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It is not obvious how to define a neurodegenerative disorder. There are several challenging questions: How should the diagnosis be made? How can we be sure that symptoms do not simply reflect normal aging of the nervous system? What are the mechanisms and what are the causes? What are the perspectives of treatment for the patients? Today, given the repetitive failures of curative and preventive treatments, the purpose of the following remarks is not to provide an additional lesson on "how to find a new treatment". Instead, the aim is to ask the difficult questions that might lead to envisaging research from another angle.

Resume Les ecrans occupent une place considerable dans la vie de chacun et plus particulierement des enfants. Le numerique a pris une importance croissante et irreversible pour ce qui concerne l’education et la culture et, de facon plus generale, la vie de notre societe. D’immenses interets economiques et commerciaux sont en jeu. Il est neanmoins apparu, au fil des annees, que cette evolution avait aussi des effets deleteres qui suscitent une grande inquietude, si bien que le developpement rapide de la presence des ecrans dans nos vies et celle de nos enfants amene chacun a s’interroger autant sur les usages qu’il en fait que sur le temps qu’il y passe. C’est pourquoi les trois academies (Academie nationale de medecine, Academie des sciences, Academie des technologies) ont souhaite faire un point sur ces questions, sous la forme d’un « appel » et non d’un « rapport », de structure classique. Une des principales questions qui se posent est de savoir si l’utilisation excessive des ecrans peut engendrer une veritable addiction comportementale. Cette notion doit etre abordee avec precaution car elle repond a une definition medicale precise, reservee a des pathologies particulierement lourdes. En outre, ces addictions comportementales caracterisees sont souvent associees a des troubles psychiatriques comorbides tels que depression, anxiete, phobies ou troubles de la personnalite. L’apprehension de cette question est compliquee chez l’enfant et l’adolescent en raison de la diversite des contextes psychologiques et des situations individuelles. On sous-estime generalement le role des vulnerabilites sociales, qui interferent de facon majeure dans le rapport aux ecrans. En effet, tous les enfants et adolescents ne sont pas places dans des contextes familiaux, culturels et sociaux equivalents et les consequences du mauvais usage des ecrans apparaissent d’autant plus serieuses que l’enfant est en situation de vulnerabilite : l’absence ou l’insecurite de l’emploi, les difficultes materielles de la famille, une trop grande distance aux services educatifs, sociaux ou medicaux, un contexte culturel appauvri, sont autant de facteurs qui peuvent rendre difficile, voire inaccessible, la comprehension du numerique, l’education aux usages des ecrans, la distance critique et l’indispensable autoregulation. On observe chez certains jeunes enfants (âges de moins de 3 ans) une surexposition importante aux ecrans, veritable mesusage en termes de temps consacre. D’un usage recreatif a un usage utilitaire, on passe a un usage a visee exclusivement « calmante », propose puis maintenu par les parents. Fascine par les bruits et les lumieres vives, totalement passif, le tres jeune enfant peut apparaitre comme deja victime d’un trouble comportemental : surexposition chez l’enfant « scotche » a l’ecran et reactions de colere lors du retrait. La question est posee du retentissement de ce comportement sur le developpement psychomoteur et relationnel du jeune enfant, ainsi que sur ses capacites d’apprentissage. Independamment de la reponse a cette question tres preoccupante, il est difficile de departager ce que serait, d’une part, la possible nocivite intrinseque des ecrans pour les jeunes enfants, et, d’autre part, des pratiques parentales inadaptees dont la gestion des ecrans ne serait qu’un aspect parmi d’autres. L’objectif n’est pas uniquement de limiter l’acces aux ecrans, sauf, dans une large mesure, chez les plus jeunes enfants, mais de toujours en accompagner une utilisation raisonnable et raisonnee. Chez l’enfant plus âge, et plus particulierement chez l’adolescent, le probleme est tout autant celui du contenu que celui de la quantite. En particulier, la facilite d’acces a des scenes violentes ou pornographiques constitue un danger. Les reseaux sociaux permettent un elargissement des possibilites de communication et un soutien contre la solitude. A ce titre ils peuvent etre consideres comme positifs. En meme temps, ils sont une source d’inquietude chez l’adolescent, notamment en raison des risques de desinhibition de la communication et de harcelement facilites par la possibilite de l’anonymat. Cela est aggrave par les strategies des reseaux, visant a retenir l’attention des utilisateurs et a en obtenir toujours plus d’informations susceptibles d’alimenter des bases de donnees. Les jeux video representent un autre motif d’inquietude, largement mediatise. On peut se poser la question de la violence vehiculee par certains d’entre eux, mais aussi de l’absence de frontiere absolue entre les jeux de casino et certains jeux video, d’autant plus que certains editeurs, utilisant les services de psychologues et de specialistes des neurosciences, introduisent des procedes issus des jeux de hasard et d’argent. Cependant, si, dans des cas extremes, le basculement dans l’addiction aux jeux video peut se produire sous l’effet conjoint de facteurs de vulnerabilite personnelle ou sociale et du caractere particulierement addictogene de certains jeux, il convient de garder a l’esprit que la tres grande majorite des joueurs trouve dans cette distraction une source de satisfactions positives et d’amelioration de certaines performances. Sur le plan strictement medical, les effets negatifs d’une mauvaise utilisation des ecrans concernent tous les âges, mais sont evidemment plus deleteres pour l’enfant et l’adolescent. Ces problemes sont principalement lies aux consequences de l’utilisation vesperale ou nocturne des ecrans, dont la lumiere, en particulier la composante bleue, accroit la vigilance en inhibant la secretion de melatonine, hormone cle de l’endormissement. Les troubles du sommeil qui en resultent peuvent entrainer une fatigue, des troubles de l’attention et affecter les resultats scolaires et la vie sociale. Ici encore, le role des parents est capital. D’autre part, l’eventuelle toxicite pour la retine de la lumiere diffusee par les ecrans doit etre prise en consideration. Elle fait l’objet d’etudes importantes qui n’apportent pour l’instant pas de conclusion significative. Tous les risques qui viennent d’etre evoques ne doivent pas occulter le fait que, bien utilises, les ecrans, et l’information dont ils permettent l’echange, constituent des outils de connaissance et d’ouverture sur le monde dont l’interet est incontestable. Il faut rappeler avec force que le role des parents, aussi bien en tant que modele d’imitation que comme autorite educatrice, reste absolument capital pour le bon usage des ecrans et la construction de l’enfant. Vis-a-vis des adolescents, il faut egalement rappeler le role des enseignants pour un bon usage et pour l’education au discernement sur l’information recue. C’est pourquoi les campagnes alarmistes axees sans distinctions sur les « dangers des ecrans » ne risquent pas seulement de faire ignorer aux parents et aux educateurs les avantages potentiels des technologies numeriques, largement argumentes a ce jour. Elles risquent aussi de faire oublier les veritables determinants de la sante mentale et l’importance des problemes sociaux. La fracture entre ceux qui sont prepares a beneficier des apports du numerique et ceux pour lesquels celui-ci peut aggraver des difficultes preexistantes constitue aujourd’hui un probleme de justice sociale autant que de sante publique. La convergence numerique a d’ores et deja rapproche le cinema, la radio, la television et la telephonie en leur imposant un support technologique commun. Tres bientot, de nouvelles formes d’interactions s’y associeront, utilisant l’intelligence artificielle sous des formes multiples et encore imprevisibles. Une attitude de vigilance positive devra rester de mise face a ces evolutions.

Summary Background Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. Methods In this randomised, double-blind, controlled trial, we recruited patients aged 18–60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. Findings Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR −23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [–10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). Interpretation 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. Funding French Ministry of Health.

The aim of this study was to evaluate the efficacy of the new optimised levodopa, Stalevo® (levodopa, carbidopa and entacapone) in patients with Parkinson’s disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess®/Comtan®). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of levodopa/DDCI to either an equivalent dose of Stalevo or levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson’s Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for levodopa DDCI preparations.

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.

Mutations of the parkin gene on chromosome 6 cause autosomal recessive, early onset parkinsonism. This is the most frequent form of monogenic parkinsonism so far identified. The associated phenotypical spectrum encompasses early onset, levodopa-responsive parkinsonism (average onset in the early 30s in Europe), and it overlaps with dopa-responsive dystonia in cases with the earliest onset, and with clinically typical Parkinson's disease in cases with later onset. Despite clinical features, Lewy bodies are not found at autopsy in brains of patients with parkin mutations. The parkin protein possesses ubiquitin ligase activity, which is abolished by the pathogenic mutations.

The question has been raised as to whether neuromelanin, a by-product of catecholamine metabolism which accumulates during aging in primate midbrain neurons, contributes to the selective vulnerability of subgroups of dopaminergic neurons in Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP+) a metabolite of 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) is toxic to dopaminergic neurons, particularly in primates, producing a motor syndrome similar to that observed in Parkinson's disease. To test whether this neurotoxin preferentially affects melanized neurons, the survival of melanized and non-melanized catecholaminergic neurons was analysed after MPTP intoxication in the midbrain of the cynomolgus monkey (Macaca fascicularis). Experiments were performed on six animals chronically treated with MPTP (two were severely disabled, four moderately affected) and two age-matched control monkeys. Two populations of neurons were examined on regularly spaced sections throughout the midbrain: catecholaminergic neurons, identified by tyrosine hydroxylase immunohistochemistry and neuromelanincontaining neurons, visualized by Masson's method. The total number of neurons of each type was estimated in the different midbrain catecholaminergic cell groups using computer assisted image analysis. In the midbrains of control animals not all catecholaminergic neurons contained neuromelanin. The percentage of melanized neurons compared to the total population of tyrosine hydroxylase-positive neurons was high in the substantia nigra pars compacta (81.5%) and in the locus coeruleus (98%), intermediate in the substantia nigra pars lateralis (70%), in the catecholaminergic cell group A8 (50%), and in the ventral tegmental area (41.5%) and almost nil in the central gray substance. In MPTP-treated monkeys, the severity of the loss of catecholaminergic neurons was variable within the different midbrain cell groups, though of similar intensity in severely and mildly disabled monkeys. A relationship was found between the loss of dopaminergic neurons in the different mesencephalic cell groups of MPTP-intoxicated animals and the percentage of melanized neurons they normally contain (r = 0.98; P = 0.04). The percentage loss of catecholaminergic neurons in the locus coeruleus, the only noradrenergic cell group studied, was lower than expected from the correlation curve obtained for dopaminergic cell groups. Altogether, these findings indicate: (i) that dopaminergic neurons are more vulnerable to MPTP-toxicity than noradrenergic neurons; and (ii) that among dopaminergic neurons, those containing neuromelanin are more susceptible, indicating a possible role of neuromelanin in MPTP-toxicity. Nevertheless, neuromelanin may only represent one of the factors involved in the neurotoxin-induced neuronal death, since some nigral melanized neurons also survive MPTP-intoxication.

Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms.

SummaryPerformance of patients with schizophrenia (n = 15) was compared to that of patients with vascular ischemic lesions of the dorsolateral prefrontal cortex (n= 10) and to age-matched controls (n= 15) in delayed reaction tasks known to be specific markers of the functions of the frontal lobe. The performance of patients with schizophrenia was similar to that of patients with prefrontal lesions in the delayed response task (DR) and the spatial discrimination-reversal task (SD and RV) but not in the delayed alternation task (DA) in which they performed as well as controls. The behavioural profile of responses in delayed reaction tasks for the schizophrenic patients was identical to that of patients with basal ganglia lesions reported in a previous study. These results suggest that in some patients with schizophrenia, a frontal lobe deficit could be indirectly induced by a dysfunction of the basal ganglia. This problem could be due either to the pathological process itself or to the effect of the neuroleptic treatment.

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.

There have been numerous important recent advances in our understanding of the causes of Parkinson's disease (PD), the treatments available and how these are best applied for the long-term management of patients. Novel genes causing familial PD have been discovered and mechanisms leading to cell dysfunction and death identified. The PD prodrome is now a subject of great interest and clinical markers are being defined that may in future, together with biochemical markers, support an early, pre-motor diagnosis of PD. This will become important as new therapies are developed to modify disease progression. In the interim, the optimization of existing therapies remains an important priority. The value of existing and novel continuous drug delivery systems in PD is seen as providing simplified regimens, maintenance of motor control, reduction in motor complications and improved patient adherence to drug use.

Objective: To establish phenotype–genotype correlations in early-onset Parkinson disease (EOPD), we performed neurologic, neuropsychological, and psychiatric evaluations in a series of patients with and without parkin mutations.Background: Parkin (PARK2) gene mutations are the major cause of autosomal recessive parkinsonism. The usual clinical features are early-onset typical PD with a slow clinical course, an excellent response to low doses of levodopa, frequent treatment-induced dyskinesias, and the absence of dementia.Methods: A total of 44 patients with EOPD (21 with and 23 without parkin mutations) and 9 unaffected single heterozygous carriers of parkin mutations underwent extensive clinical, neuropsychological, and psychiatric examinations.Results: The neurologic, neuropsychological, and psychiatric features were similar in all patients, except for significantly lower daily doses of dopaminergic treatment and greater delay in the development of levodopa-related fluctuations (p < 0.05) in parkin mutation carriers compared to noncarriers. There was no major difference between the two groups in terms of general cognitive efficiency. Psychiatric manifestations (depression) were more frequent in patients than in healthy single heterozygous parkin carriers but did not differ between the two groups of patients.Conclusion: Carriers of parkin mutations are clinically indistinguishable from other patients with young-onset Parkinson disease (PD) on an individual basis. Severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta in these patients is associated with an excellent response to low doses of dopa-equivalent and delayed fluctuations, but cognitive impairment and special behavioral or psychiatric symptoms were not more severe than in other patients with early-onset PD.

The gene for autosomal recessive juvenile Parkinsonism (AR-JP) recently has been mapped to chromosome 6q25.2-27 in Japanese families. We have tested one Algerian and 10 European multiplex families with early-onset Parkinson disease for linkage to this locus, with marker D6S305. Homogeneity analysis provided a conditional probability in favor of linkage of >.9 in eight families, which were analyzed further with eight microsatellite markers spanning the 17-cM AR-JP region. Haplotype reconstruction for eight families and determination of the smallest region of homozygosity in two consanguineous families reduced the candidate interval to 11.3 cM. If the deletion of two microsatellite markers (D6S411 and D6S1550) that colocalize on the genetic map and that segregate with the disease in the Algerian family is taken into account, the candidate region would be reduced to

Rest tremor, one of the main symptoms in Parkinson's disease (PD), is dramatically improved following subthalamic nucleus stimulation (STN). Results are often better than after l-dopa treatment. The occurrence of rest tremor after neurosurgery in patients without preoperative tremor is uncommon.The aim of this work was to investigate the role of subthalamic nucleus stimulation in the appearance of parkinsonian rest tremor. PATIENTS-RESULTS: Thirty PD patients (14%) out of 215 undergoing STN deep brain stimulation had an akinetorigid form of the disease, without preoperative tremor 11 years after onset of the disease. Six of them experienced the appearance of tremor six months after bilateral STN stimulation when the stimulator was switched off in the Off medication state. This de novo parkinsonian tremor was improved by l-dopa treatment and disappeared when the stimulator was turned on.This finding suggests that infraclinical parkinsonian tremor is probably present in all PD patients.

Three characteristic observations are presented along with three tables presenting 24 patients with the following elements in common: excessively repeated use of an instrument such as a pen, a musical instrument or a tool. The appearance after that use of a central pathological phenomenon that includes a local dystonia of a hand or the mouth, a tremor, or the association of a tremor and a dystonia, all within the muscular domain corresponding to that of the use. The discussion, which is based exclusively on the clinical findings, deals with the following elements: the role of the use of the instrument rather than task itself, the predominant pathogenic factor which is the repetitive action, to which is added a genetic component in one incompletely penetrant case of DYT 1, and a probable genetic susceptibility in the others. The absence of improvement with rest distinguishes this central pathology from rheumatologic or orthopaedic problems involving repetitive activities. The evolution is slowly declining when the responsible action is continued. This occurs in three stages: a specific disorder involving only the use of the particular instrument, a more enlarged involvement affecting other activities and eventually a dystonia associated with a tremor or a postural tremor always located to the initial area. The therapeutic interventions suggested by the pathologic role of the repetitive movement is: (1) to advise a new training for the instrument that excludes the habitual movement; (2) to advise the patient to vary any newly acquired repetitive movements.

The aim of this study was to evaluate the efficacy of the new optimised levodopa, Stalevo (levodopa, carbidopa and entacapone) in patients with Parkinson's disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess/Comtan). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of levodopa/DDCI to either an equivalent dose of Stalevo or levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for levodopa DDCI preparations.

The term athetosis has progressively disappeared from the anglo-saxon literature which considers that athetosis is part of the spectrum of dystonia. These two clinical entities can be distinguished, however. Athetosis can be identified, searching for subtle semiological traits, in particular at the level of the hand. The earlier appearance of athetosis may be result from its onset during the early phases of development of the central nervous system. Despite its rarity, the clinical diagnosis of athetosis is important to consider from a prognostic point of view. Indeed, it results from brain lesions, and is therefore not a hereditary disorder as it may be the case for dystonia, and its evolution is relatively stable. The efficacy of treatments used in patients with dystonia, in particular high frequency pallidal stimulation, remains to be assessed in patients with athetosis. The concept of athetosis is still helpful in clinical practice.

To evaluate the possible involvement of glutamate AMPA receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of LY293558, a competitive AMPA receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of LY293558 was studied to evaluate the possible reversion or prevention of these levodopa effects. In the first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 LY293558 (5 mg/kg, i.p.) was administered immediately before levodopa. In the second set of experiments, rats were treated daily for 22 days with levodopa and LY293558 (5 mg/kg, twice daily, i.p.). In the third set of experiments, the effect of LY293558 (5 mg/kg, i.p.) administration on selective dopamine D-1 (SKF38393, 1.5 mg/kg, s.c.) and D-2 agonist (quinpirole, 0.1 mg/kg, i.p.)-induced rotational behavior after daily levodopa treatment was studied. The duration of the rotational behavior induced by chronic levodopa decreased by 30% after 22 days. Acute administration of LY293558 on day 23 reversed this effect. The group of animals that were chronically treated with levodopa and LY293558 did not show the decrease in this motor response duration. Chronic levodopa treatment attenuated the rotational response to the D-1 agonist SKF38393 and increased the response to the D-2 agonist quinpirole. LY293558 did not reverse the effect of levodopa on rotational behavior induced by the D-1 agonist but significantly reduced the rotational response to the D-2 agonist in levodopa-treated animals by 40%. Our results demonstrate that an AMPA receptor antagonist reverses and prevents levodopa-induced motor alterations in parkinsonian rats and that this effect on motor fluctuations induced by chronic levodopa is probably due to a modulation of the indirect output pathway of the basal ganglia.

Bax is a proapoptotic member of the Bcl-2 family of proteins. It is believed to exert its action primarily by facilitating the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, leading to caspase activation and cell death. Because alterations in mitochondrial respiratory function, caspase activation and cell death with morphologic features compatible with apoptosis have been observed post mortem in the brain of patients with Parkinson's disease, we tried to clarify the potential role of Bax in this process in an immunohistochemical study on normal and Parkinson's disease post-mortem brain and primary mesencephalic cell cultures treated with MPP(+). We found that Bax is expressed ubiquitously by dopaminergic (DA) neurons in post-mortem brain of normal and Parkinson's disease subjects as well as in vitro. Using an antibody to Bax inserted into the outer mitochondrial membrane as an index of Bax activation, no significant differences were observed between control and Parkinson's disease subjects, regardless of the mesencephalic subregion analysed. However, in Parkinson's disease subjects, the percentage of Bax-positive melanized SNpc neurons containing Lewy bodies, suggestive of DA neuronal suffering, was significantly higher than the overall percentage of Bax-positive neurons among melanized neurons. Furthermore, all melanized SNpc neurons in Parkinson's disease subjects with activated caspase-3 were also immunoreactive for Bax, suggesting that Bax anchored in the outer mitochondrial membrane of melanized SNpc neurons showing signs of neuronal suffering or apoptosis is increased compared with DA neurons that are apparently unaltered. Surprisingly, MPP(+) treatment of tyrosine hydroxylase (TH)-positive neurons in primary mesencephalic cultures did not cause redistribution of Bax, although cytochrome c was released from the mitochondria and nuclear condensation/fragmentation was induced. Taken together, these findings suggest that in the human pathology, Bax may be a cofactor in caspase activation, but our in vitro data fail to indicate a central role for Bax in apoptotic death of DA neurons in an experimental Parkinson's disease paradigm.

To ascertain whether variations in central dopaminergic transmission can differentially affect motor and cognitive processing, we studied the effects of apomorphine (APO) in 9 patients with Parkinson's disease (PD). The UPDRS motor scores and auditory event-related potentials (ERPs) obtained in the 'odd-ball' (OB) and in the 'covert orientation of attention' (COA) tasks were studied in the 'off' and in the 'on' state after an injection of APO. Although APO injection improved patients' motor status, it induced a significant increase in the latencies of the P2 and P3 ERP components in the OB. In the COA task, right-hand reaction times (RTs) were markedly shortened in the 'on' state while left hand RTs remained unchanged. The contrasting effects of dopaminergic stimulation on the motor performance and on some aspects of cognitive processing suggest the existence of complex interactions within pre- and postsynaptic brain dopamine receptors, and an intervention of segregated basal ganglia-prefrontal cortex loops in motor and cognitive behaviour.

The usefulness of the detection of 14-3-3 protein in the cerebrospinal fluid (CSF) in the diagnosis of Creutzfeldt-Jakob disease transmitted from human growth hormone was evaluated in 20 French patients. The 14-3-3 protein was rarely detectable within the first 3 months of the disease but always positive after 7 months associated with the aggravation of the disease and the occurrence of dementia. 14-3-3 detection was not predictive of the survival time of the patients. The genotype at PRNP codon 129 could influence the timing of appearance of the 14-3-3 protein in the CSF.

Mitochondrial free calcium levels measured by Rhod-2 fluorescence and ultrastructure were examined during cell death in nerve growth factor (NGF)-differentiated PC12 cells that were 1) exposed to C2-ceramide, 2) deprived of serum to induce endogenous ceramide production, or 3) treated with calcium ionophore A23187. Rhod-2 fluorescence in mitochondria and also in the nucleolus increased to a maximum within 3 hours after C2-ceramide treatment or serum withdrawal. In A23187-treated cells, Rhod-2 fluorescence remained at baseline levels. In all three models, enlargement of the endoplasmic reticulum was the first ultrastructural alteration, followed by mitochondrial shrinkage in ionophore-treated cells, but by mitochondrial swelling in the ceramide-dependent models, in which rupture of the outer mitochondrial membrane and unfolding of the inner membrane were frequently seen. Dihydro-C2-ceramide, which did not cause cell death, had no effect on cellular ultrastructure. NGF, which inhibits ceramide-dependent cell death, prevented the effects of serum deprivation on mitochondrial ultrastructure but not on endoplasmic reticulum morphology or Rhod-2 fluorescence. Nuclear shrinkage with loss of nuclear membrane integrity, characterized by nuclear pores, free or surrounded by electron-dense filaments, was a late event in ceramide-dependent cell death. Chromatin condensation and other morphological features associated with apoptosis were seen in only a few atypical cells. Ceramide-mediated cell death, therefore, did not involve classical apoptosis but was mediated by a reproducible series of events beginning in the endoplasmic reticulum, followed by the mitochondria, and then the nucleus. NGF-dependent cell death inhibition intervenes at the mitochondrial level, not by blocking the increase in Rhod-2 fluorescence but by preventing the ultrastructural changes that follow.

Autosomal dominant DOPA-responsive dystonia (DRD) is usually caused by mutation in the gene encoding guanosine triphosphate-cyclohydrolase I (GTPCH I). We studied 22 families with a phenotype of levodopa-responsive dystonia by sequencing the six coding exons, the 5'-untranslated region and the exon-intron boundaries of the GTPCH I gene. Eleven heterozygous mutations were identified, including five missense mutations, one splice site mutation, two small deletions and two nonsense mutations, in 12 families that included 27 patients and 13 asymptomatic carriers. Six mutations were new and five had already been reported. Four of the mutations caused truncation of the GTPCH I protein. One family carried a base-pair change in the 5'-untranslated region, not detected in controls, that could be responsible for the phenotype. Three of the remaining 10 families had deletions in the parkin gene on chromosome 6, underlining how difficult it is to distinguish, in some cases, between DRD and parkin mutations. No mutations were identified in seven families. The clinical spectrum extended from the classical DRD phenotype to parkinsonism with levodopa-induced dyskinesias, and included spastic paraplegia as well as the absence of dystonia.

Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease are considered to result from the severity of dopaminergic denervation in the striatum, which is an irrevocable phenomenon, and sensitization induced by long-term intermittent administration of levodopa. Taking advantage of the 64% reduction of levodopa treatment allowed in 12 Parkinson's disease patients by continuous high-frequency stimulation of the subthalamic nucleus, we evaluated the severity of parkinsonian motor disability and LIDs during two levodopa challenges performed before the surgical implantation of the stimulation electrodes and after 8.8 months of continuous bilateral subthalamic nucleus stimulation that was interrupted 2 hours before the levodopa test. Motor disability during the "off" and "on" drug periods was unchanged. The severity of LIDs during the "on" period and dystonia during the "off" period decreased by 54% and 62%, respectively. The reduced severity of LIDs in the absence of subthalamic nucleus stimulation demonstrates that the sensitization phenomenon resulting from long-term intermittent levodopa administration is partially reversible.

Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the nigrostriatal pathway. However, not all dopaminergic neurons degenerate in this disease, and calcium has been suspected of playing a role in this differential vulnerability. An overexpression of the calcium-dependent protease calpain II has recently been reported in the parkinsonian substantia nigra, suggesting that a rise in intracellular calcium concentrations may be involved in the mechanism leading to cell death. The proteasic activity of calpain is regulated by an endogenous inhibitory protein called calpastatin. Because little is known about the distribution of calpastatin in the primate brain, we first analyzed immunohistochemically the calpastatin expression in normal human and monkey brain. A ubiquitous distribution of calpastatin immunostaining was observed in both cases, but its expression was variable from one region to another. In the basal ganglia, staining was intense in the striatum, in the pallidal complex, and in some nuclei of the thalamus. The cerebellum was stained intensely, particularly in the granular and Purkinje cell layers. A dense, heterogeneous staining was observed in the hippocampal formation, mostly in the pyramidal and granular layers. The distribution of staining was similar in the different cerebral cortices studied, and it was most intense in layer V. In the brainstem, staining was particularly prominent in the substantia nigra pars reticulata and compacta, the central gray substance, the superior colliculus, and the cuneiform nucleus, and staining was moderate in the tegmenti pedonculopontinus nucleus and the griseum pontis. In the second part of the study, the authors compared calpastatin expression in the mesencephalon between patients with Parkinson's disease and control subjects. Sequential double staining revealed that some dopaminergic neurons coexpress calpastatin, the proportion of double-stained neurons ranging between 52% and 76% among the different dopaminergic cell groups. Quantitative analysis of the number of calpastatin-stained neurons evidenced a loss of both calpastatin-positive and calpastatin-negative neurons in the substantia nigra of patients with Parkinson's disease. These data suggest that calpain II overexpression in Parkinson's disease is not compensated for by a concomitant increase in calpastatin expression.

Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity.

What is the role of genetic factors in the pathophysiology of idiopathic Parkinson's disease, one of the most frequent neurodegenerative disorders? In the past two years, identification of two genes and localization of a third one have supported the hypothesis that genetics factors are involved in idiopathic Parkinson's disease. We present arguments that support such hypothesis, and describe recent advances in genetic studies of idiopathic Parkinson's disease.The first gene identified on chromosome 4 encodes alpha-synuclein. It causes a rare form of autosomal dominant Parkinson's disease. A locus on the short arm of chromosome 2 was recently identified in families with autosomal dominant Parkinson's disease. More recently, the gene encoding Parkin (located on chromosome 6) has been described. It already appears to be an important locus for juvenile parkinsonism with autosomal recessive transmission.We now have to understand how mutations in these genes lead to selective degeneration of dopaminergic neurons, and to determine whether or not they participate in the genetic susceptibility of idiopathic Parkinson's disease.

Parkinson's disease is characterized by massive degeneration of dopamine-containing neurons in the midbrain. However, the vulnerability of these neurons is heterogeneous both across different midbrain dopamine-containing cell groups and within the substantia nigra, the brain structure most affected in this disease. To determine the exact pattern of cell loss and to map the cellular distribution of candidate pathogenic molecules, it is necessary to have landmarks independent of the degenerative process by which to subdivide the substantia nigra. We have developed a protocol for this purpose based on immunostaining for calbindin D(28K), a protein present in striatonigral afferent fibres. We used it to examine post-mortem brain samples from seven subjects who had had no history of neurological or psychiatric disease. We found intense immunostaining for calbindin D(28K) associated with the neuropil of the ventral midbrain. Within the calbindin-positive region, there were conspicuous calbindin-poor zones. Analysed in serial sections, many of the calbindin-poor zones seen in individual sections were continuous with one another, forming elements of larger, branched three-dimensional structures. Sixty per cent of all dopamine-containing neurons in the substantia nigra pars compacta were located within the calbindin-rich zone, which we named the nigral matrix, and 40% were packed together within the calbindin-poor zones, which we named nigrosomes. We identified five different nigrosomes. This organization was consistent from one control brain to another. We propose that subdivision of the human substantia nigra based on patterns of calbindin immunostaining provides a key tool for analysing the organization of the substantia nigra and offers a new approach to analysing molecular expression patterns in the substantia nigra and the specific patterns of nigral cell degeneration in Parkinson's disease.

Parkinson's disease is characterized by a massive loss of nigral dopamine neurons that results in a reduction of dopamine concentrations in the striatum. The most commonly used treatment for this disease is levodopa therapy to restore striatal dopamine. This treatment is mediated by dopamine receptors, but the effect of treatment and the disease on receptor distribution is unknown. In this study, the distribution of D1 dopamine receptors was analyzed at the cellular and subcellular level in the striatum of 5 patients with Parkinson's disease (all treated with levodopa) and 4 control subjects. In the control brains, D1 dopamine receptors were mostly detected on the plasma membrane of medium-sized spiny neurons. The quantitative analysis performed at the ultrastructural level in patients with Parkinson's disease revealed an increase in immunostaining in the cytoplasm of medium-sized neurons. This effect was likely the result of the treatment rather than the dopaminergic denervation, as such changes were not observed in the striatum of rats with a unilateral 6-hydroxydopamine nigrostriatal lesion, but were present in normal or lesioned rats treated with a D1 dopamine agonist. Altered localization of D1 dopamine receptors may participate in the occurrence of side effects of levodopa therapy such as dyskinesia and fluctuations in motor performances.

Objectifs Ce travail visait a correler les caracteristiques biomecaniques de la marche a la volumetrie cerebrale obtenue en IRM, dans la maladie de Parkinson. Materiels et methodes Etude prospective de la volumetrie cerebrale par IRM chez 32 patients parkinsoniens, confrontee aux parametres biomecaniques de la marche calcules sur une plateforme de force. Ces donnees biomecaniques etaient comparees a celles obtenues chez 32 sujets temoins. L’utilisation d’une technique validee de volumetrie cerebrale normalisee permettait le calcul du volume du parenchyme cerebral, des noyaux caudes, des putamens et de la surface axiale du mesencephale. Resultats Le volume cerebral etait correle a l’âge, la duree de la maladie et la severite des troubles de la marche. La longueur et la velocite du premier pas etaient diminuees chez les parkinsoniens. Sous traitement, 15 patients gardaient une alteration de leur capacite a freiner la chute du centre de gravite (CG), et avaient plus de troubles de la marche que les patients chez qui cette capacite etait normale. La surface du mesencephale etait plus petite chez les patients ayant une incapacite a freiner la chute du CG. Conclusion L’alteration de la capacite a freiner la chute du CG contribue aux troubles de la marche dans la maladie de Parkinson et pourrait traduire des lesions cerebrales additionnelles dans le mesencephale.