Gantenerumab reduces amyloid-ß plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis.

BACKGROUND: We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-ß by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-ß plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD). METHODS: A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-ß plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. RESULTS: Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-ß plaque levels below the amyloid-ß positivity threshold. CONCLUSION: Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-ß plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-ß plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

The implications of memory profiles in schizophrenia on vocational and neuropsychological functioning.

Studies in schizophrenia suggest that verbal learning and memory may distinguish three subgroups of patients: an unimpaired memory profile group and two groups that have memory profiles similar to those seen in cortical and subcortical dementias. Using the Hopkins Verbal Learning Test, Revised edition (HVLT-R), this study attempted to differentiate patients into three memory profile groups and to examine the validity of these groups with respect to vocational outcomes and neuropsychological functioning. Results from this study replicated previous findings and extended them by demonstrating a link to vocational outcome. In addition, the proportion of patients in each group closely resembled that obtained in previous studies. Specifically, the relatively unimpaired memory group (42%) showed overall better memory and neuropsychological performance than the two impaired groups, the subcortical group (38%) showed impaired recall but intact recognition and deficits in visuospatial functioning, and the cortical group (20%) showed deficits in recall, recognition, and sustained attention/executive functioning. There were no clinical differences between the three groups, but both the unimpaired and subcortical groups increased the number of hours worked following a vocational rehabilitation program. Given these differences, more research is warranted to explore the effect of memory impairment subtypes on vocational outcome measures.

Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms.

Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms. A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy-avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit. A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.

Feasibility, safety, and efficacy of the combination of D-serine and computerized cognitive retraining in schizophrenia: an international collaborative pilot study.

The combination of pharmacotherapy and cognitive retraining (CRT) for the cognitive deficits of schizophrenia may be more efficacious than either approach alone, but this has not yet been tested. This study evaluated the feasibility, safety, tolerability, and efficacy of 12 weeks of D-serine, combined with CRT in the treatment of cognitive deficits in schizophrenia at two academic sites in parallel, in India and the United States. In a randomized, partial double-blind, placebo-controlled, parallel-group design, 104 schizophrenia subjects (US site=22, Indian site=82) were randomized to: (1) D-serine (30 mg/kg)+CRT (5 h/week), (2) D-serine+control CRT, (3) CRT+placebo D-serine, and (4) placebo+control CRT. Completion rates were 84 and 100% in the Indian and US samples, respectively. On various outcome measures of safety and tolerability, the interventions were well tolerated. D-Serine and CRT did not show any significant effect on the Global Cognitive Index, although both interventions showed differential site effects on individual test performance. CRT resulted in a significant improvement in Verbal Working Memory, and a trend toward improvement in Attention/Vigilance. This is the first study to demonstrating the feasibility, safety, and tolerability of combination pharmacotherapy and CRT in a multicenter international clinical trial. These preliminary findings provide support for future studies using higher doses of D-serine that have been shown to be efficacious or other pharmacotherapies, along with the newer cognitive remediation strategies that are individualized and that target basic information processing.

The effect of alcohol on the neuropsychological functioning of recently abstinent cocaine-dependent subjects.

Neuropsychological deficits in the areas of learning, memory, attention, and abstraction abilities have been associated with cocaine dependence, especially during the period of early abstinence. Although cocaine users tend to be multidrug users, few studies have focused on the combined effect of alcohol and cocaine on neuropsychological functioning. Consistent with prior research, results from the current study indicated that cocaine-dependent subjects showed a significantly greater degree of neuropsychological impairment as compared to controls. In addition, cocaine-dependent subjects with a history of alcohol disorder showed less memory impairment but similar impairments in attention and overall neuropsychological functioning as cocaine subjects with no such history. The vasodilatation produced by alcohol may attenuate some of the vasoconstriction and neurotoxic effects of cocaine, accounting for the fewer deficits in this group.