A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer's disease: the DARAD trial.

OBJECTIVES: Preliminary evidence suggested that doxycycline and rifampin might stop or slow the progression of Alzheimer's disease (AD). We carried out a randomized trial to confirm or refute these findings. METHODS: A multicenter, blinded, randomized, 2 × 2 factorial controlled trial, set at 14 geriatric outpatient clinics in Canada. Four hundred and six patients with mild to moderate AD (standardized mini mental state examination (SMMSE) score 14-26) participated. The intervention was 12 months' treatment with doxycycline 100 mg twice daily + rifampin 300 mg daily or doxycycline 100 mg twice daily + placebo-rifampin daily or rifampin 300 mg daily + placebo-doxycycline twice daily or placebo-doxycycline twice daily + placebo-rifampin daily. Coprimary outcomes were the Standardized Alzheimer's Disease Assessment Scale-Cognitive Subscale (SADAS-cog) and the Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB). Secondary outcomes were the SMMSE, Quick mild cognitive impairment screen, Geriatric Depression Scale, Cornell Scale for Depression in Dementia, activities of daily living (Lawton Scale), and the Dysfunctional Behavior Rating Instrument frequency and reaction subscales. RESULTS: There was a significant deterioration in SADAS-cog over time with both rifampin and doxycycline in comparison with placebo. When the two were used together, there was no statistically significant decline/deterioration in comparison with placebo (n = 305). For the CDR-SB, there were no significant effects of either rifampin or doxycycline. Secondary outcome results followed similar patterns. CONCLUSION: Twelve months' treatment with doxycycline or rifampin, alone or in combination, has no beneficial effects on cognition or function in AD.

Effects of acute exposure to aluminum on cognition in humans.

There is epidemiological evidence suggesting an association between aluminum in drinking water and Alzheimer's disease (AD), and between aluminum in dialysate and dialysis dementia. The exact role of aluminum in the pathogenesis of these and other dementias is not clear. This study examined the acute effects of aluminum on cognitive function in patients with AD and related dementias and in age-matched and younger volunteers with normal cognitive function. Whether individuals with AD and/or the APOE epsilon4 genotype had enhanced gastrointestinal absorption of aluminum was tested, and whether individuals with elevated blood aluminum concentrations exhibited acute cognitive effects was determined. Subjects were randomized to receive a single dose of aluminum orally (Amphojel plus citrate) for 3 d followed by a 3-wk washout, and then 3 d of matched placebo administration, or vice versa. Serum aluminum levels were measured and the daily dose of Amphojel was adjusted to a target aluminum level between 50 and 150 microg/L. Neuropsychological tests were administered at baseline and 90 min after the third dose of Amphojel or placebo. There was a large interindividual variation in aluminum serum levels in all study groups after the same initial dose of Amphojel. There were no significant differences in neuropsychological test scores after aluminum ingestion in normal volunteers or in patients with cognitive impairment. There was no association between APOE epsilon4 genotype and aluminum absorption. The results did not support the hypothesis that aluminum ingested at these doses produces acute effects on cognition or adverse effects, nor did they reveal that AD patients are more vulnerable to such outcomes. Further inquiry is required to explore any possible association between aluminum and cognition, but controlled trials may be limited by safety concerns.

Improved reliability of the Standardized Alzheimer's Disease Assessment Scale (SADAS) compared with the Alzheimer's Disease Assessment Scale (ADAS).

OBJECTIVES: To compare the interrater and intrarater reliability of the Alzheimer's Disease Assessment Scale (ADAS) with the Standardized Alzheimer's Disease Assessment Scale (SADAS). DESIGN: A randomized, double blind trial. Sixteen university students were randomized to administer either version of the instrument. Subjects were randomized to three assessments, at 2-week intervals, using the ADAS or the SADAS. Each subject's first and third tests were administered by the same rater, the second by a different rater. SETTING: A geriatric outpatient clinic in a university teaching hospital. PARTICIPANTS: Fifty-four patients with possible or probable Alzheimer's disease living in the community or in a long-term care facility. MEASUREMENTS: The primary outcome was the interrater reliability of total ADAS and SADAS scores. Secondary outcomes were ADAS and SADAS cognitive scores, noncognitive scores, duration of testing, and sample size estimates. RESULTS: The interrater reliability of the SADAS total score was significantly better than that of the ADAS (interrater ICC 0.93 SADAS vs 0.83 ADAS), and the interrater standard deviation of the total SADAS score was lower than that of the ADAS (38%, P < .05). The SADAS cognitive subscale inter and intrarater reliability, although higher than the ADAS, was not significantly different when used by different raters (interrater ICC 0.91 SADAS vs 0.90 ADAS; intrarater ICC 0.88 SADAS vs 0.86 ADAS). The SADAS noncognitive subscale was significantly more reliable than the ADAS (interrater ICC 0.89 SADAS vs 0.42 ADAS; intrarater ICC 0.87 SADAS vs 0.70 ADAS; P < or = .05) and had a lower standard deviation between raters (59%; P < .01) and within raters (40%; P < .05) compared with the ADAS. CONCLUSION: The improved reliability of the SADAS total score means that investigators can now use this score as a primary outcome measure, and important behavioral symptomatology can be included as a marker for treatment efficacy in AD. The smaller standard deviation of the SADAS means that clinical trials using the SADAS as a primary outcome will demonstrate differences, if present, with smaller sample sizes than with the ADAS.

Clinical experience with Cerebrolysin.

Cerebrolysin is a peptidergic drug which displays neurotrophic action in various animal models. It is used for the treatment of dementia and in this report we provide evidence for the long-term clinical efficacy of Cerebrolysin in Alzheimer's disease. This evidence is based on our clinical experience with Cerebrolysin, stemming from our participation in a double-blind, placebo-controlled clinical trial, a compassionate use programme initiated thereafter, and a PET study. Our data suggests, that Cerebrolysin is a safe and effective treatment for Alzheimer's disease and that repeat treatments may maintain function in patients over the long-term.

A guide to the standardized Mini-Mental State Examination.

The Mini-Mental State Examination (MMSE) is a widely used screening test for cognitive impairment in older adults. Because the guidelines for its application are brief, the administration and scoring of the test can vary between different individuals. This can diminish its reliability. Furthermore, some of the items must be changed to accommodate different settings, such as the clinic, home, or hospital. Because there are no time limits, it is not clear how long one should wait for a reply to a question. It is also not clear how one deals with answers that are "near misses." The goal of the Standardized Mini-Mental State Examination (SMMSE) was to impose strict guidelines for administration and scoring to improve the reliability of the instrument. The reliability of the MMSE was compared with the reliability of the SMMSE in 48 older adults who had the tests administered by university students on three different occasions to assess the interrater and intrarater reliability of the tests. The SMMSE had significantly better interrater and intrarater reliability compared with the MMSE: The interrater variance was reduced by 76% and the intrarater variance was reduced by 86%. It took less time to administer the SMMSE compared with the MMSE (average 10.5 minutes and 13.4 minutes, respectively). The intraclass correlation for the MMSE was .69, and .9 for the SMMSE. Administering and scoring the SMMSE on a task-by-task basis are discussed.