Brain Aging and Late-Onset Alzheimer's Disease: A Matter of Increased Amyloid or Reduced Energy?

Alzheimer's disease (AD) represents the most common form of dementia in old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved. The definition of AD has changed over the past years, offering an ever more detailed definition of pre-morbid and pre-clinical status, but without a similar strong emphasis on the role of aging as the main risk factor. In fact, while early-onset AD is a clear consequence of gene mutations, late-onset AD is more likely due to a gradual accumulation of age-related damages. The pathogenetic amyloid cascade hypothesis has been recently questioned due to multiple clinical failures. Furthermore, several studies reported that cognitively normal elderly have a high amyloid deposition in the brain comparable to the levels observed in old age subjects with AD. This suggests that amyloid accumulation enters into the normal process of aging and what really triggers neuronal death and clinical manifestation in late-onset AD still needs further explanation. In this context, 'normal brain aging' and AD might represent a different pathway of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes affecting the brain may be considered as biologic manifestations of increasing entropy. Bioenergetic deficits due to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. So, increased amyloid in the brain of old age subjects may represent the downstream event expression of a biological system that is cooling down because of its exhaustion and not the core causative factor of late-onset dementia.

Hypertension and cognitive function in the elderly.

Alzheimer's disease is the most prevalent and common form of cognitive impairment, ie, dementia, in the elderly followed in second place by vascular dementia due to the microangiopathy associated with poorly-controlled hypertension. Besides blood pressure elevation, advancing age is the strongest risk factor for dementia. Deterioration of intellectual function and cognitive skills that leads to the elderly patient becoming more and more dependent in his, her, activities of daily living, ie, bathing, dressing, feeding self, locomotion, and personal hygiene. It has been known and demonstrated for many years that lowering of blood pressure from a previous hypertensive point can result in stroke prevention yet lowering of blood pressure does not prevent the microangiopathy that leads to white matter demyelinization which when combined with the clinical cognitive deterioration is compatible with a diagnosis of vascular dementia. It is known from many large studies, ie, SHEP, SCOPE, and HOPE, that lowering of blood pressure gradually will not and should not worsen the cognitive impairment. However, if the pressure is uncontrolled a stroke which might consequently occur would further worsen their cognitive derangement. So an attempt at slow reduction of blood pressure since cerebral autoregulation is slower as age increases is in the patient's best interest. It is also important to stress that control of blood glucose can also be seen as an attempt to prevent vascular dementia from uncontrolled hyperglycemia. Vascular dementia is not considered one of the reversible causes of dementia. Reversible causes of cognitive impairment are over medication with centrally acting drugs such as sedatives, hypnotics, antidepressants, and antipsychotics, electrolyte imbalance such as hyponatremia, azotemia, chronic liver disease, and poor controlled chronic congestive heart failure. Criteria for the clinical diagnosis of vascular dementia include cognitive decline in regards to preceding functionally higher level characterized by alterations in memory and in two or more superior cortical functions that include orientation, attention, verbal linguistic capacities, visual spacial skills, calculation, executive functioning, motor control, abstraction and judgment. Patients with disturbances of consciousness, delirium (acute confusional states), psychosis, serious aphasia, or sensory-motor alterations that preclude proper execution of neuro-psychological testing are also considered to have probably vascular dementia. Furthermore, these are ten of the other essential cerebral or systematic pathologies present that would be able to produce a dementia syndrome.

Uric acid and dementia in community-dwelling older persons.

BACKGROUND: The biological action of uric acid (UA) in humans is controversial. UA is considered an antioxidant compound, but preclinical evidence suggests a proinflammatory action. Epidemiological studies found that hyperuricemia is associated with conditions leading to dementia. Our aim is to investigate the relationship between UA levels and dementia in older persons. METHODS: Cross-sectional study performed in 1,016 community-dwelling older persons participating in the InCHIANTI study. Participants underwent determination of circulating UA levels and neuropsychological evaluation. A multivariate logistic regression model was used to estimate the probability of participants belonging to the highest and middle UA tertile to be affected by dementia compared to those in the lowest tertile. RESULTS: Demented persons had higher UA levels (p = 0.001) and the prevalence of persons affected by dementia increased across UA tertiles (p < 0.0001). Independent of several confounders, persons belonging to the highest UA tertile had a threefold (OR = 3.32; 95% CI: 1.06-10.42) higher probability to suffer from a dementia syndrome while those in the middle UA tertile tended to have a higher probability of being demented compared to those in the lowest tertile. CONCLUSION: In a population-based sample, high circulating UA levels are associated with an increased likelihood to be affected by a dementia syndrome.

Improving the diagnostic accuracy of depression in older persons: the Depression in the Aged Female National Evaluation cluster randomized trial.

OBJECTIVES: To evaluate whether a training intervention can improve the ability of geriatricians to recognize depression in older persons. DESIGN: Multicenter, cluster randomized clinical trial. SETTING: Fourteen geriatric outpatient clinics in Italy, each representing the unit of randomization. PARTICIPANTS: After training, a total of 1,914 outpatients aged 65 years and older in both arms, not on antidepressant at entry, were blindly evaluated by the clinic geriatrician, in charge of routine clinical management, and by a field researcher, who formally diagnosed depression by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), taken as the criterion standard. INTERVENTION: After randomization, geriatricians belonging to the intervention arm were assigned to receive a residential 3-day educational program on depression. Those in the control arm received a generic course on disease management in elderly people. MEASUREMENTS: Sensitivity and specificity of the diagnosis of depression made by geriatricians, compared with the DSM-IV diagnosis. RESULTS: Sensitivity and specificity were significantly higher in trained than in untrained geriatricians (49 vs 35% and 91 vs 88%, respectively; P=.002 in marginal regression models). Effectiveness of training was confirmed, adjusting for age, sex, and cognitive performance (P=.02). CONCLUSION: The ability of geriatricians to diagnose depression in older outpatients can be improved with a specific training intervention. Improvement of diagnostic performance might translate into more-appropriate clinical management.

High basal metabolic rate is a risk factor for mortality: the Baltimore Longitudinal Study of Aging.

BACKGROUND: Despite longstanding controversies from animal studies on the relationship between basal metabolic rate (BMR) and longevity, whether BMR is a risk factor for mortality has never been tested in humans. We evaluate the longitudinal changes in BMR and the relationship between BMR and mortality in the Baltimore Longitudinal Study of Aging (BLSA) participants. METHODS: BMR and medical information were collected at the study entry and approximately every 2 years in 1227 participants (972 men) over a 40-year follow-up. BMR, expressed as kcal/m(2)/h, was estimated from the basal O(2) consumption and CO(2) production measured by open-circuit method. Data on all-cause and specific-cause mortality were also obtained. RESULT: BMR declined with age at a rate that accelerated at older ages. Independent of age, participants who died had a higher BMR compared to those who survived. BMR was a significant risk factor for mortality independent of secular trends in mortality and other well-recognized risk factors for mortality, such as age, body mass index, smoking, white blood cell count, and diabetes. BMR was nonlinearly associated with mortality. The lowest mortality rate was found in the BMR range 31.3-33.9 kcal/m(2)/h. Participants with BMR in the range 33.9-36.4 kcal/m(2)/h and above the threshold of 36.4 kcal/m(2)/h experienced 28% (hazard ratio: 1.28; 95% confidence interval, 1.02-1.61) and 53% (hazard ratio: 1.53; 95% confidence interval, 1.19-1.96) higher mortality risk compared to participants with BMR 31.3-33.9 kcal/m(2)/h. CONCLUSION: We confirm previous findings of an age-related decline of BMR. In our study, a blunted age-related decline in BMR was associated with higher mortality, suggesting that such condition reflects poor health status.

Hypertension and cognitive function in the elderly.

Alzheimer's disease is the most prevalent and common form of cognitive impairment, ie, dementia, in the elderly followed in second place by vascular dementia due to the microangiopathy associated with poorly-controlled hypertension. Besides blood pressure elevation, advancing age is the strongest risk factor for dementia. Deterioration of intellectual function and cognitive skills that leads to the elderly patient becoming more and more dependent in his, her, activities of daily living, ie, bathing, dressing, feeding self, locomotion, and personal hygiene. It has been known and demonstrated for many years that lowering of blood pressure from a previous hypertensive point can result in stroke prevention yet lowering of blood pressure does not prevent the microangiopathy that leads to white matter demyelinization which when combined with the clinical cognitive deterioration is compatible with a diagnosis of vascular dementia. It is known from many large studies, ie, SHEP, SCOPE, and HOPE, that lowering of blood pressure gradually will not and should not worsen the cognitive impairment. However, if the pressure is uncontrolled a stroke which might consequently occur would further worsen their cognitive derangement. So an attempt at slow reduction of blood pressure since cerebral autoregulation is slower as age increases is in the patient's best interest. It is also important to stress that control of blood glucose can also be seen as an attempt to prevent vascular dementia from uncontrolled hyperglycemia. Vascular dementia is not considered one of the reversible causes of dementia. Reversible causes of cognitive impairment are over medication with centrally acting drugs such as sedatives, hypnotics, antidepressants, and antipsychotics, electrolyte imbalance such as hyponatremia, azotemia, chronic liver disease, and poor controlled chronic congestive heart failure. Criteria for the clinical diagnosis of vascular dementia include cognitive decline in regards to preceding functionally higher level characterized by alterations in memory and in two or more superior cortical functions that include orientation, attention, verbal linguistic capacities, visual spacial skills, calculation, executive functioning, motor control, abstraction and judgment. Patients with disturbances of consciousness, delirium (acute confusional states), psychosis, serious aphasia, or sensory-motor alterations that preclude proper execution of neuro-psychological testing are also considered to have probably vascular dementia. Furthermore, these are ten of the other essential cerebral or systematic pathologies present that would be able to produce a dementia syndrome.

The interplay between uric acid and antioxidants in relation to physical function in older persons.

OBJECTIVES: To investigate the relationship between circulating uric acid (UA) levels and plasma antioxidants and whether antioxidant levels modulate the association between UA and physical function. DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: Nine hundred sixty-six elderly persons participating in the baseline assessment of the Invecchiare in Chianti Study. MEASUREMENTS: UA, carotenoid, tocopherol, and selenium concentrations were assayed. Physical function was measured using the Short Physical Performance Battery (SPPB) and difficulties in instrumental activities of daily living (IADLs). Potential confounders were assessed using standardized methods. RESULTS: Total carotenoids (P=.008), in particular alpha-carotene (P=.02), lutein (P<.001), zeaxanthin (P<.001), lycopene (P=.07), cryptoxanthin (P=.29), and selenium (P=.04) were inversely associated with UA levels. Total tocopherols (P=.06) and alpha-tocopherol (P=.10) had a positive trend across UA levels. SPPB (P=.01) and IADL disability (P=.002) were nonlinearly distributed across the UA quintiles. Participants within the middle UA quintile (4.8-5.3 mg/dL) were less disabled in IADLs and had better SPPB scores than those in the extreme UA quintiles. There was a significant interaction between UA and selenium in the model predicting SPPB score (P=.02). CONCLUSION: UA levels are inversely associated with circulating carotenoids and selenium. Participants with intermediate UA levels had a higher prevalence of good physical functions, higher SPPB scores, and lower IADL disability. This study suggests that older subjects with intermediate UA levels may have an optimum balance between proinflammatory and antioxidant compounds that may contribute to better physical performance.

Usefulness of uric acid to predict changes in C-reactive protein and interleukin-6 in 3-year period in Italians aged 21 to 98 years.

The role of uric acid (UA) in the process of atherothrombosis is controversial. Although serum UA has powerful antioxidant properties, epidemiological studies showed that UA was a risk factor for cardiovascular diseases and was positively associated with proinflammatory markers. Relations between baseline UA and changes in UA circulating levels with C-reactive protein (CRP) and interleukin-6 (IL-6) after 3 years of follow-up in a cohort of 892 Italian men and women aged 21 to 98 years was investigated. Subjects had complete baseline and follow-up data for UA, inflammatory markers, and covariates. An autoregressive approach was used to study such a relation. In adjusted analyses, baseline UA and changes in UA predicted a 3-year change in CRP (p = 0.028), but not IL-6 (p = 0.101). The relation between UA and CRP persisted after adjustment for baseline IL-6. Subjects with high UA at baseline had a progressively higher probability of developing clinically relevant increased IL-6 (>2.5 pg/ml) and CRP (>3 mg/L) during 3 years. In conclusion, our study suggests that in a population-based cohort, baseline UA and changes in circulating UA during 3 years of follow-up predict changes in circulating CRP independent of relevant confounders, including baseline IL-6.

White blood cell count and mortality in the Baltimore Longitudinal Study of Aging.

OBJECTIVES: We investigated the secular trend in white blood cell (WBC) count and the relationship between WBC count and mortality between 1958 and 2002. BACKGROUND: The WBC count is a clinical marker of inflammation and a strong predictor of mortality. Limited data exist on the WBC count secular trend and the relationship between WBC and mortality. METHODS: One thousand eighty-three women and 1,720 men were evaluated longitudinally in the Baltimore Longitudinal Study of Aging. Blood samples and medical information were collected at the study entry and every 2 years during follow-up visits. The WBC count and all-cause, cardiovascular, and cancer mortality were assessed. RESULTS: A downward trend in WBC count was observed from 1958 to 2002. The secular downward trend was independent of age, gender, race, smoking, body mass index, and physical activity. The WBC count was nonlinearly associated with all-cause mortality and almost linearly associated with cardiovascular mortality. Participants with baseline WBC <3,500 cells/mm3 and WBC >6,000 cells/mm3 had higher mortality than those with 3,500 to 6,000 WBC/mm3. Within each WBC group, age-adjusted mortality rates declined in successive cohorts from the 1960s to the 1990s. Participants who died had higher WBC than those who survived, and the difference was statistically significant within 5 years before death. CONCLUSIONS: Our study provides evidence for a secular downward trend in WBC count over the period from 1958 to 2002. Higher WBC counts are associated with higher mortality in successive cohorts. We found no evidence that the decline of age-specific mortality rates that occurred from 1960 to 2000 was attributable to a secular downward trend in WBC.

Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease.

The proteins cathepsin D, encoded by CTSD gene, and alpha2-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of beta-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C-->T and A2M-Ile/Val A-->G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI)=1.01-3.72], and 2.07 (95% CI=1.01-4.21) after adjustment for age, sex and APOE epsilon4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI=1.13-6.34) [2.82 (95% CI=1.12-7.17) after adjustment], and to 3.29 (95% CI=1.33-8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk.

Uric acid and inflammatory markers.

AIMS: The role of uric acid (UA) in the process of atherosclerosis and atherotrombosis is controversial. Epidemiological studies have recently shown that UA may be a risk factor for cardiovascular diseases and a negative prognostic marker for mortality in subjects with pre-existing heart failure. METHODS AND RESULTS: We evaluate a relationship between UA levels and several inflammatory markers in 957 subjects, free of severe renal failure, from a representative Italian cohort of persons aged 65-95. Plasma levels of UA and white blood cell (WBC) and neutrophil count, C-reactive protein, interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6r), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-alpha) were measured. Complete information on potential confounders was collected using standard methods. WBC (P=0.0001), neutrophils (P<0.0001), C-reactive protein (P<0.0001), IL-1ra (P<0.0001), IL-6 (P=0.0004), sIL-6r (P=0.002), IL-18 (P<0.0001), TNF-alpha (P=0.0008), and the percentage of subjects with abnormally high levels of C-reactive protein (P=0.004) and IL-6 (P=<0.0001) were significantly higher across UA quintiles. After adjustment for age, sex, behaviour- and disease-related confounders, results were virtually unchanged. In subjects with UA within the normal range, UA was significantly and independently associated with neutrophils count, C-reactive protein, IL-6, IL-1ra, IL-18, and TNF-alpha, whereas non-significant trends were observed for WBC (P=0.1) and sIL-6r (P=0.2). CONCLUSION: A positive and significant association between UA and several inflammatory markers was found in a large population-based sample of older persons and in a sub-sample of participants with normal UA. Accordingly, the prevalence of abnormally high levels of C-reactive protein and IL-6 increased significantly across UA quintiles.

Conversion of MCI to dementia: Role of proton magnetic resonance spectroscopy.

Mild cognitive impairment (MCI) represents a heterogeneous group of cognitive disturbances at high risk of dementia. The amnestic subtype (aMCI) might be a prodromal state of Alzheimer's disease (AD). The aim of this study is the identification, by proton magnetic resonance spectroscopy (1H MRS), of modifications in brain metabolites able to detect subjects with aMCI at risk of conversion towards AD. Twenty-five subjects with aMCI and 29 normal elderly were enrolled; they underwent a comprehensive clinical and instrumental assessment, a cerebral 1H MRS scan to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI) and creatine (Cr) in the paratrigonal white matter, bilaterally. After 1 year, 5 MCI subjects became demented (progressive MCI, pMCI). Their baseline levels of metabolites were compared with those evaluated in stable MCI (sMCI) and in controls. We observed a significant difference of the NAA/Cr ratio between pMCI (1.48+/-0.08) and sMCI (1.65+/-0.12) and between pMCI and controls (1.63+/-0.16) in the left hemisphere, suggesting that this metabolic alteration can be detected before the clinical appearance of dementia.

Markers of inflammation, vitamin E and peripheral nervous system function: the InCHIANTI study.

BACKGROUND: Aging of the peripheral nervous system is associated with several morphologic and functional changes, including a decrease of the nerve conduction velocity. There is evidence that these changes contribute to age-related-decline in muscle strength, sensory discrimination, and autonomic responses. The aim of this study was to characterize the decline in nerve conduction velocity in the peripheral nervous system over the aging process and to identify factors that, independent of age, affect nerve conduction velocity. METHODS: We measured motor nerve conduction velocity of the right superficial peroneal nerve using a standard neurophysiologic technique in a population-based sample of subjects aged between 20 and 103 years old enrolled in the InCHIANTI study. RESULTS: Average conduction velocities in the peripheral nerve decreased linearly with age in both sexes. We found that diabetes, cognitive impairment, uric acid, sIL-6R and alpha-tocopherol were significant predictors of nerve conduction velocity independently of the potential confounding effect of age, sex, sex x age interaction term, height, lymphocytes, neutrophils number, alpha1 and alpha2-globulin serum protein. CONCLUSIONS: Our findings are consistent with the hypothesis that inflammation and inadequate antioxidant defenses are associated with accelerated decline of nerve conduction velocity over the aging process.

Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers.

AIMS: Persons with high intake of polyunsaturated fatty acids (PUFAs) have lower cardiovascular morbidity and mortality. The protective effect of PUFAs is mediated by multiple mechanisms, including their antiinflammatory properties. The association of physiological PUFA levels with pro- and antiinflammatory markers has not been established. METHODS AND RESULTS: In 1123 persons (aged 20-98 yr), we examined the relationship between relative concentration of fatty acids in fasting plasma and level of inflammatory markers. Adjusting for age, sex, and major confounders, lower arachidonic and docosahexaenoic acids were associated with significantly higher IL-6 and IL-1ra and significantly lower TGFbeta. Lower alpha-linolenic acid was associated with higher C-reactive protein and IL-1ra, and lower eicosapentaenoic acid was associated with higher IL-6 and lower TGFbeta. Lower docosahexaenoic acid was strongly associated with lower IL-10. Total n-3 fatty acids were associated with lower IL-6 (P = 0.005), IL-1ra (P = 0.004), and TNFalpha (P = 0.040) and higher soluble IL-6r (P < 0.001), IL-10 (P = 0.024), and TGFbeta (P = 0.0012). Lower n-6 fatty acid levels were significantly associated with higher IL-1ra (P = 0.026) and lower TGFbeta (P = 0.014). The n-6 to n-3 ratio was a strong, negative correlate of IL-10. Findings were similar in participants free of cardiovascular diseases and after excluding lipids from covariates. CONCLUSIONS: In this community-based sample, PUFAs, and especially total n-3 fatty acids, were independently associated with lower levels of proinflammatory markers (IL-6, IL-1ra, TNFalpha, C-reactive protein) and higher levels of antiinflammatory markers (soluble IL-6r, IL-10, TGFbeta) independent of confounders. Our findings support the notion that n-3 fatty acids may be beneficial in patients affected by diseases characterized by active inflammation.

Cognitive impairment is the major risk factor for development of geriatric syndromes during hospitalization: results from the GIFA study.

OBJECTIVE: To detect the main factors associated with the occurrence of specific geriatric syndromes (namely pressure sores, fecal incontinence, urinary incontinence and falls) in elderly patients during hospitalization. DESIGN: Observational prospective study. SETTING: Eighty-one community and university hospitals throughout Italy. PARTICIPANTS: 13,729 patients aged 65 years and more, consecutively admitted to medical or geriatric acute wards during 20 months in the period between 1991 and 1998. MEASUREMENTS: Occurrence of pressure sores, fecal incontinence, urinary incontinence and falls during the stay in hospital. RESULTS: Pressure sores were already present in 3% of hospitalized subjects, fecal incontinence in 7.3%, while urinary incontinence, evaluated on a subgroup of total population (4,268 subjects), had a prevalence of 22.3%. During hospitalization (mean stay of 15 days), 74 subjects developed new pressure sores, 55 became fecal and 35 urinary incontinent, and 279 subjects had at least one episode of fall. In multivariate analyses, cognitive impairment, advanced age (85+ years), length of stay (more than 3 weeks) and severe disability were the main independent predictors of development of the four geriatric syndromes, with cognitive impairment as the most significant risk factor for all the four outcomes (OR 4.9, 95% CI 2.4-9.9 for pressure sores; OR 6.3, 95% CI 3.0-13.0 for fecal incontinence; OR 5.3, 95% CI 2.3-12.0 for urinary incontinence; OR 1.6, 95% CI 1.2-2.3 for falls). CONCLUSION: Very old people have a significant increased risk of several geriatric syndromes during the stay in hospital, particularly if it is long and they are cognitively impaired. A standardized comprehensive geriatric evaluation at admission could be helpful in detecting all subjects at risk and preventing the development of hospital-acquired geriatric syndromes.

Treatment with angiotensin-converting enzyme inhibitors is associated with a reduction in short-term mortality in older patients with acute ischemic stroke.

BACKGROUND: Stroke is the third cause of death in older people living in Western countries. We tested the hypothesis that angiotensin-converting enzyme inhibitors (A-I) might affect short-term (30 day) mortality in older persons with severe acute ischemic stroke. METHODS: We analyzed data from a retrospective study including 475 consecutive older patients hospitalized for acute ischemic stroke. Mean age was 78.4 +/- 9.2 years; 58.2% were female. Stroke type was classified according to the Oxford Community Stroke Project (OCSP). RESULTS: Mortality rate was 28%. Thirty-two percent of patients were treated with A-I; mortality was 16.5% in patients treated compared with 33.3% in those not treated (chi(2) p =.001). The odds ratio for mortality in treated patients was: 0.47 (0.25-0.89) after full adjustment (age, sex, mean diastolic and systolic blood pressure, previous stroke and/or transient ischemic attack, congestive heart failure, atrial fibrillation, diabetes, hypertension, coronary heart disease, and previous treatment with A-I); 0.29 (0.09-0.89) in patients with altered level of consciousness after full adjustment; 0.60 (0.33-1.12) after adjustment for OCSP classification, age, and sex; and 0.30 (0.08-0.97) in total anterior circulation infarction stroke type after full adjustment. CONCLUSIONS: Our data suggest that treatment with A-I might reduce short-term mortality in older patients with acute ischemic stroke. Randomized clinical trials should confirm this possible specific effect of A-I.

The Caregiver Burden Inventory in evaluating the burden of caregivers of elderly demented patients: results from a multicenter study.

BACKGROUND AND AIMS: The burden perceived by caregivers of patients with dementia is a fundamental prognostic aspect in the history of the disease. The aim of this study was to demonstrate the internal consistency of the Caregiver Burden Inventory (CBI), a scale used to quantify burdens in different aspects of a caregiver's life, and the influence of patients' and caregivers' characteristics on its different dimensions. METHODS: In this cross-sectional study, 419 demented patients and their caregivers were evaluated in 16 geriatric centers in Italy. Cognitive status and behavioral disturbances were assessed by the Mini Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI), respectively. Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) were also evaluated. Comorbidity was assessed by the Cumulative Illness Rating Scale (CIRS). The severity of dementia was evaluated by the Clinical Dementia Rating (CDR) score. Caregiver distress due to the behavioral problems of the patient was assessed by the Neuropsychiatric Inventory-Distress, a subscale of the NPI which evaluates stress caused by each behavioral disturbance of the patient, and by the Brief Symptom Inventory which evaluates anxiety and depression. Burden was evaluated by the CBI. RESULTS: The CBI showed very high internal consistency (Cronbach's alpha value > 0.80). Factor analysis showed that the items clustered into four dimensions, and not five as originally proposed. Multiple regression analysis revealed that patients' behavioral disturbances and disability were the major predictors of the time-dependent burden; the psychophysical burden was explained mainly by caregiver anxiety and depression. CONCLUSIONS: The CBI proved to be an effective multidimensional tool for evaluating the impact of burden on many aspects of caregivers' lives.

Vitamin E levels, cognitive impairment and dementia in older persons: the InCHIANTI study.

There is conflicting evidence that antioxidants contribute to maintaining cognitive function in elderly subjects. We investigated whether vitamin E plasma levels are related to the presence of dementia and cognitive impairment in a population-based cohort study conducted in Italy. A total of 1033 participants aged at least 65 years received clinical and neuropsychological examinations, donated blood for vitamin E analysis and had their diets assessed. Participants with plasma vitamin E levels in the bottom tertile had a significantly higher probability of being demented (OR 2.6, 95% CI 1.0-7.1) and also of suffering from cognitive impairment (OR 2.2, 95% CI 1.2-4.2) compared to those in the highest vitamin E tertile after adjustment for age, gender, education, lipid levels, energy intake, vitamin E intake, and smoking. This study supports the notion that higher vitamin E plasma levels might provide significant protection against cognitive impairment and dementia in elderly subjects.

Effects of vitamin C and aspirin in ischemic stroke-related lipid peroxidation: results of the AVASAS (Aspirin Versus Ascorbic acid plus Aspirin in Stroke) Study.

A condition of oxidative stress is known to occur in ischemic stroke, the current therapeutic intervention of which is largely limited to thrombolysis. To assess the effect of vitamin C - in conjunction to aspirin - in ischemic stroke-related lipid peroxidation, we measured plasma levels of ascorbate, of 8,12-isoprostanes F2alpha-VI (8,12-iPF2alpha-VI) and activities and levels of a broad spectrum of antioxidant enzymes and micronutrients in stroke patients randomized to receive, from stroke onset and up to three months, either vitamin C (200 mg/day) plus aspirin (300 mg/day) or only aspirin (300 mg/day). By the end of the first week, patients treated with vitamin C plus aspirin had higher vitamin C levels (p = 0.02) and lower 8,12-iPF2alpha-VI levels (p = 0.01) than patients treated with aspirin alone. The significance was maintained for the increase of vitamin C after three months of therapy (p < 0.01). The clinical functional outcome for both groups of patients similarly ameliorated after three months of treatment. We conclude that vitamin C, at the dose of 200 mg/day and in conjunction with aspirin, significantly decreases ischemic stroke-related lipid peroxidation in humans. Further studies are warranted to clarify whether the use of vitamin C may add clinical long-term beneficial effects in patients with stroke.