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Indexado en SciELO Introducción: En el proceso diagnóstico de los trastornos psicológicos, podemos encontrar características comunes a diferentes problemas, pudiendo explicar variedad de dificultades clínicas y comorbilidades desde esta categoría trans-versal, lo cual ha sido llamada transdiagnóstico. Siendo la regulación emocional una variable transdiagnóstica que se define como la capacidad de la persona de hacer uso de recursos o habilidades para modular la respuesta conductual producida posteriormente a la experimentación de una emoción de moderada a elevada intensidad. Objetivo: Explicar el impacto de la variable regulación emocional en la teoría y práctica clínica a través de una mirada transdiagnóstica. Discusión: El término transdiagnóstico nace por una serie de inconvenientes en su fundamentación y práctica, siendo estás: la insatisfacción por los modelos tradicionales como la Clasificación Internacional de las Enfermedades y Trastor-nos relacionados con la Salud Mental (CIE-10) y Manual Diagnóstico y Estadístico de Trastornos Mentales (DSM-5), la comorbilidad y el riego de la medicalización. Por eso, este modelo propone comprender los procesos causales básicos comunes entre distintos trastornos o grupos de estos. Para tocar el tema de regulación emocional se debe hablar de las emociones. Estás son adaptativas para las personas. Sin embargo, pueden transformarse en problemáticas si se responde de forma automática bajo el nivel emocional, ya que interfiere con objetivos y bienestar personal. Todos los seres humanos contamos con procesos reguladores de la emoción, es decir, somos capaces de decidir cómo responder ante la aparición de una emoción. Ello es llamado regulación emocional, la cual se vuelve efectiva cuando se adapta el contexto y a los metas a largo plazo. Esta forma de responder es un producto personal aprendido que depende de las contingencias y las reglas que la comunidad verbal de referencia haya organizado a lo largo de la historia personal; por lo que, a veces, puede ser destructiva en la medida que su aplicación rígida y, muchas veces evitativa, impide a la persona construir una vida con sentido. La investigación reciente demuestra que una cantidad importante de diag-nósticos clínicos en salud mental podría ser explicada por los problemas en la regulación emocional, entre los cuales hemos destacado los trastornos de ansiedad, depresivos, el trastorno límite de la personalidad, los trastornos por uso de sustancias y los trastornos de la conducta alimentaria. Conclusión: Los procesos transdiagnósticos se ven cada vez más valorados debido a las variadas teorías explicativas que aparecen en estos últimos años. Generando tratamientos enfocados al déficit de habilidades en regulación emocional, todo con el fin de mejorar la calidad de vida de los consultantes. Cabe agregar que al revisar toda esta literatura podemos concluir que es posible conceptualizar y explicar los trastornos psicológicos desde el déficit de regulación emocional. Sobre todo, desde los puntos biológicos, contextuales y teniendo en cuenta los aprendizajes para su mantenimiento. In the diagnostic process of psychological disorders, we can find common characteristics to different problems, being able to explain a variety of clinical difficulties and comorbidities from this cross-sectional category, which has been called transdi-agnostic. Being emotional regulation a transdiagnostic variable that is defined as the ability of the person to make use of resources or skills to modulate the behavioral response produced after experiencing a moderate to high intensity emotion. Objective: To explain the impact of the emotional regulation variable in clinical theory and practice through a transdiagnostic look. Discussion:The term transdiagnosis arises from a series of drawbacks in its foundation and practice, being these: dissatisfaction with tradition-al models such as the International Classification of Diseases and Disorders related to Mental Health (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders (DSM-5), comorbidity and the risk of medicalization. For this reason, this model proposes to understand the common basic causal processes between different disorders or groups of these. To touch on the subject of emo-tional regulation, one must talk about emotions. These are adaptive for people. However, they can become problematic if they respond automatically under the emotional level, since it interferes with goals and personal well-being. All human beings have emotion regulatory processes, that is, we are capable of deciding how to respond to the appearance of an emotion. This is called emotional regulation (ER), which becomes effective when the context and long-term goals are adapted. This way of responding is a personal learned product that depends on the contingencies and the rules that the verbal community of reference has organized throughout personal history; so, at times, it can be destructive insofar as its rigid and often avoidant application prevents a person from building a meaningful life. Recent research shows that a significant number of clinical diagnoses in mental health could be explained by problems in emotional regulation, among which we have highlighted anxiety and depressive disorders, borderline personality disorder, and substance use disorders. and eating disorders. Conclusion: Transdiagnostic processes are increasingly valued due to the various explanatory theories that appear in recent years. Generating treatments focused on the deficit of skills in emotional regulation, all in order to improve the quality of life of the consultants. It should be added that when reviewing all this literature we can conclude that it is possible to conceptualize and explain psychological disorders from the deficit of emotional regulation. Especially from the biological and contextual points and taking into account the learning for its maintenance.Keywords: transdiagnosis, emotional regulation, mental disorders, diagnosis, clinical psychology. Revisión por pares

Objetives: The goal of this study was to determine if systemic and peritoneal oxidative stress biomarkers are related to each other and to retrograde menstruation in endometriosis. Methods: Plasma and peritoneal fluid oxidative stress biomarkers and hemoglobin and erythrocytes in peritoneal fluid as retrograde menstruation indicators, were measured in 28 patients with endometriosis and 23 without endometriosis. Results: In the peritoneal fluid, carbonyls and lipohydroperoxides, indicative of protein and lipid oxidative damage, were higher in endometriosis group (21%, p = 0.016 and 46%, p = 0.009, respectively). However, these biomarkers were not different in the blood plasma of both groups, and only protein dityrosine, was increased in the plasma of endometriosis group (31%, p = 0.04). The peritoneal fluid hemoglobin content was not higher in the endometriosis group, nor related to carbonyls and lipohydroperoxides. Additionally, the peritoneal fluid oxidative biomarkers were not correlated with the blood plasma ones, and only malondialdehyde, and ischemia-modified albumin were almost two times higher in peritoneal fluid. Discussion: Our results show a peritoneal and systemic oxidative stress biomarkers increase in endometriosis, but not related to each other, and do not support the hypothesis of an increase in hemoglobin-iron supply towards the peritoneal cavity that causes oxidative damage.

Background: Parkinson's disease (PD) and essential tremor (ET) may share some etiopathogenic factors. A genome-wide association study has shown that LINGO1 gene variants are associated with increased risk of ET. We hypothesized that LINGO1 variants could increase susceptibility to PD. Methods: A large series of PD subjects and healthy controls were genotyped for rs9652490 and rs11856808 LINGO1 single nucleotide polymorphisms (SNPs). Results: We found an increased frequency of the rs11856808T/T genotype in PD compared with controls (odds ratio = 1.46; corrected P value = 0.02). A recessive genetic model was the best fit for rs11856808 influence on PD (recessive gene action test: corrected P value = 0.01). Stratification analysis showed that rs11856808T/T genotype frequency was higher in the tremor-dominant PD and the classical PD (C-PD) subgroups (recessive gene action test for the C-PD subgroup: corrected P value = 0.004). Discussion: Our results indicate that LINGO1 variants could increase risk of PD, specifically those presenting the non-rigid-akinetic phenotypes, which suggests that LINGO1 may have a role in the etiology of tremor in PD at least in the Spanish population. © 2010 Movement Disorder Society

Background: Essential tremor (ET) is a frequent movement disorder with a substantial family aggregation. A genome-wide association study has recently shown that LINGO1 gene variants are associated with increased risk of ET. Methods: We intended to replicate these findings by genotyping rs9652490 and rs11856808 in a series of 226 familial ET subjects and 1117 healthy controls from referral movement disorder clinics in Spain. Results: We were unable to replicate the association between LINGO1 variants and familial ET. Conclusions: Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population.

Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n = 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype.

We report the radiological and biochemical data of a familial X-adrenoleucodystrophy with an extreme phenotypic variability, in which the diagnosis of several affected members was delayed for several years. The propositus developed a progressive dementia, while two of his brothers were diagnosed of primary Addison's disease several years previously. MRI in two cases with different phenotypes revealed hyperintense diffuse white matter lesions, and the diagnosis was confirmed by increased serum levels of very long chain fatty acids. We conclude that X-adrenoleucodystrophy should be included in the differential diagnosis of adult Addison's disease even though no neurological involvement or family history is recorded, and that MRI is a useful tool for diagnosis and follow-up of neurological involvement in this disease.

Sporadic Alzheimer's disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors. Binding with the transporter associated with antigen processing (TAP) is thought to be the main way in which herpes simplex virus type 1 (HSV-1) evades immune surveillance. Several TAP gene polymorphisms were examined and a TAP2 SNP (rs241448) associated with AD found in two independent case-control samples, especially in carriers of the APOE4 allele. These findings are consistent with the hypothesis that human genetic variants facilitating the access of HSV-1 to the brain might result in susceptibility to AD.

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.

Introduction Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. Methods This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. Results There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203–29.626; p = 0.042), but it was not replicated in other populations. Conclusions These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed.

Apolipoprotein E (apoE), the lipoprotein receptor related protein (LRP) and alpha-2 macroglobulin (α2M) have been proposed as a functional complex involved in amyloid clearance, a crucial event for Alzheimer's disease development. In this work, we present an epidemiological approach aimed to study the interactions among these genes, age and gender. This approach did not reveal significant associations between the genes; however, the present study indicated that the risk associated with APOE promoter and LRP gene polymorphisms is modulated by gender.

We herein report the case of a 84-year-old man with a 4-year history of freezing of gait (FOG) consistent with the diagnosis of primary progressive freezing gait. Single photon emission tomography (SPECT) with a radiolabeled ligand of the dopamine transporter (DAT-SPECT) showed integrity of striatal dopaminergic terminals, whereas brain perfusion SPECT disclosed multiple areas of decreased perfusion in frontal and parietal lobes, as well as in the subcortical gray nuclei of both sides. Treatment with the new irreversible monoamine oxidase B inhibitor rasagiline at standard doses resulted in a rapid, dramatic, and sustained improvement of the frequency and duration of FOG episodes. In addition, brain perfusion SPECT after treatment showed a marked increase of the activity in all cortical areas as well as in the basal ganglia and thalamus. Rasagiline may prove to be an effective and safe treatment for this disabling condition.

To determine the frequency and the linkage distribution of seven mutations at the polymorphic gene coding for the arylamine N-acetyl transferase (NAT2; EC 2.3.1.5) in 121 unrelated patients with sporadic PD and in 121 unrelated healthy volunteers.The study was performed with mutation-specific PCR using genomic DNA obtained from blood of the probands.Comparison of the NAT2 genotypes of the overall PD patients and control subjects did not indicate statistically significant differences. However, patients with early-onset PD (onset before the age of 50 years, n=37) showed a higher frequency of slow-acetylation genotypes (78.4% patients) compared with both healthy control subjects (55.4%) and with late-onset (onset after 51 years of age, n=84) PD patients (54.8%). Such a difference was statistically significant (p0.015) and was the result of a homogeneous increase in the frequency of slow-acetylation alleles. All subgroups analyzed in the study were in Hardy-Weinberg equilibrium for mutations at the NAT2 gene.Slow-acetylation-mutated alleles may be considered low-penetrance genes in early-onset PD pathogenesis, with a relative risk ratio for individuals with slow-acetylation genotype of 2.92 (95% CI, 1.26 to 6.78). This study provides evidence for the interaction of genetic and environmental factors in the etiology of sporadic PD.

Recent reports have shown an association between cytochrome P450IID6 (CYP2D6) polymorphism and Parkinson''s disease. We investigated the association between this polymorphism and the risk for developing essential tremor (ET). Leukocytic DNA from 91 unrelated ET patients and a control group of 258 unrelated healthy individuals was studied for the occurrence of eight different CYP2D6 allelic variants by using allele-specific PCR amplification Xbal and .EroRI-RFLP''s analyses. The prevalence for these allelic variants in the ET and control groups were, respectively: CYP2D6*1 76.9 and 78.7%, CYP2D6*2 0.5 and 0.2%, CYP2D6*3 0 and 1%, CYP2D6*4 12.1 and 12.2%, CYP2D6*5 1.6 and 1.7%, CYP2D6*9 4.4 and 2.9%, CYP2D6*2x2 4.4 and 3.2%. The prevalence of subjects with absent CYP2D6 activity (those carrying two defect genes) was 1.1 and 3.1% in ET and control groups, respectively. Both groups studied were in Hardy-Weinberg equilibrium. These results indicate that mutations at the CYP2D6 gene do not seem to be a major factor in determining susceptibility to ET, and reinforces the view that ET and parkinsonism are distinct conditions.

The cerebral amyloid angiopathies comprise a heterogeneous group of disorders that are characterized clinically by ischaemic and/or haemorrhagic strokes, and histologically by deposition of amyloid in the wall of leptomeningeal and cerebral cortical blood vessels. On the basis of the molecular composition of the amyloid, two forms can be distinguished. Cystatin C amyloid angiopathy is a rare autosomal dominant disorder confined to several families from Iceland. beta-amyloid cerebral amyloid angiopathies may be hereditary or sporadic, and share clinical, pathological and biochemical features with Alzheimer's disease. Both types of vascular amyloid derive from precursor proteins synthesized in situ by astrocytes (cystatin C) or smooth muscle cells (beta-amyloid), and induce progressive degeneration of smooth muscle cells, blood vessel rupture and haemodynamic changes. In recent years, it has been reported that mutations underlying both types of hereditary cerebral amyloid angiopathy directly involve the gene encoding the precursor protein. These findings have increased our understanding of the amyloidogenic mechanisms and allowed preclinical diagnosis. Nevertheless, the aetiopathogenetic factors involved in the more frequent sporadic form of amyloid angiopathy remain unknown.

A questionnaire designed to screen Parkinson's disease (PD) in literate populations has been developed. It consists of nine questions, self-administered at medical facilities or by mail, and a scale of weights for ascribing scores to specific questions when the answer is positive. The questions were chosen to be symptom specific for PD and the weights were determined from answers provided by 37 PD patients in a neurological outpatient clinic. The questionnaire sensitivity was tested on a different PD population from the same outpatient clinic--50 individuals--and the specificity on a group of 100 ophthalmological patients. The sensitivity was 100% and the specificity was 100%. Three individuals who screened positive among the 100 ophthalmological patients were assessed and given a new diagnosis of PD. This questionnaire therefore constitutes an instrument that should prove valuable as the first stage of a door-to-door survey. It has high sensitivity and specificity.

In order to test the value of Hodkinson's test (HT) for the detection of dementia and other milder forms of cognitive impairment in community surveys, we have studied two separate groups of 50 individuals; one of the groups included individuals with dementia or mild cognitive impairment (MCI), and the other individuals with no cognitive disturbances. Both groups were drawn from the same rural population and subjected to HT and a neuropsychological exam for positive and differential diagnosis of cognitive impairment. The gold standard criteria for the diagnosis of dementia and MCI were the DSM-IIIR criteria and a simplified and adapted version of the criteria established for age-associated memory impairment. We found that the best cutoff of HT providing maximum sensitivity and specificity for the diagnosis of both dementia and MCI was 7. For this cutoff, sensitivity and specificity for the diagnosis of MCI were 94 and 90%, respectively; for the diagnosis of dementia sensitivity and specificity were 100 and 53%, respectively. This together with its brevity, low cost and independence of sensory impairment and cultural background makes the HT useful for large population-based screening of dementia and MCI.

Background Isolated action tremor (IAT) is the hallmark clinical feature of essential tremor (ET), but it may also be a prominent feature of some individuals with Parkinson’s disease (PD) suggesting a pathogenic relationship between these two disorders. Objectives We investigated the integrity of the striatal presynaptic dopaminergic system in subjects presenting IAT to improve the diagnostic accuracy and to explore any putative relationships between ET and PD. Methods The striatal dopaminergic system was examined by means of dopamine transporter imaging using 123I-(fluoropropyl)-2s-carbomethoxy-3s-(4-iodophenyl) nortropane ([123I]-FP-CIT) single-photon emission tomography (DAT-SPECT) in a clinical series of individuals with IAT, excluding those with associated resting tremor and bradykinesia. Results Among 167 incidental individuals with IAT eligible for DAT-SPECT (Male/Female = 58.9/41.1%; Age = 67.8 ± 14.3 years), reduced striatal uptake was observed in 114 out of 167 (68.3%), whereas normal striatal binding was observed in the remaining 53 subjects (31.7%). Onset of tremor after 50 years and asymmetrical distribution of tremor were predictive variables of nigrostriatal denervation, whereas gender, family history and the presence of intentional, cephalic or voice tremors were not associated with nigrostriatal denervation. Conclusions Our findings suggest that IAT is a frequent presenting symptom in a subset of individuals with PD, often misdiagnosed as ET, and that DAT-SPECT can help differentiate between these two disorders. Current diagnostic criteria for ET should be revised to include asymmetry and late-onset tremor as predictors of nigrostriatal denervation.

Essential tremor (ET) is a frequent movement disorder with a substantial family aggregation. A genome-wide association study has recently shown that LINGO1 gene variants are associated with increased risk of ET. We intended to replicate these findings by genotyping rs9652490 and rs11856808 in a series of 226 familial ET subjects and 1117 healthy controls from referral movement disorder clinics in Spain. We were unable to replicate the association between LINGO1 variants and familial ET. Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population.

We report on the clinical, electrophysiological, and pathological findings in a patient with pure motor and axonal Guillain-Barre syndrome, who died 29 days after onset. There was marked reduction of compound motor action potential amplitudes and denervation potentials in the tibialis anterior muscle. Motor and sensory conduction velocities of median nerve were normal. Peroneal nerve was inexcitable at the ankle but its latency from knee to tibialis anterior was normal. F waves were absent or delayed. The major burden of pathological changes fell on ventral spinal roots. Fundamental lesions included segmental demyelination, axonal degeneration, widespread endoneurial lipid-laden macrophage infiltrates, remyelination, and clusters of small regenerating fibers. These findings suggest that axonal damage in the axonal form of Guillain-Barre syndrome is secondary to demyelination.

In this study, we have compared the cellular pathology associated with beta-amyloid (beta A) deposits which characterize Alzheimer's disease (AD) in demented patients with pathologically confirmed AD, with that in non-demented aged individuals. Brain sections from two severely demented AD cases, six non-demented individuals with beta A deposits, and six age-matched controls devoid of beta A deposits were double-immunostained with antibodies against beta A, and antibody markers for neurofibrillary tangles (NFT), astrocytes and microglial cells. We found that the severely demented patients displayed numerous plaques of variable morphology, most of which were associated with NFT, hypertrophied astrocytes and reactive microglial cells. In contrast, non-demented patients showed fewer plaques, few or not NFT and less astroglial and microglial reaction. The number of plaques with associated abnormal cellular elements were much lower in non-demented than in demented cases. Furthermore, classical plaques were more likely to be associated with abnormal cellular elements than diffuse plaques, which were most often devoid of any associated cellular change. These findings suggest that: (i) beta A plaques in non-demented individuals may represent an early stage of AD; (ii) beta A deposition is the first recognizable pathological abnormality of AD; and (iii) NFT, and astro- and microglial proliferation are later features, possibly secondary to the known dystrophic effects of the beta A peptide and other fragments of its precursor protein.

Alzheimer's disease and cerebral amyloid angiopathies (CAA) are clinically heterogeneous diseases, but pathogenically related by the deposition of beta A4-amyloid in the brain in the form of neuritic plaques and/or vascular infiltrates. Antibodies directed against the N-terminal region of the predicted sequence of the beta A4 amyloid protein precursor (APP) were used to investigate the cellular distribution of this protein in the brain of normal humans and rats. We found a widespread presence of APP throughout the nervous tissue, including neurons, blood vessels, meningeal membranes, choroid plexus and ependymal cells. The highest APP immunoreactivity in both species was found in neuronal cell bodies and their processes, and around blood vessels. These findings may account for the clinical, pathological and aetiological differences found among the beta A4-amyloidosis.

Schwann cell hypertrophy is an early change observed in lead-induced neuropathy in the rat. In order to quantify this cell hypertrophy, a morphometric analysis of Schwann cell cytoplasmic and nuclear areas and their relationship to the cross-sectional area of the associated myelinated fibre was performed. The study was carried out on sural and peroneal nerves from three groups of adult rats. Group I was intoxicated with 4% lead acetate in the drinking water for 6 weeks; group II animals were treated as in group I and then restored to standard laboratory conditions for 30 days; and group III were controls. The results showed that: (a) after 6 weeks of lead exposure, cytoplasmic and nuclear areas were significantly greater in intoxicated, compared with control rats; (b) after 30 days recovery, Schwann cell cytoplasmic and nuclear areas did not differ from control rats.

The deafness-dystonia syndrome (DDS) or Mohr-Tranebjaerg syndrome (MTS, MIM 304700) is a rare X-linked recessive neurological disorder resulting from loss-of-function mutations in the nuclear DDP1/TIMM8A gene, involved in the transport and sorting of proteins to the mitochondrial inner membrane. A Mohr-Tranebjaerg patient and his mother were subjected to clinical and molecular studies. Screening of mutations were performed in TIMM8A, TIMM13, and other mitochondrial protein transport genes by conformation sensitive gel electrophoresis (CSGE), followed by direct DNA sequencing of tissue samples from the patient. Mitochondrial DNA of the patient was also sequenced at the genes for COX subunits and some mitochondrial tRNAs. Respiratory chain activities in a muscle biopsy and cultured fibroblasts from the patient were assessed using biochemical methods. mRNA expression of TIMM8A and TIMM13 was determined by RT-PCR in cultured fibroblasts. We identified a new case of Mohr-Tranebjaerg syndrome and report the characteristics of a new pathogenic de novo mutation (c.112C>T, pGln38X) in the TIMM8A gene. Biochemical measures of respiratory chain complex activities in muscle biopsy and fibroblasts did not show a major deficiency or alteration. mRNA expression studies demonstrated increased TIMM8A mRNA levels in cultured fibroblasts from the patient. Phenotypic differences among published cases seem not to be related with the mutation location or type. Our results support the idea that dysfunctions of mitochondrial protein transport, in addition to OXPHOS deficiency, can be the basis of important mitochondrial pathologies.

Alzheimer's disease (AD) results from the progressive accumulation of a specific protein (beta peptide) in the brain parenchyma in the form of amyloid deposits.Amyloid deposition in AD may be the result of multiple genetic and environmental factors which may alter the metabolism and degradation of the beta amyloid precursor protein. Amyloid deposits are toxic to the nervous tissue and lead to synaptic loss, neurofibrillary tangle formation and progressive neuronal loss.Synaptic loss is related to memory decline in the early stages of the disease and neurofibrillary tangle formation and neuronal loss to dementia in later stages of the disease. This series of events, known as the amyloid cascade, is supported by many genetic and experimental studies.

Objective: To suggest that intranasal delivery may offer an effective alternative to subcutaneous injection of apomorphine. Methods: Four patients (3 men, 1 woman) with idiopathic Parkinson's disease, with disabling “on-off” fluctuations in motor performance, despite optimal adjustment in the levodopa regimen and use of dopamine agonists, were included in this study. Their mean age was 61.5 years (range 58–65) and the mean duration of the disease was 13.5 years (range 5–18). The mean duration of levodopa treatment was 12.2 years (range 5–16). Disabling fluctuations had been present in these patients for more than 1 year. The Hoehn and Yahr stage was III-IV during the off periods. All four patients had dyskinesia when receiving the peak dose. Levodopa and dopamine agonist medications were unchanged for 1 month before the study. All four patients had already received intermittent subcutaneous apomorphine injections for a mean of 12.25 months (range 7–16). Apomorphine solution 10 mg/mL was administered with the use of a metered-dose nebulizer that delivered 1 mg of solution with each puff. Results: All patients showed a clear clinical response, with a mean reduction in daily off period of 94.5% with respect to the basal off period. No loss of therapeutic effect or increase in dyskinesia was observed compared with subcutaneous apomorphine. The speed, quality, and duration of response were comparable with that found with injection of apomorphine. One patient showed a slight vestibulitis, but it did not interfere with the efficacy of apomorphine. Conclusions: Intranasal apomorphine is a comfortable and easy alternative to subcutaneous apomorphine in the treatment of off phases in patients with Parkinson's disease and severe refractory motor fluctuations.

Apolipoprotein E-ɛ4 (ApoEɛ4 allele is a major risk factor of late-onset Alzheimer's disease (AD). We now report that: (1) this allelic variant is more frequent among patients with age-associated memory impairment (AAMI) than among healthy control subjects; (2) after a 3 year follow-up, those AAMI patients who developed dementia had ApoEɛ4 more frequently than those who did not; (3) ApoE allele distribution did not differ significantly between demented AAMI and late-onset AD patients. These results suggest that ApoEɛ4 predicts the development of dementia in AAMI patients, and that AAMI, an idiopathic amnesic syndrome of high prevalence among the elderly, and late-onset AD are different stages of the same disorder.

Cisapride, a substituted piperidinyl benzamide that is chemically related to metoclopramide, is a prokinetic agent that facilitates motility of the gastrointestinal tract (1). The mechanism by which cisapride exerts its actions is not clear. It enhances acetylcholine release in the myenteric plexus of the gut, and evidence exists that it has an agonistic action on a serotonin receptor, probably the 5-HT4 receptor (2). The drug is well tolerated, and no central nervous system side effects have been reported. We describe two patients with parkinsonism who experienced aggravation of tremor while on therapy with cisapride.

To investigate the potential involvement of adrenergic signaling in Alzheimer's disease (AD) pathogenesis, we performed genetic and functional studies of genes initiating the cascade. We chose two functional single-nucleotide polymorphisms (SNPs) in the beta1-adrenergic receptor (ADRB1) and the G protein beta3 subunit (GNB3) genes, respectively, and analyzed their allelic frequencies in a case-control sample of AD. We found that the GNB3 T allele produces a significant risk for AD in individuals homozygous for the ADRB1 C allele, suggesting that the combined effect of both polymorphisms influences AD susceptibility. Interestingly, the co-expression of GNB3 T and ADRB1 C alleles, compared with GNB3 C and ADRB1 G, produced increased cAMP levels and MAPK activation following adrenergic stimulation of transfected human cell lines. Furthermore, the co-expression of these alleles also produced increases in APP expression. These data strongly indicate that the combination of GNB3 and ADRB1 polymorphisms produces AD susceptibility by changing the cell responsiveness to adrenergic stimulation, pointing to the modulation of brain adrenergic receptors as a potential target for novel AD therapeutic strategies.

A 56 year-old patient, with a history of surgically removed breast cancer three years earlier, presented with incoordination of hand movements while playing piano. Neurological examination disclosed mild position sensory loss and limb-kinetic apraxia of the distal part of the right upper extremity. The most conspicuous neurological sign was a dystonic posturing of the right hand, which was only elicited when the patient outstretched her arms with the eyes closed. MRI revealed a metastatic lesion involving the left parietal cortex. The association of focal dystonic postures with lesions of the parietal association cortex indicates that dystonia may feature damage of brain cortical areas far from the basal ganglia. In addition, this provides support to the hypothesis that impairment of sensory pathways may play a role in the origin of some hyperkinetic movement disorders, such as dystonia and athetosis.

The case is reported of a 70 year-old woman with isolated gelastic seizures (GS) secondary to a rare form of focal obstructive hydrocephalus, called entrapment of the lateral horn. Laughing attacks started five years after conservative intracranial surgery for a giant basilar aneurysm. Serial neuro-imaging studies revealed a progressive cystic enlargement of the right temporal horn, damaging the baso-lateral temporal cortex. An ictal EEG recording confirmed the epileptic nature of laughing attacks, and showed that the epileptiform activity originated in the right temporal lobe. Complete seizure control was achieved with current doses of diphenilhydantoin. Analysis of this and other previously reported cases, indicate that symptomatic GS may originate in multiple sites of both cerebral hemispheres, although related to the limbic system. The fact that this case exhibited isolated GS stresses the importance of the baso-lateral temporal cortex in the genesis of this type of seizures.

We report a new case of Whipple's disease (WD) confined to the central nervous system. The patient presented with ataxia, ophthalmoplegia, hypersomnia, hemiparesis and generalized myorhythmia. The diagnosis was confirmed by identification of specific sequences of the causal agent of WD, the actinobacteria Tropheryma whippelii (TW), by PCR of DNA extracted from peripheral blood. An epidemiological survey of TW in patients with dementia suggests that WD is an uncommon cause of dementia in our population. Molecular methods may allow rapid identification of TW in peripheral fluids, and non-invasive diagnosis of this disorder.

Searching for tau genetic variations which could be associated with risk for Alzheimer's disease (AD), we have performed a mutational analysis of a region containing the whole exon 11 of the tau gene, which encodes a microtubule binding region critical for tau self-assembly, and we have found a biallelic polymorphism at position +34 of intron 11 (IVS11+34G/A). We have analyzed the allelic frequencies of this polymorphism in a case-control sample (167 clinically diagnosed AD and 194 controls) and found that the presence of any G allele (genotypes AG+GG) is associated with a five-fold AD risk in individuals carrying the apolipoprotein E4 allele, strongly suggesting that the combined effect of tau and apoE is relevant in relation with AD pathogenesis., This work was supported by Fundación Ramón Areces, Fondo de Investigación Sanitaria (Grant 98–0729), and Comunidad de Madrid (Grant 08.5/0010/98).

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population.

A questionnaire designed to screen Parkinson's disease (PD) in literate populations has been developed. It consists of nine questions, self-administered at medical facilities or by mail, and a scale of weights for ascribing scores to specific questions when the answer is positive. The questions were chosen to be symptom specific for PD and the weights were determined from answers provided by 37 PD patients in a neurological outpatient clinic. The questionnaire sensitivity was tested on a different PD population from the same outpatient clinic--50 individuals--and the specificity on a group of 100 ophthalmological patients. The sensitivity was 100% and the specificity was 100%. Three individuals who screened positive among the 100 ophthalmological patients were assessed and given a new diagnosis of PD. This questionnaire therefore constitutes an instrument that should prove valuable as the first stage of a door-to-door survey. It has high sensitivity and specificity.

Currently, there is no biochemical marker clinically available to test for the presence of Alzheimer's disease (AD). Recent studies suggest that the core component of AD-associated neurofibrillary tangles (NFTs), the microtubule-associated protein tau, might be present in CSF. This study focuses on establishing both the presence of tau in CSF and its potential utility in the diagnosis of AD. We obtained CSF from 181 individuals; 71 of these were diagnosed as having probable AD by NINCDS-ADRDA criteria. The remaining 110 individuals were divided into three groups: (1) age-matched demented non-AD patients (n = 25), (2) neurologic controls (n = 59), and (3) other controls (n = 26). We developed a sensitive enzyme-linked immunosorbent tau assay using monoclonal antibodies prepared against recombinant human tau. We confirmed specificity of the antibodies by a combination of immunoprecipitation and immunoblot results. By this assay we measured that the AD population has a mean level of tau 50% greater than the non-AD dementia patients. Comparing AD patients with all other groups, the difference in tau levels as analyzed by one-way ANOVA is highly statistically significant (p0.001). Postmortem analysis of two AD patients with high levels of CSF tau revealed a high density of NFTs in the hippocampus. There was no significant correlation between tau and age in the non-AD groups. This study suggests that CSF tau is elevated in AD and might be a useful aid in antemortem diagnosis.

The frequency of five cytochrome P450IID6 allelic variants was studied in deoxyribonucleic acid from 123 patients with Parkinson's disease and 150 healthy volunteers. This was achieved by the use of mutation-specific polymerase chain reaction and restriction fragment length polymorphism. The analyses of the CYP2D6 genotype revealed no evidence for a higher prevalence of poor metabolizers among patients with Parkinson's disease. However, increased frequency of patients with Parkinson's disease with the genotype CYP2D6wt/CYP2D6B was observed. This is attributable exclusively to subjects with early onset of the disease (28 to 49 years), with a relative risk ratio of 4.16 (95% confidence limits, 2.0 to 8.3; p0.0005). The subjects who had late-onset Parkinson's disease (or = 50 years) had genotypes and CYP2D6 allele frequencies similar to the healthy subjects. This indicates that the oxidative polymorphism is related to early-onset but not to late-onset Parkinson's disease. A different influence of CYP2D6 genotype on the risk of development of Parkinson's disease is observed in Spaniards, compared with previous findings in British subjects. These results suggest the combined effect of environmental toxins and CYP2D6 in the cause of Parkinson's disease.

Alzheimer's disease (AD) is rapidly moving from the obscure category of degenerative diseases to the more precise one of metabolic disorders. Recent discoveries have substantiated the hypothesis that AD results from the deposition of beta-amyloid, which is formed by polymers of a proteolytic fragment of the amyloid protein precursor (APP), and may induce intraneuronal aggregation of the microtubule-associated protein tau into paired helical filaments and neuronal death. There is also evidence that AD is a heterogeneous age-related disorder of multifactorial origin, which may arise as a consequence of point mutations of genes encoding APP or other proteins involved in its metabolism (familial AD), or a combination of genetic and non-genetic factors (sporadic AD). Familial AD displays genetic and phenotypic heterogeneity, meaning that mutations of different genes may cause the AD phenotype, and that different mutations of the same gene may cause phenotypically distinct disorders, including Alzheimer-type dementia and cerebral amyloid angiopathy with cerebral hemorrhages and stroke. On the other hand, aging, gender, head trauma, and variants of the apolipoprotein E gene have been shown to increase the risk of developing the more prevalent sporadic form of AD. The mechanisms by which these factors influence amyloidogenesis are beginning to be understood, and this will provide a rational basis for future therapy. Knowledge of the molecular basis of AD would eventually allow accurate risk prediction before the disease becomes clinically apparent, and better chances for early treatment and prevention.

We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE e4. Rs5158 (APOC4 intron 1) and rs10413089 (3′ to APOC2) showed a trend toward an increase in AD risk independently from APOE e4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk.

The efficacy of PRD was evaluated in 21 patients with Parkinson's disease who presented motor fluctuations or a bad quality "on" time despite treatment with L-dopa or dopaminergic agonists. Eighteen of the 21 patients completed three months of treatment and only 14 (66.6%) were able to complete 12 months. The four patients who stopped treatment in this period did so because of subjective complaints despite obtaining good clinical response to PRD. Only three patients suspended the dietetic regime during first month of treatment. The 14 who completed the year of treatment showed a decrease in the "off" time (4.10 to 1.65: p0.01) and an improvement in motor response (14.89 to 10.39; p0.05) during the follow up period. Improvement appeared at the end of the second week of initiation of treatment. The diet was well tolerated with scarce complications, with only one patient presenting visual hallucinations. Other secondary effects were mild and did not require discontinuation of the diet. We conclude that proteic redistribution diet improves the "on" time in patients with Parkinson disease receiving L-dopa and delays the possibility of increasing the doses of L-dopa. The dietetic regimens with proteic redistribution seems a simple, useful and cheap approach without morbidity for the patients with Parkinson's disease showing a poor response or oscillation to L-dopa treatment.