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Background and Purpose: Creutzfeldt-Jakob disease (CJD) is a rare, rapidly fatal neurodegenerative disorder. The gold standard test for a positive diagnosis of definite CJD is histopathological confirmation, usually post-mortem; however, an autopsy study is not always feasible in all health settings., Materials and Methods: We performed a cross-sectional analysis of a retrospectively enrolled cohort of patients with suspected prion disease between 2008 and 2019. Only patients with complete medical histories who fulfilled a diagnostic checklist were enrolled. The magnetic resonance imaging (MRI) sequences (T2-FLAIR and DWI) were analyzed, and the apparent diffusion coefficients (ADCs) were calculated for five regions of interest (ROIs) in each cerebral hemisphere., Results: In total, 72 MRI scans were post-processed. The series included 47 cases of CJD, including 25 genetic and 22 sporadic cases, in addition to 25 age-paired controls with non-prion encephalopathies. The neostriatum showed the most significant difference in ADC values (×10 -3 mm 2 /s) at 0.5946 in the left anterior putamen vs. 0.8644 in the control encephalopathies (p < 0.001; 95% confidence interval: 0.5751-0.6142 vs. 0.7812-0.9476), while the other ROIs also showed significant differences. The best cut-off value to differentiate CJD from other encephalopathies was identified as 0.65×10 -3 mm 2 /s, with no significant differences in this coefficient between sporadic and genetic cases., Conclusions: Quantitative ADC measurements made in the basal ganglia seem to be the most useful ante-mortem diagnostic tool for differentiating CJD from non-prion encephalopathies when cerebrospinal fluid real-time quaking-induced conversion or other specific misfolded protein detection tests are inaccessible., (Copyright © 2024 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

Introduction: Huntington's disease (HD) is a genetic neurodegenerative disorder with dominant inheritance. Our center in Mexico City has offered presymptomatic testing (PT) since 1995., Objective: To describe the main clinical and demographic characteristics of at-risk HD individuals who applied to the PT program, the reasons for seeking it, and the molecular results., Methods: A cross-sectional study was conducted with sociodemographic and clinical data of all PT applicants from 1995-2023. Reasons for seeking PT were assessed using a modified questionnaire. In addition, anxiety, and depressive symptoms before and after PT were evaluated with Beck's instruments; cognitive impairment (CI) was assessed with the Mini-Mental State Examination (MMSE) and molecular results., Results: 214 people applied for PT (2.1% of the at-risk population identified in our center); 63% were women (mean age of 37.11 years). 204 (95.3%) were accepted and 190 received results. 70% indicated that the main reason for applying for PT was to inform their offspring about the risk of inheriting HD. Significant differences were observed in the reasons for seeking PT by age group. Although some subjects received treatment, Beck's instrument scores did not indicate special attention or pharmacological treatment. The MMSE showed probable CI in 20 subjects. Of those who received results, 37% were carriers of a full penetrance allele., Conclusion: Our center has the only formal PT program for HD in Mexico. The reasons for seeking PT are varied and age-related. Although PT is offered to all subjects at risk for HD, uptake remains low., (Copyright © 2024. Published by Elsevier Inc.)

Background: Few treatments are currently available for amyotrophic lateral sclerosis (ALS). A combination of lithium carbonate and valproic acid (VPA-Li) was shown to inhibit motor neuron death and delay disease progression., Methods: Outpatients with a typical ALS presentation were enrolled in a randomized, placebo-controlled trial to assess the efficacy of orally administered VPA-Li. Changes in a functional scale score (ALSFRS-R) and survival rate were chosen as primary outcome variables. Secondary outcome variables included BMI, respiratory monitoring, quality of life, and a global impression of the treatment., Results: Out of 42 patients enrolled, 20 individuals receiving VPA-Li and 18 on placebo treatment were included in the final analysis. Forty-five percent of patients receiving VPA-Li completed the trial, whereas only 22.22% of patients in the placebo group attended the final visit 18 months later (P = 0.09). Major changes in the ALSFRS-R score were observed, including a decrease of 1.195 points/month in the placebo group (95% CI: 0.7869-1.6031) and of 0.5085 under VPA-Li treatment (95% CI: 0.2288-0.7882) between months 6 and 14. Adverse events included bad mouth taste, constipation, and anorexia. Survival rate, body weight, and quality of life were positive outcomes by the end of the trial despite a high sample reduction, especially in the placebo group. The inclusion of 212 subjects in each group would confirm these differences., Conclusions: Combined VPA-Li treatment associated with slower ALS progression and better secondary outcomes. This dual treatment overcame the futility threshold and merits further investigation in ALS., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Background: Friedreich's ataxia (FRDA) is caused by homozygous GAA repeat expansions or compound heterozygous (CH) mutations in FXN gene. Its broad clinical spectrum makes it difficult to identify, thus an accurate diagnosis can only be made by genetic testing., Objective: This study aims to present data on FXN variants observed in patients with sporadic or recessive ataxia, including detailed data of the first CH Mexican patients., Materials and Methods: One hundred and eight patients with recessive or sporadic cerebellar ataxia were referred to our institution between 2009 and 2019 for FXN molecular testing. This was achieved using a combined methodology of triplet repeat-primed PCR (polymerase chain reaction), long PCR, FXN sequencing and multiplex-ligation probe-amplification., Results: Eighteen patients had a homozygous FXN genotype; whereas five were CH patients with a slow progression and phenotypic variability, including a late-onset case with spastic paraparesis, and a Charcot-Marie-Tooth-like case., Conclusions: These first Mexican CH patients pose important implications for genetic counseling and FRDA management., Competing Interests: None

Parkinson's disease (PD), the second most frequent neurodegenerative disease, has been linked to increased central and peripheral inflammation. Although the response of the immune system to dopaminergic treatment remains to be fully understood, dopaminergic agonists are known to exhibit immunoregulatory properties which may, at least in part, explain their therapeutic effect in PD. This highlights the need of analyzing immune parameters in longitudinal studies on PD patients receiving specific therapeutic regimes. In this work, PD patients were included in a two-year prospective study comparing the effect of levodopa alone and a levodopa/pramipexole combo therapy on several regulatory and pro-inflammatory immune cell populations. We demonstrated that PD patients show decreased circulating levels of several important regulatory subpopulations, as determined by flow cytometry. Notably, when administered alone, levodopa decreased the levels of functional Bregs and SLAMF1+ tolerogenic DCs and increased the levels of total and HLA-DR+ classical monocytes, while the pramipexole/levodopa combo may promote Treg- and tolerogenic DC-mediated regulatory responses. These results suggest that a regime based on levodopa alone may promote a pro-inflammatory-type response in PD patients, but when combined with pramipexole, it promotes a clinically beneficial regulatory-type environment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events., Methods: Studies 113413 (NCT01336621), 114873 (NCT01777139), 115097 (NCT00310388), and 115098 (NCT00310375) were multicenter, open-label extension studies of retigabine (300-1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments., Results: The safety population (patients receiving ≥1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%-96% and 4%-27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%-73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%-83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively., Conclusions: The safety profile of retigabine in adults with POS across four open-label studies was generally consistent with data from previous placebo-controlled studies. Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Various studies have suggested that the immune response plays a key role in this pathology. While a predominantly pro-inflammatory peripheral immune response has been reported in treated and untreated PD patients, the study of the role of the regulatory immune response has been restricted to regulatory T cells. Other immune suppressive populations have been described recently, but their role in PD is still unknown. This study was designed to analyze the pro and anti-inflammatory immune response in untreated PD patients, with emphasis on the regulatory response., Methods: Thirty-two PD untreated patients and 20 healthy individuals were included in this study. Peripheral regulatory cells (CD4+Tregs, Bregs, CD8+Tregs, and tolerogenic dendritic cells), pro-inflammatory cells (Th1, Th2, and Th17 cells; active dendritic cells), and classical, intermediate, and non-classical monocytes were characterized by flow cytometry. Plasmatic levels of TNF-α, IFN-γ, IL-6, GM-CSF, IL-12p70, IL-4, IL-13, IL-17α, IL-1β, IL-10, TGF-β, and IL-35 were determined by ELISA., Results: Decreased levels of suppressor Tregs, active Tregs, Tr1 cells, IL-10-producer CD8regs, and tolerogenic PD-L1+ dendritic cells were observed. With respect to the pro-inflammatory response, a decrease in IL-17-α and an increase in IL-13 levels were observed., Conclusion: A decrease in the levels of regulatory cell subpopulations in untreated PD patients is reported for the first time in this work. These results suggest that PD patients may exhibit a deficient suppression of the pro-inflammatory response, which could contribute to the pathophysiology of the disease.

Huntington disease (HD) is an autosomal dominant genetic disorder characterized by movement disorders, cognitive impairment, and psychiatric symptoms. Relatives of HD patients experience a great burden as the latter suffer from altered social conduct and deterioration of interpersonal relationships. Theory of mind (ToM) is the ability to attribute mental states (to oneself and others). Deficits in ToM are thought to have a role in the changes in empathy and interpersonal difficulties that HD patients face. METHODS We conducted a cross sectional study to compare ToM task scores of patients with mild to moderate HD, their relatives (spouse or at-risk first-degree relative with a negative gene test) and controls.Individuals with dementia or depression were excluded. The ToM test battery included Spanish versions of the Reading Mind in the Eyes Test (RMET), Happé's Strange Stories (Social and Physical Stories subtests) and the Hinting Task. RESULTS The series comprised 12 HD patients, 12 relatives and 12 controls. The HD patients showed lower affective ToM scores than controls (RMET 19 [3.5] vs 23.9 [2.7], p = 0.016). Cognitive ToM tasks scores were lower in HD patients than controls as well (Happé's Social Stories 9 [2.6] vs 13 [1.9], p = 0.001; the Hinting Task 13.6 [3.4] vs 17.5 [4.0], p = 0.009). In the Hinting Task, HD relatives had lower scores in than controls (13 [3.2] vs 17.5 [4.0], p = 0.009) and similar scores to controls in the rest of the battery. CONCLUSION The HD patients with mild to moderate disease severity and their relatives show ToM deficits.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease that targets motor neurons. Upper motor neurons degeneration is pathologically characterized by brain iron accumulation. Signal attenuation in the shape of a ribbon at the posterior border of the precentral gyrus can be observed on conventional magnetic resonance imaging (MRI) sequences including T2-weighted sequence., Methods: With the aim to know the qualities of this potential marker of ALS, we conducted a prospective study. Patients with definite ALS in the age range of 40-70 years and healthy controls underwent 3T brain MRI using a standardized sequence. A second MRI was performed 18 months later under the same conditions in the patients with ALS., Results: Most of the patients with ALS (91.66%) exhibited a "black ribbon" (BR) with an average area of 79.98 mm3. Signal attenuation discriminated ALS with a mean value of 63.97 arbitrary units (AU) on the left BR (95% CI: 60.67-67.27), a mean value of 59.15 AU (95% CI: 54.78-63.53) on the right BR, and a significant difference with control subjects presenting a mean value of 107.85 AU (p &lt; 0.001). The optimal cut-off point for differentiating patients with ALS from controls (sensitivity, 0.92; specificity, 0.93) was 83 AU. Forced vital capacity and muscle strength in the contralateral upper extremity were significantly correlated with the ribbon intensity in ALS. Patients who underwent a second study exhibited significant changes in the BR related to the rapid evolution of the disease., Conclusions: This marker represents a valuable tool for the selection of candidates and their follow-up in clinical trials.

Objective: Parkinson's disease (PD) patients are usually treated with L-dopa and/or dopaminergic agonists, which act by binding five types of dopaminergic receptors (DRD1-DRD5). Peripheral immune cells are known to express dopamine receptors on their membrane surface, and therefore they could be directly affected by the treatment. Regulatory cells are the main modulators of inflammation, but it is not clear whether dopaminergic treatment could affect their functions. While only regulatory T cells (Tregs) have been proved to express dopamine receptors, it is not known whether other regulatory cells such as CD8regs, regulatory B cells (Bregs), tolerogenic dendritic cells, and intermediate monocytes also express them., Methods: The expression of dopamine receptors in Tregs, CD8regs, Bregs, tolerogenic dendritic cells, and intermediate monocytes was herein evaluated. cDNA from 11 PD patients and 9 control subjects was obtained and analyzed., Results: All regulatory cell populations expressed the genes coding for dopamine receptors, and this expression was further corroborated by flow cytometry. These findings may allow us to propose regulatory populations as possible targets for PD treatment., Conclusions: This study opens new paths to deepen our understanding on the effect of PD treatment on the cells of the regulatory immune response., (© 2019 S. Karger AG, Basel.)

Background: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke., Objective: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke., Methods: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum., Results: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 ( p = 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke ( p = 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p = 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p = 0.001); however, upon adjustment by multiple linear regression, it was not longer significant., Conclusion: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study., Competing Interests: Conflict of interest: The authors state that there are no conflicts of interest.

Intrastriatal injection of 1-methyl-4-phenylpyridinium (MPP + ) is considered a model to reproduce some biochemical alterations observed in Parkinson's disease (PD) patients. Among those alterations, inhibition of mitochondrial complex I activity, increased free radical production and reduced antioxidant responses have been reported. Copper (Cu) plays an important role in the metabolism and antioxidative responses through its participation as a cofactor in the cytochrome c oxidase enzyme (COX), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and metallothioneins. We tested the effect of copper sulfate (CuSO 4 ) pretreatment on the mitochondrial electron transport chain (METC) in the striatum after MPP + toxicity in rats. The results showed that the MPP + intrastriatal injection reduced mitochondrial complex I, II, IV and V activities; while 10 μmol of CuSO 4 pretreatment counteracted this damage. Activities of complexes I, II and IV, were coincident with ATP recovery. Moreover, Cu/Zn-SOD activity was reduced as a consequence of MPP + damage; however, copper pre-treatment kept the striatal Cu/Zn-SOD activity unchanged in MPP + -damaged animals. We observed that MPP + also reduced the metallothionein (MT) content and that CuSO 4 pretreatment maintained baseline values. CuSO 4 pretreatment also reduced the striatal caspase-3 and caspase-9 activities that were increased three days after MPP + -induced damage. The present study provided evidence that copper pretreatment reduced MPP + -induced apoptotic damage, probably through direct action on copper-dependent proteins or indirectly on proteins in the apoptotic pathway., (Copyright © 2017. Published by Elsevier B.V.)

Background and Purpose: There is a scarcity of information on the effect of white matter degeneration in patients with spinocerebellar ataxia type 7. Therefore, we investigated the WM integrity in a large group of patients with spinocerebellar ataxia type 7 by using Tract-Based Spatial Statistics., Materials and Methods: Thirty-three patients with a molecular diagnosis of spinocerebellar ataxia type 7 and their age- and sex-matched healthy controls participated in this study. The patients' ataxia severity was evaluated with the Scale for the Assessment and Rating of Ataxia. Voxelwise analyses of diffusion metrics, including fractional anisotropy and mean diffusivity, were performed with Tract-Based Spatial Statistics. The correlation between WM abnormalities and ataxia severity was then calculated., Results: Tract-Based Spatial Statistics analysis revealed WM abnormalities in the cerebellum and the cerebellar peduncles, as well as in other major cortical and subcortical pathways. Further analysis between the Scale for the Assessment and Rating of Ataxia score and WM mean diffusivity showed significant associations only in key areas related to motor control and visuospatial processing, including the cerebellar WM, the middle occipital WM, the superior cerebellar peduncle, and bilateral anterior thalamic radiation. No significant associations between fractional anisotropy and the Scale for the Assessment and Rating of Ataxia were found., Conclusions: These results suggest a significant contribution of local cerebellar and cerebellar-midbrain connections to ataxic impairment in spinocerebellar ataxia type 7. The results also suggest an involvement of cortical WM abnormalities including tracts within the occipital and frontal cortices. These findings contribute to a more comprehensive view of the clinical impact of the white matter degeneration in spinocerebellar ataxia type 7., (© 2016 by American Journal of Neuroradiology.)

Background: The metabolic syndrome (MetS) is a cluster of metabolic abnormalities including insulin resistance, dyslipidemia, high blood pressure, and abdominal adiposity. Obese patients develop leptin resistance, and an increased waist circumference (WC) due to deposition of abdominal fat. The aim of this study was to evaluate the association between circulating leptin levels and MetS among sample adult Mexican workers., Method: A total of 204 workers aged 20-56 were evaluated. Anthropometric index, blood pressure, fasting plasma glucose, and lipid profile were measured by spectrophotometric methods. Fasting insulin and leptin were measured by inmunoenzimatic methods. Furthermore, homeostasis model assessment for insulin resistance (HOMA-IR) was calculated., Results: The prevalence of MetS according to the ATP-III criteria was 33.8% and leptin concentrations were 2.5 times higher in women than men. Subjects with MetS had higher levels of leptin (26.7 ± 13.7) compared with those without MetS (20.1 ± 13.9; P <0.001). Leptin increased significantly while BMI increased as well (normal 14.0 ± 8.9, overweight 22.7 ± 11.7 and obese 31.4 ± 14.6) in addition to other variables such as WC, HDL-C, insulin levels, and HOMA index. Each component of MetS was stratified by sex and submitted by linear regression with a 95% of accuracy. The 50% and 53% of the BMI is explained by the concentration of leptin in men and women, respectively (P < 0.001)., Conclusion: This study found that leptin was associated with the MetS, especially in obesity and insulin resistance, indicating a high risk for university workers to develop hypertension, DM2, and cardiovascular disease., (© 2014 Wiley Periodicals, Inc.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dementia is a frequent complication of idiopathic Parkinsonism or PD, usually occurring later in the protracted course of the illness. Some risk factors to develop dementia in PD are aging, severe Parkinson´s symptoms, rigid-akinetic form, hallucinations, and mild cognitive impairment documented at the first examinations. It is not yet clear if some genetic factors are either risk or protector for progression to dementia. In a review of the literature, we found that mutations in the alpha-synuclein gene are the most responsible for developing dementia, either from PARK1 or 4 mutations. GBA (glucocerebrosidase) is another accountable factor. However, the vast majority of patients suffer from non-Mendelian or complex forms of PD, which are likely caused by the combined effects of genetic and environmental factors. There is not until now a clear relation between some polymorphisms in candidate genes and cognitive deterioration, as many studies have not clearly identified this phenotype.

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Quinolinic acid (QUIN) striatal injection in rat reproduces the main neurochemical features of Huntington's disease (HD), including oxidative damage. In this study, we evaluated the effect of a copper (Cu) supplement in drinking water (90 ppm Cu, 28 days) on the QUIN-induced HD model in the rat. Copper exposure caused no signs of liver toxicity; however, it produced significant Cu accumulation in striatum. It is noteworthy that QUIN also caused increased striatal Cu content; when the supplement was administered to animals with QUIN-injury, an even higher metal striatal accumulation was observed. Cu pre-treatment preserved striatal gamma-aminobutyric acid (GABA) content, which was reduced by QUIN intrastriatal injection. Similarly, apomorphine-induced circling behavior was reduced in Cu-pretreated QUIN-damaged rats. Metal supplement in drinking water prevented both lipid peroxidation and reactive oxygen species (ROS) formation caused by QUIN in striatum. In Cu-treated groups, superoxide dismutase-1 (SOD1) activity showed a significant increase, while SOD2 activity was slightly enhanced. Although the pathophysiological role for higher Cu levels in patients with HD and in experimental models of the disease is not fully understood, results in the present study suggest that Cu oral intake stimulates anti-oxidant defenses, an effect that may be a potential factor for reducing the progression of HD.

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Visuomotor adaptation is often driven by error-based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning-free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB-independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non-EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia., (© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Increased area of the substantia nigra (SN) associated to iron deposition has been proposed as a specific marker for Parkinson's disease (PD). Echogenicity, assessed by transcranial sonography (TCS), has been used to measure such an iron deposition. On the other hand, ferroxidase activity is known to play a role in brain iron metabolism and thus could be involved in increased SN echogenicity of PD patients. The present study was conducted to search for a possible correlation between both markers: TCS of SN and plasma ferroxidase activity. Twenty-one PD patients and 13 healthy volunteers (HV) were included. Mean SN sonographic areas were 0.31 cm² for PD patients and 0.12 cm² for HV (P < 0.001), while plasma ferroxidase activity was reduced in PD patients (P < 0.001). Interestingly, plasma ferroxidase activity was inversely correlated with the SN size by TCS (R² = 0.31), suggesting a relationship between the two markers.

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.

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) account for as much as 5-6% of familial Parkinson's 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., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

We report the characteristics of 691 Mexican patients with Huntington's 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.

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.

Citrulline and nitric oxide (NO) are synthesized by NO synthase (NOS) in a 1:1-stoichiometry. In this study, we determined by HPLC arginine and citrulline concentrations by fluorescence detection and nitrate levels by UV absorbance detection in the cerebrospinal fluid (CSF) from patients with acute hydrocephalus that underwent ventricular drainage. We found increased citrulline concentration (50.6+/-17.2 versus 20.9+/-2.0 microM) and decreased arginine/citrulline molar ratio (0.42+/-0.11 versus 1.12+/-0.16) in hydrocephalus patients, while arginine and nitrate concentrations and citrulline/nitrate molar ratio remained with little change. Citrulline has been determined as a marker of NOS activity in some studies, but it remains to be determined the extent at which this statement holds true, since other biochemical pathways also regulate the concentration of this amino acid. Our results suggest that citrulline is primarily synthesized from NOS in acute hydrocephalus. The evaluation of sample deproteinization by addition of methanol for the analysis of amino acids in CSF is also reported.

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-epsilon4 allele and APOE epsilon4/epsilon3 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).

Objective: This study assessed the effect of oral nutritional supplements on the nutritional status of patients with Huntington's disease., Methods: This was an experimental, longitudinal, prospective study of 30 patients with Huntington's disease. We performed neurologic evaluation and dietary assessment and measured anthropometric indexes and biochemical indicators; in addition, patients were questioned about their weight, appetite, chewing difficulty, and dysphagia. Patients consumed two cans daily of a nutritional supplement that contributed an extra 473 kcal to their diet for a 90-d period. At the study's end, the supplement was suspended and the same variables were reassessed., Results: After 90 d, 68.7% of patients had increased body weight, 68.7% had ideal body weight percentages and body mass indexes, 53.3% had increased midarm circumferences, and 60.0% had increased arm muscle circumferences and body fat percentages; these changes were statistically significant (P < 0.05). The neurologic evaluation subscales and the biochemical indicators did not change significantly. With regard to subjective variables, patients who reported losing weight during the 3 mo before the study did not lose more weight and patients who reported having an increased appetite before the study remained stable during the study., Conclusions: The nutritional intervention stabilized or slightly improved the anthropometric variables assessed; however, no significant change in body mass index occurred in 87% of patients. For the purpose of maintaining an acceptable nutritional status in patients who have Huntington's disease and normal nutritional status, we suggest oral nutritional supplements that contribute an average of 473 kcal/d in addition to a normal diet.

Some amino acids are involved in the biosynthesis of nitric oxide (NO), which has a physiological and pathophysiological role. To study NO biosynthesis, we compared arginine and citrulline levels in the cerebrospinal fluid (CSF) from patients with infectious and/or inflammatory processes within the central nervous system (CNS), with those from patients without those disorders. Arginine concentration was not significantly different between the groups (P = 0.115), whereas citrulline was significantly elevated in the first group (P = 0.020). We propose a simple chromatographic method to estimate NO biosynthesis ex vivo within the CNS, that may be applicable for the study of neurodegenerative and psychiatric diseases such as Parkinson's disease and schizophrenia.

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.

Objective: The purpose of the present study was to compare the nutrition status of patients with Huntington's disease (HD) with that of control subjects by analyzing anthropometric and biochemical indicators, energy, and macronutrient intake and to determine which indicators are most altered in HD patients., Methods: We assessed the nutrition status of 25 HD patients and 25 age- and sex-matched controls by measuring anthropometric and biochemical indicators. Food intake data were obtained by the 3-d record method to assess mean daily energy and macronutrient intake. We studied variables reported by the patients such as increased or decreased appetite, mastication difficulties, and solid food and liquid food dysphagia. A neurologist assessed the clinical features of HD patients by using the Unified Huntington's Disease Rating Scale., Results: HD patients showed significantly lower anthropometric variables but significantly higher kilocalorie intake. Among the subjective variables analyzed, patient-referred weight loss, increased appetite, mastication, and solid food dysphagia were significantly more frequent in HD patients than in controls. We also found relations between motor disability and some anthropometric parameters in HD patients. In particular, we found a significant correlation between total motor disability score and body mass index and arm muscle circumference (r = -0.464 and -0.445, respectively; P < 0.05) and with percentage of body fat (r = -0.496, P = 0.012)., Conclusions: It is of the utmost importance to identify nutritional alterations in HD patients and to find strategies to cover their kilocalorie and nutrient requirements to improve their quality of life.

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.

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 Parkinson's 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.

The first medical book edited in the American Continent was printed by Pierre Ochart in Mexico City (1570). He was born in Normandy in the City of Rouen, France, and learned the profession of printer in Mexico City. We have done an examination of the book written by Francisco Bravo, a Spanish doctor in medicine who practiced in Mexico City since the XVIth century second half.