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Synaptosomal-associated protein of 25 kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer's disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD, we analyzed five gene polymorphisms in patients with AD (n = 607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI) (n = 148) and in two groups of age-matched healthy controls (HC1: n = 615 and HC2: n = 310). Results showed that the intronic rs363050 (A) and rs363043 (T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo-parietal (angular gyrus) area. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD.

AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria.We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intraspecies diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch-specific selection at the catarrhini lineage for IFI16. Application of a population genetics-phylogenetics approach also allowed identification of positive selection events in the human lineage. Positive selection in primates targeted sites located at the DNA-binding interface in both IFI16andAIM2. InIFI16, several sites positively selected inprimates andin thehumanlineagewere located in the PYDdomain,which is involved in protein-protein interaction and is bound by a human cytomegalovirus immune evasion protein. Finally, positive selection was found to target nuclear localization signals in IFI16 and the spacer region separating the two HIN domains. Population genetic analysis in humans revealed that an IFI16 genic region has been a target of long-standing balancing selection, possibly acting on two nonsynonymous polymorphisms located in the spacer region. Data herein indicate that ALRs have been repeatedly targeted by natural selection. The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy. We propose that the underlying scenario is the result of an ancestral and still ongoing host- pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.

IFI16 encodes a nucleic acid-sensor which detects latent EBV and triggers inflammasome activation. We analysed IFI16 variants in two multiple sclerosis (MS) case-control cohorts from Italy and Spain; results were combined with a previous study. A risk variant for celiac disease/rheumatoid arthritis, a polymorphic exon 7 duplication, and a copy number variant (CNV) in the 5' region were genotyped. No significant association was detected, although heterogeneity was noted for the 5' CNV in the Italian plus GeneMSA cohorts and the Spanish sample. Thus, IFI16 variants do not contribute to MS susceptibility, although some heterogeneity may exist for the 5' CNV.

The effect of statins on functional status in older patients is unclear. Statins might carry a deleterious effect on muscle function leading to myopathy and therefore affecting functional recovery. We evaluated the relationship between statin exposure at in-hospital rehabilitation admission and functional outcome at discharge. This was a retrospective cohort study of older patients 70 years and older consecutively admitted to an in-hospital rehabilitation after an acute hospitalization. Statin exposure was measured at the time of rehabilitation admission. Functional status was defined with the Barthel Index score at the time of discharge. A multivariable linear regression model was used to evaluate the association between statin exposure and functional status at discharge adjusting for potential confounders through a propensity score for statin exposure. A total of 2,435 patients were included. The cohort had a mean age of 81.1 years. Of these 9% (N=220) were on statins at the time of admission. In the multivariable analysis, the use of statins at the time of admission was independently associated with an improved functional status at discharge (Point Estimate 5.2; 95% Confidence Interval: 1.5-8.9; p<0.01) after adjusting for relevant confounders; patients who were receiving statins at the time of admission had a Barthel Index score 5 points higher compared to those who were not receiving statins. The use of statins was overall safe in a group of comorbid older patients undergoing rehabilitation training after an acute hospitalization. Additionally, a possible benefit was found given the positive association between statin use and higher functional status at discharge

Objective: to evaluate the performance of the 4 'A's Test (4AT) in screening for delirium in older patients. The 4AT is a new test for rapid screening of delirium in routine clinical practice. Design: prospective study of consecutively admitted elderly patients with independent 4AT and reference standard assessments. Setting: an acute geriatrics ward and a department of rehabilitation. Participants: two hundred and thirty-six patients (aged ≥70 years) consecutively admitted over a period of 4 months. Measurements: in each centre, the 4AT was administered by a geriatrician to eligible patients within 24 h of admission. Reference standard delirium diagnosis (DSM-IV-TR criteria) was obtained within 30 min by a different geriatrician who was blind to the 4AT score. The presence of dementia was assessed using the Alzheimer's Questionnaire and the informant section of the Clinical Dementia Rating scale. The main outcome measure was the accuracy of the 4AT in diagnosing delirium. Results: patients were 83.9 ± 6.1 years old, and the majority were women (64%). Delirium was detected in 12.3% (n =29), dementia in 31.2% (n = 74) and a combination of both in 7.2% (n = 17). The 4AT had a sensitivity of 89.7% and specificity84.1% for delirium. The areas under the receiver operating characteristic curves for delirium diagnosis were 0.93 in the whole population, 0.92 in patients without dementia and 0.89 in patients with dementia. Conclusions: the 4AT is a sensitive and specific method of screening for delirium in hospitalised older people. Its brevity and simplicity support its use in routine clinical practice.

Objective: Delirium superimposed on dementia (DSD) is common in many settings. Nonetheless, little is known about the association between DSD and clinical outcomes. The study aim was to evaluate the association between DSD and related adverse outcomes at discharge from rehabilitation and at 1-year follow-up in older inpatients undergoing rehabilitation. Design: Prospective cohort study. Setting: Hospital rehabilitation unit. Participants: A total of 2642 patients aged 65 years or older admitted between January 2002 and December 2006. Measurements: Dementia predating rehabilitation admission was detected by DSM-III-R criteria. Delirium was diagnosed with the DSM-IV-TR. The primary outcome was that of walking dependence (Barthel Index mobility subitem score of <15) captured as a trajectory from discharge to 1-year follow-up. A mixed-effects multivariate logistic regression model was used to analyze the association between DSD and outcome, after adjusting for relevant covariates. Secondary outcomes were institutionalization and mortality at 1-year follow-up, and logistic regression models were used to analyze these associations. Results: The median age was 77 years (interquartile range: 71-83). The prevalence of DSD was 8%, and the prevalence of delirium and dementia alone were 4% and 22%, respectively. DSD at admission was found to be significantly associated with almost a 15-fold increase in the odds of walking dependence (odds ratio [OR] 15.5; 95% Confidence Interval [CI] 5.6-42.7; P < .01). DSD was also significantly associated with a fivefold increase in the risk of institutionalization (OR 5.0; 95% CI 2.8-8.9; P < .01) and an almost twofold increase in the risk of mortality (OR 1.8; 95% CI 1.1-2.8; P = .01). Conclusions: DSD is a strong predictor of functional dependence, institutionalization, and mortality in older patients admitted to a rehabilitation setting, suggesting that strategies to detect DSD routinely in practice should be developed and DSD sh

ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [(3)H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.

Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

Objectives Rehospitalizations for elderly patients are an increasing health care burden. Nonetheless, we have limited information on unplanned rehospitalizations and the related risk factors in elderly patients admitted to in-hospital rehabilitation facilities after an acute hospitalization. Setting In-hospital rehabilitation and aged care unit. Design Retrospective cohort study. Participants Elderly patients 65 years or older admitted to an in-hospital rehabilitation hospital after an acute hospitalization between January 2004 and June 2011. Measurements The rate of 30-day unplanned rehospitalization to hospitals was recorded. Risk factors for unplanned rehospitalization were evaluated at rehabilitation admission: age, comorbidity, serum albumin, number of drugs, decline in functional status, delirium, Mini Mental State Examination score, and length of stay in the acute hospital. A multivariable Cox proportional regression model was used to identify the effect of these risk factors for time to event within the 30-day follow-up. Results Among 2735 patients, with a median age of 80 years (interquartile range 74–85), 98 (4%) were rehospitalized within 30 days. Independent predictors of 30-day unplanned rehospitalization were the use of 7 or more drugs (hazard ratio [HR], 3.94; 95% confidence interval, 1.62–9.54; P = .002) and a significant decline in functional status (56 points or more at the Barthel Index) compared with the month before hospital admission (HR 2.67, 95% CI: 1.35–5.27; P = .005). Additionally, a length of stay in the acute hospital of 13 days or more carried a twofold higher risk of rehospitalization (HR 2.67, 95% CI: 1.39–5.10); P = .003). Conclusions The rate of unplanned rehospitalization was low in this study. Polypharmacy, a significant worsening of functional status compared with the month before acute hospital admission, and hospital length of stay are important risk factors.

A score for identifying post-hip-fracture surgery patients at various levels (high, medium, and low) of risk for unsuccessful recovery of pre-fracture walking ability was developed. Three hundred ninety-eight HF patients were enrolled in the study. The score significantly and independently predicted failure to walk independently at discharge, failure to walk independently after 12 months, and death after 12 months. The score may be useful for clinicians and healthcare administrators to target populations for rehabilitative programs. INTRODUCTION: To develop a model predicting at the time that elderly hip-fracture (HF) patients undergo rehabilitation if they will have recovered walking independence at discharge. METHODS: Data from all patients admitted to a Department of Rehabilitation in Italy between January 2001 and June 2008 after HF surgery were used. Variables concerning cognitive, clinical, functional, and social parameters were evaluated. Predominant measures were identified through correspondence analysis, and a variable score was defined. Three risk classes (minimum, moderate, and high) were identified and univariate and multivariate logistic regressions were used to assess the model's predictivity and risk classes for the various outcomes. RESULTS: Three hundred ninety-eight HF patients were enrolled. The variables selected to construct the score were age, gender, body mass index, number of drugs being taken, the Mini Mental State Examination, the Instrumental Activity of Daily Living, and the pre-fracture Barthel index. According to univariate analysis, the score was not better than the pre-fracture Barthel's index, but, according to multivariate analysis, it was an independent predictor for all the outcomes, while the pre-fracture Barthel index predicted only outcomes at discharge. In particular, the score significantly predicted failure to walk independently at discharge, failure to walk independently after 12 months, and death after 12 months. CONCLUSI

Early diagnosis of infections is often a challenge in older patients, since this age group may have atypical presentation. We report here the cases of 3 old patients, in whom a sudden decline in mobility status occurred shortly before the onset of the classically recognized features of infection. The decline was interpreted as an anticipatory marker of imminent infection. We discuss the possible implications of our findings and the opportunity that they offer to improve routine clinical practice in older patients

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2, 3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5, 6, 7, 8, 9, 10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Background: In HIV-infected individuals, mechanisms underlying unsatisfactory immune recovery during effective combination antiretroviral therapy (cART) have yet to be fully understood. We investigated whether polymorphism of genes encoding immune-regulating molecules, such as killer immunoglobulin-like receptors (KIR) and their ligands class I human leukocyte antigen (HLA), could influence immunological response to cART. Methods: KIR and HLA frequencies were analyzed in 154 HIV-infected and cART-treated patients with undetectable viral load divided into two groups: 'immunological non responders' (INR, N = 50, CD4 + T-cell count <200/mm 3) and full responders (FR, N = 104, CD4 + T-cell count >350/mm 3). Molecular KIR were typed using polymerase chain reaction-based genotyping. Comparisons were adjusted for baseline patient characteristics. Results: The frequency of KIR2DL3 allele was significantly higher in FR than in INR (83.7% vs. 62%, P = 0.005). The functional compound genotype HLA-C1 +/KIR2DL3 +, even at multivariable analysis, when adjusted for nadir CD4 + T-cell count, was associated with reduced risk of INR status: odds ratio (95% Confidence Intervals) 0.34 (0.13-0.88), P = 0.03. Conclusions: Reduced presence of the inhibitory KIR2DL3 genotype detected in INR might provoke an imbalance in NK function, possibly leading to increased immune activation, impaired killing of latently infected cells, and higher proviral burden. These factors would hinder full immune recovery during therapy. © 2011 Soria et al.

The activation of natural killer (NK) cells is modulated by surface molecules. We analyzed NK cells in human immunodeficiency virus (HIV)-exposed seronegative (HESN) individuals by means of molecular typing of HLA B, Cw, and killer cell immunoglobulin-like receptor (KIR) molecules. In HESN individuals, compared with HIV patients, the frequency of the inhibitory KIR3DL1 allele and of the KIR3DL1+/Bw4+ inhibitory complex was reduced, whereas that of the activatory KIR3DS1+ ligand and the activatory Bw4+/3DL1-/3DS1+ complex was increased, resulting in a statistically significant diversion from Hardy-Weinberg equilibrium (KIR3DS1 homozygote) in HESN individuals. The reciprocal equilibrium between inhibitory and activatory NK receptors and their ligands favors NK activation in HESN individuals. © The Author 2011.

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Objectives: To assess the impact of clinical instability (CI) and delirium on admission to a rehabilitation unit on clinical and functional outcomes (death, transfer to acute care, poor functional recovery) at discharge, in a population of elderly patients. Design: Observational study. Setting: Rehabilitation and Aged Care Unit (RACU). Participants: Participants were 583 consecutively and firstly admitted elderly patients. Measurements: On admission, all patients underwent a comprehensive geriatric assessment including sociodemographics, cognitive and depressive symptoms, nutritional status, physical health, and functional status. CI was recorded for all patients on admission, assessing 5 vital signs (temperature, heart rate, systolic blood pressure, respiratory rate, and oxygen saturation). Delirium was assessed daily with the Confusion Assessment Method. Results: Patients were on average old (mean age: 77.8 ± 9.8), predominantly female (68.6%), with mild cognitive deterioration (MMSE: 22.1 ± 6.3) and depressive symptoms (GDS: 5.9 ± 3.5). They had moderate comorbidity (means CIRS: 3.1 ± 1.9), and functional impairment both before (Barthel Index pre-admission: 84.5 ± 19.2; IADL: 3.3 ± 3.0) and on admission (Barthel Index: 55.8 ± 27.5). On admission, 136 (23.3%) patients were classified as clinically unstable: 76 (13%) had either CI or delirium, and 60 (10.3%) had CI associated to delirium. At discharge, 26 patients were transferred to acute care hospitals, and 14 died. Transfer to acute care occurred in more than 10% of patients with almost one altered condition (CI or delirium), and in one fifth of patients with the association of CI and delirium. In-RACU death was observed only in this latter group. Functional recovery at discharge was significantly higher in stable patients than in patients with CI and/or delirium. Conclusions: CI and delirium are useful prognostic markers of adverse clinical and functional outcomes in a population of elderly subjects admitted to

The objective of the present prospective observational study is to evaluate the effect of depressive symptoms on 1-year mortality in a population of elderly patients discharged from a rehabilitation unit after orthopaedic surgery of the lower limbs. A total of 222 elderly inpatients were included, and stratified according to 12-months survival. 14 (6.3%) of the patients who were eligible for this study died during the 12-months period after discharge. As expected, patients who died were significantly older, lower cognitive performance, more depressive symptoms, poorer nutritional status and higher comorbidity in comparison to those who survived. Furthermore, they were generally more functionally dependent on admission to the Department, had worse functional recovery and were more disable at discharge, although a longer length of stay comparing to survived patients. In the adjusted logistic regression model, after adjustment for possible confounders and covariates, the presence of severe depressive symptoms significantly predicted a four-fold risk of death at 12 months. The only other factor associated poor 12-months survival was comorbidity, that predicted a 6-fold risk of death. In conclusions this study suggests that severe depressive symptoms on admission predicts 1-year mortality in elderly patients discharged from a post-acute care unit after orthopaedic rehabilitation.

Background: Postmarketing surveillance studies (PMS) are an important tool for evaluating a drugs effectiveness and safety in clinical practice. To our knowledge, no PMS on memantine monotherapy for moderately-severe-to-severe Alzheimers disease (AD) according to National Institute of Neurological and Communicative Disorders and Stroke Alzheimers Disease and Related Disorders Association criteria has been conducted to date. Objective: The Lombardy Health Office, Italy, promoted this PMS to evaluate the effectiveness and safety of memantine in the treatment of moderately-severe-to-severe AD in clinical practice. Methods: A total of 451 patients with moderately-severe-to-severe AD (meanage 77 7 years; 72% female), free of cholinergic medication, received memantine (standard titration to 10 mg twice daily). After 6 months of therapy, treatment effectiveness was evaluated according to two definitions of response (no deterioration and improvement), as measured by changes in baseline scores on the Clinical Global Impression of Change, Mini-Mental State Examination, Neuropsychiatric Inventory and Activities of Daily Living scales. The safety measure was the frequency of adverse events (AEs). Results: At 6-month assessment, 26.8% of subjects showed no deterioration and 3.8% showed improvement. In those showing no deterioration, response to treatment at the 3-month assessment was associated with a greater probability of a response at 6 months (adjusted odds ratio = 8.54; 95% CI 4.54, 16.05). Seventy patients (15.5%) experienced at least one AE and 39 (8.6%) discontinued treatment prematurely because of an AE. Of those who experienced an AE, 27 (38.6%) manifested behavioural and psychological symptoms of dementia. Conclusion: The proportion of responders to memantine treatment in this PMS was similar to that reported in a previous randomized clinical trial (26.8% vs 29%, respectively). The proportion of patients who discontinued treatment prematurely because of an AE (8.6%) w

Objective: To test whether subcortical vascular lesions are associated with falls in elderly patients with gait disorder discharged from a rehabilitation ward. Design: Secondary 12-month follow-up analysis of an observational survey focusing on the prevalence of subcortical vascular lesions in a population of elderly patients discharged from rehabilitation hospitals. Setting: A rehabilitation and aged care unit. Participants: Consecutively admitted elderly patients (N=214) with gait disorder. Interventions: Not applicable. Main Outcome Measures: On admission, all patients underwent comprehensive geriatric assessment including sociodemographics, cognitive and depressive symptoms, nutritional status, physical health, and functional status. Subcortical vascular lesions were assessed on computed tomography films with a validated rating scale. All patients received a standardized rehabilitative program. Twelve months after discharge, all patients were interviewed by telephone, mainly focusing on the occurrence of falls during the follow-up period. Potential predictors of falls were assessed in univariate and multivariate analyses. Results: Univariate predictors of falls were age, sex, Mini-Mental State Examination, Barthel Index on admission, and subcortical vascular lesions. In multivariate analyses, subcortical vascular lesions were the only significant predictor of risk of falling; patients with moderate and severe subcortical vascular lesions scores had a greater risk of falling (odds ratio [OR]=3.0; 95% confidence interval [CI], 1.3-7.1; P=.012; OR=3.9; 95% CI, 1.6-9.2; P=.002, respectively) than those with no subcortical vascular lesions. Conclusions: Subcortical vascular lesions are associated with falls at 12 months in elderly patients with gait disorder discharged from a rehabilitative ward. Future research is needed to confirm our results. © 2008 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

This study aimed to assess whether subcortical vascular lesions (SVLs) predict functional recovery after rehabilitation in elderly patients with gait disorders (GD) due to multiple etiology (GD-ME). All patients consecutively admitted with GD-ME (n=103) in our Rehabilitation and Aged Care Unit (RACU) underwent a standardized rehabilitative program. The outcome measure was the Barthel Index (BI) Relative Functional Gain (RFG), a measure of improvement adjusting for baseline functional level. Potential predictors included cognition, depression, functional and nutritional status, physical health, occurrence of adverse clinical events during hospital stay, and SVLs, assessed with a validated visual rating scale based on brain CT scans. Predictors were divided into quartiles and the association with RFG was assessed. In a multivariate linear regression model, SVLs maintained its predictive power on RFG after adjustment for age, gender, and adverse clinical events, which was the only variable associated to RFG in the bivariate model (adjusted p=0.002 for trend). The study shows that SVLs is a predictor of functional recovery in elderly patients with GD-ME.

Objective: Data about the relationship of blunted reduction of night-time blood pressure (BP) with cognitive deterioration (CD) are conflicting. This study aims to explore this possible association in elderly people with long-standing hypertension. Methods: Twenty-six hypertensive subjects consecutively admitted to a rehabilitation unit over a six-month period were recruited. Exclusion criteria concerned all clinical conditions potentially related to BP variability or leading to CD. All patients underwent a clinic and 24-h BP non-invasive monitoring assessment of BP, as well as a cognitive assessment with the Mini Mental State Examination (MMSE). The presence of cerebrovascular disease (CVD) was assessed on CT films, with a standardized visual rating scale. Results: Blunted reduction of both systolic and diastolic night-time BP were significantly associated with poorer cognitive performances (r = 0.61, p = 0.001 for systolic; and r = 0.57, p = 0.002 for diastolic, respectively). In a multiple regression model, blunted reduction of night-time BP (B = 0.17, [95% confidence intervals: 1.1-1.3], p = 0.008 for systolic; and B = 0.15, [95% confidence intervals: 1.0-1.3], p = 0.02 for diastolic) independently predicted poorer cognitive performances. Conclusions: In subjects with long-standing hypertension the blunted reduction of night-time BP is independently associated with lower cognitive performances

Oxidative stress, linked to Abeta-lipid interactions, plays a pathogenetic role in Alzheimer's disease. We investigated modifications of lipid peroxidation products in plasma of 52 AD patients, 42 healthy controls and 16 patients with amyotrophic lateral sclerosis, a neurodegenerative disease where oxidative stress also plays a pathogenetic role. Final lipid peroxidation products were measured in plasma by thiobarbituric acid reactive substances (TBARS) assay before and after ex vivo oxidative stress catalysed by copper. There were no significant changes at basal conditions, but after copper-induced oxidation TBARS levels were higher in AD patients (19.0 microM +/- 2.2) versus both controls (5.2 microM +/- 0.8, p<0.001) and ALS patients (7.6 microM +/- 2.1, p<0.01). Stimulated TBARS levels were significantly higher in mild and moderate AD (p<0.0001) with respect to controls, but not in severe AD patients, with a significant inverse correlation between disease severity and lipid peroxidation (p<0.005, r2=0.21). Treatment of a subgroup (13) of mild and moderate AD patients with vitamin C and E for three months decreased plasma lipoperoxidation susceptibility by 60%. Thus, oxidative stress, expressed as ex vivo susceptibility to lipid peroxidation, appears to be an early phenomenon, probably related to AD pathogenetic mechanisms.