Marie-Catherine Boll

Free Copper, Ferroxidase and SOD1 Activities, Lipid Peroxidation and NO x Content in the CSF. A Different Marker Profile in Four Neurodegenerative Diseases

The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.

Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease

Recent evidence suggest the implication of transition metals leading to overproduction of free radicals as a possible causal factor in the death of nigral cells associated to Parkinsons disease (PD). Iron depots in the basal ganglia of PD patients have been described; in addition, contents of nigral copper have been found decreased, while its concentration in cerebrospinal fluid (CSF) is raised, particularly the free form of the metal. To search for a possible link between altered copper concentrations and PD, we advanced the hypothesis that ferroxidase activity of ceruloplasmin is decreased in the CSF of PD patients. We studied 35 untreated PD patients, 14 L-3,4-dihydroxyphenylalanine (L-DOPA)-treated PD patients and 26 controls. Both CSF ferroxidase activity and CSF copper content were measured and correlated with the clinical stage of the disease. We found that untreated PD patients had a significant reduction of 40% in CSF ferroxidase while CSF copper was slightly increased as compared with both the values in L-DOPA-treated PD patients and controls. We also found that the fraction of copper linked to ferroxidase in untreated PD is inversely related to the clinical stage of the disease.

Low concentration of nitrite and nitrate in the cerebrospinal fluid from schizophrenic patients: a pilot study

Some evidence suggests a dysfunctional nitric oxide (NO) system in the brain of schizophrenic subjects. We measured the concentrations of the stable metabolites of NO, nitrite, and nitrate in the cerebrospinal fluid (CSF) from schizophrenic and control patients with other neurological disorders and found lowered levels in the schizophrenic group as compared with the control group. This finding supports the hypothesis of a NO system reduction in the brain of schizophrenic subjects.

Clinical and genetic characteristics of Mexican Huntington's disease patients.

We report the characteristics of 691 Mexican patients with Huntingtons disease (HD). These patients, representing 401 families, constitute the largest series of Mexican HD cases as yet described in the literature. We found the clinical characteristics of these patients to be similar to those of other populations, but we observed a higher frequency of infantile cases, a shorter disease duration and a lower suicide rate. In 626 cases, for which molecular analyses were available, CAG‐trinucleotide expansion size ranged from 37–106 repeats. The large number of CAG repeats (19.04 ± 3.02) in normal alleles and the presence of new mutations suggest that the overall prevalence of HD in the Mexican population could be expected to be within range of, or higher than, that reported for Europeans.

Medical Management of Parkinson’s Disease: Focus on Neuroprotection

Neuroprotection refers to the protection of neurons from excitotoxicity, oxidative stress and apoptosis as principal mechanisms of cell loss in a variety of diseases of the central nervous system. Our interest in Parkinson’s disease (PD) treatment is focused on drugs with neuroprotective properties in preclinical experiments and evidence-based efficacy in human subjects. To this date, neuroprotection has never been solidly proven in clinical trials but recent adequate markers and/or strategies to study and promote this important goal are described. A myriad of compounds with protective properties in cell cultures and animal models yield to few treatments in clinical practice. At present, markers of neuronal vitality, disease modifying effects and long term clinical stability are the elements searched for in clinical trials. This review highlights new strategies to monitor patients with PD. Currently, neuroprotection in subjects has not been solidly achieved for selegiline and pramipexole; however, a recent rasagiline trial design is showing new indications of disease course modifying effects. In neurological practice, it is of utmost importance to take into account the potential neuroprotection exerted by a treatment in conjunction with its symptomatic efficacy.

Raised Nitrate Concentration and Low SOD Activity in the CSF of Sporadic ALS Patients

To determine whether or not the occurrence of sporadic amyotrophic lateral sclerosis (sALS) is associated with both excess nitric oxide (NO) metabolites and decreased protective superoxide dismutase (SOD) activity in the cerebrospinal fluid (CSF), we measured nitrate concentration and SOD activity in the CSF of sALS patients and in age- and gender-matched controls. We found stable NO metabolite levels to be significantly higher and SOD activity lower in the CSF of sALS patients. In addition, SOD showed a negative correlation with motor neuron axonal damage expressed as the amplitude of motor action potentials in upper limbs. Our results provide new evidence in vivo suggesting that NO products and SOD activity play a role in oxidant/antioxidant imbalance in sporadic ALS.

Low frequency of common LRRK2 mutations in Mexican patients with Parkinson's disease.

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) account for as much as 5-6% of familial Parkinsons disease (PD) and 1-2% of sporadic PD. These mutations represent the most frequent cause of autosomal dominant PD, particularly in certain ethnic groups. In this first report concerning LRRK2 mutations in Mexican-mestizos, we screened 319 consecutive PD patients (186 males; 133 females; mean age at onset: 52.4 years) for LRRK2 mutations in exons 31 and 41 and for the mutation in exon 35, which produces the Y1699C substitution. Three (0.94%) patients, two with sporadic PD and one with familial PD (disease mean age at onset, 53.3 years), were heterozygous for LRRK2 mutations. Of these three, two patients had one of two different mutations in exon 31 (R1441G and R1441H, respectively); the other patient carried the G2019S mutation in exon 41. The Y1699C mutation was absent from this PD sample. Four additional subjects, unaffected relatives of one PD patient with a mutation in LRRK2, were subsequently genetically tested. None of the three LRRK2 mutations identified was present in 200 neurologically healthy Mexican control individuals. These findings have important implications for molecular testing of LRRK2 mutations in Mexican PD patients.

Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis.

The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.

Parahippocampal gray matter alterations in Spinocerebellar Ataxia Type 2 identified by voxel based morphometry

Spinocerebellar Ataxia Type 2 (SCA2) is a genetic disorder causing cerebellar degeneration that result in motor and cognitive alterations. Voxel-based morphometry (VBM) analyses have found neurodegenerative patterns associated to SCA2, but they show some discrepancies. Moreover, behavioral deficits related to non-cerebellar functions are scarcely discussed in those reports. In this work we use behavioral and cognitive tests and VBM to identify and confirm cognitive and gray matter alterations in SCA2 patients compared with control subjects. Also, we discuss the cerebellar and non-cerebellar functions affected by this disease. Our results confirmed gray matter reduction in the cerebellar vermis, pons, and insular, frontal, parietal and temporal cortices. However, our analysis also found unreported loss of gray matter in the parahippocampal gyrus bilaterally. Motor performance test ratings correlated with total gray and white matter reductions, but executive performance and clinical features such as CAG repetitions and disease progression did not show any correlation. This pattern of cerebellar and non-cerebellar morphological alterations associated with SCA2 has to be considered to fully understand the motor and non-motor deficits that include language production and comprehension and some social skill changes that occur in these patients.

Apolipoprotein E ε4 allele is associated with Parkinson disease risk in a Mexican Mestizo population

We investigated the association between apolipoprotein E (APOE) alleles and genotypes and Parkinson disease (PD) in 229 unrelated Mexican Mestizo PD patients and 229 controls. Results showed that both APOE‐ε4 allele and APOE ε4/ε3 genotype are associated with PD (OR = 1.736, P = 0.011; OR = 1.688, P = 0.019, respectively). Mean age at onset of PD was not associated to any APOE allele or genotype, but was significantly earlier in familial PD when compared to sporadic cases (P = 0.025).