Pan-Woo Ko

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.

Non-Invasive Screening for Alzheimer's Disease by Sensing Salivary Sugar Using Drosophila Cells Expressing Gustatory Receptor (Gr5a) Immobilized on an Extended Gate Ion-Sensitive Field-Effect Transistor (EG- ISFET) Biosensor

Body fluids are often used as specimens for medical diagnosis. With the advent of advanced analytical techniques in biotechnology, the diagnostic potential of saliva has been the focus of many studies. We recently reported the presence of excess salivary sugars, in patients with Alzheimer’s disease (AD). In the present study, we developed a highly sensitive, cell-based biosensor to detect trehalose levels in patient saliva. The developed biosensor relies on the overexpression of sugar sensitive gustatory receptors (Gr5a) in Drosophila cells to detect the salivary trehalose. The cell-based biosensor was built on the foundation of an improved extended gate ion-sensitive field-effect transistor (EG-ISFET). Using an EG-ISFET, instead of a traditional ion-sensitive field-effect transistor (ISFET), resulted in an increase in the sensitivity and reliability of detection. The biosensor was designed with the gate terminals segregated from the conventional ISFET device. This design allows the construction of an independent reference and sensing region for simultaneous and accurate measurements of samples from controls and patients respectively. To investigate the efficacy of the cell-based biosensor for AD screening, we collected 20 saliva samples from each of the following groups: participants diagnosed with AD, participants diagnosed with Parkinson’s disease (PD), and a control group composed of healthy individuals. We then studied the response generated from the interaction of the salivary trehalose of the saliva samples and the Gr5a in the immobilized cells on an EG-ISFET sensor. The cell-based biosensor significantly distinguished salivary sugar, trehalose of the AD group from the PD and control groups. Based on these findings, we propose that salivary trehalose, might be a potential biomarker for AD and could be detected using our cell-based EG-ISFET biosensor. The cell-based EG-ISFET biosensor provides a sensitive and direct approach for salivary sugar detection and may be used in the future as a screening method for AD.

Astrocyte‐derived lipocalin‐2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia

Lipocalin‐2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post‐tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2‐deficient mice, compared with wild‐type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood–brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1‐neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF‐1α–LCN2–VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.

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.

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.

Frontal Assessment Battery and Cerebrospinal Fluid Tap Test in Idiopathic Normal-Pressure Hydrocephalus

Background and Purpose: Our aim in this study was to assess whether the frontal assessment battery (FAB) could contribute to the differential diagnosis of cerebrospinal fluid tap test (CSFTT) responders and nonresponders with the hypothesis that CSFTT nonresponders had greater frontal lobe dysfunction. We also explored whether a relationship exists between FAB scores and gait disturbance in idiopathic normal-pressure hydrocephalus (INPH) patients. Methods: INPH subjects were selected in a consecutive order from a prospectively enrolled INPH registry. Fifty-one INPH patients constituted the final sample for analysis. Results: Logistic regression analysis using the FAB score as independent variable showed a significant influence of the FAB on the differential diagnosis of CSFTT responders and nonresponders (p = 0.025; OR 1.186; 95% CI 1.022-1.377). The FAB scores were negatively correlated with the Timed Up and Go test score (r = -0.382; p = 0.007), 10-meter walking test score (r = -0.351; p = 0.014), Gait Status Scale score (r = -0.382; p = 0.007), and INPH Grading Scale gait score (r = -0.370; p = 0.009). Conclusions: Our findings may indicate a possibility for considering FAB scores in patients with ventriculomegaly as potential cognitive markers for the prediction of CSFTT response. Association between gait function and FAB scores suggests the involvement of similar circuits producing gait symptom and frontal lobe functions in INPH.

Diffusion tensor metrics as biomarkers in idiopathic normal-pressure hydrocephalus

patients and care plan altered in 22 patients). A positive PET scan resulted in change of management plans (either medication, care, or both) nine times more often than a negative PET scan (n1⁄461 vs. n1⁄47; p<0.001). For 43 (22%) patients, additional ancillary investigations were planned after PET results were disclosed, predominantly when PET results were negative (n1⁄433; p<0.001). In patients with a pre-PET AD diagnosis and a positive PET scan, additional ancillary investigations were less often requested compared to patients with a negative PET scan (p<0.001). Conclusions: [F]Flutemetamol PET increased physician’s overall confidence in clinical diagnosis. In addition, it altered diagnostic work-up and healthcare management plan of young onset dementia patients visiting a tertiary memory clinic.