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Objective The aim of the study was to investigate the role of L-DOPA/carbidopa (CD) therapy on vitamin B6 levels in patients with Parkinson disease (PD). Methods This is a cross-sectional retrospective study of vitamin B6 plasma levels in 24 patients with PD treated with L-DOPA/CD for 3 or more years, orally or intraduodenally. Vitamin B6 levels in plasma were measured by ELISA. Results All patients treated with intraduodenal L-DOPA/CD (6 of 6) and 13 of 18 patients receiving L-DOPA/CD orally had low plasma levels of vitamin B6. Eight of the 19 patients with low vitamin B6 levels had symptoms of hypovitaminosis B6. Patients with low vitamin B6 had been treated with larger doses of L-DOPA/CD, although the differences did not have statistical significance. Patients treated with intraduodenal L-DOPA/CD have vitamin B6 levels significantly lower than those treated with oral L-DOPA/CD. The variables that most correlated with vitamin B6 levels were the cumulative annual doses of CD (r = -0.36) and L-DOPA (r = -0.33) during the year preceding the study and the time to develop dyskinesias or fluctuations (r = +0.43). Conclusions Vitamin B6 could play an important role in PD and its levels seem to be influenced by L-DOPA/CD. Plasma vitamin B6 levels should be monitored in patients receiving high L-DOPA/CD doses, especially those treated with intraduodenal infusion.

Huntington's disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD. We conducted a double-blind, randomized, placebo-controlled, cross-over pilot clinical trial with Sativex(®), a botanical extract with an equimolecular combination of delta-9-tetrahydrocannabinol and cannabidiol. Both Sativex(®) and placebo were dispensed as an oral spray, to be administered up to 12 sprays/day for 12 weeks. The primary objective was safety, assessed by the absence of more severe adverse events (SAE) and no greater deterioration of motor, cognitive, behavioral and functional scales during the phase of active treatment. Secondary objectives were clinical improvement of Unified Huntington Disease Rating Scale scores. Twenty-six patients were randomized and 24 completed the trial. After ruling-out period and sequence effects, safety and tolerability were confirmed. No differences on motor (p = 0.286), cognitive (p = 0.824), behavioral (p = 1.0) and functional (p = 0.581) scores were detected during treatment with Sativex(®) as compared to placebo. No significant molecular effects were detected on the biomarker analysis. Sativex(®) is safe and well tolerated in patients with HD, with no SAE or clinical worsening. No significant symptomatic effects were detected at the prescribed dosage and for a 12-week period. Also, no significant molecular changes were observed on the biomarkers. Future study designs should consider higher doses, longer treatment periods and/or alternative cannabinoid combinations.Clincaltrals.gov identifier: NCT01502046.

Objective: To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease. Methods: Patients received pridopidine 45 mg/day for 4 weeks then pridopidine 90 mg/day for 22 weeks in this 6-month open-label extension (OLE) of the 6-month MermaiHD randomized controlled trial (RCT). Any adverse events (AEs) were recorded. Patients were categorized by their RCT treatment group (placebo, pridopidine 45 mg/day, pridopidine 90 mg/day). Results: Of the 386 patients who completed the RCT, 353 entered the OLE and 305 (86.4%) completed. In 1 year, similar percentages of patients from each group reported ≥1 AE (placebo, 79.6% [n = 90/113]; 45 mg/day, 80.8% [n = 101/125]; 90 mg/day, 82.6% [n = 95/115]) and ≥1 serious AE (8.0% [n = 9/113], 12.8% [n = 16/125], and 8.7% [n = 10/115], respectively). The AE profile across both studies was similar; falls and worsening of chorea were most commonly reported. During the OLE, more patients previously receiving pridopidine reported ≥1 AE (67.9% [n = 163/240]) than those who had received placebo (56.6% [n = 64/113]). Early in the RCT, small increases in heart rate were reported in patients receiving pridopidine. During 1 year, no clinically meaningful changes in laboratory parameters or EKG-related safety concerns were identified. Conclusion: Pridopidine (≤90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year. Classification of evidence: This study provides Class IV evidence that pridopidine (≤90 mg/day) is generally safe and well-tolerated in patients with Huntington disease for up to 1 year.

International audience; OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry.METHODS: We assessed a cohort of participants at risk with RESULTS: Of 12,190 participants, 657 (5.38%) with CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling.CLINICALTRIALSGOV IDENTIFIER: NCT01590589.

Estrogens are considered neurotrophic for dopamine neurons. Parkinson's disease is more frequent in males than in females, and more prevalent in females with short reproductive life. Estrogens are neuroprotective against neurotoxic agents for dopamine neurons in vivo and in vitro. Here, we have investigated the role of estrogens in wild-type (WT) and parkin null mice (PK-/-). WT mice present sexual dimorphisms in neuroprotective mechanisms (Bcl-2/Bax, chaperones, and GSH), but some of these inter-sex differences disappear in PK-/-. Tyrosine hydroxylase (TH) protein and TH+ cells decreased earlier and more severely in female than in male PK-/- mice. Neuronal cultures from midbrain of WT and PK-/- mice were treated with estradiol from 10 min to 48 h. Short-term treatments activated the mitogen-activated protein kinase pathway of WT and PK-/- neurons and the phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase-3 pathway of WT but not of PK-/- cultures. Long-term treatments with estradiol increased the number of TH+ neurons, the TH expression, and the extension of neurites, and decreased the level of apoptosis, the expression of glial fibrillary acidic protein, and the number of microglial cells in WT but not in PK-/- cultures. The levels of estrogen receptor-alpha were elevated in midbrain cultures and in the striatum of adult PK-/- male mice, suggesting that suppression of parkin changes the estrogen receptor-alpha turnover. From our data, it appears that parkin participates in the cellular estrogen response which could be of interest in the management of parkin-related Parkinson's disease patients.

Leptin, a peptide hormone secreted by adipose tissue, exhibits a large range of central and peripheral actions. It has been proposed that the participation of leptin in diseases such as obesity is due to, at least in part, its impaired transport across the blood-brain barrier (BBB). Since, the mechanisms by which brain takes up leptin remain unclear, we set out to study how leptin may cross the BBB. We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans. We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium. Indeed, the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer's disease was correlated with poor entry of leptin into the brain. Moreover, amyloid beta (Abeta) deposits of choroid plexus could be disturbing megalin function. The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain.

The pathological hallmark of Huntington disease (HD) is the intracellular aggregation of mutant huntingtin (mHTT) in striatal neurons and glia associated with the selective loss of striatal medium-sized spiny neurons. Up to the present, the role of glia in HD is poorly understood and has been classically considered secondary to neuronal disorder. Trehalose is a disaccharide known to possess many pharmacological properties, acting as an antioxidant, a chemical chaperone, and an inducer of autophagy. In this study, we analyzed at an early postnatal development stage the abnormalities observed in striatal glial cell cultures of postnatal R6/1 mice (HD glia), under baseline and stressing conditions and the protective effects of trehalose. Our data demonstrate that glial HD alterations already occur at early stages of postnatal development. After 20 postnatal days in vitro, striatal HD glia cultures showed more reactive astrocytes with increased expression of glial fibrillary acidic protein (GFAP) but with less replication capacity, less A2B5(+) glial progenitors and more microglia than wild-type (WT) cultures. HD glia had lower levels of intracellular glutathione (GSH) and was more susceptible to H2O2 and epoxomicin insults. The amount of expressed GDNF and secreted mature-BDNF by HD astrocytes were much lower than by WT astrocytes. In addition, HD glial cultures showed a deregulation of the major proteolytic systems, the ubiquitin-proteasomal system (UPS), and the autophagic pathway. This produces a defective protein quality control, indicated by the elevated levels of ubiquitination and p62 protein. Interestingly, we show that trehalose, through its capacity to induce autophagy, inhibited p62/SQSTM1 accumulation and facilitated the degradation of cytoplasmic aggregates from mHTT and α-synuclein proteins. Trehalose also reduced microglia activation and reversed the disrupted cytoskeleton of astrocytes accompanied with an increase in the replication capacity. In addition, trehalose up-regulated mature-BDNF neurotrophic factor expression and secretion, probably mediating cytoskeletal organization and helping in vesicular BDNF transport. Together, these findings indicate that glia suffers functional early changes in the disease process, changes that may contribute to HD neurodegeneration. Trehalose could be a very promising compound for treatment of HD and other diseases with abnormal protein aggregates. Furthermore our study identifies glial cells as a novel target for trehalose to induce neurotrophic and neuroprotective actions in HD.

Hereditary ataxias are clinically and genetically heterogeneous neurodegenerative disorders. Although many ataxia genes have been identified, about 50 % of cases await the identification of the genetic cause [1]. High-throughput sequencing, namely whole-exome sequencing (WES), has changed the paradigm of genetic analysis of rare heterogeneous Mendelian disorders [2], and allowed the identification of STUB1 mutations as the cause of autosomal recessive ataxia syndromes [3–7]. We report on clinical and pathological features of a family with spastic ataxia due to novel STUB1

We previously identified in two families with early onset Parkinson's Disease (PD) from the isolated population of Antioquia (Colombia), a parkin Cys212Tyr substitution caused by a G736A mutation. This mutation was subsequently observed in a Spanish family, suggesting that it could have been taken to Antioquia by Spanish immigrants. Here we screened for the G736A mutation in additional Antioquian early onset PD cases and used haplotype analysis to investigate the relationship between Spanish and Antioquian G736A chromosomes. We confirmed the occurrence of an extensive founder effect in Antioquia. Thirteen individuals (10 homozygotes) from seven nuclear families were identified with the G736A mutation. Genealogical investigations demonstrated the existence of shared ancestors between six of these families four to five generations ago and no evidence of Spanish ancestry during this period. A second parkin mutation (a duplication of exon 3), was detected in the three G736A heterozygote carriers. Haplotype data exclude a recent common ancestry between the Spanish and Antioquian patients studied here and is consistent with the introduction of the G736A mutation in Antioquia during early colonial times (about 16 generations ago).

The endocannabinoid transmission becomes overactive in the basal ganglia in Parkinson's disease (PD), as reported in patients and animal models of this disease. In the present study, we examined the status of cannabinoid CB(1) receptors in the basal ganglia of female and male Park-2 knockout mice, a genetic model of PD that progresses with no neuronal death and that may be considered representative of early and presymptomatic parkinsonian deficits. We found an increase in the density of CB(1) receptors in the substantia nigra compared to wild-type animals with no changes in other basal ganglia, although this occurred only in females. Despite this increase, the motor inhibition caused by the acute administration of the cannabinoid agonist Delta(9)-tetrahydrocannabinol to Park-2 knockout female mice was markedly of lesser magnitude compared with the response found in wild-type animals. By contrast, the administration of the CB(1) receptor antagonist SR141716 resulted in a hyperkinetic response in parkin-null mice, response that was almost absent in wild-type animals and that was accompanied by a decrease in tyrosine hydroxylase activity in the caudate-putamen. However, parkin-null male mice exhibited normal levels of CB(1) receptors in the substantia nigra and the remaining basal ganglia, with the only exception of a small decrease in the lateral part of the caudate-putamen. This was associated with an increase in mRNA levels for superoxide dismutase in this structure. In addition, the administration of Delta(9)-tetrahydrocannabinol to parkin-null male mice caused a motor inhibition that was significantly greater than in the case of their wild-type counterparts, and that was accompanied by an increase in tyrosine hydroxylase activity in the caudate-putamen. In summary, extending the data obtained in humans and animal models of basal ganglia neurodegeneration, changes in CB(1) receptors were also observed in parkin-null mice, a model of PD that may be considered representative of early stages of this disease. These changes are associated with differences in behavioral responses to cannabinoid agonists or antagonists between Park-2 knockout and wild-type mice, although parkin-null mice exhibited evident gender-dependent differences for both levels of CB(1) receptors and motor responses to agonists or antagonists.

Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.

Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.

Autosomal recessive-juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease (PD) and is related to mutations in the Park-2 gene, encoding for a protein ligase of ubiquitin, parkin. Different mutations located along the parkin gene have been observed in different AR-JP affected families, possibly interfering with the normal function of parkin and the proteasome system. Two cases of patients with AR-JP have been recently described presenting different homo- and heterozygous parkin mutations and limited tau pathology. We report here the case of a patient with clinical and pathological findings compatible with progressive supranuclear palsy (PSP), carrier of a single, heterozygous mutation of the parkin gene, and homozygous for the H1/H1 haplotype in the tau gene. Abnormal tau hyperphosphorylation has been observed in our patient brain samples, suggesting that a partial deficit of parkin, a protein with ubiquitin-ligase function, may trigger tau pathology in individuals with molecular genetic risk factors.

The synucleinopathies are a group of neurodegenerative disorders characterized by the presence of alpha-synuclein inclusions in neurons (Lewy body diseases, LBD) or glial cells (multiple system atrophies, MSA). Recently, nitration of alpha-synuclein has been reported as the possible modification that induces its aggregation and deposition in these disorders. In this study we investigated the distribution and relationships of alpha-synuclein inclusions and 3-nitrotyrosine (3-NT), a marker of protein nitration through oxidative mechanisms, in brains diagnosed with LBD or MSA and control brains using double immunohistochemical techniques. In LBD cases, 3-NT colocalized with alpha-synuclein immunoreactivity in classic and cortical Lewy bodies and in dystrophic neurites in substantia nigra. However, most pale bodies and diffuse deposits in substantia nigra and Lewy neurites in hippocampus lack 3-NT immunoreactivity. A majority of cases showed diffuse cytoplasmic 3-NT staining in pyramidal cells of the CA2-3 regions of the hippocampus that was independent of alpha-synuclein deposits. All MSA cases showed 3-NT immunoreactivity in glial inclusions. 3-NT neuronal staining was restricted to pontine nuclei with three cases showing nuclear and one case cytoplasmic staining. There was no colocalization of 3-NT nuclear immunoreactivity with alpha-synuclein-immunopositive nuclear inclusions in pontine neurons. These data show that protein nitration in LBD and MSA cases has a widespread distribution and is not only associated with the alpha-synuclein deposits. The presence of alpha-synuclein-positive deposits lacking 3-NT immunoreactivity suggests that nitration is not a prerequisite for alpha-synuclein deposition.

Huntington's disease is a neurodegenerative disorder caused by an expansion of CAG repeats in the huntingtin gene which produces widespread neuronal and glial pathology. We here investigated the possible therapeutic role of glia or glial products in Huntington's disease using striatal glial conditioned medium (GCM) from fetus mice (E16) continuously infused for 15 and 30 days with osmotic minipumps into the left striatum of R6/1 mice. Animals infused with GCM had significantly less huntingtin inclusions in the ipsilateral cerebral cortex and in the ipsilateral and contralateral striata than mice infused with cerebrospinal fluid. The numbers of DARPP-32 and TH positive neurons were also greater in the ipsilateral but not contralateral striata and substantia nigra, respectively, suggesting a neuroprotective effect of GCM on efferent striatal and nigro-striatal dopamine neurons. GCM increases activity of the autophagic pathway, as shown by the reduction of autophagic substrate, p-62, and the augmentation of LC3 II, Beclin-1 and LAMP-2 protein levels, direct markers of autophagy, in GCM infused mice. GCM also increases BDNF levels. These results suggest that CGM should be further explored as a putative neuroprotective agent in Huntington's disease.

Cisapride (CIS) is a prokinetic agent that increases gastrointestinal motility in normal individuals and improves constipation in Parkinson's disease (PD). We studied the effects of CIS on the clinical response and the peripheral pharmacokinetics of orally administered L-dopa given to patients with PD. Twenty patients with idiopathic PD and chronic constipation, whose response to L-dopa was suboptimal or characterized by fluctuations, agreed to participate in an open study that lasted for 2 weeks. Fourteen patients completed the study (mean age 65 +/- 9.3 years, mean duration of treatment 5.7 +/- 4.2 years, mean L-dopa daily doses 658.9 +/- 269.9 mg); six patients were excluded due to lack of compliance or changes in medication during the study. The end points of the study included the mean levels of L-dopa, the height of the peak of L-dopa in plasma, mean plasma levels of 3-OM-dopa, and the speed and quality of gait and visuomanual coordination before and during treatment with CIS. CIS increased peak plasma levels of L-dopa by 37% and the mean plasma levels of L-dopa by 13% with respect to those obtained with the same dose of L-dopa before the addition of CIS. Therefore, CIS appears to increase early absorption of L-dopa through acceleration of gastric emptying. CIS also increased plasma 3-OM-dopa levels, improved visuomanual coordination, and reduced gait disability. CIS improves gastrointestinal function and response to L-dopa in patients with PD and could be a helpful add-on medication in these patients.

Summary Background Huntington's disease is a progressive neurodegenerative disorder, characterised by motor, cognitive, and behavioural deficits. Pridopidine belongs to a new class of compounds known as dopaminergic stabilisers, and results from a small phase 2 study in patients with Huntington's disease suggested that this drug might improve voluntary motor function. We aimed to assess further the effects of pridopidine in patients with Huntington's disease. Methods We undertook a 6 month, randomised, double-blind, placebo-controlled trial to assess the efficacy of pridopidine in the treatment of motor deficits in patients with Huntington's disease. Our primary endpoint was change in the modified motor score (mMS; derived from the unified Huntington's disease rating scale) at 26 weeks. We recruited patients with Huntington's disease from 32 European centres; patients were aged 30 years or older and had an mMS of 10 points or greater at baseline. Patients were randomly assigned (1:1:1) to receive placebo, 45 mg per day pridopidine, or 90 mg per day pridopidine by use of centralised computer-generated codes. Patients and investigators were masked to treatment assignment. We also assessed the safety and tolerability profile of pridopidine. For our primary analysis, all patients were eligible for inclusion in our full analysis set, in which we used the last observation carried forward method for missing values. We used an analysis of covariance model and the Bonferroni method to adjust for multiple comparisons. We used a prespecified per-protocol population as our sensitivity analysis. The α level was 0·025 for our primary analysis and 0·05 overall. This trial is registered with ClinicalTrials.gov, number NCT00665223. Findings At 26 weeks, in our full analysis set the difference in mean mMS was −0·99 points (97·5% CI −2·08 to 0·10, p=0·042) in patients who received 90 mg per day pridopidine (n=145) versus those who received placebo (n=144), and −0·36 points (−1·44 to 0·72, p=0·456) in those who received 45 mg per day pridopidine (n=148) versus those who received placebo. At the 90 mg per day dose, in our per-protocol population (n=114), the reduction in the mMS was of −1·29 points (−2·47 to −0·12; p=0·014) compared with placebo (n=120). We did not identify any changes in non-motor endpoints at either dose. Pridopidine was well tolerated and had an adverse event profile similar to that of placebo. Interpretation This study did not provide evidence of efficacy as measured by the mMS, but a potential effect of pridopidine on the motor phenotype of Huntington's disease merits further investigation. Pridopidine up to 90 mg per day was well tolerated in patients with Huntington's disease. Funding NeuroSearch A/S.

Endocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Δ(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these receptors in patients with Huntington's disease may attenuate disease progression.

This study was designed to examine the type of changes experienced by the CB1 receptor, a key element of the cannabinoid signaling system, in the basal ganglia of different mouse mutants generated by deletion of specific genes associated with the development of Parkinson's disease in humans [PARK1 (alpha-synuclein), PARK2 (parkin) or PARK6 (PINK1)]. We observed that CB1 receptor-mRNA levels were significantly reduced in the caudate-putamen in the three models under examination when animals were analyzed at early phases (or = 12 months of age). This decrease was, in general, associated with a reduction in CB1 receptor binding in the substantia nigra and the globus pallidus, particularly in the case of alpha-synuclein-deficient mice. By contrast, both parameters, mRNA levels and binding for the CB1 receptor, showed an elevation in the same areas when animals were analyzed at older ages, mainly in the case of the CB1 receptor binding in the substantia nigra. In summary, our data revealed the existence of a biphasic response for CB1 receptors, with losses at early phases, when dopaminergic dysfunction is possibly the major event that takes place, followed by upregulatory responses at advanced phases characterized by the occurrence of evident nigrostriatal pathology including neuronal death in some cases.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic arteriopathy related to Notch3 mutations, is difficult to diagnosis. The goal of this study was to determine the value of clinical, immunohistochemical, and molecular techniques for the diagnosis of CADASIL. Clinical features and the immunohistochemical and molecular findings in 200 subjects with suspected CADASIL in whom 93 biopsies and 190 molecular studies are reported. Eighteen pathogenic mutations of the Notch3 gene, six of them previously unreported, were detected in 67 patients. The clinical features did not permit differentiation between CADASIL and CADASIL-like syndromes. The sensitivity and specificity of the skin biopsies was 97.7% and 56.5%, respectively, but increased to 100% and 81.5%, respectively, in cases with proven family history. In conclusion, a clinical diagnosis of CADASIL is difficult to determine and confirmatory techniques should be used judiciously.

Huntington's disease (HD) is a neurodegenerative disorder caused by an expansion of polyglutamines which makes huntingtin more resistant to degradation. Parkin is an ubiquitin ligase which promotes proteosomal degradation of abnormal proteins. We investigated whether partial suppression of parkin increases HD phenotype. We studied the behavior and brain histology and biochemistry of the mice produced by interbreeding of R6/1 (model of HD in mice) with Park-2(-/-) (parkin null mice): R6/1, WT (wild-type), PK(+/-) (hemizygotic deletion of Park-2) and R6/1/PK(+/-). R6/1 and R6/1/PK(+/-) mice had abnormal motor and exploratory behavior. R6/1/PK(+/-) mice were more akinetic. These two groups of mice had severe but similar loss of nigrostriatal dopamine neurons and monoamine levels in striatum. R6/1/PK(+/-) mice had fewer huntingtin inclusions and a greater number of TUNEL(+) cells than R6/1 in striatum but there were no differences in the hippocampus. DARPP-32 protein was equally reduced in striatum of R6/1 and R6/1/PK(+/-) mice. Striatal levels of GSH were increased, of HSP-70 reduced and of CHIP unchanged in both R6/1 and R6/1/PK(+/-) mice. LC-3 II/I ratios were significantly increased in striatum of R6/1/PK(+/-) mice. Partial suppression of parkin slightly aggravates the phenotype in R6/1 mice, confirming a pathogenic role of the UPS in the processing of mutant huntingtin. The absence of massive additional cellular lesions in R6/1/PK(+/-) mice suggests the existence of compensatory mechanisms, such as autophagy, for the processing of huntingtin.

Young parkin null (pk-/-) mice have subtle abnormalities of behaviour, dopamine (DA) neurotransmission and free radical production, but no massive loss of DA neurons. We investigated whether these findings are maintained while ageing. Pk-/- mice have reduced life span and age-related reduced exploratory behaviour, abnormal walking and posture, and behaviours similar to those of early Parkinson's disease (PD), reduced number of nigrostriatal DA neurons and proapoptotic shifts in the survival/death proteins in midbrain and striatum. Contrary to young pk-/- animals 24-month-old pk-/- mice do not have compensatory elevation of GSH in striatum, glutathione reductase (GR) and glutathione peroxidase (GPx) activities are increased and catalase unchanged. Aged pk-/- mice accumulate high levels of tau and fail to up-regulate CHIP and HSP70. Our results suggest that aged pk-/- mice lack of the compensatory mechanisms that maintain a relatively normal DA function in early adulthood. This study could help to explain the effects of ageing in patients with genetic risks for Parkinson's disease.

Progressive supranuclear palsy (PSP) is a mostly sporadic disorder of unknown pathogenesis. Familial PSP have been reported related to mutations of microtubule-associated protein tau (MAPT). Mutations of the Park2 gene cause autosomal recessive parkinsonism with neuropathological findings consistent with neurofibrillary tangles and tau immunoreactive lesions. We analysed the presence of MAPT and Park2 mutations and polymorphisms in sporadic and familial PSP. No patients had mutations of Park2 or MAPT but there was genetic association for the polymorphism Val380Leu in sporadic and familial PSP. Leu380 is associated with less risk of familial or sporadic PSP.

Contains fulltext : 51751.pdf (Publisher’s version ) (Closed access) OBJECTIVE: We conducted a randomized double-blind trial of riluzole in Huntington's disease to investigate the efficacy of this antiexcitotoxic drug in slowing disease progression. METHODS: The study included 537 adult patients with a clinical diagnosis of Huntington's disease confirmed by genotyping. Patients were randomized (2:1) to treatment with riluzole (50mg twice daily) or placebo for 3 years. Concomitant use of antichoreic medication was forbidden, and introduction of such medication was a predefined end point. The primary outcome measure was change in a combined score derived from the motor and total functional capacity subscores of the Unified Huntington's Disease Rating Scale. Safety was also evaluated. RESULTS: A total of 379 patients completed the study (mean age, 47 [standard deviation, 9.5] years; 50% female patients). The principal reason for discontinuation was introduction of antichoreic medication. The median change from baseline in the combined score (primary outcome) for the "per protocol" population was 13.7 (95% confidence interval, 11.1-17.2) in the placebo group and 14.3 (95% confidence interval, 11.7-16.6) in the riluzole group. No intergroup difference in outcome could thus be demonstrated (p = 0.93, Mann-Whitney U test). No differences in secondary efficacy outcome variables were observed except for more frequent recourse to antichoreic medication in the placebo group. No unexpected adverse events were reported, and tolerability was acceptable. INTERPRETATION: No neuroprotective or beneficial symptomatic effects of riluzole in Huntington's disease were demonstrated.

Patients with chronic renal failure treated with haemodialysis have vascular risk factors that, in the general population, are associated with increased prevalence of Alzheimer's disease (AD). Patients in haemodialysis, however, present different kinds of dementia but they do not have an increased risk of AD. We have hypothesized that amyloid-beta (Abeta)1-42 is washed out from plasma during the dialysis and that this procedure enhances Abeta elimination and reduces the risk of AD. We have measured plasma Abeta1-42 levels in 11 patients with renal failure, before and after haemodialysis. A single procedure reduced the plasma Abeta levels in all subjects with a mean decrement of 30% of baseline. Since Abeta deposition could be altered by certain metals like Cu and Zn, we have also measured the effects of dialysis on the levels of these ions in plasma. We found no changes in levels of Cu and Zn after dialysis. Haemodialysis, therefore, reduces very effectively plasma Abeta without modifying Cu and Zn levels. The potential use of this strategy in patients with AD requires further investigation.

Prompted by the lack of cross-cultural comparative data, and because a better understanding in the different clinical presentations of psychogenic movement disorders (PMDs) is relevant to neurological assessment and interventions, we compared the phenomenology, anatomical distribution, and functional impairment of PMDs in the United States and Spain. Consecutive patients diagnosed with PMD by a movement disorder specialist from one US site and from eight Spanish university centers were included in the study. The two groups were similar in their movement types, anatomical distribution, and functional impairment. PMDs were more prevalent in women than in men and were most common in upper and lower extremities. Gait and speech dysfunctions were distributed similarly in both countries. We found action tremor to be the most frequent PMD in both countries.

Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed.

Objectives: To compare the severity of cognitive im- pairment among groups of patients with different age ranges at the onset of Huntington disease (HD) and to evaluate the variable influence of motor and cognitive defi- cits on functional disability across different ages at the onset of HD. Design: Cross-sectional multidisciplinary evaluation of patients referred to our institution for care related to a possible diagnosis of HD. Setting: The Huntington disease program in the De- partments of Neurology and Genetics at the Fundacion Jimenez Diaz, Madrid, Spain. Participants: Seventy-one patients with Huntington dis- ease were classified into 3 groups depending on age at onset of motor symptoms: juvenile onset, 25 years of age or younger (group 1, n=15); adult onset, from 26 to 50 years (group 2, n=43); and late onset, 51 years or older (group 3, n=13). Age- and education-matched controls (n=50) were included to compare cognitive perfor- mance with patients in groups 1 and 3. Measures: Cognitive evaluation encompassed a wide neuropsychological battery to assess global cognitive func- tioning and visuospatial, prefrontal, and memory func- tions. Clinical data included motor and functional vari- ables measured by using the Unified Huntington's Disease Rating Scale. Genetic analysis determined the number of CAG trinucleotide repeats. Results: Patients in group 1 scored 2.9 points and pa- tients in group 3 scored 4.2 points below their respective controls on the Mini-Mental State Examination. Patients in groups 1 and 3 were similarly impaired in verbal memory. Visual function was much more impaired in patients in group 3, and prefrontal functions were slightly worse in patients in group 1. Cognitive scores were correlated only with time of evolution for patients in group 2. Functional scores were not significantly different among the 3 groups, but 11 (85%) of the patients in group 3 were in stage I or II vs 10 (67%) of the patients in group 1. Total functional capacity correlated better with the Mini-Mental State Ex- amination score for patients in group 3 and with motor defi- cits (akinesia) and prefrontal dysfunction for patients in group 1. The mean±SD CAG repeat length decreased from 59.9±12.6 for patients in group 1 to 46.2±3.5 for patients in group 2 and 41.7±2.6 for patients in group 3. Longer CAG repeats in the HD study population correlated with akinetic features but not with cognitive performance. Conclusions: Despite the much greater genetic defect, cognitive status is slightly better preserved in patients with juvenile-onset HD. Cognitive impairment in patients with juvenile- and late-onset HD differs in the severity of vi- sual and prefrontal deficits. Functional disability in pa- tients with late-onset HD depends more on global cog- nitive status, while in patients with juvenile-onset HD, it is conditioned more by motor deficits and prefrontal dysfunction.

Huntington's disease (HD) is a neurodegenerative and hereditary disease characterized by progressive movement disorders and mental and behavioral abnormalities. The HD gene is an expanding and unstable trinucleotide repeat (CAG repeat sequences). We studied 77 individuals from 38 families with HD in an attempt to obtain information for genetic counselling and differential diagnosis. Our results indicate that individuals with more than 40 repeats will be affected by the disease, whereas those with fewer than 30 will be healthy. There can be some overlap between 30 and 40 repeats, and one should be careful when interpreting these results.

The mechanisms by which intrastriatal grafts of chromaffin tissue alleviate the signs of clinical and experimental parkinsonism remain elusive. In the present report, we have demonstrated that, in conjunction with intraventricular infusion of nerve growth factor (NGF), ventricular grafts of either non-chromaffin or adrenal medullary tissue are equally effective in reducing apomorphine-induced circling in rats whose substantia nigra have been permanently lesioned with 6-hydroxydopamine. These treatments were much more effective than implantation of adrenal medulla without NGF. In addition, the effects persisted indefinitely, though at a reduced level, after discontinuation of the NGF infusion. The results suggest that trophic factors may be crucial to the beneficial effects of intracerebral transplanted tissues.

The biochemical, pharmacological and immunological characterization of cells derived from human neuroblastoma tumors recently acquired great interest, since these cells may be a putative donor source for transplantation in animal models of neurological disorders. We measured monoamine levels, tyrosine hydroxylase (TH) immunostaining, and the expression of major histocompatibility cell surface antigens (MHC) in 7 human neuroblastoma cell lines. Three cell lines (LAN5, NB69 and CHP126) had high levels of monoamines. TH immunostaining was strongly positive in CHP126 and LAN5, and NB69. MHC were not detected in any of the cells with high catecholamine levels. Treatment with neuroleptics increased the metabolism of dopamine in LAN5 but not in NB69. The implantation of LAN5 cells in immunocompetent, unilaterally 6-hydroxydopamine-lesioned rats decreased the apomorphine-induced contralateral rotation. The effect of the implant was greatest in animals in which LAN5 neuroblastoma cells, pretreated with dibutyryl cyclic adenosine monophosphate (DBcAMP) and prostaglandin E1 (PGE1, were implanted into the cerebral ventricle ipsilateral to the lesion, and then irrigated with DBcAMP administered through a totally implanted drug delivery system. The effect of the implant decreased after the second week. Neuroblastoma cells were found in approximately 50% of the implanted animals. TH immunostaining was weak or absent in the grafted animals. Inflammatory changes were present in the majority of the brains examined. Extensive tumor growth was present in one animal implanted with untreated cells. Grafting of cells treated with DBcAMP and PGE1 plus with mitomycin C and bromodeoxyuridine in animals immunosuppressed with cyclosporin A reduced the apomorphine-induced rotation to 40-60% of baseline levels and this reduction persisted beyond the period of infusion with DBcAMP. Intraventricular infusion of DBcAMP in animals injected with cell culture medium produced a transient reduction of rotation to 70% of baseline. The amphetamine-induced rotation was not significantly reduced during the 4 weeks follow up. Atypical cells, consistent with surviving neuroblastoma cells, were observed in the brain of all transplanted animals. TH immunostaining was weak or negative in most cases. Human neuroblastoma cells may be an alternative donor tissue for the study of the effects of transplantation in animal models of Parkinson's disease.

We investigated the environmental and genetic factors for Alzheimer's disease (AD) in Spain and performed a door to door study of a cohort of more than 500 subjects, over 70 years old, from Leganes, a suburban area near Madrid. The cohort was followed for 6 years by neurologists and other health workers and was divided in three groups: normal controls, subjects with aging-associated cognitive decline (AACD) and probable AD or dementia of Alzheimer's type (DAT). Biological variables and polymorphisms of different genes, important in neurodegeneration or reported to be associated with AD, were investigated as putative risk modifiers. These polymorphisms have also been analyzed in 94 brains, 39 from patients with pathologically confirmed AD and 55 controls. The statistical investigation included the evaluation of different individual risks and a multinomial logistic regression analysis to detect predictive factors. The risk of AACD and AD increased with age, feminine gender and history of stroke and decreased with education. The allele ApoE4 increased the risk of AD but not of AACD. When the impact of ApoE4 was added to the model, the effect of education and stroke disappeared as risk modifiers.