Familial late-onset Alzheimer's disease: description of an Italian family with four affected siblings and one case of early-onset dementia in the preceding generation.

We describe a family composed of six siblings, four of which affected by late-onset Alzheimer's disease (LOAD). We constructed the family pedigree, evaluated mutations usually associated with early-onset Alzheimer's disease (APP, PSEN1, PSEN2), and assessed polymorphisms in the apolipoprotein E (APOE) gene and in cytokine genes that we had previously found to be associated with a higher risk of LOAD (IL-10, IL-6, TNF-α). Results showed that all subjects carried one ε4 allele of the APOE gene and those with the earliest age of onset exhibited the AA (-1082) IL-10 and the CC (-174) IL-6 genotypes. The only male had a genetic profile which also included the A (-308) TNF-α allele. These data confirm the role of the APOE gene as genetic risk factor in LOAD, and suggest that the risk of developing AD may be governed by a "susceptibility profile" involving polymorphisms in inflammatory genes.

Electrocardiographic monitoring for new prescriptions of quetiapine co-prescribed with acetylcholinesterase inhibitors or memantine from 2005 to 2009. A population study on community-dwelling older people in Italy.

PURPOSE: The aims of this study are to analyse, in community-dwelling people aged 65+ living in Italy's Lombardy Region, electrocardiographic (ECG) monitoring for new users of the atypical antipsychotic quetiapine co-prescribed with acetylcholinesterase inhibitors (AChEIs) or memantine and to find independent predictors of ECG monitoring before and after the starting of this prescription. METHODS: The Lombardy Region's administrative health database was used to retrieve prescriptions of ECG exams as well as prevalence rates of subjects aged 65+ who were prescribed such psychotropic drugs from 2005 to 2009. Multivariable analyses were adjusted for age, sex, number of drugs, treatment with beta-blockers, digoxin, verapamil or diltiazem, any antiarrhythmic drug and antidepressants. RESULTS: Overall 2,623 community-dwelling older people started therapy with quetiapine, co-prescribed with AChEIs or memantine, during these 5 years. At least one ECG was performed in 714 cases (27.2 %) in the 6 months before-and in 398 cases (15.2 %) within 3 months after-the starting of this prescription. ECG monitoring was performed both before and after starting quetiapine in only 160 cases (6.1 %). At multivariable analyses, number of drugs taken, beta-blocker and antiarrhythmic drug use were found to be independent correlates of ECG monitoring whereas female sex was associated with a lower probability of receiving an ECG within 3 months after the initiation of quetiapine (odds ratio 0.78, 95 % CI 0.62-0.98). CONCLUSIONS: ECG monitoring for new prescriptions of quetiapine in older people suffering from behavioural and psychological symptoms in dementia was actually performed infrequently, independently of the age of drug users, especially in women. Our results support the need for greater awareness within the medical community of the importance of such ECG monitoring.

New prescriptions of spironolactone associated with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor blockers and their laboratory monitoring from 2001 to 2008: a population study on older people living in the community in Italy.

PURPOSE: To analyse, in older community-dwelling people living in Italy's Lombardy region, 8-year trends in new users of spironolactone co-prescribed with angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs); blood test monitoring; and independent predictors of appropriate blood test monitoring. METHODS: The region's administrative health database from 2001 to 2008 was used to retrieve yearly frequencies of subjects aged 65+ who started this co-prescription. Multivariate analyses were adjusted for age, sex, local health unit, treatment with beta-blockers, drugs for diabetes, and polypharmacy (i.e., exposure to five or more different drugs). RESULTS: Only new users of spironolactone co-prescribed with ARBs increased from 2001 to 2008 (P < 0.001). In the 6 months before starting the co-prescriptions 96 to 100% of patients measured serum creatinine (mean 99.3%), sodium (97.3%) and potassium (98.6%). Within 3 months of starting the co-prescriptions 96 to 99% of patients measured serum sodium (mean 97.3%) and potassium (98.6%), but on average only 48% of them (range 43 to 53%) measured serum creatinine, with an increase over time (odds ratio [change in regression per year] = 1.03, 95% CI 1.02-1.05, P < 0.001). At multivariate analysis polypharmacy was found to be the only independent predictor of such creatinine monitoring (P < 0.001). CONCLUSIONS: Our results support the need for greater awareness within the medical community of the potential renal toxicity of the association of spironolactone with ACE-Is and/or ARBs. Adequate short-term monitoring of serum creatinine in all older community-dwelling people who receive such co-prescription is necessary in order to ensure safe usage of these medications.

Delusion of inanimate doubles: description of a case of focal retrograde amnesia.

This paper reports the case of a patient, M.P., who developed delusion of inanimate doubles, without Capgras syndrome, after traumatic brain injury. His delusional symptoms were studied longitudinally and the cognitive impairments associated with delusion were investigated. Data suggest that M.P. did 'perceive' the actual differences between doubles and originals rather than 'confabulate' them. The cognitive profile, characterized by retrograde episodic amnesia, but neither object processing impairment nor confabulations, supports this hypothesis. The study examines the nature of object misidentification based on Ellis' and Staton's account and proposes a new account based on concurrent unbiased retrieval of semantic memory traces and biased recollection of episodic memory traces.

Frailty syndrome diagnosed according to the Study of Osteoporotic Fractures criteria and mortality in older outpatients suffering from Alzheimer's disease: a one-year prospective cohort study.

OBJECTIVE: The frailty syndrome is associated with adverse clinical outcomes independently of cognitive impairment. The recent easy-to-apply Study of Osteoporotic Fractures (SOF) criteria for frailty could be useful to diagnose such syndrome also in Alzheimer's disease (AD) patients. The aim of this study was to apply these criteria among AD outpatients in order to determine: (i) the prevalence and correlates of frailty and (ii) the one-year predictors of death in this population. METHOD: This prospective cohort study enrolled 109 community-dwelling outpatients aged 65+ (median age 84 years) consecutively diagnosed with AD at a geriatric outpatient service in Italy in 2009. At baseline, participants underwent a comprehensive geriatric assessment including the evaluation of frailty status by means of the SOF criteria. Multiple logistic regression analysis was performed to find correlates of frailty. At a one-year follow-up, data on mortality were available for 95 participants and predictors of death were evaluated by means of multiple logistic regression analysis. RESULTS: Most participants had mild (52%) or moderate (29%) dementia. Frailty status was defined for all subjects at baseline: 25 (22%) were robust, 30 (28%) pre-frail and 54 (50%) frail. Independent correlates of frailty were age and dependence in the basic activities of daily living, and in particular in dressing. One year after enrolment, frailty was an independent predictor of death (odds ratio 11.27, 95% confidence interval 1.64-77.72, p = 0.014) after correction for age, sex, dependence in the basic activities of daily living, severity of cognitive impairment and comorbidity. CONCLUSION: Frailty status was diagnosed according to the SOF criteria in all AD outpatients and it was an independent one-year predictor of death. In order to provide them with appropriate prognostic evaluation and therapeutic advice all AD outpatients, especially those with specific disabilities, could be screened by means of the SOF criteria for frailty.

Older People's Quality of Life (OPQOL) scores and adverse health outcomes at a one-year follow-up. A prospective cohort study on older outpatients living in the community in Italy.

BACKGROUND: There is limited knowledge on the ability of a poor quality of life (QOL) and health-related QOL (HRQOL) to predict mortality and other adverse health events, independently of the frailty syndrome and other confounders, in older people living in the community and not selected on the basis of specific chronic conditions. Aim of this study was to evaluate the ability of the overall QOL and of the HRQOL to predict several adverse health outcomes at a one-year follow-up in an older outpatient population living in the community. METHODS: We carried out a prospective cohort study on 210 community-dwelling outpatients aged 65+ (mean age 81.2 yrs) consecutively referred to a geriatric clinic in Milan, Italy. At baseline participants underwent a comprehensive geriatric assessment including evaluation of overall QOL and HRQOL by means of the Older People's Quality of Life (OPQOL) questionnaire. At a one-year follow-up, between June and December 2010, we investigated nursing home placement and death in all 210 participants as well as any fall, any admission to the emergency department (ED), any hospitalisation and greater functional dependence among the subset of subjects still living at home. RESULTS: One year after the visit 187 subjects were still living at home (89%) while 7 had been placed in a nursing home (3.3%) and 16 had died (7.7%). At multiple logistic regression analyses the lowest score-based quartile of the OPQOL total score at baseline was independently associated with a greater risk of any fall and any ED admission. Also, the lowest score-based quartile of the health-related OPQOL sub-score was associated with a greater risk of any fall as well as of nursing home placement (odds ratio [OR] 10.03, 95% confidence interval [CI] 1.25-80.54, P = 0.030) and death (OR 4.23, 95% CI 1.06-16.81, P = 0.041). The correlation with the latter two health outcomes was found after correction for age, sex, education, income, living conditions, comorbidity, disability and the frailty syndrome. CONCLUSIONS: In an older outpatient population in Italy the OPQOL total score and its health-related sub-score were independent predictors of several adverse health outcomes at one year. Notably, poor HRQOL predicted both nursing home placement and death even after correction for the frailty syndrome. These findings support and enhance the prognostic relevance of QOL measures.

An easy intervention to improve short-term adherence to medications in community-dwelling older outpatients. A pilot non-randomised controlled trial.

BACKGROUND: Complex interventions to improve compliance to pharmacological treatment in older people have given mixed results and are not easily applicable in clinical practice. The aim of this study was to test the short-term efficacy on self-reported medication adherence of an easy intervention in which the patient or caregiver was asked to transcribe the pharmacological treatment while it was dictated to him/her by the doctor. METHODS: Pilot non-randomised controlled trial involving 108 community-dwelling outpatients aged 65+ (54 in the intervention arm, 54 controls) referred to a geriatric service from May to July 2009 and prescribed by the geriatrician a change in therapy. The intervention was applied at the end of the visit to the person managing the medications, be it the elder or his/her caregiver. Outcome of the study was the occurrence of any adherence error, assessed at a one-month follow-up by means of a semi-structured interview. RESULTS: The socio-demographic, functional and clinical characteristics of the two compared groups were similar at baseline. At a one-month follow-up 43 subjects (40%) had made at least one adherence error, whether unintentional or intentional. In the intervention group the prevalence of adherence errors was lower than in controls (20% vs 59%; adjusted odds ratio 0.16, 95% confidence interval 0.07 - 0.39; p < 0.001) after adjusting for the person managing the medications, the adherence errors at baseline and for the number of prescribed drugs. CONCLUSIONS: In an older outpatient population the intervention considered was effective in reducing the prevalence of adherence errors in the month following the visit. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000347965.

The MCP-1 gene (SCYA2) and mood disorders: preliminary results of a case-control association study.

The aim of this case-control study was to investigate the potential role of the A-2518G polymorphism of the gene of monocyte chemoattractant protein 1 (MCP-1, a cytokine playing an important role in innate immunity) in conferring susceptibility to mood disorders. The sample studied included 96 outpatients with DSM-IV-TR diagnosis of major depressive disorder, bipolar disorder I (BD I) or BD II and 161 matched healthy controls. All subjects were genotyped for the A-2518G polymorphism of the MCP-1 gene. Genotypic and allelic associations were explored between patients and controls and across the different diagnostic groups (chi(2) tests). No genotypic (chi(2) = 8.215, d.f. = 6, p = 0.223) or allelic (chi(2) = 5.058, d.f. = 3, p = 0.168) association for the A-2518G polymorphism of SCYA2 was found considering cases and controls. Nevertheless, important correlations were observed when patients were divided into diagnostic subgroups. A significantly higher frequency of the AA genotype (chi(2) = 7.233, d.f. = 2, p = 0.027) and of the A allele (chi(2) = 4.730, d.f. = 1, p = 0.030) was observed in subjects with BD. In addition, independently from diagnosis, a higher number of lifetime suicide attempts was found in subjects with the AA genotype of the A-2518G polymorphism of the MCP-1 gene (F = 3.802, p = 0.026). The present preliminary results, though limited by the relatively small sample, suggest a possible role of the SCYA2 in conferring susceptibility to BD and, if confirmed, may represent a biological discriminative influence between mood disorder subtypes.

Dimensions and correlates of quality of life according to frailty status: a cross-sectional study on community-dwelling older adults referred to an outpatient geriatric service in Italy.

BACKGROUND: There is a lack of knowledge concerning the relationship between two closely-linked multidimensional variables: frailty and quality of life (QOL). The aim of this study was to investigate dimensions and correlates of QOL associated with frailty status among community-dwelling older outpatients. METHODS: We conducted a cross-sectional survey of 239 community-dwelling outpatients aged 65+ (mean age 81.5 years) consecutively referred to a geriatric medicine clinic in Italy between June and November 2009. Participants underwent a comprehensive geriatric assessment, including assessment of their frailty status according to the Study of Osteoporotic Fractures (SOF) criteria, and QOL, which was evaluated by using the Older People's QOL (OPQOL) questionnaire. One-way ANOVA and chi-squared tests were used to find correlates of frailty, including QOL dimensions, after stratification of participants in the "robust" (n = 72), "pre-frail" (n = 89) and "frail" (n = 78) groups. Multiple linear regression analyses were performed to find correlates of QOL in the overall sample and among "frail" and "robust" participants. RESULTS: A negative trend of QOL with frailty status was found for almost all dimensions of QOL (health, independence, home and neighbourhood, psychological and emotional well-being, and leisure, activities and religion) except for social relationships and participation and financial circumstances. Independent correlates of a poor QOL in the total sample were "reduced energy level" (SOF criterion for frailty), depressive status, dependence in transferring and bathing abilities and money management (adjusted R squared 0.39); among "frail" participants the associations were with depressive status and younger age, and among "robust" participants the association was with lower body mass index. CONCLUSIONS: Five out of seven dimensions of QOL were negatively affected by frailty, but only one SOF criterion for frailty was independently related to QOL, after correction for age, functional status and depression. A more advanced age as well as a better affective status were correlates of a better QOL among frail elders. Interventions targeting the QOL in frail community-dwelling older outpatients should consider as outcomes, not only health-related QOL, but also other domains of the QOL.

The -308 (G/A) single nucleotide polymorphism in the TNF-alpha gene and the risk of major depression in the elderly.

OBJECTIVE: The immune system (IS) plays a key role in the mechanisms underlying major depression (MD) and pro-inflammatory cytokines seem to be particularly involved in the pathogenesis of the disease. There is growing evidence of a relationship between commonly studied single nucleotide polymorphisms (SNPs) in cytokine genes and an increased risk of MD.The aim of our study was to investigate the association between the -308(G/A) SNP in the tumour necrosis factor-alpha (TNF-alpha) gene and late-life MD in elderly people without dementia. METHODS: Blood samples were obtained from 50 subjects enrolled at the Geriatric Department of the San Gerardo Hospital in Monza, Italy, after screening with the geriatric depression scale (GDS > or = 15) and mini-mental state evaluation (MMSE > or = 24). The -308 (G/A) SNP was genotyped by SSP-PCR amplification. Two hundred and forty age-matched healthy volunteers were taken as the control group. RESULTS: Genotype and allele distributions in patients with MD were significantly different from those of the controls. In subjects affected by MD we found a higher percentage of the GG genotype (84 vs. 68,3%; p = 0.007) and thus of the G allele (92 vs. 81,9%; p = 0.05).The GG genotype was associated with a greater risk of developing the disease (OR 2.433, CI 1.09-5.43). CONCLUSIONS: Our study suggests that the -308 (G/A) polymorphism in the TNF-alpha gene could play a role in determining susceptibility to MD. An activation of the TNF-alpha system could contribute to the development of MD in the elderly.

Caregiver burden as a short-term predictor of weight loss in older outpatients suffering from mild to moderate Alzheimer's disease: a three months follow-up study.

OBJECTIVE: To determine if caregiver burden (CB) can be an independent predictive factor of weight loss at three months in older outpatients suffering from mild to moderate Alzheimer's disease (AD) and living at home. METHOD: Prospective cohort study involving 105 subjects aged 70 years or more, affected by mild to moderate AD and living at home with the assistance of at least one informal caregiver, who consecutively underwent a multidimensional geriatric assessment. Body weight was re-evaluated at a three month follow-up, from December 2008 to April 2009. Those who experienced a weight loss greater than 3% of the baseline weight constituted the 'weight loss' group. RESULTS: Out of the 97 older participants attending follow-up, 22 (23%) had experienced a weight loss > 3%. At a multivariate logistic regression analysis, a greater CB at baseline, defined by a score of the caregiver burden inventory scale in the highest tertile (i.e. 36+ out of 96), turned out to predict weight loss at three months (odds ratio (OR) 13.93, 95% confidence interval (CI) 1.91-101.33, p = 0.009), independently of other factors associated with the 'weight loss' group such as age, functional dependence and the risk of malnutrition estimated by means of the Mini Nutritional Assessment Short Form (MNA-SF). CONCLUSION: For older outpatients affected by mild to moderate AD and living at home, CB constitutes a risk factor for weight loss even in the short-term, independently of other factors such as the risk of malnutrition assessed by means of the MNA-SF.

Social vulnerability, mental health and correlates of frailty in older outpatients living alone in the community in Italy.

OBJECTIVE: To determine the main social, functional and clinical characteristics of community-dwelling older outpatients living alone and to find correlates of frailty in this population. METHOD: Cross-sectional survey of 302 community-dwelling outpatients aged 65+ (median age 82 years) consecutively referred to a geriatric medicine clinic in Italy from June to November 2009. Participants underwent a comprehensive geriatric assessment including frailty status evaluated by means of the study of osteoporotic fractures (SOF) criteria. Student's t-test and the chi-squared test were used to compare subjects 'living alone' and 'not living alone' as well as 'frail' and 'not frail' subjects among the participants living alone. Multiple logistic regression analyses were performed to find independent correlates of frailty among participants living alone. RESULTS: Participants 'living alone' were 124 (41%). Compared to subjects 'not living alone' (n = 178), they were older, received less assistance from informal and formal caregivers, had poorer living and financial conditions, a better cognitive status and functional self-sufficiency but a worse emotional status. One-third of them (n = 41) were frail. Among frail elders (n = 116), subjects living alone also showed a higher prevalence of unexpected new diagnoses of dementia than those not living alone. Independent correlates of frailty among participants living alone were: having experienced a severe acute disease in the past year (odds ratio [OR] 303.9; 95% confidence interval [CI] 13-7091; p < 0.001), dependence in the bathing BADL ability (OR 62.74; 95% CI 12.17-323.32; p < 0.001), depression (OR 10.43; 95% CI 2.31-47.13; p = 0.002) and incontinence (OR 3.98; 95% CI 1.01-15.66; p = 0.048). CONCLUSION: In older outpatients living alone, including those who were frail, we found a lower availability of personal assistance, significantly more social and financial vulnerability and a higher risk of depression. In frail elders there was also a higher prevalence of underdiagnosed dementia. In order to better recognise frail subjects in this specific population, four independent correlates of frailty were identified.

[Dislipidemia and lipid lowering drugs: from guidelines to clinical practice. An updated review of the literature.] / Dislipidemia e terapia ipolipemizzante: dalle linee guida alla pratica clinicaUna rassegna aggiornata della letteratura.

The atherosclerotic cardiovascular disease (ASCVD) represents the leading cause of death and disability not only in countries with a high degree of socio-economic development but also in low- middle-income countries. The study of atherosclerosis and the strategies to control ASCVD are evolving. All strategies emphasize the need to lower LDL cholesterol through an appropriate lifestyle and the use of lipid-lowering drugs. A therapy with statin with or without other lipid lowering drugs is recommended in secondary prevention. In primary prevention, the use of the lipid-lowering drug should instead take into account the cost-benefit ratio. Available evidence coming from clinical trials is useful to inform clinical choices but must be associated with a shared decision-making process between doctor and patient.

Cytokine polymorphisms in the pathophysiology of mood disorders.

INTRODUCTION: An increasing amount of data suggests that dysregulation of the immune system, including the cytokine network, is associated with the etiology and pathophysiology of mood disorders. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. The aim of this study was to define the genetic immunologic scenario associated with major depressive disorder (MDD) and bipolar disorder. METHODS: Eighty-four Italian outpatients affected by bipolar disorder type I, bipolar disorder type II, or MDD, and 363 healthy controls were enrolled into the study. We analyzed allele and genotype distribution of -308 (G/A) tumor necrosis factor-a (TNF-a), +874 (T/A) interferon-g (IFN-g), -174 (G/C) interleukin (IL)-6, and -1082 (G/A) IL-10 promoter polymorphisms by Polymerase Chain Reaction Sequence Specific Primers technique. RESULTS: We observed different genotype and allele distributions of TNF-a, IFN-g, and IL-10 polymorphisms in the three groups of patients analyzed. In particular, bipolar II patients were characterized by an absence of adenine (A) high producer allele of TNF-a (P<.001) and a lower percentage of TT high producer genotype of IFN-g (P<.001); bipolar I individuals showed reduced percentage of AA low producer genotype of IL-10 (P<.001). Both bipolar I and bipolar II patients not carrying guanine (G) high producer IL-6 allele showed a lower mean age at onset (P=.048). CONCLUSION: These data support the existence of a genetic profile related to pro-inflammatory cytokines in patients affected by mood disorders. The differences observed across the three clinical phenotypes suggest the presence of different pathogenetic mechanisms involved in the susceptibility of phenotypically different mood disorders.

Alzheimer's disease: another target for heparin therapy.

Alzheimer's disease (AD) is the leading cause of dementia and cognitive decline in the elderly. Brain tissue changes indicate that the two main proteins involved in AD are amyloid-beta (A-beta), which is associated with the formation of senile amyloid plaques, and tau, which is associated with the formation of neurofibrillary tangles. Although a central role for A-beta in the pathogenesis of AD is indisputable, considerable evidence indicates that A-beta production is not the sole culprit in AD pathology. AD is also accompanied by an inflammatory response that contributes to irreversible changes in neuronal viability and brain function, and accumulating evidence supports the pivotal role of complement and contact systems in its pathogenesis and progression. The complexity of AD pathology provides numerous potential targets for therapeutic interventions. Compounds that interact directly with A-beta protein or interfere with its production and/or aggregation can reduce the inflammatory and neurotoxic effects of A-beta, and heparin, a glycosaminoglycan mixture currently used in the prophylaxis and treatment of thrombosis, might be a candidate, as recent research has been extended to consider its nonanticoagulant properties, including its modulation of various proteases and anti-inflammatory activity.

Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer's disease and frontotemporal lobar degeneration.

Cerebrospinal fluid (CSF) levels of interleukin (IL)-6, IL-11 and leukaemia inhibitory factor (LIF) were evaluated in 43 patients with Alzheimer's disease (AD) and 24 patients with frontotemporal lobar degeneration (FTLD) as compared with 30 agematched controls (CON), and correlated with clinical and demographic data and with CSF biomarkers amyloid beta (A beta)42, total tau and tau phosphorylated at position 181 (P-tau). CSF IL-11 mean levels were significantly increased in AD and FTLD as compared with CON (6.5 +/- 4.6 and 6.6 +/- 5.1 versus 3.1 +/- 3.3 pg/ml, P = 0.009). IL-6 mean levels did not differ between patients and CON (P > 0.05),whereas LIF levels were not detectable in patients or in CON. In AD patients, a significantly positive correlation between MMSE scores and IL-11 CSF concentration was observed (r = 0.344, P = 0.028). No correlations with CSF A beta 42, total tau and P-tau were found. IL-11, but not IL-6 levels are increased in AD and FTLD, and the highest peaks were observed in patients with a less severe degree of cognitive deterioration, therefore suggesting a role of this cytokine in early phases of neurodegeneration.

+10 T/C polymorphisms in the gene of transforming growth factor-beta1 are associated with neurodegeneration and its clinical evolution.

Transforming growth factor-beta1 (TGF-beta1) acts as an immunosuppressant by inhibiting the expression of several pro-inflammatory cytokines. Its gene contains single nucleotide polymorphisms (SNPs) at codon +10 (T-->C) and +25 (G-->C) that appear to influence the level of expression of TGF-beta1. We investigated these SNPs in 198 healthy controls (HC), 193 patients with Alzheimer's disease (AD) and 48 patients with mild cognitive impairment (MCI). Among the latter, after a 4-year follow-up, 21 were diagnosed as AD (MCI-->AD) while 18 did not progress (stable MCI). We observed that both the +10 C allele and the CC genotype were over-represented in AD when compared to HC. These variants significantly raised the risk of disease independently of the status of apolipoprotein E4. The CC genotype was also over-expressed in MCI, especially in MCI-->AD. These results suggest that TGF-beta1 may be one of the early markers involved in the inflammatory mechanisms underlying the pathogenesis of AD.

Natural aging, expression of fibrosis-related genes and collagen deposition in rat lung.

Aging lung is characterized by morpho-structural modifications, including progressive fibrosis, that lead to an altered function. Here we provide a comprehensive description of lung collagen expression and metabolism during natural aging of rats. Peribronchial collagen increased significantly in the oldest animals (p=0.05 2- vs. 6- and 19-month-old rats), as a consequence of Collagen-I and Collagen-III (COL-I, COL-III) protein accumulation (p<0.05 in 6-, 12- and 19-month-old rats versus the youngest). No changes in fibronectin (FN) protein expression and in COL-III and transforming grow factor beta-1 (TGFbeta-1) mRNA expression were observed. Conversely the transcription activity of the COL-I gene was overexpressed in the oldest animals (p<0.05). In the aged rats, the activity of lung matrix metalloproteinases (MMP), MMP-1 and MMP-2, dropped significantly (p<0.05), whilst MMP-9 levels were slightly decreased. These changes were associated with a concomitant increase of tissue inhibitors of MMP (TIMP-1 and TIMP-2). All together, these results suggest that, during natural aging, collagen accumulation in the lung and its progressive fibrosis are mainly due to a reduced proteolytic activity of MMP, in which TIMP-1 and -2 seem to be the major regulating factors.

Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer's disease.

Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been shown to be associated with AD. Tumor necrosis factor (TNF)-alpha is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60-87) and 240 non-demented age-matched healthy controls for TNF-alpha -308 G/A single nucleotide polymorphism (SNP). No significant differences were observed in genotyped frequencies between patients and controls, whereas carriers of -308A showed a significantly lower mean age at onset than non-carriers of this allele. This difference was more evident taking into account ApolipoproteinE (ApoE) status since the lowest age at onset was observed in patients carrying the -308ATNF+/APOE4+ genotypes. In conclusion, our data support previous suggestions that, at least in Caucasians, the TNF gene is a disease modifier gene in patients in which AD is rising, bringing to light the importance of genetic variation at the pro-inflammatory components in the progression of AD.