[Cervantes and Parkinson's disease]. / Cervantes y la enfermedad de Parkinson.

TITLE: Cervantes y la enfermedad de Parkinson.

Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia.

Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist.

The dopaminergic stabilizer, (-)-OSU6162, rescues striatal neurons with normal and expanded polyglutamine chains in huntingtin protein from exposure to free radicals and mitochondrial toxins.

Huntington's disease (HD) is a neurodegenerative disease characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and caused by a polyglutamine expansion in the huntingtin protein. There is so far neither cure nor approved disease-slowing therapy for HD, though recent clinical studies have shown a beneficial long-term effect of pridopidine in patients with HD. The nature of this effect, purely symptomatic or, in addition, neuroprotective, is difficult to elucidate in clinical trials. Pridopidine and (-)-OSU6162 are members of a new family of compounds referred to as dopaminergic stabilizers, which normalize abnormal dopamine neurotransmission. We investigated the effects of (-)-OSU6162 on huntingtin knocked-in striatal neurons in culture. Control neurons had normal full-length huntingtin with 7 glutamines while "mutant" neurons had large expansions (Q=111). We studied the dose-effect curves of (-)-OSU6162 on mitochondrial activity, LDH levels, necrosis and apoptosis in untreated Q7 and Q111 cells. In addition, we investigated the effects of (-)-OSU6162 on Q7 and Q111 neurons challenged with different neurotoxins such as sodium glutamate, H(2)O(2), rotenone and 3-nitropropionic acid (3NP). As we found prevention of toxicity of some of these neurotoxins, we investigated the putative neuroprotective mechanisms of action of (-)-OSU6162 measuring the effects of this dopaminergic stabilizer on expression and release of BDNF, the ratios of Bcl2/Bax proteins and of p-ERK/ERK, the levels of chaperones and GSH, and the effects of (-)-OSU6162 on dopamine uptake and release. We found that (-)-OSU6162, 3-150 µM, produces a dose dependent increase of mitochondrial activity and a reduction of cell death. (-)-OSU6162 does not change glutamate toxicity, but it partially prevents that of H(2)O(2), rotenone and 3-nitropropionic acid. (-)-OSU6162 increases the intracellular levels of BDNF and Bcl2/Bax and decreases those of p-ERK/ERK and CHIP in Q111 cells. (-)-OSU6162 increased (3)H-dopamine uptake and amphetamine-induced (3)H-dopamine release in E13 mouse mid brain neurons. Our studies demonstrate that (-)-OSU6162 improves survival and mitochondrial function in striatal Q111 neurons and the resistance of these cells to several striatal neurotoxins, suggesting that (-)-OSU6162 and related compounds should be tested for neuroprotection in animal models and, eventually, in patients with HD.

The accumulation of neurotoxic proteins, induced by proteasome inhibition, is reverted by trehalose, an enhancer of autophagy, in human neuroblastoma cells.

Neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, Huntington's disease and others are due to accumulation of abnormal proteins which fold improperly and impair neuronal function. Accumulation of these proteins could be achieved by several mechanisms including mutation, overproduction or impairment of its degradation. Inhibition of the normal protein degradation is produced by blockade of the ubiquitin proteasome system. We have shown that epoxomicin, a proteasome inhibitor, increases the levels of proteins involved in neurodegenerative disorders such as α-synuclein and hyper phosphorylated tau in NB69 human neuroblastoma cells and that such increase correlates with an enhanced rate of cell death. We then investigated whether the stimulation of autophagy, an alternative mechanism for elimination of abnormal proteins, by treatment with trehalose, counteracts the effects of proteasomal blockade. Trehalose, a disaccharide present in many non-mammalian species, known to enhance autophagy, protects cells against various environmental stresses. Treatment with trehalose produced a dose and time-dependent increase in the number of autophagosomes and markers of autophagy in NB69 cells. Trehalose did not change the number of total neither the number of dividing cells in the culture but it completely prevented the necrosis of NB69 induced by epoxomicin. In addition, the treatment with trehalose reverted the accumulation, induced by epoxomicin, of polyubiquitinated proteins, total and phosphorylated tau, p-GSK-3, and α-synuclein, as well as the α-synuclein intracellular aggregates. The effects of trehalose were not mediated through activation of free radical scavenging compounds, like GSH, or mitochondrial proteins, like DJ1, but trehalose reduced the activation of ERK and chaperone HSP-70 induced by epoxomicin. Inhibition of ERK phosphorylation prevented the epoxomicin-induced cell death. Inhibition of autophagy reverted the neuroprotective effects of trehalose in epoxomicin-induced cell death. These results suggest that trehalose is a powerful modifier of abnormal protein accumulation in neurodegenerative diseases.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

NP7 protects from cell death induced by oxidative stress in neuronal and glial midbrain cultures from parkin null mice.

Parkin mutations produce Parkinson's disease (PD) in humans and nigrostriatal dopamine lesions related to increased free radicals in mice. We examined the effects of NP7, a synthetic, marine derived, free radical scavenger which enters the brain, on H(2)O(2) toxicity in cultured neurons and glia from wild-type (WT) and parkin null mice (PK-KO). NP7, 5-10 microM, prevented the H(2)O(2) induced apoptosis and necrosis of midbrain neuronal and glial cultures from WT and PK-KO mice. NP7 suppressed microglial activation and the H(2)O(2) induced drop-out of dopamine neurons(.) Furthermore, NP7 prevented the increased phosphorylation of ERK and AKT induced by H(2)O(2). NP7 may be a promising neuroprotector against oxidative stress in PD.

On the pathogenesis and neuroprotective treatment of Parkinson disease: what have we learned from the genetic forms of this disease?

Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease. More recently, genetic alterations have been found in patients with PD. The function of the proteins coded by the genes involved in PD has been investigated in genetic models of this disease from invertebrate to rodents. Mutated proteins responsible for PD have been tested in vivo and in vitro, in cellular models or in artificial constructs. A wealth of important information about the function of alpha-synuclein, parkin, DJ-1, PINK and dardarin is available, most notably about the first two causes of familial PD discovered, alpha-synuclein and parkin, responsible for autosomal dominant and autosomal recessive PD, respectively. Different animal models of alpha-synuclein and parkin have been extensively investigated. The in vitro and in vivo studies performed in genetic models of PD have shown that the proteins involved in the pathogenesis of PD interact with one another and have multiple mechanisms of cell toxicity. From the available data, it is clear that the mechanisms leading to cell degeneration in PD are variable in the different subtypes of this disease. Neuroprotective therapies should, therefore, be multiple and tailored according to the factors involved in the different cases. In this study, we review what we have learned from the genetic models of PD and the putative strategies to be tested in the near future.

Characterization of dopaminergic dysfunction in familial progressive supranuclear palsy: an 18F-dopa PET study.

We analyzed (18)F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSP patients showed reduced (18)F-dopa uptake in the striatum, orbitofrontal cortex and amygdala. One asymptomatic subject exhibited progressive putamen dopaminergic dysfunction. 60% of subjects with abnormal (18)F-dopa scans developed PSP subsequently. This is the first in vivo documentation of cortical dopaminergic deficiency in PSP. Reduced striatal (18)F-dopa uptake in susceptible relatives may predict later clinical disease.

Suppression of Parkin enhances nigrostriatal and motor neuron lesion in mice over-expressing human-mutated tau protein.

Abnormal deposition of protein tau takes place in the brain of patients with several neurodegenerative diseases. Few of these patients present frontotemporal dementia with parkinsonism and amyotrophy (FTDPA-17), an autosomal dominant tauopathy related to mutations of the gene that codes for protein tau, localized in chromosome 17. The great majority of patients with tauopathies such as Alzheimer's disease, sporadic frontotemporal dementia or progressive supranuclear palsy do not show a Mendelian pattern of inheritance. We have occasionally seen tauopathies in patients with parkin mutations and, therefore, hypothesized that the protein tau interacts with parkin. We have tested that hypothesis in mice with combined genetic modifications of tau (over-expression of human tau with three mutations known to produce FTDPA-17) and parkin (deleted) proteins. Homozygote parkin null or over-expressing mutated-human tau mice have subtle behavioral and molecular abnormalities but do not express a clinical phenotype of neurodegenerative disease. Mice with combined homozygous mutations of these two genes show progressively abnormal walking already noticeable at 3 months of age, loss of dopamine and dopamine markers in striatum, nuclear tau immunoreactive deposits in motor neurons of the spinal cord, abnormal expression of glial markers and enhanced levels of pro-apoptotic proteins; findings that were absent or less pronounced in homozygote animals with deletions of parkin or over-expression of tau. The double transgenic mice do not express normal mechanisms of adaptation to stress such as increased levels of GSH and Hsp-70. In addition, they have reduced levels of CHIP-Hsc70, a complex known to attenuate aggregation of tau and to enhance ubiquitination of phosphorylated tau. We have found high levels of phosphorylated tau in parkin-/-+tau(VLW) mice and a relative decrease of the inactivated pSer9 to total GSK-3 levels. Our data reveal that there are interactions between tau and parkin that could be relevant for the pathogenesis and treatment of tauopathies. Similarly, we hope that the double transgenic parkin-/-+tau(VLW) mice could be useful for testing of compounds with putative therapeutic value in human tauopathies.

[Klüver-Bucy syndrome as the initial symptom of adult-type ceroid lipofuscinosis (Kufs' disease)]. / Síndrome de Klüver-Bucy como manifestación inicial de ceroidolipofuscinosis del adulto (enfermedad de Kufs).

AIMS: The purpose of this paper is to report the case of a patient with Kluver-Bucy syndrome caused by adult-type ceroid lipofuscinosis (Kufs' disease) and to review the literature dealing with the causes of this syndrome. CASE REPORT: A 38-year-old male examined because of behavioural changes and cognitive impairment. Brain biopsy findings were characteristic of adult-type ceroid lipofuscinosis. This patient fulfilled the criteria of Kufs' disease, since he had mixed clinical features belonging to both type A (neuropsychiatric disorders) and B (aphasia-apraxia-agnosia syndrome) of the disease. The initial symptoms included several clinical features of Klüver-Bucy syndrome (probable visual agnosia, apathy, increased sexual activity, lack of sexual inhibition, hypermetamorphopsia, increased oral behaviour and changes in dietary habits). CONCLUSIONS: Adult-type ceroid lipofuscinosis is an infrequent clinical entity that is difficult to diagnose owing to the absence of peripheral biological markers and the need to confirm such a diagnosis by means of a histopathological study.

[Aphasias for verbal and sign languages are due to lesions of nearly localised but not identical brain regions of the left hemisphere]. / Las afasias para lenguaje oral y de signos se producen por lesión de estructuras cercanas pero no idénticas del hemisferio dominante.

OBJECTIVES: To study the characteristics of verbal and sign language aphasia in a patient fluent in both languages, who had had a recent left hemisphere stroke as well as to localise the site responsible for Spanish sign language aphasia. PATIENT AND METHODS: 56 years old male, with risk factors for stroke, who presented an episode of sudden onset aphasia and right hemiplegia that partially recovered in a few hours. The residual deficit of language was explored with a detailed protocol that included comprehension, denomination, oral and phonetic praxis, propositional and automatic spontaneous language, reading and writing tasks. The examination of verbal and sign language was video-recorded. The lesion was localised by magnetic resonance imaging 24 days after the stroke. RESULTS: The patient, whose infarction involved the superior temporal gyrus and sylvian operculum, presented similar abnormalities for comprehension of complex sentences, many phonemic paraphasias and no trouble to repeat single words. Oral language was not fluent, but sign language was quite fluent with a rich vocabulary, but with semantic paraphasias, agrammatism and without self-criticism for his own mistakes. CONCLUSIONS: The pattern of oral and sign language alterations is partially different, more for expressive than perceptive discourse, although both types of aphasias are caused by lesions of the left hemisphere. The regions responsible for these abnormalities of both symbolic languages are localised close to each other, but not in the same place.

Unique origin and low penetrance of the 946delGAG mutation in Valencian DYT1 families.

Mutations in the DYT1 gene cause idiopathic torsion dystonia (ITD) transmitted in families as an autosomal dominant trait with incomplete penetrance. The most common mutation, 946delGAG, has been observed in populations with different ethnic and geographic origins. We have investigated 40 individuals from 22 unrelated families with ITD originating from the Land of Valencia, Spain, for the presence of this mutation and we found 5 patients and 6 unaffected subjects from 4 families who were carriers of the mutation. This finding indicates that 18% of families may be diagnosed as DYT1 and that penetrance is reduced. We detected two different geographic and linguistic origins of the Valencian families. However, by haplotype analysis using D9S1260, D9S1261, D9S63 and D9S1262 as flanking markers, we demonstrated that all affected and unaffected carriers shared a common chromosome confirming identical origin of the mutation in the four families. We postulate a unique origin for the 946delGAG mutation in the Land of Valencia and, based on linguistic criterion, we propose that the mutation might have occurred at the beginning of the second millennium. Genetic analysis of another family from Castilla-La Mancha showed a different haplotype segregating with the disease, suggesting that at least two distinct mutational events for the 946delGAG mutation have occurred in Spain.

[Glia conditioned medium offers protection against the toxicity induced by 6-OH-dopamine in vivo]. / El medio condicionado de glía protege de la toxicidad inducida in vivo con 6-OH-dopamina.

INTRODUCTION: Glia conditioned medium (GCM) is neurotrophic for dopaminergic (DA) neurons and protects against MPP+ toxicity in vitro. We present the data from the first study in vivo of the effects of GCM. MATERIAL AND METHODS: The restorative effects were examined in rats with lesions produced by 6-hydroxy-dopamine (6-OH-DA) in the medial longitudinal fasciculus. At four weeks, animals with an apomorphine induced rotation rate above three per minute were randomised for infusion with GCM, defined medium (DM) or saline through a striatal cannula for two weeks. To investigate the protective effects of GCM, the animals received a striatal injection of GCM or vehicle at the same time as the lesion was induced by 6-OH-DA and were sacrificed three weeks later. RESULTS: In the experiments on the restorative effect, the GCM infusion produced a significant increase in dopamine (DA) levels on the side with the lesion, in the limbic system (455.8 108.4 ng/g of tissue) and in the striatum (242.1 69.2 ng/g of tissue), as compared with the controls (110.8 36,4 and 108.4 22 ng/g). In the experiments on the protective effect, GCM induced higher levels of DA, 3,4-dihydroxyphenylacetic acid and 3 methoxytyramine (3-MT). In both models, the apomorphine induced rotation in animals with lesions caused by 6-OH-DA and treated with GCM was lower than that of the animals infused with DM or saline. CONCLUSIONS: These experiments show that GCM has protective and restorative effects in an experimental model of Parkinson's disease.

Tolcapone increases plasma catecholamine levels in patients with Parkinson's disease.

Tolcapone is a catechol-ortho-methyl-tranferase (COMT) inhibitor that increases the L-DOPA half-life and the duration of effect in Parkinson's disease. We investigated the effect of tolcapone on the plasma catecholamine levels. We measured plasma catecholamines 2h after the first daily dose of L-DOPA or L-DOPA+tolcapone while resting and 2 and 10min after standing. We also measured the pharmacokinetics of L-DOPA and 3-OM-DOPA and the clinical response to the medication for 6h after the early morning dose. The levels of dopamine, norepinephrine, adrenaline and total catecholamines significantly increased and 3-OM-DOPA decreased with tolcapone. We did not observe significant changes in the plasma L-DOPA levels at the doses of tolcapone used in this study. Tolcapone side effects included worsening of dyskinesia and psychosis, diarrhea and elevation of liver enzymes. Twenty-four-hour ambulatory recording of arterial blood pressure and heart rate did not reveal cardiovascular side effects in patients treated with tolcapone for less than 1year. Since adrenergic stimulation may increase the hepatotoxic potential of commonly used drugs, usually thought of as safe for the liver, we postulate that some of the already reported life threatening complications of tolcapone could be related to excessive adrenergic stimulation by high catecholamine levels caused by inhibition of COMT activity.

Unilateral 6-hydroxydopamine lesions of nigrostriatal dopaminergic neurons increased CB1 receptor mRNA levels in the caudate-putamen.

It has been recently suggested that the effects of cannabinoids on motor behavior might be different in rats with lesions of nigrostriatal dopaminergic neurons than in controls. In the present study, we examined the possible alteration in the status of cannabinoid CB1 receptors in the basal ganglia of rats with unilateral lesions of those neurons caused by 6-hydroxydopamine. We used two different experimental groups depending on the duration of the period of recovery after the lesion, and comparisons were done between the lesioned and nonlesioned sides at the level of the basal ganglia. Both groups of lesioned rats exhibited a similar marked reduction in tyrosine hydroxylase (TH)-mRNA levels, measured by in situ hybridization, in the substantia nigra of the lesioned side. In the same way, lesioned rats exhibited the characteristic rotational behavior after a single injection of apomorphine and the intensity of this rotation was stable at the two times analyzed after the lesion. Also as expected, lesioned rats exhibited an increase in proenkephalin mRNA levels in the caudate-putamen, whereas mRNA levels of substance P decreased, although differences between the two times of recovery analyzed were observed in this case. We did not find any significant changes in CB1 receptor binding, measured by [3H]WIN-55,212,2 autoradiography, or in the activation of signal transduction mechanisms, measured by WIN-55,212,2-stimulated [35S]GTPgammaS binding autoradiography, between the lesioned and nonlesioned sides at the level of the lateral caudate-putamen, globus pallidus and substantia nigra in both groups of lesioned rats. However, we found a significant increase in levels of CB1 receptor-mRNA transcripts, measured by in situ hybridization, in the lesioned side in both the lateral and medial caudate-putamen. This occurred 7-10 weeks after the lesion, but the increase was markedly waned after 17-18 weeks. In summary, the unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons originated a marked increase in CB1 receptor-mRNA levels in cell bodies of striatal efferent neurons, although accompanied by no changes in CB1 receptor binding and activation of signal transduction mechanisms. This supports a critical role for dopamine in the control of CB1 receptor gene expression. However, the magnitude of the effect significantly waned as a function of the duration of the period after lesion.

Bradykinesia in early Huntington's disease.

BACKGROUND: Huntington's disease (HD) is generally considered a hyperkinetic disorder, although hypokinetic features are part of the motor syndrome. Moreover, the striatum is considered to play a key role in initiating and executing motor programs and achieving optimal scheduling in response generation. Controversial results regarding the association between clinical features and markers of progression of the disease might be the result of inadequate restriction of clinical signs to the choreatic syndrome. OBJECTIVE: To determine the relationship of neurologic motor and cognitive indices in patients with HD with intrinsic neuronal loss in the striatum, as measured using raclopride C11 and PET. PATIENTS AND METHODS: A cross-sectional study was performed on 11 patients with mild HD (stages 0-2). Motor (Unified Huntington's Disease Rating Scale [UHDRS], saccadic and tapping speed) and cognitive (verbal fluency, Trail Making Test, Stroop Test, Symbol Digit Modalities Test, Conditioned Associative Learning Test, and silhouette identification and object decision of the Visual Object and Space Perception battery) scores were correlated with raclopride C11 binding. RESULTS: Bradykinesia (a summation of five items of the UHDRS motor scale) was the best predictor for stage, that is, functional capacity, and showed a highly significant relationship with putaminous D2 binding (r = -0.94) and with CAG expansion length x years of age (r = 0.96). The exclusion of two patients with a rigid-akinetic HD variant did not alter these coefficients. Chorea was less well correlated than bradykinesia with D2 binding in all striatal regions. Performance on different cognitive tests, especially in timed tasks, was highly correlated with raclopride C11 binding in caudate nucleus and ventral striatum. CONCLUSION: Loss of D2 binding in the striatum is highly correlated with the deficit in fast motor and cognitive processing in patients with early Huntington's Disease. Thus, impairment of rapid execution of adequate responses to environmental changes seems to be a common manifestation of striatal disorders.

The tau gene A0 allele and progressive supranuclear palsy.

BACKGROUND: Recent studies have shown an association between a polymorphic tandem repeat allele, located in intron 9, of the tau gene and progressive supranuclear palsy (PSP). OBJECTIVE: To investigate this tau polymorphism in individuals with a clinical diagnosis of sporadic or familial PSP as well as in cases confirmed by pathology. METHODS: We analyzed the frequency of tau intronic polymorphism, the presence of linkage in two families with multiple cases of PSP, the splicing of exon 10, and direct sequence of the tau gene. RESULTS: We found that patients with a clinical diagnosis of sporadic or familial PSP and individuals with PSP confirmed by neuropathology have greater prevalence of the A0 allele and A0/A0 genotype than controls. This finding, however, was also true for asymptomatic relatives of individuals with PSP. Linkage analysis in familial PSP excluded the location of the gene in the region 17q21. Furthermore, no significant differences were found in the level of expression of exon 10 in PSP, A0/A0 brain with respect to Alzheimer A3/A3 brain. We found no mutations in the tau gene in individuals with familial PSP. CONCLUSIONS: A mutation in the tau gene was not the primary cause of familial PSP. The role of tau and the tau A0 allele in white PSP patients remains unknown, although it may represent a genetic risk factor for several neurodegenerative disorders.

Clinical correlation of striatal 1H MRS changes in Huntington's disease.

OBJECTIVE: To study the clinical significance of metabolic alterations as measured in vivo with proton MRS in the striatum of patients with Huntington's disease (HD). METHODS: Localized, single-voxel MRS was performed on the basal ganglia of 10 HD patients (4 presymptomatic gene carriers and 6 akinetic patients) and 5 age-matched healthy individuals. Metabolite quantification was performed by referring the areas of the respective spectral peaks to that of water in the analyzed voxel. The spectroscopic findings were correlated with motor and cognitive performance in several specific tests and with the length of the CAG repeat expansion normalized for age. RESULTS: N-acetylaspartate (NAA) and creatine were reduced markedly in both groups of patients, particularly in the advanced group (approximately 60%), but the decrease was also significant in presymptomatic patients (approximately 30%) whose motor and cognitive performances were within the normal range. Both metabolites correlated highly with the motor score of the Unified Huntington's Disease Rating Scale and with computed measurements of saccadic and tapping speed. Creatine reduction was also well correlated with performance in cognitive timed tasks and with the length of CAG expansion (r = -0.81). CONCLUSION: The creatine signal appears to be an interesting marker for progression in HD and could be useful in assessing therapeutic outcome, particularly during the initial stages when most clinical indices are still within the normal range.