Alzheimer Disease: Fioravanti M

Winblad B, Fioravanti M, Dolezal T, Logina I, Milanov IG, Popescu DC, Solomon A. · Karolinska Institute - Alzheimer Disease Research Center, Stockholm, Sweden. · Clin Drug Investig. · Pubmed #18666801 No free full text.

Abstract: The ergot alkaloid derivative nicergoline became clinically available about 35 years ago in the 1970s. Nicergoline has a broad spectrum of action: (i) as an alpha(1)-adrenoceptor antagonist, it induces vasodilation and increases arterial blood flow; (ii) it enhances cholinergic and catecholaminergic neurotransmitter function; (iii) it inhibits platelet aggregation; (iv) it promotes metabolic activity, resulting in increased utilization of oxygen and glucose; and (v) it has neurotrophic and antioxidant properties. Acting on several basic pathophysiological mechanisms, nicergoline has therapeutic potential in a number of disorders. This article provides an overview of the published clinical evidence relating to the efficacy and safety of nicergoline (30 mg twice daily) in the treatment of dementia (including Alzheimer's disease and vascular dementia) and vascular and balance disorders. For dementia of different aetiologies, the therapeutic benefit of nicergoline has been established, with up to 89% of patients showing improvements in cognition and behaviour. After as little as 2 months of treatment, symptom improvement is apparent compared with placebo, and most patients are still improved or stable after 12 months. Concomitant neurophysiological changes in the brain indicate (after only 4-8 weeks' treatment) improved vigilance and information processing. In patients with balance disorders, mean improvements of 44-78% in symptom severity and quality of life have been observed with nicergoline. Although clinical experience with nicergoline in vascular disorders is limited to relatively short-term, small-scale studies, it has been successfully used in rehabilitation therapy of patients with chronic ischaemic stroke. Open-label evaluations suggest that nicergoline may also be valuable in glaucoma, depression and peripheral arterio-pathy. Adverse events of nicergoline, if any, are related to the central nervous system, the metabolic system and the overall body. Most are considered typical symptoms of ergot derivatives. Because of their generally mild and transient nature, treatment discontinuations occur relatively infrequently. The efficacy of nicergoline combined with a favourable safety and tolerability profile at commonly applied doses (60 mg/day) make this agent a valuable therapy in patients with mild to moderate dementia, vascular diseases and balance disorders.

Ferrari E, Casarotti D, Muzzoni B, Albertelli N, Cravello L, Fioravanti M, Solerte SB, Magri F. · Department of Internal Medicine and Medical Therapy, Chair of Geriatrics, University of Pavia, Piazza Borromeo 2, 27100, Pavia, Italy. · Brain Res Brain Res Rev. · Pubmed #11744094 No free full text.

Abstract: The biosynthetic dissociation of the adrenocortical secretion occurring with age may have a pathogenetic role in the pathophysiology of brain aging. We studied cortisol and DHEAS secretion in healthy old and young subjects, in senile dementia, in major depression of elderly subjects and in healthy centenarians. A clear age-related decline of DHEAS secretion was well evident in healthy centenarians, and a further decrease in DHEAS concentration was found in old depressed patients and moreover in the demented ones, by comparison with age-matched controls. The circadian profile of serum cortisol was clearly flattened in old subjects, due to the selective increase in the cortisol nocturnal levels, particularly evident in demented subjects; on the other hand, the morning serum cortisol levels were not significantly different among centenarians, young and old controls. The molar ratio between cortisol and DHEAS showed a significant age-related increase; the occurrence of senile dementia and of major depression played an additive role, by comparison to physiological aging. The qualitative and quantitative modifications of the adrenocortical secretion occurring with aging seem mainly dependent on age itself, but the occurrence of pathological conditions may amplify these changes. Since cortisol and DHEAS play opposite effects on the central nervous system, the evaluation of the ratio between cortisol and DHEAS seems to be a good marker of the neuroendocrine features in old subjects.

De Vreese LP, Neri M, Fioravanti M, Belloi L, Zanetti O. · Special Care Unit for Dementia Patients, Health Care Facility for Elderly, Via Paul Harris 165, 41100 Modena, Italy. · Int J Geriatr Psychiatry. · Pubmed #11536347 No free full text.

Abstract: BACKGROUND: Memory rehabilitation is a sadly misrepresented area of applied research in Alzheimer's disease. OBJECTIVES: To gather and evaluate recent evidence for the clinical effectiveness or ecologically validity of memory rehabilitation for mild to moderate Alzheimer's patients. METHODS: Computerised searches and some handsearching were conducted spanning the last five years, from 1995 to 2000, inclusively. Criteria for inclusion in this overview involved the use of a precise memory rehabilitation technique within an experimental study design applied to Alzheimer's patients with pre- and post-treatment evaluation. FINDINGS: Three potential levels of memory rehabilitation procedures with proven clinical or pragmatic efficacy were identified. The first level bears on the facilitation of residual explicit memory with structured support both at encoding and at subsequent recall; the second level of memory rehabilitation exploits the relatively intact implicit memory system (priming and procedural memory); the last deals with finding ways of coping with the patient's limited explicit memory capacities through the use of external memory aids. A proposal of suggestions for good practice and future research in memory rehabilitation is also offered with the hope to spur further development in this rapidly expanding area of applied research. CONCLUSION: The available evidence shows that alternative and innovative ways of memory rehabilitation for Alzheimer's patients can indeed be clinically effective or pragmatically useful with a great potential for use within the new culture of a more graded and proactive type of Alzheimer's disease care.

Ferrari E, Fioravanti M, Magri F, Solerte SB. · Department of Internal Medicine, Geriatrics and Gerontology Clinic, Post-graduate School of Geriatrics and Endocrinology, University of Pavia, Piazza Borromeo 2, 27100 Pavia, Italy. · Ann N Y Acad Sci. · Pubmed #11268387 No free full text.

Abstract: A link between neuroendocrine and immunological changes has been suggested in the pathophysiology of dementia of the Alzheimer's type (DAT). Healthy young and old subjects and patients with DAT were recruited to evaluate the chrononeuroendocrine organization of cortisol, GH, and melatonin (MLT) secretions. The study was carried out together with the evaluation of natural killer (NK) cell function: cytotoxic activity (NKCC) and TNF-alpha and IFN-gamma release after exposure to IL-2 (100 U/mL). Moreover, a cerebral morphometric analysis of hippocampus and temporal lobe (MRI) was performed. The activation of hypothalamo-pituitary-adrenal (HPA) axis and the decrease of GH, and MLT nocturnal peaks were associated with normal NKCC and TNF-alpha/IFN-gamma in healthy elderly subjects, whereas in DAT patients the same neuroendocrine changes occurred together with abnormal NKCC (spontaneous and IL-2/IFN-beta-modulated) and with alterations of TNF-alpha/INF-gamma generation from NK. Moreover significant correlations among the increase of NKCC and TNF-alpha and the decrease of cognitive function were found in the DAT group. These correlations were associated with the impairment of nocturnal GH and MLT levels and with the relatively higher serum cortisol concentrations. Moreover, the impairment of cortisol suppression after dexamethasone (1 mg orally at 23:00) was significantly correlated with the increase of spontaneous release of TNF-alpha and with IL-2-modulated NKCC. Finally the imunoneuroendocrine alterations found in DAT were associated with the reduction of cerebral volume in hippocampus and temporal lobes. Taken together these data indicate that the immunoneuroendocrine balance is maintained in physiological aging, whereas NK immune dysregulation in DAT could contribute to altering the neuroendocrine functions and to extend the progression of neurodegeneration and dementia.

Solerte SB, Fioravanti M, Racchi M, Trabucchi M, Zanetti O, Govoni S. · Department of Internal Medicine, University of Pavia, Italy. · Maturitas. · Pubmed #10227001 No free full text.

Abstract: The positive efficacy of estrogen replacement therapy (ERT) in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD) is a matter of intense debate among clinicians and neuroscientists. The experimental and preliminary clinical evidence supporting the use of ERT are based on epidemiological data and on the study of the effect of estrogens on several aspects of brain homeostasis, including the modulation of neurotransmitters and vascular changes. In spite of numerous data available the mechanisms underlying the putative estrogen effects in neurodegenerative diseases are largely unknown. The aim of this paper is to discuss and elaborate on some of the hypotheses and controversial findings currently present in this field.

Solerte SB, Ceresini G, Ferrari E, Fioravanti M. · Department of Internal Medicine, Geriatrics and Gerontology Clinic, School of Geriatrics, University of Pavia, Ospedale S.Margherita, Piazza Borromeo 2, 27100, Pavia, Italy. · Neurobiol Aging. · Pubmed #10867211 No free full text.

Abstract: An association between hemorheological alterations (i.e., whole-blood and plasma hyperviscosity, reduced erythrocyte deformability, increased red cell aggregation, hyperfibrinogenemia and increased acute-phase protein levels) and the mild stage of senile dementia of the Alzheimer's type (DAT) was suggested in the present study. In particular, hyperfibrinogenemia and the increase of erytrhocyte aggregation were correlated with the increased generation and release of TNF-alpha and IFN-gamma (spontaneous release and IL-2-modulated release) from natural killer (NK) lymphocytes (CD16+, CD56+, CD3- cells) of patients with DAT; whereas a normal cytokine release from NK cells was found in healthy old subjects and in patients with vascular dementia (VaD). The in vitro and in vivo administration of the hemorheologic drug pentoxifylline (PTX) significantly reduced spontaneous and IL-2-modulated cytokine overproduction from NK cells (in vitro effects with 500 U/ml and 1000 U/ml/NK cells) and improved all the hemorheological parameters. Taken together, these data suggest that disturbances of cerebrovascular flow and of hemorheology could be considered a negative component related to the pathogenesis and progression of DAT neurodegeneration. The association between hemorheological changes and alterations of TNF-alpha and IFN-gamma release from NK may indicate a potential immunorheologic mechanism associated with cerebrovascular damage in DAT and could suggest the use of vascular protective drugs as support of the main pharmacological and non-pharmacological therapy of AD.

Magri F, Terenzi F, Ricciardi T, Fioravanti M, Solerte SB, Stabile M, Balza G, Gandini C, Villa M, Ferrari E. · Department of Internal Medicine and Medical Therapy, Chair of Geriatrics, University of Pavia, Italy. · Dement Geriatr Cogn Disord. · Pubmed #10705166 No free full text.

Abstract: The circadian organization of adrenal secretion was studied in 23 healthy elderly subjects, 23 elderly demented patients and 10 healthy young subjects, in order to investigate the relationships between the hypothalamic-pituitary-adrenal axis and some cerebral morphometric parameters. The cerebral morphometric analysis was performed in some subjects of the three groups by MRI. A significant increase in cortisol levels during evening and nighttime was found in both groups of the aged subjects. In elderly subjects, particularly if demented, the mean serum dehydroepiandrosterone sulfate (DHEAs) levels throughout the 24-hour cycle were significantly lower than in young controls. A significant reduction of the hippocampal and temporal volume and an enlargement of the lateral ventricles were found in aged subjects, these changes being significantly related to subjects' age. Moreover, the hippocampal volume was positively correlated with the circadian mesor of DHEAs (i.e., the circadian rhythm adjusted mean) and with the cortisol nocturnal increase. Our data may suggest the existence of a link between the selective impairment of cortisol secretion and DHEAs levels, and the progression of hippocampal degeneration.

Fioravanti M, Carbone G, Galli N, Piccirilli E, Pierucci P. · Department of Psychiatric Science and Psychological Medicine, University of Rome La Sapienza, Rome, Italy. · J Neurol Sci. · Pubmed #17433367 No free full text.

Abstract: Vascular dementia patients show a component of their impairment as emotional. In the two studies that we present it was possible to illustrate the characteristics of such emotional component. a. The discrepancy between immediate recall and delayed recall appears to be very sensitive to anxiety interference when immediate recall is lower than delayed. b. The presence of emotional problems contributing to memory complaints in VaD patients is not equally distributed along the severity of deterioration dimension but can be identified as a specific component different from the cognitive one especially in that subgroup of patients who present an intermediate level of deterioration.

Solerte SB, Ferrari E, Cuzzoni G, Locatelli E, Giustina A, Zamboni M, Schifino N, Rondanelli M, Gazzaruso C, Fioravanti M. · Department of Internal Medicine and Geriatrics, University of Pavia, Pavia, Piazza Borromeo 2, IT-27100, Italy. · Dement Geriatr Cogn Disord. · Pubmed #15383738 No free full text.

Abstract: Changes of vascular endothelial growth factor (VEGF) secretion have recently been demonstrated in patients with Alzheimer's disease (AD). Since VEGF has been involved in brain angiogenesis, neuroprotection and cerebromicrovascular exchange of substrates and nutrients, the study of VEGF could have important relapses into the pathogenesis and treatment of AD. Within this context, 35 healthy subjects (16 of young and 19 of old age), 18 patients with dementia of the vascular type (VAD) and 22 with dementia of the Alzheimer's type (AD) were included in the study. VEGF levels were determined in the supernates of circulating natural killer (NK) immune cells isolated by immunomagnetic separation (pure CD16 + CD56 + NK cells at a final density of 7.75 x 10(6) cells/ml). VEGF was measured in spontaneous conditions (without modulation) and after exposure of NK cells with IL-2, lipopolysaccharide (LPS), dehydroepiandrosterone sulfate (DHEAS), LPS + insulin, amyloid-beta (Abeta) fragment 1-42, the inactive sequence Abeta(40-1) and Abeta(1-42) + insulin. A significant decrease in VEGF released by NK cells was demonstrated in AD subjects compared to the other groups. No differences of VEGF levels were found between healthy subjects of old age and the VAD group. The incubation with LPS and DHEAS significantly increased, in a dose-dependent manner, VEGF levels in AD as well as in healthy subjects of young and old age and in VAD patients. The incubation of NK cells with Abeta(1-42) completely suppressed VEGF generation in AD subjects, also reducing VEGF release in the other groups. The co-incubation of NK with LPS + insulin, at different molar concentrations, significantly restored (4- and 6-fold increase from LPS alone) VEGF in AD, also enhancing VEGF secretion in healthy subjects and the VAD group, while the co-incubation of NK with Abeta(1-42) + insulin promptly abolished the negative effects of Abeta(1-42) on VEGF release. These data might suggest that the decreased VEGF secretion by peripheral immune cells of AD subjects could have a negative role for brain angiogenesis, neuroprotection and for brain microvascular permeability to nutrients, increasing brain frailty towards hypoxic injuries. On the contrary, insulin and DHEAS could have beneficial effects in AD, as well as in VAD and in physiological aging, by increasing, in a dose-dependent fashion, VEGF availability by peripheral and resident immune and endothelial cells, so contributing to increase its circulating pool.

Solerte SB, Cerutti N, Mirani M, Ceresini G, Giusti A, Ferrari E, Fioravanti M. · Department of Internal Medicine, University of Pavia, Italy. · J Endocrinol Invest. · Pubmed #12508915 No free full text.

This publication has no abstract.

Solerte SB, Cravello L, Ferrari E, Fioravanti M. · Department of Internal Medicine, Geriatrics and Gerontology Clinic, Postgraduate School of Geriatrics, University of Pavia, Piazza Borromeo 2, 27100 Pavia, Italy. · Ann N Y Acad Sci. · Pubmed #11268360 No free full text.

Abstract: Alterations of natural killer (NK) function can be involved in the neuroimmune mechanism of neurodegeneration in dementia of the Alzheimer's type (DAT). NK cell cytotoxicity (NKCC) and the generation and release of IFN-gamma and TNF-alpha (spontaneous and modulated by IL-2) from pure NK cells (CD 16+, CD 56+, CD 3-) were studied together with circulating IFN-gamma and TNF-alpha levels and cognitive function in 22 old patients with DAT and 15 healthy old subjects. Higher (p < 0.001) IL-2 modulated NKCC (with IL-2 50 U/mL and 100 U/mL) was demonstrated in DAT patients (+35% and +99% from baseline) than in healthy subjects (+6% and +76% from baseline). Increased spontaneous and IL-2-induced release of IFN-gamma and TNF-alpha from NK cells were found in DAT patients compared to healthy subjects (p < 0.001), whereas no difference of serum IFN-gamma and TNF-alpha was demonstrated between DAT and control groups. Significant negative correlations among the spontaneous release of IFN-gamma and TNF-alpha from NK and the decrease of the score of cognitive function (MMSE) were found in patients with DAT. In conclusion, alterations of NKCC control and NK-derived cytokine release in DAT could be involved in the neuroinflammatory mechanism related to the progression of neurodegeneration and dementia.

Ferrari E, Arcaini A, Gornati R, Pelanconi L, Cravello L, Fioravanti M, Solerte SB, Magri F. · Department of Internal Medicine and Medical Therapy, Chair of Geriatrics, University of Pavia, P.zza Borromeo 2, 27100, Pavia, Italy. · Exp Gerontol. · Pubmed #11113605 No free full text.

Abstract: The simultaneous evaluation of the circadian rhythm of plasma melatonin and ACTH and of serum cortisol and DHEAS represents a clinically reliable tool to appreciate the neuroendocrine changes occurring in physiological and pathological brain aging.A selective impairment of the nocturnal melatonin secretion has been observed in elderly subjects, being significantly related either to the age or to the severity of dementia. A significant increase of serum cortisol levels during evening- and night-times was found in elderly subjects, particularly if demented, when compared to young controls. Besides, both the circadian amplitude of cortisol rhythm and the nocturnal cortisol increase were significantly reduced in relation either to age or to cognitive impairment. By comparison to vascular dementia, patients with Alzheimer's disease exhibited the highest cortisol concentrations throughout the 24h. The sensitivity of the hypothalamic-pituitary-adrenal axis to the steroid feedback was significantly impaired in old subjects and particularly in the demented ones. The serum DHEAS levels were significantly lower in elderly subjects and even more in demented patients than in young controls. Consequently, a significant increase of the cortisol/DHEAS molar ratio was evident when going from young controls to healthy elderly subjects and to demented patients.In conclusion, the aging process affects many neuroendocrine functions resulting in subtle but clinically relevant consequences; the occurrence of senile dementia seems to play an additive role.

Solerte SB, Gornati R, Cravello L, Albertelli N, Oberti S, Perotta D, Rossi G, Cuzzoni G, Ferrari E, Fioravanti M. · Department of Internal Medicine, Chair of Geriatrics, University of Pavia, Italy. · J Endocrinol Invest. · Pubmed #10727032 No free full text.

This publication has no abstract.