Beomseok Jeon

Re: Alpha-synuclein gene duplication is present in sporadic Parkinson disease.

Objective: α-Synuclein gene (SNCA) multiplication was found in familial Parkinson disease (PD). We examined SNCA multiplication in patients with familial and sporadic PD and multiple system atrophy (MSA). Methods: We screened 1,106 patients with parkinsonism (PD = 906, MSA = 200) for SNCA multiplication by multiplex PCR. Fluorescent in situ hybridization was done to confirm the multiplication. [123I]N-ω-Fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)-tropane ([123I]FP-CIT) SPECT was done in the patients with SNCA multiplication and their family members. Results: Three patients were identified as having SNCA duplication. One patient had a positive family history, and two patients were sporadic. Each patient had asymptomatic carriers in their families. The familial case had early onset parkinsonism with rapidly progressive course, cognitive impairment, and dysautonomia. Sporadic cases were more typical of PD. [123I]FP-CIT SPECT was abnormal in the patients and normal in the asymptomatic carriers. Conclusion: SNCA multiplication is present in sporadic Parkinson disease (PD) and needs to be screened. Low penetrance, clinical heterogeneity, and normal dopamine transporter imaging in asymptomatic carriers may suggest the presence of other genetic modifiers or environmental triggers that play a role in the pathogenesis of PD due to SNCA duplication.

Dopamine transporter imaging with [123I]-beta-CIT demonstrates presynaptic nigrostriatal dopaminergic damage in Wilson's disease.

OBJECTIVES The most common neurological manifestations in Wilson’s disease are parkinsonism and dystonia. These are assumed to be due to striatal injury, which has been repeatedly demonstrated by pathology and CT or MRI. The substantia nigra has not been shown to be damaged in pathological studies. However, there have been clinical and imaging studies suggesting presynaptic nigrostriatal injury. (1r)-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) is a specific ligand that binds to the dopamine transporter (DAT), and can examine the integrity of dopaminergic nerve terminals. Evidence for presynaptic nigrostriatal dopaminergic damage in Wilson’s disease was searched for using [123I]-β-CIT SPECT. METHODS Six patients with Wilson’s disease were studied, together with 15 healthy normal controls, and six patients with Parkinson’s disease. After injection of [123I]-β-CIT, SPECT studies were done at 18 hours. Specific striatal/occipital binding ratio (S/O ratio) was calculated as (striatal binding−occipital binding)/occipital binding. RESULTS The specific S/O ratios were 6.22 (1.32) (mean (SD)) in normal volunteers, 3.78 (0.65) in Parkinson’s disease, and 3.60 (0.49) in Wilson’s disease. CONCLUSION There was severe loss of the DAT in the striatum suggesting significant damage in presynaptic nigrostriatal dopaminergic nerve terminals. Therefore, a presynaptic lesion may contribute to neurological manifestations in Wilson’s disease.

Dopamine transporter density is decreased in parkinsonian patients with a history of manganese exposure: What does it mean?

Manganese (Mn) exposure can cause parkinsonism. Pathological changes occur mostly in the pallidum and striatum. Two patients with a long history of occupational Mn exposure presented with Mn‐induced parkinsonism. In one patient, magnetic resonance imaging (MRI) showed findings consistent with Mn exposure, and Mn concentration was increased in the blood and urine. However, this patients clinical features were typical of idiopathic Parkinson disease (PD). Previous pathological and positron emission tomography studies indicate that striatal dopamine transporter density is normal in Mn‐induced parkinsonism, whereas it is decreased in PD. Therefore, we performed [123I]‐(1r)‐2β‐carboxymethoxy‐3β‐(4‐iodophenyl)tropane ([123I]‐β‐CIT) single‐photon emission computed tomography. Severe reduction of striatal β‐CIT binding was indicated, which is consistent with PD. We propose three interpretations: (1) the patients have PD, and Mn exposure is incidental; (2) Mn induces selective degeneration of presynaptic dopaminergic nerve terminals, thereby causing parkinsonism; or (3) Mn exposure acts as a risk of PD in these patients. Our results and careful review of previous studies indicate that the axiom that Mn causes parkinsonism by pallidal lesion may be over‐simplified; Mn exposure and parkinsonism may be more complex than previously thought. Further studies are required to elucidate the relationship between Mn and various forms of parkinsonism.

Pantothenate kinase-associated neurodegeneration in Korea: recurrent R440P mutation in PANK2 and outcome of deep brain stimulation

Background and Purpose:  The purpose of this study was to evaluate the mutation status of PANK2 among Korean patients with pantothenate kinase‐associated neurodegeneration (PKAN) and to document the outcome of pallidal deep brain stimulation (DBS).

Loss of substantia nigra hyperintensity on 7 Tesla MRI of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy

BACKGROUND Seven Tesla (7T) MRI can visualize anatomical alterations occurring in a hyperintense structure of the substantia nigra in Parkinsons disease (PD). OBJECTIVE We investigated whether 7T MRI can detect the loss of substantia nigra hyperintensity in patients with PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). METHODS Using 7T MRI, we evaluated 26 healthy subjects, 30 patients with PD, 7 patients with MSA, and 3 patients with PSP. Two blinded readers independently assessed the images. We carried out a comparative analysis of five patients with hemiparkinsonism via (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ((123)I-FP-CIT) SPECT. RESULTS 7T MRI revealed a definitive shape of nigral hyperintensity in healthy subjects, nearly identical to neuropathological characterization of nigrosome 1, and enabled instantaneous determination of its presence or absence in all subjects. Nigral hyperintensity was lost in all patients with PD, MSA with predominant parkinsonism, and PSP. One of five patients with MSA with predominant cerebellar ataxia showed an intact nigral hyperintensity. The side effects were mild and tolerable, and imaging was successful in patients with dyskinesia. Motion artifact incidence was higher in elderly subjects. In hemiparkinsonism cases, we observed partial loss of nigral hyperintensity on the side of less reduced (123)I-FP-CIT binding, suggesting an ongoing iron deposition on the unaffected side in hemiparkinsonism. CONCLUSIONS The present findings suggest that 7T MRI represents an excellent tool for evaluating nigral hyperintensity in PD, MSA, and PSP, with tolerable side effects and limited motion artifacts. Thus, imaging of parkinsonism may benefit from using 7T MRI.

Mutant COQ2 in multiple-system atrophy.

To the Editor: Tsuji and colleagues (July 18 issue)1 report that variants in the gene encoding coenzyme Q2 (COQ2) increase the risk of multiple-system atrophy. They observed homozygous COQ2 variants encoding the substitutions M78V and V343A in a consanguineous Japanese family with multiple-system atrophy subtype P and noted an association between V343A and sporadic multiple-system atrophy (minor-allele frequency [MAF], 4.8% of cases vs. 1.6% of controls; odds ratio, 3.05; 95% confidence interval, 1.65 to 5.85). However, the authors erroneously labeled human COQ2 variability from the fourth ATG start codon in exon 1, which encodes the smallest protein isoform and does not functionally complement the yeast coq2-null mutant.2 On the basis of the National Center for Biotechnology Information (NCBI) Reference Sequence (NM_015697.7), M78V should be labeled COQ2 c.382A→G (p.M128V) and V343A should be labeled c.1178T→C (p.V393A). We sequenced COQ2 in 299 Korean persons with multiple-system atrophy and 365 unaffected Korean persons and observed heterozygous COQ2 c.320G→C (encoding p.S107T) and c.382A→T (encoding p.M128R) in 2 patients with sporadic multiple-system atrophy; COQ2 c.1178T→C (p.V393A) was not associated with multiple-system atrophy (MAF, 2.7% of cases vs. 2.6% of controls). It is a challenge to reconcile recessive linkage of homozygous COQ2 mutations in familial multiple-system atrophy with a heterozygous, presumably dominant-negative association in sporadic multiple-system atrophy. Respectfully, we suggest that Tsuji and colleagues reconsider whether variations in COQ2 represent a risk factor for multiple-system atrophy. Genomic multiplications of the SNCA 6.4-Mb locus telomeric to COQ2 have previously been implicated in parkinsonism and multiple-system atrophy3; copy number analysis of linked loci, or genomewide analysis, should be considered.

Loss of Nigral Hyperintensity on 3 Tesla MRI of Parkinsonism: Comparison With 123I‐FP‐CIT SPECT

The aim of this study was to investigate whether 3 Tesla susceptibility‐weighted imaging can detect the alteration of substantia nigra hyperintensity in Parkinsons disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) and to assess the concordance between the loss of nigral hyperintensity on 3 Tesla susceptibility‐weighted imaging and the nigrostriatal dopaminergic degeneration indicated by 123I‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐N‐(3‐fluoropropyl)‐nortropane single photon emission computerized tomography.

Unusual neurological presentations of vitamin B12 deficiency

Vitamin B12 deficiency (B12D) has a wide variety of neurological symptoms and signs. However, cerebellar dysfunction and cranial neuropathies other than optic neuropathy have been rarely reported. Herein, we describe two cases of unusual neurological manifestations of B12D. One patient showed prominent hoarseness with vocal cord paralysis, myelopathy, and peripheral neuropathy. The other had gait disturbance, lateral gaze limitation and cerebellar dysfunction in addition to the typical manifestations of subacute combined degeneration. Vitamin B12 deficiency can rarely affect cerebellum and cranial nerves other than optic nerve.

Classification of Parkinson gait and normal gait using Spatial-Temporal Image of Plantar pressure

The purpose of this paper is the classification of Spatial-Temporal Image of Plantar pressure (STIP) among normal step and the patients step of Parkinson disease. For this, we created a new image data, STIP, that have information of the change of plantar pressure during heel to toe motion (i.e., contain spatial and temporal information for plantar pressure). To get STIP, the walking of 21 patients with Parkinson disease and 17 age-matched healthy subjects were recorded and analyzed using in-shoe dynamic pressure measuring system with comfort walking. For feature extraction of gait, we applied Principal component analysis (PCA) to STIP and calculated weights of STIP on each principal components. Then, we build hard margin Support Vector Machine (SVM) classifier for gait recognition and test of generalization performance using normalized weights on PCs of STIP. SVM result indicated an overall accuracy of 91.73% by the RBF(Radial Basis Function) kernel function. These results demonstrate considerable potential in applying SVMs in gait classification for many applications.The purpose of this paper is the classification of Spatial-Temporal Image of Plantar pressure (STIP) among normal step and the patients step of Parkinson disease. For this, we created a new image data, STIP, that have information of the change of plantar pressure during heel to toe motion (i.e., contain spatial and temporal information for plantar pressure). To get STIP, the walking of 21 patients with Parkinson disease and 17 age-matched healthy subjects were recorded and analyzed using in-shoe dynamic pressure measuring system with comfort walking. For feature extraction of gait, we applied Principal component analysis (PCA) to STIP and calculated weights of STIP on each principal components. Then, we build hard margin Support Vector Machine (SVM) classifier for gait recognition and test of generalization performance using normalized weights on PCs of STIP. SVM result indicated an overall accuracy of 91.73% by the RBF(Radial Basis Function) kernel function. These results demonstrate considerable potential in applying SVMs in gait classification for many applications.

The G2019S LRRK2 mutation is rare in Korean patients with Parkinson's disease.

BACKGROUND A number of causative mutations such as alpha-synuclein, parkin, UCHL1, Pink-1, DJ-1 have been identified in Parkinsons disease (PD). They are usually found in the familial cases. One mutation of great interest is the G2019S mutation in the LRRK2 gene, which has been reported in both familial and sporadic PD. Its prevalence has been reported to vary markedly among different races. We examined the prevalence of the G2019S mutation in the Korean PD population for genetic study planning. METHODS We conducted a genetic analysis of the G2019S mutation by standard PCR and restriction digestion method. 453 PD patients were studied, 34% of whom had an age at onset of < 50 years and 3.8% had a positive family history. RESULTS None of the 453 study subjects carried the G2019S mutation. CONCLUSIONS Our result confirms previous reports that the G2019S mutation is rare among PD patients in the Asian population. This result supports the notion that the prevalence of this LRRK2 mutation is population specific, and that there may be a founder effect within western populations.