Biomedical subjects

P Mecocci

Publications and source records attributed to P Mecocci.

At least 55 records · Page 3Linked to original sources

PubMed1997

Cognitive enhancement therapy for Alzheimer's disease. The way forward.

Although at present there is no definitive treatment or cure for Alzheimer's disease, different pharmacological strategies are being actively investigated. At present, cholinergic therapy and nootropics and some neuronotrophic agents represent the available approaches to symptomatic treatment of Alzheimer's disease. The use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic approach to increase acetylcholine levels. Available data suggest that about 15 to 40% of Alzheimer's disease patients show a varying degree of cognitive improvement while taking these medications; however, haematological complications (neutropenia or agranulocytosis), together with hepatotoxicity, need to be considered carefully. Recent data suggest that long term administration of nootropics may lead to a significant improvement of cognitive functions in Alzheimer's disease patients compared with untreated individuals, having excellent tolerability. Protocols for the intracerebroventricular administration of neuronotrophic substances are also ongoing. The most promising approaches for the future currently undergoing investigation involve attempts to slow the production of beta-amyloid and/or to inhibit beta-amyloid aggregation. Another rational therapeutic approach would be to inhibit the formation of paired helical filaments (PHF) by increasing and/or modulating the activities of protein phosphatases and kinases. Antioxidant therapy should disrupt or prevent the free radical/beta-amyloid recirculating cascade and the progressive neurodegeneration. Idebenone, a synthetic compound acting as an 'electron trapper' and free radical scavenger, has shown some efficacy in degenerative and vascular dementia; at present, other different molecules having antioxidative properties [lazaroids (21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline, some vitamins] are under investigation. Lowering absorption or brain tissue concentrations of aluminium also offers possible therapeutic opportunities for slowing the rate of clinical progression of the disease; in this sense, some evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine). Inflammation also may play a significant pathogenetic role in Alzheimer's disease. As shown by several retrospective analyses, there is an inverse association of anti-inflammatory drug use with the frequency of Alzheimer's disease diagnosis. Consequently, clinical trials using both nonsteroidal and steroidal molecules have been proposed. These lines of pharmacological intervention represent an important premise for future therapeutic strategies capable of counteracting the pathogenesis of Alzheimer's disease.

Aluminum↗

PubMed1996

Altered mitochondrial membrane fluidity in AD brain.

Oxidative damage on biological membranes has been proposed as a cause of the alterations observed in aging brain and, more severely, in Alzheimer's disease (AD). In this study we evaluated membrane fluidity of mitochondria extracted from different areas of normal and AD brains by means of fluorescence polarization technique. AD mitochondria showed a significant reduction of membrane fluidity compared to controls except in cerebellum. This might be caused by a greater lipid peroxidation of biological membranes, as suggested by in vitro experiments we performed to this purpose. From these results the possible role of oxidative stress in AD pathogenesis is supported.

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PubMed1995

Serum anti-GFAP and anti-S100 autoantibodies in brain aging, Alzheimer's disease and vascular dementia.

Autoantibodies against glial fibrillary acidic protein (GFAP) and S100 protein were measured in sera of patients suffering from vascular dementia (VD), presenile Alzheimer's disease (AD), senile Alzheimer's disease (SDAT) and aged healthy controls by means of ELISA test. VD and SDAT showed the highest levels of both autoantibodies, AD the lowest. From these results a relationship between autoantibody titers and aging seems possible. Dosage of anti-GFAP and anti-S100 autoantibodies does not appear useful for diagnostic purpose because of the overlap observed among groups. Rather, the presence of these antibodies seems to reflect an alteration of the blood-brain barrier that promotes the access of central nervous system antigens to immunocompetent cells.

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PubMed1995

Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo.

Nitric oxide may be a key mediator of excitotoxic neuronal injury in the central nervous system. We examined the effects of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) on excitotoxic striatal lesions. 7-NI significantly attenuated lesions produced by intrastriatal injections of NMDA, but not kainic acid or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 7-NI attenuated secondary striatal excitotoxic lesions produced by the succinate dehydrogenase inhibitor malonate, and the protection was reversed by L-arginine but not by D-arginine, 7-NI produced nearly complete protection against striatal lesions produced by systemic administration of 3-nitropropionic acid (3-NP), another succinate dehydrogenase inhibitor, 7-NI protected against malonate induced decreases in ATP, and increases in lactate, as assessed by 1H magnetic resonance spectroscopy. 7-NI had no effects on spontaneous electrophysiologic activity in the striatum in vivo, suggesting that its effects were not mediated by an interaction with excitatory amino acid receptors. 7-NI attenuated increases in hydroxyl radical, 8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. The present results implicate neuronal nitric oxide generation in the pathogenesis of both direct and secondary excitotoxic neuronal injury in vivo. As such they suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.

Adenosine Triphosphate↗

PubMed1994

Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease.

Oxidative damage to DNA may play a role in both normal aging and in neurodegenerative diseases. We examined whether Alzheimer's disease (AD) is associated with increased oxidative damage to nDNA and mtDNA in postmortem brain tissue. We measured the oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (OH8dG), in DNA isolated from three regions of cerebral cortex and cerebellum in 13 AD and 13 age-matched controls. There was a significant threefold increase in the amount of OH8dG in mtDNA in parietal cortex of AD patients compared with controls. In the entire group of samples there was a small significant increase in oxidative damage to nDNA and a highly significant threefold increase in oxidative damage to mtDNA in AD compared with age-matched controls. These results confirm that mitochondrial DNA is particularly sensitive to oxidative damage, and they show that there is increased oxidative damage to DNA in AD, which may contribute to the neurodegenerative process.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1994

Pathogenetic mechanisms in vascular dementia.

Vascular dementia accounts for approximately 20% of all cases of dementia and for about 50% in subjects over 80 years. Thromboembolism with multiple cerebral infarcts was considered to be almost the only pathogenetic pathway of vascular dementia, with multi-infarct dementia as its clinical manifestation. However, there is a great heterogeneity of vascular dementia syndromes and pathological subtypes, as documented by the number of pathogenetic mechanisms now known to underlie the clinical picture. They include thromboembolism and extracerebral and cerebral factors. Among the extracerebral factors are ischemic hypoxic dementia (i.e., dementia due to hypoperfusion), vasculitis, hyperviscosity and abnormalities of hemostasis. Among the cerebral factors are lipohyalinosis, cerebral amyloid angiopathy, disruption of the blood-brain barrier and altered regulation of cerebral blood flow. Therefore, the approach to vascular dementia should take the heterogeneity into account. In this context, the importance of non-infarct type should be considered; subcortical white matter disorder seems to be a noteworthy common pathway of vascular dementia produced by various vascular mechanisms. Finally, the heterogeneity of the vascular mechanisms involved in vascular dementia--namely hypoperfusion--might be a factor that can be positively influenced by targeted therapeutic intervention.

Arteriosclerosis↗

PubMed1993

Antihistone and anti-dsDNA autoantibodies in Alzheimer's disease and vascular dementia.

In order to evaluate their prevalence in senile dementias, serum titer of antibodies against histones and double stranded deoxyribonucleic acid (dsDNA) were measured by means of the ELISA test in patients suffering from vascular dementia (VD), presenile Alzheimer's disease (AD), and senile dementia of the Alzheimer's type (SDAT). Only three subjects out of 87 had dsDNA autoantibodies. On the contrary, VD and SDAT showed high titers of antibodies against histones when compared to healthy controls. A significant relationship was also found between antihistone serum titer and degree of dementia in AD. Results were not influenced by gender, age, or duration of illness. Presence of antihistone antibodies in dementias might reflect an alteration of membrane fluidity and integrity with leakage of nuclear immunogens or disturbances of immune functions, as frequently observed in dementia disorders.

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PubMed1993

Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain.

A major theory of aging is that oxidative damage may accumulate in DNA and contribute to physiological changes associated with aging. We examined age-related accumulation of oxidative damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measured the oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (OH8dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH8dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/micrograms of DNA, increased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a significant 10-fold increase in the amount of OH8dG in mtDNA as compared with nDNA in the entire group of samples, and a 15-fold significant increase in patients older than 70 years. These results show for the first time that there is a progressive age-related accumulation in oxidative damage to DNA in human brain, and that the mtDNA is preferentially affected. It is possible that such damage may contribute to age-dependent increases in incidence of neurodegenerative diseases.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1992

Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type.

Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type. The study design comprised a 3-day basal observation period, sham treatment with repeated blood sampling; treatment with 30 mg.kg-1 i.v. [corrected] for 10 days (plasma kinetics was studied on the 7th day), and 50 days of 1.5 g/day [corrected] p.o. given in three daily doses. Total acid soluble L-carnitine, L-carnitine and acetyl-L-carnitine in plasma and CSF were evaluated using an enantioselective radioenzyme assay. Short chain L-carnitine esters were calculated as the difference between total and free-L-carnitine. The plasma concentrations of individual components of the L-carnitine family did not change during the three days of the basal period, nor were they affected during the sham therapy period. Following the i.v. bolus injections, the plasma concentrations showed a biphasic curve, with average t1/2 of 0.073 h and 1.73 h, respectively. At the end of oral treatment, plasma acetyl-L-carnitine and L-carnitine short chain esters were significantly higher than during the run-in phase. The CSF concentrations paralleled those in plasma, suggesting that ALC easily crosses the blood-brain barrier. It is concluded that i.v. and oral administration of multiple doses of ALC can increase its plasma and CSF concentration in patients suffering from Alzheimer's disease.

Acetylcarnitine↗

PubMed1992

Serum autoantibodies against glial fibrillary acidic protein in brain aging and senile dementias.

Autoantibodies against glial fibrillary acidic protein (GFAP) were investigated by ELISA test in sera of patients suffering from senile dementias and in healthy aging people. One hundred eight subjects divided into control, vascular dementia (VD), presenile Alzheimer's disease (AD), and senile Alzheimer's disease (SDAT) groups were included in the study. VD patients showed the highest antibody titers when compared to controls, whereas AD had the lowest titers when compared to the other groups. These results do not support the utility of anti-GFAP antibodies as useful markers of Alzheimer's disease, suggesting that their presence is a secondary phenomenon to blood-brain barrier disruption.

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PubMed1991

Blood-brain-barrier in a geriatric population: barrier function in degenerative and vascular dementias.

Albumin and IgG were determined in serum and cerebrospinal fluid (CSF) of patients with early-onset Alzheimer's disease (AD, n. 13), senile dementia of Alzheimer type (SDAT, n. 33), vascular dementia divided into multi-infarct (MID, n. 9) and probable vascular (PVD, n. 11) dementia. Albumin and IgG ratio and IgG index were calculated. CSF albumin and albumin ratio were significantly higher in MID patients indicating an increased BBB permeability. IgG ratio and IgG index did not show any significant difference among groups. These results do not provide evidence for BBB damage in AD/SDAT, while in MID the increase of CSF albumin and albumin ratio is suggestive of BBB dysfunction.

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PubMed1990

Neuroendocrine markers in aging brain: clinical and neurobiological significance of dexamethasone suppression test.

The dexamethasone suppression test (DST) is commonly accepted as an indicator of hypothalamus-pituitary-adrenal (HPA) axis functioning in clinical practice. In this study, DST was carried out in a geriatric population composed of patients with dementia of Alzheimer type (DAT), stroke and age-matched controls. The stress state of the subjects was also functionally assessed by the Symptoms Rating Test (SRT). The results disclosed no significant differences in basal cortisol levels in the three groups. A positive correlation between age and log-transformed basal cortisol levels was found in the entire population as well as in each group. After dexamethasone administration, 20% of controls, 49% of DAT patients, and 48% of stroke patients were non-suppressors. At 8.00 a.m. and 11.00 p.m. after dexamethasone, cortisol levels were significantly lower (p less than 0.02) in controls than in pathological groups. A significant positive correlation between age and symptoms of depression and anxiety was found. One-third of stroke patients showing lesions in the right hemisphere were non-suppressors, and presented mostly subcortical infarcts, while 1/4 of them had depressive disorders. This study demonstrated a progressive increase in basal cortisol levels and depressive symptoms with age, a poor diagnostic value of DST in age-related pathological conditions such as DAT and stroke, and the role of these cerebral pathologies in amplifying the neuroendocrine dysregulation due to the ageing process itself. DST is a useful biological marker for disclosing the vulnerability of the ageing brain, but it has no diagnostic value.

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PubMed1990

Is multi-infarct dementia representative of vascular dementias? A retrospective study.

Multi-infarct dementia (MID) indicates a dementia disorder primarily caused by multiple cerebral infarcts. Since other pathogenetic mechanisms cause vascular dementia we evaluated clinical, CT scan and CSF neurochemical parameters of 134 MID and 67 PVD (probable vascular dementia) patients. We found no differences with regard to the presence of major risk factors. Only TIA/stroke episodes and focal neurological signs were significantly more frequent in MID than in PVD cases, an anticipable result on the basis of MID definition. CT scan findings showed a prevalence of subcortical with respect to cortical lesions in both groups, with a higher frequency in MID patients. Subjects with deep infarcts more frequently showed TIA/stroke episodes and diabetes mellitus. No differences were detectable in CSF monoamine metabolite levels. We conclude that in the majority of vascular dementias subcortical damage seems to have a major pathogenetic role.

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PubMed1989

Neuropsychological results of long-term therapy with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia in comparison with a control group.

The cognitive and behavioral effects of oxiracetam therapy during long-term treatment in patients with dementia of Alzheimer type (DAT) and multi-infarct dementia (MID) were studied in comparison with a historical control group. Twenty DAT/MID outpatients, aged 54-86 years, received oxiracetam (800 mg twice a day) for a period of 6 months. Another 20 DAT/MID outpatients, aged 67-85 years, were selected from our clinical records in order to obtain a control group of patients matched for age, sex, diagnosis, baseline Mini Mental State Examination (MMSE) score and follow-up duration. All the patients were diagnosed as having mild to moderate degrees of dementia as defined by a baseline MMSE score between 14 and 24. The patients of both groups underwent, both at baseline and after 6 months, the following neuropsychological tests: MMSE, Idiopathic Cerebral Dysfunction Scale, Babcock Test, Gibson Spiral, Toulouse-Pieron Test. Statistical analysis of experimental data demonstrated that at baseline the two groups were comparable. At the end of the study period the oxiracetam group scored significantly better on the majority of the tests evaluating memory, attention, orientation, concentration and psychomotricity than the control group, in which a worsening trend was seen on the whole. No side effects were seen during oxiracetam treatment. The present study, showing positive clinical findings after long-term oxiracetam therapy in controlled conditions, confirms that this drug can be a useful pharmacological treatment for mild to moderate degrees of dementia.

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PubMedDate not supplied

Plasma levels of lipophilic antioxidants in very old patients with type 2 diabetes.

BACKGROUND: Experimental research indicates that oxidative stress is implicated in aging and in the pathogenesis of diabetes and its complications. This evidence is limited in elderly patients with non-insulin dependent diabetes, in which age- and disease-related production of reactive oxygen species might exert synergistic damaging effects on tissues and organs. METHODS: Plasma levels of lipid-soluble compounds with antioxidant properties including vitamin A, vitamin E and carotenoids (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) were measured by HPLC in 72 elderly patients with non-insulin dependent diabetes (75.7+/-0.8 years, 40 F, 32 M) and in 75 age-matched controls (77.2+/-1.2 years, 48 F, 27 M). RESULTS: All compounds measured were significantly lower in plasma from diabetic patients as compared to controls (p<0.0001). Plasma levels of vitamins A and E and of carotenoids did not significantly correlate with dietary intake and lipid profile in both groups. In patients, significant inverse correlations were found between age and levels of vitamin E, beta-cryptoxanthin, lycopene and beta-carotene. CONCLUSIONS: We conclude that patients of very old age with Type 2 diabetes show a poor plasma status of vitamins A and E and carotenoids, which negatively correlates with age. Further studies are needed to explore the possible therapeutic role of lipid-soluble vitamin supplements in elderly diabetic subjects.

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PubMedDate not supplied

Platelet MAO-B activity and vitamin B12 in old age dementias.

Platelet MAO-B activity, serum vitamin B12 levels, and plasma folate were measured in patients suffering from presenile (AD) and senile (SDAT) dementia of Alzheimer-type, and vascular dementia (VD). MAO-B was higher in the SDAT group than in AD and controls. An inverse relationship between MAO-B activity and vit. B12 levels was documented in the whole group and in each category studied; furthermore, MAO-B was positively related to age. All the patients were then divided into two groups, according to vit. B12 levels (Group I: less than 200 pg/mL; Group II: greater than or equal to 200 pg/mL); Group I showed a significantly higher MAO-B activity with respect to Group II. The results indicate the existence of a negative association between platelet MAO-B activity and serum levels of vitamin B12 and confirm the existence of biological differences between presenile and senile dementia of Alzheimer type.

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PubMedDate not supplied

CSF monoamine metabolites in old age dementias.

Cerebrospinal Fluid (CSF) levels of the main metabolites of monoamines (MHPG, 5-HIAA, and HVA) were measured in patients with early onset (AD) and late-onset (SDAT) Alzheimer's disease, vascular dementia (VD), and elderly controls. Psychobehavioral assessment was carried out by means of MMSE and GBS. Mean MHPG levels did not differ from controls; 5-HIAA was lower in VD when compared to both controls and SDAT. HVA was decreased in AD, SDAT, and VD with respect to controls. Significant correlations between HVA and psycho-behavioral parameters were observed in SDAT and VD groups, whereas no relationship was documented in AD. The SDAT group was divided in SDAT-A (age at onset: greater than 65 less than or equal to 80 yr) and SDAT-B (age at onset: greater than 80 yr). SDAT-A had significantly lower CSF HVA values than SDAT-B (165 +/- 64 vs 235.7 +/- 85). SDAT-B HVA levels were similar to those observed in controls. Correlation analysis between HVA and neuropsychological variables was significant in SDAT-A, but not in SDAT-B. These results might support the evidence of SDAT heterogeneity.

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PubMedDate not supplied

Comparative kinetics of oxiracetam in serum and CSF of patients with dementia of Alzheimer type.

The purpose of the study was to determine whether oxiracetam crosses the human blood-brain barrier and to evaluate its comparative kinetics in serum and in cerebro-spinal fluid (CSF). Six DAT patients, undergoing CSF collection for diagnostic purposes, received 2 g oxiracetam daily, by a 60 min i.v. infusion, for 7 days. On the last day, in four patients blood samples were collected at time 0, 30, 60 and 120 min, and lumbar drainage was performed at the end of infusion: at this time mean CSF concentration was 3.5 micrograms/ml, i.e. 4.0% of the serum one, demonstrating that oxiracetam crosses the blood-brain barrier. In two patients, blood samples were collected at time 0, 60, 120 and 240 min, and lumbar drainage was performed 60 min after the end of infusion: at this time mean CSF concentration was 2.8 micrograms/ml, i.e. 5.3% of the serum one, indicating a persistence of oxiracetam within this deep compartment. These results provide the first evidence in humans that oxiracetam penetrates the central nervous system and contribute to the understanding of its long-lasting pharmacodynamic effect in man.

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