Olivier Hanon

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Relationship Between Arterial Stiffness and Cognitive Function in Elderly Subjects With Complaints of Memory Loss

Background and Purpose— To evaluate the relationship between arterial stiffness and cognitive function in a population of elderly subjects reporting memory loss. Methods— We studied the association between cognitive function and arterial stiffness in 308 consecutive elderly subjects attending a geriatric outpatient clinic reporting memory impairment. Subjects were classified into 4 categories according to neuropsychological evaluation: normal cognitive function, mild cognitive impairment (MCI), Alzheimer disease (AD), or vascular dementia (VaD). Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV) measurement using Complior. Results— In this population, 78±8 years of age (women 64%), AD was present in 41%, VaD in 6%, MCI in 27%, and 26% of subjects had normal cognitive function. After adjustment for age, gender, systolic blood pressure, education level, cardiovascular diseases, and antihypertensive therapy, a significant association was observed between PWV and cognitive status (P<0.0001). PWV appears significantly higher in subjects with VaD (15.2±3.9 m/s) or AD (13.3±2.9 m/s) than in those without cognitive impairment (11.5±2.0 m/s; P<0.001). Moreover, PWV was higher in subjects with MCI (12.6±2.6 m/s) than in those without cognitive impairment (11.5±2.0 m/s; P=0.01). For each 2 m/s increment in PWV, the adjusted odds ratio (95% CI) was 1.73 (1.27 to 2.47) for AD and 3.52 (1.87 to 8.05) for VaD. Conclusion— Our results showed a relationship between arterial stiffness and cognitive impairment, suggesting that functional changes of the arterial system could be involved in the onset of dementia (VaD or AD types).

Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II

AIMS International guidelines are frequently not implemented in the elderly population with heart failure (HF). This study determined the management of octogenarians with HF enrolled in Euro Heart Failure Survey II (EHFS II) (2004-05). METHODS AND RESULTS We compared the clinical profile, 12 month outcomes, and management modalities between 741 octogenarians (median age 83.7 years) and 2836 younger patients (median age 68.4 years) hospitalized for acute/decompensated HF. Management modalities were also compared with those observed in EHFS I (2000-01). Female gender, new onset HF (de novo), hypertension, atrial fibrillation, co-morbidities, disabilities, and low quality of life were more common in the elderly (all P < 0.001). Mortality rates during hospital stay and during 12 months after discharge were increased in octogenarians (10.7 vs. 5.6% and 28.4 vs. 18.5%, P < 0.001). Underuse and underdosage of medications recommended for HF were observed in the elderly. However, a significant improvement was observed when compared with EHFS I both in the overall HF octogenarian population and in the subgroup with ejection fraction < or =45% for prescription rates of ACE-I/ARBs, beta-blockers, and aldosterone antagonists at discharge (82 vs. 71%; 56 vs. 29%; 54 vs. 18.5%, respectively, all P < 0.01), as well as for recommended combinations and dosage. Prescription rates remained stable for 12 months after discharge in survivors. CONCLUSION Our study confirms that the contemporary management of very elderly patients with HF remains suboptimal but that the situation is improving.

Relationship between blood pressure and outdoor temperature in a large sample of elderly individuals: the Three-City study.

BACKGROUND Seasonal variations of blood pressure-related diseases have been described in several populations. However, few studies have examined the seasonal variations of blood pressure in the elderly, a segment of the population particularly exposed to vascular diseases. The association of blood pressure with season and outdoor temperature was examined in 8801 subjects 65 years or older from the Three-City study, a population-based longitudinal study. METHODS Blood pressure was measured at baseline and 2-year follow-up examinations. Daily outdoor temperature measured at 11 am was provided by the local meteorological offices. RESULTS Both systolic and diastolic blood pressure values differed significantly across the 4 seasons and across the quintiles of the distribution of outdoor temperature. Systolic blood pressure decreased with increasing temperature, with an 8.0-mm Hg decrease between the lowest (< 7.9 degrees C) and the highest (> or = 21.2 degrees C) temperature quintile. Intraindividual differences in blood pressure between follow-up and baseline examinations were strongly correlated with differences in outdoor temperature. The higher the temperature at follow-up compared with baseline, the greater the decrease in blood pressure. Longitudinal changes in blood pressure according to difference in outdoor temperature were larger in subjects 80 years or older than in younger participants. CONCLUSIONS Outdoor temperature and blood pressure are strongly correlated in the elderly, especially in those 80 years or older. During periods of extreme temperatures, a careful monitoring of blood pressure and antihypertensive treatment could contribute to reducing the consequences of blood pressure variations in the elderly.

Executive functions deficit in mild cognitive impairment.

ObjectiveTo investigate whether patients diagnosed with amnestic mild cognitive impairment (MCI) have also impairment in attention/executive functions, and therefore to clarify whether all subcomponents of executive control are equally affected in MCI. BackgroundMCI refers to the transitional state between normal aging and dementia. Amnestic MCI is characterized by impaired episodic memory, although subtle impairment of executive functions has been noted on neuropsychologic tests. MethodsWe investigated 20 MCI patients and 20 normal controls using episodic memory, attention/executive functions, language, and praxis tests. ResultsMCI patients had significantly lower scores on all measures of the Free and Cued Selective Reminding Test (P<0.05 to 0.01) than controls. Furthermore, MCI had a greater number of perseverations (P<0.01) on Modified Card Sorting Test and the lowest performance on the Stroop Test (P<0.02). ConclusionsOur findings showed impairment in episodic memory performance in MCI as compared with that of controls. In addition, MCI patients had problems with response inhibition, switching, and cognitive flexibility, which encompass various aspects of executive functions. This suggests that MCI may be identified by using a more detailed procedure for the assessment of cognitive decline than the evaluation of memory alone.

Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors

Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer’s disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. β-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating β-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Aβ42 into less toxic Aβ40. Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Aβ42 brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on β-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked with a common AT1-blunting effect. In addition, they increase angiotensin II and IV formation and therefore stimulate non-opposed AT2 and AT4 receptors, whose activation in cognitive processes is well established.

Treatment With Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents The PARTAGE Study

IMPORTANCE Clinical evidence supports the beneficial effects of lowering blood pressure (BP) levels in community-living, robust, hypertensive individuals older than 80 years. However, observational studies in frail elderly patients have shown no or even an inverse relationship between BP and morbidity and mortality. OBJECTIVE To assess all-cause mortality in institutionalized individuals older than 80 years according to systolic BP (SBP) levels and number of antihypertensive drugs. DESIGN, SETTING, AND PARTICIPANTS This longitudinal study included elderly residents of nursing homes. The interaction between low (<130 mm Hg) SBP and the presence of combination antihypertensive treatment on 2-year all-cause mortality was analyzed. A total of 1127 women and men older than 80 years (mean, 87.6 years; 78.1% women) living in nursing homes in France and Italy were recruited, examined, and monitored for 2 years. Blood pressure was measured with assisted self-measurements in the nursing home during 3 consecutive days (mean, 18 measurements). Patients with an SBP less than 130 mm Hg who were receiving combination antihypertensive treatment were compared with all other participants. MAIN OUTCOMES AND MEASURES All-cause mortality over a 2-year follow-up period. RESULTS A significant interaction was found between low SBP and treatment with 2 or more BP-lowering agents, resulting in a higher risk of mortality (unadjusted hazard ratio [HR], 1.81; 95% CI, 1.36-2.41); adjusted HR, 1.78; 95% CI, 1.34-2.37; both P < .001) in patients with low SBP who were receiving multiple BP medicines compared with the other participants. Three sensitivity analyses confirmed the significant excess of risk: propensity score-matched subsets (unadjusted HR, 1.97; 95% CI, 1.32-2.93; P < .001; adjusted HR, 2.05; 95% CI, 1.37-3.06; P < .001), adjustment for cardiovascular comorbidities (HR, 1.73; 95% CI, 1.29-2.32; P < .001), and exclusion of patients without a history of hypertension who were receiving BP-lowering agents (unadjusted HR, 1.82; 95% CI, 1.33-2.48; P < .001; adjusted HR, 1.76; 95% CI, 1.28-2.41; P < .001). CONCLUSIONS AND RELEVANCE The findings of this study raise a cautionary note regarding the safety of using combination antihypertensive therapy in frail elderly patients with low SBP (<130 mm Hg). Dedicated, controlled interventional studies are warranted to assess the corresponding benefit to risk ratio in this growing population.

Validation of two devices for self-measurement of blood pressure by elderly patients according to the revised British Hypertension Society protocol: the Omron HEM-722C and HEM-735C.

BACKGROUND The validation of self-measurement devices for clinical use by elderly patients has been recommended. The Omron HEM-722C device has recently been validated according to the British Hypertension Society (BHS) protocol for use for general populations and the Omron HEM-735C is a new fully automatic device with a high capacity for storage of measurements that is integrated with a personal computer. OBJECTIVE To perform a clinical validation for use by elderly people of the Omron HEM-722C and HEM-735C devices according to the revised protocol of the BHS and the criteria of the Association for the Advancement of Medical Instrumentation (AAMI). METHODS We carried out a main validation test according to the revised BHS protocol for validation procedures for special groups on two groups of 30 subjects aged more than 65 years (29 men and 31 women), 11 of 30 with systolic blood pressures (SBP) <110mmHg, 10 of 30 with SBP >200 mmHg, 15 of 30 with diastolic blood pressures (DBP( <70 mmHg and 10 of 30 with DBP >110 mmHg. The results were graded according to the BHS system from A to D. RESULTS The Omron HEM 722C achieved an overall A/A grading and satisfied the AAMI criteria for accuracy whereas the Omron HEM-735C achieved an overall B/A grading and satisfied the AAMI criteria for accuracy. The sphygmomanometer measurements were 147 +/- 31/79 +/- 15 and 144 +/- 30/78 +/- 15 mmHg (means+/-SD) respectively, for the models 722C and 735C. The average differences between mercury sphygmomanometer and HEM-722C readings for SBP and DBP were, respectively, 0.76+/-5 and 0.41+/-8 mmHg; those for HEM-735C were, respectively, 0.24+/-8 and 0.9+/-8 mmHg. Readings of the HEM-722C device differed by less than 5 mmHg for 76% of systolic readings and 96% of the readings differed by less than 10 mmHg. Diastolic measurements differed by less than 5 mmHg for 71% and less than 10 mmHg for 71 and 87% of all readings. Readings of the HEM-735C device differed by less than 5 mmHg for 68% of systolic readings and 74% of the readings differed by less than 10 mmHg. Diastolic measurements differed by less than 5 mmHg in 74% and less than 10 mmHg in 88 and 87% of all readings. CONCLUSIONS On the basis of these results, for elderly subjects both self-measurement devices (Omron HEM-722C and HEM-735C) satisfied the validation criteria of the BHS and therefore can be recommended for the clinical measurement of blood pressure in elderly patients.

Hypertension, cognitive decline and dementia

Dementia is one of the most common neurological disorders in the elderly. Aging is associated with a large increase in the prevalence and incidence of degenerative (Alzheimers disease) and vascular dementia, leading to a devastating loss of independence. In view of increasing longevity of populations worldwide, prevention and treatment of dementia has turned into a major public health challenge. In the past decade, longitudinal studies have shown a close association between high blood pressure in middle age, cognitive decline and dementia, including Alzheimers disease, in the late life. Pathophysiologically, a summation of cerebrovascular damage, white matter changes and pre-existing asymptomatic Alzheimers brain lesions may lead to dementia, even when each type of lesion individually is not sufficiently severe to cause it. Longitudinal studies assessing the beneficial role of antihypertensive drugs on cognitive decline and dementia have produced promising results. There are few randomised placebo controlled studies, although some of these have produced positive results. Results of three recent meta-analyses are inconsistent, possibly due to methodological issues. Further long-term randomised trials, designed especially to assess a link between antihypertensive therapy and cognitive decline or dementia are therefore needed.

Renal Function in Older Hospital Patients Is More Accurately Estimated Using the Cockcroft-Gault Formula Than the Modification Diet in Renal Disease Formula

OBJECTIVES: To compare the accuracy of the two most popular creatinine clearance (CrCl) estimation formulae (Cockcroft‐Gault (CG) and Modification Diet in Renal Disease (MDRD)) in older hospitalized patients.