Faculty Bibliography

Mutations in glucocerebrosidase (GBA) are a common risk factor for Parkinson's disease (PD). The scavenger receptor class B member 2 (SCARB2) gene encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome. Two common SNPs in linkage disequilibrium with SCARB2, rs6812193 and rs6825004, have been associated with PD and Lewy Body Disease in genome wide association studies. Whether these SNPs are associated with altered glucocerebrosidase enzymatic activity is unknown. Our objective was to determine whether SCARB2 SNPs are associated with PD and with reduced GCase activity. The GBA gene was fully sequenced, and the LRRK2 G2019S and SCARB2 rs6812193 and rs6825004 SNPs were genotyped in 548 PD patients and 272 controls. GCase activity in dried blood spots was measured by tandem mass spectrometry. We tested the association between SCARB2 genotypes and PD risk in regression models adjusted for gender, age, and LRRK2 G2019S and GBA mutation status. We compared GCase activity between participants with different genotypes at rs6812193 and rs6825004. Genotype at rs6812193 was associated with PD status. PD cases were less likely to carry the T allele than the C allele (OR=0.71; p=0.004), but GCase enzymatic activity was similar across rs6812193 genotypes (C/C: 11.88 μmol/l/h; C/T: 11.80 μmol/l/h; T/T: 12.02 μmol/l/h; p=0.867). Genotype at rs6825004 was not associated with either PD status or GCase activity. In conclusion, our results support an association between SCARB2 genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity.

BACKGROUND:Identifying PD-specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well-characterized, clinically typical, moderate to advanced PD cohorts is critically needed. METHODS:BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross-sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites. RESULTS:We present the study methodology and data on the cohort's clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined off and on states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from off state PD assessments and from controls. CONCLUSION:Our cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson's Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD's broad and heterogeneous spectrum. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

BACKGROUND/OBJECTIVES/OBJECTIVE:The clinical diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) remains challenging due to heterogeneity of the diseases. AIMS/OBJECTIVE:Here we compared the clinical features of PSP and MSA to gain insight into their diagnosis and prognosis, particularly the prognostic value of down-gaze palsy latency in PSP progression. METHODS:We reviewed clinical features of pathologically confirmed 10 PSP and 13 MSA patients, incidentally matched in age-at-onset, gender, and disease duration, followed at Columbia University Medical Center during 1994-2009. RESULTS:The final antemortem diagnosis was incorrect in 30% of PSP (all lacking down-gaze palsy) and 23% of MSA patients. Falls in the first year of the disease, pyramidal involvement and freezing of gait during the course were similar between PSP and MSA. Ataxia and apraxia were in 50% of the PSP patients. Parkinsonism responsive to levodopa treatment was in 30% of the PSP (all with resting tremor) and 50% of the MSA patients. Dysautonomia in MSA could occur as early as 3 years preceding the motor symptoms, with 46% within the first year of the motor onset, but 15% did not have dysautonomia in life. The latency of down-gaze palsy and urogenital dysfunction and MMSE scores at first visit in PSP, and the latency of falls and wheelchair confinement in MSA were all associated with the disease progression. CONCLUSIONS:We confirmed most of the previously published characterizations, and identified for the first time the prognostic value of down-gaze palsy latency in PSP progression.

Dr. Stanley Fahn, the H. Houston Merritt Professor of Neurology and Director Emeritus of the Center for Parkinson's Disease and Other Movement Disorders at Columbia University, one of the founders of the field of movement disorders, was the first president of the Movement Disorders Society (subsequently renamed as the International Parkinson and Movement Disorder Society). Together with his friend and colleague, Professor David Marsden, he also served as the first co-editor of the journal Movement Disorders. By emphasizing phenomenology as the key element in differentiating various hypokinetic and hyperkinetic movement disorders, Dr. Fahn drew attention to the clinical history and the power of observation in the diagnosis of movement disorders. Dr. Fahn had major influence on the development of classifications and assessments of various movement disorders and in organizing various research groups such as the Parkinson Study Group. As the founder and president of the World Parkinson Coalition and an organizer of the initial three World Parkinson Congresses, he has demonstrated his long-standing commitment to the cause of including patients as partners. The primary goal and objective of this invited review is to highlight some of Dr. Fahn's most impactful scientific and clinical contributions to the understanding and treatment of Parkinson's disease, dystonia, and other movement disorders.

OBJECTIVES/OBJECTIVE:To study whether 60-Hz stimulation, compared with routine 130 Hz, improves swallowing function and freezing of gait (FOG) in patients with Parkinson disease (PD) who undergo bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). METHODS:We studied 7 patients with PD who experienced FOG that persisted despite routine 130-Hz stimulation and dopaminergic medication. Each patient received 3 modified barium swallow (MBS) studies in a single day under 3 DBS conditions in the medication-on state: 130 Hz, 60 Hz, or DBS off, in a randomized double-blind manner. The laryngeal penetration and aspiration events were cautiously assessed, and a swallowing questionnaire was completed. The Unified Parkinson's Disease Rating Scale, Part III motor score, axial subscore, tremor subscore, and FOG by a questionnaire and stand-walk-sit test were also assessed. The best DBS condition (60 Hz here) producing the least FOG was maintained for 3 to 8 weeks, and patients were assessed again. Changes in measurements between the 60 Hz and 130 Hz were analyzed using paired t test, with swallowing function as primary and the remainder as secondary outcomes. Changes between other DBS conditions were further explored with Bonferroni correction. RESULTS:Compared with the routine 130 Hz, 60-Hz stimulation significantly reduced aspiration frequency by 57% on MBS study and perceived swallowing difficulty by 80% on questionnaire. It also significantly reduced FOG, and axial and parkinsonian symptoms. The benefits at 60-Hz stimulation persisted over the average 6-week assessment. CONCLUSIONS:Compared with the routine 130 Hz, the 60-Hz stimulation significantly improved swallowing function, FOG, and axial and parkinsonian symptoms in patients with PD treated with bilateral STN-DBS, which persisted over the 6-week study period. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class IV evidence that for patients with PD who experience FOG, STN-DBS at 60 Hz decreases aspiration events observed during MBS compared with DBS at 130 Hz.

INTRODUCTION/BACKGROUND:α-Synuclein (α-syn) is a key protein in Parkinson's disease (PD), and one of its phosphorylated forms, pS129, is higher in PD patients than healthy controls. However, few studies have examined its levels in longitudinally collected cerebrospinal fluid (CSF) or in preclinical cases. In this study, CSF and clinical data were contributed by >300 subjects from three cohorts (the longitudinal DATATOP cohort, a large cross-sectional cohort, and a cohort of LRRK2 mutation carriers). RESULTS:Consistent with our previous observation that CSF pS129 positively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) scores, CSF pS129 in the DATATOP cohort increased over approximately two years of disease progression (mean change 5.60 pg/ml, p = 0.050). Intriguingly, in the DATATOP cohort, pS129 negatively correlated with UPDRS scores at the baseline (R = -0.244, p = 0.017), but not final point, suggesting that this association may depend on disease stage. Reanalysis of our previous cohort with stratification by PD stage, and addition of a cohort of LRRK2 mutation carriers with very early/preclinical PD, supported the idea that the relationship between CSF pS129 and disease severity over a wider range of PD stages might be represented with a U-shaped curve, in which lower pS129 levels correlated with worse clinical condition at early stages, but better condition at later stages. CONCLUSION/CONCLUSIONS:The observation of a negative-to-positive transition of correlation of pS129 to disease severity as PD progresses could have profound impact on how pS129 is used as a biomarker clinically as well as in modeling PD experimentally.

Current therapies for treating movement disorders such as Parkinson's disease are effective but limited by undesirable and intractable side effects. Developing more effective therapies will require better understanding of what causes basal ganglia dysregulation and why medication-induced side effects develop. Although basal ganglia have been extensively studied in the last decades, its circuit anatomy is very complex, and significant controversy exists as to how the interplay of different basal ganglia nuclei process motor information and output. We have recently identified the importance of an underappreciated collateral projection that bridges the striatal output direct pathway with the indirect pathway. These bridging collaterals are extremely plastic in the adult brain and are involved in the regulation of motor balance. Our findings add a new angle to the classical model of basal ganglia circuitry that could be exploited for the development of new therapies against movement disorders. In this Scientific Perspective, we describe the function of bridging collaterals and other recent discoveries that challenge the simplicity of the classical basal ganglia circuit model. We then discuss the potential implication of bridging collaterals in the pathophysiology of Parkinson's disease and schizophrenia. Because dopamine D2 receptors and striatal neuron excitability have been found to regulate the density of bridging collaterals, we propose that targeting these projections downstream of D2 receptors could be a possible strategy for the treatment of basal ganglia disorders. © 2015 International Parkinson and Movement Disorder Society.