Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

Corticalgammaoscillations(20280Hz)predictincreasesinfocusedattention,andfailureingammaregulationisahallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons atvariedfrequencies (82200Hz) selectivelyamplifies gamma oscillations. Incontrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.

/pdf/driving-fast-spiking-cells-induces-gamma-rhythm-and-controls-2nph5x6a2e.pdf

Driving fast-spiking cells induces gamma rhythm and controls sensory responses

Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.

/pdf/pathological-a-synuclein-transmission-initiates-parkinson-1zdg64n1in.pdf

Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

/pdf/large-scale-meta-analysis-of-genome-wide-association-data-36gj7mf6gp.pdf

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Cost Effectiveness in Health and Medicine.

Background Deep brain stimulation of the subthalamic nucleus (STN) improves motor symptoms of Parkinson disease. Although several studies have assessed cognitive functions before surgery and after long-term STN stimulation, only a few have assessed patients while stimulation is on and off to more specifically address the short-term cognitive effects of STN deep brain stimulation. Objective To examine the short-term effects of STN stimulation on several tests sensitive to executive function and the long-term effects of STN stimulation on a global cognitive scale. Design Twenty-three patients with Parkinson disease were tested 6 to 12 months after surgery with STN stimulation switched on and off in a random order while taking their regular medication. The Unified Parkinson's Disease Rating Scale motor score was also rated in the on and off stimulation condition. The neuropsychological battery included digit span, verbal fluency, Stroop color test, and random number generation in a single- and dual-task condition. Results Short-term stimulation improved the results on the Random Number Generation Task, requiring suppression of habitual responses, but induced more errors in the interference task of the Stroop color test. Digit span, verbal fluency, and dual-task performance results did not change. There was a significant correlation (r= 0.47,P= .02) between improved performance on the Random Number Generation Task and impaired response inhibition in the Stroop interference condition. A preoperative to postoperative comparison showed no changes in global cognitive function with long-term STN deep brain stimulation. Conclusions Short-term STN stimulation improves cognitive flexibility (giving up habitual responses) but impairs response inhibition. Long-term STN stimulation does not change global cognitive function.

/pdf/deep-brain-stimulation-of-the-subthalamic-nucleus-improves-29m8y42dk3.pdf

Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease.

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.

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

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.

Quality of life and personality in essential tremor patients.

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-dose rituximab and anti-MAG-associated polyneuropathy.

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.

Delia Lorenz

Papers

Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease.

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

Quality of life and personality in essential tremor patients.

High-dose rituximab and anti-MAG-associated polyneuropathy.

High concordance for essential tremor in monozygotic twins of old age.