Un Jung Kang

Elevated GM3 plasma concentration in idiopathic Parkinson’s disease: A lipidomic analysis

Parkinson’s disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the ‘Spot’ study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols. Each lipid species was analyzed using a logistic regression model. The plasma concentrations of two lipid subclasses, triglycerides and monosialodihexosylganglioside (GM3), were different between PD and control participants. GM3 ganglioside concentration had the most significant difference between PD and controls (1.531±0.037 pmol/μl versus 1.337±0.040 pmol/μl respectively; p-value = 5.96E-04; q-value = 0.048; when normalized to total lipid: p-value = 2.890E-05; q-value = 2.933E-03). Next, we used a collection of 20 GM3 and glucosylceramide (GlcCer) species concentrations normalized to total lipid to perform a ROC curve analysis, and found that these lipids compare favorably with biomarkers reported in previous studies (AUC = 0.742 for males, AUC = 0.644 for females). Our results suggest that higher plasma GM3 levels are associated with PD. GM3 lies in the same glycosphingolipid metabolic pathway as GlcCer, a substrate of the enzyme glucocerebrosidase, which has been associated with PD. These findings are consistent with previous reports implicating lower glucocerebrosidase activity with PD risk.

Cerebrospinal fluid, plasma, and saliva in the BioFIND study: Relationships among biomarkers and Parkinson's disease Features

Objective: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms.

Frequency of GBA Variants in Autopsy‐proven Multiple System Atrophy

Multiple system atrophy (MSA) is marked by abnormal inclusions of α‐synuclein in oligodendrogliocytes, and its etiology remains unknown. Variants in the glucocerebrosidase (GBA) gene have been associated with the other synucleinopathies, dementia with Lewy bodies, and Parkinsons disease. It is unclear whether glucocerebrosidase variants are associated with MSA. The objective of this study was to analyze the frequency of GBA variants among patients who had autopsy‐proven MSA at a brain bank in New York City.

Presynaptic striatal dopaminergic depletion predicts the later development of freezing of gait in de novo Parkinson's disease: An analysis of the PPMI cohort

INTRODUCTIONnThe current study was designed to determine whether the degree of presynaptic striatal dopamine depletion can predict the later development of freezing of gait (FOG) in Parkinsons disease (PD).nnnMETHODSnThis retrospective cohort study included 390 de novo patients with PD without FOG at baseline. The participants were divided into tertiles according to the baseline dopamine transporter (DAT) uptake of each striatal subregion, and the cumulative risk of FOG was compared using the Kaplan-Meier method. Cox proportional hazard models were used to assess the predictive power of DAT uptake of striatal subregions for the development of FOG.nnnRESULTSnDuring a median follow-up period of 4.0 years, 143 patients with PD (36.7%) developed FOG. The severe reduction group of DAT uptake in the caudate nucleus and putamen had a significantly higher incidence of FOG than that of the mild and moderate reduction groups. Multivariate Cox regression analyses showed that DAT uptakes in the caudate nucleus (hazard ratio [HR] 0.551; 95% confidence interval [CI] 0.392-0.773; pu202f=u202f0.001) and putamen (HR 0.441; 95% CI 0.214-0.911; pu202f=u202f0.027) predicted the development of FOG. In addition, male sex, higher postural instability and gait difficulty score, and a lower Montreal Cognitive Assessment score were also significant predictors of FOG.nnnCONCLUSIONnOur finding suggests that presynaptic striatal dopaminergic denervation predicts the later development of FOG in de novo patients with PD, which may provide reliable insight into the mechanism of FOG in terms of nigrostriatal involvement.

Comments on the recent viewpoint article on low‐frequency deep brain stimulation for Parkinson's disease

We read with great interest the viewpoint article by Lazzaro di Biase and Alfonso Fasano, which provides a nice summary on the effect of low-frequency stimulation (LFS) when compared with high-frequency stimulation (HFS) on PD symptoms. We appreciate their comments on our randomized, double-blind, prospective, crossover study on the effect of LFS versus HFS on dysphagia, freezing of gait (FOG), and other axial symptoms as summarized in part in their Fig. 1. We agree that “HFS was clearly associated with a significant worsening of axial functions when compared with no stimulation” based on our study conducted in medicated state and the other papers cited, and a meta-analysis study as well showing that the worsening of axial symptoms was found two years after STN DBS during medication on state. Although “there was no statistically significant difference when comparing LFS with no stimulation” in our study, their interpretation “that DBS does not improve swallowing per se” needs to be balanced with the fact that we had limited statistical power, as our study was designed to test the effect of LFS versus HFS, not LFS versus DBS Off. We did find a significant beneficial effect of LFS on axial and total motor scores when compared with the DBS Off state, besides the beneficial effect of LFS compared to HFS on swallowing function and FOG in our study patients. Another important unresolved issue that the authors raised is the correlation of total electric energy delivered (TEED) with clinical efficacy. The adjustment of TEED will bring another variable of “voltage” instead of just “frequency” change. The reduction in the total TEED by “decreased frequency without increasing the voltage” in our study is less likely to have caused the favorable changes observed with LFS, as frequency seems to be a more important variable than total TEED to produce clinical difference. In addition, we evaluated the effect of LFS on FOG with and without adjusting the TEED in a double-blind crossover study and reached the same conclusion on the beneficial effect of LFS on FOG and axial symptoms regardless of the TEED adjustment status (unpublished data). Overall, we agree that LFS should be recommended in STN DBS patients with refractory axial symptoms (particularly FOG) at HFS, as long as tremor does not worsen significantly with LFS because about 15% of the patients had to switch back to HFS for that reason. Whether LFS DBS simply addresses the detrimental effect of HFS DBS or it has beneficial effect by itself requires further studies.

Alpha galactosidase A activity in Parkinson's disease

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinsons Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (nu202f=u202f648) and controls (nu202f=u202f317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85u202fμmol/l/h versus 3.12u202fμmol/l/h, pu202f=u202f0.018; after controlling for batch effect, pu202f=u202f0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89u202fμmol/l/h versus 3.10u202fμmol/l/h, pu202f=u202f0.040; after controlling for batch effect, pu202f=u202f0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, nu202f=u202f155; control, nu202f=u202f194), alpha galactosidase A activity was lower in PD compared to controls (2.77u202fμmol/l/h versus 3.10u202fμmol/l/h, pu202f=u202f0.044; after controlling for a batch effect, pu202f=u202f0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (ORu202f=u202f0.54; 95% CI:0.31-0.95; pu202f=u202f0.032). When LRRK2 G2019S PD carriers (nu202f=u202f37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

Long-term effect of low frequency stimulation of STN on dysphagia, freezing of gait and other motor symptoms in PD

Objective To evaluate the long-term effect of 60u2009Hz stimulation of the subthalamic nucleus (STN) on dysphagia, freezing of gait (FOG) and other motor symptoms in patients with Parkinson’s disease (PD) who have FOG at the usual 130u2009Hz stimulation. Methods This is a prospective, sequence randomised, crossover, double-blind study. PD patients with medication refractory FOG at 130u2009Hz stimulation of the STN were randomised to the sequences of 130u2009Hz, 60u2009Hz or deep brain stimulation off to assess swallowing function (videofluoroscopic evaluation and swallowing questionnaire), FOG severity (stand–walk–sit test and FOG questionnaire) and motor function (Unified PD Rating Scale, Part III motor examination (UPDRS-III)) at initial visit (V1) and follow-up visit (V2, after being on 60u2009Hz stimulation for an average of 14.5 months), in their usual medications on state. The frequency of aspiration events, perceived swallowing difficulty and FOG severity at 60u2009Hz compared with 130u2009Hz stimulation at V2, and their corresponding changes at V2 compared with V1 at 60u2009Hz were set as primary outcomes, with similar comparisons in UPDRS-III and its subscores as secondary outcomes. Results All 11 enrolled participants completed V1 and 10 completed V2. We found the benefits of 60u2009Hz stimulation compared with 130u2009Hz in reducing aspiration frequency, perceived swallowing difficulty, FOG severity, bradykinesia and overall axial and motor symptoms at V1 and persistent benefits on all of them except dysphagia at V2, with overall decreasing efficacy when comparing V2 to V1. Conclusions The 60u2009Hz stimulation, when compared with 130u2009Hz, has long-term benefits on reducing FOG, bradykinesia and overall axial and motor symptoms except dysphagia, although the overall benefits decrease with long-term use. Clinical trial registration NCT02549859; Pre-results.

Reversibility of Tardive Dyskinesia Syndrome

In Response to: Zutshi D, Cloud LJ, Factor SA. Tardive syndromes are rarely reversible after discontinuing dopamine receptor blocking agents: Experience from a university-based movement disorder clinic. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8MS3R8C

Reply To: Detection of Alpha-Synuclein in Saliva: The Importance of Preanalytical Assessment: Alpha-Synuclein in Saliva

We thank Dr. Vivacqua and colleagues for their interest in our article and appreciation of the importance of easily accessible, noninvasive biomarkers such as saliva measures and the potential value of comparing different biological fluids with understand neurodegenerative mechanisms. Here, we address the 3 preanalytical aspects brought up by Vivacqua et al, which are important issues to consider when working with biofluid assays.

Hoehn and Yahr stage 3 and postural stability item in the movement disorder society-unified Parkinson's disease rating scale: H&Y Scale in the MDS-UPDRS

We read with great interest the recent letter by MartinezMartin and colleagues examining clinimetric properties of the Hoehn and Yahr (H&Y) scale in the MDS-UPDRS. It provides much needed validation for this succinct scale widely used for many decades as a critical clinical parameter. We wholeheartedly agree with the authors’ comment that there is lack of specific instructions for homogenous application of the H&Y scale. Specifically, we would like to highlight that the H&Y scale is based on the observed laterality of symptoms and signs of postural instability and gait impairment as key clinical landmark when “the first sign of impaired righting reflex” appears evident by “unsteadiness as the patient turns or is demonstrated when he is pushed from standing equilibrium with the feet together and eyes closed.” The postural stability (PS) item in the MDS-UPDRS records the response to sudden body displacement produced by a quick, forceful pull on the shoulders while the patient is standing erect with eyes open and feet comfortably apart and parallel to each other. A score of 3 on the PS item in the MDS-UPDRS indicates the absence of postural response and is generally considered a significant factor that determines H&Y stage 3 in clinical practice, although there are no formal guidelines. Therefore, we hypothesized that clinical researchers might be grading patients as H&Y stage 3 exclusively based on the observed PS scores indicating the absence of postural response. We examined the medication off-state data from the Parkinson Progression Markers Initiative (PPMI) and The Fox Investigation for New Discovery of Biomarkers (BioFIND) to test this hypothesis. We found that for patients with H&Y stage< 3, only 1 patient had a PS score5 3 in the MDS-UPDRS (Fig. 1). In comparison, for patients