Yun Joong Kim

Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease

Objective: To examine objectively the clinical effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in advanced PD. Methods: Our initial seven consecutive patients with medication-refractory motor fluctuations and levodopa-induced dyskinesias undergoing chronic STN DBS underwent a standardized preoperative evaluation followed by a 2-day double-blind evaluation of efficacy 6 to 12 months after electrode implantation. Diaries documenting motor fluctuations and dyskinesias were also completed preoperatively and postoperatively. Results: In the medication-off state, turning the stimulators on resulted in improvement in mean total Unified Parkinsons Disease Rating Scale (UPDRS) motor score by 58% including the following improvements in composite scores: akinesia 57%, rigidity 52%, tremor 82%, and gait and postural stability 49%. Additionally, the medication-off state improved 17% without stimulation, possibly as a result of electrode insertion alone or carry-over of chronic stimulation. In the medication-on, stimulation-on state, all major features of parkinsonism improved and total UPDRS motor score improved 41% compared with before surgery. Activities of daily living were improved while off medication 30%, and levodopa-induced dyskinesias were reduced 83% while total drug dosage was decreased 40%. With chronic stimulation, patients reported that the percentage of time spent in the on state (without dyskinesias) increased from 26% to 52% and off time decreased from 30% to 6%. Operative complications including cognitive worsening were not uncommon. Conclusions: STN DBS is a promising new surgical option for the treatment of advanced PD. The marked clinical benefits obtained in these severely disabled patients outweighed the adverse effects.

Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis

The Huntingtons disease (HD) mutation is a polyglutamine expansion in the N-terminal region of huntingtin (N-htt). How neurons die in HD is unclear. Mutant N-htt aggregates in neurons in the HD brain; expression of mutant N-htt in vitro causes cell death. Other in vitro studies show that proteolysis by caspase 3 could be important in regulating mutant N-htt function, but there has been no direct evidence for caspase 3-cleaved N-htt fragments in brain. Here, we show that N-htt fragments consistent with the size produced by caspase 3 cleavage in vitro are resident in the cortex, striatum, and cerebellum of normal and adult onset HD brain and are similar in size to the fragments seen after exogenous expression of human huntingtin in mouse clonal striatal neurons. HD brain extracts treated with active caspase 3 had increased levels of N-htt fragments. Compared with the full-length huntingtin, the caspase 3-cleaved N-htt fragments, especially the mutant fragment, preferentially segregated with the membrane fraction. Partial proteolysis of the human caspase 3-cleaved N-htt fragment by calpain occurred in vitro and resulted in smaller N-terminal products; products of similar size appeared when mouse brain protein extracts were treated with calpain. Results support the idea that sequential proteolysis by caspase 3 and calpain may regulate huntingtin function at membranes and produce N-terminal mutant fragments that aggregate and cause cellular dysfunction in HD.

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

BACKGROUNDnBackground The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinsons disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.nnnMETHODSnLRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinsons Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.nnnFINDINGSn121 exonic LRRK2 variants were assessed in 15u2008540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012).nnnINTERPRETATIONnThe results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.nnnFUNDINGnMichael J Fox Foundation and National Institutes of Health.

Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP

It is often difficult to differentiate clinically between Parkinsons disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP).The objective of this work was to investigate whether combined pre‐ and postsynaptic dopaminergic single photon emission computed tomography (SPECT) scanning can reliably demonstrate changes in the nigrostriatal dopaminergic system and help differentiate between normal controls, PD, MSA, and PSP patients. We performed SPECT evaluation of the dopamine transporter (DAT) and dopamine D2 receptors (D2). SPECT scans using [123I]β‐CIT (for DAT) and [123I]IBF (for D2) were performed in 18 patients with PD (12 dopa‐naïve and 6 on levodopa and/or dopamine agonists), 7 with MSA of the striatonigral degeneration type, 6 with PSP, and 29 normal controls. Antiparkinsonian drugs were withheld for at least 12 hours before the scans. DAT and D2 binding potentials (Rv = V3/V2) were measured for caudate, anterior, and posterior putamen on the sides ipsilateral and contralateral to the worst motor symptoms. DAT binding in the posterior putamen was markedly reduced in all patients. However, D2 binding in posterior putamen was significantly increased in dopa‐untreated PD, being greater than the normal range in 4 of 12 (33%), and it was significantly reduced in MSA, being below the normal range in 5 of 7 (71%). None of the patients with PD showed reduced D2 binding below the normal range in posterior putamen. The degree of DAT binding could not discriminate between the patient groups. The ratio of posterior putamen to caudate percentage D2 Rv compared with the controls showed an opposite pattern between PD or PSP and MSA; the caudate was greater in 16 of 18 with PD and 6 of 6 with PSP, whereas caudate was less in 5 of 7 with MSA. These findings suggest that DAT SPECT may be useful in differentiating parkinsonism from controls and D2 SPECT in further differentiating MSA from Parkinsons disease and possibly PSP.

SPECT imaging of pre- and postsynaptic dopaminergic alterations in l-dopa–untreated PD

Background: In PD, presynaptic dopamine transporters are known to be decreased, whereas postsynaptic striatal D2 receptors are proposed to be upregulated. However, the relationship between these alterations is not clear. Objective: To evaluate the ability of SPECT to detect both the pre- and postsynaptic dopaminergic alterations of the striatum in patients with l-dopa–untreated PD. Methods: We studied 10 l-dopa–untreated patients with clinically mild PD and 21 age-matched normal controls. Individuals had both presynaptic [123I]β-CIT dopamine transporter and postsynaptic [123I]IBF D2 SPECT studies 1 week apart. Results: In PD patients, the dopamine transporter binding potential Rv ipsilateral/contralateral to the most affected limbs was 30%/41%, 41%/50%, and 59%/68% lower than controls for caudate, anterior putamen, and posterior putamen, respectively. These bilateral Rv decreases showed a lateralized difference more reduced in the contralateral striatum as well as intrastriatal differences most reduced in the posterior putamen. In contrast, in PD patients the D2 binding potential Rv ipsilateral/contralateral was 15%/16% higher for caudate, 18%/14% higher for anterior putamen, and 28%/31% higher for posterior putamen. These bilateral Rv increases showed no lateralized differences and less marked intrastriatal differences. The motor Unified Parkinson’s Disease Rating Scale scores negatively correlated with dopamine transporter Rv but not with D2 Rv. Conclusions: SPECT imaging can detect characteristic dopaminergic alterations in the striatum of dopa-untreated PD patients including the upregulation of postsynaptic D2 receptors (denervation supersensitivity). SPECT is widely available and is a promising clinical tool to evaluate PD patients.

Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease

Mutations in five PARK genes (SNCA, PARKIN, DJ-1, PINK1, and LRRK2) are well-established genetic causes of Parkinson disease (PD). Recently, G2385R substitution in LRRK2 has been determined as a susceptibility allele in Asian PD. The objective of this study is to determine the frequency of mutations in these PARK genes in a Korean early-onset Parkinson disease (EOPD) cohort. The authors sequenced 35 exons in SNCA, PARKIN, DJ-1, PINK1, and LRRK2 in 72 unrelated EOPD (age-at-onset ≤50) recruited from ten movement disorders clinics in South Korea. Gene dosage change of the aforementioned genes was studied using multiple ligation-dependent probe amplification. We found four patients with PARKIN mutations, which were homozygous deletion of exon 4, compound heterozygous deletion of exon 2 and exon 4, heterozygous deletion of exon 4, and heterozygous nonsense mutation (Q40X). Four patients had PINK1 mutations; a compound heterozygous mutation (N367S and K520RfsX522) and three heterozygous mutations (G32R, R279H, and F385L). A missense mutation of SNCA (A53T) was found in a familial PD with autosomal dominant inheritance. Nine patients (12.5%) had heterozygous G2385R polymorphism of LRRK2, whereas none had G2019S mutation. However, no mutations were detected in DJ-1 and UCHL1 in our series. We identified genetic variants in PARKIN, PINK1, LRRK2, and SNCA as a cause or genetic risk factors for PD in 25% of Korean EOPD, and mutation of PARKIN was the most common genetic cause.

Historical and clinical features of psychogenic tremor: a review of 70 cases.

OBJECTIVESnTo review the clinical characteristics and associated features found in patients with psychogenic tremor.nnnMETHODSnTen-year retrospective review of charts of all patients and videotapes of fifty-one patients diagnosed by the senior author as having psychogenic tremor.nnnRESULTSnSeventy patients fulfilled the diagnostic criteria for clinically definite psychogenic tremors. Psychogenic tremors usually started abruptly (73%), often with the maximal disability at onset (46%), and then took static (46%) or fluctuating (17%) courses. Psychogenic tremors usually started in one limb and spread rapidly to a generalized or mixed distribution. Spontaneous resolution and recurrence, easy distractibility together with entrainment and response to suggestion were characteristic features. Presence of functional symptoms and signs and refractoriness to conventional antitremor drugs were common.nnnCONCLUSIONSnPsychogenic tremor is generally not a diagnosis of exclusion. The presence of characteristic features on history and especially clinical examination can permit an accurate diagnosis and avoid unnecessary investigations.

Lysosomal proteases are involved in generation of N-terminal huntingtin fragments.

N-terminal mutant huntingtin (N-mhtt) fragments form inclusions and cause cell death in vitro. Mutant htt expression stimulates autophagy and increases levels of lysosomal proteases. Here, we show that lysosomal proteases, cathepsins D, B and L, affected mhtt processing and levels of cleavage products (cp) known as A and B, which form inclusions. Adding inhibitors of cathepsin D, B and L to clonal striatal cells reduced mhtt, especially mhtt fragment cp A. Mutant htt fully degraded in cathepsin-L-treated lysates but formed stable N-mhtt fragments upon exposure to cathepsin D. Mutagenesis analysis of htt cDNA suggested that cathepsin D and the protease for cp A may cleave htt in the same region. Brain lysates from HD knock-in mice expressed N-mhtt fragments that accumulated with cathepsin D treatment and declined with aspartyl protease inhibition. Findings implicate lysosomal proteases in formation of N-mhtt fragments and clearance of mhtt.

Klotho is a genetic risk factor for ischemic stroke caused by cardioembolism in Korean females.

An aging-suppressor gene, klotho, is a candidate factor for vascular disease because its deficiency leads to impaired endothelium-dependent vasodilation and impaired angiogenesis. We investigated the association of polymorphisms in klotho with ischemic stroke. We searched for sequence variants in promoter and exons of klotho gene. For the association study, selected variants were genotyped in control subjects and in patients with ischemic stroke and vascular dementia. The association with ischemic stroke was further investigated with its subtypes classified based on Trial of Org 10172 in Acute Stroke Treatment (TOAST). No significant association was observed for both G-395A and C1818T with ischemic stroke and vascular dementia (P>0.05). The analysis with subtypes of ischemic stroke revealed the associations that the A allele of G-395A increased the risk of cardioembolic stroke (CE, OR=2.60; P=0.006), and subjects carrying the A allele were susceptible to CE in both of dominant (AA+GA versus GG; OR=2.50; P=0.046) and recessive (AA versus GA+GG; OR=6.52; P=0.007) models. Further analysis of data partitioned by gender showed that the associations of G-395A with CE only existed in women (A versus G; OR=4.33; P=0.002), AA+GA versus GG; OR=5.68; P=0.014, and AA versus GA+GG; OR=9.07; P=0.012), but the significance disappeared in men (P>0.05). The sequence variant of G-395A in klotho might be a genetic risk factor for CE in females.

Odour identification test and its relation to cardiac 123I‐metaiodobenzylguanidine in patients with drug induced parkinsonism

We investigated olfactory function and its relation to cardiac 123I-metaiodobenzylguanidine (MIBG) uptake in 15 patients with drug induced parkinsonism (DIP). The mean Cross Cultural Smell Identification (CCSI) score was significantly greater in patients with DIP than in those with Parkinson’s disease (PD: 6.9 (1.6) vs 4.4 (2.2); p<0.001); however, the mean CCSI score in patients with DIP was not significantly different from controls. One patient with DIP, whose CCSI score was significantly reduced, also exhibited decreased cardiac MIBG uptake. DIP patients with CCSI scores within the normal range had normal cardiac MIBG uptake. Our study suggests that an olfactory function test may be a useful tool for detecting DIP unrelated to PD and for identifying patients with DIP who have subclinical PD.