Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a ...growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a developing understanding of mechanisms responsible for their turnover. Here we will review the neurobiology of neurofilament proteins, describing current understanding of their structure and function, including recently discovered evidence for their roles in synapses. We will explore emerging understanding of the mechanisms of neurofilament degradation and clearance and review new methods for future elucidation of the kinetics of their turnover in humans. Primary roles of neurofilaments in the pathogenesis of human diseases will be described. With this background, we then will review critically evidence supporting use of neurofilament concentration measures as biomarkers of neuronal injury or degeneration. Finally, we will reflect on major challenges for studies of the neurobiology of intermediate filaments with specific attention to identifying what needs to be learned for more precise use and confident interpretation of neurofilament measures as biomarkers of neurodegeneration.
Abstract
While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We ...therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain volume (BV) and change in T2 lesion volume (T2LV), reflecting progressive tissue loss and increasing disease burden, respectively. We performed genome-wide association studies of change in BV (N = 3401) and change in T2LV (N = 3513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, OPERA I & II, and ORATORIO. Analyses were adjusted for randomized treatment arm, age, sex, and ancestry. Results were pooled in a meta-analysis, and were evaluated for enrichment of MS risk variants. Variant colocalization and cell-specific expression analyses were performed using published cohorts. The strongest peaks were in
PTPRD
(rs77321193-C/A, p = 3.9 × 10
–7
) for BV change, and
NEDD4L
(rs11398377-GC/G, p = 9.3 × 10
–8
) for T2LV change. Evidence of colocalization was observed for
NEDD4L
, and both genes showed increased expression in neuronal and/or glial populations. No association between MS risk variants and MRI outcomes was observed. In this unique, precompetitive industry partnership, we report putative regions of interest in the neurodevelopmental gene
PTPRD
, and the ubiquitin ligase gene
NEDD4L
. These findings are distinct from known MS risk genetics, indicating an added role for genetic progression analyses and informing drug discovery.
In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis.
To study this ...association in those receiving natalizumab.
Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline.
46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3.
Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing–remitting multiple sclerosis (RRMS) patients.
Objective:
To examine the ...efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients.
Methods:
Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60.
Results:
In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable.
Conclusion:
Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.
Introduction
Whether the reduction in brain amyloid beta (Aβ) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to ...Alzheimer's disease (AD) remains debated.
Methods
An instrumental variable meta‐analysis was performed to infer the effect of change in positron emission tomography (PET)–measured Aβ standardized uptake value ratio (SUVR) on cognitive and functional decline.
Results
Pooling data from 16 randomized trials demonstrates that each 0.1‐unit decrease in PET Aβ SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034–0.15), 0.33 (0.12–0.55), and 0.13 (0.017–0.24) point in the average change of the Clinical Dementia Rating–Sum of Boxes, the Alzheimer's Disease Assessment Scale–Cognitive Subscale, and the Mini‐Mental State Examination, respectively.
Discussion
This meta‐analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aβ plaque and a reduction in cognitive and functional decline in patients with AD.
Highlights
A widely cited meta‐analysis article concluded amyloid beta reduction does not substantially improve cognition.
We identified data inconsistencies in the initial publication and found new trial data.
We repeated the meta‐analysis after correcting data inconsistencies and adding new trial data.
Updated results suggested statistically significant clinical benefit of amyloid beta reduction.
Amyloid beta is a viable biological target for the treatment and prevention of AD.
Background:
The clinical relevance of serum glial fibrillary acidic protein (sGFAP) concentration as a biomarker of MS disability progression independent of acute inflammation has yet to be ...quantified.
Objective:
To test whether baseline values and longitudinal changes in sGFAP concentration are associated with disability progression without detectable relapse of magnetic resonance imaging (MRI) inflammatory activity in participants with secondary-progressive multiple sclerosis (SPMS).
Methods:
We retrospectively analyzed longitudinal sGFAP concentration and clinical outcome data from the Phase 3 ASCEND trial of participants with SPMS, with no detectable relapse or MRI signs of inflammatory activity at baseline nor during the study (n = 264). Serum neurofilament (sNfL), sGFAP, T2 lesion volume, Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and composite confirmed disability progression (CDP) were measured. Linear and logistic regressions and generalized estimating equations were used in the prognostic and dynamic analyses.
Results:
We found a significant cross-sectional association between baseline sGFAP and sNfL concentrations and T2 lesion volume. No or weak correlations between sGFAP concentration and changes in EDSS, T25FW, and 9HPT, or CDP were observed.
Conclusion:
Without inflammatory activity, changes in sGFAP concentration in participants with SPMS were neither associated with current nor predictive of future disability progression.
The timed 25-foot walk (T25FW) is widely used as a clinic performance measure, but has yet to be directly validated against gait speed in the home environment.
To develop an accurate method for ...remote assessment of walking speed and to test how predictive the clinic T25FW is for real-life walking.
An AX3-Axivity tri-axial accelerometer was positioned on 32 MS patients (Expanded Disability Status Scale EDSS 0-6) in the clinic, who subsequently wore it at home for up to 7 days. Gait speed was calculated from these data using both a model developed with healthy volunteers and
models generated from a machine learning algorithm.
The healthy volunteer model predicted gait speed poorly for more disabled people with MS. However, the accuracy of individually personalized models was high regardless of disability (
-value = 0.98,
-value = 1.85 × 10
). With the latter, we confirmed that the clinic T25FW is strongly predictive of the maximum sustained gait speed in the home environment (
-value = 0.89,
-value = 4.34 × 10
).
Remote gait monitoring with individually personalized models is accurate for patients with MS. Using these models, we have directly validated the clinical meaningfulness (i.e., predictiveness) of the clinic T25FW for the first time.
Background
Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). ...LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world.
Objectives
The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM.
Methods
Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed.
Results
Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21–85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%;
p
< 0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: − 9.99 vs. − 0.34 points;
p
< 0.001). Results were similar for MSIS-29 psychological impact.
Conclusion
No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported.
Trial Registration
ClinicalTrials.gov: NCT01480063.
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