Phase 1/2a Intravenous and Subcutaneous Oligomer-Specific Antibody KHK6640 in Mild to Moderate Alzheimer's Disease.

BACKGROUND: KHK6640 is a novel humanized anti-amyloid beta oligomer-specific antibody. Both KHK6640 and the mouse parent antibody E64 have demonstrated high potency and efficacy for cognitive improvement in several rodent Alzheimer's disease models, including an anti-amyloid beta injection mouse model and in age-matched double transgenic littermates. The favorable safety and pharmacokinetic profiles of KHK6640 reported in preclinical studies warrant clinical trials in Alzheimer's disease patients. OBJECTIVES: We evaluated the safety, pharmacokinetics, and efficacy of intravenous and subcutaneous oligomer-specific antibody KHK6640 in treating patients with prodromal Alzheimer's disease or mild to moderate Alzheimer's disease. DESIGN: Phase I/2a, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Nine sites in Europe participated in this clinical trial. PARTICIPANTS: 97 patients with prodromal Alzheimer's disease or mild to moderate Alzheimer's disease. INTERVENTION: Single and multiple ascending intravenous and subcutaneous doses of KHK6640 in doses ranging from 0.1 mg/kg to 20 mg/kg or placebo was administered to patients monthly for six months. MEASUREMENTS: Primary outcomes were safety including amyloid-related imaging abnormalities for edema and hemorrhage, assessed with magnetic resonance imaging. Plasma and cerebrospinal fluid samples were analyzed to investigate pharmacokinetics and KHK6640 effects on biomarkers. Cognition, brain glucose metabolism and amyloid load were exploratory outcomes. RESULTS: No amyloid-related imaging abnormalities for edema were observed. Amyloid-related imaging abnormalities for hemorrhage were comparable to that of placebo and population background. KHK6640 exposure was approximately dose-equivalent, with a serum terminal elimination half-life of approximately 19 days. KHK6640 pharmacokinetics in serum and cerebrospinal fluid, including cerebrospinal fluid oligomers trapped by the antibody were dose related. Positive trends seen in the positron emission tomography brain glucose metabolism and amyloid load, cerebrospinal tau but cognition assessments were inconclusive, due to low numbers. CONCLUSIONS: KHK6640 was well-tolerated across all doses, without any amyloid-related imaging abnormalities for edema, and amyloid-related imaging abnormalities for hemorrhage was as population background. The demonstrated dose-response of specific target biomarkers provides dosing guidance on dose and administration method selection for further clinical development.

Mitigation of gaseous emissions from dairy livestock: A farm-level method to examine the financial implications.

Feeding the world's population while minimising the contribution of agriculture to climate change is one of the greatest challenges facing modern society. This challenge is particularly pronounced for dairy production where the carbon footprint of products and the mitigation costs are high, relative to other food stuffs. This paper reviews a number of mitigation measures that may be adopted by dairy farmers to reduce greenhouse gas emissions from their farms. A simulation model is developed to assess the cost-benefit of a range of mitigation measures. The model is applied to data from Ireland, a country with a large export-oriented dairy industry, for a range of farms including top, middle and bottom performing farms from a profitability perspective. The mitigation measures modelled included animal productivity, grass production and utilisation, better reproductive performance, early compact calving, reduced crude protein, decreased fertiliser N, protected urea, white clover, slurry tank cover and low emission slurry spreading (LESS). The results show that over half of the greenhouse gas abatement potential and most of the ammonia abatement potential were realised with cost-beneficial measures. Animal and feed-related measures that increased efficiency drove the abatement of GHG emissions. Low-emission slurry spreading was beneficial for the bottom and middle one-third of farms, while protected urea and reducing nitrogen use accounted for most of the ammonia abatement potential for the most profitable farms. Results showed that combining mitigation measures resulted in a decrease of 23%, 19%, and 12% in GHG emissions below 2020 levels for the bottom, middle, and top performing dairy farms, respectively. The findings imply that top dairy farms, that are already managed efficiently and optimally, may struggle to achieve the national and international GHG reduction targets with existing technologies and practices.

Psychiatric consultation in the nursing home. A survey of six states.

The authors examined availability, characteristics, and perceived adequacy of psychiatric consultation in nursing homes, as reported by directors of nursing, who returned 899 questionnaires. Thirty-eight percent of nursing home residents were judged to need a psychiatric evaluation; current frequency of consultation was rated as adequate by half of nursing directors. Nearly two-thirds reported that psychiatrists adequately provided diagnostic and medication recommendations; however, advice on nonpharmacologic management techniques, staff support, and dealing with staff stress and family conflicts was largely viewed as inadequate. Findings suggest that perceived need for psychiatric services is far greater than the level actually provided. Overall, more attention must be directed to identifying incentives for psychiatrists to practice in nursing homes, determining clinical effectiveness of mental health services, and examining effects of alternative payment mechanisms on level of care.

Depressive symptomatology in first-degree family caregivers of Alzheimer disease patients: a cross-ethnic comparison.

This study investigated the prevalence of depressive symptoms among White Hispanic (WH) and White non-Hispanic (WNH) first-degree family caregivers. We screened 653 primary caregivers of family members with possible or probable Alzheimer disease who presented at our outpatient memory disorders clinic. Caregiver depression was assessed utilizing the Center for Epidemiologic Studies-Depression (CES-D) Scale. Overall, depression (CES-D scores > or = 16) was more common among WH (45%) than among WNH (36%) caregivers (p < 0.05). Elevated CES-D scores among the entire caregiving sample were also linked with being a female spouse (p=0.002), increased level of patient cognitive impairment (p=0.002), and patient psychosis (p=0.002). Risk factors for caregiver depression were identified and compared when the sample was stratified by ethnicity (WH and WNH) and generation (spouses and children). Patient cognitive impairment was a predictor of caregiver depression only among WH spouses and children, whereas patient psychosis was a predictor only among WNH spouses. Female caregiver gender was the most robust risk factor for caregiver depression, being a predictor in all groups except WH children. Implications of this study include the need for increased clinical sensitivity to depression in ethnic minority caregivers, treatment of psychiatric morbidity in dementia caregivers, and respite care for caregivers with high risk for depression.

Psychosis in Alzheimer's Disease.

The risk of psychotic symptoms in patients with Alzheimer's disease (AD) has been noted since the first case description of AD in 1907. Recent studies suggest that approximately a third of AD patients manifest psychosis at sometime during the course of their illness. Differentiating psychotic symptoms from the direct effects of cognitive dysfunction in AD can be challenging for clinicians and researchers. Nonetheless, the identification and treatment of such symptoms may be critical, as AD patients with psychosis may have a more rapid cognitive and functional decline, impose greater caregiver burden, and may be at increased risk of early institutionalization. Due to the potential side effects from neuroleptic medications, nonpharmacologic approaches to treatment should be considered, including environmental and behavioral modification and caregiver education. Some pharmacologic interventions may be necessary for symptoms not alleviated by these approaches, with specific elderly data for quetiapine and risperidone. Because there is no evidence for differential efficacy among the various neuroleptic medications, choice of an antipsychotic should be based on the side effect profiles of available medications weighed against the particular characteristics and situation of the individual patient.

Follow-up assessment of medication-treated dysthymia.

1. The objective was to assess long-term efficacy of antidepressant medications in dysthymia. 2. In a naturalistic study, patients with DSMIII-R dysthymia who had participated in previous antidepressant trials with fluoxetine and trazodone were evaluated at a mean of 40.0 weeks of follow-up to assess whether medication response persisted over time. A multivariate analysis was performed for patients on vs. off medication. Relapse rates (with relapse defined as HDRS score > 13) were also compared for these two groups. 3. Of 40 patients, the 24 still on medication showed significantly lower scores on most rating scales (HDRS, Cornell Dysthymia Rating Scale, and CGI, but not on the SCL-58) than the heterogeneous group of 16 patients not taking medication. Relapse was low (17.4%) among patients remaining on medication. 4. These preliminary findings suggest that dysthymia patients who remain on medication maintain improvement over time.

Serotonergic modulation of anticholinergic effects on cognition and behavior in elderly humans.

Cholinergic neurotransmission is thought to be modulated by serotonin as documented in animal and human studies. We examined the effects of the muscarinic antagonist scopolamine (0.4 mg IV) given alone or together with the serotonin mixed agonist/antagonist m-chlorophenylpiperazine (m-CPP, 0.08 mg/kg IV), and the selective 5-HT3 receptor antagonist ondansetron (0.15 mg/kg IV). Ten normal elderly volunteers each received five separate pharmacologic challenges (placebo, ondansetron, scopolamine, scopolamine+ondansetron, and scopolamine+m-CPP). Cognitive, behavioral, and physiologic variables were analyzed using repeated measures analysis of variance. The acute effects of scopolamine in certain cognitive, behavioral, and physiological measures were significantly exaggerated by the addition of m-CPP. Scopolamine's cognitive effects were unaffected by ondansetron at the dose tested, nor did ondansetron given alone affect basal cognitive performance. This pilot study suggests that the serotonin mixed agonist/antagonist m-CPP may influence cholinergic neurotransmission. The changes associated with the combination of scopolamine and m-CPP do not appear to be secondary to simple pharmacokinetic alterations and suggest a complex interaction between the cholinergic and serotonergic systems centrally.

Neuropsychiatric evaluation in an outpatient setting.

In a retrospective case review of 336 outpatients who underwent neuropsychiatric evaluations, patients were sorted into five groups: 1) atypical psychiatric; 2) atypical neurological; 3) prior psychiatric/new-onset neurological; 4) prior neurological/new-onset psychiatric; 5) dementia versus pseudodementia. Cluster analysis of 19 presenting complaints differentiated among groups. Post-consultation changes in preconsultation diagnosis occurred frequently overall, with more new case finding for psychiatric than for neurological disorders. For example, mood disorder diagnoses increased from 7.7% to 16.1%. Overall, dementia was the most common postconsultation diagnosis (32.8%). The authors conclude that suspicion for dementia should be high in neuropsychiatric referrals and that mood disorders may be especially common in neuropsychiatric patients.

A double FDG/PET study of the effects of scopolamine in older adults.

Two consecutive positron emission scans were done in one session using a double injection method of [18F]2-fluoro-2-deoxyglucose administration to examine the effects of the antimuscarinic drug scopolamine on cerebral glucose metabolism in ten older adults. Scopolamine causes temporary memory impairment, and its effects have been used to model aspects of the cognitive impairment that occur in Alzheimer's disease (AD). Cortical metabolic rates of patients with AD have been reported to be depressed, especially in parietal, temporal, and frontal association areas. After scopolamine administration to the elderly volunteers, absolute and normalized glucose metabolic rates were depressed in prefrontal and occipital regions and increased in parietal-occipital cortical regions and a left middle temporal region. These changes in the older volunteers are generally not consistent with changes seen in AD. We conclude that deficits in muscarinic system function may contribute to some but not all of the hypometabolic changes seen in AD patients.

A randomized double-blind study of fluoxetine versus placebo in the treatment of dysthymia.

OBJECTIVE: The purpose of this study was to assess the efficacy of fluoxetine, a selective serotonergic antidepressant, in the treatment of dysthymia. METHOD: Thirty-five patients who met criteria for dysthymia, but not major depression, began randomized, double-blind 8-week trials of fluoxetine or placebo. RESULTS: Of 32 patients who completed the study, 10 (62.5%) of the 16 patients given fluoxetine and three (18.8%) of the 16 given placebo responded to treatment. Response was defined as 1) 50% or greater decrease in Hamilton Rating Scale for Depression score and 2) a score of 1 or 2 on the Clinical Global Impression (CGI) improvement subscale. Fluoxetine subjects showed significantly greater improvement at week 8 than placebo subjects on the Hamilton depression and CGI scales, but not on the Hopkins Symptom Check-list (58-item) or the Cornell Dysthymia Rating Scale. CONCLUSIONS: When compared to placebo, fluoxetine showed short-term effectiveness in treating dysthymic symptoms.