Kyunghun Kang

Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test

Cerebrospinal fluid (CSF) biomarkers, including soluble amyloid β-42 (Aβ-42) and phosphorylated-tau (P-tau), reflect core pathophysiological features of Alzheimers disease (AD). AD is frequently a concomitant pathology in older patients with idiopathic normal-pressure hydrocephalus (iNPH), and somewhat similar altered CSF dynamics exist in both AD and iNPH. We therefore investigated relationships between lumbar CSF biomarkers Aβ-42 and P-tau and clinical parameters in iNPH patients, along with differences in these biomarkers between CSF tap test (CSFTT) responders and non-responders. Thirty-one iNPH patients (14 CSFTT responders and 17 CSFTT non-responders) were included in the final analysis. We found lower CSF Aβ-42 correlated with poor cognitive performance (r=0.687, p<0.001 for Korean Mini Mental State Examination; r=0.568, p=0.001 for Frontal Assessment Battery; r=-0.439, p=0.014 for iNPH grading scale [iNPHGS] cognitive score; r=-0.588, p=0.001 for Clinical Dementia Rating Scale), and lower CSF P-tau correlated with gait dysfunction (r=-0.624, p<0.001 for Timed Up and Go Test; r=-0.652, p<0.001 for 10meter walking test; r=-0.578, p=0.001 for Gait Status Scale; r=-0.543, p=0.002 for iNPHGS gait score). In subgroup analysis, CSF P-tau/Aβ-42 ratios were significantly higher in CSFTT non-responders compared to responders (p=0.027). Two conjectures are suggested. One, CSF biomarkers may play different and characteristic roles in relation to different iNPH symptoms such as cognition and gait. Two, comorbid AD pathology in iNPH patients may affect the response to the CSFTT. Larger studies using combinations of other biomarkers associated with AD would be necessary to evaluate these hypotheses.

Prevalence and Related Factors for High-Risk of Obstructive Sleep Apnea in a Large Korean Population: Results of a Questionnaire-Based Study

Background and Purpose A population-based door-to-door study of cross-sectional methods for assessing the prevalence and factors related to a high risk of obstructive sleep apnea (OSA) was conducted using the Korean version of the Berlin Questionnaire (K-BQ). Methods Pooled data collected from Community Health Surveys by the Korea Center for Disease Control and Prevention were analyzed. Of 8,140 respondents from the population, 7,955 were finally included in this study. Results Of the 7,955 included subjects, 15.7% of the men and 9.8% of the women were at high risk of OSA. Significant differences were found in the following factors between the subjects with a high risk of OSA: gender, age, marital status, educational level, occupation, and presence of smoking, harmful alcohol use, and chronic diseases. Male sex, harmful alcohol use, and the presence of chronic diseases were identified as factors independently associated with a high risk of OSA. Conclusions This is the first study to confirm the usefulness of the K-BQ to study the prevalence of OSA in the Korean general population. The findings demonstrate that harmful alcohol use and chronic diseases are very common characteristics among those with a high risk of OSA.

Idiopathic normal-pressure hydrocephalus, cortical thinning, and the cerebrospinal fluid tap test

When considering the underlying pathophysiological mechanisms involved in idiopathic normal pressure hydrocephalus (iNPH), white matter is often the main locus of investigation. However, when an axon in the brain is damaged, degeneration of the neuron can occur proximally (dying back) and Alzheimers disease (AD), associated with cortical thinning, is a common pathologic comorbidity with iNPH. We investigated differences in cortical thickness between CSF tap test (CSFTT) responders and non-responders in iNPH patients and compared patterns of cortical thickness in iNPH patients with that of AD patients. Thirty-two iNPH patients (16 CSFTT responders and 16 CSFTT non-responders) and 16 AD patients were imaged with MRI, including 3-dimensional volumetric images for cortical thickness analysis across the entire brain. Among the iNPH patients, CSFTT non-responders, when compared to responders, had statistically significant cortical thinning in the left superior frontal gyrus at the level of a false discovery rate (FDR) p<0.05, and tended to show widespread cortical thinning in most areas of the brain. Relative to the CSFTT responders, AD patients showed statistically significant cortical thinning in superior and medial frontal gyrus, left precentral gyrus, postcentral gyrus, paracentral lobule, precuneus, and superior parietal lobule after FDR correction (p<0.05). However, comparing patterns of cortical thinning between AD patients and CSFTT non-responders revealed no statistically significant differences. Differences in cortical thickness correlated with CSFTT response for iNPH patients may indicate a possibility for considering patterns of cortical thinning in patients with ventriculomegaly as potential brain imaging markers for the prediction of CSFTT responders. And, our findings suggest that comorbid AD pathology might be related to the cortical thinning patterns found in CSFTT non-responders. Larger studies, using normal controls and combinations of other biomarkers associated with AD, would be necessary to evaluate these hypotheses.

Asymmetric and Upper Body Parkinsonism in Patients with Idiopathic Normal-Pressure Hydrocephalus.

Background and Purpose Our aims were to analyze the characteristics of parkinsonian features and to characterize changes in parkinsonian motor symptoms before and after the cerebrospinal fluid tap test (CSFTT) in idiopathic normal-pressure hydrocephalus (INPH) patients. Methods INPH subjects were selected in consecutive order from a prospectively enrolled INPH registry. Fifty-five INPH patients (37 males) having a positive response to the CSFTT constituted the final sample for analysis. The mean age was 73.7±4.7 years. The pre-tap mean Unified Parkinsons Disease Rating Scale motor (UPDRS-III) score was 24.5±10.2. Results There was no significant difference between the upper and lower body UPDRS-III scores (p=0.174). The parkinsonian signs were asymmetrical in 32 of 55 patients (58.2%). At baseline, the Timed Up and Go Test and 10-meter walking test scores were positively correlated with the total motor score, global bradykinesia score, global rigidity score, upper body score, lower body score, and postural instability/gait difficulties score of UPDRS-III. After the CSFTT, the total motor score, global bradykinesia score, upper body score, and lower body score of UPDRS-III significantly improved (p<0.01). There was a significant decrease in the number of patients with asymmetric parkinsonism (p<0.05). Conclusions In the differential diagnosis of elderly patients presenting with asymmetric and upper body parkinsonism, we need to consider a diagnosis of INPH. The association between gait function and parkinsonism severity suggests the involvement of similar circuits producing gait and parkinsonian symptoms in INPH.

Diffusion tensor imaging of idiopathic normal-pressure hydrocephalus and the cerebrospinal fluid tap test.

We evaluated relationships between diffusion tensor imaging (DTI) findings and clinical profiles in idiopathic normal-pressure hydrocephalus (INPH) patients, along with differences in DTI parameters between cerebrospinal fluid tap test (CSFTT) responders and non-responders. Fifty-four INPH patients constituted the final group for analysis. Fractional anisotropy (FA), axial diffusivity, radial diffusivity, and mean diffusivity were assessed using atlas-based tract-mapping methods on 20 different fiber tracts. Uncorrected results revealed that CSFTT non-responders, when compared to responders, exhibited lower FA in the left anterior thalamic radiation (ATR), left cingulum-hippocampus (CgH), and left inferior fronto-occipital fasciculus (IFO) and higher axial diffusivity, radial diffusivity, and mean diffusivity in the left CgH and left inferior longitudinal fasciculus (ILF). FA values in the ATR (bilateral), corticospinal tract (right), IFO (bilateral), and ILF (bilateral) were negatively correlated with Unified Parkinsons Disease Rating Scale motor scores. In the right CgH, FA values showed significant positive correlations with Korean-Mini Mental State Examination scores and negative correlations with Clinical Dementia Rating Scale scores. Our findings may suggest a possibility for considering microstructural changes of white matter in patients with ventriculomegaly as potential imaging markers for the prediction of CSFTT responders. Unique patterns of white matter microstructural changes, as measured using DTI, might underlie impairments in distinct symptom domains in patients with INPH.

Unusual idiopathic normal pressure hydrocephalus patient with marked asymmetric and upper body parkinsonism

Asymmetry of parkinsonian symptoms is strong evidence toward the diagnosis of Parkinsons disease (PD). Lower body parkinsonism is characteristic in idiopathic normal pressure hydrocephalus (INPH). We report an unusual INPH patient with marked asymmetric and upper body parkinsonism. An 83-year-old man presented with gait impairment and asymmetric clumsiness of movement. According to the Unified Parkinsons Disease Rating Scale (UPDRS), the motor subscore was 12 in the left limb and 8 in the right. The score was 14 for both the upper and lower body. After the cerebrospinal fluid tap test (CSFTT), he showed marked improvement in the upper body score. A loss of asymmetry of parkinsonian signs, with greater improvement in the left limb, was presented. Fluorinated N-3-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)-nortropane (F-18 FP-CIT) positron emission tomography (PET) imaging was normal. In the differential diagnosis of elderly patients presenting with parkinsonism compatible with PD, we might need to consider a diagnosis of INPH.

Abnormal White Matter Integrity in Elderly Patients with Idiopathic Normal-Pressure Hydrocephalus: A Tract-Based Spatial Statistics Study

We investigated white matter integrity utilizing diffusion tensor imaging in patients with idiopathic normal-pressure hydrocephalus (INPH) who had a positive response to the cerebrospinal fluid tap test and in age- and gender-matched Alzheimers disease (AD) patients. We enrolled 28 patients with INPH, 28 patients with AD and 20 healthy controls. Tract-based spatial statistics demonstrated that INPH patients had lower fractional anisotropy (FA) in the anterior corona radiate (bilateral), corpus callosum, superior longitudinal fasciculus (bilateral), posterior thalamic radiation (bilateral), external capsule (bilateral) and middle cerebellar peduncle in comparison with the AD and control groups. Volume-of-interest analysis revealed that INPH patients, when compared to the AD and control groups, showed higher mean diffusivity in the anterior corona radiate (bilateral), corpus callosum, superior longitudinal fasciculus (bilateral), posterior thalamic radiation (left), external capsule (bilateral) and middle cerebellar peduncle. And gait dysfunction was significantly correlated with decreased FA in the splenium of the corpus callosum and right external capsule in INPH patients. Our findings may suggest a possibility for considering microstructural changes in white matter integrity in elderly patients as potential imaging markers for differentiation between INPH and AD and may help us understand the potential pathophysiology of gait disturbances associated with INPH.

Lateral Ventricle Enlargement and Cortical Thinning in Idiopathic Normal-pressure Hydrocephalus Patients

We utilized three-dimensional, surface-based, morphometric analysis to investigate ventricle shape between 2 groups: (1) idiopathic normal-pressure hydrocephalus (INPH) patients who had a positive response to the cerebrospinal fluid tap test (CSFTT) and (2) healthy controls. The aims were (1) to evaluate the location of INPH-related structural abnormalities of the lateral ventricles and (2) to investigate relationships between lateral ventricular enlargement and cortical thinning in INPH patients. Thirty-three INPH patients and 23 healthy controls were included in this study. We used sparse canonical correlation analysis to show correlated regions of ventricular surface expansion and cortical thinning. Significant surface expansion in the INPH group was observed mainly in clusters bilaterally located in the superior portion of the lateral ventricles, adjacent to the high convexity of the frontal and parietal regions. INPH patients showed a significant bilateral expansion of both the temporal horns of the lateral ventricles and the medial aspects of the frontal horns of the lateral ventricles to surrounding brain regions, including the medial frontal lobe. Ventricular surface expansion was associated with cortical thinning in the bilateral orbitofrontal cortex, bilateral rostral anterior cingulate cortex, left parahippocampal cortex, left temporal pole, right insula, right inferior temporal cortex, and right fusiform gyrus. These results suggest that patients with INPH have unique patterns of ventricular surface expansion. Our findings encourage future studies to elucidate the underlying mechanism of lateral ventricular morphometric abnormalities in INPH patients.

Wilson’s disease: a reversible cause of ataxia

Dear Editor, Patients with adult-onset progressive ataxia present a diagnostic challenge because there are several disease categories that may manifest with ataxia including toxicity, immunemediated conditions, vitamin deficiencies, infectious diseases, degenerative disorders, and genetic conditions [1]. The accurate diagnosis of ataxia is also complicated by the limitations of the investigative strategies. Most diseases that cause progressive ataxia are untreatable and progressive. For all of these reasons, clinicians often do not make the effort to reach an exact diagnosis. However, some causes of secondary ataxia can be treated, and treatment often inhibits progression of the ataxia. Therefore, clinicians need to be able to differentiate causes of secondary ataxia. We evaluated a 57-year-old man who presented with a 2year history of a progressive gait disturbance. He also complained of progressive worsening of both slurred speech and a hand tremor. He had been diagnosed with sporadic adult-onset cerebellar ataxia at another tertiary medical center 1 year prior and visited our neurology clinic to confirm the diagnosis. On neurologic examination, he had slightly staccato, slurred speech. His upper and lower limbs exhibited ataxia but had normal tone, power, and sensation. He displayed mild parkinsonism, including bradykinesia and cogwheel rigidity of both upper extremities. He had obvious difficulties with gait and could not walk without assistance. He did not complain of any difficulty performing activities of daily living other than walking. His initial Scale for the Assessment and Rating of Ataxia (SARA) score was 16.5. Magnetic resonance imaging (MRI) of the brain showed obvious cerebellar atrophy and a subtle hyperintense signal in the pons on T2weighted imaging (Fig. 1). Imaging using fluoroPropylCarbomethoxylodopropyl-nor-B-Tropane (18F) positron emission tomography (FP-CIT PET) showed even distribution of dopamine uptake in both striatum. Serologic and cerebrospinal fluid investigation for infection and metabolic or malignant causes was unremarkable. A genetic panel, including spinocerebellar ataxia testing, showed no mutations. However, slit lamp examination revealed Kayser-Fleischer rings on both corneas. The patient also had a low serum ceruloplasmin level (< 3.0 mL/dL) and high urine copper excretion (392.3 μg/24 h). The final diagnosis was Wilson’s disease manifesting as ataxia with parkinsonism. The patient was treated with penicillamine, 1000 mg daily. After 6 months of treatment, he still had a subtle ataxic gait but showed a dramatic improvement in balance, and he was able to walk without assistance. His follow-up SARA score was 9. Ataxia can be seen in a variety of conditions. When a patient complains of progressive ataxia, the clinician usually follows a defined diagnostic flow because of the complex differential diagnosis [2]. A detailed history of present illness and a neurologic examination are the initial steps in the workup. It is also important to obtain a detailed family history to evaluate for hereditary causes such as spinocerebellar ataxia, Friedreich’s ataxia, and fragile X-associated tremor-ataxia syndrome. If a patient has a suspicious family history or symptoms, or if the patient is young at the onset of symptoms, clinicians should perform genetic and biochemical testing to evaluate for a hereditary ataxia syndrome. However, the most challenging diagnostic situation is when ataxia symptoms arise after 40 years of age, when almost the entire spectrum of hereditary and acquired causes of ataxia needs to be investigated. Because the workup is extremely complicated and expensive and involves an enormous number of diagnostic tests, clinicians usually perform only selected tests to arrive at a probable or possible diagnosis. This strategy is supported by the fact that most diseases that cause ataxia do not have definitive treatment that can improve the ataxia. We were able to focus on finding a rare disease mimicking cerebellar ataxia * Ho-Won Lee neuromd@knu.ac.kr

Amyloid Deposits and Idiopathic Normal-Pressure Hydrocephalus: An 18 F-Florbetaben Study

Background: The first aim of our study was to determine whether cortical 18F-florbetaben retention was different between healthy controls and idiopathic normal-pressure hydrocephalus (INPH) patients. Our second aim was to investigate whether there were any relationships between 18F-florbetaben retention and either hippocampal volume or clinical symptoms in INPH patients. Methods: Seventeen patients diagnosed with INPH and 8 healthy controls underwent studies with magnetic resonance imaging and 18F-florbetaben positron emission tomography imaging. Results: Automated region-of-interest analysis showed significant increases in 18F-florbetaben uptake in several brain regions in INPH patients compared to control subjects, with especially remarkable increases in the frontal (bilateral), parietal (bilateral), and occipital (bilateral) cortices. In the INPH group, right hippocampal volume was found to be negatively correlated with right frontal 18F-florbetaben retention. Korean-Mini Mental State Examination scores negatively correlated with right occipital 18F-florbetaben retention. Higher 18F-florbetaben retention correlated significantly with a higher Clinical Dementia Rating Scale score in the right occipital cortex. Conclusions: Our results indicate that INPH might be a disease exhibiting a characteristic pattern of cortical 18F-florbetaben retention. 18F-florbetaben retention in the frontal cortex may be related to hippocampal neuronal degeneration. Our findings may also help us understand the potential pathophysiology of cognitive impairments associated with INPH.