L. Teillet, Ph. van den Bosch de Aguilar, G. Hamon, B. Corman, T. Cudennec, F. Puisieux

The authors of the present highlights section are members of the S@database editorial board. Contact: info@successaging.com

Benefits of inpatient and outpatient geriatric evaluation and management
L. Teillet

The specialized multidisciplinary approach to geriatric assessment has unquestionably helped to improve the care of frail elderly patients. The results of this management depend though on the care setting, and the remarkable results published by a given hospital unit may not always be matched by another unit. Likewise, it is difficult to measure the benefits that accrue from geriatric assessment. These are probably rather modest, even if some studies show that such assessment yields improvements for patients: perceived well-being, maintained activities of daily living, reduced depression scores, preserved social activity.
One study by the Veterans Affairs Cooperative Studies Program has determined the effects of specialized geriatric units on outcome in elderly patients. The methodological quality of the study was ensured by a randomized, multicenter design in 11 medical centers throughout the United States. Once the patients' initial clinical situation was stabilized, those over 65 years of age were randomized for admission either to a geriatric hospital unit or to a usual inpatient department. After the hospitalization period, patients were again randomized for usual outpatient care or outpatient care by a specialized geriatric team including a geriatrician, a nurse and a social worker.
The 1388 patients included in the study (98% men because a war veterans program; mean age 74.2 years) considered to be frail. They met two or more of the following criteria: a recent stroke, a history of falls, difficulty walking, dementia, malnutrition, depression, unplanned admission in the previous three months, incontinence, prolonged bed rest, or inability to perform one or more basic activities of daily living.
Four groups of patients were defined on the basis of the care setting: inpatient care in a geriatric evaluation and management unit or usual inpatient care, followed by outpatient care in a geriatric evaluation and management clinic or usual outpatient care. Whatever the management, geriatric or otherwise, one-year mortality was close to 21% in all four groups and therefore did not differ significantly. Geriatric management nonetheless had two clear advantages. First, when patients were initially admitted to a geriatric unit, loss of autonomy was significantly limited. Second, with care by a specialized geriatric team, mental health status was better. These two definite advantages for the patient were achieved at no additional cost.
These results, which concord with the findings of other American studies, are probably in part due to training and to improvements in practices and in management of the frail elderly, trends which should also occur in France.
Cohen HJ, Feussner JR, Weinberger M, Carnes M, Hamdy RC, Hsieh F, Phibbs C, Lavori P. A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med 2002 ; 346 : 905-912.

Brain atrophy and Alzheimer's disease
Ph. van den Bosch de Aguilar

Senile dementia or Alzheimer's disease (AD) is a progressive neurodegenerative condition which results in altered brain function due to the formation of neurofibrillary tangles and invasion of the brain parenchyma by neuritic amyloid plaques. These processes result in cell death and atrophy of the affected nerve centers. As brain atrophy is progressive, clear symptoms are often absent at the start of the disease, thus preventing implementation of a therapeutic strategy.
Magnetic resonance imaging can be used for in vivo measurement of volume changes in brain regions and hence to identify the affected regions and to assess atrophy at an early stage. Five groups of subjects were included in this study: 1) pre-symptomatic subjects belonging to families predisposed to early-onset familial dementia, 2) subjects affected by mild AD, 3) subjects affected by moderate AD, 4 and 5) two control groups of subjects age-matched respectively to group 1 and to groups 2 and 3. The degree of AD was measured by means of a psychometric test. Magnetic resonance analysis clearly shows atrophy of the brain regions associated with expansion of the ventricles in subjects predisposed to or affected by AD In predisposed subjects, brain atrophy is more marked in the hippocampus, followed by the anterior frontal cortex. In mildly affected subjects, atrophy also affects the lower and lateral parts of the temporal cortex and the posterior part of the limbic system. In moderately affected subjects, atrophy is more extensive in the frontal cortex. In the three groups of patients, the left hemisphere is more involved than the right hemisphere. This study confirms in vivo the progressive and extensive nature of brain atrophy already noted by post mortem examination. The atrophy first affects the phylogenetically "old" parts of the brain, the hippocampus and the limbic system and then extends to the more recent frontal region. This explains the clinically observed effects on memory (hippocampus) and behavior (limbic system), and then more generally on personality and cognitive processes (frontal and temporal cortex).
This study is valuable in terms of the longitudinal follow-up of patients and the adjustment of palliative therapy. It also raises essential questions. Why are certain regions more susceptible to involvement? What are the underlying mechanisms of the progression of atrophy? Which factors predispose to the disease?
Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC. Mapping the evolution of regional atrophy in Alzheimer'disease: Unbiased analysis of fluid-registered serial MRI. PNAS 2002; 99: 4703-4707.

The fatty acid oxidation capacity of skeletal muscle is impaired with age
G. Hamon

Among metabolic anomalies likely to occur with age are a reduced capacity for oxidation of fatty acids and altered insulin sensitivity of tissues. There seems to be an inverse relation between insulin sensitivity and the muscle's triglyceride content. In addition, skeletal muscles seem to play an important part in the assimilation and elimination of excess fatty acids. An altered capacity of the muscles to metabolize fatty acids could therefore play a role in the development of certain age-related metabolic anomalies.
To analyze the effects of age on fatty acid metabolism in striated muscle, a study was recently conducted by a Californian team on laboratory rats aged 5, 15 and 24 months. Under euglycemic conditions in the presence of low insulin levels, palmitate (used as substrate) oxidation and palmitate incorporation into muscle triglycerides were measured.
Whereas palmitate incorporation was the same in the three age groups, the percentage of palmitate oxidized decreased by 42 and 49% respectively in the rats aged 15 and 24 months, compared with the younger animals. In the 24-month-old rats, lactate release dropped by 38% but was unaffected in the two other groups. Initial triglyceride concentration in the red gastrocnemius muscle and white gastrocnemius muscle was 145 to 166% higher in the 24-month-old animals than in those aged 5 months, and these differences were maintained throughout the experiment. Triglyceride synthesis was similar in the three groups, as were the concentration and synthesis of glycogen. The plasma membrane fatty acid-binding protein, one of the hypothetical transporters of fatty acids, was more abundant (40 to 63%) in the older than younger rats. Hormone-sensitive lipase content decreased by 28% in the older rats in the red quadriceps muscle only.
These results lend support to the hypothesis of an age-dependent decrease in the capacity of striated muscles to oxidize fatty acids. A chronic increase in baseline levels of glucose and fatty acids, as observed by the authors in the older rats, could account for the accumulation of triglycerides in the muscle of these animals. These data also point to a diminished ability of the muscles of aging animals to hydrolyze and use triglycerides.
Tucker MZ and Turcotte LP. Impaired fatty acid oxidation in muscle of aging rats perfused under basal conditions. Am J Physiol 2002; 282: E1102-E1109.

Can dietary restriction and a favorable genetic mutation have cumulative effects on longevity?
B. Corman

There are several experimental approaches to study the mechanisms of longevity. In some, the effects of overexpression or suppression of a gene on survival are investigated. In others, the effects of changes in the environment such as temperature, hygiene or dietary supplements are studied. Still others focus on the administration of drugs likely to slow the effects of aging. These approaches are designed to enhance understanding of the influence of a particular metabolic pathway or signaling system in determining the aging processes, and, if possible, to develop treatments or advice on prevention applicable to humans.
The results obtained in recent years have been highly encouraging. Mean or maximum lifespan has been increased by 50 to 100% in experimental models such as the fruit fly Drosophila, the nematode Caenorhabditis elegans, and laboratory mice and rats. The variety of these experimental approaches obviously raises the question of a common mechanism or of the juxtaposition of independent processes. To address this question, one method consists in combining different types of interventions and seeing whether their effects are additive or not. This was the approach adopted by British and German teams who investigated the effects of dietary restriction in Drosophila carrying the chico mutation. This mutation affects the signaling pathway of the insulin/insulin-like growth factor (IIS), which binds to insulin receptors.
The life expectancy of Drosophila bearing the chico mutation is greater than that of control fruit flies. Besides experiments now considered classical showed that the mean lifespan of Drosophila fruit flies can be extended by dietary restriction, achieved by diluting the nutrient solution available to them. The effect on survival was progressive and peaked at a 35% dilution, beyond which the lifespan of the Drosophila decreased, probably because of dietary deficiency.
If the chico mutation extends the lifespan of Drosophila by the same mechanism as dietary restriction, the latter should have no additional effect. However, if the two affect longevity through different mechanisms, then their effects should be cumulative. When the authors varied the dilution of the nutrient solution, they found that survival peaked at a 0.65 dilution in control Drosophila and at a 0.80 dilution in mutant flies. This suggests that the chico mutation tends to reduce either the Drosophila's spontaneous food intake or the assimilation of nutrients. The lifespans reached by the control and mutant Drosophila were identical when their food intakes were optimized by these dilutions, indicating that the effects of the chico mutation and dietary restriction are not cumulative.
These experiments show first that in studies of longevity, comparisons of different treatments or genetic manipulations should be made under optimal conditions, which may differ between experimental groups. They also suggest that changes in the IIS pathway involves mechanisms common to those of dietary restriction, or inversely that the reduction in food intake influences the substrates or receptors of the IIS pathway.
Clancy DI, Gems D, Hafen E, Leevers SJ, Partridge L. Dietary restriction in long-lived dwarf flies. Science 2002, 296:319.

Are red blood cell methylfolate and plasma homocysteine risk factors for venous thromboembolism?
T. Cudennec

Moderately elevated plasma homocysteine is a risk factor for venous thromboembolism. However, to date no clear causal link has been forged between homocysteine concentration itself or one of the components of the homocysteine-remethylation pathway, like methylfolate, and thromboembolic disease. A case-control study has analyzed the relation between the main components of the homocysteine-remethylation pathway and the risk of venous thrombosis.
A French-Swiss team has assayed plasma levels of homocysteine, methionine, serum folate, total red blood cell folate and methylfolate, 5,10- methylenetetrahydrofolate reductase (MTHFR) C677T genotype, and other risk factors known to be implicated in the onset of venous thromboembolism. Samples were collected from 243 patients under 75 years of age with deep vein thrombosis or a pulmonary embolism. The data were then age- and sex-matched.
The plasma homocysteine concentrations differed significantly between patients and controls. High concentrations were correlated with red blood cell methylfolate and with the risk of venous thromboembolism. Matching gave odds ratios of 1.0 for methylfolate = 249 µg/l, and 7.1 for methylfolate £ 141 µg/l. Methionine concentrations below the mean (i.e. < 27 µmol/l) were associated with an increased risk of venous thromboembolism. They are also a recognized risk factor, as are high body mass index, a personal history of cancer, a family history of venous thromboembolism, use of an estrogen/progestagen oral contraceptive, and a mutation in Leiden factor V. The link between red blood cell methylfolate and the risk of venous thromboembolism varies with the level of the MTHFR C677T genotype.
The principal result of this study is that there is a strong, concentration-dependent correlation between red blood cell folate, and more particularly methylfolate, and the risk of venous thromboembolism. This correlation is stronger than that noted with plasma folate and homocysteine, and seems to be independent of other known risk factors. This correlation should now be validated in patients over 75 years of age. Red blood cell methylfolate could then be used to screen for persons likely to develop venous thromboembolism.
Quere I, Perneger TV, Zittoun J, Bellet H, Gris JC, Daures JP, Schved JF, Mercier E, Laroche JP, Dauzat M, Bounameaux M, Janbon C, De Moerloose P.Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. The Lancet 2002: 359; 747-752.

A single intravenous infusion of zoledronic acid increases bone mineral density in postmenopausal osteoporotic women
F. Puisieux

Biphosphonates constitute an effective treatment of postmenopausal osteoporosis. In long-term use, they raise bone mineral density and lower the risk of vertebral and nonvertebral fractures. However, daily oral dosing poses several problems: long-term compliance, gastrointestinal intolerance, and low and variable gastrointestinal absorption.
In other indications, such as malignant hypercalcemia or Paget's disease, biphosphonates are used discontinuously by the intravenous route. Preliminary studies also suggest that biphosphonates administered intravenously could have a positive impact on bone mineral density. This is what the authors of this article sought to verify by examining the effect of discontinuous intravenous administration of zoledronic acid, the most potent biphosphonate currently available, on bone turnover and mineral density in osteoporotic postmenopausal women.
The study included 351 osteoporotic women 45 to 80 years of age who had been menopausal for at least five years. The osteoporosis was documented by a T-score of bone mineral density in the lumbar vertebrae at least two standard deviations lower than the mean value in young adults. Initially, the mean T-score was -2.9, which shows that this population was mildly osteoporotic and so at a moderate risk of fracture.
The participants were randomized to receive in a double blind manner one of the six following therapeutic regimens: (1) placebo; (2) zoledronic acid 0.25 mg every three months; (3) zoledronic acid 0.5 mg every three months; (4) zoledronic acid 1 mg every three months; (5) zoledronic acid 2 mg every six months; (6) zoledronic acid 4 mg in one dose. To maintain the double blind, all participants received every three months an intravenous infusion of 20 ml, containing either placebo or a variable quantity of zoledronic acid.
Bone mineral density was measured at 0, 6, 9 and 12 months at the lumbar spine, femoral neck, and distal extremity of the radius. Bone turnover was quantified by the assay at 0, 3, 6, 9 and 12 months of several biochemical markers: bone alkaline phosphatases, serum osteocalcin and C-telopeptide of type I collagen, and the ratio of N-telopeptide of type I collagen over urinary creatinine.
After one year, lumbar and femoral bone mineral density had increased significantly in all the zoledronic acid groups compared with the placebo group, with no notable between-group difference. The lumbar increase was between 4.3 and 5.1 %, depending on the group. The markers of bone resorption were significantly decreased at one year in all zoledronic acid groups compared with the placebo group, with no notable between-group difference: about -50% for serum C-telopeptide of type I collagen and the ratio of N-telopeptide of type I collagen over urinary creatinine. At three months, the effect on these markers was dose-dependent. As expected, there were few (a total of 8) fractures during the year of follow-up, with no significant between-group difference.
The safety of the treatment was good. No serious adverse reaction was observed. Minor side effects were reported more often in the zoledronic acid groups, notably at the first infusion. These were principally myalgia, arthralgia, pyrexia and nausea. However, there were no more drop-outs in the zoledronic acid groups than in the placebo group.
The authors conclude that the discontinuous administration of zoledronic acid in one or more intravenous injections each year raises bone mineral density in a proportionally identical manner to daily oral treatment with conventional biphosphonates (alendronate, risedronate). This mode of administration could therefore constitute an effective and readily acceptable treatment for postmenopausal osteoporotic patients. It remains to be demonstrated whether such a treatment effectively prevents fractures in populations at high risk of fractures.
Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P and al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med, 2002; 346: 653-61.