Serum NfL but not GFAP predicts cognitive decline in active progressive multiple sclerosis patients.

BACKGROUND: Cognitive decline is inadequately captured by the standard neurological examination. Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are biomarkers of neuronal damage and astrocytic reactivity that may offer an accessible measure of the multiple sclerosis (MS) pathology linked to cognitive decline. OBJECTIVE: To investigate the association of sNfL and sGFAP with cognitive decline in MS patients at high risk for progressive pathology. METHODS: We included 94 MS patients with sustained Expanded Disability Status Score (EDSS) ⩾ 3, available serum samples and cognitive assessment performed by symbol digit modalities test (SDMT) over a median of 3.1 years. The visit for sGFAP/sNfL quantification was at confirmed EDSS ⩾ 3. Linear regression analysis on log-transformed sGFAP/sNfL assessed the association with current and future SDMT. Analyses were adjusted for age, sex, EDSS, treatment group, and recent relapse. RESULTS: sNfL was significantly associated with concurrent SDMT (adjusted change in mean SDMT = -4.5; 95% confidence interval (CI): -8.7, -0.2; p = 0.039) and predicted decline in SDMT (adjusted change in slope: -1.14; 95% CI: -1.83, -0.44; p = 0.001), particularly in active patients. sGFAP was not associated with concurrent or future SDMT. CONCLUSIONS: Higher levels of sNfL were associated with cognitive impairment and predicted cognitive decline in MS patients at high risk for having an underlying progressive pathology.

Younger age at multiple sclerosis onset is associated with worse outcomes at age 50.

OBJECTIVE: Older age at multiple sclerosis (MS) onset has been associated with worse 10-year outcomes. However, disease duration often exceeds 10 years and age-related comorbidities may also contribute to disability. We investigated patients with>10 years disease duration to determine how age at MS onset is associated with clinical, MRI and occupational outcomes at age 50. METHODS: We included patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital with disease duration>10 years. Outcomes at age 50 included the Expanded Disability Status Scale (EDSS), development of secondary-progressive multiple sclerosis (SPMS), brain T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and occupational status. We assessed how onset age was independently associated with each outcome when adjusting for the date of visit closest to age 50, sex, time to first treatment, number of treatments by age 50 and exposure to high-efficacy treatments by age 50. RESULTS: We included 661 patients with median onset at 31.4 years. The outcomes at age 50 were worse the younger first symptoms developed: for every 5 years earlier, the EDSS was 0.22 points worse (95% CI: 0.04 to 0.40; p=0.015), odds of SPMS 1.33 times higher (95% CI: 1.08 to 1.64; p=0.008), T2LV 1.86 mL higher (95% CI: 1.02 to 2.70; p<0.001), BPF 0.97% worse (95% CI: 0.52 to 1.42; p<0.001) and odds of unemployment from MS 1.24 times higher (95% CI: 1.01 to 1.53; p=0.037). CONCLUSIONS: All outcomes at age 50 were worse in patients with younger age at onset. Decisions to provide high-efficacy treatments should consider younger age at onset, equating to a longer expected disease duration, as a poor prognostic factor.

Brain anatomical correlates of fatigue in multiple sclerosis.

Fatigue is one of the most debilitating symptoms in patients with multiple sclerosis (MS). Despite its clinical significance, the aetiology and pathophysiology of MS-related fatigue are not well understood. Current evidence and understanding of the neuroanatomical underpinnings of MS-related fatigue are reviewed in this article. The aims of this paper are to (1) review the findings of previous structural neuroimaging studies on MS-related fatigue and summarize consistent findings regarding brain circuitry associated with fatigue in MS, (2) contextualize these findings with the neurochemistry of the relevant circuits and (3) discuss future perspectives with regard to impact on fatigue management of MS patients and methodological challenges towards improved understanding of fatigue pathogenesis. The detailed understanding of the neuroanatomical underpinnings of fatigue might contribute to the identification of novel treatment targets and factors determining treatment resistance to drugs used in current clinical practice.

A novel classification of fatigue in multiple sclerosis based on longitudinal assessments.

BACKGROUND: Magnetic resonance imaging (MRI) studies of multiple sclerosis-related fatigue had limited reproducibility. Temporal fatigue fluctuations have not been considered. OBJECTIVE: To investigate whether a novel group allocation that reflects temporal dynamics of fatigue improves our ability to detect fatigue-associated structural brain abnormalities. METHODS: Patient stratification based on biennial fatigue assessments: sustained fatigue (SF, n = 29, fatigued at the latest ⩾2 assessments), one time-point fatigue (1F, n = 15, fatigued at the latest, but non-fatigued at the penultimate assessment), reversible fatigue (RF, n = 31, non-fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 54). Brain parenchymal fraction (BPF) and T2 lesion volume (T2LV) were compared between these groups and were derived using a conventional, single time-point fatigued versus non-fatigued stratification. RESULTS: The SF versus NF stratification yielded improved power. SF (p = 0.005) and RF (p = 0.043) showed significantly higher T2LV than NF. T2LV showed no significant differences in SF versus 1F, SF versus RF, or 1F versus RF. Fatigued versus non-fatigued patients showed significantly higher T2LV (p = 0.030). We found no significant differences in BPF between the groups. CONCLUSION: Taking into account temporal fatigue dynamics increases the statistical power with respect to T2LV and may improve characterization of brain pathological correlates of MS-related fatigue.

Microstructural fronto-striatal and temporo-insular alterations are associated with fatigue in patients with multiple sclerosis independent of white matter lesion load and depression.

BACKGROUND: Fatigue in multiple sclerosis (MS) has been inconsistently associated with disruption of specific brain circuitries. Temporal fluctuations of fatigue have not been considered. OBJECTIVE: The aim of this study was to investigate the association of fatigue with brain diffusion abnormalities, using robust criteria for patient stratification based on longitudinal patterns of fatigue. METHODS: Patient stratification: (1) sustained fatigue (SF, n = 26): latest two Modified Fatigue Impact Scale (MFIS) ⩾ 38; (2) reversible fatigue (RF, n = 25): latest MFIS < 38 and minimum one previous MFIS ⩾ 38; and (3) never fatigued (NF, n = 42): MFIS always < 38 (five assessments minimum). 3T brain magnetic resonance imaging (MRI) was used to perform voxel-wise comparison of fractional anisotropy (FA) between the groups controlling for age, sex, disease duration, physical disability, white matter lesion load (T2LV), and depression. RESULTS: SF and, to a lesser extent, RF patients showed lower FA in multiple brain regions compared to NF patients, independent of age, sex, disease duration, and physical disability. In cingulo-postcommissural-striato-thalamic regions, the differences in FA between SF and NF (but not between RF and NF or SF) patients were independent of T2LV, and in ventromedial prefronto-precommissuro-striatal and temporo-insular areas, independent of T2LV and depression. CONCLUSION: Damage to ventromedial prefronto-precommissuro-striatal and temporo-insular pathways appears to be a specific substrate of SF in MS.

Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis.

BACKGROUND: Reports on the relationships between white matter lesion load (WMLL) and fatigue and anxiety in multiple sclerosis (MS) are inconsistent. OBJECTIVE: To investigate the association of total and tract-specific WMLL with fatigue and anxiety. METHODS: Total and regional T2 WMLL was assessed for 19 tracts in 48 MS patients (30 females). ICBM-DTI-81 Atlas-based parcellation was combined with WMLL segmentation of T2-weighted magnetic resonance imaging (MRI). Fatigue, anxiety, and depression were assessed using Fatigue Impact Scale, State Trait Anxiety Inventory, and Beck Depression Inventory, respectively. RESULTS: Fatigue, anxiety, and depression showed significant inter-correlation. We found no association between fatigue and total or regional WMLLs, whereas anxiety was associated with total and regional WMLLs in nine tracts. After adjusting for total WMLL, age, and depression, only the column and body of the fornix (CBF) remained significantly associated with anxiety. Post hoc analyses showed no CBF lesions on T1-weighted MRI and suggested, but could not confirm, that the septum pellucidum might play a role in the pathogenesis of anxiety. CONCLUSION: Our results suggest that anxiety in MS patients may have a neuropathological substrate in the septo-fornical area, which requires further validation using larger sample size and ultra-high-field MRI in targeted prospective studies.

Hippocampal microstructural damage correlates with memory impairment in clinically isolated syndrome suggestive of multiple sclerosis.

OBJECTIVE: We investigated whether diffusion tensor imaging (DTI) could reveal early hippocampal damage and clinically relevant correlates of memory impairment in persons with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). METHODS: A total of 37 persons with CIS, 32 with MS and 36 controls prospectively included from 2011 to 2014 were tested for cognitive performances and scanned with 3T-magnetic resonance imaging (MRI) to assess volumetric and DTI changes within the hippocampus, whole brain volume and T2-lesion load. RESULTS: While there was no hippocampal atrophy in the CIS group, hippocampal fractional anisotropy (FA) was significantly decreased compared to controls. Decrease in hippocampal FA together with increased mean diffusivity (MD) was even more prominent in MS patients. In CIS, hippocampal MD was correlated with episodic verbal memory performance ( r = -0.57, p = 0.0002 and odds ratio (OR) = 0.058, 95% confidence interval (CI) = 0.0057-0.59, p = 0.016 adjusted for age, gender, depression and T2-lesion load), but not with cognitive tasks unrelated to hippocampal functions. Hippocampal MD was the only variable discriminating memory-impaired from memory-preserved persons with CIS (area under the curve (AUC) = 0.77, sensitivity = 90.0%, specificity = 70.3%, positive predictive value (PPV) = 52.9%, negative predictive value (NPV) = 95.0%). CONCLUSION: DTI alterations within the hippocampus might reflect early neurodegenerative processes that are correlated with episodic memory performance, discriminating persons with CIS according to their memory status.

Multiple sclerosis lesion formation and early evolution revisited: A weekly high-resolution magnetic resonance imaging study.

BACKGROUND: Several magnetic resonance imaging (MRI) studies investigated the evolution of multiple sclerosis (MS) lesions to understand the pathophysiological mechanisms leading to blood-brain barrier breakdown and lesion formation. Only a few assessed the early natural history of MS lesions using short-interval longitudinal MRI. OBJECTIVE: The purpose of this study was to characterize MS lesion occurrence and early evolution on high-resolution MRI acquired at weekly intervals. METHODS: Active lesions were characterized on 3D fluid attenuation inversion recovery (FLAIR) and gadolinium-enhanced 3D T1-weighted MRI performed weekly (seven weeks) on five untreated patients with relapsing-remitting MS (RRMS). RESULTS: Active lesions (n=212) were detected in all patients. All showed contrast-enhancement on at least one time-point. Most new lesions (83.5%) were visible on FLAIR and post-contrast T1-weighted images at first detection; 11.2% showed activity on FLAIR images, one or more weeks before the appearance of contrast-enhancement; 12.5% enhanced before being apparent on FLAIR. CONCLUSION: Blood brain barrier disruption is a constant step in the natural history of active MS lesions, but does not always constitute the initial event. These findings are consistent with the existence of a subpopulation of lesions with an 'inside-out' genesis, where neurodegenerative processes might precede microglial activation, and a subsequent adaptive immune response.

Fatigue predicts disease worsening in relapsing-remitting multiple sclerosis patients.

BACKGROUND: It is unclear whether fatigue is a consequence or a predictive trait of disease worsening. OBJECTIVE: To investigate the predictive value of fatigue toward conversion to confirmed moderate-severe disability in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women's Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (⩾2 years) Expanded Disability Status Scale (EDSS) score ⩾3 within a follow-up period ⩾3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS ⩾3, with that of 33 non-converter RRMS patients matched for baseline characteristics. RESULTS: Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS ⩾3. CONCLUSION: Fatigue is a promising indicator of risk for conversion to confirmed moderate-severe disability in RRMS patients.

Cerebral blood flow MRI in the nondemented elderly is not predictive of post-operative delirium but is correlated with cognitive performance.

Three-dimensional Arterial Spin Labeling (ASL) MRI was performed before surgery in a cohort of 146 prospectively enrolled subjects ≥ 70 years old scheduled to undergo elective surgery. We investigated the prospective association between ASL-derived measures of cerebral blood flow (CBF) before surgery with postoperative delirium incidence and severity using whole-brain and globally normalized voxel-wise analysis. We also investigated the cross-sectional association of CBF with patients' baseline performance on specific neuropsychological tests, and with a composite general cognitive performance measure (GCP). Out of 146 subjects, 32 (22%) developed delirium. We found no significant association between global and voxel-wise CBF with delirium incidence or severity. We found the most significant positive associations between CBF of the posterior cingulate and precuneus and the Hopkins Verbal Learning Test - Revised total score, Visual Search and Attention Test (VSAT) score and the GCP composite. VSAT score was also strongly associated with right parietal lobe CBF. ASL can be employed in a large, well-characterized older cohort to examine associations between CBF and age-related cognitive performance. Although ASL CBF measures in regions previously associated with preclinical Alzheimer's Disease were correlated with cognition, they were not found to be indicators of baseline pathology that may increase risk for delirium.

Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage.

White matter hyperintensities (WMH) in elderly individuals with vascular diseases are presumed to be due to ischemic small vessel diseases; however, their etiology is unknown. We examined the cross-sectional relationship between cerebrovascular hemodynamics and white matter structural integrity in elderly individuals with vascular risk factors. White matter hyperintensity volumes, fractional anisotropy (FA), and mean diffusivity (MD) were obtained from MRI in 48 subjects (75±7years). Pulsatility index (PI) and dynamic cerebral autoregulation (dCA) was assessed using transcranial Doppler ultrasound of the middle cerebral artery. Dynamic cerebral autoregulation was calculated from transfer function analysis (phase and gain) of spontaneous blood pressure and flow velocity oscillations in the low (LF, 0.03 to 0.15 Hz) and high (HF, 0.16 to 0.5 Hz) frequency ranges. Higher PI was associated with greater WMH (P<0.005). Higher phase across all frequency ranges was associated with greater FA and lower MD (P<0.005). Lower gain was associated with higher FA in the LF range (P=0.001). These relationships between phase and FA were significant in the territories limited to the middle cerebral artery as well as across the entire brain. Our results show a strong relationship between impaired cerebrovascular hemodynamics (PI and dCA) and loss of cerebral white matter structural integrity (WMH and DTI metrics) in elderly individuals.