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1.  Huge familial colloid cyst of the third ventricle: An extraordinary presentation 
Surgical Neurology International  2015;6(Suppl 11):S349-S353.
Since the use of computed tomography and magnetic resonance imaging, colloid cysts (CCs) are discovered more frequently and subsequently their true incidence exceeds the numbers previously estimated. In 1986, the first familial case was reported in two identical twin brothers. To date, a total of 17 of these cases have been reported, all differing in the pattern of affected family members.
Case Description:
Here, we describe a unique presentation of a familial case and review the relevant literature on CCs and their natural history to improve our understanding of these cases.
Familial CC can present in various patterns, sizes, and forms. A genetic factor is likely to be responsible in these cases, and further research is warranted to clarify this phenomenon.
PMCID: PMC4521314
Colloid cyst; familial; genetics; tumor
2.  Clivus Chordoma in Continuity with a Large Pontine Cyst 
Skull Base  2009;19(2):177-181.
Chordomas are tumors commonly of extradural origin associated with bone destruction; their central nervous system invasion has rarely been reported. The authors describe a rare case of a 37-year-old man presenting with a clivial chordoma invading the brainstem with a large pontine cyst. A median suboccipital approach was selected to remove the tumor.
PMCID: PMC2671305  PMID: 19721775
Chordoma; skull base; cyst; clivus
3.  Has Management of Epidermoid Tumors of the Cerebellopontine Angle Improved? A Surgical Synopsis of the Past and Present 
Skull Base  2008;18(2):85-98.
We compared the surgical outcomes of recent patients with cerebellopontine angle (CPA) epidermoids treated with advanced surgical tools with those of patients treated in earlier series. From November 2000 to June 2004, we treated 12 patients with epidermoid tumors. One patient had a strict CPA lesion. Tumors extended into the prepontine region in seven cases and supratentorially in two. In two cases the CPA was involved bilaterally. All patients but one underwent a lateral suboccipital approach in a semi-sitting position with microsurgical technique. Endoscopic assistance was used in cases with extensions beyond the CPA. In one case, a subtemporal route was used. The mean follow-up was 27 months (range, 8 to 50 months). There were no deaths. Total removal was achieved in 7 of the 10 patients with unilateral CPA epidermoids. Preoperative status improved in eight (80%) patients, particularly the function of cranial nerves (CNs) V and VII. Only two patients had permanent CN deficits. Complete excision with preservation of CN function should be the goals of management of epidermoids of the CPA. In some cases, these goals can be difficult to achieve, even with contemporary surgical equipment. Bilateral and extensive tumors should be removed in staged procedures. The function of CN V and CN VII may recover after decompression, but the outcome of symptoms related to CN VIII is less certain. The endoscope is a reliable tool for assessing the extension of epidermoids, but it cannot be used for tumor removal.
PMCID: PMC2435477  PMID: 18769651
Epidermoid; cerebellopontine angle; cranial nerve deficits; suboccipital; subtemporal
4.  Thrombophilia Due to Factor V and Factor II Mutations and Formation of a Dural Arteriovenous Fistula: Case Report and Review of a Rare Entity 
Skull Base  2008;18(2):135-143.
Genetic mutations underlying thrombophilia are often recognized in patients with thromboembolic episodes. However, the clinical and therapeutic implications of such findings often remain unclear. We report the first case of a dural arteriovenous fistula (DAVF) in a patient with a combined factor II and factor V Leiden mutation. A 40-year-old man presented with a large left temporal and intraventricular hemorrhage. An initial angiogram showed thrombosis of the left sigmoid sinus but no evidence of a vascular malformation. One year after the hemorrhage, an angiographic study showed the appearance of a right DAVF. During the follow-up period, the patient was found to harbor heterozygosity for a mutation of factor V and a mutation of factor II. Recognition of the patient's thrombophilia led to prolonged oral anticoagulation therapy to reduce the risk of a recurrent thrombotic episode. Despite the increased risk of bleeding, the therapy was considered justified. DAVFs may occur after sinus thrombosis in patients with combined factor II and factor V mutations. This observation indicates the association of multiple hematological disorders with DAVFs in individual patients. Moreover, it raises the clinical conundrum of how to manage patients with thrombophilia, intracranial hemorrhage, and DAVFs.
PMCID: PMC2435475  PMID: 18769649
Factor V Leiden mutation; G20210A mutation; arteriovenous malformation; anticoagulation; hypercoagulable state
5.  Posterior Cranial Fossa Gangliogliomas 
Skull Base  2007;17(4):253-264.
Ganglioglioma (GG) is an uncommon primary lesion of the central nervous system that is typically located supratentorially. There are only a few reports of GG arising from the cerebellum. To the best of our knowledge this is the first case of a cerebellar GG with supratentorial extension and a longstanding history before its recognition. In fact, this 29-year-old male presented with an 11-year history of intermittent headaches. A cranial computerized tomography (CT) performed at the onset of his complaints failed to reveal the tumor. After a particularly longstanding cephalalgic episode, the patient underwent a new CT scan that was also negative. However, magnetic resonance (MR) imaging of the brain revealed a space-occupying lesion in the right cerebellar hemisphere with extension to the level of the superior colliculi and pineal recess. The tumor was partially removed through a midline suboccipital craniotomy and supracerebellar approach. Pathological examination of the tumor showed composition of atypical ganglion cells and astrocytes, indicating the diagnosis of cerebellar GG. At last follow-up, 24 months after surgery, the patient reported a marked improvement of his clinical condition with significant reduction of intensity and frequency of the headache. The present report illustrates how cerebellar GG may remain undetectable by CT and may therefore present with a longstanding history and nonspecific signs and symptoms. MR investigation can lead to the proper diagnosis. Even after partial removal the prognosis remains good and remission of the symptoms may be achieved. In this article, we review the literature and summarize the current understanding of infratentorial GGs.
PMCID: PMC2039715  PMID: 18174926
Ganglioglioma; posterior cranial fossa; cerebellum; brainstem; neuronal tumors; history
6.  Hematologic modifications in natalizumab-treated multiple sclerosis patients 
To monitor the hematologic modifications in the peripheral blood of patients with relapsing-remitting multiple sclerosis treated with natalizumab.
The cohort included 44 patients with relapsing-remitting multiple sclerosis treated monthly with natalizumab for 18 months. Peripheral blood was collected before treatment initiation and on a monthly basis during the treatment course. Complete blood cell count was performed using automated hematology systems. Blood smears were prepared and analyzed when abnormal values were detected.
Mean total white blood cell, lymphocyte, and eosinophil counts were significantly higher 1 month after treatment initiation and remained stable during the 18 months of follow-up. Monocyte counts increased progressively during the 18-month treatment with natalizumab. Erythroblasts and neutrophil precursors were absent before treatment initiation but were present in 16% and 6.8% of patients, respectively, 1 month after the first natalizumab infusion. The proportion of patients with erythroblasts and neutrophil precursors remained stable throughout the 18-month follow-up period. On an individual patient basis, a fluctuating level of erythroblasts and neutrophil precursors was observed. No difference in mean erythrocyte, hemoglobin, hematocrit, thrombocyte, and neutrophil levels was observed before and after 18 months of natalizumab treatment. No cases of myelodysplastic syndrome or acute leukemia were observed.
Chronic treatment with natalizumab is associated with significant modifications in complete blood cell count, including emergence of hematopoietic precursors that are not present in peripheral blood under normal conditions. None of these modifications were associated with malignancy.
PMCID: PMC4476051  PMID: 26140281
7.  Common NOTCH3 Variants and Cerebral Small-Vessel Disease 
Supplemental Digital Content is available in the text.
Background and Purpose—
The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly.
We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency >0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method.
We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association.
Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease.
PMCID: PMC4442025  PMID: 25953367
CADASIL; cerebral small vessel diseases; genetic association studies; stroke, lacunar
8.  Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies 
Bone Marrow Research  2015;2015:980924.
Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5–4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance (P = 0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.
PMCID: PMC4385613  PMID: 25874131
9.  Neurochemical correlates of caudate atrophy in Huntington disease 
The precise pathogenic mechanisms of Huntington disease (HD) are unknown, but can be tested in vivo using proton magnetic resonance spectroscopy (1H MRS) to measure neurochemical changes.
To evaluate neurochemical differences in HD gene mutation-carriers (HGMC) vs. controls, and to investigate relationships among function, brain structure and neurochemistry in HD. Since previous 1H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two 1H MRS data analysis approaches.
HGMC with pre-manifest to early HD and controls underwent evaluation of motor function, MR imaging and localized 1H MRS in caudate and frontal lobe. Analytical approaches tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel).
We identified a suite of neurochemicals reduced in concentration proportionally to loss of caudate volume in HGMC. Caudate concentrations of NAA, creatine, choline, and caudate and frontal concentrations of glutamate+glutamine and glutamate correlated with caudate volume in HGMC subjects. The relative, but not the absolute quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in caudate of HGMC subjects vs. controls.
This is the first study to demonstrate correlation among structure, function and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable magnification of subtle differences between groups. Observation of decreased glutamate-glutamine signals suggests that glutamate signaling may be disrupted relatively early in HD, with important implications for therapeutic approaches.
PMCID: PMC3960319  PMID: 24442623
Huntington disease; caudate; magnetic resonance spectroscopy; magnetic resonance imaging; glutamate
10.  Association mapping of the PARK10 region for Parkinson’s disease susceptibility genes 
Previous studies indicate that as many as six genes within the PARK10 region (RNF11, UQCRH, HIVEP3, EIF2B3, USP24, ELAVL4) might modify susceptibility or age at onset in Parkinson’s disease (PD).
We sought to identify new PD susceptibility genes and to validate previously nominated candidate genes within the PARK10 region using a two-stage design. We used data from a large, publicly-available genome-wide association study (GWAS) in the discovery stage (n=2000 cases and 1986 controls) and data from three independent studies for the replication stage (total n=2113 cases and 2095 controls). Marker density was increased by imputation using HapMap3 and 1000 Genomes reference panels, and over 40,000 single nucleotide polymorphisms (SNPs) were used in the final analysis. The association between each SNP and PD was modeled using logistic regression with an additive allele dosage effect and adjusted for sex, age, and axes of geographical variation.
Although the discovery stage yielded promising findings for SNPs in several novel genes, including DAB1, none of the results were validated in the replication stage. Furthermore, in meta-analyses across all datasets no genes within PARK10 reached significance after accounting for multiple testing.
Our results suggest that common variation in the PARK10 region is not associated with PD risk. However, additional studies are needed to assess the role of PARK10 in modifying age at onset and to determine whether rare variants in this region might affect PD susceptibility.
PMCID: PMC3946853  PMID: 24156912
PARK10; Parkinson’s Disease; Replication; GWAS
11.  17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischemic Stroke, But Not With Lacunar Stroke Status 
Background and Purpose
Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke.
We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke.
Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke.
This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.
PMCID: PMC3771337  PMID: 23674528
genetics; Genome-wide Association Study; leukoaraiosis; small-vessel disease; stroke
12.  Risk prediction for complex diseases: application to Parkinson disease 
The aim of this study was to evaluate the risk of Parkinson disease using clinical and demographic data alone and when combined with information from genes associated with Parkinson disease.
A total of 1,967 participants in the dbGAP NeuroGenetics Research Consortium data set were included. Single-nucleotide polymorphisms associated with Parkinson disease at a genome-wide significance level in previous genome-wide association studies were included in risk prediction. Risk allele scores were calculated as the weighted count of the minor alleles. Five models were constructed. Discriminatory capability was evaluated using the area under the curve.
Both family history and genetic risk scores increased risk for Parkinson disease. Although the fullest model, which included both family history and genetic risk information, resulted in the highest area under the curve, there were no significant differences between models using family history alone and those using genetic information alone.
Adding genome-wide association study–derived genotypes, family history information, or both to standard demographic risk factors for Parkinson disease resulted in an improvement in discriminatory capacity. In the full model, the contributions of genotype data and family history information to discriminatory capacity were similar, and both were statistically significant. This suggests that there is limited overlap between genetic risk factors identified through genome-wide association study and unmeasured susceptibility variants captured by family history. Our results are similar to those of studies of other complex diseases and indicate that genetic risk prediction for Parkinson disease requires identification of additional genetic risk factors and/or better methods for risk prediction in order to achieve a degree of risk prediction that is clinically useful.
PMCID: PMC3687522  PMID: 23222663
genetics; Parkinson disease; risk prediction
13.  A rare case of primary cutaneous follicle centre lymphoma presenting as a giant tumour of the scalp and combined with JAK2V617F positive essential thrombocythaemia 
Biomarker Research  2014;2:7.
Primary cutaneous follicle centre lymphoma (PCFCL) is a rare cutaneous B cell lymphoma in middle-age adults with excellent prognosis. Here we present a case of a patient with a PCFCL in the form of a giant tumour of the scalp in combination with a myeloproliferative neoplasm, JAK2V617F positive essential thrombocythaemia. This case may be of interest because of the favourable outcome in spite of the large size of the PCFCL, the rare combination with essential thrombocythaemia and because it contributes to discussion on the role of JAK2 mutation in such patients.
PMCID: PMC3978001  PMID: 24690328
Primary cutaneous follicle centre lymphoma; PCFCL; Essential thrombocythaemia; JAK2V617F; Myeloproliferative neoplasm
14.  Play it again, Sam: brain correlates of emotional music recognition 
Background: Music can elicit strong emotions and can be remembered in connection with these emotions even decades later. Yet, the brain correlates of episodic memory for highly emotional music compared with less emotional music have not been examined. We therefore used fMRI to investigate brain structures activated by emotional processing of short excerpts of film music successfully retrieved from episodic long-term memory.
Methods: Eighteen non-musicians volunteers were exposed to 60 structurally similar pieces of film music of 10 s length with high arousal ratings and either less positive or very positive valence ratings. Two similar sets of 30 pieces were created. Each of these was presented to half of the participants during the encoding session outside of the scanner, while all stimuli were used during the second recognition session inside the MRI-scanner. During fMRI each stimulation period (10 s) was followed by a 20 s resting period during which participants pressed either the “old” or the “new” button to indicate whether they had heard the piece before.
Results: Musical stimuli vs. silence activated the bilateral superior temporal gyrus, right insula, right middle frontal gyrus, bilateral medial frontal gyrus and the left anterior cerebellum. Old pieces led to activation in the left medial dorsal thalamus and left midbrain compared to new pieces. For recognized vs. not recognized old pieces a focused activation in the right inferior frontal gyrus and the left cerebellum was found. Positive pieces activated the left medial frontal gyrus, the left precuneus, the right superior frontal gyrus, the left posterior cingulate, the bilateral middle temporal gyrus, and the left thalamus compared to less positive pieces.
Conclusion: Specific brain networks related to memory retrieval and emotional processing of symphonic film music were identified. The results imply that the valence of a music piece is important for memory performance and is recognized very fast.
PMCID: PMC3927073  PMID: 24634661
musical memory; episodic memory; emotions; brain-processing
15.  Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease 
Neurology  2008;70(16 0 2):1456-1460.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.
We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.
The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30 –79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.
The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.
PMCID: PMC3906630  PMID: 18337586
Multidetector contrast enhanced computed tomography with acquisition of 0.625-mm thick transverse images was used to measure the extent of appendicular osteosarcoma in 10 dogs. The measured length of tumor based on CT was compared to the true length of tumor using histopathology. There was a statistically significant association with good correlation between the true length of osteosarcoma compared to the length of intramedullary/endosteal abnormalities on CT with a mean overestimation of 1.8% (SD = 15%). There was not a statistically significant association between the true tumor length and the length of periosteal proliferation on CT with a mean overestimation of 9.7% (SD = 30.3%). There was a statistically significant association, but with poor correlation, between the true tumor length compared to the length of abnormal contrast enhancement with a mean overestimation of 9.6% (SD = 34.8%). The extent of intramedullary/endosteal CT abnormalities assessed from submillimeter transverse images may be of value in assessing patient candidacy and surgical margins for limb-sparing surgery
PMCID: PMC3868340  PMID: 22413965
canine; computed tomography; CT; dog; OSA; osteosarcoma; multidetector
17.  Common Variation in the LRRK2 Gene is a Risk Factor for Parkinson’s Disease 
Common variants in the LRRK2 gene influence risk of Parkinson’s disease (PD) in Asians, but whether the same is true in European-derived populations is less clear.
We genotyped 66 LRRK2 tagging single nucleotide polymorphisms (SNPs) in 575 PD patients and 689 controls from the Northwestern U.S. (Tier 1). PD-associated SNPs (p<0.05) were then genotyped in an independent sample of 3617 cases and 2512 controls from the U.S. and Spain (Tier 2). Logistic regression was used to model additive SNP genotype effects adjusted for age and sex among white individuals.
Two regions showed independent association with PD in Tier 1, and SNPs in both regions were successfully replicated in Tier 2 (rs10878226, combined odds ratio [OR], 1.20; 95% confidence interval [CI], 1.08-1.33; p=6.3×10−4; rs11176013, OR, 0.89; CI, 0.83-0.95; p=4.6×10−4).
Our data suggest that common variation within LRRK2 conveys susceptibility for PD in individuals of European ancestry.
PMCID: PMC3536918  PMID: 23115130
Parkinson’s disease; LRRK2; SNP
18.  Platelet-activating factor receptor antagonism targets neuroinflammation in experimental epilepsy 
Epilepsia  2011;52(3):551-561.
Temporal lobe epilepsy is associated with the inflammatory process related to the basic mechanisms that lead to seizure susceptibility and brain damage. Platelet-activating factor (PAF), a potent, short-lived phospholipid mediator of inflammation participates in physiological signaling in the brain. However, after seizures PAF accumulates in the brain and activates intracellular signaling related with inflammation-mediated excitotoxicity and hippocampal hyperexcitability. The objective of this study is to evaluate the effect of PAF antagonism on hippocampal hyperexcitability, seizure susceptibility and neuroprotection using the kindling paradigm and pilocarpine-induced seizure damage models.
The PAF antagonist, LAU-0901 (60 mg/kg, i.p.), or vehicle was administrated each day of kindling or daily during the four weeks after status epilepticus (SE). We analyzed seizure severity, electrical activity, cellular damage and inflammation in the hippocampi of both treated groups.
LAU-0901 limits the progression of kindling and attenuates seizure susceptibility one week after the kindling procedure. Also, under the seizure-damage conditions studied here, we observed that LAU-0901 induces hippocampal neuroprotection and limits somatostatin interneuronal cell loss and inflammation.
Our results indicate that modulation of PAF over-activity attenuates seizure susceptibility, hippocampal hyperexcitability and neuroinflammation.
PMCID: PMC3800107  PMID: 21204830
Kindling; epileptogenesis; platelet-activating factor; neuroinflammation; seizures; neuroprotection; somatostatin
19.  Randomized trial of deep brain stimulation for Parkinson disease 
Neurology  2012;79(1):55-65.
Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial.
Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinson's Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function.
Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI −15.8 to −9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall.
The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life.
Classification of Evidence:
This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology® 2012;79:55–65
PMCID: PMC3385495  PMID: 22722632
20.  Gender differences in reward-related decision processing under stress 
Recent research indicates gender differences in the impact of stress on decision behavior, but little is known about the brain mechanisms involved in these gender-specific stress effects. The current study used functional magnetic resonance imaging (fMRI) to determine whether induced stress resulted in gender-specific patterns of brain activation during a decision task involving monetary reward. Specifically, we manipulated physiological stress levels using a cold pressor task, prior to a risky decision making task. Healthy men (n = 24, 12 stressed) and women (n = 23, 11 stressed) completed the decision task after either cold pressor stress or a control task during the period of cortisol response to the cold pressor. Gender differences in behavior were present in stressed participants but not controls, such that stress led to greater reward collection and faster decision speed in males but less reward collection and slower decision speed in females. A gender-by-stress interaction was observed for the dorsal striatum and anterior insula. With cold stress, activation in these regions was increased in males but decreased in females. The findings of this study indicate that the impact of stress on reward-related decision processing differs depending on gender.
PMCID: PMC3324572  PMID: 21609968
stress; decision making; fMRI; gender differences; cortisol
21.  Observation of sonified movements engages a basal ganglia frontocortical network 
BMC Neuroscience  2013;14:32.
Producing sounds by a musical instrument can lead to audiomotor coupling, i.e. the joint activation of the auditory and motor system, even when only one modality is probed. The sonification of otherwise mute movements by sounds based on kinematic parameters of the movement has been shown to improve motor performance and perception of movements.
Here we demonstrate in a group of healthy young non-athletes that congruently (sounds match visual movement kinematics) vs. incongruently (no match) sonified breaststroke movements of a human avatar lead to better perceptual judgement of small differences in movement velocity. Moreover, functional magnetic resonance imaging revealed enhanced activity in superior and medial posterior temporal regions including the superior temporal sulcus, known as an important multisensory integration site, as well as the insula bilaterally and the precentral gyrus on the right side. Functional connectivity analysis revealed pronounced connectivity of the STS with the basal ganglia and thalamus as well as frontal motor regions for the congruent stimuli. This was not seen to the same extent for the incongruent stimuli.
We conclude that sonification of movements amplifies the activity of the human action observation system including subcortical structures of the motor loop. Sonification may thus be an important method to enhance training and therapy effects in sports science and neurological rehabilitation.
PMCID: PMC3602090  PMID: 23496827
22.  CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion 
Lee, J.-M. | Ramos, E.M. | Lee, J.-H. | Gillis, T. | Mysore, J.S. | Hayden, M.R. | Warby, S.C. | Morrison, P. | Nance, M. | Ross, C.A. | Margolis, R.L. | Squitieri, F. | Orobello, S. | Di Donato, S. | Gomez-Tortosa, E. | Ayuso, C. | Suchowersky, O. | Trent, R.J.A. | McCusker, E. | Novelletto, A. | Frontali, M. | Jones, R. | Ashizawa, T. | Frank, S. | Saint-Hilaire, M.H. | Hersch, S.M. | Rosas, H.D. | Lucente, D. | Harrison, M.B. | Zanko, A. | Abramson, R.K. | Marder, K. | Sequeiros, J. | Paulsen, J.S. | Landwehrmeyer, G.B. | Myers, R.H. | MacDonald, M.E. | Gusella, J.F. | Durr, Alexandra | Rosenblatt, Adam | Frati, Luigi | Perlman, Susan | Conneally, Patrick M. | Klimek, Mary Lou | Diggin, Melissa | Hadzi, Tiffany | Duckett, Ayana | Ahmed, Anwar | Allen, Paul | Ames, David | Anderson, Christine | Anderson, Karla | Anderson, Karen | Andrews, Thomasin | Ashburner, John | Axelson, Eric | Aylward, Elizabeth | Barker, Roger A. | Barth, Katrin | Barton, Stacey | Baynes, Kathleen | Bea, Alexandra | Beall, Erik | Beg, Mirza Faisal | Beglinger, Leigh J. | Biglan, Kevin | Bjork, Kristine | Blanchard, Steve | Bockholt, Jeremy | Bommu, Sudharshan Reddy | Brossman, Bradley | Burrows, Maggie | Calhoun, Vince | Carlozzi, Noelle | Chesire, Amy | Chiu, Edmond | Chua, Phyllis | Connell, R.J. | Connor, Carmela | Corey-Bloom, Jody | Craufurd, David | Cross, Stephen | Cysique, Lucette | Santos, Rachelle Dar | Davis, Jennifer | Decolongon, Joji | DiPietro, Anna | Doucette, Nicholas | Downing, Nancy | Dudler, Ann | Dunn, Steve | Ecker, Daniel | Epping, Eric A. | Erickson, Diane | Erwin, Cheryl | Evans, Ken | Factor, Stewart A. | Farias, Sarah | Fatas, Marta | Fiedorowicz, Jess | Fullam, Ruth | Furtado, Sarah | Garde, Monica Bascunana | Gehl, Carissa | Geschwind, Michael D. | Goh, Anita | Gooblar, Jon | Goodman, Anna | Griffith, Jane | Groves, Mark | Guttman, Mark | Hamilton, Joanne | Harrington, Deborah | Harris, Greg | Heaton, Robert K. | Helmer, Karl | Henneberry, Machelle | Hershey, Tamara | Herwig, Kelly | Howard, Elizabeth | Hunter, Christine | Jankovic, Joseph | Johnson, Hans | Johnson, Arik | Jones, Kathy | Juhl, Andrew | Kim, Eun Young | Kimble, Mycah | King, Pamela | Klimek, Mary Lou | Klöppel, Stefan | Koenig, Katherine | Komiti, Angela | Kumar, Rajeev | Langbehn, Douglas | Leavitt, Blair | Leserman, Anne | Lim, Kelvin | Lipe, Hillary | Lowe, Mark | Magnotta, Vincent A. | Mallonee, William M. | Mans, Nicole | Marietta, Jacquie | Marshall, Frederick | Martin, Wayne | Mason, Sarah | Matheson, Kirsty | Matson, Wayne | Mazzoni, Pietro | McDowell, William | Miedzybrodzka, Zosia | Miller, Michael | Mills, James | Miracle, Dawn | Montross, Kelsey | Moore, David | Mori, Sasumu | Moser, David J. | Moskowitz, Carol | Newman, Emily | Nopoulos, Peg | Novak, Marianne | O'Rourke, Justin | Oakes, David | Ondo, William | Orth, Michael | Panegyres, Peter | Pease, Karen | Perlman, Susan | Perlmutter, Joel | Peterson, Asa | Phillips, Michael | Pierson, Ron | Potkin, Steve | Preston, Joy | Quaid, Kimberly | Radtke, Dawn | Rae, Daniela | Rao, Stephen | Raymond, Lynn | Reading, Sarah | Ready, Rebecca | Reece, Christine | Reilmann, Ralf | Reynolds, Norm | Richardson, Kylie | Rickards, Hugh | Ro, Eunyoe | Robinson, Robert | Rodnitzky, Robert | Rogers, Ben | Rosenblatt, Adam | Rosser, Elisabeth | Rosser, Anne | Price, Kathy | Price, Kathy | Ryan, Pat | Salmon, David | Samii, Ali | Schumacher, Jamy | Schumacher, Jessica | Sendon, Jose Luis Lópenz | Shear, Paula | Sheinberg, Alanna | Shpritz, Barnett | Siedlecki, Karen | Simpson, Sheila A. | Singer, Adam | Smith, Jim | Smith, Megan | Smith, Glenn | Snyder, Pete | Song, Allen | Sran, Satwinder | Stephan, Klaas | Stober, Janice | Sü?muth, Sigurd | Suter, Greg | Tabrizi, Sarah | Tempkin, Terry | Testa, Claudia | Thompson, Sean | Thomsen, Teri | Thumma, Kelli | Toga, Arthur | Trautmann, Sonja | Tremont, Geoff | Turner, Jessica | Uc, Ergun | Vaccarino, Anthony | van Duijn, Eric | Van Walsem, Marleen | Vik, Stacie | Vonsattel, Jean Paul | Vuletich, Elizabeth | Warner, Tom | Wasserman, Paula | Wassink, Thomas | Waterman, Elijah | Weaver, Kurt | Weir, David | Welsh, Claire | Werling-Witkoske, Chris | Wesson, Melissa | Westervelt, Holly | Weydt, Patrick | Wheelock, Vicki | Williams, Kent | Williams, Janet | Wodarski, Mary | Wojcieszek, Joanne | Wood, Jessica | Wood-Siverio, Cathy | Wu, Shuhua | Yastrubetskaya, Olga | de Yebenes, Justo Garcia | Zhao, Yong Qiang | Zimbelman, Janice | Zschiegner, Roland | Aaserud, Olaf | Abbruzzese, Giovanni | Andrews, Thomasin | Andrich, Jurgin | Antczak, Jakub | Arran, Natalie | Artiga, Maria J. Saiz | Bachoud-Lévi, Anne-Catherine | Banaszkiewicz, Krysztof | di Poggio, Monica Bandettini | Bandmann, Oliver | Barbera, Miguel A. | Barker, Roger A. | Barrero, Francisco | Barth, Katrin | Bas, Jordi | Beister, Antoine | Bentivoglio, Anna Rita | Bertini, Elisabetta | Biunno, Ida | Bjørgo, Kathrine | Bjørnevoll, Inga | Bohlen, Stefan | Bonelli, Raphael M. | Bos, Reineke | Bourne, Colin | Bradbury, Alyson | Brockie, Peter | Brown, Felicity | Bruno, Stefania | Bryl, Anna | Buck, Andrea | Burg, Sabrina | Burgunder, Jean-Marc | Burns, Peter | Burrows, Liz | Busquets, Nuria | Busse, Monica | Calopa, Matilde | Carruesco, Gemma T. | Casado, Ana Gonzalez | Catena, Judit López | Chu, Carol | Ciesielska, Anna | Clapton, Jackie | Clayton, Carole | Clenaghan, Catherine | Coelho, Miguel | Connemann, Julia | Craufurd, David | Crooks, Jenny | Cubillo, Patricia Trigo | Cubo, Esther | Curtis, Adrienne | De Michele, Giuseppe | De Nicola, A. | de Souza, Jenny | de Weert, A. Marit | de Yébenes, Justo Garcia | Dekker, M. | Descals, A. Martínez | Di Maio, Luigi | Di Pietro, Anna | Dipple, Heather | Dose, Matthias | Dumas, Eve M. | Dunnett, Stephen | Ecker, Daniel | Elifani, F. | Ellison-Rose, Lynda | Elorza, Marina D. | Eschenbach, Carolin | Evans, Carole | Fairtlough, Helen | Fannemel, Madelein | Fasano, Alfonso | Fenollar, Maria | Ferrandes, Giovanna | Ferreira, Jaoquim J. | Fillingham, Kay | Finisterra, Ana Maria | Fisher, K. | Fletcher, Amy | Foster, Jillian | Foustanos, Isabella | Frech, Fernando A. | Fullam, Robert | Fullham, Ruth | Gago, Miguel | García, RocioGarcía-Ramos | García, Socorro S. | Garrett, Carolina | Gellera, Cinzia | Gill, Paul | Ginestroni, Andrea | Golding, Charlotte | Goodman, Anna | Gørvell, Per | Grant, Janet | Griguoli, A. | Gross, Diana | Guedes, Leonor | BascuñanaGuerra, Monica | Guerra, Maria Rosalia | Guerrero, Rosa | Guia, Dolores B. | Guidubaldi, Arianna | Hallam, Caroline | Hamer, Stephanie | Hammer, Kathrin | Handley, Olivia J. | Harding, Alison | Hasholt, Lis | Hedge, Reikha | Heiberg, Arvid | Heinicke, Walburgis | Held, Christine | Hernanz, Laura Casas | Herranhof, Briggitte | Herrera, Carmen Durán | Hidding, Ute | Hiivola, Heli | Hill, Susan | Hjermind, Lena. E. | Hobson, Emma | Hoffmann, Rainer | Holl, Anna Hödl | Howard, Liz | Hunt, Sarah | Huson, Susan | Ialongo, Tamara | Idiago, Jesus Miguel R. | Illmann, Torsten | Jachinska, Katarzyna | Jacopini, Gioia | Jakobsen, Oda | Jamieson, Stuart | Jamrozik, Zygmunt | Janik, Piotr | Johns, Nicola | Jones, Lesley | Jones, Una | Jurgens, Caroline K. | Kaelin, Alain | Kalbarczyk, Anna | Kershaw, Ann | Khalil, Hanan | Kieni, Janina | Klimberg, Aneta | Koivisto, Susana P. | Koppers, Kerstin | Kosinski, Christoph Michael | Krawczyk, Malgorzata | Kremer, Berry | Krysa, Wioletta | Kwiecinski, Hubert | Lahiri, Nayana | Lambeck, Johann | Lange, Herwig | Laver, Fiona | Leenders, K.L. | Levey, Jamie | Leythaeuser, Gabriele | Lezius, Franziska | Llesoy, Joan Roig | Löhle, Matthias | López, Cristobal Diez-Aja | Lorenza, Fortuna | Loria, Giovanna | Magnet, Markus | Mandich, Paola | Marchese, Roberta | Marcinkowski, Jerzy | Mariotti, Caterina | Mariscal, Natividad | Markova, Ivana | Marquard, Ralf | Martikainen, Kirsti | Martínez, Isabel Haro | Martínez-Descals, Asuncion | Martino, T. | Mason, Sarah | McKenzie, Sue | Mechi, Claudia | Mendes, Tiago | Mestre, Tiago | Middleton, Julia | Milkereit, Eva | Miller, Joanne | Miller, Julie | Minster, Sara | Möller, Jens Carsten | Monza, Daniela | Morales, Blas | Moreau, Laura V. | Moreno, Jose L. López-Sendón | Münchau, Alexander | Murch, Ann | Nielsen, Jørgen E. | Niess, Anke | Nørremølle, Anne | Novak, Marianne | O'Donovan, Kristy | Orth, Michael | Otti, Daniela | Owen, Michael | Padieu, Helene | Paganini, Marco | Painold, Annamaria | Päivärinta, Markku | Partington-Jones, Lucy | Paterski, Laurent | Paterson, Nicole | Patino, Dawn | Patton, Michael | Peinemann, Alexander | Peppa, Nadia | Perea, Maria Fuensanta Noguera | Peterson, Maria | Piacentini, Silvia | Piano, Carla | Càrdenas, Regina Pons i | Prehn, Christian | Price, Kathleen | Probst, Daniela | Quarrell, Oliver | Quiroga, Purificacion Pin | Raab, Tina | Rakowicz, Maryla | Raman, Ashok | Raymond, Lucy | Reilmann, Ralf | Reinante, Gema | Reisinger, Karin | Retterstol, Lars | Ribaï, Pascale | Riballo, Antonio V. | Ribas, Guillermo G. | Richter, Sven | Rickards, Hugh | Rinaldi, Carlo | Rissling, Ida | Ritchie, Stuart | Rivera, Susana Vázquez | Robert, Misericordia Floriach | Roca, Elvira | Romano, Silvia | Romoli, Anna Maria | Roos, Raymond A.C. | Røren, Niini | Rose, Sarah | Rosser, Elisabeth | Rosser, Anne | Rossi, Fabiana | Rothery, Jean | Rudzinska, Monika | Ruíz, Pedro J. García | Ruíz, Belan Garzon | Russo, Cinzia Valeria | Ryglewicz, Danuta | Saft, Carston | Salvatore, Elena | Sánchez, Vicenta | Sando, Sigrid Botne | Šašinková, Pavla | Sass, Christian | Scheibl, Monika | Schiefer, Johannes | Schlangen, Christiane | Schmidt, Simone | Schöggl, Helmut | Schrenk, Caroline | Schüpbach, Michael | Schuierer, Michele | Sebastián, Ana Rojo | Selimbegovic-Turkovic, Amina | Sempolowicz, Justyna | Silva, Mark | Sitek, Emilia | Slawek, Jaroslaw | Snowden, Julie | Soleti, Francesco | Soliveri, Paola | Sollom, Andrea | Soltan, Witold | Sorbi, Sandro | Sorensen, Sven Asger | Spadaro, Maria | Städtler, Michael | Stamm, Christiane | Steiner, Tanja | Stokholm, Jette | Stokke, Bodil | Stopford, Cheryl | Storch, Alexander | Straßburger, Katrin | Stubbe, Lars | Sulek, Anna | Szczudlik, Andrzej | Tabrizi, Sarah | Taylor, Rachel | Terol, Santiago Duran-Sindreu | Thomas, Gareth | Thompson, Jennifer | Thomson, Aileen | Tidswell, Katherine | Torres, Maria M. Antequera | Toscano, Jean | Townhill, Jenny | Trautmann, Sonja | Tucci, Tecla | Tuuha, Katri | Uhrova, Tereza | Valadas, Anabela | van Hout, Monique S.E. | van Oostrom, J.C.H. | van Vugt, Jeroen P.P. | vanm, Walsem Marleen R. | Vandenberghe, Wim | Verellen-Dumoulin, Christine | Vergara, Mar Ruiz | Verstappen, C.C.P. | Verstraelen, Nichola | Viladrich, Celia Mareca | Villanueva, Clara | Wahlström, Jan | Warner, Thomas | Wehus, Raghild | Weindl, Adolf | Werner, Cornelius J. | Westmoreland, Leann | Weydt, Patrick | Wiedemann, Alexandra | Wild, Edward | Wild, Sue | Witjes-Ané, Marie-Noelle | Witkowski, Grzegorz | Wójcik, Magdalena | Wolz, Martin | Wolz, Annett | Wright, Jan | Yardumian, Pam | Yates, Shona | Yudina, Elizaveta | Zaremba, Jacek | Zaugg, Sabine W. | Zdzienicka, Elzbieta | Zielonka, Daniel | Zielonka, Euginiusz | Zinzi, Paola | Zittel, Simone | Zucker, Birgrit | Adams, John | Agarwal, Pinky | Antonijevic, Irina | Beck, Christopher | Chiu, Edmond | Churchyard, Andrew | Colcher, Amy | Corey-Bloom, Jody | Dorsey, Ray | Drazinic, Carolyn | Dubinsky, Richard | Duff, Kevin | Factor, Stewart | Foroud, Tatiana | Furtado, Sarah | Giuliano, Joe | Greenamyre, Timothy | Higgins, Don | Jankovic, Joseph | Jennings, Dana | Kang, Un Jung | Kostyk, Sandra | Kumar, Rajeev | Leavitt, Blair | LeDoux, Mark | Mallonee, William | Marshall, Frederick | Mohlo, Eric | Morgan, John | Oakes, David | Panegyres, Peter | Panisset, Michel | Perlman, Susan | Perlmutter, Joel | Quaid, Kimberly | Raymond, Lynn | Revilla, Fredy | Robertson, Suzanne | Robottom, Bradley | Sanchez-Ramos, Juan | Scott, Burton | Shannon, Kathleen | Shoulson, Ira | Singer, Carlos | Tabbal, Samer | Testa, Claudia | van, Kammen Dan | Vetter, Louise | Walker, Francis | Warner, John | Weiner, illiam | Wheelock, Vicki | Yastrubetskaya, Olga | Barton, Stacey | Broyles, Janice | Clouse, Ronda | Coleman, Allison | Davis, Robert | Decolongon, Joji | DeLaRosa, Jeanene | Deuel, Lisa | Dietrich, Susan | Dubinsky, Hilary | Eaton, Ken | Erickson, Diane | Fitzpatrick, Mary Jane | Frucht, Steven | Gartner, Maureen | Goldstein, Jody | Griffith, Jane | Hickey, Charlyne | Hunt, Victoria | Jaglin, Jeana | Klimek, Mary Lou | Lindsay, Pat | Louis, Elan | Loy, Clemet | Lucarelli, Nancy | Malarick, Keith | Martin, Amanda | McInnis, Robert | Moskowitz, Carol | Muratori, Lisa | Nucifora, Frederick | O'Neill, Christine | Palao, Alicia | Peavy, Guerry | Quesada, Monica | Schmidt, Amy | Segro, Vicki | Sperin, Elaine | Suter, Greg | Tanev, Kalo | Tempkin, Teresa | Thiede, Curtis | Wasserman, Paula | Welsh, Claire | Wesson, Melissa | Zauber, Elizabeth
Neurology  2012;78(10):690-695.
Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695
PMCID: PMC3306163  PMID: 22323755
23.  Systemic Inflammatory Effects of Traumatic Brain Injury, Femur Fracture, and Shock: An Experimental Murine Polytrauma Model 
Mediators of Inflammation  2012;2012:136020.
Objective. Despite broad research in neurotrauma and shock, little is known on systemic inflammatory effects of the clinically most relevant combined polytrauma. Experimental investigation in an animal model may provide relevant insight for therapeutic strategies. We describe the effects of a combined injury with respect to lymphocyte population and cytokine activation. Methods. 45 male C57BL/6J mice (mean weight 27 g) were anesthetized with ketamine/xylazine. Animals were subjected to a weight drop closed traumatic brain injury (WD-TBI), a femoral fracture and hemorrhagic shock (FX-SH). Animals were subdivided into WD-TBI, FX-SH and combined trauma (CO-TX) groups. Subjects were sacrificed at 96 h. Blood was analysed for cytokines and by flow cytometry for lymphocyte populations. Results. Mortality was 8%, 13% and 47% for FX-SH, WD-TBI and CO-TX groups (P < 0.05). TNFα (11/13/139 for FX-SH/WD-TBI/CO-TX; P < 0.05), CCL2 (78/96/227; P < 0.05) and IL-6 (16/48/281; P = 0.05) showed significant increases in the CO-TX group. Lymphocyte populations results for FX-SH, WD-TBI and CO-TX were: CD-4 (31/21/22; P = n.s.), CD-8 (7/28/34, P < 0.05), CD-4-CD-8 (11/12/18; P = n.s.), CD-56 (36/7/8; P < 0.05). Conclusion. This study shows that a combination of closed TBI and femur-fracture/ shock results in an increase of the humoral inflammation. More attention to combined injury models in inflammation research is indicated.
PMCID: PMC3316998  PMID: 22529516
24.  A SNCA Variant Associated with Parkinson’s Disease and Plasma α-Synuclein Level 
Archives of neurology  2010;67(11):1350-1356.
A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson’s disease (PD). There is also increasing evidence that SNPs elsewhere in the gene associate with risk. We sought to further explore the disease association, determine whether evidence of allelic heterogeneity exists, and examine the correlation between PD-associated variants and plasma α-synuclein levels.
We performed a two-tiered analysis of 1,956 PD patients and 2,112 controls from the NeuroGenetics Research Consortium using a comprehensive tagSNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 cases and 78 controls using a highly sensitive Luminex assay.
Five of the 15 SNPs genotyped were associated with PD under an additive model in Tier 1 (α=0.05). Of these, four were successfully replicated in Tier 2. In the combined sample, the most significant marker was rs356219 (OR, 1.41; CI, 1.28–1.55; p = 1.6 × 10−12) located ~ 9 kb downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r2=0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in cases under an adjusted additive model (p = 0.005).
Our data suggest that one or more unidentified functional SNCA variants modify risk for PD, and that the effect is larger than, and independent of, REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.
PMCID: PMC3010848  PMID: 21060011
25.  Safety and Efficacy of Dronedarone in the Treatment of Atrial Fibrillation/Flutter 
Dronedarone is an amiodarone analog but differs structurally from amiodarone in that the iodine moiety was removed and a methane-sulfonyl group was added. These modifications reduced thyroid and other end-organ adverse effects and makes dronedarone less lipophilic, shortening its half-life. Dronedarone has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In addition to its rhythm control properties, dronedarone has rate control properties and slows the ventricular response during AF. Dronedarone is approved in Europe for rhythm and rate control indications. In patients with decompensated heart failure, dronedarone treatment increased mortality and cardiovascular hospitalizations. However, when dronedarone was used in elderly high risk AF/AFl patients excluding such high risk heart failure, cardiovascular hospitalizations were significantly reduced and the drug was approved in the USA for this indication in 2009 by the Food and Drug Administration. Updated guidelines suggest dronedarone as a front-line antiarrhythmic in many patients with AF/Fl but caution that the drug should not be used in patients with advanced heart failure. In addition, the recent results of the PALLAS trial suggest that dronedarone should not be used in the long-term treatment of patients with permanent AF.
PMCID: PMC3201110  PMID: 22084608
dronedarone; atrial fibrillation; amiodarone

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