Hortensia Alonso-Navarro

Brain structural changes in essential tremor: Voxel-based morphometry at 3-Tesla

BACKGROUND Abnormalities in cerebello-thalamo-cortical pathways have been suggested as a basis for essential tremor (ET). Two voxel-based morphometry (VBM) studies, each using a 1.5-T magnet, evaluated ET patients, leading to contradictory results. Using a 3-T magnet, we assessed whether white or gray matter changes occurred in ET patients vs. controls. METHODS We recruited 19 ET patients (mean age 69.8+/-9.4 years) and 20 age and gender-matched controls. 3-T MRI data were analyzed using the Statistical Parametric Mapping (SPM) 5 package. RESULTS In case-control comparisons, white matter changes were seen in several areas (right cerebellum, left medulla, right parietal lobe, and right limbic lobe); gray matter changes were seen in several areas as well (bilateral cerebellum, bilateral parietal lobes, right frontal lobe, and right insula) (p<0.001, uncorrected at a voxel level). Compared with controls, ET patients with severe tremor had white matter changes in the midbrain, both occipital lobes, and right frontal lobe, and gray matter changes bilaterally in the cerebellum (p<0.001, uncorrected at a voxel level). CONCLUSIONS Structural white and gray abnormalities may be detected in ET patients using VBM and a high-field MRI scanner. Such changes may be related to the pathological substrates associated with this disease.

Impairment of rapid repetitive finger movements and visual reaction time in patients with essential tremor

Background and purpose:  The question whether patients with essential tremor (ET) have slowed movements as part of their clinical manifestations is still a matter of controversy. We analyzed basic motor function in patients with ET and in healthy matched controls.

Influence of age and gender in motor performance in healthy subjects

BACKGROUND/OBJECTIVES Slowing of motor performance in human aging is a well demonstrated clinical observation. Information on the influence of gender in motor performance is less well-established. With the aim of analyzing the possible influence of age and gender in motor performance, we studied basic motor function in a large series of healthy sex-matched individuals aged >40 years. METHODS We studied 246 subjects (123 males and 123 females; mean age 63.67 ± 10.79 and 63.61 ± 11.04 years, respectively), stratified by age in 7 groups for each gender. Evaluation included four timed tests (pronation-supination, finger tapping and movement between two points, all with both hands, and walking test), and the three tests performed on a personal computer (speed for pressing repetitively a key - frequency, visual reaction time and movement time, all with both hands). Statistical analysis included two-way analysis of variance (ANOVA) for two factors (age and gender) and Pearsons or Spearmans correlation tests where appropriate. RESULTS The analysis of motor performance between subgroups showed a clear influence of age on motor performance of all the tests, with the exception of the left visual reaction time. The results of all the motor tests performed were inversely correlated with age. Gender influenced the performance (the speed of motor performance was significantly better in males) of all the tasks with the exception of left pronation-supination, and left and right visual reaction time. CONCLUSION Our results confirm in a large series of healthy subjects that basic motor performance deteriorates with age and is influenced by gender.

Environmental risk factors for essential tremor.

We conducted a case-control study searching for a possible role of environment in the risk of essential tremor (ET). We interviewed 142 ET patients and 284 age- and sex-matched controls about a family history of ET, exposure to environmental products containing lead, mercury, manganese, solvents and β-carbolines, and exposure to agricultural work, well water, pesticides, and cigarette smoking and alcohol drinking habits. In a univariate study, reported family history of ET and exposure to agricultural work, pesticides, smelting, frosted glass, paintings, wheat, corn, and barley were more frequent in the ET patient group. With a multivariate study, only reported family history of ET and exposure to agricultural work and frosted glass remained significant. Time of exposure to agricultural work, wheat and barley was significantly higher in ET patients. Age at onset of ET was significantly lower in patients with a family history of tremor and higher in patients exposed to iron-manganese alloys and alcohol. Time of exposure, but not total consumption of alcohol and cigarettes, was correlated with age at onset of ET. In conclusion, our study shows that the association between ET and reported family history of ET was robust, and that there were also associations between ET and exposure to some environmental factors (agricultural work and frosted glass).

Vitamin D3 Receptor (VDR) Gene rs2228570 (Fok1) and rs731236 (Taq1) Variants Are Not Associated with the Risk for Multiple Sclerosis: Results of a New Study and a Meta-Analysis

Background Some epidemiological, genetic, and experimental data suggest a possible role of vitamin D in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis. Data on the possible contribution of several single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene to the risk for MS are controversial. Several studies suggested an interaction between some SNPs in the VDR gene and HLADRB1*1501 in the risk for MS. Objectives The aim of this study was to investigate a possible influence of the SNPs rs2228570 and rs731236 in the VDR gene in the risk for MS. A secondary objective was to address the possible interactions between VDR genes and HLADRB1*1501. Methods We analyzed the allelic and genotype frequency of VDR rs2228570, rs731236, and HLADRB1*1501 (rs3135388) in 303 patients with MS and 310 healthy controls, using TaqMan Assays. We also conducted a meta-analysis, that was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic. Results VDR rs2228570 and rs731236 allelic and genotype frequencies did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. HLADRB1*1501 showed a high association with the risk of developing MS 4.76(95% C.I.  = 3.14–7.27; p<0.0001). The meta-analysis, after excluding data of one study that was responsible of heterogeneity for rs731236 polymorphism, showed lack of relation of both SNPs with the risk for MS. HLADRB1*1501 showed lack of interaction with VDR rs2228570 and rs731236 in increasing MS risk. Conclusions These results suggest that VDR rs2228570 and rs731236 polymorphisms are not related with the risk for MS, and did not confirm interaction between these VDR SNPs and HLADRB1 in the risk for MS.

Oxidative stress in skin fibroblasts cultures from patients with Parkinson's disease

BackgroundIn the substantia nigra of Parkinsons disease (PD) patients, increased lipid peroxidation, decreased activities of the mitochondrial complex I of the respiratory chain, catalase and glutathione-peroxidase, and decreased levels of reduced glutathione have been reported. These observations suggest that oxidative stress and mitochondrial dysfunction play a role in the neurodegeneration in PD. We assessed enzymatic activities of respiratory chain and other enzymes involved in oxidative processes in skin fibroblasts cultures of patients with PD.MethodsWe studied respiratory chain enzyme activities, activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, and coenzyme Q10 levels in skin fibroblasts cultures from 20 Parkinsons disease (PD) patients and 19 age- and sex- matched healthy controls.ResultsWhen compared with controls, PD patients showed significantly lower specific activities for complex V (both corrected by citrate synthase activity and protein concentrations). Oxidized, reduced and total coenzyme Q10 levels (both corrected by citrate synthase and protein concentrations), and activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, did not differ significantly between PD-patients and control groups. Values for enzyme activities in the PD group did not correlate with age at onset, duration, scores of the Unified Parkinsons Disease Rating scales and Hoehn-Yahr staging.ConclusionsThe main result of this study was the decreased activity of complex V in PD patients. This complex synthesizes ATP from ADP using an electrochemical gradient generated by complexes I-IV. These results suggest decreased energetic metabolism in fibroblasts of patients with PD.

Most of the Quality of Life in Essential Tremor Questionnaire (QUEST) psychometric properties resulted in satisfactory values

OBJECTIVE This study sought to assess the psychometric attributes of the Quality of Life in Essential Tremor Questionnaire (QUEST) by undertaking an independent validation. STUDY DESIGN AND SETTING This was an observational, multicenter, cross-sectional study carried out in Neurology Departments of general hospitals. The following assessments were applied: Louis Rating Scale, Clinical Assessment of Tremor, Clinical Global Impression of Severity (CGI-ET), Hospital Anxiety and Depression Scale (HADS), EQ-5D, and QUEST (Spanish version). RESULTS One hundred and eighteen consecutive patients were included. According to the CGI-ET, most of patients had mild (42.4%) or moderate (43.2%) impact of tremor on performing daily activities. Fully computable QUEST data were 60.2%. The QUEST Summary Index (QUEST-SI) displayed marginal floor or ceiling effect. On the whole, QUEST internal consistency and reproducibility were satisfactory (Cronbachs alpha values: 0.73-0.86; QUEST-SI intraclass correlation coefficient: 0.77). Factor analysis identified eight factors (73.6% of the variance) that could be grouped into six, relatively coincident with the questionnaires dimensions. The QUEST-SI correlated moderately with the EQ-5D index (r(S)=-0.40), HADS-Depression (r(S)=0.39), and CGI-ET (r(S)=0.39), and strongly with the QUEST scale for self-evaluation of tremor severity (r(S)=0.63). The standard error of measurement was 8.00. CONCLUSION Apart from a substantial problem of acceptability, most of the tested psychometric attributes of the QUEST resulted satisfactory.

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

LINGO1 and risk for essential tremor: Results of a meta-analysis of rs9652490 and rs11856808

BACKGROUND/OBJECTIVES Recently, a genome-wide association study revealed a significant statistical association between LINGO1 rs9652490 and rs11856808 polymorphisms and the risk of developing essential tremor (ET) in Icelandic people. Because the results of further association studies were controversial, we conducted a meta-analysis including all the studies published on the risk of ET related with these polymorphisms. METHODS The metaanalysis included 11 association studies between LINGO1 rs9652490 (3972 ET patients, 20,714 controls) and 7 association studies between LINGO1 rs11856808, and risk for ET (2076 ET patients, 18,792 controls), and was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic. RESULTS Global diagnostic odds-ratios (ORs) and 95% confidence intervals (CI) for rs9652490 and rs11856808 of the total series were, respectively, 1.17 (1.00-1.36) (p=0.069) and 1.20 (1.05-1.36) (p=0.016). After excluding data on Icelandic people of the discovery series (that was responsible of a high degree of heterogeneity for rs9652490 polymorphism), the ORs and CI were 1.10 (0.97-1.26) (p=0.063) and 1.12 (0.99-1.27) (p=0.034). Global ORs and 95% CI for rs9652490 and rs11856808 of familial ET patients were, respectively, 1.27 (1.03-1.57) (p=0.014) and 1.21 (1.10-1.44) (p=0.031). CONCLUSIONS The results of the meta-analysis suggest a relationship between LINGO1 rs11856808 polymorphism and the risk for ET and for familial ET, while rs9652490 polymorphism was only related with the risk for familial ET.

Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease

The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinsons disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD.