Clinical Trial on the Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia

Objective  To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide–quinidine sulfate for Alzheimer disease–related agitation.

Design, Setting, and Participants  Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012–August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions–Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed.

Interventions  In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60).

Main Outcomes and Measures  The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]).

Results  A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, −3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, −1.5; 95% CI, −2.3 to −0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, −1.6; 95% CI, −2.9 to −0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation.

Conclusions and Relevance  In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated.

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Off-the-Shelf Drug Rapidly Clears Alzheimer’s Protein in Mice

A drug that is already approved by the FDA for treating a rare skin cancer greatly reduces brain levels of Alzheimer’s-associated amyloid beta (A-beta) protein in mouse models. The drug, bexarotene, works in the mice by boosting the activity of apolipoprotein E, a fat-carrying molecule that normally helps to clear A-beta from the brain (see “Why Does apoE4 Make Alzheimer’s More Likely?”). If bexarotene’s A-beta clearance effect in mice translates to humans, then it may prove useful against Alzheimer’s—though perhaps more as a preventive than as a treatment for established Alzheimer’s dementia.
“This is quite an exciting paper; the effect on A-beta clearance is dramatic and rapid,” says Sam Gandy, who chairs the Alzheimer’s research program at Mount Sinai School of Medicine.
“The drug reduces the soluble forms of A-beta within hours,” says Paige Cramer, the PhD student who was first author of the paper. Cramer works in the laboratory of Gary Landreth, director of the Alzheimer’s Research Laboratory at Case Western Reserve University School of Medicine in Cleveland, Ohio, and principal investigator for the study, which appears today in Science Express.
The study is based on observations, going back to the early 1990s, of a strong connection between Alzheimer’s and apolipoprotein-E (apoE). Researchers have found that apoE proteins normally bind strongly to A-beta, and that apoE4, one of the normal variants of apoE in the population, is linked to a much higher and earlier risk of Alzheimer’s.
Recently scientists have determined the likely reason for the connection: A-beta aggregates, which have a high affinity for fat molecules, normally cling to the fats carried by apo-E molecules, and in this way are brought into, and disposed within, immune-type cells in the brain called microglial cells. ApoE4 is comparatively inefficient at handling fat molecules, and so it does a poorer job of removing A-beta aggregates. Regardless of which apoE variants a person has, boosting apoE production should enhance the clearance of A-beta from the brain—mainly because more apoE means more A-beta-carrying capacity. ApoE production also seems to stimulate the readiness of microglial cells to digest A-beta aggregates.
Bexarotene, a drug approved by the FDA in 2000 for cutaneous T-cell lymphoma, binds and activates the retinoid X receptor, a protein that in brain cells happens to be involved in promoting apoE production. Since bexarotene can cross from the bloodstream into the brain, Landreth reasoned that it might work as an apoE-boosting, A-beta-clearing drug.
In the new study, he and Cramer and their colleagues tested it on “Alzheimer’s mice” that had been genetically engineered to overproduce aggregates of A-beta. Such mice, as they age, show subtle cognitive deficits – which are presumed to be caused by small, soluble “oligomer” aggregates of A-beta. The team found that within only a few days, a modest daily dose of the drug reduced soluble forms of A-beta in the mouse brains by about one-third, compared to control mice, and reduced insoluble A-beta deposits, or “plaques,” by about half. They observed microglial cells stuffed with A-beta, as well as increases in the levels of proteins that normally work with apoE. In mice that lacked apoE, these A-beta clearing effects did not occur. The treated mice showed immediate improvements in standard memory tests, suggesting that the drug quickly reduced brain levels of toxic A-beta oligomers.
Because the drug is already FDA-approved, its safety is already mostly known. “For skin cancer treatment, patients are often on bexarotene doses that are far higher than [the human equivalent of] the dose that we used in mice, and for long periods,” says Cramer. Long-term use of bexarotene can raise triglyceride levels and have other potentially dangerous side-effects, but Cramer says that such side-effects are generally treatable with other drugs, and bexarotene is tolerated by most cancer patients.
Cramer says that she and Landreth are forming a company and hope to set up clinical trials of bexarotene against Alzheimer’s. Even without such trials, neurologists in the U.S. could legally prescribe the drug “off-label” to people with Alzheimer’s, since bexarotine is already approved by the FDA.

Donepezil Impairs Memory in Healthy Older Subjects: Behavioural, EEG and Simultaneous EEG/fMRI Biomarkers

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week followups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.

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Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment

OBJECTIVE:

To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).

DESIGN:

Randomized, double-blind, placebo-controlled trial.

SETTING:

Clinical research unit of a Veterans Affairs medical center.

PARTICIPANTS:

The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).

MAIN OUTCOME MEASURES:

Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.

RESULTS:

Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.

A, Areas of hypometabolism at baseline (scan 1) and month 4 (scan 2), along with changes in hypometabolism ( time 2 – time 1) within each group, and differences in change between the placebo group and the 20-IU or 40-IU dose insulin group ( nasal insulin – placebo). The red and orange colors, compared with the green and blue colors, indicate areas of greater hypometabolism from time 1 to time 2, and from placebo group to insulin groups. B, Change in mean regional z scores with standard errors of mean (error bars) for the right and left frontal regions and the left parietal region for the placebo, 20-IU dose insulin, and 40-IU dose insulin groups. For the right and left frontal volume-of-interest (VOI) values, placebo-assigned participants had reduced activity during the 4-month period, whereas the 20-IU and 40-IU dose insulin groups had preserved or slightly increased activity (treatment group x time interaction: P = .04 for comparison between placebo group and 20-IU dose insulin group; P = .03 for similar comparison between placebo group and 40-IU dose insulin group). Similar analyses for left medial parietal VOI values revealed reduced activity over time for the placebo group compared with the 40-IU dose insulin group (time x treatment group interaction: P = .05).

CONCLUSIONS:

These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568.

Reference: Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol. 2011 Sep 12 Full text

Donepezil for language dysfunction in Alzheimer's disease

Introduction

Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language helps maintain emotional connection to caregivers and supports management of AD functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.

Methods

In the original randomized, double-blind clinical trial, 1467 patients with moderate to severe AD (baseline Mini-Mental State Examination [MMSE] scores 0-20) were randomized 2:1 to receive donepezil 23 mg/d or to continue on donepezil 10 mg/d for 24 weeks. In this post hoc analysis, the Severe Impairment Battery language (SIB-L) scale and a new 21-item SIB-derived language scale (the SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity/Change-plus caregiver input (CIBIS/CIBIC-plus), and the MMSE were also investigated.

Results

At Week 24, treatment with donepezil 23 mg/d was associated with an improvement in language in the full intention-to-treat (ITT) population, whereas language function declined with donepezil 10 mg/d (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE, 0-16). At baseline and Week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but were stronger between the language scales and MMSE.

Conclusions

Patients with moderate to severe AD receiving donepezil 23 mg/d showed greater language benefits compared with those receiving 10 mg/d, as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/d may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical. ClinicalTrials.gov identifier: NCT00478205.

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