Delia Lorenz

Genome-wide association study reveals genetic risk underlying Parkinson's disease

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinsons disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Two‐year follow‐up of subthalamic deep brain stimulation in Parkinson's disease

We studied 48 patients after bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) who were evaluated 6 months after the surgical procedure using the Unified Parkinsons Disease Rating Scale (UPDRS) in a standardized levodopa test. Additional follow‐up was available in 32 patients after 12 months and in 20 patients after 24 months. At 6 months follow‐up, STN‐DBS reduced the UPDRS motor score by 50.9% compared to baseline. This improvement remained constant at 12 months with 57.5% and at 24 months with 57.3%. Relevant side effects after STN‐DBS included intraoperative subdural hematoma without neurological sequelae (n = 1), minor intracerebral bleeding with slight transient hemiparesis (n = 1), dislocation of impulse generator (n = 2), transient perioperative confusional symptoms (n = 7), psychotic symptoms (n = 2), depression (n = 5), hypomanic behaviour (n = 2), and transient manic psychosis (n = 1). One patient died because of heart failure during the first postoperative year. The current series demonstrates efficacy and safety of STN‐DBS beyond the first year after surgical procedure. Complications of STN‐DBS comprise a wide range of psychiatric adverse events which, however, were temporary.

Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies.

No causative or curative therapy exists for the polyneuropathy associated with antibodies to myelin‐associated glycoprotein (anti‐MAG). Rituximab is a mouse‐human chimeric antibody that specifically eliminates B‐cells and B‐cell precursors. Preliminary results suggest a beneficial effect on antibody‐dependent autoimmune diseases. Nine patients with an anti‐MAG–associated IgM polyneuropathy received rituximab once weekly for 4 weeks. In all patients, the number of B‐cells in the peripheral blood declined below levels of detection, and the IgM levels decreased between 35% and 82% (median, 58%). In eight patients, lowering of the anti‐MAG antibody titers of more than 52% was observed. Clinical status improved in six patients, remained stable in two, and worsened in one. The motor nerve conduction velocity improved by at least 10% in one ulnar nerve in seven patients and worsened in two. Rituximab was well tolerated and is a promising new drug in the treatment of patients with anti‐MAG–associated polyneuropathy. Muscle Nerve 27:611–615, 2003

High-dose rituximab and anti-MAG-associated polyneuropathy

Rituximab has been administered successfully in patients with polyneuropathy associated with antibodies to myelin-associated glycoprotein (anti-MAG). The authors present a follow-up study with high-dose rituximab. Increase of rituximab from 375 mg/m2 to a dose of 750 mg/m2 was well tolerated and led to clinical improvement in four of eight patients, along with improvement of nerve conduction velocities and a reduction of anti-MAG antibody titers.

High concordance for essential tremor in monozygotic twins of old age

Objective: To assess the relative contribution of genetic and environmental factors for the etiology of essential tremor (ET) and to explore the effect of different diagnostic criteria. Methods: A total of 2,448 twins of the Danish twin registry aged 70 years or more were screened for ET by an interview and an Archimedes spiral test. All twin pairs (n = 162) with a positive screening test of at least one of the twins were recontacted and 218 individuals (109 pairs) were interviewed and examined by a movement disorder specialist. The consensus criteria of the Tremor Investigation Group were applied to diagnose ET. Results: Twenty-nine twins fulfilled the criteria of definite, 7 of probable, and 56 of possible ET. The probandwise concordance rate for the broadest definition of ET was 77% for monozygotic twins (MZ) and 59% for dizygotic twins (DZ). However, in an analysis restricted to cases of probable and definite ET, the concordance rates were 93% and 29%. The heritability for the liability to ET ranged from 93% to 99% using a general population prevalence of 1.2% for white 70+-year-olds. The inclusion of probable and exclusion of possible cases in the diagnosis of ET produced the highest concordance rates. Conclusion: The high concordance among MZ twins of very old age in this first population-based twin study of ET suggests that a disease phenotype consisting of definite and probable ET has a high heritability and hence is a good candidate for a phenotype to be used in linkage studies.

Quality of life and personality in essential tremor patients

The aim of this study was to determine the impact of essential tremor (ET) on quality of life and its relation with tremor severity and the personality profile of ET patients. One hundred and five patients with definite or probable ET from an outpatient population were tested with the Short‐Form 36‐Item Health Survey (SF36) and the Eysenck Personality Questionnaire (EPQ‐R). Compared to controls, the ET patients scored worse in all eight domains of the SF36. The physical component score (PCS) did not differ significantly from the normal population, whereas ET patients older than 40 years were significantly more affected with regard to the mental domains measured by the mental component score (MCS) with their median below the 20th percentile of the German controls. Tremor severity correlated with some of the physical domains and the PCS as well as with social function of the mental domains. ET patients showed significantly lower scores in the psychoticism (P) scale of the EPQ‐R, with a median value on the 11th percentile of normal German population, indicating a more tender‐minded personality type. The MCS correlated highly significant with the neuroticism (N) scale and extraversion (E) scale of EPQ‐R. Multiple regression analysis identified age as the only predictive factor for the PCS and the N‐scale as the only predictive factor for the MCS. Although ET is considered a pure movement disorder, the mental components of quality of life are more affected than the physical dimensions. A more controlled personality type may in part contribute to this.

Evaluation of healthcare utilization and health status of patients with Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus

Abstract.Objective: To assess the effects on motor functioning, health status and direct medical costs of high-frequency stimulation of the subthalamic nucleus (DBS-STN) in patients with idiopathic Parkinsons disease (PD). In addition, the cost-effectiveness of DBS-STN vs. drug treatment was investigated. Methods: 16 consecutive patients with PD from two centers (Düsseldorf/Cologne; Kiel) treated by DBS-STN were prospectively evaluated. Clinical evaluations were done at baseline and 1, 3, 6, 12 months following surgery by means of the Unified Parkinsons disease Rating Scale (UPDRS). Health status of PD patients was assessed using the Sickness Impact Profile (SIP) at baseline and 6 months following surgery. Relevant economic data were taken from the medical records and costs (1999) were derived from different German medical economic resources. Costs were determined from the perspective of the health care provider. Results: Following DBS-STN UPDRS scores (subscores and sum score) as well as health status improved considerably in PD patients. The overall SIP score and the physical dimension score (p < 0.009) were significantly different (p < 0.01) six month after surgery compared with baseline values. Mean costs of DM 40,020 (US

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

20,810, EURO 20,410, GB£ 12,810) per patient were spent during the 12 month observation period for in-patient and out-patient care. These expenses included already the costs for the electronic device for bilateral stimulation. Following DBS-STN medication was considerably reduced. Mean daily drug costs at baseline were DM 46.7±21.8 (US

Update on pathogenesis and treatment of essential tremor.

24, EURO 24, GB£ 15) and DM 18.3±17.7 (US

Correlation between mitotic and Ki-67 labeling indices in paraffin-embedded carcinoma specimens

10, EURO 9, GB£ 6) at 12 months following DBS-STN. Accounting for the decreased drug consumption, total annual costs amounted to DM 31,400 (US