Françoise Forette

A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon).

Rivastigmine is a carbamate acetylcholinesterase (AChE) inhibitor with central selectivity. Early studies showed that daily doses up to 6 mg/day have some efficacy in patients with dementia of the Alzheimer type (DAT). The present study was designed to assess the safety, tolerability and efficacy of rivastigmine at doses up to 12 mg/day. A total of 114 patients with mild‐moderate DAT were randomly assigned to either rivastigmine (b.i.d. (twice daily) or t.i.d. (three times daily)) or placebo in a double‐blind fashion titrated to their maximum tolerated dose over 10 weeks followed by an eight‐week maintenance phase. The mean maximum tolerated dose was approximately 10 mg/day (b.i.d. or t.i.d.). Gastrointestinal complaints, the majority of which were mild to moderate, were the most frequently reported adverse events. No clinically relevant changes in vital signs, haematology or organ function were detected. Significantly more patients taking rivastigmine b.i.d. were considered improved according to the Clinicians Interview‐Based Impression of Change‐Plus (CIBIC‐Plus) vs. placebo (57% vs. 16%, respectively; P=0.027). The Nurses Observation Scale for Geriatric Patients (NOSGER) (memory component) and the Alzheimers Disease Assessment Scale‐cognitive subscale (ADAS‐cog) also improved in the rivastigmine b.i.d. group vs. placebo (mean change from baseline on NOSGER =−0.7 vs. +1.3, respectively; P=0.037: mean change from baseline on ADAS‐cog=−2.7 vs. +0.2, respectively; P=0.054). Despite the relatively small size and limited duration of the study, the finding that rivastigmine induced changes in the same (positive) direction in all three dimensions measured suggests that rivastigmine at doses of up to 12 mg/day has useful efficacy in patients with mild‐moderate DAT. Reports from larger phase III studies confirm this finding. The results of this study also suggest that b.i.d. is the more efficacious regimen and has comparable tolerability to the t.i.d. regimen.

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease

Controversy exists regarding the apolipoprotein E (ApoE) ɛ4 allele association with vascular dementia (VaD), ranging from increased ɛ4 frequency, similar to that found for Alzheimers disease (AD), to no association between the ɛ4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE ɛ4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE ɛ4 allele‐bearing individuals had greater risk of having late‐onset AD (OR=8.8; 95% Cl 3.7–21.0), or non‐vascular cognitive impairment (OR=7.0; 95% Cl 2.5–19.0).

The Prognostic Significance of Isolated Systolic Hypertension in the Elderly. Results of a Ten Year Longitudinal Survey

A ten year longitudinal survey of 191 female elderly subjects (mean age 80--Range 61 to 100 years) was set up to demonstrate that even a moderate isolated systolic hypertension is a powerful contributor to the incidence of cardiovascular complications in the elderly. The incidence of all cardiovascular events was carefully recorded and was correlated with a number of parameters registered at entry into the study. The results show that isolated systolic hypertension as well as diastolic hypertension is significantly correlated to the incidence of strokes and myocardial infarction independently of other parameters (Blood Cholesterol, Blood Sugar) which do not appear in this population as risk factors of cardiovascular morbidity. This underlines the high interest of controlled therapeutic studies run in this field in elderly patients.

In vivo PET study of cerebral [11C] methyltetrahydroaminoacridine distribution and kinetics in healthy human subjects

It is unclear whether the palliative effects of tetrahydroaminoacridine (THA) (tacrine, Cognex) on the clinical symptoms of patients affected by Alzheimers disease (AD) are the result of its inhibitory activity on acetylcholinesterase or on other complex sites of action. In order to investigate the cerebral distribution and kinetics of THA in the human brain in vivo, we performed positron emission tomography (PET) imaging with [11C[N‐methyl‐tetrahydro‐aminoacridine (MTHA) in healthy human volunteers. After intravenous injection, [11C[MTHA crossed the blood‐brain barrier and reached its maximum uptake between 10 and 40 minutes, depending on the brain regions. Uptake was higher in the grey matter structures, and lower in the white matter. After this peak, the radioactivity remained quasi‐constant until 60 minutes in all regions with a half‐life varying from 2.44 hours in the thalamus to 3.42 hours in the cerebral cortex. The ratios of regional to whole cerebral cortex brain radioactivity calculated between 50 and 70 minutes after the tracer injection were 1.14 ± 0.04, 1.07 ± 0.03 and 1.06 ± 0.04 in the putamen, cerebellum and thalamus, respectively. Overall, these results show that: (1) [11C]MTHA crosses the blood‐brain barrier easily and is highly concentrated in the brain; (2) the regional brain distribution of [11C]MTHA does not parallel that of in vivo acetylcholinesterase (AChE) concentrations; and (3) the cerebral kinetics of [11C]MTHA are consistent with known plasmatic pharmacokinetics of THA in AD patients. We conclude that PET imaging with [11C]MTHA is a useful method for assessing the cerebral distribution and kinetics of THA in vivo.

Nicardipine in elderly patients with hypertension: A review of experience in France

A double-blind, placebo-controlled clinical trial in France has studied the efficacy and safety of nicardipine in 31 elderly patients, aged 57 to 95 years (mean age 84 years), 16 of whom were actively treated with nicardipine, 10 to 30 mg three times a day (mean dose 69.4 mg/day). After 4 weeks, nicardipine lowered mean blood pressure (186/99 to 150/83 mm Hg; p less than 0.001), and the changes in systolic and diastolic blood pressure were significantly greater in the nicardipine group than in the placebo group. Nicardipine was well tolerated; orthostatic hypotension was not observed and there was no change in heart rate. Plasma renin activity (PRA) was measured in eight patients, but there was no correlation between PRA and the antihypertensive effect of nicardipine. Results of a pharmacokinetic study performed in 15 elderly patients showed a rapid rate of absorption and higher plasma levels than those observed in younger patients with hypertension (mean age 54 years). The results support those of the major French multicenter open study of 29, 104 elderly patients with hypertension (mean age 64 +/- 12 years) treated with nicardipine. The findings of this trial are reviewed and discussed, and recommendations made on the directions for future research in cardiovascular medicine with calcium channel blockers. Results of the trials discussed in this article show that nicardipine is an effective and well-tolerated drug in elderly patients and has wide-ranging effects on the cardiovascular system.

Dermatoglyphic patterns in dementia of the Alzheimer type: a case-control study.

STUDY OBJECTIVE--The aim was to compare digital and palmar dermatoglyphics in subjects with dementia of Alzheimer type and in mentally healthy elderly controls. DESIGN--This design was a case-control study. SETTING--The study was carried out in geriatric units and retirement communities in the Paris area. PARTICIPANTS--Cases were women with clinically diagnosed Alzheimer type dementia according to DSM III-R criteria (n = 82), mainly with late onset of the disease. Controls were women aged 85 years or older without cognitive deterioration (n = 76). MEASUREMENTS AND MAIN RESULTS--Finger and palm prints obtained from both hands by the classical ink method were examined. Fingerprints were classified into four types of figures. On palms, palmar flexion creases, palmar axial triradii, true patterns of the hypothenar area, and main line terminations were described. Examinations were performed by two examiners blind to the subjectss diagnostic category. For the different patterns studied, no major differences between dementia patients and elderly controls were found. Nor was there evidence of high frequencies of features commonly observed in Downs syndrome (trisomy 21), which have previously, though sporadically, been reported. CONCLUSIONS--On one of the largest samples of Alzheimer dementia patients studied, and with evaluation blind to diagnosis, no evidence has been found that particular dermatoglyphic patterns occur like those observed in Downs syndrome, a disease which is related to dementia of the Alzheimer type.

Rationale for ACE inhibition in the elderly: treatment of arterial hypertension with enalapril.

A randomized, double-blind, placebo-controlled trial was conducted with 32 elderly patients (aged 75-97 years) with uncomplicated essential hypertension, to evaluate the efficacy and tolerance of enalapril, an angiotensin-converting enzyme inhibitor. It was given over an 8-week period in doses from 20 to 40 mg/day and was compared with an identical placebo. Enalapril caused a significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by the 2nd week, an effect that persisted through to the 8th week (190 +/- 16/102 +/- 7 to 151 +/- 19/85 +/- 11 mm Hg); 67% of patients had their pressures normalized (less than 160/95 mm Hg). BP was also significantly decreased by the 8th week under placebo (183 +/- 16/101 +/- 9 to 165 +/-21/91 +/- 13 mm Hg), but only 35% of patients attained a normal pressure. Heart rate did not change with treatment. Enalapril caused an increase in plasma renin activity (1.22 +/- 0.08 to 3.66 +/- 2.50 ng/ml/h), whereas aldosterone levels remained unchanged. There was a mild, significant elevation of creatinine level with enalapril but other laboratory parameters, including serum potassium, were unaltered. Two deaths occurred in the enalapril group, but were not considered to be treatment-related. The drug was otherwise well tolerated. Serum enalapril concentration was assessed in 10 patients taking 20 mg/day over an 8-day period. At equilibrium, the level was 22.3 +/- 5.0 ng/l and it correlated both with converting enzyme inhibition and with renal function. Enalapril is shown to be an effective and well-tolerated antihypertensive medication in elderly patients.

Two faller risk functions for geriatric assessment unit patients

This study was done in order to construct a simple clinical failer predictor model, which quantifies risk for the individual elderly patient. Fifty patients sequentially admitted to a geriatric assessment unit were assessed systematically at admission for six potential failer risk factors: age, gait, speed, gait quality, gender, symptoms of urinary urgency, and symptoms of dizziness. Falls were systematically recorded during admission. Only age, abnormal gait, and self-selected gait speed were found to be associated with fallers. Multivariate analysis revealed that the two best models for predicting those most likely to be fallers were the factor subgroups: 1) age plus gait quality, and 2) age plus gait speed. The difference between the two models is the choice of gait measure incorporated. Gait speed is a continuous quantitative variable with no known limit of normal. Gait quality is a qualitative variable where abnormal gait is defined by clinical criteria. The predictability of each model was verified in another population (N=78).