Tau Positron Emission Tomography Imaging in Degenerative Parkinsonisms

In recent years, several radiotracers that selectively bind to pathological tau proteins have been developed. Evidence is emerging that binding patterns of in vivo tau positron emission tomography (PET) studies in Alzheimer's disease (AD) patients closely resemble the distribution patterns of known neurofibrillary tangle pathology, with the extent of tracer binding reflecting the clinical and pathological progression of AD. In Lewy body diseases (LBD), tau PET imaging has clearly revealed cortical tau burden with a distribution pattern distinct from AD and increased cortical binding within the LBD spectrum. In progressive supranuclear palsy, the globus pallidus and midbrain have shown increased binding most prominently. Tau PET patterns in patients with corticobasal syndrome are characterized by asymmetrical uptake in the motor cortex and underlying white matter, as well as in the basal ganglia. Even in the patients with multiple system atrophy, which is basically a synucleinopathy, ¹⁸F-flortaucipir, a widely used tau PET tracer, also binds to the atrophic posterior putamen, possibly due to off-target binding. These distinct patterns of tau-selective radiotracer binding in the various degenerative parkinsonisms suggest its utility as a potential imaging biomarker for the differential diagnosis of parkinsonisms.

Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism

OBJECTIVE: Patients with drug-induced parkinsonism (DIP) may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP. METHODS: Forty-one DIP patients were classified into normal and abnormal [¹⁸F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied. RESULTS: Twenty-eight patients had normal (Group I) and 13 patients had abnormal (Group II) scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040). Three patients of Group I and six of Group II had hyposmia (p = 0.018). After drug withdrawal, Group I showed greater improvement in Unified Parkinson's Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity. CONCLUSION: None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP.

Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans

OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. METHODS: We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN). RESULTS: Four subtypes of NBIA including PKAN (n = 30), PLA2G6-related neurodegeneration (n = 2), beta-propeller protein-associated neurodegeneration (n = 1), and aceruloplasminemia (n = 1) have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG). Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN. CONCLUSIONS: We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

Cortical Hypometabolism in Opsoclonus-Myoclonus Syndrome

Opsoclonus-myoclonus syndrome (OMS) is characterized by opsoclonus and arrhythmic myoclonic jerks predominantly involving the trunk, limbs, and head. We present two patients with OMS after respiratory tract infection who exhibited diffuse cerebral hypometabolism, particularly in the parieto-occipital cortex on 18F-fluorodeoxyglucose positron-emission tomography (F-FDG PET). This metabolic change might be a consequence rather than a direct cause of motor symptoms, which may be attributable to brainstem or cerebellar pathology.

Factors Related to Outcomes of Subthalamic Deep Brain Stimulation in Parkinson's Disease

OBJECTIVE: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment of choice for patients with advanced idiopathic Parkinson's disease (PD) who have motor complication with medication. The objectives of this study are to analyze long-term follow-up data of STN DBS cases and to identify the factors related to outcomes. METHODS: Fifty-two PD patients who underwent STN DBS were followed-up for more than 3 years. The Unified Parkinsons Disease Rating Scale (UPDRS) and other clinical profiles were assessed preoperatively and during follow-up. A linear regression model was used to analyze whether factors predict the results of STN DBS. We divided the study individuals into subgroups according to several factors and compared subgroups. RESULTS: Preoperative activity of daily living (ADL) and the magnitude of preoperative levodopa response were shown to predict the improvement in UPDRS part II without medication, and preoperative ADL and levodopa equivalent dose (LED) were shown to predict the improvement in UPDRS part II with medication. In UPDRS part III with medication, the magnitude of preoperative levodopa response was a predicting factor. CONCLUSION: The intensity of preoperative levodopa response was a strong factor for motor outcome. And preoperative ADL and LED were strong factors for ADL improvement. More vigorous studies should be conducted to elucidate how levodopa-induced motor complications are ameliorated after STN DBS.

A Patient with Genetically Confirmed Myoclonus-Dystonia Responded to Anticholinergic Treatment and Improved Spontaneously

BACKGROUND: The various medical treatments applied to myoclonus-dystonia patients with a mutation of the epsilon-sarcoglycan gene (SGCE) have not been beneficial in most cases. Most patients experience progressive deterioration or static clinical courses, with only rare cases of spontaneous remission. CASE REPORT: A 19-year-old girl presented with a 14-year history of myoclonus and dystonia that severely affected her left arm, neck, and trunk. Genetic studies showed a mutation in SGCE [deletion in exon 6 (c.771_772delAT, Cys258X)]. Both myoclonus and dystonia responded to anticholinergic treatment for 7 years and improved spontaneously. CONCLUSIONS: The possibility of spontaneous improvement should be kept in mind when considering the therapeutic strategy in myoclonus-dystonia patients, especially when contemplating deep-brain stimulation.

Scoliosis in Patients with Parkinson's Disease

BACKGROUND AND PURPOSE: Scoliosis is more common in patients with Parkinson's disease (PD) than in the general elderly population. We compared clinical characteristics between PD patients with and without scoliosis, to identify the relationship between the direction of scoliosis and the laterality of the dominant symptoms of PD. We also studied the associations between dopaminergic pharmacotherapy and scoliosis (defined by a spinal curvature deviation of 10 degrees or larger). METHODS: The study population comprised 97 patients (42 men and 55 women) with idiopathic PD. All of the patients submitted to a whole-spine scanograph to allow measurement of the degree of scoliosis by Cobb's method. RESULTS: True scoliosis was found in 32 of the 97 PD patients, and was observed more frequently in women than in men (28 vs. 4, respectively; p=0.006). The age of patients without scoliosis was significantly lower than that of those with scoliosis (66.5+/-9.2 years vs. 72.8+/-7.3 years, respectively, mean+/-SD, p<0.001). There was no correlation between PD symptom laterality and scoliosis. The rate of occurrence of scoliosis did not differ between de novo and levodopa (L-dopa)-treated patients. CONCLUSIONS: We suggest that neither L-dopa treatment nor the laterality of the initial symptoms of PD is related to the appearance of scoliosis.

Trinucleotide Repeats Number in SCA2, SCA3, and SCA17 in Early-Onset Parkinson's Disease

BACKGROUND: Abnormal expansion of trinucleotide repeats in genes causing spinocerebellar ataxias such as SCA2, SCA3, SCA8, or SCA17 was reported in sporadic or familial Parkinson's disease. Genetic factors play an important role especially in early-onset Parkinson's disease (EOPD). To investigate mutations of ATXN2, ATXN3, and TBP as a possible cause in Korean EOPD, we analyzed mutations in these genes. We also investgated the possibility that trinucleotide repeats numbers in these genes contribute to the development of EOPD. METHODS: Mutation analysis of ATXN2, ATXN3, and TBP was done in 153 EOPD defined as age-at-onset before 51. Distribution of CAG repeats numbers were compared between EOPD and age- and sex-matched controls. RESULTS: No patients with EOPD had CAG repeats numbers in ATXN2, ATXN3, and TBP in mutation range. There was no difference in the distribution of CAG repeats between EOPD and controls, although we found a trend that CAG repeats numbers in ATXN3 appear larger in EOPD than in controls. CONCLUSIONS: Mutations of genes causing SCA2, SCA3, or SCA17 may not be a common genetic cause in Korean EOPD.

Three Patients With Classic and Atypical Neurodegeneration With Brain Iron Accumulation

Neurodegeneration with brain iron accumulation (NBIA) is a disorder characterized by various mixtures of extrapyramidal, pyramidal or psychiatric abnormalities associated with iron accumulation in the basal ganglia. The mutations in the pantothenate kinase gene (PANK2) were found in approximately two thirds of the patients with NBIA. We report three patients wtih NBIA, and two of them showed mutations in the PANK2 gene.

Use of the Putamen/Caudate Volume Ratio for Early Differentiation between Parkinsonian Variant of Multiple System Atrophy and Parkinson Disease

BACKGROUND AND PURPOSE: Neuropathological studies have demonstrated that multiple system atrophy (MSA) produces selective atrophy of the putamen with sparing of the caudate nucleus, while both structures are spared in idiopathic Parkinson's disease (PD). In this study we evaluated the clinical efficacy of using putaminal atrophy in brain MRI to differentiate MSA and PD. METHODS: We measured the putamen/caudate volume ratio on brain MRI in 24 patients with MSA and 21 patients with PD. Two clinicians who were blinded to the patients' diagnoses and to each other's assessments measured the volume ratio using a computer program. RESULTS: The measured volume ratios of the two investigators were highly correlated (r=0.72, p<0.0001). The volume ratio was significantly lower in MSA (1.29+/-0.28) than PD (1.91+/-0.29, p<0.0001). Setting an arbitrary cutoff ratio of 1.6 resulted in about 90% of patients with MSA falling into the group with a lower ratio, whereas more than 80% of patients with PD belonged to the other group. CONCLUSIONS: The present results demonstrate that putaminal atrophy in MSA as measured on brain MRI represents an effective tool for differentiating MSA from PD.

Subthalamic Deep Brain Stimulation for Parkinson's Disease

The recent progress in the basic knowledge of basal ganglia pathways and advances in the techniques of the neuroimaging studies enabled subthalamic deep brain stimulation (STN DBS). In Korea, more than three hundreds and fifty patients with PD have been treated with STN DBS since the first trial at March 2000. STN DBS effectively improves all parkinsonian deficits occurring especially during levodopa 'off' period and decreases the daily 'off' time. The daily requirement of levodopa dosage can be reduced to about half of the preoperative one. The favorable responses to the STN DBS can be maintained even after five years. However, parkinsonian deficits during levodopa 'on' period can not be controlled as effectively as those during the levodopa 'off' period. The axial symptoms including gait disturbance and postural instability during the levodopa 'on' period cannot be improved or even are worsen by STN DBS. Patients aged over 70 frequently show less remarkable improvement of parkinsonian deficits than the younger ones. Therefore, selection of appropriate candidate for STN DBS is the most important factor deciding the outcome of the STN DBS.

Parkin Gene Mutation in Korean Patients with Young Age Onset Sporadic Parkinson's Disease

BACKGROUND: Abnormalities of the parkin gene is the most frequently found genetic abnormality in patients with sporadic young age onset of Parkinson's disease (PD). We investigated the frequency of abnormalities of the parkin gene in Korean patients with young age onset PD (YOPD). METHODS: This study included 18 patients (M : F=10:8) who developed PD before the age of 45. DNA was isolated from peripheral blood leukocytes. Exonal deletion and nucleotide sequence changes in the parkin gene was searched by quantitative PCR and sequencing of all coding regions. RESULTS: Only one patient had a heterozygous mutation at the nucleotide position 1473 in exon 12 (A1473C). The remaining 17 patients showed no mutations in the coding region of the parkin gene. In all 18 patients, we could not find any compound heterozygotic as well as homozygotic exonal deletion. The patient who had the heterozygotic point mutation in the parkin gene did not present any clinical features differentiating the patient from the others with YOPD. The frequency of parkin mutation in patients with YOPD in our series was 5.6 percent. CONCLUSIONS: In Korean patients with YOPD, the frequency of parkin mutation seems to be lower than that of other ethnic groups. Further studies with a larger number of patients with YOPD are needed to support this suggestion.

The Quantitative 18-fluorodeoxyglucose PET Study in the Differential Diagnosis between Idiopathic Parkinson's Disease and Multiple System Atrophy

BACKGROUND: Overlapping clinical features of idiopathic Parkinson's disease (IPD) and multiple system atrophy (MSA) make it difficult to conduct an accurate differential diagnosis. We performed a quantitative F18- fluorodeoxyglucose PET (FDG PET) and measured the striatal and cerebellar glucose metabolism to evaluate the efficacy of a FDG PET study in the differential diagnosis between IPD and MSA. METHODS: This study included 19 patients with IPD, 28 patients with MSA (MSA-P : MSA-C = 19 : 9) and 12 age matched normal controls. A FDG PET study was performed in all subjects and the original PET image was corrected with the radioactivity curve obtained by repetitive sampling of the radial arterial blood. RESULTS: The measurements of striatal and cerebellar glucose metabolisms of the patients with MSA-P were significantly lower than those of the patients with IPD (P<0.001). However, the measurement of the caudate nucleus provided the most reliable clue for the differential diagnosis between IPD and MSA-P (sensitivity 94.7% and specificity 94.7%). In the patients with MSA-C, the glucose metabolism of the cerebellar vermis (P<0.001), cerebellar cortex (P<0.001) and putamen (P<0.05) was significantly lower than those of the patients with IPD. CONCLUSIONS: Quantitative FDG PET is a useful and reliable method in making a differential diagnosis between IPD and MSA.

Efficacy and Safety of Entacapone in the Patients with Parkinson's Disease Experiencing Wearing-off Phenomenon: Multicenter Randomized Placebo-controlled Double Blind Study

BACKGROUND: The purpose of this study was to assess the efficacy and safety of entacapone, a catechol-O-methyltransferase (COMT) inhibitor in Parkinson's disease (PD) patients with wearing-off phenomenon. METHODS: A total of 197 PD patients were included in this 2-month multi-center, randomized, placebo-controlled, double blind, parallel-group study. After a 2-week screening period, each patient was randomly allocated to receive either entacapone (n=98) or placebo (n=99) as an adjunct to levodopa. The efficacy was evaluated with the changes of "on" and "off" time percentage while awake, the reduction of the levodopa dose, Unified Parkinson's Disease Rating Scale (UPDRS), and the clinical global impression (CGI) by the examiner. RESULTS: The percentage of "on" time increased by 9.4 +/- 18.0% in the entacapone group, 7.4 +/- 15.6% in the placebo group. The percentage of "off" time was reduced by 8.6 +/- 16.9% in the entacapone group, 6.6 +/- 18.2% in the placebo group. These parameters did not show a statistical significance between the two groups. However, the levodopa dose was significantly reduced in the entacapone group (51.6 +/- 154.5 mg/day) compared with the placebo group (0.7 +/- 130.0 mg/day) (p=0.009). The total and motor scores of the UPDRS were significantly decreased in the entacapone group (p=0.039, p=0.017, respectively). The most common adverse drug reactions in the entacapone group were urine discoloration (22%), dyskinesia (13%), dizziness (7%). CONCLUSIONS: Entacapone was a safe and well-tolerated drug. Although the changes of "on" and "off" time were not significant, entacapone showed an overall significant beneficial effect in the PD patients with wearing-off phenomenon.

Inadequate Efficacy of Deep Brain Stimulation in a Patient with Parkinson's disease due to Partial Breakage of Electrode Lead

A patient with Parkinson's disease developed fluctuation in the deep brain stimulation (DBS) effect, an unpleasant left facial paresthesia and the left limb dystonia. Impedance of the right DBS was over 2000 ohm in three proximal contacts. Skull X-ray studies showed partial breakage of right electrode lead below the mastoid process. Partial electrode breakage must be considered when there is a deterioration of the DBS effect, an unexpected side effect of DBS, and an alteration of impedance.

Effects of Subthalamic Nucleus Deep Brain Stimulation on the Phonation and Articulation of the Patients with Parkinson's Disease

BACKGROUND: The purpose of this study was to investigate the effects of the subthalamic nucleus (STN) deep brain stimulation (DBS) on the phonation and articulation of patients with Parkinson's disease (PD). METHODS: Seven PD patients who underwent bilateral STN DBS were included. The patients were asked to make and sustain the vowel sounds /a/ and /i/ as long as possible and to repeat nonsense syllables, /pa/, /ta/, /ka/ and /pataka/ as quickly as possible for 3 seconds. When the patients were administered levodopa `on' and `off' treatments, we evaluated the effect of DBS on the maximum phonation time (MPT), jitter (pitch perturbation), shimmer (intensity perturbation), tremor index and diadochokinetic rate (DDK). In each condition, using a Unified Parkinson's Disease Rating Scale score, we also measured the motor disability of the patients. RESULTS: During levodopa `off', both the DBS and levodopa treatment caused significant prolongation of the MPT of the vowels /a/ and /i/. Acoustic analysis showed that DBS had an effect on shimmer only when the patients were levodopa `off'. At the articulatory level, no significant changes were found in the diadochokinetic rate under any conditions. However, there was a correlation between the amount of improvement of voice tremor and sum of UPDRS scores measuring `tremor at rest' and `postural tremor'. CONCLUSIONS: In patients with advanced PD, STN DBS improves phonation, but had limited effects on articulation.

Measurements of Brain Stem and Cerebellum on Brain MRI: for the Differential Diagnosis Between Multiple System Atrophy and Idiopathic Parkinson's Disease

BACKGROUND: Multiple system atrophy (MSA) and idiopathic Parkinson's disease (IPD) are two common neurodegenerative disorders presenting with parkinsonism. Since a brain MRI study is an available method for differentiating MSA from IPD, we tried to find further values of brain MRI studies in differentiating MSA from IPD. METHODS: We measured anteroposterior and transverse diameters (AD and TD, respectively) of the brain stem of T2-weighted axial images. We graded the severity of atrophy (grade 0: none; grade 1: mild; grade 2: moderate; and grade 3: severe) of cerebellar vermis and hemispheres on the midsagittal and parasagittal planes. RESULTS: There were 36 patients with probable MSA and 40 patients with IPD. We calculated a parameter multiplying AD of the midbrain by TD of the midbrain. The mean of the AD x TD of the midbrain was 1007.5 +/- 161.8 mm2 in patients with MSA, and it was significantly smaller than that of those with IPD (1113.3 +/- 118.7 mm2). When the cut off value was decided as 1050 mm2, the sensitivity of the parameter for the diagnosis of MSA was 83.3% and specificity was 80%. The frequency of cerebellar atrophy was 72.2% in patients with MSA, and it was significantly higher than that of those with IPD (37.5%). CONCLUSIONS: Measurements of the brain stem, particularly the midbrain, and cerebellum areas on brain MRI are helpful methods for the differential diagnosis of patients with MSA from those with IPD.

A Case of Spinocerebellar Ataxia Type 7 with Torticollis

The spinocerebellar ataxia type 7 is an autosomal dominant neurodegenerative disorder with expansion of unstable CAG trinucleotide repeats in a gene on chromosome 3p, and is classified as autosomal dominant cerebellar ataxia type II. Extrapyramidal findings are uncommonly recognized in autosomal dominant cerebellar ataxia type II. A 27-year-old woman showed progressive ataxia, visual disturbance and torticollis. We report a case of genetically confirmed spinocerebellar ataxia type 7 with extrapyramidal finding.

A Familial Case of Myoclonus-Dystonia

BACKGROUND: Myoclonus-dystonia is a rare familial disease characterized by autosomal dominant inheritance, nonor slowly progressive axial myoclonus combined with dystonic posture, normal electroencephalography (EEG) finding, and dramatic response to alcohol intake. METHODS: Clinical manifestations were studied in a family with myoclonus-dystonia. Response to alcohol intake was investigated in affected adult patients. Brain magnetic resonance imaging (MRI) and other laboratory examination were performed in 3 patients. RESULTS: Eight (male: 5, female: 3) of the 14 biological family members through 4 generations were found to be affected by myoclonus-dystonia on neurological examinations. Another 5 members (male: 3, female: 2) were suspected to be affected in family history. All eight affected members showed axial myoclonus affecting the neck, trunk, and proximal muscles of the limbs. Six of them also had dystonia affecting the neck or the distal part of the arm. Myoclonus and dystonia were ameliorated dramatically after small dose of alcohol intake. Brain MRI, EEG study, and ophthalmologic examination showed no abnormalities. CONCLUSIONS: Our patients showed clinical features compatible with myoclonus-dystonia. This is the first Korean family with myoclonus-dystonia.

The Effect of Subthalamic Nucleus Stimulation in Patients with Advanced Idiopathic Parkinson's Disease

BACKGROUND: To determine the efficacy and safety of subthalamic nucleus (STN) stimulation in patients with advanced Parkinson's disease (PD). METHODS: In 5 patients with PD, we evaluated the effect of bilateral STN stimula-tion. Using the Unified PD Rating Scale (UPDRS), Clinical Dyskinesia Rating Scale, Activities of Daily Living(ADL) Score and patient's diary, we evaluated the patients before and at one, three and 12 months after surgery. We examined the patients while they were drug "off" and "on". RESULTS: While patients were "off", stimulation induced a signifi-cant reduction in the UPDRS part III score by 46% at 12 months after the operation, compared to the baseline state. During drug "on" state, levodopa-induced dyskinesias were reduced by 88% at 12 months after the operation. Off-peri-od dystonia was reduced by 45% at 12 months after the operation. ADL scores also improved after the stimulation. Patients' diaries showed significant reduction in the "off" period while awake (73% reduction at 12 months). The daily dose of levodopa was reduced by 56% at 12 months after the operation. There was no significant complication related to the surgical procedure or electrical stimulation. CONCLUSIONS: We conclude that STN stimulation is an effective and safe treatment strategy for the patients with advanced PD.