R.O. Domínguez

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.

Combining physical training with transcranial direct current stimulation to improve gait in Parkinson’s disease: a pilot randomized controlled study

Objective: To improve gait and balance in patients with Parkinson’s disease by combining anodal transcranial direct current stimulation with physical training. Design: In a double-blind design, one group (physical training; n = 8) underwent gait and balance training during transcranial direct current stimulation (tDCS; real/sham). Real stimulation consisted of 15 minutes of 2 mA transcranial direct current stimulation over primary motor and premotor cortex. For sham, the current was switched off after 30 seconds. Patients received the opposite stimulation (sham/real) with physical training one week later; the second group (No physical training; n = 8) received stimulation (real/sham) but no training, and also repeated a sequential transcranial direct current stimulation session one week later (sham/real). Setting: Hospital Srio Libanes, Buenos Aires, Argentina. Subjects: Sixteen community-dwelling patients with Parkinson’s disease. Interventions: Transcranial direct current stimulation with and without concomitant physical training. Main measures: Gait velocity (primary gait outcome), stride length, timed 6-minute walk test, Timed Up and Go Test (secondary outcomes), and performance on the pull test (primary balance outcome). Results: Transcranial direct current stimulation with physical training increased gait velocity (mean = 29.5%, SD = 13; p < 0.01) and improved balance (pull test: mean = 50.9%, SD = 37; p = 0.01) compared with transcranial direct current stimulation alone. There was no isolated benefit of transcranial direct current stimulation alone. Although physical training improved gait velocity (mean = 15.5%, SD = 12.3; p = 0.03), these effects were comparatively less than with combined tDCS + physical therapy (p < 0.025). Greater stimulation-related improvements were seen in patients with more advanced disease. Conclusions: Anodal transcranial direct current stimulation during physical training improves gait and balance in patients with Parkinson’s disease. Power calculations revealed that 14 patients per treatment arm (α = 0.05; power = 0.8) are required for a definitive trial.

Type 2 diabetes and/or its treatment leads to less cognitive impairment in Alzheimer's disease patients

AIM To evaluate the cognitive performance of a homogeneous population of Alzheimers disease (AD), non-demented Type 2 Diabetes Mellitus (DIAB), demented with concomitant diseases (AD+DIAB) and healthy control subjects. AD is a progressive dementia disorder characterized clinically by impairment of memory, cognition and behavior. Recently, a major research interest in AD has been placed on early evaluation. Diabetes is one of the clinical conditions that represent the greatest risk of developing oxidative stress and dementia. Glucose overload, leading to the development of impaired-induced insulin secretion in DIAB and has been suggested to slow or deter AD pathogenesis. METHODS The degree of cognitive impairment was determined on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) and the Folsteins Mini Mental State Examination (MMSE); the severity of dementia was quantified applying the Clinical Dementia Rating (CDR) test; the Hamilton test was employed to evaluate depressive conditions; the final population studied was 101 subjects. RESULTS The cognitive deterioration is statistically significantly lower (p<0.05) in AD+DIAB patients as compared with AD patients. CONCLUSIONS In this longitudinal study the superimposed diabetic condition was associated with a lower rate of cognitive decline, while diabetic non-demented patients and controls present normal scores.

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.

Spanish Cross-Cultural Adaptation and Validation of the National Institutes of Health Stroke Scale

OBJECTIVES To adapt and validate a Spanish-language version (SV) of the National Institutes of Health Stroke Scale (NIHSS) to facilitate its use in Spanish-speaking contexts. PATIENTS AND METHODS The methods recommended by the International Quality of Life Assessment Project were followed. Two forward translations and 1 back translation of the NIHSS were developed to ensure lingual and cultural equivalence. A final revised SV-NIHSS was administered by 8 physicians to patients with stroke in 3 clinics in Buenos Aires, Argentina, from September 2003 to December 2003. RESULTS The study included 102 patients (mean +/- SD age, 73.3+/-6.5 years; 56% women) with stroke (86% ischemic). The SV-NIHSS mean baseline score was 9.78+/-7.04. Interrater reliability was Independently evaluated for 98 patients, showing a high agreement: kappa, 0.77 to 0.99 for the 15 items; interrater correlation coefficient, 0.991 (95% confidence Interval, 0.987-0.994). Intrarater reliability was excellent: kappa, 0.86 to 1.00 for the 15 items; mean intrarater correlation coefficient, 0.994 (95% confidence interval, 0.991-0.996). Construct validity was also adequate; the SV-NIHSS had a negative correlation with baseline Glasgow Coma Scale (Spearman coefficient = -0.574, P < .001) and with Barthel index at 3 months (Spearman coefficient = -0.658, P < .001). Patients with different Rankin scores at 3 months also had significantly different baseline SV-NIHSS scores, from a mean of 4.29+/-2.21 for Rankin score of 0 to a mean of 29.40+/-3.97 for Rankin score of 6 (P < .001). CONCLUSION This study shows that a Spanish-language version of the NIHSS developed with internationally recommended methods is reliable and valid when applied in a Spanish-speaking setting.

Improving Gait and Balance in Patients With Leukoaraiosis Using Transcranial Direct Current Stimulation and Physical Training An Exploratory Study

Background. Leukoaraiosis describes ischemic white matter lesions, a leading cause of gait disturbance in the elderly. Objective. Our aim was to improve gait and balance in patients with leukoaraiosis by combining a single session of transcranial direct current stimulation (tDCS) and physical training (PT). Methods. We delivered anodal tDCS over midline motor and premotor areas in 9 patients with leukoaraiosis. Patients underwent gait and balance training during tDCS stimulation (real/sham). This was repeated 1 week later with the stimulation crossed-over (sham/real) in a double-blind design. Assessments included gait velocity, stride length, stride length variability (primary gait outcomes), and a quantitative retropulsion test (primary balance outcome). Results. Combining tDCS and PT improved gait velocity, stride length, stride length variability, and balance (all at P ≤ .05). Overall, training without tDCS showed no significant effects. Conclusions. Combined anodal tDCS and PT improves gait and balance in this patient group, suggesting that tDCS could be an effective adjunct to PT in patients with leukoaraiosis, for whom no treatment is currently available.

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.

Enfermedad de Alzheimer y deterioro cognitivo asociado a la diabetes mellitus de tipo 2: relaciones e hipótesis

INTRODUCTION Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased risk of developing Alzheimer disease, but the relationship between the 2 entities is not clear. DEVELOPMENT Both diseases exhibit similar metabolic abnormalities: disordered glucose metabolism, abnormal insulin receptor signalling and insulin resistance, oxidative stress, and structural abnormalities in proteins and β-amyloid deposits. Different hypotheses have emerged from experimental work in the last two decades. One of the most comprehensive relates the microvascular damage in diabetic polyneuritis with the central nervous system changes occurring in Alzheimer disease. Another hypothesis considers that cognitive impairment in both diabetes and Alzheimer disease is linked to a state of systemic oxidative stress. Recently, attenuation of cognitive impairment and normalisation of values in biochemical markers for oxidative stress were found in patients with Alzheimer disease and concomitant diabetes. Antidiabetic drugs may have a beneficial effect on glycolysis and its end products, and on other metabolic alterations. CONCLUSIONS Diabetic patients are at increased risk for developing Alzheimer disease, but paradoxically, their biochemical alterations and cognitive impairment are less pronounced than in groups of dementia patients without diabetes. A deeper understanding of interactions between the pathogenic processes of both entities may lead to new therapeutic strategies that would slow or halt the progression of impairment.

Excessive urokinase-type plasminogen activator activity in the euglobulin fraction of patients with Alzheimer-type dementia

We examined the activity of the serine protease urokinase-type plasminogen activator (uPA) present in the euglobulin fraction of plasma from 17 demented patients with probable Alzheimers disease (AD), 12 patients with vascular dementia (VD) and 10 healthy controls. Euglobulin protein fractions were separated by electrophoresis and gels were incubated at the surface of plasminogen-rich casein-agarose underlays. The degradative activity of uPA in this system was measured by densitometric analysis. In 8/17 (47%) patients with AD we observed an excessive uPA activity (> 200 mIU/ml). In contrast, only 2/12 (16%) patients with VD and 1/10 (10%) control subjects revealed a comparable increase in circulating uPA activity. Further evaluation of dementia stage in patients with AD allow us to associate high levels of uPA activity with severity of disease. uPA levels were significantly elevated (2.8-fold increase) in AD patients with severe cognitive and memory impairments (Alzheimer Disease Assessment Scale) with respect to controls, VD patients or AD patients with moderate cognitive and memory impairments (P < 0.001, ANOVA). Our data suggest that the anormalities in circulating fibrinolytic enzymes could be correlated with the severity of dementia. In light of this findings, the free uPA activity in euglobulin plasma fraction should be considered a marker of serious damage in patients with AD.