Erwin Ott

The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval.

Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.

Sleep attacks in patients taking dopamine agonists: review

Abstract Objectives: To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinsons disease, the type of drugs implicated, and strategies for prevention and treatment. Design: Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinsons disease. Results: 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Conclusion: Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinsons disease. Prospective population based studies are needed to provide this information.

Long‐term antidyskinetic efficacy of amantadine in Parkinson's disease

Several randomized placebo‐controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinsons disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LIDs) wear off after about 9 months of treatment. This randomized placebo‐controlled parallel‐group study was performed to assess the long‐term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year‐ were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patients diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1–4.03) at baseline to 4.28 (95% CI, 3.1–5.4) at three‐week follow‐up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1–4.4) to follow‐up 3.6 (95% CI, 2.3–4.8) in patients staying on amantadine. These findings argue for long‐term antidyskinetic efficacy of amantadine in PD patients with LIDs.

High Blood Viscosity Syndrome in Cerebral Infarction

Determinations of whole blood viscosity by means of a cone plate viscometer at 37°C and at shear rates of 212, 42, 21 and 11 sec−1 were done in 50 patients with recent cerebral infarction of the carotid system, and the values compared to a control group of 50 patients of the same age. In stroke patients a statistically significant elevation of blood viscosity over the whole range of shear rates was demonstrated, more obviously significant at low shear rates (P < 0.0001) such as occur in small vessels. Since the mean hematocrit levels of both groups were in the normal range, it was considered that hematocrit values estimated from peripheral blood do not necessarily give accurate information about viscosity levels existing at the same time. In cases of severe cerebral infarction without angiographically demonstrable stenotic or obstructive lesions, it was suggested that high blood viscosity impairs hemodynamic conditions in the cerebral microvasculature in addition to narrow arteriosclerotic vessels, changes in flow velocity gradients and insufficient collateral circulation.

Sleep Alterations in Ischemic Stroke

In 19 patients with cerebral infarctions in the middle cerebral artery territory, investigations of sleep using a mobile EEG recording system were performed. Sleep was found to be markedly altered compared to a normal group. Although an increase of time in bed and sleep period time was observed, total sleep time did not rise in a parallel manner, so that a distinct reduction of the sleep efficiency index was found. This increase of quantitative parameters was particularly caused by a higher amount of NREM time, whereas REM sleep was found to be deeply suppressed. Regarding the different NREM sleep stages, stage 0 (time spent awake during the night) and stage 1 had increased, whereas stage 4 was reduced. Interhemispheric differences were noticed referring to the sleep period time, which was found to be increased particularly in right-sided infarctions (because of an increase of NREM time) and a reduction of REM sleep in lesions of the right hemisphere (worsening of the REM to NREM ratio). Slow-wave sleep (stage 4), on the contrary, was found to be decreased in infarctions of the left hemisphere. These results support the hypothesis of a REM-inducing and regulating function of the right hemisphere and will lead to a new understanding of sleep-controlling mechanisms.

Gait Analysis in Patients With Parkinson's Disease Off Dopaminergic Therapy

OBJECTIVE To compare time-distance, kinematic, and kinetic gait parameters in patients with idiopathic Parkinsons disease (PD) off dopaminergic therapy with a group of healthy control subjects. DESIGN A group-comparison study. SETTING Gait analysis laboratory. PARTICIPANTS Patients with PD (n=20) and healthy age-matched controls (n=20). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Time-distance, kinematic, and kinetic gait variables. RESULTS PD patients walked slower with shorter stride-length, comparable cadence, and longer double support times. Kinematics showed a reduction of the range of motion in the hip, knee, and ankle joints. Maximum hip extension and the ankle plantar flexion were significantly reduced. Kinetic gait parameters showed reduced push-off ankle power and lift-off hip power generation. Strong correlations between these important body advancement mechanisms and the walking velocity were observed. CONCLUSIONS In addition to previously described dysfunctional kinematics, abnormal kinetic parameters play an important role in the characterization of gait in PD patients off therapy. Hence, these parameters could be used to document treatment effects of parkinsonian gait disorders.

Efficacy and safety of radiosurgical callosotomy: a retrospective analysis.

Summary:  Purpose: Anterior callosotomy is a surgical option for the treatment of generalized tonic or atonic seizures associated with drop attacks. Besides open surgery, a radiosurgical callosal disconnection using the gamma knife (GK) also can be performed, but reliable data about tolerability and efficacy are sparse.

The Bradykinesia Akinesia Incoordination Test (BRAIN TEST), an objective and user-friendly means to evaluate patients with parkinsonism.

The BRAIN TEST©, a computerized alternating finger tapping test, was performed on 154 patients with parkinsonism to assess whether the test could be used as an objective tool to evaluate reliably the severity of Parkinsons disease (PD). Patients were instructed to tap two marked computer keyboard keys as fast and as accurately as possible for 60 seconds. The test generates the following variables: (1) kinesia score (KS)—number of keystrokes/min, (2) akinesia time (AT)—cumulative time that keys are depressed, (3) dysmetria score (DS)—a weighted score generated from incorrectly hit keys and corrected for speed, and (4) arrhythmia score (AS)—variance of the time interval between individual keystrokes. Among parkinsonian patients, we found a significant correlation between the four test parameters and PD rating scores of the Hoehn & Yahr, Schwab & England, and Unified PD Rating Scales (KS, AS, and AT p <0.001 and DS p <0.05). When compared with 73 parkinsonian patients 73 age‐ and sex‐matched control subjects showed significantly higher KS and lower AT (p <0.001) as well as lower DS and AS (p = 0.05). The BRAIN TEST© is a reliable and practical tool for evaluating the severity of parkinsonism and for distinguishing subjects with parkinsonism from normal control subjects. A version of the BRAIN TEST© is available by FTP on the worldwide web (http://www.anaesthetist.com/software/brain.htm).

Point mutations in exon 1 of the NR4A2 gene are not a major cause of familial Parkinson′s disease

Sirs, Parkinson’s disease (PD) is a neurodegenerative disorder, clinically characterized by a triad of rigidity, resting tremor, and bradykinesia. To date, mutations in four separate PD genes have been identified: the genes for alpha-synuclein and for ubiquitin C-terminal hydrolase L1 both cause autosomal dominant forms of PD, whereas mutations in the parkin gene and DJ-1 are associated with early onset recessive parkinsonism [1, 2]. Recently, two variants (-245T!G and 291Tdel) in exon1 of the NR4A2 gene were identified in 2 and 8 patients, respectively of 107 patients with familial PD [3]. Neither of these two variants was found in 94 sporadic PD patients or age-matched controls (n=221). NR4A2 is a member of the superfamily of “zinc finger” transcription factors and has been shown to be an absolute requirement for the development of dopaminergic neurons [4]. Although both described variants are located in the 5́UTR of exon 1 and do not change the amino acid composition of the protein, they resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. We aimed to replicate this study by sequencing exon 1 of 44 cases of familial PD. All index patients of Caucasian ethnicity were diagnosed with PD according to United Kingdom brain bank criteria. The mean age at onset was 58€9.3 years (range 35–73 years). Family history was regarded positive in all cases, since levodopa-responsive rest tremor and/or hyopkinetic symptoms were reported in at least one first-degree relative (sibling or parent). Of 44 cases (32 male, 12 female), 14 had one or more affected siblings and 30 showed a parent-child transmission. All patients were parkin negative. A 269-bp PCR fragment of NR4A2 exon 1 was generated and directly sequenced using genomic DNA (NR4A2Ex1F: cgc aag cca cat aaa caa ag and Nurrex1R: act gca tgg gct gca tct act). Neither the 291Tdel nor the 245T!G mutation occurred in any of our PD patients. No other sequence variants relative to the published sequence in the exon 1 region were identified. The mutations found by Le et al. [3] were present in a heterozygous state, suggesting an autosomal dominant transmission. Therefore the most-significant result in our study was that no mutations were found in the 30 families with known parent-child transmission. The 14 affected siblings might either be associated with recessive mutations or with a dominant inheritance with reduced penetrance. Our findings show that sequence alterations in exon 1 of the NR4A2 gene are not a major cause of familial PD in central Europe. The NR4A2 mutations associated with familial PD reported by Le et al. [3] are apparently caused by strong A. Zimprich · F. Asmus · P. Leitner · T. Gasser ()) Center of Neurology, University of Tuebingen, Department of Neurology and Hertie-Institute of Clinical Brain Research, Section for Neurodegenerative Diseases, Hoppe-Seyler Strasse 3, 72076 Tuebingen, Germany e-mail: Thomas.Gasser@med.uni-tuebingen.de Tel.: +49-7071-2986529 Fax: +49-7071-294839

Artistic profession: A potential risk factor for dopamine dysregulation syndrome in Parkinson's disease?†

A small proportion of patients with Parkinsons disease (PD) develop a dopamine dysregulation syndrome (DDS). Management of such patients can be difficult; hence, early identification and careful monitoring of at‐risk individuals are important. Based on four illustrative cases, we wish to draw attention to the risk of developing DDS in PD patients engaged in a creative and artistic profession, who compulsively abuse dopaminergic drugs to maintain or enhance their artistic creativity. Balancing the drug requirement for treating motor symptoms on one hand and improving creativity on the other hand has to be carefully evaluated and early neuropsychiatric intervention may be necessary. Apart from the known risk factors—young age at PD onset, male gender, heavy alcohol consumption, illegal drug use, and history of affective disorder—engagement in a creative or artistic profession may be an additional risk factor for developing DDS.