Jorge A. Serra

Parkinson's disease is associated with oxidative stress: comparison of peripheral antioxidant profiles in living Parkinson's, Alzheimer's and vascular dementia patients

Summary. Antioxidant profiles in Parkinsons disease (PD; n = 15), dementias of Alzheimers type (DAT; 18) and Vascular (VD; 15), and control subjects (C; 14) were studied. Cu-Zn superoxide dismutase (SOD), catalase (CAT), glutathione system (GLU) and thiobarbituric acid reactive substances (TBARS) were measured in erythrocytes; antioxidant capacity (TRAP) in plasma. Biochemical variables were analyzed simultaneously using multivariate and non-parametric methods. Clinical diagnostic resulted associated with the main source of variability in antioxidant variables (Kruskal-Wallis: H = 32.58, p = 0.000001). Comparison of PD and C resulted highly significant (z = 4.47, p = 0.000047), demonstrating an association between oxidative stress and PD. SOD and TBARS were significantly higher in pathological groups against C (p = 0.0000001, p = 0.051); TRAP resulted lower (p = 0.00015). Discriminant functions constructed using biochemical variables separated pathological groups (93% success) from C, and DAT (88.9%) from VD (73.3%); but not PD from DAT or VD. Antioxidant profiles of PD patients showed characteristics overlapping with DAT (60%) and with VD (40%), suggesting biochemical similarities between them.

Copper-zinc superoxide dismutase activity in red blood cells and serum in demented patients and in aging

The activity of the enzyme copper-zinc superoxide dismutase (Cu-Zn SOD) has been investigated in serum and red blood cells (RBC) homogenate obtained from demented patients with associated vascular lesions (VD), demented patients with probable Alzheimers disease (DAT) and healthy controls (CG) of the same age. The increase in SOD activity was statistically significant (P < 0.01) in RBCs homogenate of DAT and VD patients, when compared to controls, but no differences appear between the two diseases groups. Additionally, a statistically significant increase in SOD activity (P < 0.01) in DAT patients above 70 years as compared to those 50-70 years old, and a relation between SOD and age were found. No changes in SOD activity with age in healthy controls nor in vascular dementia group were detected. A statistically significant increase in Circulating SOD activity (P < 0.01) was observed in vascular patients compared to controls. The observed increase in DAT Circulating SOD activity (against CG) was not significant. The increased levels of Cu-Zn SOD, probably represent a general alteration of the oxidative processes characteristic of these dementias and suggest that the enzyme might be used as a marker.

The antioxidant enzymatic blood profile in Alzheimer's and vascular diseases. Their association and a possible assay to differentiate demented subjects and controls

A study of several elements of the antioxidative system: Cu-Zn superoxide dismutase (SOD), catalase (CAT), glutathione system (GLU), chemiluminescence (CHE), and antioxidant capacity (AOX), was conducted in 20 demented probable Alzheimers (DAT), and 15 vascular demented (VD) patients, 19 control (C) subjects, and 11 relatives (F) of one DAT patient. A significant association was found between the variables of the antioxidant system, measured in blood samples, and the neurological pathologies VD and DAT: Kruskal-Wallis test; p = 0.0006 (p = 0.014 when the analysis did not include SOD). This demonstrated that VD and DAT diseases are accompanied by oxidative disorders. The VD and DAT diseases are differentially distinguishable by changes in blood profiles. A graphical method for classification, the Principal Components Analysis (PCA), distinguished between demented and non-demented subjects on the basis of their laboratory variables. A numerical method, Discriminant Functions (DF), constructed to separate the clinical groups on the basis of the same variables, obtained relatively high percentages of success: 92% of demented were detected against healthy subjects; of the latter 82% have been correctly identified as non-demented. Discrimination between VD and DAT patients was achieved for 100% of VD and 86% of DAT patients. DF were similarly successful in detecting the healthy condition of DAT relatives. Possible different mechanisms involved in H2O2 elimination in DAT and VD patients are proposed, where CAT is the responsible enzyme of this reaction in DAT patients, while in VD this function would be achieved mainly through the action of GLU. It seems that SOD levels are stable, at least, within one year. Variations appear to be linked with clinical changes.

Copper-zinc superoxide dismutase activity in red blood cells in probable Alzheimer's patients and their first-degree relatives

The activity of the enzyme copper-zinc superoxide dismutase (Cu-Zn SOD) has been investigated in red blood cell (RBC) homogenate obtained from demented patients with probable Alzheimers disease (DAT), from their first-degree relatives (sisters/brothers and sons/daughters), and from healthy control families of the same age. A statistically significant increase in SOD activity (P < 0.01) was found in RBCs homogenate between families of DAT patients (not including the demented individual) and control families. Variability in SOD activity due to differences between families was not significant for DAT relatives; a significant variance component (P < 0.05) was found between control families. Additionally, a statistically significant increase in SOD activity (P < 0.001) with age in DAT patients up to 70 years and a significant decrease above this age were found, confirming a previously found relation. No changes in SOD activity with age were detected in healthy controls nor in DAT relatives. The increased levels of Cu-Zn SOD, probably represent a general alteration of the oxidative processes characteristic of this dementia and support the proposal that the enzyme could be used as an early diagnostic peripheral marker of the Alzheimers disease (AD), and to determine to which subgroup the patient belongs, as well as a risk factor in non-demented first-degree relatives.

Oxidative stress in Alzheimer's and vascular dementias: masking of the antioxidant profiles by a concomitant Type II diabetes mellitus condition

Oxidative stress is associated with Alzheimers (DAT) and vascular (VD) dementias, as well as Type II diabetes mellitus (DIAB) and affected by hypoglycemic therapy. The population (n = 122; males = 60; mean age = 72.57 +/- 7.06) consisted of controls (CTR), DAT and VD patients, with (DAT + DIAB, VD + DIAB) and without concomitant DIAB, resulting in six groups where the antioxidant profile was determined: copper-zinc superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), and total antioxidant capacity (TRAP). The results were analyzed using a two-way ANOVA design and Bonferroni statistic. The ANOVAs yielded significant differences between groups for all components of the profile: SOD, p = 0.00000006; TBARS, p = 0.0000012; TRAP, p = 0.0000003. The significance level for comparisons between groups was set at alpha = 0.05. The comparisons DIAB vs. CTR, DAT+DIAB vs. DAT, and DIAB demented vs. DIAB non-demented resulted significant for all variables. VD + DIAB vs. VD resulted significant for all variables except TRAP. The antioxidant profiles of DIAB and CTR are different. The differences cannot be directly related with what is observed in dementias. The differences in profiles of demented and non-demented are somewhat hidden when demented patients are affected by a concomitant DIAB condition and/or hypoglycemic treatment, thus conditioning the diagnostic value for dementias of the profiles.

Comparison of the determination of superoxide dismutase and antioxidant capacity in neurological patients using two different procedures

As oxidative stress in relation with neurological diseases has become an important point in recent research, simple methods to be used in epidemiological studies and clinical practice are required. The hypothesis that the analytical methods used in research laboratories (RLM) can be used interchangeably with commercial kits (CKM) for SOD and TRAP is tested. Both methods were compared using linear transformations of the RLM measurements into the CKM scales. Data were obtained from Alzheimers, Parkinsons, and vascular dementia patients and controls. The lack of fit and the runs test of residuals were not significant, but the same sign method detected significant nonlinearities (P<0.000001 for SOD, P<0.01 for TRAP). The intragroup CVs of both methods were comparable for TRAP, while in the RLM determinations of SOD resulted in <50% of those obtained with the CKM. The ANCOVA comparison of the regression parameters across the clinical groups resulted significant for SOD (P<0.0001) and not significant for TRAP. Both methods agree in describing the features of the clinical groups, but the degree of agreement at the individual concentration was poor and they could not be readily intercalibrated. Normal and pathological values should be obtained independently for the CKM to insure their applicability to large populations.

Free Radicals, Oxidative Stress and Oxidative Damage in Parkinson's Disease

Parkinson’s disease (PD) is an adult-onset disease of unknown etiology, with a prevalence of 0.3% in the entire population, affecting more than 1% of humans over 60 years of age. Primary degeneration occurs in pigmented dopamine-containing neurons in the pars compacta of the substantia nigra, with projections to the striatum and typical motor signs that appear with a loss of 60% of the dopaminergic neurons of the brain area. While 90-95% of PD cases have no known genetic basis, approximately 5-10% arises from inherited mutations (Farooqui & Farooqui, 2011). While the actual physiopathology of PD remains uncertain, it is currently suggested that the molecular mechanism of the vulnerability of dopaminergic neurons in the substantia nigra involves monoamine oxidase-mediated abnormal dopamine metabolism, hydrogen peroxide generation, and abnormal mitochondrial and proteosomal dysfunctions along with microglia cell activation which may be closely associated with neurodegenerative process. The loss of dopaminergic neurons in the substantia nigra may be related to resting tremor, rigidity, bradykinesia, postural instability, and gait disturbance in PD patients. Also associated with PD neuropathology are disrupted iron homeostasis, intracellular deposition of proteins in Lewy bodies, and oxidative stress and neuronal damage. PD is considered the paradigm of -synucleinopathies within the spectrum of neurodegenerative diseases that exhibit -synuclein in cytosolic protein aggregates (Navarro et al., 2009). There is evidence that oxidative stress participates in the neurodegeneration (Lustig et al., 1993; Famulari et al., 1996; Repetto et al., 1999; Fiszman et al., 2003; Dominguez et al., 2008); neutrophils express a primary alteration of nitric oxide release in PD patients, where reactive oxygen species and oxidative stress parameters are more probably related to the evolution of PD (Gatto et al., 1996; Gatto et al., 1997; Repetto & Llesuy, 2004). Peripheral markers of oxidative stress in red blood cells of neurological patients could be a reflection of the brain condition and suggests that oxygen free radicals are partially responsible for the damage observed in PD living patients (Serra et al., 2001; Repetto, 2008). Other reports suggest that mitochondrial dysfunction and impairment of the respiratory complexes are associated with the neuronal loss (Boveris & Navarro, 2008). Moreover, increased mDNA deletions were recognized in nigral neurons in PD (Bender et al., 2006).

Daily Living Activities and Cognition in Aged Patients: Effect of Acute Systemic Diseases and Stroke on Leukoaraiosis

Background: Acute Systemic Diseases (ASD) impact on extended leukoaraiosis (ExL-A) have been seldom described. We study the deterioration in daily life activities (DLA) and cognition associated with ASD events compared with the well-described impacts of stroke in patients with leu-koaraiosis (L-A). Methods: Cross-sectional surveys of aged adults from the emergency room after an acute event of ASD or stroke, hospitalized or receiving home care, were followed for one year. From 268 initial pa-tients 206 were included in the study, all with moderate to severe L-A (Fazekas 2 and 3). The Clinical Deterioration Rating (CDR) and the modified Rankin scale with structured interview were obtained one week previous to admission and after 3 and 12 months of evolution. Comparisons were conduct-ed within and between groups with nonparametric techniques. Results: We formed three groups of similar age, A: Inpatients with one Stroke, B: Inpatients with one ASD, and C: Outpatients with one ASD. A sudden deterioration in Rankin was evident in Group A, while in B and C impairment was progressive. Impairment in CDR was smooth in all groups while in Rankin it was always greater than in cognition (CDR). No differences were found in the associations between groups and risk factors, hypertension being the most frequent one. Conclusion: ASD in ExL-A causes a worsening of DLA and cognition similar to that observed in ExL-A with concomitant stroke indicating the need, in ageing patients, of differential diagnosis in or-der to achieve the best possible treatment.