Trial of Cinpanemab in Early Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).

Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Adaptation of the Tumor Antigen Presentation Machinery to Ionizing Radiation.

Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell-mediated immunity, including enhanced expression of MHC class I (MHC-I), ß2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors in vivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and in vivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor-host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

Quantification of Cinpanemab (BIIB054) Binding to α- Synuclein in Cerebrospinal Fluid of Phase 1 Single Ascending Dose Samples.

Through its pathological and genetic association to Parkinson's Disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Whereas published studies from some immunotherapy trials have demonstrated engagement in plasma, none have shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system (CNS). Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low affinity binding to monomeric forms. The avidity-driven binding, low drug concentration, and the very low α-syn levels plus its heterogeneous nature in cerebrospinal fluid (CSF) made it not possible to measure drug-target interactions by conventional assays. Here we overcame these challenges by using zero-length crosslinking to stabilize the BIIB054-α-syn complexes and then quantified the crosslinked complexes using a Meso Scale Discovery (MSD) electrochemiluminescence assay. CSF samples from healthy volunteers (HV, n=46) and individuals with PD (PD, n=18) from study 228HV101 (Phase I clinical trial of BIIB054), demonstrated dose- and time- dependent binding of cinpanemab to α-syn with measurable complexes detected at doses {greater than or equal to}15 mg/kg. Complex formation displayed a direct positive correlation to drug concentration (Spearman rank correlation = 0.8295 (HV), 0.8032 (PD) p < 0.0001 (HV, PD)). The observed binding of cinpanemab to α-syn in CSF is consistent with its low intrinsic affinity for α-syn monomer and provides evidence that the drug is behaving with expected binding dynamics in the central nervous system compartment. Significance Statement A zero-length cross-linking method with MSD detection was developed to enable quantification of cinpanemab-α-syn complexes in Phase 1 clinical CSF samples by preventing signal loss caused by their rapid dissociation. Observed dose- and time-dependent binding were consistent with cinpanemab's affinity for α-syn and provided confidence that the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the CNS.

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers.

BACKGROUND: The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. METHODS: Patients aged 50-74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. RESULTS: In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P < .029), larger total brain ventricle volume (P < .021), less synaptic injury (Ng, P < .001), and less tau pathophysiology (p-tau181, P < .005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P = .002), more synaptic injury (Ng, P < .001), and higher levels of glial activation (YKL-40, P = .01). CONCLUSION: These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype. TRIAL REGISTRATION: NCT03186989 since June 14, 2017.

Information-Rich, Dual-Function 13C/2H-Isotopic Crosstalk NMR Assay for Human Serine Racemase (hSR) Provides a PLP-Enzyme "Partitioning Fingerprint" and Reveals Disparate Chemotypes for hSR Inhibition.

The first dual-function assay for human serine racemase (hSR), the only bona fide racemase in human biology, is reported. The hSR racemization function is essential for neuronal signaling, as the product, d-serine (d-Ser), is a potent N-methyl d-aspartate (NMDA) coagonist, important for learning and memory, with dysfunctional d-Ser-signaling being observed in some neuronal disorders. The second hSR function is ß-elimination and gives pyruvate; this activity is elevated in colorectal cancer. This new NMR-based assay allows one to monitor both α-proton-exchange chemistry and ß-elimination using only the native l-Ser substrate and hSR and is the most sensitive such assay. The assay judiciously employs segregated dual 13C-labeling and 13C/2H crosstalk, exploiting both the splitting and shielding effects of deuterium. The assay is deployed to screen a 1020-compound library and identifies an indolo-chroman-2,4-dione inhibitor family that displays allosteric site binding behavior (noncompetitive inhibition vs l-Ser substrate; competitive inhibition vs adenosine 5'-triphosphate (ATP)). This assay also reveals important mechanistic information for hSR; namely, that H/D exchange is ∼13-fold faster than racemization, implying that K56 protonates the carbanionic intermediate on the si-face much faster than does S84 on the re-face. Moreover, the 13C NMR peak pattern seen is suggestive of internal return, pointing to K56 as the likely enamine-protonating residue for ß-elimination. The 13C/2H-isotopic crosstalk assay has also been applied to the enzyme tryptophan synthase and reveals a dramatically different partition ratio in this active site (ß-replacement: si-face protonation ∼6:1 vs ß-elimination: si-face protonation ∼1:3.6 for hSR), highlighting the value of this approach for fingerprinting the pyridoxal phosphate (PLP) enzyme mechanism.

Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. METHODS: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose. CONCLUSIONS: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).

Lifelong Imaging Surveillance is Indicated for Patients with Primary Retroperitoneal Liposarcoma.

BACKGROUND: Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) after surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined because the natural history of RP-LPS after treatment is poorly understood. This study evaluated the long-term risk of recurrence and disease-specific survival (DSS) for a cohort of patients with at least 10 years of progression-free survival (10yr-PFS) from their primary resection. METHODS: The prospective University of California, Los Angeles (UCLA) Sarcoma Database identified RP-LPS patients with 10yr-PFS after initial resection. The patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. The time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS. RESULTS: From 1972 to 2010, 76 patients with RP-LPS had at least 10 years of follow-up evaluation. Of these 76 patients, 39 (51%) demonstrated 10yr-PFS. The median follow-up period was 15 years (range 10-33 years). Among the 10yr-PFS patients, 49% (19/39) experienced a recurrence at least 10 years after surgery. Of those who experienced recurrence, 42% (8/19) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or perioperative treatment with radiation or chemotherapy. CONCLUSION: Patients who have primary RP-LPS treated with surgical resection ± multimodality therapy face a long-term risk of recurrence and disease-specific death unacknowledged by current surveillance imaging guidelines. Among the patients with 10yr-PFS, 49% experienced a recurrence, and 42% of those died of disease. These findings suggest a need for lifelong surveillance imaging for patients with RP-LPS.

LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. METHODS: Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. RESULTS: A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7-1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). CONCLUSIONS: At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Conceptualizing college-going volition in rural Appalachian high school students.

Understanding the gap between students' aspirations for postsecondary education and their actual postsecondary attainment is key to understanding and reducing educational and vocational inequities. Just as work volition has emerged as a key factor in understanding access to decent work, students' sense of control over or volition in the college-going process may be a key factor in understanding their access to postsecondary education. In the current study, we adapted a common measure of work volition to create a measure of college-going volition (CGV). In a large sample of rural Appalachian high school students, the measure showed good psychometric properties and strong measurement invariance across gender and prospective college-generation groups. There were no gender differences in CGV, but prospective first-generation college students demonstrated significantly lower CGV than their continuing-generation peers. CGV also accounted for significant unique variance in college-going self-efficacy beyond educational barriers.

Perceptions of COVID-19 self-testing and recommendations for implementation and scale-up among Black/African Americans: implications for the COVID-19 STEP project.

BACKGROUND: COVID-19 self-testing (ST) is an innovative strategy with the potential to increase the access and uptake of testing and ultimately to limit the spread of the virus. To maximize the uptake and reach of this promising strategy and inform intervention development and scale up, research is needed to understand the acceptability of and willingness to use this tool. This is vital to ensure that Black/African Americans are reached by the Biden-Harris Administration's free national COVID-19 ST program. This study aimed to explore the acceptability and recommendations to promote and scale-up the uptake of COVID-19 ST among Black/African Americans. METHODS: We conducted a cross-sectional qualitative study using a semi-structured questionnaire to assess barriers and facilitators to the uptake of COVID-19 ST among a convenience sample of 28 self-identified Black/African Americans from schools, community centers, and faith-based institutions in Ohio and Maryland. Inductive content analysis was conducted to identify categories and subcategories related to acceptability and recommendations for implementing and scaling up COVID-19 ST in communities. RESULTS: Participants perceived COVID-19 self-testing as an acceptable tool that is beneficial to prevent transmission and address some of the barriers associated with health facility testing, such as transportation cost and human contact at the health facility. However, concerns were raised regarding the accurate use of the kits and costs. Recommendations for implementing and scaling up COVID-19 ST included engagement of community stakeholders to disseminate information about COVID-19 self-testing and creating culturally appropriate education tools to promote knowledge of and clear instructions about how to properly use COVID-19 ST kits. Based on these recommendations, the COVID-19 STEP (Self-Testing Education and Promotion) Project is being developed and will involve engaging community partners such as barbers, church leaders, and other community-based organizations to increase the uptake and use of free COVID-19 ST kits among Black/African Americans. CONCLUSION: Findings showed that most participants considered COVID-19 ST valuable for encouraging COVID-19 testing. However, cost and accuracy concerns may pose barriers. Future work should consider implementing interventions that leverage the benefits of COVID-19 ST and further assess the extent to which these identified facilitators and barriers may influence COVID-19 ST uptake.

Nitrogen fixation in a landrace of maize is supported by a mucilage-associated diazotrophic microbiota.

Plants are associated with a complex microbiota that contributes to nutrient acquisition, plant growth, and plant defense. Nitrogen-fixing microbial associations are efficient and well characterized in legumes but are limited in cereals, including maize. We studied an indigenous landrace of maize grown in nitrogen-depleted soils in the Sierra Mixe region of Oaxaca, Mexico. This landrace is characterized by the extensive development of aerial roots that secrete a carbohydrate-rich mucilage. Analysis of the mucilage microbiota indicated that it was enriched in taxa for which many known species are diazotrophic, was enriched for homologs of genes encoding nitrogenase subunits, and harbored active nitrogenase activity as assessed by acetylene reduction and 15N2 incorporation assays. Field experiments in Sierra Mixe using 15N natural abundance or 15N-enrichment assessments over 5 years indicated that atmospheric nitrogen fixation contributed 29%-82% of the nitrogen nutrition of Sierra Mixe maize.

The BB0345 Hypothetical Protein of Borrelia burgdorferi Is Essential for Mammalian Infection.

During the natural enzootic life cycle of Borrelia burgdorferi (also known as Borreliella burgdorferi), the bacteria must sense conditions within the vertebrate and arthropod and appropriately regulate expression of genes necessary to persist within these distinct environments. bb0345 of B. burgdorferi encodes a hypothetical protein of unknown function that is predicted to contain an N-terminal helix-turn-helix (HTH) domain. Because HTH domains can mediate protein-DNA interactions, we hypothesized that BB0345 might represent a previously unidentified borrelial transcriptional regulator with the ability to regulate events critical for the B. burgdorferi enzootic cycle. To study the role of BB0345 within mammals, we generated a bb0345 mutant and assessed its virulence potential in immunocompetent mice. The bb0345 mutant was able to initiate localized infection and disseminate to distal tissues but was cleared from all sites by 14 days postinfection. In vitro growth curve analyses revealed that the bb0345 mutant grew similar to wild-type bacteria in standard Barbour-Stoenner-Kelley II (BSK-II) medium; however, the mutant was not able to grow in dilute BSK-II medium or dialysis membrane chambers (DMCs) implanted in rats. Proteinase K accessibility assays and whole-cell partitioning indicated that BB0345 was intracellular and partially membrane associated. Comparison of protein production profiles between the wild-type parent and the bb0345 mutant revealed no major differences, suggesting BB0345 may not be a global transcriptional regulator. Taken together, these data show that BB0345 is essential for B. burgdorferi survival in the mammalian host, potentially by aiding the spirochete with a physiological function that is required by the bacterium during infection.

Characterization of tau binding by gosuranemab.

Deposition of tau aggregates in the brain is a pathological hallmark of several neurodegenerative diseases, termed tauopathies, such as Alzheimer's disease (AD), corticobasal degeneration, and progressive supranuclear palsy (PSP). As transcellular spread of pathological tau aggregates has been implicated in disease progression, immunotherapy is being considered as a treatment for tauopathies. Here we report a detailed biochemical and biophysical characterization of the tau-binding properties of gosuranemab, a humanized monoclonal antibody directed against N-terminal tau that is currently being investigated as a treatment for AD. Binding experiments showed that gosuranemab exhibited high affinity for tau monomer, tau fibrils, and insoluble tau from different tauopathies. Epitope mapping studies conducted using X-ray crystallography and mutagenesis showed that gosuranemab bound to human tau residues 15-22. Immunodepletion of pathological human brain homogenates and transgenic mouse interstitial fluid (ISF) with gosuranemab resulted in reduced tau aggregation in tau biosensor cells. Preincubation of seed-competent AD-tau with gosuranemab significantly inhibited tau aggregation in mouse primary cortical neurons. Gosuranemab also significantly reduced unbound N-terminal tau in cerebrospinal fluid (CSF) from individuals with PSP and AD, and in ISF and CSF of treated transgenic mice. These results are consistent with the >90% target engagement observed in the CSF of some clinical trial dosing cohorts and support the evaluation of gosuranemab as a potential treatment for AD.

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression.

BACKGROUND: The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker. METHODS: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. RESULTS: In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. CONCLUSIONS: Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Low Rates of Chemotherapy Use for Primary, High-Grade Soft Tissue Sarcoma: A National Cancer Database Analysis.

BACKGROUND: There is conflicting evidence regarding the role of chemotherapy for high-grade soft tissue sarcoma (STS) in adults. We sought to characterize patterns of chemotherapy use, including multiagent and neoadjuvant chemotherapy, in the United States. PATIENTS AND METHODS: Using the National Cancer Database, we identified 19,969 adult patients who underwent surgical resection for primary high-grade STS from 2004 to 2016. Using logistic regression, we examined factors associated with overall, multiagent, and neoadjuvant chemotherapy use. RESULTS: Chemotherapy was administered to 22% (n=4,377) of the study population. Among patients treated using chemotherapy, 85% received multiagent treatment and 47% received neoadjuvant treatment. On multivariate analysis, factors associated with chemotherapy use included tumor size, depth, histology, and primary site; receipt of radiation treatment; younger age; higher patient income; and academic treatment facility. Factors associated with multiagent chemotherapy use included tumor histology, tumor primary site, and younger age. Factors associated with neoadjuvant chemotherapy use included tumor size, depth, margin status, and primary site; receipt of radiation treatment; higher patient income; academic treatment facility type; and distance to treatment facility. Treatment at a high-volume facility was the only factor associated with overall, multiagent, and neoadjuvant chemotherapy use. No significant temporal trend was seen in overall, multiagent, or neoadjuvant chemotherapy use. CONCLUSIONS: Overall chemotherapy use was low (22%). The variability in chemotherapy use was driven by clinical, patient, demographic, and facility factors. Among patients treated with chemotherapy, the use of multiagent chemotherapy was high (85%), and nearly half received neoadjuvant therapy. There was a discrepancy in the use of chemotherapy-including neoadjuvant and multiagent chemotherapy-between high- and low-volume treatment centers.

Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054.

BACKGROUND: Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression. OBJECTIVE: This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease. METHODS: A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma. RESULTS: Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation. CONCLUSIONS: BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

INTRODUCTION: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). METHODS: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. RESULTS: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DISCUSSION: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.

Rural Appalachian High School Students' College-Going and STEMM Perceptions.

The authors examined perceptions of key social cognitive career theory (Lent, Brown, & Hackett, 1994) variables related to college-going and science, technology, engineering, math, and medical (STEMM) careers in 10th and 11th graders (N = 892) attending 3 rural Appalachian high schools. The authors examined differences in perceptions related to gender, prospective 1st-generation college student status, and the presence or absence of aspirations to pursue a STEMM career. Young women and young men scored similarly on all but 1 dependent variable, college-going self-efficacy (young women scored higher). Students who had STEMM career aspirations had higher scores on every measure than those who did not. Results suggest examining a 3rd prospective 1st-generation college student status group-students who are unsure of their parents' education level-as a distinct group in future research. By examining the college-going and STEMM attitudes of rural Appalachian high school students, this study advances the literature and informs practitioners on reducing educational and vocational inequalities in this region.

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for ß-elimination function.

There is currently great interest in human serine racemase, the enzyme responsible for producing the NMDA co-agonist d-serine. Reported correlation of d-serine levels with disorders including Alzheimer's disease, ALS, and ischemic brain damage (elevated d-serine) and schizophrenia (reduced d-serine) has further piqued this interest. Reported here is a structure/activity relationship study of position Ser84, the putative re-face base. In the most extreme case of functional reprogramming, the S84D mutant displays a dramatic reversal of ß-elimination substrate specificity in favor of l-serine over the normally preferred l-serine-O-sulfate (∼1200-fold change in kcat/Km ratios) and l (l-THA; ∼5000-fold change in kcat/Km ratios) alternative substrates. On the other hand, the S84T (which performs l-Ser racemization activity), S84A (good kcat but high Km for l-THA elimination), and S84N mutants (nearly WT efficiency for l-Ser elimination) displayed intermediate activity, all showing a preference for the anionic substrates, but generally attenuated compared with the native enzyme. Inhibition studies with l-erythro-ß-hydroxyaspartate follow this trend, with both WT serine racemase and the S84N mutant being competitively inhibited, with Ki = 31 ± 1.5 µm and 1.5 ± 0.1 mm, respectively, and the S84D being inert to inhibition. Computational modeling pointed to a key role for residue Arg-135 in binding and properly positioning the l-THA and l-serine-O-sulfate substrates and the l-erythro-ß-hydroxyaspartate inhibitor. Examination of available sequence data suggests that Arg-135 may have originated for l-THA-like ß-elimination function in earlier evolutionary variants, and examination of available structural data suggests that a Ser84-H2O-Lys114 hydrogen-bonding network in human serine racemase lowers the pKa of the Ser84re-face base.