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Background Elayta (CT1812) is a novel allosteric antagonist of the sigma-2 receptor complex that prevents and displaces binding of Aβ oligomers to neurons. By stopping a key initiating event in Alzheimer's disease, this first-in–class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer's disease. Methods A phase 1, two-part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (, Highlights • CT1812 was safe and well tolerated in healthy subjects over the dose range tested. • Adverse events were generally mild and included headache and GI disturbances. • Plasma concentrations of drug increased slightly greater than dose proportionally. • CSF concentrations of drug increased with dose. • CT1812 is suitable for advancement to later stages of clinical development.

Background: Ubiquitous digital technologies such as smartphone sensors promise to fundamentally change biomedical research and treatment monitoring in neurological diseases such as PD, creating a new domain of digital biomarkers. Objectives: The present study assessed the feasibility, reliability, and validity of smartphone‐based digital biomarkers of PD in a clinical trial setting. Methods: During a 6‐month, phase 1b clinical trial with 44 Parkinson participants, and an independent, 45‐day study in 35 age‐matched healthy controls, participants completed six daily motor active tests (sustained phonation, rest tremor, postural tremor, finger‐tapping, balance, and gait), then carried the smartphone during the day (passive monitoring), enabling assessment of, for example, time spent walking and sit‐to‐stand transitions by gyroscopic and accelerometer data. Results: Adherence was acceptable: Patients completed active testing on average 3.5 of 7 times/week. Sensor‐based features showed moderate‐to‐excellent test‐retest reliability (average intraclass correlation coefficient = 0.84). All active and passive features significantly differentiated PD from controls with P

Introduction Extracellular tau is hypothesized to mediate the onset and progression of tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and a subset of frontotemporal lobar degenerations. A putative strategy for treating these disorders is to reduce extracellular tau levels using tau-directed immunotherapy. The results of the first-in-human study of BIIB092 (formerly BMS-986168/IPN007), a humanized monoclonal antibody that binds to N-terminal tau, are reported here. This randomized, double-blind, single ascending dose study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity profile of BIIB092 after a single intravenous infusion in healthy participants. Methods Sixty-five participants were randomized to receive a single intravenous infusion of placebo or BIIB092 at doses of 21, 70, 210, 700, 2100, or 4200 mg (or 700 or 2100 mg for Japanese participants). Serial blood and cerebrospinal fluid samples were obtained for assessment of pharmacokinetic parameters and unbound N-terminal tau suppression. Results There were no deaths, serious adverse events (AEs), severe AEs, or discontinuations due to an AE. The majority of AEs were mild. Serum BIIB092 concentrations increased in a dose-proportional manner and suppressed unbound cerebrospinal fluid N-terminal tau by 67%–97% at 28 days after dose, with doses of ≥210 mg producing persistent unbound N-terminal tau suppression over 12 weeks. Levels of cerebrospinal fluid N-terminal tau suppression were similar for Japanese and non-Japanese participants. Discussion BIIB092 was generally safe and well tolerated after a single dose of up to 4200 mg, and up to 2100 mg in Japanese participants. BIIB092 exhibited a dose-dependent increase in the extent and duration of unbound N-terminal tau suppression., Highlights • BIIB092 was generally safe and well tolerated after a single dose of up to 4200 mg. • BIIB092 doses ≥210 mg resulted in persistent CSF N-terminal tau suppression for 12 weeks. • Increases in serum concentrations and CSF N-terminal tau suppression were dose proportional.

Author(s): Dam, Tien; Boxer, Adam L; Golbe, Lawrence I; Hoglinger, Gunter; Morris, Huw R; Litvan, Irene; Corvol, Jean-Christophe; Lang, Anthony; Grundman, Michael; Yang, Lili; O'Gorman, John; Olsson, Tina; Haeberlein, Samantha Budd

Background: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice. Methods: This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.3, 1, 3, 10, or 30 mg/kg; n = 6/cohort) or placebo (n = 2/cohort). Results: PRX002 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity. No serious adverse events, discontinuations as a result of adverse events, or dose-limiting toxicities were reported. Serum PRX002 exposure was dose proportional; the average terminal half-life across all doses was 18.2 days. A significant dose-dependent reduction in free serum α-synuclein (unbound to PRX002) was apparent within 1 hour after PRX002 administration, whereas total α-synuclein (free plus bound) increased dose-dependently, presumably because of the expected change in kinetics following antibody binding. Conclusions: This study demonstrates that serum α-synuclein can be safely modulated in a dose-dependent manner after single intravenous infusions of an anti–α-synuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson's disease. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.

OBJECTIVES: To develop and evaluate the psychometric properties of a new measure of agitation, the Agitated Behavior in Dementia scale (ABID). The ABID consists of 16 items designed specifically to evaluate frequency of and caregiver reaction to common agitated behaviors in community-residing dementia patients. DESIGN: The ABID was administered at the baseline assessment of a multi-site controlled treatment study to reduce agitation in Alzheimer's Disease (AD). Reliability was assessed by evaluating internal consistency and test-retest correlations. Validity was assessed by examining correlations with other constructs, including demographics, cognitive status, and overall behavioral disturbance. SETTING: Twenty-one sites across the US, comprising the Alzheimer's Disease Cooperative Study, contributed subjects to the investigation. PARTICIPANTS: A total of 148 community-residing AD patients, living with a spouse or adult relative who acted as an informant. Mean age was 75 years, and mean Mini-Mental State Exam (MMSE) score was 13. MEASUREMENTS: Cognitive status was assessed using the MMSE. Behavioral disturbance was assessed using the Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer's Disease, the Revised Memory and Behavior Problems Checklist, and the Cohen-Mansfield Agitation Inventory. RESULTS: Reliability of the ABID was excellent, with internal consistency of 0.70 and test-retest reliability of 0.60 to 0.73. Validity was confirmed by correlations with related measures and lack of correlation with unrelated constructs. CONCLUSIONS: The ABID is brief, easy to administer, and provides objectively anchored observations of problems. It is a promising measure for studies of community-residing AD patients. J Am Geriatr Soc 47:1354–1358,1999.

Background The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) has been used widely as a cognitive end point in Alzheimer's Disease (AD) clinical trials. Efforts to treat AD pathology at earlier stages have also used ADAS-Cog, but failure in these trials can be difficult to interpret because the scale has well-known ceiling effects that limit its use in mild cognitive impairment (MCI) and early AD. A wealth of data exists in ADAS-Cog from both historical trials and contemporary longitudinal natural history studies that can provide insights about parts of the scale that may be better suited for MCI and early AD trials. Methods Using Alzheimer's Disease Neuroimaging Initiative study data, we identified the most informative cognitive measures from the ADAS-Cog and other available scales. We used cross-sectional analyses to characterize trajectories of ADAS-Cog and its individual subscales, as well as other cognitive, functional, or global measures across disease stages. Informative measures were identified based on standardized mean of 2-year change from baseline and were combined into novel composite endpoints. We assessed performance of the novel endpoints based on sample size requirements for a 2-year clinical trial. A bootstrap validation procedure was also undertaken to assess the reproducibility of the standardized mean changes of the selected measures and the corresponding composites. Results All proposed novel endpoints have improved standardized mean changes and thus improved statistical power compared with the ADAS-Cog 11. Further improvements were achieved by using cognitive–functional composites. Combining the novel composites with an enrichment strategy based on cerebral spinal fluid beta-amyloid (Aβ 1-42 ) in a 2-year trial yielded gains in power of 20% to 40% over ADAS-Cog 11, regardless of the novel measure considered. Conclusion An empirical, data-driven approach with e xisting instruments was used to derive novel composite scales based on ADAS-Cog 11 with improved performance characteristics for MCI and early AD clinical trials. Together with patient enrichment based on Aβ 1-42 pathology, these modified endpoints may allow more efficient clinical trials in these populations and can be assessed without modifying current test administration procedures in ongoing trials.

Although computed tomography (CT) and magnetic resonance imaging scans often appear normal after mild head trauma, many patients experience attentional or other cognitive disturbances that are difficult to quantify by neuropsychological testing in the absence of a premorbid profile. Within 2 days of mild head trauma, 14 patients with normal-appearing brain CTs were studied with single-photon emission computed tomography (SPECT). They were compared to 15 normal control subjects and to 12 patients with mild human immunodeficiency virus (HIV) encephalopathy. Ten of 14 head trauma patients were separated from the normal control subjects by both independent readers, blinded to the clinical diagnosis. None of the SPECT results from normal control subjects were "read" as trauma. Trauma could not be differentiated from HIV encephalopathy. The observed percentage agreement between raters was 0.83 (kappa = 0.72). SPECT is more sensitive than CT in detecting brain injury after mild head trauma.

RECRUITMENT IN TRIALS OF MILD COGNITIVE IMPAIRMENT Ronald C. Petersen, Ronald G. Thomas, Michael Grundman, David A. Bennett, Jeffrey Kaye, Allan I. Levey, Eric Pfeiffer, Mary Sano, Christopher H. van Dyck, Leon J. Thal; Mayo Clinic, Rochester, MN, USA; University of California, San Diego, La Jolla, CA, USA; Elan Pharmaceuticals, San Diego, CA, USA; Rush University Medical Center, Chicago, IL, USA; Oregon Health And Science University, Portland, OR, USA; Emory University, Atlanta, GA, USA; University of South Florida College of Medicine, Tampa, FL, USA; Mount Sinai School of Medicine, New York, NY, USA; Yale University School of Medicine, New Haven, CT, USA; University of California at San Diego, San Diego, CA, USA