSPT) is a self-administered, iPad®-based, computerized system for quantifying neuroperformance (cognition, upper and lower extremity motor function, and vision) in patients with multiple sclerosis (MS). OBJECTIVE: The goal of the study is to provide regression-based norms for the four MSPT test modules to adjust for the influence of demographic variables (age, education, and sex). METHODS: The MSPT was administered to 428 cognitively intact, healthy adults (ages 18 to 89 years). Participants were recruited to achieve a demographically stratified sample from four geographically diverse United States testing sites. RESULTS: The amount of shared variance in test performance accounted for by demographic variables was 18-23% for an upper extremity motor test, 31% for a walking speed test, 32% for a low contrast visual acuity test, and 48% for a cognitive test. All four test modules were significantly influenced by age (linear and non-linear effects) and education. Additionally, sex influenced performance on the cognitive and walking speed tests. CONCLUSION: This study provides regression-based equations that can enhance the clinical interpretation of MSPT scores by adjusting for the potential influences of age, education, and sex.

Brain Injury and Mental Health Among the Victims of Intimate Partner Violence: A Case-Series Exploratory Study.

Intimate partner violence (IPV) survivors frequently report face, head, and neck as their injury site. Many mild traumatic brain injuries (TBIs) are undiagnosed or underreported among IPV survivors while these injuries may be linked to changes in brain function or pathology. TBI sustained due to IPV often occurs over time and ranges in severity. The aim of this case-series study was to explore risk factors, symptoms, and brain changes unique to survivors of intimate partner violence with suspicion of TBI. This case-series exploratory study examines the potential relationships among IPV, mental health issues, and TBI. Participants of this study included six women: 3 women with a history of IPV without any experience of concussive blunt force to the head, and 3 women with a history of IPV with concussive head trauma. Participants completed 7T MRI of the brain, self-report psychological questionnaires regarding their mental health, relationships, and IPV, and the Structured Clinical Interview. MRI scans were analyzed for cerebral hemorrhage, white matter disturbance, and cortical thinning. Results indicated significant differences in resting-state connectivity among survivors of partner violence as well as differences in relationship dynamics and mental health symptoms. White matter hyperintensities are also observed among the survivors. Developing guidelines and recommendations for TBI-risk screening, referrals, and appropriate service provision is crucial for the effective treatment of TBI-associated IPV. Early and accurate characterization of TBI in survivors of IPV may relieve certain neuropsychological consequences.

Is computerized screening for processing speed impairment sufficient for identifying MS-related cognitive impairment in a clinical setting?

BACKGROUND: Annual screening for processing speed impairment (PSI) is recommended for patients with multiple sclerosis (pwMS). However, cognitive deficits in pwMS are heterogeneous, and whether PSI screening identifies patients with impairment in other cognitive domains is unclear. The objective of this study was to examine sensitivity and specificity of the self-administered, computerized Processing Speed Test (PST) in identifying cognitive impairment defined by a comprehensive neuropsychological battery (NPT). METHODS: Ninety-one pwMS completed PST and NPT, with raw scores demographically adjusted. Cognitive impairment on NPT was defined as performance <5th percentile in at least one domain. Receiver operating characteristic (ROC) analyses were performed to determine the ability of the PST to discriminate between cognitively normal (CN) and cognitively impaired with PSI (CI-PSI) and cognitively impaired with normal processing speed (CI-PSN) groups. RESULTS: Cognitive impairment was observed in 23.1% of pwMS on PST and in 42.9% on NPT. PST demonstrated excellent ability to discriminate between CN (57.1%) and CI-PSI (20.9%) groups (Area Under the Curve [AUC] = 0.86, p < 0.001). In contrast, PST was unable to discriminate CN and CI-PSN (22.0%) groups (AUC = 0.42, p = 0.32). CONCLUSION: The PST demonstrates excellent ability to detect PSI in pwMS but is unable to identify cognitively impaired pwMS without PSI, highlighting the importance of developing additional screening measures.

Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis.

Cognitive impairment is a common symptom in individuals with Multiple Sclerosis (MS), but meaningful, reliable biomarkers relating to cognitive decline have been elusive, making evaluation of the impact of therapeutics on cognitive function difficult. Here, we combine pathway-based MRI measures of structural and functional connectivity to construct a metric of functional decline in MS. The Structural and Functional Connectivity Index (SFCI) is proposed as a simple, z-scored metric of structural and functional connectivity, where changes in the metric have a simple statistical interpretation and may be suitable for use in clinical trials. Using data collected at six time points from a 2-year longitudinal study of 20 participants with MS and 9 age- and sex-matched healthy controls, we probe two common symptomatic domains, motor and cognitive function, by measuring structural and functional connectivity in the transcallosal motor pathway and posterior cingulum bundle. The SFCI is significantly lower in participants with MS compared to controls (p = 0.009) and shows a significant decrease over time in MS (p = 0.012). The change in SFCI over two years performed favorably compared to measures of brain parenchymal fraction and lesion volume, relating to follow-up measures of processing speed (r = 0.60, p = 0.005), verbal fluency (r = 0.57, p = 0.009), and score on the Multiple Sclerosis Functional Composite (r = 0.67, p = 0.003). These initial results show that the SFCI is a suitable metric for longitudinal evaluation of functional decline in MS.

Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer's Disease with Mild Cognitive Impairment.

Sleep dysfunction has been identified in the pathophysiology of Alzheimer's disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.

Five-Year Change in Body Mass Index Predicts Conversion to Mild Cognitive Impairment or Dementia Only in APOE ɛ4 Allele Carriers.

BACKGROUND: Body mass index (BMI) has been identified as an important modifiable lifestyle risk factor for dementia, but less is known about how BMI might interact with Apolipoprotein E ɛ4 (APOE ɛ4) carrier status to predict conversion to mild cognitive impairment (MCI) and dementia. OBJECTIVE: The aim of this study was to investigate the interaction between APOE ɛ4 status and baseline (bBMI) and five-year BMI change (ΔBMI) on conversion to MCI or dementia in initially cognitively healthy older adults. METHODS: The associations between bBMI, ΔBMI, APOE ɛ4 status, and conversion to MCI or dementia were investigated among 1,289 cognitively healthy elders from the National Alzheimer's Coordinating Center (NACC) database. RESULTS: After five years, significantly more carriers (30.6%) converted to MCI or dementia than noncarriers (17.6%), p < 0.001, OR = 2.06. Neither bBMI (OR = 0.99, 95%CI = 0.96-1.02) nor the bBMI by APOE interaction (OR = 1.02, 95%CI = 0.96-1.08) predicted conversion. Although ΔBMI also did not significantly predict conversion (OR = 0.90, 95%CI = 0.78-1.04), the interaction between ΔBMI and carrier status was significant (OR = 0.72, 95%CI = 0.53-0.98). For carriers only, each one-unit decline in BMI over five years was associated with a 27%increase in the odds of conversion (OR = 0.73, 95%CI = 0.57-0.94). CONCLUSION: A decline in BMI over five years, but not bBMI, was strongly associated with conversion to MCI or dementia only for APOE ɛ4 carriers. Interventions and behaviors aimed at maintaining body mass may be important for long term cognitive health in older adults at genetic risk for AD.

Does obesity exacerbate brain lesion volume and atrophy in patients with multiple sclerosis?

BACKGROUND: Obesity is common among patients with multiple sclerosis (pwMS) and has been shown to exacerbate central inflammation, a key factor in disease progression. The purpose of this cross-sectional study is to examine the possible relationships between obesity, as measured by body mass index (BMI), and MS-related brain changes in atrophy and lesion volume, as measured from MRI, in a large, representative sample of pwMS. METHODS: BMI and MRI data, along with demographic and disease variables, were acquired from the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) registry. Unadjusted and adjusted partial correlations, controlling for gender, race, age, education level, MS phenotype, disability and disease duration, examined the associations between BMI and MRI outcomes, which included brain parenchymal fraction, white matter fraction, gray matter fraction, thalamic volume, and T2 lesion volume. RESULTS: The sample consisted of 3,046 pwMS. Unadjusted and adjusted BMI-MRI correlations accounted for between 0.4% and 2.0% of shared variance (R2). When considering the relationship between MRI outcomes and BMI category (normal weight, overweight, obese), multiple regression analyses continued to show minimal association, with BMI category accounting for no more than 1.5% of shared variance. CONCLUSIONS: No clinically meaningful associations were found between BMI and MRI outcomes in this large, representative sample of MS patients, regardless of demographics and disease variables. These unexpected negative results will require replication with a longitudinal design using more precise measures of obesity.

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

BACKGROUND: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice. METHOD: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments. RESULTS: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates. CONCLUSIONS: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.

Is Obesity Related to Processing Speed Impairment in Patients with Multiple Sclerosis: Results of a Large-Scale, Multicenter Study.

BACKGROUND: Obesity is linked to greater physical disability and increased comorbidities among patients with multiple sclerosis (MS). Its contribution to cognition in this group is unclear. This observational study examines the link between obesity and processing speed in a large sample of patients with MS (PwMS). METHODS: As part of routine clinical care at our center, PwMS completed the Processing Speed Test (PST), an electronic implementation of the Symbol Digit Modalities Test (SDMT). Height and weight were used to calculate body mass index (BMI). Bivariate correlations were conducted to examine the association between PST and BMI in the group overall and in subgroups based on demographic and clinical variables. A one-way ANOVA examined differences in PST by BMI categories (normal weight, overweight, obese). RESULTS: The sample included 8,713 patients. No association between PST and BMI was found in the entire sample (r = .01), nor within subgroups based on demographic and disease variables. No difference in PST score was found between BMI categories. CONCLUSIONS: No association between BMI and processing speed was found among PwMS regardless of demographic or disease-specific patient characteristics.

Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

OBJECTIVE: To determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration. METHODS: A longitudinal study of MCI-AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty-three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform. Inflammatory analytes that predict clinical progression on Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Mini Mental State Exam scores were assessed in multivariate regression models. To provide context, key analyte results in ADNI were compared against biomarkers of neurodegeneration, hippocampal volume, and CSF neurofilament light (NfL), in receiver operating characteristic (ROC) analyses evaluating highest quartile of CDR-SB change over two years (≥3 points). RESULTS: Cerebrospinal fluid inflammatory analytes in relation to cognitive decline were best described by gene ontology terms, natural killer cell chemotaxis, and endothelial cell apoptotic process and in plasma, extracellular matrix organization, blood coagulation, and fibrin clot formation described the analytes. CSF CCL2 was most robust in predicting rate of cognitive change and analytes that correlated to CCL2 suggest IL-10 pathway dysregulation. The ROC curves for ≥3 points change in CDR-SB over 2 years when comparing baseline hippocampal volume, CSF NfL, and CCL2 were not significantly different. INTERPRETATION: Baseline levels of immune cell chemotactic cytokine CCL2 in the CSF and IL-10 pathway dysregulation impact longitudinal cognitive and functional decline in MCI-AD. CCL2's utility appears comparable to biomarkers of neurodegeneration in predicting rapid decline.

Episodic Memory and Hippocampal Volume Predict 5-Year Mild Cognitive Impairment Conversion in Healthy Apolipoprotein ε4 Carriers.

OBJECTIVE: The Apolipoprotein (APOE) ε4 allele increases the risk for mild cognitive impairment (MCI) and dementia, but not all carriers develop MCI/dementia. The purpose of this exploratory study was to determine if early and subtle preclinical signs of cognitive dysfunction and medial temporal lobe atrophy are observed in cognitively intact ε4 carriers who subsequently develop MCI. METHODS: Twenty-nine healthy, cognitively intact ε4 carriers (ε3/ε4 heterozygotes; ages 65-85) underwent neuropsychological testing and MRI-based measurements of medial temporal volumes over a 5-year follow-up interval; data were converted to z-scores based on a non-carrier group consisting of 17 ε3/ε3 homozygotes. RESULTS: At follow-up, 11 ε4 carriers (38%) converted to a diagnosis of MCI. At study entry, the MCI converters had significantly lower scores on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT) Trials 1-5, and RAVLT Immediate Recall compared to non-converters. MCI converters also had smaller MRI volumes in the left subiculum than non-converters. Follow-up logistic regressions revealed that left subiculum volumes and RAVLT Trials 1-5 scores were significant predictors of MCI conversion. CONCLUSIONS: Results from this exploratory study suggest that ε4 carriers who convert to MCI exhibit subtle cognitive and volumetric differences years prior to diagnosis.

Necessity of technicians for computerized neuropsychological assessment devices in multiple sclerosis.

OBJECTIVE: Determine the influence of technician supervision on computer-administered cognitive tests in multiple sclerosis (MS). METHODS: Eighty MS patients underwent assessment using the CogState Brief Battery (CSBB) and the Cleveland Clinic Cognitive Battery (C3B). Each was administered twice, once with a technician guiding assessment, and once with technician-absent. Twenty-eight healthy controls were also evaluated. RESULTS: The influence of technician guidance was not statistically significant for group means on either test. For CSBB, administration problems were more common in the technician-absent condition. CONCLUSION: In this MS sample, reliable and valid test results were obtained from computer-assisted cognitive testing without technician guidance.

Technology-enabled comprehensive characterization of multiple sclerosis in clinical practice.

BACKGROUND: Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets. OBJECTIVES: To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort. METHODS: NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result. RESULTS: 997 unique patients (age 47.7 ±â€¯11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R2=0.46). For CST, significant variables included age and NQ-LE (adjusted R2 = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R2=0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R2=0.39). CONCLUSIONS: Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.

Key inflammatory pathway activations in the MCI stage of Alzheimer's disease.

OBJECTIVE: To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). METHODS: A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aß42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules. RESULTS: Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aß42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters. INTERPRETATION: A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD.