Antihypertensive drugs and cognitive function in older people.
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Biomedical subjects
F Forette
Publications and source records attributed to F Forette.
Health care for older persons, a country profile: France.
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Detection of cerebral aging, an absolute need: predictive value of cognitive status.
Cognitive performance is predictive of functional status, morbidity and mortality in the elderly. In the SYST-EUR study, the Vascular Dementia Project run on 3,111 subjects 60 years old and over, with isolated systolic hypertension, has shown that the cognitive status as measured by the MMSE was inversely correlated with systolic blood pressure (p < 0.001) and age (p < 0.001) and positively correlated with the level of education (p < 0.001). It is significantly lower in patients with cardiovascular complications (p = 0.0001). Moderate alcohol consumption is linked to a higher MMSE score in women (p < 0.001) but not in men. In this study, the incidence of dementia is low and significantly related to the baseline value of the MMSE score and further analysis will show the influence of the treatment of systolic hypertension with calcium antagonists as first step on this incidence.
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Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.
BACKGROUND: Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint. METHODS: All patients (> 60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160-219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10-40 mg daily, with the possible addition of enalapril 5-20 mg daily and hydrochlorothiazide 12.5-25.0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat. FINDINGS: At a median of 2 years' follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n = 2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n = 2398). The between-group differences were systolic 10.1 mm Hg (95% CI 8.8-11.4) and diastolic, 4.5 mm Hg (3.9-5.1). Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years (42% reduction; p = 0.003). Non-fatal stroke decreased by 44% (p = 0.007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p = 0.03). Non-fatal cardiac endpoints decreased by 33% (p = 0.03) and all fatal and non-fatal cardiovascular endpoints by 31% (p < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, p = 0.07), but all-cause mortality was not influenced (-14%; p = 0.22). INTERPRETATION: Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.
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Protocols to demonstrate slowing of Alzheimer disease progression. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. The Disease Progression Sub-Group.
Two suggested clinical trial designs for assessing progression of Alzheimer disease are the randomized withdrawal design and the randomized start design. The most promising of these, the randomized start design, has the potential to demonstrate a delay in progression, but there remain problematic design, ethical, and statistical issues to be solved before the protocol can be used in a clinical trial. The development of biological markers of the disease process using neuroimaging or other measures also may provide a robust method of measuring disease progression and demonstrating the biological effect of a drug on the disease process.
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[Isolated systolic hypertension and cognitive function in the aged. Experience of the Syst-Eur study].
OBJECTIVE: To determinate cognitive status and its correlates in older patients with isolated systolic hypertension. METHODS: Syst-Eur is a double-blind placebo-controlled outcome trial conducted in European patients over 60 years of age with isolated systolic hypertension. Moreover, a side-project--the Vascular Dementia Project--is designed to assess cognitive functions and to follow-up their evolution to determine the influence of antihypertensive therapy on vascular dementia incidence. Cognitive functions were evaluated at entry with the MiniMental State Examination (MMSE) in 2250 patients included in Syst-Eur. Cognitive impairment was defined with a MMSE score < or = 23 and led to further evaluation. Baseline blood pressure (BP) was based on the average of six sitting blood pressure readings at three run-in visits 1 month apart. Statistical analysis used Spearman correlation. RESULTS: The MMSE was analysed in 1374 women and 751 men whose mean age was 70 years (range: 60-100). The median level of education expressed as the age at which they stopped their education at school, was 15 years. Baseline blood pressure averaged 173 +/- 10/86 +/- 6 mmHg. Before randomisation in the trial, 899 (40%) patients had received antihypertensive therapy and 602 (27%) had experienced cardiovascular complications. The MMSE-scores ranged from 15 to 30 (median = 29). The maximal score of 30 was reached by 609 (30%) subjects. Among the 59 (3%) patients with a MMSE-score of 23 or less, 5 were considered to be demented according to the DSM IIIR criteria. The MMSE-scores decreased with advancing age in men (r = -0.16; p < 0.001) and women alike (r = -0.24; p < 0.001). In both men and women, they were positively correlated with the level of education (r = 0.30 and 0.32, respectively; p < 0.001). They were negatively correlated with systolic blood pressure (r = 0.10; p < 0.001) and slightly positively correlated with diastolic blood pressure (r = 0.05; p = 0.03). Previously treated patients or patients reporting cardiovascular complications at baseline had lower MMSE-scores than their non-treated counterparts or subjects without cardiovascular complications (median = 28 and 29, respectively, p < 0.003). CONCLUSION: In a European cohort of 2225 patients over 60 years of age with isolated systolic hypertension, the level of cognitive functions evaluated with the MMSE decreases with advancing age or lesser educational level. It also decreases with higher systolic blood pressure or lower diastolic blood pressure. The influence of antihypertensive therapy on cognitive status will be prospectively evaluated in Syst-Eur Vascular Dementia Project.
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Antihypertensive therapy in older patients with isolated systolic hypertension: the Syst-Eur experience in general practice
Background and objective. This interim report from the Syst-Eur trial investigated the level of blood pressure control achieved during the double-blind period in patients followed in general practices. Methods. In the Syst-Eur trial elderly patients (60 years or older) with isolated systolic hypertension were randomized to either active or placebo treatment. Active treatment consisted of nitrendipine combined with enalapril and/or hydrochlorothiazide to reduce systolic pressure to Results. This analysis was restricted to patients of general practitioners who had been followed for at least 12 months. The placebo (N = 204) and active treatment (N = 217) groups had similar characteristics at randomization. At one year, the difference in sitting pressure between the two treatment groups was 10 mmHg systolic and 4 mmHg diastolic. Fewer patients remained on monotherapy in the placebo than in the active treatment group and on placebo the second and third line medications were started earlier. Nitrendipine tablets were discontinued in 10 patients on placebo and in 21 patients assigned to active treatment (P Conclusions. A significant blood pressure reduction can be achieved and maintained in older patients with isolated systolic hypertension followed by general practitioners. Whether this blood pressure reduction results in a clinically meaningful decrease of cardiovascular complications is under investigation. Keywords. Antihypertensive treatment, general practice, isolated systolic hypertension, randomized clinical trial.
Journal Article↗
Antihypertensive therapy in older patients with isolated systolic hypertension: the Syst-Eur experience in general practice. The Syst-Eur Investigators.
BACKGROUND AND OBJECTIVE: This interim report from the Syst-Eur trial investigated the level of blood pressure control achieved during the double-blind period in patients followed in general practices. METHODS: In the Syst-Eur trial elderly patients (60 years or older) with isolated systolic hypertension were randomized to either active or placebo treatment. Active treatment consisted of nitrendipine combined with enalapril and/or hydrochlorothiazide to reduce systolic pressure to < 150 mmHg and by > or = 20 mmHg. Matching placebos were used in the control group. RESULTS: This analysis was restricted to patients of general practitioners who had been followed for at least 12 months. The placebo (N = 204) and active treatment (N = 217) groups had similar characteristics at randomization. At one year, the difference in sitting pressure between the two treatment groups was 10 mmHg systolic and 4 mmHg diastolic. Fewer patients remained on monotherapy in the placebo than in the active treatment group and on placebo the second and third line medications were started earlier. Nitrendipine tablets were discontinued in 10 patients on placebo and in 21 patients assigned to active treatment (P < 0.001 for all comparisons). CONCLUSIONS: A significant blood pressure reduction can be achieved and maintained in older patients with isolated systolic hypertension followed by general practitioners. Whether this blood pressure reduction results in a clinically meaningful decrease of cardiovascular complications is under investigation.
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[Alzheimer's disease. A medical and social challenge].
Up to now, Alzheimer's disease was a devastating, untreatable and irreversible condition leading to a complete physical and intellectual deterioration in a "no-care" zone. The past ten years have seen important progress. Substitutive drug treatments, mainly, cholinergic approaches are able to allow a significant symptomatic improvement in around 30 to 40% of responders. THA is the first antidementia drug released by the registration agencies in a number of countries. It does not alter the course of the disease but the symptomatic improvement may last for some years. Other cholinergic and non cholinergic treatments are under study. Future treatments are based on aetiological and physiopathological mechanisms. A number of pathological pathways lead to a final consequence, the production and deposit of the neurotoxic beta amyloid protein. Interventions on different infectious, inflammatory, degenerative processes are being tried. Abnormal cleavage of the precursor APP, production and deposition of non soluble beta amyloid appears as the central event in the aetiology of the disease. The most logical approach is to intervene on the production, deposition or neurotoxicity of the amyloid at early stages of the disease. Several mechanisms may be addressed: inhibition of proteolytic enzymes which abnormally cleave the precursor, inhibition of the amyloid neurotoxicity, reduction of APP synthesis, reduction of inflammatory reaction around the plaques, slowing of the polymerization of soluble proteins into amyloid fibrils etc.... The, now, well established genetic predisposition will help in detecting subjects at high risk to develop the disease. Alzheimer's disease is a striking medical and social challenge. The medical team may, today, treat many symptoms of the disease and care for the patient and family. Tomorrow, it will be possible to prevent or, at least slow down the course of the disease.
Alzheimer Disease↗
Phospholipid abnormalities in early Alzheimer's disease. In vivo phosphorus 31 magnetic resonance spectroscopy.
OBJECTIVE: To determine whether changes in phosphomonoester and phosphodiester levels could be detected in vivo with phosphorus magnetic resonance spectroscopy in the early stage of Alzheimer's disease (AD). DESIGN: Survey-type of case-control study using neuropsychological testing as criterion standard with blinded data analysis. SETTING: Patients were from a neurology clinic in Paris, France. The controls were from the community. Magnetic resonance measurements were performed in the prefrontal region of the brain with a clinical 1.5-T scanner. Blinded data analysis. PARTICIPANTS: Twenty-four patients with mild AD and 15 age-matched healthy volunteers. Subjects were separated into two groups, both composed of patients with AD and healthy volunteers. Two successive acquisition protocols were used in the two groups. RESULTS: A significant increase in the phosphomonoester-total phosphorus ratio was found in patients with AD compared with controls. In this series, use of a ratio above 11% as a threshold to test our sample yielded an 83.3% sensitivity and a 73.3% specificity test for AD. Other metabolite ratios (inorganic phosphate, phosphodiesters, phosphocreatine, and nucleotide phosphates to total phosphorus) were not significantly different between patients and controls. No metabolite ratio correlated with the neuropsychological status as assessed by the Mini-Mental State Examination. CONCLUSION: Changes in phospholipid metabolism can be detected in vivo in the early stage of AD. Discrepancies in the literature may be due to differences in technical setting or in subject population types.
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Survival in institutionalized patients. Influence of dementia and loss of functional capacities.
BACKGROUND: Several studies have shown a negative correlation between dementia and survival. To our knowledge, the simultaneous effect of other factors has not been systematically studied in institutionalized patients. OBJECTIVE: To determine survival in demented inpatients compared with that in a matched population of nondemented patients institutionalized for other chronic debilitating diseases. DESIGN: The sample consisted of 213 patients with dementia and 157 patients without dementia. We studied the effect on survival of gender, age, loss of functional capacities, and cognitive functions with the method of Kaplan and Meier and with the model of Cox. RESULTS: Demented patients had significantly shorter survival when other factors were kept constant in the multivariate analysis. There was a strong correlation between survival and the degree of autonomy as measured by ability to walk, continence, and preserved activities of daily living. Survival was significantly shorter for men. No correlation was found with neuropsychological measures of severity of dementia or with age on admission. CONCLUSIONS: Survival of demented patients is shorter than that of patients institutionalized for other invalidating conditions. The lack of correlation between neuropsychological test results and survival indicates that in the population we studied, the severity of dementia did not predict length of survival. The data show that the combination of dementia and loss of functional capacities is the most important factor in predicting survival.
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Assessing vascular dementia.
Vascular dementia is the most common cause of dementia in the elderly after Alzheimer's disease. Many forms of vascular dementia have been described: multi-infarct dementia, lacunar dementia, Binswanger's subcortical encephalopathy, cerebral amyloid angiopathy, white matter lesions associated with dementias, single infarct dementia, dementia linked to hypoperfusion and haemorrhagic dementia. The difficulty of diagnosing vascular dementia must not be underestimated and an international consensus is needed for epidemiological studies. The NINCDS-AIREN group has recently published diagnostic criteria. The State of California Alzheimer's Disease Diagnostic and Treatment Centers also proposed some which differ from the NINCDS-AIREN criteria in considering only ischaemic vascular dementia and not other mechanisms such as haemorrhagic or hypoxic lesions. Most studies stress hypertension as the most powerful risk factor for all forms of vascular dementia. The incidence rate ranges from 7 per 1000 person-years in normal volunteers to 16 per 1000 person-years in hypertensive patients. No therapeutic attempt has influenced the course of the disease once the dementing condition is established. The only effective approach is preventive treatment. The objective of the SYST-EUR Vascular Dementia project is to confirm that the treatment of isolated systolic hypertension is able to reduce its incidence.
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[Internal medicine and geriatrics in the United States. Face to face].
Chiefs of American University medical departments met with their geriatrician counterparts, in order to define the role of Geriatrics within the discipline of Internal Medicine. Options for pregraduate training, practical courses during the period of study and specific teaching during specialization or during further education were carefully chosen. Fundamental and clinical research is considered indispensable, for this alone will permit the dawning of "Centres of excellence" in Geriatrics, which will be the guarantee of a training that has been rendered necessary by demographic and public health considerations.
Geriatrics↗
[Treatment of arterial hypertension in elderly patients. Value and indications].
The prevalence of high blood pressure increases with age and, in elderly subjects, it is a major risk factor not only for cardiovascular diseases but also for other diseases including vascular dementia. Data concerning mortality are more controversial, but it is known that up to the age of 90, mortality is increased in hypertensive subjects. Two pathological conditions can be distinguished, systolo-diastolic hypertension with a systolic pressure above 160 mmHg and diastolic pressure above 95 mmHg and systolic hypertension alone when the systolic pressure is above 160 mmHg and diastolic below 95 (or 90) mmHg. The European working party on high blood pressure in the elderly (EWPHE) and the Medical Research Council trial of treatment of hypertension in older adults have demonstrated the beneficial effect of treating systolo-diastolic hypertension. Active therapy significantly reduces the risk of mortality due to cardiovascular disease, notably myocardial infarction, and in morbidity due to left ventricular failure and non-mortal cerebral vascular events. The current debate centers on the pressure level which should be attained, especially in patients with a history of ischaemic cardiopathy. Treatment of elderly patients with systolic hypertension alone is also probably beneficial, although only the systolic hypertension in the elderly program (SHEP) was able to demonstrate a significant reduction in cerebral vascular events and in the incidence of myocardial infarction, even in subjects over 80. A multicentric European study (Syst-Eur), which includes patients treated with calcium inhibiteurs and conversion enzyme inhibiteurs, is being conducted in order to confirm the beneficial effect of treating systolic hypertension in subjects over 60. In addition, this study also includes a complementary project specifically designed to evaluate the effect of treatment on vascular dementia.
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Are calcium antagonists the best option in elderly hypertensives?
SUITABILITY OF CALCIUM ANTAGONISTS FOR THE ELDERLY: The efficacy and safety of calcium antagonists have been clearly demonstrated in elderly hypertensive patients. In a double-blind placebo-controlled study in 31 elderly hypertensives treated with nicardipine, we found no consistent electrocardiogram changes, nor in the heart rate, plasma levels of potassium, sodium or creatinine, or uric acid; nor did we find any postural hypotension. The mechanism of action of this class of drugs appears to be particularly appropriate in the treatment of elderly patients, in whom hypertension is characterized by an increase in peripheral resistance and a decrease in arterial compliance. Since vascular tone is ultimately controlled by the intracellular calcium concentration in smooth muscles, agents such as calcium inhibitors, which inhibit calcium influx and induce dilation of small and large arteries, are of particular interest. EXPERIMENTAL EVIDENCE: There is some experimental evidence in hypertensive rats and hypercholesterolaemic rabbits that calcium antagonists can provide some protection against atherosclerotic degeneration. However, the validity of extrapolating these findings to humans is still disputed. POSSIBLE CEREBRAL EFFECT: Calcium antagonists might also have a beneficial cerebral effect. The acute administration of these drugs has been shown to increase cerebral blood flow. Moreover, several studies have shown a protective action against cerebral ischaemia and this may be of particular importance in the very elderly.
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[Neuropathology of 20 centenarians. I. Clinical data].
We report a clinical study of 20 patients aged more than 100 years, and deceased in Charles Foix Hospital, Ivry/Seine, France, where they had stayed for 10 days to 16 years (mean: 3.3 years, median: 4 years). Each of them was studied neuropathologically (the results of this study will be published later on). The case selection excluded only those patients whose neuropathological study could not be complete. The prevalence of sensorial deficits was high: 15/20 patients had deterioration of hearing, 8 of them were deaf; 14/20 patients had deterioration of sight, 4 of them were blind. Motor deficits were numerous: 15 patients were not ambulatory. The patients were classified as demented or not, according to the criteria of the DSMIII R (American Psychiatric Association 1987), on the basis of a retrospective evaluation of clinical records, and of an inquiry among the caring staff. Their mental status was also evaluated by the Global Deterioration Scale of Reisberg et al (1985). Five patients had been demented, four had been intellectually normal, and 11 had suffered from mild disturbances of memory or cognitive functions. This series was not representative of the general population of centenarians, but probably of those institutionalized in France. We observed a low proportion of demented patients despite the prevalence expected from epidemiological studies. This is difficult to interpret. The low proportion of dementia in this small sample is not due to the short duration of the course of diseases responsible for dementia.(ABSTRACT TRUNCATED AT 250 WORDS)
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Amygdala atrophy in Alzheimer's disease. An in vivo magnetic resonance imaging study.
OBJECTIVES: To study the ability of magnetic resonance imaging to measure the volume of the amygdala and detect amygdala atrophy in patients with early Alzheimer's disease. DESIGN: Prospective case-control study and "blind" measurements. SETTING: Subjects were ambulatory outpatients selected from an institutional practice in Paris, France. PATIENTS: We studied 11 patients with probable Alzheimer's disease according to National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) inclusion and exclusion criteria, as well as six age-matched control subjects. INTERVENTION: None. MAIN OUTCOME MEASURE: A 1.5-T magnetic resonance imager was used to acquire the images. Two neuroradiologists independently and blindly measured the volume of the right and left amygdalas on high-resolution contiguous slices. In addition, other cerebral structures, ie, the sylvian fissures, temporal lobes, lateral and third ventricles, corpus callosum, and hippocampal formation, were measured on a single slice. RESULTS: The values obtained by the two observers correlated highly (r = .90), and interrater variability was 13%. The Alzheimer's disease group showed significant (33%, P < .0001) atrophy of the amygdala when compared with the control group. The other structures showed less variation. CONCLUSION: Significant amygdala atrophy can be detected in vivo in patients with early Alzheimer's disease by means of standard magnetic resonance imaging. This technique may be useful in the early diagnosis of Alzheimer's disease.
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Antihypertensive therapy in elderly patients with isolated systolic hypertension: third progress report of the Syst-Eur trial.
The Syst-Eur trial is a randomised, double-blind, placebo-controlled trial that examines the hypothesis that antihypertensive treatment can prevent or delay cardiovascular complications in elderly patients (> 60 years) with isolated systolic hypertension. On March, 1st 1993 a total of 1395 patients with a sitting systolic blood pressure on placebo averaging 160-219 mmHg and a diastolic blood pressure < 95 mmHg were randomised into this trial. The placebo and active treatment groups were similar at randomisation with respect to age (72 +/- 7 years, mean +/- SD), percentage of women (68%), percentage of patients with cardiovascular complications (30%) and sitting blood pressures (175 +/- 12/85 +/- 6 mmHg). The fall in sitting systolic and diastolic blood pressures from baseline to 2 years was significantly more pronounced (p < 0.001) in the actively treated (-22 +/- 18/-6 +/- 9 mmHg) as compared with the placebo treated Syst-Eur patients (-10 +/- 20/-1 +/- 9 mmHg). Active treatment consists of nitrendipine if necessary associated with a converting-enzyme inhibitor and a thiazide. Whether treatment with these antihypertensive agents results in a clinically meaningful reduction of cardiovascular morbidity and mortality is the subject of investigation in this trial.
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