Biomedical subjects

Patrizia Mecocci

Publications and source records attributed to Patrizia Mecocci.

At least 19 recordsLinked to original sources

PubMed2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Journal Article↗

PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗

PubMed2006

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.

Aged↗

PubMed2006

Congestive heart failure and Alzheimer's disease.

The increase in average life expectancy is resulting in an increasing prevalence of major invalidating illnesses, such as cardiovascular disease and dementia. Congestive heart failure (CHF) is a chronic, progressive disease representing the advanced stage of cardiac illnesses. Cognitive impairment is known to be a frequent feature of CHF patients. The epidemiologic pictures of mild cognitive impairment (MCI), Alzheimer's disease (AD) and CHF are predicted to worsen with the demographic expansion of the elderly population. Nevertheless, there has been little structured research on cognitive impairment in patients with CHF. This is unfortunate not only because CHF is the leading cause of hospitalization in the elderly and a leading cause of disability and death, but also for important clinical and socioeconomic implications including those related to comorbidity in advanced age and the need to early detect factors which may precipitate the conversion of MCI to AD. In this review, several aspects of the role of CHF in cognitive impairment are evaluated. Owing to the lack of studies focusing on CHF in AD, the pathophysiology of cardiac failure in cognitive impairment is addressed in light of possible preventive strategies against the onset of AD. These include prevention of oxygen radical and peroxynitrite production, supplementation of nitric oxide (NO) donors, as well as the achievement of an adequate antioxidant supply, better if obtained with a targeted and individualized nutritional approach. A systematic neuropsychologic testing of older patients with heart failure is to identify those with early cognitive impairment and promptly establish traditional therapies such as angiotensin converting enzyme (ACE) inhibitors, digoxin or beta-blockers. The neuropsychologic assessment in CHF patients is also fundamental to disclose conditions potentially favoring the onset of cognitive impairment such as depression. Finally, management schemes should include exercise training programs as well as patient and caregiver education.

Alzheimer Disease↗

PubMed2005

Potential markers of oxidative stress in stroke.

Free radical production is increased in ischemic and hemorrhagic stroke, leading to oxidative stress that contributes to brain damage. The measurement of oxidative stress in stroke would be extremely important for a better understanding of its pathophysiology and for identifying subgroups of patients that might receive targeted therapeutic intervention. Since direct measurement of free radicals and oxidized molecules in the brain is difficult in humans, several biological substances have been investigated as potential peripheral markers. Among lipid peroxidation products, malondialdehyde, despite its relevant methodological limitations, is correlated with the size of ischemic stroke and clinical outcome, while F2-isoprostanes appear to be promising, but they have not been adequately evaluated. 8-Hydroxy-2-deoxyguanosine has been extensively investigated as markers of oxidative DNA damage but no study has been done in stroke patients. Also enzymatic and nonenzymatic antioxidants have been proposed as indirect markers. Among them ascorbic acid, alpha-tocopherol, uric acid, and superoxide dismutase are related to brain damage and clinical outcome. After a critical evaluation of the literature, we conclude that, while an ideal biomarker is not yet available, the balance between antioxidants and by-products of oxidative stress in the organism might be the best approach for the evaluation of oxidative stress in stroke patients.

Aldehydes↗

PubMed2005

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.

Accidental Falls↗

PubMed2005

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.

Aged↗

PubMed2005

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.

Ascorbic Acid↗

PubMed2005

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.

Activities of Daily Living↗

PubMed2005

Dietary habits are major determinants of the plasma antioxidant status in healthy elderly subjects.

Previous studies indicate that regular consumption of a diet rich in fruits and vegetables is associated with a lower risk for age-related diseases. The aim of the present study was to evaluate whether the often-reported age-related decrease of plasma antioxidants in man depends on differences in dietary intake or on other age- and gender-related factors. In this observational case-control study, thirty-nine community-dwelling healthy subjects aged 65 years and older consuming high intakes of fruits and vegetables daily (HI) and forty-eight healthy subjects aged 65 and older consuming low intakes of fruit and vegetables daily (LI) were enrolled. Plasma levels of retinol, tocopherols, carotenoids and malondialdehyde (MDA) as well as content of protein carbonyls in Ig G were measured. Plasma levels of retinol, tocopherols and carotenoids were significantly higher in group HI than in group LI subjects independent of age and gender. MDA levels were inversely correlated with vitamin A and alpha-carotene. Protein carbonyls were inversely correlated with gamma-tocopherol. In the elderly, a higher daily intake of fruits and vegetables is associated with an improved antioxidant status in comparison to subjects consuming diets poor in fruits and vegetables. Modification of nutritional habits among other lifestyle changes should be encouraged to lower prevalence of disease risk factors in later life.

Age Factors↗

PubMed2005

Elderly patients with cognitive impairment have a high risk for functional decline during hospitalization: The GIFA Study.

BACKGROUND: We tested the hypothesis that cognitive impairment upon admission (CIA) and cognitive decline (CD) during hospitalization are associated with an increased risk for functional decline (FD) in older inpatients. METHODS: The Italian Group of Pharmacoepidemiology in the Elderly (Gruppo Italiano di Farmacoepidemiologia nell'Anziano, GIFA) project was a multicenter survey of 9061 older patients admitted to Italian hospitals between 1991 and 1997. CIA was defined as a Hodkinson Abbreviated Mental Test score <7 on admission. The percentage of participants who developed FD, defined as loss of the ability to perform without help one or more activities of daily living between admission and discharge, was compared in patients who did and did not have CIA, and between those who lost at least one point in Hodkinson Abbreviated Mental Test score (CD) and those who did not. RESULTS: Mean age was 77.4 years, and women represented 52.3% of the sample. CIA was present in 21.0% of the patients. During hospitalization, 176 patients (1.9%) experienced FD (4% of those with CIA vs 1.3% of those without CIA). In multivariate analysis, CIA was an important risk factor for FD (odds ratio 2.4; 95% confidence interval, 1.7-3.5; p <.001), independent of age, gender, comorbidity, polypharmacy, and disability on admission. CD occurred in 3.7% of the sample and was strongly associated with an increased risk for FD (odds ratio 16.0; 95% confidence interval, 10.8-23.6; p <.001). CONCLUSIONS: Elderly patients with CIA have a higher risk for FD. New strategies should be implemented to prevent FD in patients with cognitive impairment, who account for a high percentage of older persons who are admitted to hospitals.

Activities of Daily Living↗

PubMed2005

Development of a short form of the Severe Impairment Battery.

OBJECTIVE: The authors sought to develop a short form of the Severe Impairment Battery (SIB). METHODS: Authors describe the development of an empirically-derived short form of the SIB (SIB-S) by use of data from 191 subjects with severe dementia in the United States and France. RESULTS: Mean (standard deviation) Mini-Mental State Exam scores for the American and French samples were 7.7 (4.8) and 5.7 (3.4), respectively, and original SIB scores were 71.87 (18.34) and 58.38 (26.86), respectively. Exploratory factor analyses were conducted separately and in combination for the two samples, to determine the number of clinically meaningful factors. An eight-factor model, explaining 60.2% of the common variance, was selected. The eight constructs were described as: expressive language, memory (verbal and nonverbal), social interaction, color-naming, praxis, reading and writing, fluency, and attention. Derived SIB-S scores were 38.41 (9.12) and 29.79 (13.17) for the American and French samples, respectively. CONCLUSIONS: The original SIB is a valid and reliable research tool developed to enable reliable assessment of patients with severe dementia; it takes approximately 30 minutes to administer. The SIB-S takes only 10-15 minutes to administer, making it more appropriate for use in patients with very severe dementia, while it maintains the attributes of the original SIB.

Aged↗

PubMed2005

Guidelines for the treatment of Alzheimer's disease from the Italian Association of Psychogeriatrics.

A committee of experts from the Italian Association of Psychogeriatrics compiled the following report, which was then approved by a Steering Committee (comprising 20 specialists in neurology, psychiatry or geriatrics) from the Association and by two Alzheimer associations representing patients and families: the Italian Association for Alzheimer's Disease and the Italian Federation for Alzheimer's Disease. The report is based on a comprehensive review of the scientific literature on the treatment of Alzheimer's disease, discusses methodological aspects of dementia management, and details the limitations of current therapies. These guidelines are, in general, consistent with the principles of evidence-based medicine; however, for some controversial or poorly investigated issues, the guidelines integrate scientific evidence with experience and opinions from experts working in the clinical setting. In particular, the clinical experience of experts has been used to define recommendations for starting and interrupting pharmacotherapy, and to critically review evidence about the efficacy of non-pharmacological interventions. The principal pharmacotherapeutic interventions covered in the guidelines are acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and memantine. The main non-pharmacological interventions reviewed are memory training, reality orientation therapy, and combined non-pharmacological interventions. Other issues covered are opportunities for Alzheimer's disease prevention, various modalities of care, and the treatment of comorbidities.

Aged↗

PubMed2004

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.

Aged↗

PubMed2004

Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia.

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of beta-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature-vascular or degenerative-dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.

Aged↗

PubMed2004

Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation.

To assess the effects of short-term and long-term vitamin C supplementation in humans on plasma antioxidant status and resistance to oxidative stress, plasma was obtained from 20 individuals before and 2h after oral administration of 2g of vitamin C, or from eight subjects enrolled in a vitamin C depletion-repletion study using increasing daily doses of vitamin C from 30 to 2500 mg. Plasma concentrations of ascorbate, but not other physiological antioxidants, increased significantly after short-term supplementation, and increased progressively in the long-term study with increasing vitamin C doses of up to 1000 mg/day. Upon incubation of plasma with a free radical initiator, ascorbate concentrations were positively correlated with the lag phase preceding detectable lipid peroxidation. We conclude that vitamin C supplementation in humans dose-dependently increases plasma ascorbate concentrations and, thus, the resistance of plasma to lipid peroxidation ex vivo. Plasma and body saturation with vitamin C in humans appears desirable to maximize antioxidant protection and lower risk of oxidative damage.

Adult↗

PubMed2004

Depression in the elderly: new concepts and therapeutic approaches.

Depression is one of the leading causes of suffering in the elderly, but it is often under-diagnosed and under-treated, partly due to the false belief that depression is a common aspect of aging. Depression in the elderly is frequently comorbid with medical illnesses, may often be expressed by somatic complaints, and may be a risk factor for other diseases such as dementia and coronary artery disease. Depression decreases the quality of life and increases disability and the risk of mortality, also due to suicide. Although several effective antidepressant drugs are available, with a favorable therapeutic index, non-pharmacological treatments, such as psychotherapy and exercise, should receive greater attention, since combination therapy is probably more effective.

Aged↗

PubMed2004

Increased F2 isoprostane plasma levels in patients with congestive heart failure are correlated with antioxidant status and disease severity.

BACKGROUND: A growing body of evidence supports the pathophysiologic role of oxidative stress and the protective role of naturally occurring antioxidants in congestive heart failure (CHF). Circulating levels of a sensitive and specific marker of lipid peroxidation and levels and activities of a broad spectrum of essential antioxidant micronutrients, vitamins, and enzymes, however, have been never simultaneously evaluated in well-characterized CHF patients. METHODS AND RESULTS: Plasma levels of 8,12-isoprostane F(2alpha)-VI; vitamins A, C, and E; uric acid; and five carotenoids as well as activities of plasma superoxide dismutase and glutathione peroxidase were measured in 30 patients with class II and III New York Heart Association (NYHA) CHF and in 30 controls. Ejection fraction was measured in all patients. Significantly higher 8,12-isoprostane F(2alpha)-VI levels and lower antioxidant levels and activities were found in CHF patients in comparison to controls. Levels of 8,12-isoprostane F(2alpha)-VI were higher in class III than in class II NYHA CHF patients (P=.0012), and inversely correlated with ejection fraction; vitamins A, C, and E; uric acid; carotenoid levels; and superoxide dismutase activity. CONCLUSION: There is an association between increased lipid peroxidation and both antioxidant status and disease severity in CHF in humans. These findings support the rationale for intervention trials aiming at exploring beneficial effects of antioxidant micronutrients in this disease.

Aged↗