Person: Cudkowicz, Merit
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Cudkowicz
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Merit
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Cudkowicz, Merit
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Publication Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Propagate Neuronal Loss(Science Press / AAAS, 2021-07-07) Rodriguez, Steve; Sahin, Asli; Schrank, Benjamin R.; Al Lawati, Hawra; Costantino, Isabel; Benz, Eric; Fard, Darian; Albers, Alefiya; Cao, Luxiang; Gomez, Alexis; Evans, Kyle; Ratti, Elena; Cudkowicz, Merit; Frosch, Matthew; Talkowski, Michael; Sorger, Peter; Hyman, Bradley; Albers, MarkTriggers of innate immune signaling in the CNS of amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) patients remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. Presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced Type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction, and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in ALS/FTD patients.Publication Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS(John Wiley and Sons Inc., 2018) Goutman, Stephen A.; Brown, Morton B.; Glass, Jonathan D.; Boulis, Nicholas M.; Johe, Karl; Hazel, Tom; Cudkowicz, Merit; Atassi, Nazem; Borges, Lawrence; Patil, Parag G.; Sakowski, Stacey A.; Feldman, Eva L.Abstract Objective: Intraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs. Methods: Survival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20. Results: Survival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study. Interpretation Comparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study.Publication Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS(Lippincott Williams & Wilkins, 2018) Benatar, Michael; Wuu, Joanne; Andersen, Peter M.; Atassi, Nazem; David, William; Cudkowicz, Merit; Schoenfeld, DavidObjective: To examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS). Methods: This was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS). Results: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32–1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI −0.63 to 1.63) and 1.24 percent predicted/month (95% CI −2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol. Conclusions: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol. Clinicaltrials.gov identifier NCT00706147. Classification of evidence This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.Publication Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial(Public Library of Science, 2014) Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, JensThe neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330Publication Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: Assessed with [11C]-PBR28(Elsevier, 2015) Zürcher, Nicole R.; Loggia, Marco; Lawson, Robert; Chonde, Daniel B.; Izquierdo-Garcia, David; Yasek, Julia E.; Akeju, Oluwaseun; Catana, Ciprian; Rosen, Bruce; Cudkowicz, Merit; Hooker, Jacob; Atassi, NazemEvidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [11C]-PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38–68 years) and ten age- and [11C]-PBR28 binding affinity-matched healthy volunteers (six males, four females, 33–65 years) completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (pFWE < 0.05). Region of interest analysis revealed increased [11C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15) compared to controls (1.03, p < 0.05). In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05), and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = –0.66, p < 0.05). Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [11C]-PBR28 as a marker of treatments that target neuroinflammation.Publication Military Service and Amyotrophic Lateral Sclerosis in a Population-based Cohort(Lippincott Williams & Wilkins, 2015) Weisskopf, Marc; Cudkowicz, Merit; Johnson, NormanBackground: Military service has been suggested to be associated with an increased risk of amyotrophic lateral sclerosis (ALS), but only one prospective study—of a volunteer cohort—has examined this question. Methods: We prospectively assessed the relation between service in the military and ALS mortality among participants in the National Longitudinal Mortality Study, a population-representative cohort of U.S. men and women surveyed from 1973 through 2002. Participant follow-up was conducted from 1979 through 2002 for ALS mortality. There were 696,743 men and 392,571 women who were 25 years old or more with military service data. In this group, there were 375 male ALS deaths and 96 female ALS deaths. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards. Results: Men who served in the military had an increased adjusted ALS death rate [HR: 1.23; 95% confidence interval (CI): 0.98, 1.53] compared with those who did not serve. An increase in ALS mortality was found among those who served during World War II (HR: 1.47; 95% CI: 1.13, 1.91) but not during other time periods. This pattern of results was similar for women, but with larger confidence intervals (HR for military service: 1.26; 95% CI: 0.29, 5.59; HR for service during World War II: 2.03; 95% CI: 0.45, 9.05). Conclusions: Military personnel have an increased risk of ALS, which may be specific to certain service periods although there was no data on actual deployment. Because of the longer follow-up time for World War II veterans, we cannot rule out that increased risk for those who served during other periods would be seen with further follow-up.Publication Race/ethnicity, socioeconomic status, and ALS mortality in the United States(Lippincott Williams & Wilkins, 2016) Roberts, Andrea L.; Johnson, Norman J.; Chen, Jarvis; Cudkowicz, Merit; Weisskopf, MarcObjective: To determine whether race/ethnicity and socioeconomic status are associated with amyotrophic lateral sclerosis (ALS) mortality in the United States. Methods: The National Longitudinal Mortality Study (NLMS), a United States–representative, multistage sample, collected race/ethnicity and socioeconomic data prospectively. Mortality information was obtained by matching NLMS records to the National Death Index (1979–2011). More than 2 million persons (n = 1,145,368 women, n = 1,011,172 men) were included, with 33,024,881 person-years of follow-up (1,299 ALS deaths , response rate 96%). Race/ethnicity was by self-report in 4 categories. Hazard ratios (HRs) for ALS mortality were calculated for race/ethnicity and socioeconomic status separately and in mutually adjusted models. Results: Minority vs white race/ethnicity predicted lower ALS mortality in models adjusted for socioeconomic status, type of health insurance, and birthplace (non-Hispanic black, HR 0.61, 95% confidence interval [CI] 0.48–0.78; Hispanic, HR 0.64, 95% CI 0.46–0.88; other races, non-Hispanic, HR 0.52, 95% CI 0.31–0.86). Higher educational attainment compared with < high school was in general associated with higher rate of ALS (high school, HR 1.23, 95% CI 1.07–1.42; some college, HR 1.24, 95% CI 1.04–1.48; college, HR 1.10, 95% CI 0.90–1.36; postgraduate, HR 1.31, 95% CI 1.06–1.62). Income, household poverty, and home ownership were not associated with ALS after adjustment for race/ethnicity. Rates did not differ by sex. Conclusion: Higher rate of ALS among whites vs non-Hispanic blacks, Hispanics, and non-Hispanic other races was not accounted for by multiple measures of socioeconomic status, birthplace, or type of health insurance. Higher rate of ALS among whites likely reflects actual higher risk of ALS rather than ascertainment bias or effects of socioeconomic status on ALS risk.Publication Transcranial magnetic stimulation of the brain: guidelines for pain treatment research(Wolters Kluwer, 2015) Klein, Max; Treister, Roi; Raij, Tommi; Pascual-Leone, Alvaro; Park, Lawrence; Nurmikko, Turo; Lenz, Fred; Lefaucheur, Jean-Pascal; Lang, Magdalena; Hallett, Mark; Fox, Michael; Cudkowicz, Merit; Costello, Ann; Carr, Daniel B.; Ayache, Samar S.; Oaklander, AnneAbstract Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.Publication Job-related formaldehyde exposure and ALS mortality in the USA(BMJ Publishing Group, 2016) Roberts, Andrea L; Johnson, Norman J; Cudkowicz, Merit; Eum, Ki-Do; Weisskopf, MarcPublication Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis(Lippincott Williams & Wilkins, 2016) Alshikho, Mohamad; Zürcher, Nicole R.; Loggia, Marco; Cernasov, Paul; Chonde, Daniel B.; Izquierdo Garcia, David; Yasek, Julia E.; Akeju, Oluwaseun; Catana, Ciprian; Rosen, Bruce; Cudkowicz, Merit; Hooker, Jacob; Atassi, NazemObjective: In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. Methods: Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [11C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [11C]-PBR28 uptake. Results: In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [11C]-PBR28 binding in the left motor cortex was correlated with FA (r = −0.68, p < 0.05) and cortical thickness (r = −0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = −0.77, p < 0.05), and cortical thickness (r = −0.75, p < 0.05) in the motor cortex. Conclusions: Increased uptake of the glial marker [11C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS.