Search

Oxidative stress is thought to be involved in the aging process in aerobic organisms and to play a role in the pathogenesis of several disease states. Since free radicals are extremely reactive, shortly half-lived and therefore very difficult to measure directly, oxidative stress has been mainly studied through the search of indirect biomarkers of free radical-induced damage. In aerobic organisms, oxidative damage to tissues and organs is prevented by a network of defenses which includes antioxidant and repairing enzymes as well as small molecules with scavenging ability, such as antioxidant vitamins. For these reasons, the assay of antioxidant vitamins and of small molecular free radical scavengers in biological milieus may be used, if appropriately performed, to quantify the defense status against oxidative damage and to provide an indirect estimate of free radical production in aging humans. Since several conflicting data have been reported in this area, this review is aimed to summarize the existing evidence and possible faults of the research focusing on the role of plasma concentrations of small-molecular, non-enzymatic antioxidants in the process of senescence in healthy humans.

A reduction in muscle mass, with consequent decrease in strength and resistance, is commonly observed with advancing age. In this study we measured markers of oxidative damage to DNA, lipids and proteins, some antioxidant enzyme activities as well Ca2+ transport in sarcoplasmic reticulum membranes in muscle biopsies from vastus lateralis of young and elderly healthy subjects of both sexes in order to evaluate the presence of age- and sex-related differences. We found a significant increase in oxidation of DNA and lipids in the elderly group, more evident in males, and a reduction in catalase and glutathione transferase activities. The experiments on Ca2+ transport showed an abnormal functional response of aged muscle after exposure to caffeine, which increases the opening of Ca2+ channels, as well a reduced activity of the Ca2+ pump in elderly males. From these results we conclude that oxidative stress play an important role in muscle aging and that oxidative damage is much more evident in elderly males, suggesting a gender difference maybe related to hormonal factors.

Background and Purpose: Experimental studies provide evidence of an association between ischemic stroke and increased oxidative stress, but data in humans are still limited and controversial. The purpose of this study was to investigate the time course of plasma antioxidant changes in ischemic stroke patients., Methods: Plasma antioxidants, including water-soluble (vitamin C and uric acid) and lipid-soluble (vitamins A and E) compounds as well as antioxidant enzyme activities in plasma (superoxide dismutase [SOD] and glutathione peroxidase) and erythrocytes (SOD), were measured by high-performance liquid chromatography (antioxidant vitamins) and by spectrophotometry (antioxidant enzymes) in 38 subjects (25 men and 13 women aged 77.2+/-7.9 years) with acute ischemic stroke of recent onset (<24 hours) on admission, after 6 and 24 hours, and on days 3, 5, and 7. Antioxidant levels in patients on admission were compared with those of age- and sex-matched controls., Results: Mean antioxidant levels and activities in patients on admission were lower than those of controls and showed a gradual increase over time. Patients with the worst early outcome (death or functional decline) had higher vitamin A and uric acid plasma levels and lower vitamin C levels and erythrocyte SOD activity than those who remained functionally stable., Conclusions: These results suggest that the majority of antioxidants are reduced immediately after an acute ischemic stroke, possibly as a consequence of increased oxidative stress. A specific antioxidant profile is associated with a poor early outcome.

The consequences of natural disasters on the social and health status of older people have not been deeply considered. The aim of this study was to evaluate the socioenvironmental and psychophysical conditions of an elderly population after a devastating earthquake. A randomly selected group of 332 older people (> or =64 years) was selected among 1548 eligible subjects living in the city of Nocera Umbra four months after an earthquake of 5.6 magnitude on the Richter scale. Three geriatricians evaluated the study subjects by means of a structured interview, and standardized scales, which considered physical and mental status, mood and anxiety, and self-perception of well-being, as well as the characteristics of family composition and social interactions. Of the study subjects, 11.1% lived alone, and 33.4% with the spouse only. Most were self-sufficient in the basic activities of daily life. Musculoskeletal diseases and hypertension were the most frequently observed pathologies in this geriatric population. In addition, 47.9% of the subjects lived in temporary houses; this group more frequently suffered from hypertension, and had a higher score of comorbidity as measured by Cumulative Illness Rating Scale (CIRS) compared to people who remained at home. People living in the pre-fabricated huts also showed a higher score on the Geriatric Depression Scale and the Hamilton scale for anxiety, and complained more often of their health status, evaluated as self-perception of well-being, when compared to the home dwellers. Although all the studied subjects suffered from the discomforts caused by the earthquake, the precariousness of living in temporary houses, whose structural characteristics do not take the needs of elderly subjects into account, could justify the higher distress experienced by persons housed in the huts. These observations suggest that, after natural disasters, emergency programs should be more adapted to elderly people, whose needs and expectations are often different from those of young adults.

A large body of experimental research indicates that oxidative stress contributes to the processes related to aging and to the pathogenesis of several age-related diseases. Vitamins and antioxidant enzymes have a fundamental role in defending the organism from oxidative stress. To better understand the role of antioxidants in human aging, we measured plasma levels of vitamin C (ascorbic acid), uric acid, vitamin E (alpha-tocopherol), vitamin A (retinol), carotenoids, total thiol groups, and the activity of plasma superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as the activity of red blood cell (RBC) SOD in 32 healthy centenarians-17 elderly subjects aged 80-99 years, 34 elderly subjects aged 60-79 years, and 24 adults aged less than 60 years. Considering the "noncentenarians" only, we observed a consistent behavior in the antioxidant pattern, with a decrease of the nonenzymatic antioxidants and an increase of the enzymatic antioxidant activities relative to age. Remarkably, centenarians were characterized as having the highest levels of vitamins A and E, whereas the activities of both plasma and RBC SOD, which increase with age, decreased in centenarians. From these results, it is evident that healthy centenarians show a particular profile in which high levels of vitamin A and vitamin E seem to be important in guaranteeing their extreme longevity.

Physical activity and exercise have several beneficial effects for physical and psychological health in young and aged subjects. Exercise may reduce age-related lean body mass loss and risk for several chronic diseases including coronary artery disease, hypertension, non-insulin-dependent diabetes mellitus, anxiety, depression, functional decline, and frailty. Exercise, however, especially when performed strenuously, is associated with increased production of reactive oxygen species, able to consume endogenous antioxidants and eventually to damage biological molecules and key cellular components. Therefore, the balance between beneficial and potentially harmful effects of exercise might be of particular importance in the elderly, in which nutritional deficiencies, sedentary lifestyle, and comorbidity commonly concur to a depletion of the antioxidant reservoir of the organism and increased susceptibility to oxidative stress. The aim of this review is to summarize current experimental, clinical, and epidemiological knowledge regarding known associations and potential links between oxidative stress and physical activity/exercise during aging. Before a final recommendation can be made with respect to the possible preventive and therapeutical role of antioxidant supplementation in aged exercising people, there is a substantial need for further studies to be performed on this topic.

Background: Experimental research indicates that oxidative stress is implicated in aging and in the pathogenesis of diabetes and its complications. This evidence is limited in elderly patients with non-insulin dependent diabetes, in which age- and disease-related production of reactive oxygen species might exert synergistic damaging effects on tissues and organs., Methods: Plasma levels of lipid-soluble compounds with antioxidant properties including vitamin A, vitamin E and carotenoids (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) were measured by HPLC in 72 elderly patients with non-insulin dependent diabetes (75.7+/-0.8 years, 40 F, 32 M) and in 75 age-matched controls (77.2+/-1.2 years, 48 F, 27 M)., Results: All compounds measured were significantly lower in plasma from diabetic patients as compared to controls (p<0.0001). Plasma levels of vitamins A and E and of carotenoids did not significantly correlate with dietary intake and lipid profile in both groups. In patients, significant inverse correlations were found between age and levels of vitamin E, beta-cryptoxanthin, lycopene and beta-carotene., Conclusions: We conclude that patients of very old age with Type 2 diabetes show a poor plasma status of vitamins A and E and carotenoids, which negatively correlates with age. Further studies are needed to explore the possible therapeutic role of lipid-soluble vitamin supplements in elderly diabetic subjects., (Copyright 2000 John Wiley & Sons, Ltd.)

Alzheimer's disease (AD) is a multifactorial disorder determined by the interaction of genetic, metabolic, and environmental factors. In the common late-onset familial and sporadic forms of AD apolipoprotein E type 4 allele (APOE-epsilon4) is now widely accepted as a major risk factor. The association of estrogen treatment with a reduction in the risk of AD together with the modulation by estrogen of the secretory metabolism of the amyloid precursor protein offers new possibilities for identification of other AD susceptibility genes, as those encoding for the estrogen receptors (ERs). A total of 193 patients with sporadic late-onset AD, meeting the NINCDS-ADRDA criteria, and a total of 202 control subjects, age and education matched, were included in this study. PvuII and XbaI ERalpha and HhaI APOE gene polymorphisms were evaluated in genomic DNA by Polymerase Chain Reaction (PCR). The frequency of the various ERalpha genotypes by the combination of P, p and X, x was calculated for controls and AD patients stratified based on ApoE typing. When the two ERalpha gene polymorphisms were analyzed in combination, 7 genotypes were recognized, with a significantly increased prevalence of PPXX genotype in AD patients compared to controls (P = 0.0001). Risk of AD increased by a factor of 7.6 (CI [1.10-62.3]) in homozygous APOE-epsilon4 individuals with PPXX ERalpha genotype. These results are consistent with a segregation of PPXX ERalpha genotype with a higher risk of developing late-onset sporadic AD in the Italian population. The ERalpha gene appears to interact with the APOE-epsilon4 genotype in determining AD susceptibility., (Copyright 1999 Academic Press.)

One hundred and sixty-nine severely demented patients were tested in a multicenter study with the short version of the Severe Impairment Battery which was translated into Italian with the purpose of adapting and validating it for an Italian population. Patients were enrolled in Italian geriatric centers participating in the Study Group on Aging Brain of the Italian Society of Gerontology and Geriatrics. Following thorough clinical and instrumental examinations, they were evaluated with the Mini Mental State Examination, the Clinical Dementia Rating, the Severe Impairment Battery (SIB), the Gottfries-Bråne-Steen Rating Scale for Dementia, the Activity of Daily Living index, and the Bedford Alzheimer Nursing Severity scale (BANS.s). The inter-rater reliability of the SIB was highly significant for the total score and its subtests; test-retest reliability showed the same significance in all items. Also concurrent validity, performed comparing the total SIB score with the total BANS.s score, was significant. The short Italian version of the SIB proved to be a very reliable tool for the evaluation of severely demented patients; it has the advantage of being easy to administer, it evaluates more cognitive domains that, are typically assessed in dementia, and has a wide enough range of scores to detect even small differences in the examined abilities.

The levels of mitochondrial DNA 4977 bp deletion (mtDNA4977) and mitochondrial DNA 8'-hydroxy-2'-deoxyguanosine (OH8dG) were determined in the same samples from two brain areas of healthy subjects and Alzheimer's disease (AD) patients. A positive correlation between the age-related increases of mtDNA4977 and of OH8dG levels was found in the brain of healthy individuals. On the contrary, in both brain areas of AD patients, mtDNA4977 levels were very low in the presence of high OH8dG amounts. These results might be explained assuming that the increase of OH8dG above a threshold level, as in AD patients, implies consequences for mtDNA replication and neuronal cell survival.

The aim of this study was to evaluate factors predicting length of stay in hospital of geriatric patients. Study participants were 402 patients (183 males and 219 females) consecutively admitted to four geriatric wards located in Chieti, Perugia, Pescara and Prato, Italy. Information on potential predictors of length of stay was collected; in particular, we assessed the presence and severity of specific chronic medical conditions, level of physical function, cognitive status, and depressive symptoms. Moreover, information on family and social support was obtained. In general, participants were old, often cognitively impaired and physically disabled. Average length of stay ranged from 9.4 +/- 3.3 days (Perugia) to 14.1 +/- 7.2 days (Chieti), and was statistically different across centers (p < 0.001). None of the specific medical diagnoses was associated with different length of stay. However, higher comorbidity score (p < 0.001), living alone (p < 0.01), lower MMSE score (p = 0.03), and poor functional status (p = 0.05) were all associated with longer length of stay. When these variables were included in a multivariate model predicting length of stay, differences between centers were no longer statistically significant. Findings of this study show that specific medical diagnoses are not adequate instruments to estimate length of stay in geriatric units. Other assessment systems based on extension of the social network, comorbidity, and the cognitive as well as the functional level need to be developed.

Densitometric measurements are prone to imprecision in elderly subjects and the present study was primarily designed to dissect out the effects of age and bone mineral density on proximal femur dual energy x-ray absorptiometry (DXA) reproducibility. The study comprised 17 elderly women (mean age 74.6 years, range 65-84 years), 13 early postmenopausal women with osteopenia (mean age 56.2 years, range 50-63 years), and 17 elderly men (mean age 73.8 years, range 65-86 years). Each subject was given triplicate proximal femur scans by a QDR 2000 Densitometer (Hologic Inc., Waltham, MA) with repositioning between scans. Because of subject selection in the early postmenopausal women there were no significant differences in bone mineral density (BMD) at any site among the three groups. Despite this, reproducibility errors expressed as either coefficient of variation (CV) % or mean standard deviation (SD) were greater in the elderly subjects, regardless of gender, when compared with the younger female subjects. The variability in measurement errors with age were least marked for the total hip and trochanteric sites. Within the elderly subjects, BMD appeared to exert little influence on measurement errors. We conclude that short-term proximal femur reproducibility is dependent on age-related factors other than BMD. There is no influence of gender on the measurement errors. It is likely that local factors (e.g., hip osteoarthritis) or general frailty may influence repositioning but this needs further exploration. In the meantime, the total hip and trochanteric sites should be used as they provide the most reproducible measurements in the elderly.

Objective: Several studies show structural and functional alterations in peripheral cells in AD. The purpose of this study was to evaluate oxidative stress in AD lymphocytes., Background: The literature supports the role of reactive oxygen species in the pathogenesis of AD because several markers of oxidative damage have been detected in AD brain., Methods: 8-hydroxy-2'-deoxyguanosine (8OHdG), a marker of oxidative stress in DNA, was measured in lymphocytes of AD patients and healthy aged controls with high-pressure liquid chromatography with electrochemical detection, both at basal condition and after acute oxidative stress with hydrogen peroxide., Results: A significantly higher concentration of 8OHdG in lymphocytes occurred in AD patients compared with controls. In this latter group, 8OHdG increased progressively with age. After acute oxidative stress, levels of formed 8OHdG did not differ between AD patients and controls., Conclusions: Our results support that AD is affected by oxidative stress, detectable not only in the brain but also in peripheral cells; oxidative mechanisms may contribute to the pathogenesis of AD. Additional studies in other neurodegenerative diseases are needed to evaluate these findings.

Tau is the main protein of paired helical filaments. It can be detected and measured in cerebrospinal fluid (CSF) and for this reason it has been proposed as a possible in vivo marker of Alzheimer disease (AD). To evaluate the usefulness of CSF tau in the diagnosis of AD we measured it in patients with AD, frontal lobe dementia (FLD), vascular dementia (VD), and in healthy controls by means of a specific enzyme-linked immunosorbent assay test. Individuals with AD had significantly higher tau levels than FLD, VD, and controls. Individuals with late onset AD had significantly higher levels than those with early onset disease. In AD, CSF tau level did not correlate with age, duration, or severity of the disease, whereas a correlation with age was found in FLD and controls. In the nine AD patients in whom CSF tau measurement was repeated after 2 years, mean levels did not differ from baseline, although a worsening of cognitive performances occurred. The overlap among the different groups and the absence of any modification over time suggest that CSF tau measurement, more than in confirming or staging overt AD, might be useful in revealing the disease at its preclinical phase.

The aim of the study was to evaluate which characteristics of geriatric patients account for readmission to hospital, 6 months after discharge. All patients (203 females, 176 males) consecutively admitted over a two-month period to four acute geriatric care units, located in the cities of Chieti, Perugia, Pescara and Prato, participated in the study. Data that could potentially explain early and late readmissions were collected for each patient. Prevalence of diseases and comorbidity were assessed with the Cumulative Illness Rating Scale (CIRS); physical function by self-report (ADL, IADL) and objective (Stand and Walking Speed) measures; cognitive level by MMSE; and depressive symptoms by the Geriatric Depression Scale (GDS). Information on family and social support were also obtained. After discharge, data on hospital readmissions were collected for six months. For each readmitted patient (cases), medical records were reviewed, and supplementary information was obtained from families and general practitioners. Readmissions were classified as "early" (within the first three months), "late" (within the third and sixth month), and "multiple" (2 or more readmissions irrespective of the period). Patients not readmitted (alive at home) were considered as controls. Systematic differences between centers and between periods of readmissions were evaluated using one-way analyses of variance, and Pearson's chi 2 test. Factors related to early, late, and multiple readmission were identified in multivariate logistic regression models. On univariate analysis, patients readmitted over the first three-month period were sicker than controls (CIRS classes 3-4: 52.1% vs 34.1%), had more social problems or behavioral symptoms, and were more functionally impaired (ADL dependencies 3.3 +/- 0.4 vs 2.1 +/- 0.2). Patients who were readmitted between the third and the sixth month after discharge had a significantly higher CIRS total score (p = 0.006). Patients with multiple readmissions had more severe diseases, and more social problems. On multivariate analysis, early readmission was associated with unsatisfactory social conditions, living alone, severity of diseases and cognitive impairment, while late readmission was associated with comorbidity only. Multiple readmissions were related only to social factors, and to hospital admission before the baseline evaluation. The findings of this study suggest that interventions aimed at improving unfavorable social conditions may reduce the rate of rehospitalization in geriatric patients.

CV performance declines over time in healthy elderly subjects due to aging, as well as declining physical activity. Recent studies with older, often sedentary individuals, demonstrate that aerobic endurance exercise may improve several measures of CV function. Although further research is needed to characterize the CV effects of exercise, particularly in elderly women and the oldest old population, aerobic endurance exercise should be advocated in the healthy elderly.

People over the age of 65 constitute a growing proportion of the world population both in western and in developing countries. A unique feature of this group is the high prevalence of cardiovascular diseases, which negatively affect its quality of life as well as its life expectancy. Among the interventions able to reduce the health burden of cardiovascular diseases is physical activity. The benefits of physical activity have been demonstrated both in healthy and chronically ill elderly subjects, while the risks have been found to be modest. Physicians should recommend moderate-intensity physical activity to sedentary older subjects, who are still the majority within the elderly population.

Apolipoprotein-E (Apo-E) genotype and allele frequencies were evaluated in patients with late-onset probable Alzheimer's disease (LOAD; n = 64), early-onset probable Alzheimer's disease (EOAD; n = 32), possible Alzheimer's disease (pAD; n = 44), vascular dementia (VD; n = 12), age-associated memory impairment (AAMI; n = 15) and 40 healthy age-matched controls. APO-E was performed by polymerase chain reaction products digested by the restriction enzyme HhaI. A statistically significant increase of epsilon4 frequency was found in LOAD as compared to the other groups, and in pAD with respect to controls, while VD and AAMI groups did not disclose any difference as regards to control subjects. Multivariate analysis showed a significant association of epsilon4 with female gender. Our results confirm the increased frequency of epsilon4 in both probable and possible LOAD, failing to show a similar trend in VD and AAMI.

In order to evaluate the biological effects on some haemostasis factors of antithrombotic-hemorheological treatments on patients with vascular dementia, a multicenter, randomized, double-blind, double-dummy, study comparing sulodexide (Sdx, 50 mg bid orally for 6 months) and pentoxifylline (Ptx, 400 mg tid orally for six months) was carried out. Eighty-six patients, 46 in Sdx group, 40 in Ptx group, fulfilling the NINDS-AIREN criteria for probable vascular dementia were evaluated. Plasma fibrinogen levels showed a significant reduction in both groups, in patients with high basal levels (> or = 350 mg/dl), the reduction being earlier in Sdx group (2nd month of therapy) than in Ptx group (4th month of therapy). In Sdx group a significant reduction in factor VII-Ag (baseline 102.8 U/dl; 6th month 90.1 U/dl) was also observed. Both drugs induced a slight reduction in activated factor VII levels as well. A parallel improvement of G.B.S. Rating Scale for dementia scores was observed in Sdx group. These results seem to indicate that sulodexide treatment can have positive effects in vascular dementia.

Oxidative damage on biological molecules has been proposed as a major cause of alterations observed in aging brain as well as in neurodegenerative diseases. In this study, we measured membrane fluidity in mitochondria extracted from three cerebral regions and cerebellum of Alzheimer disease (AD) patients and age-matched controls by means of fluorescence polarization technique. A significant reduction of mitochondrial membrane fluidity was found in AD, except in cerebellum. In controls, a decrease of membrane fluidity was observed along with age, and it was also related to the content of the oxidized nucleoside 8-hydroxy-2'-deoxyguanosine (OH8dG) in mitochondrial DNA (mtDNA). Alteration in membrane fluidity seems to be a result of lipid peroxidation, since it dramatically decreased when mitochondria were exposed to FeCl2 and H2O2. The parallel increase of viscosity in mitochondrial membrane and the amount of OH8dG in mtDNA is suggestive of a relationship between these biological markers of oxidative stress. These results provide further evidence that oxidative stress may play a role in the pathogenesis of AD.

Although at present there is no definitive treatment or cure for Alzheimer's disease, different pharmacological strategies are being actively investigated. At present, cholinergic therapy and nootropics and some neuronotrophic agents represent the available approaches to symptomatic treatment of Alzheimer's disease. The use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic approach to increase acetylcholine levels. Available data suggest that about 15 to 40% of Alzheimer's disease patients show a varying degree of cognitive improvement while taking these medications; however, haematological complications (neutropenia or agranulocytosis), together with hepatotoxicity, need to be considered carefully. Recent data suggest that long term administration of nootropics may lead to a significant improvement of cognitive functions in Alzheimer's disease patients compared with untreated individuals, having excellent tolerability. Protocols for the intracerebroventricular administration of neuronotrophic substances are also ongoing. The most promising approaches for the future currently undergoing investigation involve attempts to slow the production of beta-amyloid and/or to inhibit beta-amyloid aggregation. Another rational therapeutic approach would be to inhibit the formation of paired helical filaments (PHF) by increasing and/or modulating the activities of protein phosphatases and kinases. Antioxidant therapy should disrupt or prevent the free radical/beta-amyloid recirculating cascade and the progressive neurodegeneration. Idebenone, a synthetic compound acting as an 'electron trapper' and free radical scavenger, has shown some efficacy in degenerative and vascular dementia; at present, other different molecules having antioxidative properties [lazaroids (21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline, some vitamins] are under investigation. Lowering absorption or brain tissue concentrations of aluminium also offers possible therapeutic opportunities for slowing the rate of clinical progression of the disease; in this sense, some evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine). Inflammation also may play a significant pathogenetic role in Alzheimer's disease. As shown by several retrospective analyses, there is an inverse association of anti-inflammatory drug use with the frequency of Alzheimer's disease diagnosis. Consequently, clinical trials using both nonsteroidal and steroidal molecules have been proposed. These lines of pharmacological intervention represent an important premise for future therapeutic strategies capable of counteracting the pathogenesis of Alzheimer's disease.

Objectives: To describe the Gottfries-Bråne-Steen (GBS) Rating Scale more fully with instruments commonly used for the diagnostic assessment of older patients with cognitive disturbances--the Mini Mental State Examination (MMSE), Hamilton Depression Rating Scale (HDRS), and Global Deterioration Scale (GDS)--and to characterize the specific diagnostic value of the GBS., Design: A multicenter study including patients diagnosed with senile dementia of the Alzheimer type (SDAT; age at onset: > 75 years) and age-matched non-demented subjects., Subjects: One hundred thirty-eight consecutively referred SDAT patients and 116 non-demented age-matched healthy subjects selected from among relatives of the patients., Methods: The MMSE, GBS and HDRS were used for assessing patients and controls. The GDS was utilized for dementia staging., Findings: Principal component analysis carried out on GBS scores yielded three factors explaining 74% of variance: factor 1, general functioning; factor 2, depression, and factor 3, restlessness. The actual composition of these factors was analyzed after computing factor scores for each subject by means of forward selection regressions, each using the MMSE, GDS and HDRS as predictors of scores on a given factor. The best predictors were MMSE and GDS scores for factor 1; HDRS for factor 2, and MMSE for factor 3. A GBS cutoff of 8 (obtained after a quality receiver operating characteristic analysis) best discriminated between demented and non-demented subjects (positive-predictive value: 0.88; negative-predictive value: 0.90)., Conclusions: The GBS Rating Scale for dementia can be a useful tool in routine clinical assessment of older subjects with cognitive impairment and distinguishes between demented and non-demented subjects; it gives comprehensive information on functional and psychobehavioral characteristics of demented patients, being composed of factors related to the MMSE and HDRS.

In order to evaluate in vivo the entity of endosteal and periosteal changes with age in the two sexes, and their relative contribution to age-related cortical bone loss, we undertook a cross-sectional study on a population of normal Caucasian subjects. The group included 189 women and 107 men who were studied by photodensitometry and radiogrammetry of the second metacarpal bone, derived from the same standard hand X-ray. Of the subjects, 134 were 65 years of age or older (75 women and 59 men). Metacarpal bone mineral density (BMD) correlated with age in both sexes, with an annual bone loss rate of 0.5% in women and 0.15% in men. In the over 65 group, correlation was significant only in women, who underwent an acceleration in the rate of bone loss (1% per year). Marrow cavity width (M), cortical index at the second metacarpal shaft (MI) and external width (W) all correlated with age in both sexes, although generally better in the female than in the male sex. M almost doubled from the fourth to the ninth decade in women and increased 50% in men. In the same age interval, MI showed an annual decrease of 0.49% in females and 0.33% in males. In the over 65 group, cortical thinning rate was significant in women (0.39% per annum) but not in men (0.14% per annum), whereas correlation of W was not significant in either sex. Finally, MI correlated with BMD in the whole study population and in the over 65, with a female prevalence in correlation strength maintained throughout life. The following conclusions can be derived for metacarpal aging: (1) an acceleration in cortical bone loss occurs in females after age 65; (2) age-related growth in periosteal diameter, although significant in the whole population, is negligible in the elderly of both sexes; (3) age-related cortical bone loss is generally more dependent on cortical thinning in women than in men.

The pharmacokinetics and endocrine effects of a therapeutic dose (10 mg/day) of posatirelin (L-pyro-2-aminoadipyl-L-leucyl-L-prolinamide) were investigated in healthy elderly subjects. Posatirelin was given once daily by intramuscular injection for 7 days. Pharmacokinetic parameters were estimated using a model-independent approach. The plasma concentrations of free triiodotyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) and the circadian rhythms of prolactin and cortisol were considered as indicator variables of endocrine response to posatirelin administration. Posatirelin was well tolerated and no significant adverse effects were observed during the study. Peak plasma concentration (Cmax), time of peak plasma concentration (tmax), area under the plasma concentration-time curve from time zero to infinity (AUC0-infinity), elimination half-life (t1/2), and total clearance (CI/F) were measured after single-dose intramuscular injection (day 1) and after multiple-dose administration (day 7). There were no significant changes in these parameters after multiple-dose administration (day 7). Posatirelin induced a progressive reduction in basal TSH levels and maximum response. There were no significant changes during treatment in the time at which basal levels of FT3 and FT4 occurred, and these levels remained within the normal range throughout the study. The circadian rhythms of cortisol and prolactin were not influenced by posatirelin treatment. The pharmacokinetics of posatirelin were not time dependent, and the drug did not accumulate after multiple-dose administration. Short-term treatment with posatirelin did not induce clinically relevant endocrine consequences in healthy elderly subjects.

Introduction: The usefulness of posatirelin (L-pyro-2-aminoadipyl-L-leucyl-L-prolinamide), a synthetic peptide having modulatory activity on the monoaminergic and cholinergic systems and neurotrophic effects, was evaluated in vascular dementia., Patients and Methods: A multicentre, parallel groups, double-blind clinical study vs placebo was carried out with patients suffering from probable vascular dementia according to the NINDS-AIREN criteria. The study consisted of a two-week run-in of a once daily, orally administered, placebo phase, followed by 12 weeks of intramuscular treatment with posatirelin 10 mg/ml or placebo given once a day and a follow-up after one month's withdrawal. Efficacy was assessed using the Gottfries-Bråne-Steen (GBS) Rating Scale for dementia, the Randt Memory Test and the Toulouse-Piéron Attention Test. Data were evaluated using analysis of variance and covariance., Results: As regards GBS scores, patients treated with posatirelin showed a significant improvement in intellectual performance, in orientation, motivation and memory as compared to controls. The improvement of memory performance was also confirmed by the acquisition score and memory index of the Randt Memory Test. At the end of the follow-up period the differences between treatments were still maintained. Tolerability was good., Conclusions: The significant improvement observed in cognitive functions, attention and motivation of demented patients treated with posatirelin suggests the potential usefulness of this drug in vascular dementia. Furthermore, the presence of a long-lasting effect after drug withdrawal suggests the possibility of administering the drug cyclically.

Cathepsin B activity and its regulation by interleukin 1 beta (IL-1 beta) and parathyroid hormone (PTH) was investigated in normal human osteoblast-like cells (hOB) and in the human osteoblastic osteosarcoma cell line MG-63. Cathepsin B activity was measured using a fluorescent synthetic substrate, 7-N-benzyloxycarbonyl-L-arginyl-L-arginylamide-4-methylcoumarin, and its specificity was checked with E-64, a specific inhibitor of cysteine proteinases and CA074, a specific inhibitor of the enzyme. Cathepsin B activity was detected in crude extracts of cell monolayers and in conditioned media. In both cell types, basal activity was detected essentially in cell extracts, since in media only approximately 1.2% (hOB) and approximately 6% (MG-63) of the total activity was released. IL-1 beta (1-100 U/ml) and PTH (10(-9) M-10(-6) M) significantly stimulated cathepsin B activity in cell extracts and in conditioned media. In both cell types, the increase in proteolytic activity appeared to require RNA and protein synthesis after adding IL-1 beta or PTH. Using the above substrate, we also evaluated some biochemical properties of the enzyme, and its pH-stability and pH-optimum. In both cell types, intracellular cathepsin B activity was not resistant to neutral or slightly alkaline pH, whereas extracellular cathepsin B activity was stable. This study provides evidence that osteoblast-like cells produce and secrete active cathepsin B. The production and secretion was stimulated by IL-1 beta and PTH. The physiological role of cathepsin B produced by osteoblasts and stimulated by the bone resorbing agents remains to be elucidated. Since extracellular activity is stable under relatively physiological conditions, it is possible that the extracellular as well as intracellular form of the enzyme may play a role in matrix turnover.

Since it has not been established to what extent abnormalities of hemostasis contribute to the occurrence and development of dementia, selected measurements of coagulation and fibrinolysis were obtained in elderly patients with Alzheimer's disease (n = 22) or vascular dementia (n = 29), compared with healthy individuals in the same age range (n = 61). Hemostasis abnormalities were more frequent and marked in vascular dementia, being expressed as significant increases of plasminogen activator inhibitor type 1, von Willebrand factor, D-dimer and activated factor VII. However, some hemostasis measurements (von Willebrand factor, activated factor VII) were abnormally high also in the patients with Alzheimer's disease, a condition in which vascular damage is not considered to play a major pathogenetic role. It could not be established in this study whether or not these hemostatic abnormalities play a casual role in the pathogenesis of dementia, or whether they are secondary to inflammation and chronic vascular disease. Nevertheless, their presence may contribute to aggravating vascular disease.

Objective: To better understand how to differentiate the "in vivo" normal aging brain from pathological conditions, namely dementia of the Alzheimer type (DAT), by means of magnetic resonance imaging (MRI), single photon emission computerized tomography (SPECT), and proton magnetic resonance spectroscopy (1H-MRS), to show neuroanatomical, perfusional and neurochemical details, respectively., Design: 1H-MRS, MRI-based hippocampal volumetry and 99mTc-HMPAO SPECT were performed in healthy older subjects as well as patients suffering from age-associated memory impairment (AAMI) and dementia of Alzheimer type (DAT)., Subjects and Setting: Eighteen subjects were selected from those referred to an outpatient clinic for diagnostic evaluation of cognitive impairment entered the study. Six patients fulfilled NINCDS-ADRDA diagnostic criteria for DAT, six subjects were affected by AAMI, and six cognitively healthy subjects, selected from among relatives of the patients, were defined as controls., Methods: The 1H-MRS and MRI studies were performed on a 1.5 Tesla NMR-imaging system equipped with a spectroscopy research package. SPECT scans were performed on a Gamma 11 computer system., Findings: 1H-MRS showed significantly lower N-acetylasparatate concentration in DAT and AAMI compared with controls. Conversely, mean inositol concentration was significantly higher in DAT than in controls, whereas AAMI subjects registered intermediate values. MRI measurements showed significantly reduced volumes of hippocampal formations in DAT and AAMI groups compared with controls. Finally, 99mTc-HMPAO SPECT showed a significant frontal, temporo-parietal, and occipital hypoperfusion in DAT patients only., Conclusions: These findings support the hypothesis of a continuum among the three conditions studied, or at least between AAMI and DAT, where AAMI seems to be an early, monosymptomatic stage of Alzheimer disease. Accepting this view, it would be questionable to maintain the term "age-associated memory impairment" as a discrete entity.

Methods of research and clinical practice have been developed in young subjects and are now inadequate to solve the health problems of the older population. This is also the case for pharmacological research, which has routinely excluded elderly people, although they are major consumers of drugs. Reasons contributing to this exclusion are greater susceptibility to drug effects, difficulties in recruitment and higher drop-out rates. The necessity to make a separate evaluation of drugs in the elderly has been clearly demonstrated by recent studies. In this regard, the Food and Drug Administration published a guideline concerning the study of drugs likely to be used in aged patients. Since preservation and improvement of quality of life and functional autonomy are often more appropriate goals than reduction of mortality, evaluation of therapeutic benefits requires suitable instruments. Questionnaires for the assessment of quality of life are available, but few of them have been designed specifically for older people.

Impaired energy metabolism is an early, predominant feature in Alzheimer's disease. In order to find out simple, reliable 'in vivo' markers for the clinical-biological typization of the disorder, we measured cerebrospinal fluid (CSF) glucose, lactate and pyruvate levels in patients suffering from dementia of Alzheimer type (DAT) and in healthy elderly controls. DAT group showed remarkably higher levels of pyruvate (P = 0.01), with no overlap with the values obtained in controls. CSF pyruvate levels were also significantly associated with the severity of dementia. Therefore, CSF pyruvate levels neatly separate DAT patients from controls, having also pathogenetic value.

In order to evaluate the prevalence of non-suppression after dexamethasone in psychogeriatrics and to further verify the reliability of the neurobiological information obtained, dexamethasone suppression test was carried out in a geriatric population composed of patients with dementia of Alzheimer type, vascular dementia, stroke and age and sex-matched controls. Basal cortisol levels did not differ among groups and was positively correlated to age. Prevalence of non-suppression, defined according to Carroll's criterion was high in the pathological groups studied, and relatively high in controls, showing no diagnostic value. Unlikely suppressors, the time course of mean plasma corticol levels of non-suppressors was highly heterogeneous in each group considered, especially in the pathological groups. More restrictive criteria for the definition of non-suppressors are proposed, in order to increase the specificity of the test when applied to psychogeriatrics.

Levels of alpha 1-antichymotrypsin (alpha 1-ACT) in cerebrospinal fluid (CSF) and serum from patients with probable Alzheimer disease (AD) of both early (e-AD) and late (l-AD) onset assessed by a competitive enzyme-linked immunosorbent assay were higher than those found in controls or in patients with vascular dementia (VD). A negative correlation between CSF levels of alpha 1-ACT and the stage of the disease was present in patients with both e-AD and l-AD. No difference in alpha 2-macroglobulin levels in CSF and serum from patients with e-AD, l-AD, VD, and nondemented controls was found. Serum concentrations of alpha 1-antitrypsin from l-AD subjects were within the normal range. Thus, increased levels of alpha 1-ACT in CSF and serum were specifically associated with AD, and the detection of this serpin in CSF may be useful in monitoring the progression of the disease.

Distal radius photodensitometric and second metacarpal radiogrammetric measurements were obtained from computerized analyses of standard hand X-Ray films of 296 Caucasian subjects (189 women and 107 men). This sample included 134 subjects > or = 65 years old (75 women and 59 men). Distal radius bone density and metacarpal index showed a significant linear decrease with age in both sexes. Rates of bone loss, calculated from the regression curves, were -0.7% per year in women and -0.5% per year in men by distal radial photodensitometry, and -0.49% per year in women and -0.33% per year in men by metacarpal radiogrammetry. In the elderly subgroup, women > or = 65 years of age showed an even faster bone loss, with an annual decrease of -1.4% by distal radial photodensitometry. Conversely, men > or = 65 years of age had no significant bone loss, not even by metacarpal radiogrammetry. In conclusion, these data suggest that appendicular cortical bone loss occurs at a higher rate in elderly females than in the elderly males, both at the distal radial and at the metacarpal site.

Autoantibodies against glial fibrillary acidic protein (GFAP) and S100 protein were measured in sera of patients suffering from vascular dementia (VD), presenile Alzheimer's disease (AD), senile Alzheimer's disease (SDAT) and aged healthy controls by means of ELISA test. VD and SDAT showed the highest levels of both autoantibodies, AD the lowest. From these results a relationship between autoantibody titers and aging seems possible. Dosage of anti-GFAP and anti-S100 autoantibodies does not appear useful for diagnostic purpose because of the overlap observed among groups. Rather, the presence of these antibodies seems to reflect an alteration of the blood-brain barrier that promotes the access of central nervous system antigens to immunocompetent cells.

Levels of neuron-specific enolase (NSE), a glycolytic enzyme localized in neurons, were measured in serum and cerebrospinal fluid (CSF) of patients with early-onset (e-AD) and late-onset (l-AD) Alzheimer's disease, vascular dementia (VD) and controls. Mean CSF NSE levels in patients with Alzheimer's disease did not significantly differ from those in controls, although in the AD group a correlation was found between NSE levels and severity of cognitive deficits. In VD patients, CSF NSE was lower than in controls or in AD patients. These findings are of physiopathological interest but suggest that CSF NSE is not a useful biological marker in dementia disorders.

To test the hypothesis that the therapeutic effects of glycosaminoglycan polysulfate (GAP) in primary degenerative dementia of the Alzheimer type (PDD) is associated with a reversal of biochemical changes seen in PDD, a two-phase, clinical-biochemical study was conducted. In the first phase of this study a number of biochemical parameters were compared in 12 patients with PDD and their sex- and age-matched controls, and it was found that platelet monamine oxidase B activity was significantly higher and cerebrospinal fluid (CSF) homovanillic acid levels significantly lower in the PDD than in the normal control group. In the second phase of this study the same 12 PDD patients were treated with GAP at a daily dosage of 250 lipasemic-releasing units for a period of 1 month and it was found that all four biochemical parameters shifted towards normal values during therapy with the changes in CSF 5-hydroxy-indole acetic acid levels attaining statistical significance. Although clinical changes were minimal, in light of prior clinical findings in studies conducted with GAP in similar populations, the possibility was entertained that clinical improvement with GAP in PDD patients is preceded by biochemical changes.

Both low and high platelet MAO-B (pMAO-B) activity is considered an indicator of increased vulnerability in psychopathology. How the activity of this peripheral enzyme can be linked with the sophisticated functions of the central nervous system (CNS) is not clear; in man, evidence exists that the genetic mechanisms determining the size or capacity of the central serotonin system are common to platelet and brain MAO. In the present study pMAO-B activity was evaluated in demented patients suffering from early-onset Alzheimer's disease (AD), late-onset Alzheimer's disease (SDAT), vascular dementia (VD), and controls. In these dementia categories, the relationship between pMAO-B activity and clinical features, and between pMAO-B activity and cerebrospinal fluid (CSF) monoamine metabolites (3-methoxy-4-hydroxyphenyl-glycol, MHPG; 5-hydroxy-indoleacetic acid, 5-HIAA; homovanillic acid, HVA) was also investigated. pMAO-B activity was significantly higher in SDAT patients, compared to controls and AD. Age, as covariate, failed to show any significant effect, and no association was found between pMAO-B activity and CSF monoamine metabolites. The correlation analysis between pMAO-B and neuropsychological scores showed a highly significant positive relationship with GBS-emotional impairment (N = 40, r = 0.72, p < 0.01) in the SDAT group. This result suggests the importance of platelet MAO-B activity as biological marker also in old-age dementias, namely senile dementia of Alzheimer type, where the increased activity of this enzyme might constitute a marker for vulnerability toward behavioural disturbance, i.e., emotional deterioration.

Vascular dementia accounts for approximately 20% of all cases of dementia and for about 50% in subjects over 80 years. Thromboembolism with multiple cerebral infarcts was considered to be almost the only pathogenetic pathway of vascular dementia, with multi-infarct dementia as its clinical manifestation. However, there is a great heterogeneity of vascular dementia syndromes and pathological subtypes, as documented by the number of pathogenetic mechanisms now known to underlie the clinical picture. They include thromboembolism and extracerebral and cerebral factors. Among the extracerebral factors are ischemic hypoxic dementia (i.e., dementia due to hypoperfusion), vasculitis, hyperviscosity and abnormalities of hemostasis. Among the cerebral factors are lipohyalinosis, cerebral amyloid angiopathy, disruption of the blood-brain barrier and altered regulation of cerebral blood flow. Therefore, the approach to vascular dementia should take the heterogeneity into account. In this context, the importance of non-infarct type should be considered; subcortical white matter disorder seems to be a noteworthy common pathway of vascular dementia produced by various vascular mechanisms. Finally, the heterogeneity of the vascular mechanisms involved in vascular dementia--namely hypoperfusion--might be a factor that can be positively influenced by targeted therapeutic intervention.

The efficacy and tolerability of nimodipine, a calcium antagonist selective for the central nervous system, was evaluated in old age dementias in two multicenter, clinical trials. A total of 755 elderly patients suffering from mental deterioration of degenerative or vascular origin were enrolled in the studies. In the first study, 352 patients received nimodipine 30 mg TID orally for 3 months; in the second study, 403 patients received the same treatment for 6 months. In both studies, psychobehavioral instruments showed a highly significant improvement of the global functional state. In hypertensive patients, nimodipine had a synergistic effect with the antihypertensive drugs. These results confirm the therapeutic efficacy and safety of nimodipine in the treatment of old age dementias.

A multicentre, randomised, controlled study compared the efficacy of l-alpha-glyceryl-phosphorylcholine (alpha GPC) and ST200 (acetyl-l-carnitine) among 126 patients with probable senile dementia of Alzheimer's type (SDAT) of mild to moderate degree. Efficacy was evaluated by means of behavioural scales and psychometric tests. The results showed significant improvements in most neuropsychological parameters in the alpha GPC recipients. Improvements also occurred in the ST200 recipients but to a lesser extent. Tolerability was good in both groups. These positive findings require replication in larger, double-blind, longitudinal studies coupling clinical and biological determinations.