Han Soo Yoo

Repeated thrombolytic therapy in patients with recurrent acute ischemic stroke.

Background and Purpose Widespread use of thrombolytic treatments, along with improved chances of survival after an initial ischemic stroke, increases the possibility of repeated thrombolysis. There are few reports, however, regarding repeated thrombolysis in patients who have suffered acute ischemic stroke. We explored the number and outcome of patients with repeated thrombolytic therapy in the era of multimodal thrombolytic treatments. Methods We investigated patients with acute ischemic stroke who had received thrombolytic treatments for a period of 10 years. Number of thrombolysis was determined in each patient. Recanalization was defined as Thrombolysis in Cerebral Infarction grading ≥2a. Symptomatic hemorrhagic transformation was defined as any increase in the National Institutes of Health Stroke Scale score that could be attributed to intracerebral hemorrhage. A good outcome was defined as a modified Rankin scale score ≤2. Results Of the 437 patients who received thrombolytic treatments, only 7 underwent repeated thrombolysis (1.6%). The median age at the time of repeated thrombolytic therapy was 71 years old; 4 of the patients were female. All patients had 1 or more potential sources of cardiac embolism. Recanalization was achieved in all patients, in both the first and the second thrombolysis. No symptomatic intracranial hemorrhage occurred after repeated thrombolytic treatments. Five patients (71.4%) showed good outcomes at 3 months. Conclusions Repeated thrombolysis for recurrent acute ischemic stroke appears to be safe and feasible. Among patients who experience recurrent acute ischemic stroke, thrombolytic therapy could be considered even if the patient has had previous thrombolytic treatments.

Patterns of Neuropsychological Profile and Cortical Thinning in Parkinson’s Disease with Punding

Background Punding, one of dopamine replacement treatment related complications, refers to aimless and stereotyped behaviors. To identify possible neural correlates of punding behavior in patients with Parkinson’s disease (PD), we investigated the patterns of cognitive profiles and cortical thinning. Methods Of the 186 subjects with PD screened during the study period, we prospectively enrolled 10 PD patients with punding and 43 without punding on the basis of a structured interview. We performed comprehensive neuropsychological tests and voxel-based and regions-of-interest (ROIs)-based cortical thickness analysis between PD patients with and without punding. Results The prevalence of punding in patients with PD was 5.4%. Punding behaviors were closely related to previous occupations or hobbies and showed a temporal relationship to changes of levodopa-equivalent dose (LED). Significant predisposing factors were a long duration of PD and intake of medications of PD, high total daily LED, dyskinesia, and impulse control disorder. Punding severity was correlated with LED (p = 0.029). The neurocognitive assessment revealed that PD patients with punding showed more severe cognitive deficits in the color Stroop task than did those without punding (p = 0.022). Voxel-based analysis showed that PD-punders had significant cortical thinning in the dorsolateral prefrontal area relative to controls. Additionally, ROI-based analysis revealed that cortical thinning in PD-punders relative to PD-nonpunders was localized in the prefrontal cortices, extending into orbitofrontal area. Conclusions We demonstrated that PD patients with punding performed poorly on cognitive tasks in frontal executive functions and showed severe cortical thinning in the dorsolateral prefrontal and orbitofrontal areas. These findings suggest that prefrontal modulation may be an essential component in the development of punding behavior in patients with PD.

Early-onset drug-induced parkinsonism after exposure to offenders implies nigrostriatal dopaminergic dysfunction

Objectives The onset of parkinsonism in patients with drug-induced parkinsonism (DIP) exhibits extensive individual variability following exposure to offending drugs. We investigated whether the individual variations in the onset time of parkinsonism reflected the underlying subtle dopaminergic dysfunction in DIP. Methods We enrolled 71 patients with DIP who had visually normal striatal dopamine transporter (DAT) availability in 18F-FP-CIT positron emission tomography scans. According to their exposure durations to the offending drugs prior to onset of the parkinsonism, the patients were divided into the early-onset group (duration ≤6 months; n=35) and delayed-onset group (duration >6 months; n=36). We performed the quantitative analysis of the DAT availability in each striatal subregion between the groups. Results No patients with DIP had DAT availability that was more than 2 SD below the normal mean of DAT availability. Compared with the delayed-onset group, the early-onset DIP group had decreased DAT availability in the striatal subregions including the posterior putamen (p=0.018), anterior putamen (p=0.011), caudate (p=0.035) and ventral striatum (p=0.027). After adjusting for age, sex and cross-cultural smell identification test scores, a multivariate analysis revealed that the DAT availability in the striatal subregions of the patients with DIP was significantly and positively associated with the natural logarithm of the duration of drug exposure. Conclusions These results suggest that a short exposure to the offending drugs before the development of parkinsonism would be associated with subtle nigrostriatal dopaminergic dysfunction in patients with DIP.

Sleep Disturbance May Alter White Matter and Resting State Functional Connectivities in Parkinson’s Disease

Study Objectives To clarify whether sleep disturbance would alter the patterns of structural and functional networks underlying cognitive dysfunction in patients with Parkinsons disease (PD). Methods Among the 180 patients with nondemented PD in our cohort, 45 patients were classified as the group with sleep disturbance according to the 5-item scales for outcomes in Parkinsons disease nighttime scale. Based on propensity scores, another 45 PD patients without sleep disturbance were matched to this group. We performed a comparative analysis of cortical thickness, diffusion tensor imaging-based white matter integrity, resting-state functional connectivity, and cognitive performance between PD patients with and without sleep disturbance. Results PD patients with sleep disturbance showed poorer performance in attention and working memory and a tendency toward a lower score in frontal executive function relative to those without sleep disturbance. The PD with sleep disturbance group exhibited widespread white matter disintegration compared to the PD without sleep disturbance group, although there were no significant differences in cortical thickness between the PD subgroups. On functional network analysis, PD patients with sleep disturbance exhibited less severely decreased cortical functional connectivity within the default mode network, central executive network, and dorsal attention network when compared to those without sleep disturbance. Conclusions The present study suggests that sleep disturbance in PD patients could be associated with white matter and functional network alterations in conjunction with cognitive impairment.

A Case of Isolated Middle Cerebral Artery Stenosis with Hemichorea and Moyamoya Pattern Collateralization

Isolated middle cerebral artery (MCA) stenosis in young patients with no other medical condition may be a unique pathologic entity with a benign long-term course. Generally, moyamoya disease shows a progression of stenosis from internal cerebral artery (ICA) to other intracranial vessel. A 26-year-old woman was admitted for choreic movements of the right arm and leg. Brain magnetic resonance imaging showed no stroke. Conventional angiography revealed 48% stenosis of the left M1 without ICA stenosis. Single photon emission computed tomography revealed perfusion asymmetry after acetazolamide injection, suggesting decreased uptake in the left basal ganglia and the cerebral cortex. Her hemichorea was mildly decreased with risperidone. One year later, follow-up angiography showed complete occlusion of the left M1 with neovascularization suggestive of moyamoya disease. The patient underwent bypass surgery and her hemichorea disappeared. This may be an atypical presentation of moyamoya disease. The bypass surgery was an effective measure for restoring the vascular insufficiency and, resultantly, controlling her hemichorea.

Effect of striatal dopamine depletion on cognition in de novo Parkinson's disease

INTRODUCTION To investigate the relationship between the sub-regional pattern of striatal dopamine depletion and cognitive impairment in early-stage Parkinsons disease (PD), and determine the effect of striatal dopamine density on cognitive prognosis. METHODS Patients with drug-naïve non-demented PD were divided into mild cognitive impairment (PD-MCI; n = 129) and cognitively normal (PD-CogN; n = 182) groups. Using quantification of the dopamine transporter (DAT) availability in each striatal sub-region with 18F-FP-CIT PET scans, we performed inter-group comparative analysis of DAT availability and multivariate linear regression analysis to assess the association between DAT availability and cognitive performance. Additionally, the effect of baseline DAT availability on the cognitive decline across time as well as on changes in the cognitive status was estimated. RESULTS The PD-MCI group exhibited more severely decreased DAT availability in all the striatal sub-regions compared to the PD-CogN group, although there was no significant difference in PD duration. The DAT availability in the caudate, anterior putamen, and ventral striatum was directly associated with attention/working memory, frontal/executive, and visuospatial functions, while the DAT availability of the posterior putamen was not. However, the baseline DAT availability of the striatal sub-regions did not influence the cognitive decline or cognitive status in the longitudinal cognitive assessment. CONCLUSION Our results suggest that striatal DAT availability may determine MCI in patients with de novo PD. Dopamine loss in the associative and limbic striatum is closely linked to cognitive deficits in early-stage PD, although it does not affect cognitive prognosis.

Detrimental effect of type 2 diabetes mellitus in a large case series of Parkinson's disease

INTRODUCTION To investigate the effect of diabetes mellitus (DM) on the clinicoradiological features in patients with Parkinsons disease (PD). METHODS 671 patients with de novo PD were classified into two groups according to the presence of DM (106 with DM and 565 without). We performed inter-group comparative analyses of the striatal dopamine transporter (DAT) availability in all patients and level of cognitive performances in 312 patients (58 with DM and 254 without). Neuroimaging analyses of cortical thickness were performed in 42 patients with DM and 42 matched patients without DM. We assessed the longitudinal changes in the levodopa-equivalent dose (LED) across time in 549 patients who were treated for at least two years (86 with DM and 463 without) using a linear mixed model. RESULTS The PD patients with DM were older at the onset of parkinsonism and had more severely decreased baseline DAT availability in the caudate and ventral striatum than those without DM. The PD group with DM showed poorer performances in attention/working memory and frontal/executive function than the group without DM. Cortical thinning in the right inferomedial temporal lobe was observed in PD with DM group relative to PD without DM group. During follow-up, the PD patients with DM showed a more rapid longitudinal increase in LED than those without DM. CONCLUSION Our results suggest that coexistent DM may have a detrimental effect on disease progression as well as baseline striatal dopamine loss, brain structural alterations, and cognitive performances in patients with PD.

A Novel Heterozygous ANO3 Mutation with Basal Ganglia Dysfunction in a Patient with Adult-Onset Isolated Segmental Dystonia

Dear Editor, Mutations of ANO3 have recently been found to cause isolated dystonia (DYT24, MIM 615034), predominantly involving the craniocervical area, with the age at onset ranging from childhood to the sixth decade of life. This report describes a Korean patient with segmental dystonia caused by a novel variant c.860G>A (p.Arg287Gln) in ANO3 (NM_031418.3 and NP_113606.2), with brain PET showing basal ganglia (BG) dysfunction. A 60-year-old left-handed woman presented with abnormal posture in her left arm and the neck that had first appeared 6 years previously. She had not taken any medication that can cause dystonia, and there was no family history of tremor or dystonia (Fig. 1A). A neurological examination showed an abnormal posture with slow and large-amplitude jerky tremors in her left arm. She also exhibited mild left torticollis combined with retrocollis arm (Supplementary Video 1 in the online-only Data Supplement). Brain MRI produced normal findings. Brain 18F-fluorodeoxyglucose (18F-FDG) PET showed increased uptake in the right putamen, with decreased uptake in the right subthalamic nucleus (STN) (Fig. 1B). Next-generation sequencing using a targeted panel of 93 genes for dystonia identified a novel heterozygous missense variant (a G to A substitution at position 860 of ANO3; transcript ID: ENST00000256737) that resulted in the replacement of an arginine residue by a glutamine residue at position 287 of the anoctamin 3 protein (p.Arg287Gln). This variant was confirmed by Sanger sequencing (Fig. 1C). The arginine residue at codon 276 is in the cytoplasmic domain of ANO3, which is highly conserved throughout evolution (Fig. 1D). The in silico prediction algorithms UMD-Predictor (http://umd-predictor.eu/) and MutationTaster2 (http://www.mutationtaster.org/) predicted that this missense mutation was pathogenic and disease-causing, respectively. The Combined Annotation-Dependent Depletion tool (CADD, version 1.3; http://cadd.gs.washington.edu/) produced a score of 34.0. No mutations were detected in other genes known to cause dystonia. The guidelines of the American College of Medical Genetics and Genomics classify p.Arg287Gln of ANO3 as a variant of uncertain significance. The ANO3 variant in the present patient is possibly causative for DYT24 for the following reasons: First, the patient presented with segmental dystonia similar to findings in previous published dystonia cases with ANO3 mutations (Supplementary Table 1 in the online-only Data Supplement). Second, in silico analyses of this novel variant have predicted that this mutation is pathogenic. To date, 17 missense mutations and 1 in-frame insertion mutation in ANO3 have been reported as possible variants causing DYT24 (Supplementary Table 1 in the online-only Data Supplement). The CADD score of p.Arg276Gln is equal to the highest score of previously reported mutations. Third, this mutation has not been reported in patients with dystonia or in large public databases such as gnomAD, ExAC, and 1,000 Genomes Project. Han Soo Yoo Hyunjoo Lee Seok Jong Chung Jin-Sung Lee Sang-Kyoon Hong Phil Hyu Lee Yun Joong Kim Young Ho Sohn Hae-Won Shin

A NOMOGRAM FOR PREDICTING AMYLOID PET POSITIVITY IN AMNESTIC MILD COGNITIVE IMPAIRMENT

load (participants with positive versus negative brain amyloid load) will be determined. Results:Hyperspectral retinal imaging will be completed for the remaining n1⁄440 participants, aged 60 years and above. Data will be analysed via image processing and preliminary findings presented at the conference. Conclusions:Successful validation of hyperspectral retinal imaging will serve as an early, non-invasive and economical diagnostic tool for preclinical AD.

Olfactory dysfunction in Alzheimer's disease– and Lewy body–related cognitive impairment

Olfactory dysfunction is common in Alzheimers disease– and Lewy body–related disorders, but its neural correlates have not been clearly elucidated.