[Show abstract][Hide abstract] ABSTRACT: Proinflammatory cytokines and heat shock proteins play relevant roles in the pathogenesis of inflammatory diseases. We investigated whether Hsp70 1267 A/G and TNF-α -308 G/A polymorphisms are associated with proinflammatory mediators, zinc status and laboratory parameters in 1,078 healthy elderly from ZincAge study. Hsp70 1267 A/G genotype and allele distribution were similar among various European countries, while a TNF-α genetic heterogeneity was observed between the Northern and the Southern European populations, with a major frequency of the -308 A variant in France, Germany and Poland. We used linear regression models to test additive, dominant or recessive associations of each SNP with proinflammatory mediators, laboratory parameters, metallothioneins and zinc status. Hsp70 1267 A/G SNP, but not TNF-α -308 G/A SNP, influences TNF-α and IL-6 plasma levels under additive, dominant and recessive models (for TNF-α only). An association between Hsp70 1267 A/G SNP and zinc plasma levels was observed in the dominant model. In particular, G allele carriers showed increased circulating pro-inflammatory cytokines and zinc. Moreover, both these SNPs affect creatinine levels suggesting a possible influence on renal function. In conclusion, Hsp70 1267 A/G SNP is associated with pro-inflammatory cytokine production in healthy elderly and might represent a possible determinant of individual susceptibility to inflammatory diseases.
[Show abstract][Hide abstract] ABSTRACT: Elderly patients with dementia have a higher risk of falls and fractures as compared to cognitively intact elderly subjects. To investigate whether psychological distress of the caregiver might predispose older persons with Alzheimer disease (AD) to falls and fractures, we performed a prospective cohort study.
A consecutive series of 110 subjects with dementia underwent baseline and follow-up clinical and functional evaluations. The burden of the caregivers was recorded at baseline. Any intervening fall or fracture was ascertained at the 1-year follow-up.
The caregiver burden was significantly higher in persons involved in the care of patients with AD who subsequently fell. In a multivariate regression model, the caregiver burden score predicted falls and fractures.
Part of the increased risk of falls and fractures in AD might be due to the distress of caregivers, a factor potentially amenable to treatment.
[Show abstract][Hide abstract] ABSTRACT: A higher daily intake of fruits and vegetables in healthy elderly is associated with an improved antioxidant status in comparison to subjects consuming diets poor in fruits and vegetables, but the impact on cognitive performance is unclear. Healthy community dwellers (45 to 102 years old, n=193) underwent cognitive testing and blood withdrawal for the measurement of antioxidant micronutrients and biomarkers of oxidative stress as well as administration of a food frequency questionnaire to assess the daily intake of fruits and vegetables (high intake HI, low intake LI). Ninety-four subjects of the HI group had significantly higher cognitive test scores, higher levels of carotenoids, alpha- and gamma-tocopherol as well as lower levels of F2 alpha isoprostanes than the 99 subjects of the LI group. Cognitive scores were directly correlated with blood levels of alpha-tocopherol and lycopene and negatively correlated with F2 alpha isoprostanes and protein carbonyls. The results were independent of age, gender, body mass index, education, total cholesterol, LDL- and HDL-cholesterol, triglycerides, and albumin. Healthy subjects of any age with a high daily intake of fruits and vegetables have higher antioxidant levels, lower levels of biomarkers of oxidative stress, and better cognitive performance than healthy subjects of any age consuming low amounts of fruits and vegetables. Modification of nutritional habits aimed at increasing intake of fruits and vegetables should be encouraged to lower prevalence of cognitive impairment in later life.
[Show abstract][Hide abstract] ABSTRACT: i) to describe the neuropsychiatric profile of elderly subjects with dementia by comparing vascular (VaD) and degenerative dementias, i.e. dementia with Lewy bodies (DLB) and Alzheimer's disease (AD); ii) to assess whether the severity and type of dementia are associated with clinically relevant neuropsychiatric symptoms (CR-NPS).
One hundred and thirty-one out-patients with VaD, 100 with DLB and 690 with AD were studied. NPS were evaluated by the neuropsychiatric inventory (NPI).
Vascular dementia had lower total and domain-specific NPI scores and a lower frequency of CR-NPS than AD and DLB, for which frequency of CR-NPS increased significantly with disease severity, particularly in AD. Logistic regression analysis showed that a higher CDR score and a diagnosis of degenerative dementia were independently associated with CR-NPS.
Vascular dementia is associated less with CR-NPS than AD and DLB. Frequency of CR-NPS increases with disease severity in AD and, to a lesser extent, in DLB.
[Show abstract][Hide abstract] ABSTRACT: A large body of experimental research indicates that oxidative stress contributes to the processes related to aging and age-related diseases. Trace elements, particularly zinc (Zn), are essential components of the endogenous enzymatic antioxidant defenses. The aim of this study was to determine the activity of three main antioxidant enzymes in plasma [i.e. superoxide dismutase (pSOD), catalase (CAT), glutathione peroxidase (GPx)] and of SOD in erythrocyte (eSOD) in a group of 1108 healthy elderly subjects from different European countries. The same enzymatic activities were evaluated in a subgroup of 108 subjects before and after Zn supplementation. We observed that eSOD activity increased with age, whereas plasma Zn decreased. Moreover, we found that women showed higher eSOD activity and lower plasma Zn compared to men. There were no age and gender-related differences in the activities of pSOD, CAT and GPx. After Zn supplementation, the activities of Zn-dependent enzymes (pSOD and eSOD), as well as plasma Zn concentration, were significantly higher than before supplementation. These results were not influenced by age, gender, plasma Zn variations (Delta Zn) and geographic area. These data suggest the potential beneficial effects of Zn supplementation on Zn-dependent antioxidant enzymes in healthy elderly subjects.
[Show abstract][Hide abstract] ABSTRACT: To investigate whether amnestic mild cognitive impairment (aMCI) is characterised by restriction in instrumental activities of daily living (IADL). Further, to examine the role of comorbidity and cognitive performance on IADL changes in aMCI subjects.
The study included 132 subjects with aMCI and 249 subjects with no cognitive impairment (NCI), consecutively enrolled as outpatients in a multicentric Italian clinical-based study, the ReGAl Project. All subjects underwent a comprehensive evaluation including clinical examination, laboratory screening, neuroimaging and cognitive and behavioral assessments. Functional status was evaluated by the Lawton's Instrumental Activities of Daily Living (IADL) scale. Comorbidity was evaluated by the Cumulative Illness Rating Scale (CIRS). Cognitive evaluation included tests assessing episodic memory, language, attention/executive functioning and praxis, as well as the the Mini-Mental State Examination (MMSE) as a measure of global cognition.
Subjects with aMCI had higher IADL changes than NCI. Among IADL items, aMCI subjects showed a significant impairment in shopping, taking drugs, and handling economy; however also NCI had minor IADL changes regarding cooking, washing and cleaning. IADL restriction in aMCI subjects was significantly associated with cognitive performance, mainly related to executive functioning, but not with comorbidity. On the contrary, in NCI sensory impairment accounts for slight IADL changes.
In aMCI subjects a mild degree of cognitive deterioration has a stronger impact on IADL than somatic comorbidity. Current diagnostic criteria for MCI should include a mild impairment in IADL.
International Journal of Geriatric Psychiatry 06/2008; 23(5):523-30. · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Understanding the molecular mechanisms of neurodegeneration represents a scientific priority as it will allow scientists to more specifically target and simultaneously interrupt the multiple pathologic mechanisms that contribute to the progression of dementia in Alzheimer's disease (AD). Oxidative stress represents one of the key processes in AD pathogenesis, related to formation of both amyloid plaques and neurofibrillary tangles as well as to alteration of many biomolecules. For this reason several antioxidant molecules have been tested in in vitro and in vivo studies in order to detect more efficacious treatments. Dietary antioxidants seem also to have an important role in AD prevention, as shown by several epidemiological studies. Ongoing clinical trials to assess whether antioxidant supplementation has a role in primary prevention of AD or in delaying the progression of disease in individuals with Mild Cognitive Impairment (MCI), are in progress or planned. Thus, research involving new antioxidants and their potential clinical applications will provide new insights into the molecular basis of neuroprotective mechanisms that may be relevant to AD and other age-related neurodegenerative disorders.
Central Nervous System Agents in Medicinal Chemistry(Formerly Current Medicinal Chemistry - Central Nervous System Agents) 02/2008; 8(1):48-63.
[Show abstract][Hide abstract] ABSTRACT: MCI is a nosological entity proposed as an intermediate state between normal aging and dementia. The syndrome can be divided into two broad subtypes: amnestic MCI (aMCI) characterized by reduced memory, and non-amnestic MCI (naMCI) in which other cognitive functions rather than memory are mostly impaired. aMCI seems to represent an early stage of AD, while the outcomes of the naMCI subtypes appear more heterogeneous--including vascular dementia, frontotemporal dementia or dementia with Lewy bodies--but this aspect is still under debate. MCI in fact represents a condition with multiple sources of heterogeneity, including clinical presentation, etiology, and prognosis. To improve classification and prognosis, there is a need for more sensitive instruments specifically developed for MCI as well as for more reliable methods to determine its progression or improvement. Current clinical criteria for MCI should be updated to include restriction in complex ADL; also the diagnostic and prognostic role of behavioral symptoms and motor dysfunctions should be better defined. A multidisciplinary diagnostic approach including biological and neuroimaging techniques may probably represent the best option to predict the conversion from MCI to dementia. In this review we discuss the most recent aspects related to the epidemiological, clinical, neuropathological, neuroimaging, biochemical and therapeutic aspects of MCI, with specific attention to possible markers of conversion to dementia.
[Show abstract][Hide abstract] ABSTRACT: In this study, 153 Italian centenarians from four different geographical areas, including Modena (northern Italy), Ancona (central Italy), Perugia (central Italy) and Sardinia island (AKEA Project) were enrolled. Plasma levels of vitamin C, uric acid, vitamin A and vitamin E as well as the activities of superoxide dismutase and glutathione peroxidase were measured. Subjects were compared to a younger control population of the same areas, divided into three age groups: <or=60; 61-80 and 81-99 years. The main result of this study is that, whereas in Italian population elevated levels of plasma vitamins A and E seem to be important for longevity, this do not apply to centenarians from Sardinia, in which probably other factors play a more important role.
European Journal of Clinical Nutrition 07/2007; 61(7):922-4. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lipid peroxidation plays an important role in the development of atherosclerosis, a chronic, age-related disease process of the arterial wall with onset decades prior to its clinical manifestations. The aim of the study was to assess the association between the intima media thickness (IMT) of the major arteries as a clinical marker of atherosclerosis and markers of lipid peroxidation along with the antioxidant status in humans.
A university-affiliated outpatient clinic.
Thirty patients (22 males, 8 females; 70.4 +/- 7.3 years) with atherosclerosis of the carotid or iliofemoral arteries and 62 healthy controls (30 males, 32 females; 68.3 +/- 4.3 years).
Plasma levels of 8,12-isoprostane F2alpha-VI (8,12-IPF2alpha-VI) were measured by gas chromatography/mass spectrometry, whereas levels of malondialdehyde (MDA), vitamins A (retinol) and E (alpha- and gamma-tocopherol), and carotenoids were determined by high-performance liquid chromatography. The IMT was measured by B-mode ultrasonography.
Patients showed, independent of fruit and vegetable intake, significantly lower plasma levels of retinol, alpha-tocopherol, and all carotenoids excluding beta-cryptoxanthin compared with controls. On the contrary, plasma 8,12-IPF2alpha-VI levels were almost doubled (p < .001) and MDA levels increased by one-third (p < .01) in atherosclerotic patients compared with controls.
The analyses of isoprostanes and antioxidant nutrients in plasma as markers of oxidative stress and the parallel evaluation of IMT as a structural marker of atherosclerosis are suitable tools for investigating the role of antioxidants and oxidative stress in atherosclerosis.
Journal of Investigative Medicine 06/2007; 55(4):163-7. · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the role of vascular risk factors in different subtypes of mild cognitive impairment (MCI) in a multicentric, clinic-based, cross-sectional study.
Two-hundred and seven subjects with MCI were included in the study: 33 with single non-memory MCI (snmMCI), 42 with multiple-domain amnestic MCI (mdMCI-a) and 132 with amnestic MCI (aMCI). Several clinical vascular risk factors and magnetic resonance imaging (MRI) brain lesions were evaluated.
snmMCI showed a higher frequency of ischaemic heart disease and of transient ischaemic attack (TIA)/stroke, a higher Hachinski ischaemic score and a higher frequency of white-matter lesions on MRI compared to aMCI. Subjects with mdMCI-a showed clinical characteristics similar to aMCI, except for a higher frequency of a history of TIA/stroke.
Our findings suggest that snmMCI may be considered a vascular cognitive disorder.
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, has been linked to a condition of oxidative and nitrosative stress, arising from the imbalance between increased reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and antioxidant defences or efficiency of repair or removal systems. The effects of free radicals are expressed by the accumulation of oxidative damage to biomolecules: nucleic acids, lipids and proteins. In this review we focused our attention on the large body of evidence of oxidative damage to protein in Alzheimer's disease brain and peripheral cells as well as in their role in signalling pathways. The progress in the understanding of the molecular alterations underlying Alzheimer's disease will be useful in developing successful preventive and therapeutic strategies, since available drugs can only temporarily stabilize the disease, but are not able to block the neurodegenerative process.
[Show abstract][Hide abstract] ABSTRACT: 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.
Neurological Research 10/2006; 28(6):588-94. · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Enzymatic activities of plasma superoxide dismutase (pSOD), catalase (CAT) and glutathione peroxidase (GPx) and erythrocyte superoxide dismutase (eSOD) were assayed in 981 healthy community dwelling old subjects participating in the Zincage Project. The relationship between antioxidant enzyme activities and, respectively, gender, age and zinc status were assessed. eSOD activity was higher in nonagenarians than in 80 year old subjects. Plasma Zn was lower in nonagenarians compared with younger subjects. The prevalence of Zn deficiency increased with age, with normal Zn levels observed in about 80% of adult subjects and only in 37% of the nonagenarians. Women showed higher eSOD and CAT activities compared to men, whereas plasma Zn was higher in men than in women. There was a positive correlation between eSOD activity and age and a negative correlation between eSOD activity and plasma Zn concentrations. An inverse correlation was also found between plasma Zn concentration and age. Further studies on different aspects of Zn metabolism--intake, plasma concentration, peripheral cell concentration, activity and amount of Zn-dependent enzymes--are warranted.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of the Neurological Sciences 09/2006; 247(2):187-91. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Neurobiology of Aging 08/2006; 27(7):926-32. · 6.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There have been inconclusive results to date on the association between the Apolipoprotein E (ApoE) genotype and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We investigated whether ApoE epsilon4 allele is associated with NPS in probable AD.
Data for 197 subjects with probable AD were analysed. The Neuropsychiatric Inventory was used to evaluate the frequency and severity of NPS. Multiple logistic regression models were used to test the association between ApoE genotype and NPS in AD.
The ApoE epsilon3/3 genotype was present in 52.3%, epsilon3/4 in 44.1%, and epsilon4/4 in 3.6% of patients. ApoE epsilon4 carriers showed a higher frequency of apathy than non-carriers. After multiple adjustments, the ApoE epsilon4 allele was significantly associated with apathy.
Our results suggest a relationship between the ApoE epsilon4 allele and apathy in patients with AD.