John Fang

Design innovations and baseline findings in a long-term parkinson’s trial: The national institute of neurological disorders and stroke exploratory trials in parkinson’s disease long-term study-1

Based on the preclinical data and the results of a phase II futility study, creatine was selected for an efficacy trial in Parkinsons disease (PD). We present the design rationale and a description of the study cohort at baseline. A randomized, multicenter, double‐blind, parallel‐group, placebo‐controlled phase III study of creatine (10 g daily) in participants with early, treated PD, the Long‐term Study–1 (LS‐1), is being conducted by the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinsons Disease network. The study utilizes a global statistical test (GST) encompassing five clinical rating scales to provide a multidimensional assessment of disease progression. A total of 1,741 PD participants from 45 sites in the United States and Canada were randomized 1:1 to either 10 g of creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS‐1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. LS‐1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10 g/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5‐year follow‐up visit against the background of dopaminergic therapy and best PD care.

Familial essential tremor with apparent autosomal dominant inheritance: Should we also consider other inheritance modes?

A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1‐BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non‐Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors.

Reappraisal of the role of the DRD3 gene in essential tremor

OBJECTIVES Analyze the distribution of polymorphism in the dopamine receptor D3 (DRD3) gene, which was previously reported as a susceptibility risk for essential tremor (ET), in a large cohort of ET. METHODS The role of 312G>A DRD3 polymorphism was analyzed using linkage analysis, association study and transmission disequilibrium test in a group of 433 ET patients, and two unrelated control groups with 121 and 151 individuals. RESULTS Allelic frequencies of glycine and serine forms of the DRD3 gene did not differ between patients and both control groups, and were in Hardy-Weinberg equilibrium. Linkage analysis identified obligatory recombinants in every large pedigree, even in those with relatively high frequency of glycine allele, thus excluding the linkage to this locus. Both alleles were transmitted with an equal likelihood to affected offspring. We also failed to replicate the relationship between glycine homozygosity and an earlier age of onset or more severe tremor course. CONCLUSIONS Our comprehensive genetic analysis in a large ET cohort strongly argues against the role of the DRD3 gene in ET pathogenesis.

Prevalence of unilateral tremor in autosomal dominant essential tremor

The presence of bilateral arm tremor is a key diagnostic feature of essential tremor (ET). We analyzed the presence of unilateral arm tremor in familial ET cohort of 133 autosomal dominant ET kindreds with 412 affected individuals. Inclusion criteria in patients with unilateral arm postural and/or kinetic tremor required the duration of tremor for at least 5 years, without hypokinetic‐rigid syndrome, dystonic posturing, or history of sudden onset of tremor. Only subjects with at least one living first degree relative who met diagnostic criteria for definite ET were included. Eighteen subjects met the inclusion criteria and five had postural tremor only, while the majority (13/18) had a combination of postural and kinetic tremor. Our data shows that unilateral tremor associated with ET is relatively rare and can be identified in 4.4% patients in a cohort of familial ET.

Confined Stimulation Using Dual Thalamic Deep Brain Stimulation Leads Rescues Refractory Essential Tremor: Report of Three Cases

Background/Aims: Deep brain stimulation (DBS) of the nucleus ventralis intermedius (VIM) provides a safe and effective therapy for medically refractory essential tremor (ET). However, as many as 9% of VIM DBS patients deteriorate after several years of good tremor control. For these patients, the high voltage needed to adequately control tremor also generates circumferential current spread causing intolerable adverse effects. Methods: We report 3 ET patients where adding a second parallel thalamic lead anterior-medially to the original and connecting the 2 adjacent leads to a dual-channel pulse generator (Medtronic Synergy, model No. 7427) successfully recaptured tremor control with fewer adverse effects. Results: This approach allowed us to direct the stimulation field away from nearby structures responsible for the adverse effects. Such confined stimulation can be achieved by connecting 2 adjacent DBS leads to a common voltage source, providing current flow between leads. Conclusion: This dual lead stimulation method can be used as a reversible rescue therapy in ET patients who require unacceptably high intensity stimulation.

Progranulin gene mutation with an unusual clinical and neuropathologic presentation.

Progranulin gene (PGRN) mutations cause frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U). Patients usually present with a frontotemporal dementia syndrome and have prominent atrophy and neuronal loss in frontal and temporal cortices and the striatum, with neuronal intranuclear and cytoplasmic inclusions. Clinical, neuropathological, and genetic studies are reported on an individual with PGRN mutation and her family members. We describe a patient with a PGRN c.26C>A mutation who presented with progressive stuttering dysarthria, oculomotor abnormalities, choreic buccolingual movements, and mild parkinsonism. Two other family members were affected, one with a behavioral variant frontotemporal dementia syndrome, the other with a diagnosis of probable Alzheimers disease. At autopsy there was no neuronal loss in the cortex or medial temporal lobe structures, but there was striatal gliosis. Immunohistochemistry for ubiquitin and TDP‐43 revealed neuronal cytoplasmic and intranuclear inclusions as well as neurites. This study further expands the clinical and pathological spectrum of PGRN mutations, and suggests the diagnosis could be missed in some individuals with atypical presentations.

Multisite, double‐blind, randomized, controlled study of pregabalin for essential tremor

This prospective, double-blind, randomized, placebo-controlled crossover trial was approved by institutional review boards at participating institutions. Adult ET patients with a Fahn-Tolosa-Marin (FTM) postural tremor score of at least 2 in the dominant upper limb were enrolled. Patients with DBS, clinically significant liver, kidney, or cardiac abnormalities, previous lack of response to propranolol and primidone, or current treatment with gabapentin were excluded. Concomitant antitremor medications at a stable dose were permitted. Patients were randomized to pregabalin or matching placebo according to a 1:1 schedule generated using SAS 9.2 software (SAS Institute Inc., Cary, NC). Investigators, raters, participants, and caregivers were blinded. Medication was initiated at a dose of 75 mg twice-daily (BID), titrated to a maximum daily dose of 225 mg BID, and maintained at maximum dose for 40 days (see Supporting Appendix 1). After a 3-week washout, participants crossed over to the alternative treatment. Participants were allowed to down-titrate by one level if adverse events (AEs) occurred; titration could be halted if tremor completely resolved or if side-effects prevented an increase. The primary outcome measure was the FTM total score. The two spirals and three lines of the FTM were drawn on an electronic digitizing table (Wacom Intuos 3; www.wacom.com) and rated with the FTM and quantified for tremor using spectral analysis. As a result of technical difficulties at one center, tablet data were obtained from 23 of the 29 participants. Baseline characteristics were compared using the Student’s t test and chi-square test; treatment effects were assessed using the GLM procedure in SAS to account for treatment order and the crossover design. The analysis used an intention-to-treat approach, and last observation carried forward if patients withdrew prematurely. The study was powered to detect a 30% change in the FTM total score (required n 1⁄4 7, assuming a 1⁄4 0.05 and power 1⁄4 0.9).

Positive family history of essential tremor influences the motor phenotype of Parkinson's disease.

Previous reports have suggested that essential tremor (ET) represents a risk factor for the development of Parkinsons disease (PD). Patients with long‐standing ET who develop PD tend to have a tremor‐dominant subtype. To further clarify this association, we examined patients from kindreds with autosomal dominant ET who had signs of isolated PD but did not meet criteria for overlapping ET. We identified 22 patients with PD meeting these diagnostic criteria, and 90% (20 of 22) had tremor‐predominant subtype of PD. Unilateral rest tremor was the presenting symptom in 15 of 22 patients, bradykinesia or rigidity in 5 of 22, and gait problems in 2 of 22. Postural tremor was relatively mild, and the severity of kinetic tremor tightly correlated with rest tremor (r = 0.83, P < 0.001). Tremor‐dominant subtype of PD in patients with a positive family history of ET suggests that these patients have inherited a genetic susceptibility factor for tremor, which affects the motor phenotype of PD.

The role of deep brain stimulation in Parkinson’s disease: an overview and update on new developments

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of neuronal dopamine production in the brain. Oral therapies primarily augment the dopaminergic pathway. As the disease progresses, more continuous delivery of therapy is commonly needed. Deep brain stimulation (DBS) has become an effective therapy option for several different neurologic and psychiatric conditions, including PD. It currently has US Food and Drug Administration approval for PD and essential tremor, as well as a humanitarian device exception for dystonia and obsessive-compulsive disorder. For PD treatment, it is currently approved specifically for those patients suffering from complications of pharmacotherapy, including motor fluctuations or dyskinesias, and a disease process of at least 4 years of duration. Studies have demonstrated superiority of DBS and medical management compared to medical management alone in selected PD patients. Optimal patient selection criteria, choice of target, and programming methods for PD and the other indications for DBS are important topics that continue to be explored and remain works in progress. In addition, new hardware options, such as different types of leads, and different software options have recently become available, increasing the potential for greater efficacy and/or reduced side effects. This review gives an overview of therapeutic management in PD, specifically highlighting DBS and some of the recent changes with surgical therapy.

The Optimal Pallidal Target in Deep Brain Stimulation for Dystonia: A Study Using a Functional Atlas Based on Nonlinear Image Registration

Background: Deep brain stimulation (DBS) of the globus pallidus internus is established as efficacious for dystonia, yet the optimal target within this structure is not well defined. Published evidence suggests that spatial normalization provides a better estimate of DBS lead location than traditional methods based on standard stereotactic coordinates. Methods: We retrospectively reviewed our pallidal implanted dystonia population. Patient imaging scans were morphed into an MRI atlas using a nonlinear image registration algorithm. Active contact locations were projected onto the atlas and clusters analyzed for the degree of variance in two groups: (1) good and poor responders and (2) cervical (CD) and generalized dystonia (GD). Results: The average active contact location between CD and GD good responders was distinct but not significantly different. The mean active contact for CD poor responders was significantly different from CD responders and GD poor responders in the dorsoventral direction. Conclusions: A normalized imaging space is arguably more accurate in visualizing postoperative leads. Despite some separation between groups, this data suggests there was not an optimal pallidal target for common dystonia patients. Degrees of variance overlapped due to a large degree of individual target variation. Patient selection may ultimately be the key to maximizing patient outcomes.