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Parkinson¢s disease (PD) is a common disablingneurodegenerative disorder characterized bybradykinesia, rest tremor, rigidity, and posturalinstability with a prevalence of 2% in elderlypersons (1). Although the causative mechanismsare poorly understood for the classical form of PD,a genetic contribution to its etiology has unambig-uously been demonstrated. To date, at least eightgenes have been identified in families with inheritedparkinsonism, either with an autosomal recessivemode of inheritance [Parkin⁄PARK2 (2), PINK1⁄-PARK6 (3), DJ-1⁄PARK7 (4), ATP13A2⁄PARK9(5), PLA2G6⁄PARK14 (6), and FBXO7⁄PARK15(7)] or dominant transmission [SNCA⁄PARK1 (8)and LRRK2⁄PARK8 (9, 10)]. Moreover, severalgenes were shown to influence the susceptibility toor the age of onset of PD although the results arepartially inconsistent, for example, as for poly-morphisms in the apolipoprotein E gene (11, 12).Although parkinsonism is the clinical hallmarkof all of these inherited forms, there is evidence formarked intrafamilial phenotypic variability includ-ing cognitive and psychiatric disturbances, dysto-nia, or isolated tremor in at least a subset ofpedigrees. In some cases, there is also phenotypicoverlap with a subtype of hereditary fronto-temporal lobar degeneration combined withparkinsonism, caused by mutations in the

We studied 18 patients with a single ischemic thalamic lesion, who had somatosensory disturbances and/or central pain in the opposite hemibody, by correlating their clinical symptoms, somatosensory evoked potentials (SEPs), and computed tomography (CT) findings. Patients were divided into three groups: (1) those with somatosensory deficits, central pain, and abnormal SEPs, which comprised two thirds of the patients (classic thalamic pain syndrome), (2) those with somatosensory deficits, no central pain, and abnormal SEPs (analgetic thalamic syndrome), and (3) those with almost normal sense perception, central pain, and normal SEPs (pure algetic thalamic syndrome). CT evidence of a paramedian or anterolateral thalamic lesion might be an indicator for the development of central pain, because these types of infarctions occurred only in patients with the classic thalamic syndrome or the pure algetic thalamic syndrome. The differentiation of the thalamic syndrome into three subtypes is of prognostic value, because patients with a loss of cortical SEPs and a posterolateral ischemic thalamic lesion on the CT scan probably will not exhibit central pain.

The multidrug resistance protein 1 (MDR1 or ABCB1) gene encodes a P-glycoprotein that protects the brain against neurotoxicants. Certain MDR1 genetic variants are known to compromise the function of this transporter and may thus be associated with Parkinson disease (PD). We therefore conducted a large case-control study investigating the potential relationship between MDR1 variants and PD. We determined the frequency of three MDR1 variants in 599 European PD patients and controls and further stratified the population by ethnicity, age at onset, and exposure to pesticides. We detected no relevant association in either the entire sample, or when separately investigating by ethnic origin or age at onset. However, the distribution of c.3435C/T differed significantly between PD patients exposed to pesticides compared to those non-exposed (odds ratio = 4.74; confidence interval = [1.009; 22.306]); p = 0.047), suggesting that common MDR1 variants might influence the risk to develop PD in conjunction with exposure to pesticides.

Falls in the elderly are frequent. They may lead to restrictions of social life, immobility and loss of competence in everyday activities. A vicious circle starts when immobility results in reduction of physical achievements and vice versa. There is a high incidence of falls with neurological diseases of the elderly. The treating physician should consider not only the adequate management of these conditions, but also identify risk factors of falling, and provide adequate measures of physiotherapy as well as instrumental aids for walking and balance. Social services should be alerted to check for extrinsic risks of falls in the patient?s domestic environment.

Genetic findings have changed our views on Parkinson's disease (PD) and parkinsonism, which will be collectively referred to as Parkinsonian Syndrome (PS) in the present manuscript. Mutations in several genes are found to cause monogenic forms of the disorder. Point mutations, duplications and triplications in the alpha-synuclein gene cause a rare dominant form of PS in families. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as a much more common cause for dominant PS, especially in certain ethnic groups, while mutations in the parkin gene, in DJ-1, PINK1 and ATP13A2 cause autosomal recessive parkinsonism of early onset. The monogenic variants are important tools in identifying cellular pathways that also shed light on the molecular pathogenesis of sporadic PS and some of these genes may play a role in the etiology of the common sporadic form of PS. Here we add recent findings to a greatly challenging puzzle.

Gangstorungen fuhren zu einem Verlust der Mobilitat und damit der Autonomie. Sturze sind haufig die Folge und fuhren zu weiterer Immobilitat. Der groste Risikofaktor fur Gangstorungen ist das Alter. Daneben spielen Pharmaka, kognitive Storungen und ein Alkoholabusus eine grose Rolle. Beim „gesunden“ Altern findet man lediglich eine geringe, kontinuierlich Abnahme der Gehgeschwindigkeit. Klassifiziert werden Gangstorungen in solche unterer Ebene (periphere Ursachen), mittlerer Ebene (spinale, zerebellare, Basalganglienstorungen) und hochster Ebene (frontale Gangstorung, psychogene Gangstorung). Diese Einteilung ist jedoch nicht unumstritten. Besonders haufig sind Gangstorungen bei neurologischen Erkrankungen. Besonderheiten im Gangmuster bei hypokinetischen Gangstorungen, dystonen Gangstorungen, Hemi- und Paraspastik, Ataxien, vestibularen, peripher neuromuskularen und psychogenen Storungen werden detailliert beschrieben. Neben einer Reduktion von Risikofaktoren spielen in der Therapie von Gangstorungen 1. eine Verbesserung des physischen Zustands (Physiotherapie, Ausdauersportarten), 2. die Verschreibung von adaquaten Hilfsmitteln und 3. eine Sturzpravention die wichtigste Rolle.

An association of the H1 haplotype and subhaplotypes in the microtubule-associated protein Tau (MAPT) gene with Parkinson's disease (PD) has been reported. To further evaluate their role in PD, we genotyped a sample set of 765 cases and controls consisting of two large European subgroups of German (n=418) and Serbian (n=347) origin for the MAPT haplotypes H1 and H2. The H1/H1 carriers were tested for three additional MAPT polymorphisms. In the Serbian sample, there was significant evidence (P=0.0108) of an association of the H1/H1 genotype and PD. Surprisingly, in the German sample, we did not find significant differences in genotype or haplotype frequencies between patients and controls. These results suggest that the role of H1 haplotypes in the etiology of PD may be ethnically dependent.

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinsons disease (PD), dopa-responsive dystonia (DRD), and myoclonus-dystonia (M-D) should include screening for small sequence changes and for large exonic rearrangements in disease-associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real-time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation-dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M-D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large-scale and cost-effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype-genotype correlations. (C) 2007 Movement Disorder Society.

Mutations in LRRK2 (leucine-rich repeat kinase 2) have been associated with autosomal dominant Parkinson's disease (PD) and cluster in several 3' exons of the gene. The majority of mutations have been detected in late-onset cases (age at onset >50 years). We screened 5 of the 51 exons of LRRK2 that previously have been reported to harbor mutations in 98 early-onset and 42 late-onset PD patients. We identified two mutations (c.4321C>T, c.6055G>A) in three early-onset patients. Screening of an additional 220 early-onset PD patients for these mutations revealed another mutation carrier. In conclusion, LRRK2 mutations need to be considered also in early-onset PD.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.

Objective: To identify a haplotype influencing onset age for Parkinson’s disease (PD) in the PARK3 region on chromosome 2p13. Methods: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. Results: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset ( p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) ( SPR ) gene, rs1876487 ( p = 0.02) and rs1150500 ( p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394 . The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP—rs2421095, rs1876487, rs1561244—revealed an association with onset age ( p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD ( p = 0.005). Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Objectives – To determine the frequency of familial focal and segmental dystonias in a large patient cohort with primary dystonia from north-western Germany. Material and methods –In this study, 130 patients with focal or segmental dystonia were examined and a family history was obtained. Whenever possible, affected relatives were examined (a total of 789 first-degree relatives). Data on disease duration, age at disease onset and age of the patients were investigated by Student's t-test and a segregation analysis was performed by Weinberg's proband method. Results –Age at onset of disease was significantly later in the blepharospasm group. Only in the writer's cramp group were women outnumbered by men. A positive family history was found in 15 of the 130 index patients (11.5%). None of 102 index patients tested carried the GAG deletion in the DYT1 gene. Conclusion –In accordance with previous series our study provides evidence that primary focal dystonia may have a genetic etiology, most probably caused by an autosomal dominant trait with reduced penetrance.

Early-onset parkinsonism is frequently reported in connection with mutations in the parkin gene. In this study, we present the results of extensive genetic screening for parkin mutations in 111 community-derived early-onset parkinsonism patients (age of onset

Rationale: Cholecystokinin (CCK) is a neuropeptide which is colocalized with dopamine (DA) in neurons of the mesolimbic-frontocortical and nigrostriatal DA system. In animals CCK enhances DA activity in these systems. Objectives: The present study examined the effects of a single intranasal administration of CCK-8 on auditory brain potential (AEP) signs of cognitive processing and on motor performance in patients with Parkinson's disease (PD), known to originate from degeneration of DA neurons primarily in the nigrostriatal DA system. Methods: Thirteen PD patients were examined after medication withdrawal, on two occasions after administration of placebo and 25 µg CCK-8, and compared with healthy controls matched for age and sex. AEPs were recorded while subjects performed an attention task (oddball paradigm). Results: In the placebo condition, AEPs in the PD patients did not show marked alteration but were rather comparable to those in the controls. In healthy controls, CCK-8 enhanced the P3 complex (P

Objective. Lower frequencies of slow oscillations of the posturographic signals can be removed using high-pass filtering. This procedure releases postural reflexes possessing higher frequencies and lower amplitude range. Mutual dependence between thexandycomponents of posturographic signals was analyzed using principal component analysis (PCA). The posturographic signals of old patients with idiopathic gait disturbance were compared with the control group of similar age and with younger patients. There was also the analysis of the influence of the eyes state (open versus closed) and the head position (normal or bent back). The statistically significant differences in the mutual dependence betweenxandycomponents between the groups of patients were analyzed using MANOVA. The significant differences were observed mainly in the range of filter frequenciesf=0.1–1.5 Hz andf=2.2–5.5 Hz with a maximum effect at approximately4-5 Hz. A detailed post-hoc analysis is also presented. The differences in the higher frequency range suggest the main disturbance to be connected with the spinal reflexes. Visual and vestibular support appear insufficient for postural stability control in the idiopathic gait disturbance group. The results suggest that idiopathic gait disturbance is the final stage of the aging process of postural system.

Early-onset parkinsonism (EOP) may be associated with different mutations in the parkin gene, including exon deletions and duplications. To test for gene dosage alterations, we developed a new method of quantitative duplex PCR using the fluorescence resonance energy transfer technique on the LightCycler (Roche Diagnostics). In 21 patients with EOP, three mutations (a single base pair substitution in exon 3 and small deletions in exon 9) were detected by conventional mutational screening (single-strand conformation polymorphism and sequence analysis), while alterations of gene dosage were found in seven patients. We identified heterozygous and compound heterozygous deletions of exons 2, 3, 5 and 7. The latter was also found in the homozygous state. In addition, two heterozygous duplications of exon 4 were observed. Remarkably, two patients carried more than two parkin mutations. This is the first study systematically screening all 12 exons of parkin by real-time, kinetic quantification and clearly shows that mutational analysis of the parkin gene should include gene dosage studies. Furthermore, our method of quantitative PCR is easily applicable to any other gene to be screened for deletions or duplications of whole exons.

Objectives It has been hypothesized that the dopaminergic deficit of older patients with Parkinson's disease (PD) is associated with a reduction in the dopamine-dependent personality trait "novelty seeking". It is unknown whether this may also be found in younger patients with PD whose dopaminergic deficit is considered to be purely motor. Material and methods We interviewed 122 patients below 51 years of age and 122 age- and sex-matched healthy controls with regard to clinical and sociodemographic data. Both groups had to fill out the Tridimensional Personality Questionnaire (TPQ) of Cloninger. Neuropsychological testing of formal intelligence and depression was also applied. Results "Novelty seeking" was not different between both groups. Patients were more often depressed than controls, explaining their difference in "harm avoidance" on the TPQ. "Persistence", a sub-scale of the third TPQ dimension "reward dependence", was significantly higher in patients. Neither sex, nor age, nor educational status were correlated with one of the three personality traits. Conclusions The higher rate of depression explains our finding of more "harm avoidance" among young PD patients. According to a literature review the choice and performance of controls is crucial whether personality traits in PD patients may be assessed as abnormal.

Department of Neurology, Medical University of Cologne, Germany.A kindred from South Tyrol (northern Italy) with familial, adult-onset parkinsonism of pseudo-dominant inheritance and mutations in the parkin gene was recently described. To gain insight into basal ganglia dysfunction in this form of hereditary parkinsonism, positron emission tomography (PET) with 18-fluorodopa (FDOPA) and 11C-raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozygous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Parkinson's disease. Similar to findings in the sporadic Parkinson's disease group, presynaptic striatal FDOPA storage was decreased in patients with compound heterozygous parkin mutations, with the most prominent reduction in the posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal 11C-raclopride binding index in all affected family members as compared to asymptomatic family members carrying a heterozygous parkin mutation, sporadic Parkinson's disease, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction similar to idiopathic Parkinson's disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a single parkin mutation with an apparently normal allele, we found a mild but statistically significant decrease of mean FDOPA uptake compared to control subjects in all striatal regions. These data indicate a preclinical disease process in these subjects.PMID: 11261512 [PubMed - indexed for MEDLINE]

A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early-onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult-onset, clinically typical tremor-dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinson's disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa-induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late-onset typical Parkinson's disease.

Gait analysis in disabled and old probands may be considerably altered by applied devices and the artificial surrounding of a gait laboratory. To circumvent distractions from such factors, we evaluated the gait pattern of healthy women on a simple walkway and supplemented the analysis by reliability measurements. In order to consider age-related changes of gait parameters in health, healthy young (YHW) and old women (OHW) were investigated. Five gait parameters were assessed during 10 independent runs of each individual on the walkway. Multiple-regression analysis revealed a significant relationship between age and gait velocity, stride length, and the coefficient of variation (CV) of step width. Standard errors of mean were uniformly low across all parameters and groups, except for some increase in step width (OHW) and cadence (YHW). Across groups, CV was small for stride length, larger for foot angle, and largest for step width. An acceptably low within-session variability of the stride parameters was found.

An involvement of immunological events in the process of neurodegeneration has frequently been reported. We investigated the cytokine producing capacity for interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) in whole blood cultures of de-novo patients with idiopathic Parkinson's disease (PD) at the time of first diagnosis and after oral amantadine treatment. Before treatment, productions of IL-2 and IFN-gamma were markedly decreased in PD patients compared to patients with major depressive disorder and healthy controls. After amantadine treatment, the in vitro IL-2 secretion defect was corrected to normal levels in half of the patients, and the increase in IL-2 production was correlated with an increase in IFN-gamma secretion. Our findings suggest that immunological abnormalities occur in the course of PD and that a formerly unappreciated therapeutic potential of amantadine may arise from its immunomodulatory effects on altered T cell function in patients with PD.

We report three women between 80 and 87 years of age who had longstanding essential tremor. Due to an erroneous diagnosis of Parkinsonism they had received levodopa preparations for 13, 16 and 25 years, respectively, with cumulative levodopa equivalent doses of 18.0, 9.0, and 4.1 kg. The patients showed neither dyskinesias nor signs of Parkinsonism. These observations do not support a detrimental role of chronic levodopa exposure in elderly individuals with essential tremor.

SummaryBoth the discovery of the DYT1 gene on chromosome 9q34 in autosomal dominant early-onset torsion dystonia and the detection of linkage for one form of adult-onset focal dystonia to chromosome 18p (DYT7) in a family from northern Germany provide the opportunity to further investigate genetic factors in the focal dystonias. Additionally, reports of linkage disequilibrium between several chromosome 18 markers and focal dystonia, both in sporadic patients from northern Germany and in members of affected families from central Europe suggest the existence of a founder mutation underlying focal dystonia in this population. To evaluate the role of these loci in focal dystonia, we tested 85 patients from northern Germany who had primary focal dystonia, both for the GAG deletion in the DYT1 gene on chromosome 9q34 and for linkage disequilibrium at the chromosome 18p markers D18S1105, D18S1098, D18S481, and D18S54. None of these patients had the GAG deletion in the DYT1 gene. Furthermore, Hardy-Weinberg analysis of markers on 18p in our patient population and in 85 control subjects from the same region did not support linkage disequilibrium. Taken together, these results suggest that most cases of focal dystonia in patients of northern German or central European origin are due neither to the GAG deletion in DYT1 nor to a proposed founder mutation on chromosome 18p but must be caused by other genetic or environmental factors.

Nichtepileptische paroxysmale Bewegungsstorungen sind durch unterschiedliche Formen von extrapyramidalen Hyperkinesen (Dystonie, Chorea, Athetose, Ballismus) in variabler Kombination bzw. durch Kleinhirnsymptome gekennzeichnet. Es lassen sich die folgenden Hauptgruppen unterscheiden: 1. Paroxysmale Dystonien und Choreoathetosen (Paroxysmale dystone Choreoathetose (PDC), Paroxysmale kinesiogene Choreoathetose, Intermediarform), 2. Paroxysmale Ataxien (PA) (PA mit Myokymie/Neuromyotonie, Azetazolamid-responsive PA). Die nachtliche paroxysmale Dystonie wird jetzt als eine Form der nachtlichen Frontallappen-Epilepsie angesehen. Molekulargenetische Forschung hat in jungster Zeit zum atiologischen Verstandnis der paroxysmalen Dyskinesien einen entscheidenden Beitrag geleistet: In verschiedenen Familien gelang eine Kopplung fur PDC (Chromosom 2q) und PA (Chromosomen 12p, 19p). Die PA konnten als Kanal-Erkrankungen identifiziert werden, denen Mutationen im Kalium- (PA mit Myokymie/Neuromyotonie) bzw. im Kalzium-Kanal (Azetazolamid-responsive PA) zugrundeliegen.

We report two siblings with palatal tremor (PT) and ear clicks who can voluntarily elicit or suppress both PT and ear clicks by just "thinking" about starting or stopping the sounds. The patients were also able to voluntarily modulate the frequency of their ear clicks and PT. They did not have any signs of cerebellar, brain stem, or other neurologic disease. These familial palatal movements may represent a variant of palatal tremor but can not satisfactorily be classified as either symptomatic or essential PT.

Parkinson's disease (PD) is a common degenerative neurologic disorder, which is pathologically characterized by a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta, and the presence of characteristic eosinophilic inclusions, known as Lewy-bodies in affected brain areas. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease. Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects and questioned earlier studies which had denied such influences. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically and in some cases also neuropathologically. Recently, a disease locus has been mapped to chromosome 4q21-22 in a large Mediterranean pedigree, in which disease expression is clinically and pathologically within the spectrum of sporadic PD; being atypical only for a relatively young mean age at onset of 46 years and rapid course of 10 years from onset to death. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding alpha-synuclein. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkinsonism was not linked to the 4q-locus and was not associated with the alpha-synuclein mutation (unpublished data). We describe a different genetic locus that appears to be involved in the development of parkinsonism closely resembling sporadic PD including a similar mean age of onset (59 years in the families, 59.7 years in sporadic PD; ref. 12). This locus was detected in a group of families of European origin. In two of these families, there is genetic evidence for a common founder. The penetrance of the mutation appears to be low, most likely below 40%. This is compatible with a possible role of this locus not only in familial, but also in typical (sporadic) PD.

Present personality traits (Freiburg personality inventory, FPI-R), depression (von Zerssen's depression scale), and self assessed state of health were evaluated in 15 twin pairs (six monozygotic and nine dizygotic; mean age 62.5 years) discordant for idiopathic Parkinson's disease and in 17 unrelated healthy control subjects. The twins had additional questionnaire based interviews on premorbid lifestyle. For disability, twins with Parkinson's disease scored lower on FPI-R than controls in "achievement orientation" and "extraversion", higher in "inhibitedness", "somatic complaints", and "emotionality". They scored higher for depression and for state of health than unaffected twins and controls. For zygosity, monozygotic twins scored lower than dizygotic twins in "achievement orientation", "aggressiveness", and "strain". Monozygotic twins had less "achievement orientation" and "extraversion" and more "somatic complaints" than controls. Monozygotic twins had a lower within pair difference than dizygotic twins in "social orientation". During premorbid times the affected twin with later Parkinson's disease was estimated to have been "less often the leader" in the twin pair. Although small in sample size, this twin study indicates a genetic impact for some personality features beyond the Parkinson's disease motor syndrome.

Background. In a hospital based case-control study, we investigated the role of environmental factors in the aetiology of Parkinson's disease. This paper describes our results on smoking habits. Methods. The smoking histories of 380 Parkinson's disease (PD) patients recruited from nine German clinics were compared to those of age- and sex-matched control subjects (379 neighbourhood controls and 376 controls from the same region). Detailed information on smoking behaviour was collected in structured personal interviews in order to calculate the number of pack-years smoked up to the time of diagnosis. Conditional logistic regression was used to calculate odds ratios (OR) and control for potential confounders. Results. Among PD patients, 44% had ever smoked, as compared to 59% in both control groups. Among ever-smoking patients, 74% quit prior to the date of diagnosis, as compared to roughly 45% of the ever-smoking control subjects. The OR for ever having smoked was 0.5 (95% confidence interval [Cl] : 0.3-0.7), P trend < 0.00005). Conclusions. The results are considered in terms of criteria for causality. Plausible explanations for the observed inverse association between smoking and PD include: 1. A genetic predisposition that increases the risk for PD (such as defective detoxification enzymes) simultaneously decreases the likelihood of smoking. 2. Inherently lower dopamine levels in predestined PD patients cause them to be less prone to addiction. 3. Smoking is neuroprotective.

Stride parameters were established in 17 patients with idiopathic Parkinson's disease (PD; mean age 68.8 yrs.; Hoehn-Yahr stages 2 and 3) and in 33 healthy age-matched controls. Free-walking speed was lower in PD as were stride length and cadence. Impaired locomotor synergies in PD were reflected by a higher coefficient of variation of stride length; step width and its coefficient of variation (the latter related to postural imbalance in locomotion) were not changed. No stride parameter correlated with any total score of either the Hoehn-Yahr Scale, the Unified Parkinson's Disease Rating Scale Motor Examination ("UPDRS-III"), the Columbia Rating Scale (CURS) or the Webster Rating Scale. Stride length correlated with a CURS-Bradykinesia-Score, whereas gait velocity correlated with UPDRS-III-Axial-Motor-Score and with the CURS-Bradykinesia-Score. Hypokinesia of gait in moderately disabled PD patients is best assessed by combined analysis of stride parameters and locomotion-related subscores from conventional rating scales.

We could quantify the tetrahydroisoquinoline derivative salsolinol in urine of patients with Parkinson's disease and normal control subjects by means of high performance liquid chromatography and electrochemical detection. Urine levels of salsolinol were positively related to the homovanillic acid/3-O-methyl-dopa ratio in the cerebrospinal fluid that reflects dopamine metabolism. In the patient group with visual hallucinations, mean salsolinol level was significantly increased to almost the 3-fold of those found in patients without hallucinations. Since the daily L-dopa doses of both patient groups were nearly identical this result is not due to different L-dopa medications. Additionally, either high values of the main serotonin metabolite, 5-hydroxyindole acetic acid (HIAA) or the L-dopa/3-O-methyl-dopa ratio were found in cerebrospinal fluid of patients with hallucinations. The enhanced salsolinol levels in patients with visual hallucinations seem to be due to an overloaded dopaminergic pathway with an imbalance between dopaminergic and serotonergic systems. Thus, salsolinol appears as a predictor for hallucinosis in Parkinson's disease.

Selective attention refers to the ability to focus on one channel of information in the presence of distracting other channels. For the visual modality, results on impairments of selective attention have been conflicting in patients with idiopathic Parkinson's disease (PD). Independent of possible interferences from visual or movement disturbances selective attention can be measured as the so-called ‘processing negativity’ (PN) using auditory evoked potentials. Therefore, auditory selective attention with the PN was measured in 14 patients with PD and 16 control subjects. Subjects had to attend to tones presented to one ear (i.e. to press a button to occasionally presented longer tones) and ignore tones presented to the other ear. Tones were presented at a rate of 1/s (‘slow’) or 2/s (‘fast’). PN was measured as the difference of the potentials evoked by attended minus ignored standard tones. PN was significantly smaller in the PD patients than in the controls with slow presentation. There was no difference between both groups with fast presentation. PN remained unchanged when patients had a 12-h withdrawal of their usual anti-Parkinsonian drug therapy. PD patients and controls did not differ in their P3 component evoked in the usual ‘oddball’ task nor in the mismatch negativity evoked by the occasionally longer tones in the PN task. The results provide evidence for an impairment of auditory selective attention that is specific for patients with PD (i.e. independent of the P3 component).

To determine the influence of cerebellar involvement on the preparatory state of the cerebral cortex for voluntary movements, we studied the movement-related cortical potentials (Bereitschaftspotential, BP) preceding sequential and goal-directed finger and arm movements in patients with cerebellar atrophy (CA). The first task (paradigm 1) consisted of a sequential finger movement at a self-placed rate of every 3 sec or longer, in which patients and control subjects pushed rapidly 7 keys on a keyboard in a sequence visually predetermined on a screen. The second task (paradigm 2) consisted of a goal-directed self-paced movement with visual feedback on a screen. In both paradigms, control subjects and patients had distinct movement-related cortical potentials, but peak amplitudes (close to movement onset) were reduced in the patient group (paradigm 2), whereas in the overall analysis the mean amplitude 600–800 msec before movement onset (NS1) was larger in the patient group (paradigms 1 and 2). Accordingly, the difference (NS2) between peak amplitude and NS1 was smaller in the patient group (paradigms 1 and 2). Whereas control subjects' peak amplitude (paradigm 2) and NS2 (paradigm 1) were focused at Cz, this topographical differentiation was abolished in the patient group. The onset of the BP was earlier in the patients than in the control subjects (paradigms 1 and 2). Our results suggest that pathways from the cerebellum to the cortex do play a role in generating movement-related cortical potentials. A strong input from the cerebellum seems to be crucial for the generation of a normal motor potential close to the movement onset, reflecting a specific deficit in patients with CA. Patients with CA may try to compensate for their motor deficits by a longer cortical activation preceding voluntary movements (earlier onset of the BP). The increased NS1 could be the result of larger effort, by which patients try to compensate for their motor deficits as well.

Voluntary palatal tremor in a patient with essential palatal tremor induced activation predominantly within regions corresponding to the inferior olive, adjacent brainstem, and dentate nuclei. Finger movements elicited only ipsilateral lobular cerebellar activation, suggesting a dysfunctional nuclear activation by palatal tremor.

Multiple system atrophy (MSA) is a form of atypical parkinsonism with unknown etiology. The epidemiological studies conducted up to now on this disease are scarce. The incidence rate is about 0.6 cases per 100 000 persons per year. The prevalence rates show 4–5 cases per 100 000 persons. In Italy, about 4900 prevalent cases have been estimated. The mean onset age is about 54 years; the median survival is 7–9 years. Only one case-control study has been performed on this disease. This study showed an increased risk MSA associated with occupational exposure to organic solvents, plastic monomers and additives, pesticides and metals. Smoking habits seem to be less frequent in MSA cases (as in Parkinson's disease cases) than in healthy controls. Quinn's clinical criteria and those of the Consensus Conference promoted by the American Academy of Neurology are in fair agreement. We have performed a case-control study on 73 MSA cases, 146 hospital controls and 73 population controls.

Progressive supranuclear palsy (PSP) is a rare form of parkinsonism. The incidence rates are about 0.3–1.1 cases per 100 000 persons. The only two-case-control studies performed up to now show conflictual results as regards education and residence in rural areas. Recently, a cluster of PSP and atypical parkinsonism has been observed in French Antilles. The hypothesis is that a consumption of both tropical fruit and herbal tea may be associated with PSP onset. Some PSP families with a probably autosomal dominant transmission have been described. A high frequency of a tau haplotype (H1/H1) associated with PSP is reported by some authors. The significance of this association is still not clear. We have performed a case-control study on 58 PSP cases, 116 hospital controls and 58 population controls.

Answers from a multiple choice questionnaire on the opinions about public sexual attitudes, on emotion from personal sexual practice, on personal sexual function, and on general health perception were compared between 121 patients with Parkinson's disease (mean age 45 years) and 126 age and sex matched community derived controls. Patients were more dissatisfied with their present sexual functioning and relationship, and perceived their general health as poorer than the controls, whereas opinions about public sexual attitudes were only marginally different. No differences were found for sexual function. Further analysis showed that the perception of sexual functioning and general health in younger patients with Parkinson's disease is considerably influenced by depression and state of unemployment.

The P3 component reaches its peak later in elderly subjects than in young subjects. The aim of this study was to repeat this finding in the usual auditory oddball task and to look for reasons for the delay by analysing other components and by applying another task, the visual Push/Wait task. It was found in the oddball that the age delay was present for mismatch negativity already but further increased until P3's peak. In the Push/Wait task, the size of the age delay was independent of another delay caused by reduced visual intensity of the stimuli. Further, the age delay had its onset after the occipital P140 component whereas the intensity delay was present before this component. Within the elderly, P3 latencies correlated between the auditory and the visual tasks, and the common factor extracted from both latencies correlated with a test of short-term memory span. It is concluded that the age delay of P3 is not due to a delay of perceptual encoding but perhaps due to delayed memory processes in the elderly. As usual, P3 amplitudes were larger and more parietally focussed in the young than in the elderly. Possible differences in motivation might account for this finding.

Follow-up data are presented of ten patients with autopsy-proven postencephalitic Parkinson's syndrome (PEP) (mean age at death: 56.0 years) with regard to motor and psychic deterioration over a period of institutional observation between 3 and 30 years. Four patients showed deterioration of their Hoehn-Yahr score of at least one grade. These patients did not differ statistically with respect to age of occurrence of lethargic encephalitis, interval to PEP, age at start of PEP, duration of survival with PEP, and age at death. Motor deterioration in these patients seems to be attributed more to inherent disease progression, rather than to an age-related process. Clinical and pathological evidence for this conclusion is presented.

Extrapyramidal, frontal release, and other neurological signs were studied in 54 demented and non-demented patients with Down's syndrome (DS). Fourteen patients were demented and five showed extrapyramidal signs, mainly of the rigid-hypokinetic spectrum and similar to Parkinsonian features in advanced Alzheimer's disease (AD). None of the non-demented patients had Parkinsonian signs. The mean age of the demented DS patients with extrapyramidal signs was significantly higher than that of the patients without. Frontal release signs were present in demented and non-demented patients. A questionnaire showed no increase in either the proportion of early- or senile-onset dementia or Parkinsonism among first- and second-degree relatives of DS patients. Parkinsonian signs appear to be present at a lower frequency in DS than in advanced AD. A speculative hypothesis about a gene dosage effect of Cu/Zn-superoxide dismutase in preventing toxic radical formation in the substantia nigra of DS patients is presented.

Zu Beginn der Globalisierungsdebatte gab es eine Diskussionsrichtung, die davon ausging, dass durch die Globalisierung der Standort eines Unternehmens austauschbar und damit unbedeutend wird. Heute hat sich die Diskussionsrichtung umgekehrt und es wird deutlich, dass es gerade das regionale Umfeld ist, das wichtige Erfolgsfaktoren fur die Wettbewerbsfahigkeit eines Unternehmens beisteuert.

Major hallmarks in the pathophysiology of Parkinson disease are cellular energy depletion and oxidative stress leading to cellular dysfunction and death. Coenzyme Q(10) (CoQ(10)) is an electron acceptor bridging mitochondrial complexes I and II/III and a potent antioxidant that consistently partially recovers the function of dopaminergic neurons.To determine whether nanoparticular CoQ(10) is safe and displays symptomatic effects in patients with midstage Parkinson disease without motor fluctuations.Multicenter, randomized, double-blind, placebo-controlled, stratified, parallel-group, single-dose trial.Academic and nonacademic movement disorder clinics.One hundred thirty-one patients with Parkinson disease without motor fluctuations and a stable antiparkinsonian treatment. Intervention Random assignment to placebo or nanoparticular CoQ(10) (100 mg 3 times a day) for a treatment period of 3 months. Stratification criterion was levodopa treatment.The subjects underwent evaluation with the Unified Parkinson's Disease Rating Scale (UPDRS) at each visit on a monthly basis. The primary outcome variable was the change of the sum score of the UPDRS parts II and III between the baseline and 3-month visits.One hundred thirty-one subjects were randomized according to the protocol. The mean changes of the sum UPDRS parts II/III score were -3.69 for the placebo group and -3.33 for the CoQ(10) group (P = .82). Statistical analysis according to the stratification did not result in significant changes of the primary outcome variable. No secondary outcome measure showed a significant change between the placebo group and the CoQ(10) group. The frequency and quality of adverse events were similar in both treatment groups.Nanoparticular CoQ(10) at a dosage of 300 mg/d is safe and well tolerated and leads to plasma levels similar to 1200 mg/d of standard formulations. Add-on CoQ(10) does not display symptomatic effects in midstage Parkinson disease.