Gianluigi Vendemiale

Late-life depression, mild cognitive impairment, and dementia: possible continuum?

Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%-83%) than in population-based studies (median: 15.7%, range: 3%-63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.

Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia–reperfusion injury

Background: The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in the progression of non-alcoholic steatohepatitis (NASH) as mitochondria are the main cellular site of fatty acid oxidation, ATP synthesis and reactive oxygen species (ROS) production. Aims: (1) To evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH rats and humans; and (2) to assess the acute liver damage induced by ischaemia–reperfusion in rats with NASH. Methods: Mitochondria were extracted from the livers of NASH humans and rats fed a methionine and choline deficient diet. Proton leak, H2O2 synthesis, reduced glutathione/oxidised glutathione, 4-hydroxy-2-nonenal (HNE)–protein adducts, uncoupling protein-2 (UCP2) expression and ATP homeostasis were evaluated before and after ischaemia–reperfusion injury. Results: NASH mitochondria exhibited an increased rate of proton leak due to upregulation of UCP2. These results correlated with increased production of mitochondrial hydrogen peroxide and HNE–protein adducts, and decreased hepatic ATP content that was not dependent on mitochondrial ATPase dysfunction. The application of an ischaemia–reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibited UCP2 over-expression and mitochondrial oxidative stress. Conclusions: Upregulation of UCP2 in human and rat NASH liver induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischaemia–reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.

Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress

Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in primary biliary cirrhosis and prolongs survival free of liver transplantation. Recently, it was suggested that the cytoprotective mechanisms of UDCA may be mediated by protection against oxidative stress, which is involved in the development of cirrhosis induced by chronic cholestasis. The aims of the current study were 1) to identify the mechanisms involved in glutathione depletion, oxidative stress, and mitochondrial impairment during biliary cirrhosis induced by chronic cholestasis in rats; and 2) to determine the mechanisms associated with the protective effects of UDCA against secondary biliary cirrhosis. The findings of the current study indicate that UDCA partially prevents hepatic and mitochondrial glutathione depletion and oxidation resulting from chronic cholestasis. Impairment of biliary excretion was accompanied by decreased steady‐state hepatic levels of γ‐glutamyl cysteine synthetase and γ‐cystathionase messenger RNAs. UDCA treatment led to up‐regulation of γ‐glutamyl cysteine synthetase in animals with secondary biliary cirrhosis and prevented the marked increases in mitochondrial peroxide production and hydroxynonenal‐protein adduct production that are observed during chronic cholestasis. A population of damaged and primarily apoptotic hepatocytes characterized by dramatic decreases in mitochondrial cardiolipin levels and membrane potential as well as phosphatidylserine exposure evolves in secondary biliary cirrhosis. UDCA treatment prevents the growth of this population along with the decreases in mitochondrial cardiolipin levels and membrane potential that are induced by chronic cholestasis. In conclusion, UDCA treatment enhances the antioxidant defense mediated by glutathione; in doing so, this treatment prevents cardiolipin depletion and cell injury in animals with secondary biliary cirrhosis. (HEPATOLOGY 2004;39:711–720)

Nutraceutical properties of Mediterranean diet and cognitive decline: possible underlying mechanisms.

Recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from mild cognitive impairment to Alzheimers disease (AD), reduced risk of AD, and decreased mortality in AD patients. Furthermore, the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. At present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids, and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA), and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for vascular dementia, cognitive decline, and predementia syndromes, the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally support a protective role of these macronutrients against cognitive decline, dementia, and AD. We reviewed evidence on the possible mechanisms underlying the suggested protective role of MeDi against age-related changes in cognitive function, predementia syndromes, and dementia, examining the possible role of macronutrients and food nutrients of the MeDi and their nutraceutical properties in modulating the risk of cognitive decline. Although vascular variables are likely to be in the causal pathway between MeDi and dementia syndromes and should be considered as possible mediators, other nonvascular biological mechanisms (i.e., metabolic, oxidative, and inflammatory) may be invoked to explain the complex epidemiological association between MeDi and cognitive decline.

Metabolic Syndrome and Cognitive Impairment: Current Epidemiology and Possible Underlying Mechanisms

A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimers disease, AD) or vascular origin (vascular dementia, VaD). At present, cumulative evidence suggests that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome (MetS) has been associated with the risk of cognitive decline, overall dementia, and VaD, but contrasting findings also existed on the possible role of MetS in AD. If MetS is associated with increased risk of developing cognitive impairment, regardless of mechanism, then early identification and treatment of these individuals at risk might offer new avenues for disease-course modification. Strategies towards early and effective risk factor management could be of value in reducing risk of metabolic and cognitive decline. Future research is needed to confirm the association between MetS and cognitive impairment and to determine the exact mechanism linking them. Such would provide important insights into the causes and interdependencies of predementia and dementia syndromes, and inspire novel strategies for treating and preventing these disorders. At present, vascular risk factor and MetS management could be employed to delay the onset of dementia syndromes or to prevent the progression of predementia syndromes. In the future, trials could be undertaken to determine whether modifications of these risk factors, including inflammation, could lower risk of developing cognitive decline.

Free radical biology for medicine: learning from nonalcoholic fatty liver disease

Reactive oxygen species, when released under controlled conditions and limited amounts, contribute to cellular proliferation, senescence, and survival by acting as signaling intermediates. In past decades there has been an epidemic diffusion of nonalcoholic fatty liver disease (NAFLD) that represents the result of the impairment of lipid metabolism, redox imbalance, and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the processes leading toward the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) α/γ/δ, PPARγ coactivators 1α and 1β, sterol-regulatory element-binding proteins, AMP-activated protein kinase, liver-X-receptors, and farnesoid-X-receptor, play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate various metabolic pathways in response to specific molecules that act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to metabolism alterations in fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.

Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing

Objective The authors investigated the relationship of metabolic syndrome (MetS) and its individual components with incident dementia in a prospective population-based study with a 3.5-year follow-up. Methods A total of 2097 participants from a sample of 5632 subjects (65–84 years old) from the Italian Longitudinal Study on Ageing were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Dementia, Alzheimer disease (AD) and vascular dementia (VaD) were classified using current published criteria. Results MetS subjects (N=918) compared with those without MetS (N=1179) had an increased risk for VaD (1.63% vs 0.85%, adjusted hazard ratio (HR) 3.71, 95% CI 1.40 to 9.83). After excluding 338 subjects with baseline undernutrition, MetS subjects compared with those without MetS had an elevated risk of VaD (adjusted HR, 3.82; 95% CI 1.32 to 11.06). Moreover, those with MetS and high inflammation had a still further higher risk of VaD (multivariate adjusted HR, 9.55; 95% CI 1.17 to 78.17) compared with those without MetS and high inflammation. On the other hand, those with MetS and low inflammation compared with those without MetS and low inflammation did not exhibit a significant increased risk of VaD (adjusted HR, 3.31, 95% CI 0.91 to 12.14). Finally, a synergistic MetS effect versus its individual component effects was verified on the risk of VaD. Conclusion In our population, MetS subjects had an elevated risk of VaD that increased after excluding patients with baseline undernutrition and selecting MetS subjects with high inflammation.

Oxidation of circulating proteins in alcoholics: role of acetaldehyde and xanthine oxidase

BACKGROUND/AIMS This study aimed to evaluate the protein and lipid redox status in plasma erythrocytes and erythrocyte ghosts of alcoholics and of patients with non-alcoholic liver disease; we also investigated the relation to glutathione levels and the role of acetaldehyde and xanthine oxidase activity in plasma. METHODS Carbonyl and sulfhydryl proteins, glutathione and malondialdehyde levels and the activity of the circulating xanthine oxidase were determined in: active and abstinent alcoholics, patients with chronic viral hepatitis and healthy controls. RESULTS Active alcoholics showed a decrease of sulfhydryl protein and glutathione concentrations in plasma, erythrocytes and ghosts compared to the other groups. Also, an increase of the carbonyl protein and malondialdehyde levels and of the activity of circulating xanthine oxidase (9.2 +/- 1.8 nmol.min.ml, p < 0.001) were observed. Significant correlations between carbonyl protein and malondialdehyde concentrations in plasma (r = 0.775, p < 0.001), as well as between daily alcohol intake and carbonyl protein content in plasma (r = 0.879, p < 0.001) and erythrocytes (r = 0.605, p < 0.01) were observed. However, carbonyl protein levels did not correlate with the degree of liver injury. Incubation of plasma with acetaldehyde, but not with ethanol, significantly increased the carbonyl protein formation. Administration of N-Ethylmaleimide, a thiol depletor, or glutathione significantly increased or delayed, respectively, the carbonyl protein formation. CONCLUSIONS Proteins are oxidatively modified in plasma and erythrocytes of active alcoholics, whereas no such alterations are detectable in patients with non-alcoholic liver disease. Protein oxidation in alcoholics does not seem to result directly from ethanol; circulating xanthine oxidase, delivered from injured cells, may play a contributory role and glutathione appears to be directly involved in the protection of plasma proteins against acetaldehyde toxicity.

Dietary fatty acids in dementia and predementia syndromes: epidemiological evidence and possible underlying mechanisms.

Drugs currently used in the treatment of cognitive impairment and dementia have a very limited therapeutic value, suggesting the necessity to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. An increasing body of epidemiological evidence suggested that elevated saturated fatty acids (SFA) could have negative effects on age-related cognitive decline (ARCD) and mild cognitive impairment (MCI). Furthermore, a clear reduction of risk for cognitive decline has been found in population samples with elevated fish consumption, high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. Epidemiological findings demonstrated that high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. Several hypotheses could explain the association between dietary unsaturated fatty acids and cognitive functioning, including mechanisms through the co-presence of antioxidant compounds in food groups rich in fatty acids, via atherosclerosis and thrombosis, inflammation, accumulation of b-amyloid, or via an effect in maintaining the structural integrity of neuronal membranes, determining the fluidity of synaptosomal membranes that thereby regulate neuronal transmission. However, recent findings from clinical trials with n-3 PUFA supplementation showed efficacy on depressive symptoms only in non-apolipoprotein E (APOE) epsilon4 carriers, and on cognitive symptoms only in very mild Alzheimers disease (AD) subgroups, MCI patients, and cognitively unimpaired subjects non-APOE epsilon4 carriers. These data together with epidemiological evidence support a possible role of fatty acid intake in maintaining adequate cognitive functioning and possibly for the prevention and management of cognitive decline and dementia, but not when the AD process has already taken over.

Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat

Changes in cell energy metabolism and mitochondrial dysfunction have been observed after acetaminophen administration. Because consumption of hepatic glutathione is closely related to acetaminophen toxicity, we investigated the kinetics of: 1. glutathione depletion in liver mitochondria and cytosol; 2. State 3 and 4 respiratory rates of succinate-supplemented mitochondria; 3. rate of ATP synthesis; 4. oligomycin-sensitive ATP hydrolase activity and passive proton conductivity of inside-out vesicles of the inner mitochondrial membrane; and 5. changes in hepatic and mitochondrial malondialdehyde in the rat after in vivo acetaminophen administration. Two hours after acetaminophen injection, hepatic glutathione decreased and malondialdehyde increased. In the same interval, an increase in both State 3 and 4 respiratory rates of succinate-supplemented mitochondria was observed. This was accompanied by a decrease in the rate of ATP synthesis and the P/O ratio and by an increase in the passive proton permeability of the inner mitochondrial membrane, which was insensitive to oligomycin. No significant change in oligomycin-sensitive ATP hydrolase activity was observed. Four hours after APAP injection, the respiratory rates, as well as the proton conductivity, decreased, the rate of ATP synthesis was restored, and the mitochondrial glutathione started to increase; the cytosolic levels of glutathione were still low and the cytosolic and mitochondrial levels of malondialdehyde remained high for 2 more hr. The concentrations of these indices were completely restored 24 hr postdosing. Our findings suggest that acetaminophen administration selectively depletes (within 2 hr) mitochondrial glutathione, and produces local toxicity by altering membrane permeability and decreasing the efficiency of oxidative phosphorylation. This renders mitochondria more susceptible to oxidative damage, especially during increased free radical production, as in the case of enhanced mitochondrial respiration in State 4. The concomitant restoration of mitochondrial respiration, oxidative phosphorylation, membrane permeability, and glutathione levels is consistent with the importance of the mitochondrial glutathione pool for the protection of the mitochondrial membrane against oxidative damage.