Background

There are currently no treatments for empathy deficits in neuropsychiatric disorders. Acute administration of the hormone oxytocin has been associated with symptomatic improvements across animal models and several neuropsychiatric disorders, but results of the majority of oxytocin randomised controlled trials (RCTs) of longer duration have been negative or inconclusive. This lack of efficacy of may be due to rapid habituation to oxytocin with chronic dosing. The objective of the present study is to describe the design of a phase 2 adaptive randomised controlled crossover trial of intranasal oxytocin in frontotemporal dementia (FOXY) as an efficient model for future investigations of symptomatic treatments in neuropsychiatric and neurodegenerative disorders.

Methods

Stage 1 will identify which of three dose schedules is most promising based on change in the primary outcome measure, the Neuropsychiatric Inventory apathy/indifference domain score, over 6 weeks of treatment. In stage 2, additional patients are enrolled at the most promising dose for preliminary efficacy analysis when combined with stage 1 to determine if a phase 3 trial is warranted. Objective measures include facial expression recognition, cerebrospinal fluid (CSF) oxytocin levels, and behavioural ratings of videotaped interactions.

Results

A total of 20 patients per arm will be entered into stage 1 for a total of 60 patients. In stage 2, an additional 40 patients will be enrolled in the most promising dose arm.

Conclusions

The use of adaptive, crossover designs and inclusion of objective measures of change in CSF oxytocin levels and social behaviour will improve the efficiency and conclusiveness of RCTs of oxytocin and other symptomatic treatments in neuropsychiatric disorders.

Trial registration

ClinicalTrials.gov, NCT03260920 . Registered on August 24, 2017.

Alzheimer's disease is a major cause of morbidity and mortality. Currently, there are no disease-modifying pharmacotherapies for this condition. Aducanumab, an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid-beta in the brains of people with Alzheimer's disease, has raised hopes that such a therapy has been discovered, but its approval by the US Food and Drug Administration has engendered a good deal of controversy. A similar application for approval has been submitted to Health Canada. In response to this, a group of Canadian clinical dementia experts representing a number of organizations, including the Canadian Geriatrics Society, was convened by the Canadian Consortium on Neurodegeneration in Aging (CCNA) to discuss the evidence currently available on this agent and seek consensus on what advice they would offer Health Canada on the application. There was wide-spread agreement that it would be premature for aducanumab to receive approval for the treatment of Alzheimer's disease. It was also noted that the Canadian health-care system is poorly prepared at this time to deal with a disease-modifying therapeutic with targeting, administration, and monitoring characteristics like aducanumab. In this paper, the consensus reached is presented along with its underlying rationale.

Objective

We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.

Methods

In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants.

Results

No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.

Conclusions

Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.

Clinicaltrialsgov identifier

NCT00818662.

Classification of evidence

This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.

Introduction

Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these "adjusted" Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.

Methods

In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).

Results

Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R².

Discussion

Nonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.

Introduction

We created global rating scoring rules for the CDR^® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.

Methods

The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.

Results

The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants.

Discussion

The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Background

Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively.

Methods

Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype.

Results

The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls.

Conclusions

In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.