Scholarly Activity

Introduction: The Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) is the gold standard for measuring disease progression. Interest has grown in developing fluid progression biomarkers to assess risk and prognosis in ALS. We present findings on the effectiveness of exploratory fluid biomarkers as indicators of ALS disease progression. Methods: In this study we analyze data from the ALS/MND Natural History Consortium to evaluate three proposed blood biomarkers in disease progression models. Blood was collected from people living with ALS and analyzed for neurofilament light chain (NfL), plasma phosphorylated tau-181 (pTau181), and cardiac troponin T (cTnT). We used blood biomarker values measured at a single time point, along with the initial ALSFRS-R score and the slope between the first and last observed scores, adjusted for the interval between assessments. Analyses accounted for the delay from diagnosis to ALSFRS-R and blood sample collection. Associations between biomarkers and disease progression were studied using a linear regression model comparing ALSFRS-R slope to biomarker measurements. To study the relationship with overall survival, Cox proportional hazards models were fitted using biomarkers and the ALSFRS-R derived variables. The predictive performance of the models was assessed through the Integrated Brier Score (IBS), dynamic AUC, and C-index. Results: Data from 123 participants were available for analysis. NfL had a significant negative correlation with ALSFRS-R slope (r = −0.45, p < 0.001). NfL was also significantly associated with overall survival (HR=1.02, p = 0.015), accounting for the first ALSFRS-R measurement and its slope. Other biomarkers were not significantly associated with survival. The predictive capability of a model containing only the first observed ALSFRS-R score (C-index: 0.79) improved with the addition of NfL (C-index: 0.89). A model with the ALSFRS-R slope (C-index: 0.88) also showed improved predictive metrics after adding NfL (C-index: 0.90). Predictive metrics for these models were high when including NfL, showing the added value of a single NfL value at any point during disease course in predicting survival. Discussion: A single NfL value improved prediction of survival when compared with ALSFRS-R metrics alone. pTau181 and cTnT, while potentially useful as markers of phenotype, did not contribute significantly to predictions of overall survival.

Background: Adverse events (AEs) observed during clinical trials may represent either genuine treatment-related side effects or manifestations of underlying disease progression. This analysis examines potential associations between frequently reported in the PRO-ACT database AEs and irreversible functional decline. Methods: We extracted adverse events and ALSFRS-R scores from PRO-ACT's dataset comprising 12,600 longitudinal records and over 5,700 unique AEs. The analysis centered on the 20 most frequent AEs, each affecting at least 150 participants and cumulatively accounting for over 60% of all recorded events in the dataset. ALSFRS-R scores were aligned to the date of AE (day 0), and ALSFRS-R scores were evaluated over the one-year periods preceding and following each event to detect changes in the trajectory of functional decline. Results: Of the 20 most common AEs, 19 were linked to a persistent increase in the rate of functional decline, as measured by ALSFRS-R scores post-event. On average, the rate of functional decline accelerated from -0.68 points/month before the AE to -1.22 points/month after, with no signs of subsequent recovery. Vomiting (n = 312) was the sole exception with affected participants exhibiting a partial rebound. Bulbar subscores (questions 1-3: speech, salivation, swallowing) and dyspnea (question R-1) dropped sharply at the time of the event (mean—0.45 points) but showed measurable recovery (+0.21 points) within 90 days. Conclusion: The most frequently reported AEs in ALS trials appear to signify irreversible disease progression rather than transient, recoverable complications. These findings underscore an importance to distinguish between symptoms attributable to natural disease progression and those arising from genuine treatment-related safety concerns—particularly in early-phase trials, where safety signals determine the advancement to subsequent phases. Attributing disease progression events to investigational treatments may result in the early termination of promising therapies. Reevaluating current safety assessment strategies could provide insights into the persistently high failure rate of ALS trials.

Introduction: The Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) is the gold standard for measuring disease progression. Interest has grown in developing fluid progression biomarkers to assess risk and prognosis in ALS. We present findings on the effectiveness of exploratory fluid biomarkers as indicators of ALS disease progression. Methods: In this study we analyze data from the ALS/MND Natural History Consortium to evaluate three proposed blood biomarkers in disease progression models. Blood was collected from people living with ALS and analyzed for neurofilament light chain (NfL), plasma phosphorylated tau-181 (pTau181), and cardiac troponin T (cTnT). We used blood biomarker values measured at a single time point, along with the initial ALSFRS-R score and the slope between the first and last observed scores, adjusted for the interval between assessments. Analyses accounted for the delay from diagnosis to ALSFRS-R and blood sample collection. Associations between biomarkers and disease progression were studied using a linear regression model comparing ALSFRS-R slope to biomarker measurements. To study the relationship with overall survival, Cox proportional hazards models were fitted using biomarkers and the ALSFRS-R derived variables. The predictive performance of the models was assessed through the Integrated Brier Score (IBS), dynamic AUC, and C-index. Results: Data from 123 participants were available for analysis. NfL had a significant negative correlation with ALSFRS-R slope (r = −0.45, p < 0.001). NfL was also significantly associated with overall survival (HR=1.02, p = 0.015), accounting for the first ALSFRS-R measurement and its slope. Other biomarkers were not significantly associated with survival. The predictive capability of a model containing only the first observed ALSFRS-R score (C-index: 0.79) improved with the addition of NfL (C-index: 0.89). A model with the ALSFRS-R slope (C-index: 0.88) also showed improved predictive metrics after adding NfL (C-index: 0.90). Predictive metrics for these models were high when including NfL, showing the added value of a single NfL value at any point during disease course in predicting survival. Discussion: A single NfL value improved prediction of survival when compared with ALSFRS-R metrics alone. pTau181 and cTnT, while potentially useful as markers of phenotype, did not contribute significantly to predictions of overall survival.

Background: Understanding ALS disease progression, and factors influencing the risk of specific outcomes, can inform clinical decision making and optimize clinical trial design. However, study of disease course in real-world ALS cohorts is limited. Here, we leverage the ALS/MND Natural History Consortium (NHC) dataset to calculate the median time-to-event for several clinical outcomes and evaluate the impact of prognostic factors on predicted risk. Methods: Longitudinal data from 2744 participants in the NHC dataset were used in time-to-event analyses based on time since diagnosis. Overall survival was considered along with gastrostomy and four intermediate outcomes determined from ALSFRS-R scores: loss of ambulation, loss of useful speech, non-invasive ventilation (NIV) usage, and continuous NIV usage. The median time-to-event was calculated along with traditional Kaplan-Meier curves. Cox proportional hazards models were then fit for each outcome to determine the impact of several prognostic factors: biological sex, riluzole use, race, onset location, diagnostic delay, age at diagnosis, baseline ALSFRS-R subscores, and the initial rate of change (slope) in ALSFRS-R scores. Adjusted hazard ratios (HR) were estimated for each factor. Results: Median times for intermediate outcomes ranged from 0.863 years from diagnosis for NIV usage to 2.997 years for continuous NIV usage, with a median time to death of 1.995 years. A higher slope was the greatest risk factor for all outcomes (HRs between 2.44 and 5.12), and an older age at diagnosis increased risk of loss of ambulation, gastrostomy, NIV use, and death (HRs 1.18–1.44). Limb onset decreased risk for loss of speech, gastrostomy, and NIV use (HRs 0.54–0.76), but increased risk for loss of ambulation (HR=1.27). White (relative to non-white) participants had decreased risk for loss of ambulation (HR=0.69) and continuous NIV use (HR=0.71), while females had increased risk for loss of speech (HR=1.52) and gastrostomy (HR=1.22). Discussion: Our findings from a large, population-based natural history sample provide insights into the typical course of ALS disease progression. The results also demonstrate that certain factors can be expected to affect the risk of certain intermediate events, which may refine clinical decision making.

Background: For many individuals with ALS, several clinically relevant events occur prior to death. The times to these clinically relevant events are valuable both for modeling disease progression and for personal planning. However, at present, there is limited ability to obtain predictions for a particular set of patient characteristics that incorporates ongoing disease progression. We developed dynamic individualized prediction models for time-to-events for several outcomes and incorporated them into a publicly available application that can aid in clinical guidance and planning. Methods: Longitudinal data from 2121 participants in the ALS Natural History Consortium dataset were used to implement landmark time-to-event analysis. Five outcomes were considered: loss of ambulation, loss of useful speech, gastrostomy, non-invasive ventilation (NIV) usage, and continuous NIV usage. In the models for each outcome, the time-varying ALSFRS-R values at the landmark time (“s”) are treated as fixed covariates in a Cox regression model from s onward. Six landmark times, between date of diagnosis and 3 years, were implemented. Covariates included age at diagnosis, sex, diagnostic delay, onset location, riluzole use, ALSFRS-R scores at the landmark time, and ALSFRS-R rates of change from baseline. Shiny™ was used to implement and present the modeling results in a freely accessible online interactive dashboard. Results: Our Shiny application allows the user to specify an outcome, landmark time, and specific covariate values (e.g., ALSFRS-R scores, onset location, etc.) to obtain predictions. The application uses these inputs to automatically produce a time-to-event prediction curve for the selected outcome using the fitted models. Additionally, the application presents risk prediction intervals for each outcome and landmark time to illustrate how covariates affect risk. Discussion: We created an interactive dashboard that leverages a dynamic landmark modeling approach to illuminate how risk for outcomes changes across time, based on a number of inputs. Our application enables users to explore risk profiles and predicted trajectories for specified sets of characteristics, providing a valuable resource for both clinical use and for those living with ALS. The application will be continuously updated and additional modeling variables, such as biomarkers like NfL, will be incorporated as they become available.

Chronic pain affects over 50% of traumatic brain injury (TBI) patients, which has been strongly linked to neuroinflammation. Although opioids like morphine (MOR) are prescribed for post-TBI pain, they paradoxically worsen neuroinflammation, producing opioid-induced hyperalgesia. Therefore, identification of mechanisms underlying post-TBI pain, inflammation, and MOR action, are necessary to optimize post-TBI analgesia. The kynurenine pathway (KP) responds robustly to inflammation, producing kynurenic acid (KYNA, anti-inflammatory) and quinolinic acid (QUIN, proinflammatory), although their roles in TBI-induced pain, inflammation and MOR action remain unclear. Therefore, the KP was examined after 5 days of escalating MOR treatment (1-2 days post-injury (dpi), 4 mg/kg; 3-5 dpi, 8 mg/kg) in C57Bl/6 male mice (n=4-6) following closed-skull impact. Tactile thresholds (Von Frey), inflammatory cytokines (enzyme-linked immunosorbent assays), and KP metabolites (liquid-chromatography tandem mass spectrometry) were measured by 30 dpi. Tactile threshold in TBI-saline mice was significantly reduced at 5 dpi (p<0.0001 vs. sham-saline), which was reversed by MOR. However, at 30 dpi TBI-MOR mice exhibited significantly lower tactile thresholds than TBI-saline controls (p<0.0001). At 30 dpi, MOR exacerbated TBI-induced elevations in the pro-inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, within the prefrontal and anterior cingulate cortices (all p<0.0001 vs. TBIsaline). TBI-induced elevations in cortical QUIN were further elevated by MOR at 30 dpi (p=0.04 vs. TBI-saline). These findings suggest that MOR treatment exacerbates TBIinduced elevations in chronic pain, neuroinflammation, and the central KP response, warranting future studies to explore the KP as a therapeutic target for post-TBI pain management.

Purpose : Traumatic optic neuropathy (TON) is an uncommon vision threatening condition caused by either ocular or blunt/penetrating head trauma which is characterized by direct or indirect TON. We have earlier shown that remote ischemic post-conditioning (RIC) therapy is protective and reduces TON related retinal dysfunction but the molecular mechanisms underlying is unknown. Interestingly, the metabolic sensor, AMP-activated protein kinase alpha 1 (AMPKα1), plays significant role in M polarization andtranscriptional regulation of interleukin-10 (IL-10), an anti-inflammatory cytokine that alsopolarizes Ms to M2. However, a mechanistically-driven therapeutic study of myeloid-specific AMPKα1/IL-10 in TON remains completely unexplored. Here we proposed that RICtherapy is protective in TON via AMPKα1/IL10 activation in mice.Methods : We induced TON in mice by using controlled impact system as reportedpreviously. Male and female; C57BL/6 mice (8-10 wk old; Jackson) were injected with 250μg of mouse anti-IL-10r (clone 1B1.3a) or isotype-matched IgG1 (clone R3-34) antibodies in100 μl of PBS i.p. daily, starting one day prior to Sham/TON injury. 5-7 days post TON inpresence and absence of RIC therapy, the above mice are sacrificed. RIC therapy was givenevery day (5-7 days following TON). Western blotting, Immunohistochemistry, Flowcytometry and TEM technique were used to generate research data.Results : Our data demonstrated that IL10 depletion effects macrophages polarization inTON. We found that CD206+ (M1 marker) decreased in TON and CD68+ (M2 marker)increased compared with Sham however, RIC significantly attenuated this process but IL10inhibition further increased CD68+ expression and RIC didn't change the expression. Wechecked the expression of microglial marker Iba-1, ganglion cell marker Brn3 and axonalmarker GAP43 and found that after IL-10 depletion RIC has no significant effect.Transmission electron microscopy (TEM) data of optic nerve showed increaseddemyelination and axonal degeneration in TON group and TON+RIC showed improvedmyelination however, IL-10 depletion caused more damage and RIC didn't help.Conclusions : Overall, these data suggest that RIC therapy is neuroprotective via myeloidAMPKα1/IL10 signaling by regulating macrophages polarization and inflammation in eyetrauma. Further investigation of RIC and.

Introduction: We report a case of new-onset movement disorder and encephalopathy in a 57-year-old female with IgA lambda multiple myeloma. Case Description: The patient was evaluated for persistent encephalopathy and hyperkinetic movements. Previously, she was hospitalized for hypercalcemia and diagnosed with IgA lambda myeloma (IgA >6000 mg/dL, positive bone marrow biopsy). Her hospital course included sepsis, respiratory failure requiring intubation, and fluctuating mentation. She exhibited persistent upper extremity hyperkinetic movements. A hyperviscosity panel showed elevated plasma viscosity of 1.91 (normal <1.6), prompting transfer for plasmapheresis. At our institution, examination revealed encephalopathy with frequent hyperkinetic movements in bilateral upper extremities, including abduction, choreiform, and near-ballistic patterns. MRI brain showed microbleeds at the gray-white junction without other abnormalities. EEG indicated mild-to-moderate encephalopathy. Lumbar puncture revealed elevated lactate (3.1 mmol/L), with unremarkable autoimmune and viral studies. Lab work showed anemia (Hb 7.4 g/dL) and elevated IgA (5525 mg/dL). The patient underwent plasmapheresis to reduce IgA below 2000 mg/dL, followed by three cycles of bortezomib and dexamethasone. Over three weeks, her mentation improved, and she regained the ability to follow commands and answer yes/no questions. Her hyperkinetic movements resolved. Unfortunately, her hospital stay was prolonged by complications, and she expired two months later. Discussion: This case highlights hyperviscosity-associated encephalopathy and hyperkinetic movement disorder in IgA lambda myeloma, managed effectively with plasmapheresis and chemotherapy. It also highlights the importance of CSF lactate as a surrogate marker for microvascular hypoxia leading to encephalopathy and chorea. The existing literature lacks reports of choreiform or other hyperkinetic movement disorders linked to IgA myeloma or other monoclonal gammopathies. Hyperviscosity-induced movement disorders, however, are documented in polycythemia vera. It has been hypothesized that similar hyperviscosity-driven mechanisms underlie diabetic striatopathy via cytotoxic edema affecting basal nuclei. This case underscores the importance of early recognition and treatment of hyperviscosity to address neurological complications in myeloma.

Background: In the phase 3, active-controlled BouNDless study (NCT04006210), investigational ND0612 (24-hour subcutaneous levodopa/carbidopa infusion) demonstrated superiority in reducing motor fluctuations and improving motor experiences of daily living (m-EDL; MDS-UPDRS Part II), compared to oral immediate-release levodopa/carbidopa (IR-LD/CD). Our aim was to use the MDS-UPDRS to evaluate the efficacy of ND0612 in improving motor signs of PD and m-EDL. Methods: In the present study, we evaluated MDS-UPDRS Part II and Part III (at OFF-state) subscores at the time of ND0612 initiation (ie, start of open-label ND0612 treatment) and at Weeks 8 and 12 of the double-blind double-dummy maintenance period. Descriptive analyses of changes from start of ND0612 treatment to each double-blind visit are presented here. Additionally, we performed a post hoc analysis with grouped symptom-related items (from Parts II and III) for several parameters, including tremor, rigidity, bradykinesia, postural instability-gait disorder (PIGD), speech and oral health, and self-care, using a Mixed Model for Repeated Measures. P values are displayed nominally with no adjustment. Results: Mean [95%CI] treatment differences (ND0612 vs IR-LD/CD) in Part II subscores were –2.4 [–3.5, –1.3] at Week 8 and –3.1 [–4.3, –1.8] at Week 12. Similarly, treatment differences in Part III subscores favored ND0612 treatment and were –4.2 [–6.7, –1.7] at Week 8 and –2.4 [–5.2, 0.4] at Week 12. Additionally, we observed differences favoring ND0612 vs IR-LD/CD for the following parameters: PIGD (–0.26 vs 0.02, p=0.0012), speech and oral health (–0.11 vs 0.05, p=0.0140), tremor (–0.15 vs –0.05, p=0.0992), and self-care (–0.08 vs 0.09, p=0.0528). No relevant differences were observed for rigidity and bradykinesia. Conclusions: In addition to reducing motor fluctuations, these results provide further evidence supporting the clinical benefit of ND0612 therapy across different symptom domains of MDS-UPDRS II and III.

Objective: Present a rare case of subacute cervical posttraumatic ascending myelopathy (SPAM). Background: SPAM is a rare, delayed complication of spinal cord injury (SCI), which manifests as a neurological deterioration involving at least 4 segments above the initial injured level occurring within the first few weeks following SCI. Given its rarity, there is no consensus on how to manage this condition. We present a case of SPAM with initial injury level at C6 who progressed to involve myelopathic changes up to the C2 level. Design/Methods: NA Results: A 62-year-old female presents for acute onset weakness in the bilateral hands after lifting heavy objects. Within hours, the weakness extended caudally producing paraplegia and sensory loss to T4 level. MRI C-spine showed severe canal stenosis with cord compression by a disc osteophyte complex at C6-C7. The patient underwent a posterior decompression and fusion at C5-C7. Over the next two weeks, weakness ascended to upper extremities, graded between 4 and 4+/5. Sensory loss ascended to C8 level. Lumbar puncture only showed mild elevation of protein. Autoimmune, metabolic and toxic workup was negative. EMG showed no evidence of primarily demyelinating polyneuropathy. Given persistence of symptoms, MRI C-spine was repeated three weeks following injury which showed extensive high signal intensity extending from C2 to T3, with cord enhancement at C6-7. A few days later, the patient started improving, and repeat MRI C-spine showed significant decrease in T2 signal abnormality involving the cervical cord, only focally involving C6-7 and C4-5 level corresponding to residual spinal stenosis. Repeat CSF studies were normal. The clinical and radiographic improvement wasattributed to resolving SPAM. The patient received no corticosteroids/immunotherapy. Conclusions: Following SCI, SPAM is an important clinical and radiological pattern of neurological deterioration that is frequentlyunderrecognized. This case study provides insight into this disease's natural clinical and radiological progress with nomodifying therapy.