Promising Blood Biomarkers for Clinical Use in Alzheimer’s Disease: A Focused Update

Alzheimer’s disease (AD) is the most-common cause of neurodegenerative dementia, and it is characterized by abnormal amyloid and tau accumulation, which indicates neurodegeneration. AD has mostly been diagnosed clinically. However, ligand-specific positron emission tomography (PET) imaging, such as amyloid PET, and cerebrospinal fluid (CSF) biomarkers are needed to accurately diagnose AD, since they supplement the shortcomings of clinical diagnoses. Using biomarkers that represent the pathology of AD is essential (particularly when disease-modifying treatment is available) to identify the corresponding pathology of targeted therapy and for monitoring the treatment response. Although imaging and CSF biomarkers are useful, their widespread use is restricted by their high cost and the discomfort during the lumbar puncture, respectively. Recent advances in AD blood biomarkers shed light on their future use for clinical purposes. The amyloid β (Aβ)42/Aβ40 ratio and the concentrations of phosphorylated tau at threonine 181 and at threonine 217, and of neurofilament light in the blood were found to represent the pathology of Aβ, tau, and neurodegeneration in the brain when using automatic electrochemiluminescence technologies, single-molecule arrays, immunoprecipitation coupled with mass spectrometry, etc. These blood biomarkers are imminently expected to be incorporated into clinical practice to predict, diagnose, and determine the stage of AD. In this review we focus on advancements in the measurement technologies for blood biomarkers and the promising biomarkers that are approaching clinical application.We also discuss the current limitations, the needed further investigations, and the perspectives on their use.

The Change in Circadian Rhythms in P301S Transgenic Mice is Linked to Variability in Hsp70-related Tau Disaggregation

Circadian disruption often involves a neurodegenerative disorder, such as Alzheimer’s disease or frontotemporal dementia, which are characterized by intraneuronal tau accumulations. The altered sleep pattern and diurnal rhythms in these disorders are the results of tau pathology. The circadian disturbance in reverse is thought to develop and potentially aggravate the condition. However, the underlying mechanism is not fully understood. In this study, perturbed oscillations in BMAL1, the core clock gene, were observed in P301S tau transgenic mice. Tau fractionation analysis of the hippocampus revealed profound fluctuations in soluble and insoluble tau protein levels that were in opposite directions to each other according to zeitgeber time. Interestingly, a diurnal oscillation was detected in the heat shock 70 kDa protein 1A (Hsp70) chaperone that was in-phase with soluble tau but out-of-phase with insoluble tau. Tau protein levels decreased in the soluble and insoluble fractions when Hsp70 was overexpressed in HEK293T cells. Transfection of the BMAL1 carrying vector was continual with the increase in Hsp70 expression and diminished tau protein levels, and it was effectively attenuated by the knockdown of Hsp70, suggesting that BMAL1 could modulate tau protein by Hsp70. Our results suggest that altered circadian oscillations affect tau status and solubility by modulating Hsp70 expression in an experimental model of tau pathology. These findings suggest Hsp70 as a possible pathogenic link between circadian disruption and aggravations of tau pathology.

Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed 18F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

Region-Specific Differences in the Apoe4-dependent Response to Focal Brain Injury

Apolipoprotein E (apoE) plays a role in various physiological functions including lipid transport, synaptic plasticity, and immune modulation.Epidemiological studies suggest that the apoE4 allele increases the risk of post-traumatic sequelae. This study was performed to investigate regionspecific effects of the apoE4 isoform on post-traumatic neurodegeneration. Two focal brain injuries were introduced separately in the motor cortex and hippocampus of apoE4 knock-in, apoE3 knock-in, apoE knockout, and wild-type (WT) mice. Western blotting showed that the expression levels of pre-synaptic and post-synaptic markers at the recovery stage were lower in the hippocampal injury core in apoE4 mice, compared with apoE3 and WT mice. Fast glial activation (determined by immunohistochemistry with glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and cluster of differentiation 45 antibodies) was characteristic of apoE4 mice with hippocampal injury penumbra. apoE4-specific changes were not observed after cortical injury. The intensity of microglial activation in the hippocampus was inversely correlated with the volume of injury reduction on sequential magnetic resonance imaging examinations, when validated using matched samples. These findings indicate that the effects of the interaction between apoE4 and focal brain damage are specific to the hippocampus. Manipulation of inflammatory cell responses could be beneficial for reducing post-traumatic hippocampal neurodegeneration in apoE4 carriers.

Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed 18F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

Region-Specific Differences in the Apoe4-dependent Response to Focal Brain Injury

Apolipoprotein E (apoE) plays a role in various physiological functions including lipid transport, synaptic plasticity, and immune modulation.Epidemiological studies suggest that the apoE4 allele increases the risk of post-traumatic sequelae. This study was performed to investigate regionspecific effects of the apoE4 isoform on post-traumatic neurodegeneration. Two focal brain injuries were introduced separately in the motor cortex and hippocampus of apoE4 knock-in, apoE3 knock-in, apoE knockout, and wild-type (WT) mice. Western blotting showed that the expression levels of pre-synaptic and post-synaptic markers at the recovery stage were lower in the hippocampal injury core in apoE4 mice, compared with apoE3 and WT mice. Fast glial activation (determined by immunohistochemistry with glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and cluster of differentiation 45 antibodies) was characteristic of apoE4 mice with hippocampal injury penumbra. apoE4-specific changes were not observed after cortical injury. The intensity of microglial activation in the hippocampus was inversely correlated with the volume of injury reduction on sequential magnetic resonance imaging examinations, when validated using matched samples. These findings indicate that the effects of the interaction between apoE4 and focal brain damage are specific to the hippocampus. Manipulation of inflammatory cell responses could be beneficial for reducing post-traumatic hippocampal neurodegeneration in apoE4 carriers.

Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Largescale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.

Cerebrospinal Fluid Levels of β-Amyloid 40 and β-Amyloid 42 are Proportionately Decreased in Amyloid Positron-Emission Tomography Negative Idiopathic Normal-Pressure Hydrocephalus Patients

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) could be misleading in idiopathic normal-pressure hydrocephalus (iNPH). We therefore investigated the CSF biomarkers in 18F-florbetaben amyloid-negative positron-emission tomography (PET) [amyloid PET(−)] iNPH, amyloid-positive PET [amyloid PET(+)] AD, and cognitively normal (CN) subjects. METHODS: Ten amyloid PET(+) AD patients (56.7±5.6 years old, mean±standard deviation), 10 amyloid PET(−) iNPH patients (72.8±4.5 years old), and 8 CN subjects (61.2±6.5 years old) were included. We measured the levels of β-amyloid (Aβ)40, Aβ42, total tau (t-tau) protein, and phosphorylated tau (p-tau) protein in the CSF using enzyme-linked immunosorbent assays. RESULTS: The level of Aβ42 and the Aβ42/Aβ40 ratio in the CSF were significantly lower in AD than in iNPH or CN subjects. The Aβ40 level did not differ significantly between AD and iNPH (p=1.000), but it did between AD and CN subjects (p=0.032). The levels of both t-tau and p-tau were higher in AD than in iNPH or CN subjects. The levels of Aβ42, Aβ40, t-tau, and p-tau were lower in iNPH than in CN subjects, but there was no significant difference after controlling for age. CONCLUSIONS: Our results suggest that the mechanism underlying low CSF Aβ levels differs between amyloid PET(−) iNPH and amyloid PET(+) AD subjects. The lower levels of all CSF biomarkers in iNPH patients might be due to reduced clearances from extracellular fluid and decreased brain metabolism of the periventricular zone in iNPH resulting from glymphatic dysfunction.

A Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes: Protocol of a Multicenter, Randomized Controlled Trial

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) is the most common cause of vascular dementia and a major contributor to mixed dementia. CSVD is characterized by progressive cerebral white matter changes (WMC) due to chronic low perfusion and loss of autoregulation. In addition to its antiplatelet effect, cilostazol exerts a vasodilating effect and improves endothelial function. This study aims to compare the effects of cilostazol and aspirin on changes in WMC volume in CSVD.METHODS: The comparison study of Cilostazol and aspirin on cHAnges in volume of cerebral smaLL vEssel disease white matter chaNGEs (CHALLENGE) is a double blind, randomized trial involving 19 hospitals across South Korea. Patients with moderate or severe WMC and ≥ 1 lacunar infarction detected on brain magnetic resonance imaging (MRI) are eligible; the projected sample size is 254. Participants are randomly assigned to a cilostazol or aspirin group at a 1:1 ratio. Cilostazol slow release 200 mg or aspirin 100 mg are taken once daily for 2 years. The primary outcome measure is the change in WMC volume on MRI from baseline to 104 weeks. Secondary imaging outcomes include changes in the number of lacunes and cerebral microbleeds, fractional anisotropy and mean diffusivity on diffusion tensor imaging, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability.CONCLUSIONS: CHALLENGE will provide evidence to support the selection of long-term antiplatelet therapy in CSVD.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01932203

Neurological Complications Resulting from Non-Oral Occupational Methanol Poisoning

Methanol poisoning results in neurological complications including visual disturbances, bilateral putaminal hemorrhagic necrosis, parkinsonism, cerebral edema, coma, or seizures. Almost all reported cases of methanol poisoning are caused by oral ingestion of methanol. However, recently there was an outbreak of methanol poisoning via non-oral exposure that resulted in severe neurological complications to a few workers at industrial sites in Korea. We present 3 patients who had severe neurological complications resulting from non-oral occupational methanol poisoning. Even though initial metabolic acidosis and mental changes were improved with hemodialysis, all of the 3 patients presented optic atrophy and ataxia or parkinsonism as neurological complications resulting from methanol poisoning. In order to manage it adequately, as well as to prevent it, physicians should recognize that methanol poisoning by non-oral exposure can cause neurologic complications.

Effects on Stress, Problem Solving Ability and Quality of Life of as a Stress Management Program for Hospitalized Schizophrenic Patients: Based on the Stress, Appraisal-Coping Model of Lazarus & Folkman

PURPOSE: The study was done to evaluate the effects a Stress Management Program (SMP) on stress, problem solving skills, and quality of life for hospitalized patients with Schizophrenia. METHODS: A mixed method design was used: a combination of a repeated-measure design with a non-equivalent control group and qualitative data collection. The participants were 40 patients with schizophrenia admitted in three psychiatric hospitals. The experimental group (n=20) received the SMP twice a week for a total of 8 weeks. RESULTS: Study results revealed that the SMP was effective for stress (F=321.02, p<.001), problem solving ability (F=246.28, p<.001), and quality of life (F=63.35,p<.001) for hospitalized persons with schizophrenia. CONCLUSION: The results suggest that a SMP can be an effective strategy to reduce patients' hospitalization stress, and improve problem solving skills and quality of life. Therefore, it is recommended that mental health nurses use this stress management program in clinical practice to assist adaptation to hospitalization for persons with schizophrenia.

The Correlation Study between Plasma Aβ Proteins and Cerebrospinal Fluid Alzheimer's Disease Biomarkers

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β proteins (Aβ). In this study we explored the correlation of plasma Aβ40 and Aβ42 concentrations with Aβ42, total tau (tTau) and phosphorylated tau 181 (pTau181) levels in cerebrospinal fluid (CSF) in AD and control subjects to further understand the characteristics of plasma Aβ proteins levels. METHODS: The consecutive subjects (44 AD and 47 controls) in this study were recruited. The plasma levels of Aβ40 and Aβ42 were measured using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits. And the corresponding CSFs were analyzed in terms of Aβ42, tTau and pTau181 concentrations using INNOTEST ELISA kits. Further, the albumin levels were measured both in serum and CSF and albumin ratio was obtained to check the integrity of blood-brain barrier. RESULTS: CSF Aβ42 concentrations were significantly decreased while tTau and pTau181 levels were significantly increased in AD subjects. The plasma levels of Aβ42 were significantly lower (p=0.007), while the Aβ40/Aβ42 ratio was significantly higher (p<0.001) in AD patients than in controls. The overall plasma Aβ42 levels showed a positive correlation with those of CSF Aβ42 (p=0.001), but not with the others in CSF. In subgroup analysis, the CSF Aβ42 demonstrated positive correlation with not only plasma Aβ42 but also Aβ40 levels in controls. However, no significant relationship was noted between plasma and CSF Aβ proteins in AD group. CONCLUSIONS: The plasma Aβ42 and Aβ40 concentrations were shown to have a close relationship with CSF Aβ42 levels in controls, but not in AD subjects. Our results suggest that the correlation between plasma Aβ40 and CSF Aβ42 levels is perturbed in AD.

The Clinical Characteristics according to the Educational Level in the Elderly Patients with Mild Alzheimer's Disease Dementia

BACKGROUND AND PURPOSE: Cognitive reserve is important for the individual susceptibility to dementia. Among the various determinants of cognitive reserve, the number of years of formal education would be of prime importance. We performed this study to explore its contribution to the clinical characteristics of dementia. METHODS: We included consecutive mild Alzheimer's disease (AD) dementia patients (clinical dementia rating, CDR=0.5 or 1) who visited our memory clinic and were older than 70 years at the evaluation from October 2013 to September 2015. According to the number of years of education, the corresponding subjects was grouped into two extreme educational groups, low education (illiterate or partially illiterate, LE, n=43) vs. high education (more than 9 years of education, HE, n=34). Among these patients, we compared various demographic, neuropsychological and neuroimaging characteristics. RESULTS: The groups were comparable in terms of age, frequency of hypertension and diabetes, and CDR and its sum of box. However, female gender was more frequent in the LE group (p=0.000). Also this group showed a more depressive mood on the geriatric depression scale (p=0.007). The raw scores on Korean Version of Mini-Mental State Examination and well-validated neuropsychological tests were lower in the LE group. However, the cognitive performance was found to be more preserved in the LE group than in the HE group when assessed using the z-score in certain specified tests on univariate and multivariate analyses (p<0.05). The Schelten's grade of medial temporal atrophy was similar between the two educational groups. Also, the degree of combined ischemic burden did not differ between the two groups. CONCLUSIONS: We identified that the prevalence of depressive mood and the extent of decline from the corresponding norm in a particular neuropsychological performance differ according to the educational level of mild AD patients.

Clinical Characteristics in Lacunar Infarction with Less Than 50% Stenosis in the Parent Artery

BACKGROUND: Contrary to the initial hypothesis, there is accumulating evidence that the pathogenesis of lacunar infarction (LI) is heterogeneous. LI is often accompanied by intracranial stenosis, and while the clinical significance of severe stenosis of the intracranial parent artery in LI has been demonstrated, that of mild stenosis in LI has not been. Thus the aim of this study was to determine the clinical relevance of mild intracranial stenosis in LI. METHODS: Ninety-three consecutive patients with acute LI were enrolled between March 2011 and December 2013. The patients were divided according to the presence of intracranial stenosis in the parent artery into pure LI (PLI) and LI with mild intracranial stenosis (<50% stenosis, BAD). Various clinical and laboratory characteristics were compared between the two groups. RESULTS: PLI group were older and, had a less frequent history of smoking, a larger infarct, lower likelihood of a favorable outcome, and higher National Institute of Health Stroke Scale score at discharge in the univariate analysis. After adjusting for confounding factors, BAD was associated with older age at onset [odds ratio (OR) = 1.113, 95% confidence interval (95% CI) = 1.056-1.172, p<0.001), no history of previous statin medication (OR = 13.362, 95% CI = 1.014-176.062, p=0.049), and nonsignificant stenosis in the parent artery was associated with larger infarct (beta=0.296, p=0.01) in the multivariate analyses. CONCLUSIONS: LI with mild parent-artery disease was demonstrated to have distinct clinical characteristics compared to LI without parent artery disease. Thus, even mild branch atheromatous disease in LI should be evaluated thoroughly and treated via a planned and systematic approach.

A Consensus in Korea Regarding a Protocol to Reduce Preanalytical Sources of Variability in the Measurement of the Cerebrospinal Fluid Biomarkers of Alzheimer's Disease

Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Abeta42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer's disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.

Atypical Early-Onset Alzheimer's Disease Dementia Diagnosed by Biomarker Study

BACKGROUND: The described clinical characteristics of early-onset Alzheimer's disease (EOAD) are distinct from that of late-onset AD. We reported a patient with atypical EOAD. CASE REPORT: A 54-year-old, truck driver developed gradual visuospatial, language and calculation deficits for 3 months. The neuropsychological impairments were extensive. Brain MRI revealed asymmetric atrophy in left medial temporal lobe along with distinct widening of sylvian fissure. (18)F-florbetapir-positron emission tomography (PET) showed a high uptake in the cortex. Further, the profiles of cerebrospinal fluid (CSF) biomarker were compatible with AD. CONCLUSIONS: We diagnosed the patient as EOAD based on the result of biomarker study. Increased Abeta burden was identified through amyloid PET imaging and decreased CSF Abeta level. The high rise of CSF Tau proteins was in agreement with the patient's extensive and rapid cognitive decline. This case report demonstrates the importance of AD biomarker study in confronting early-onset dementia with atypical clinical presentation.

A Case of Creutzfeldt-Jakob Disease Presenting Mainly with Abnormal Eye Movements / 대한평형의학회지

Creutzfeldt-Jakob disease (CJD) is a human prion disease with rapidly progressive neurodegeneration. The major clinical manifestations of CJD include mental deterioration, myoclonus, cerebellar dysfunction, and neuro-ophthalmic symptoms and signs. However, abnormal eye movements as an early sign of CJD are rare. We report a 49-year-old man with periodic alternating nystagmus in early disease course.

Development of a Measurement of Stress for Hospitalized Schizophrenic Patient

PURPOSE: This study was done to develop a measurement for stress experienced by patients with schizophrenia during hospitalization. METHODS: The preliminary tool was developed through in-depth interviews and a validity verification test of content. For data collection, 15 inpatients with schizophrenia were selected as participants for in-depth interviews and 195 patients admitted to one of eight psychiatric hospitals in four provinces were recruited as participants to test reliability and validity of the preliminary tool. RESULTS: The questionnaire was developed as a four-point Likert-type scale in a self-report form with 28 items. Factor analysis showed 28 items in six factors. Factors were named 'Unjust human rights infringement', 'Futureless life', 'Alienation from other family members', 'Infringement of basic needs', 'Infringement of personal preference' and 'Inconvenience of shared living'. The six factors explained 63.5% of the total variance. Cronbach's alpha for the total items was .93 and for the factors ranged from .65 to .87. CONCLUSION: A tool to measure stress in patients hospitalized with schizophrenic was developed based on identified hospitalization stress experiences. Study results indicate that this tool can be used to evaluate hospitalization stress in these patients and will contribute to establishing nursing interventions for relief of hospitalization stress.

Logopenic Progressive Aphasia Revealing Positive Cerebrospinal Fluid Biomarkers for Alzheimer's Disease

Primary progressive aphasia (PPA) is classified into agrammatic, semantic, and logopenic variants, but differential diagnosis is often challenging. There is accumulating evidence that the neuropathology of logopenic PPA is distinct from that of the other types. We report herein a woman with logopenic PPA who was diagnosed by clinical, neuropsychological, and radiologic data during 2 years of follow-up. Interestingly, her cerebrospinal fluid biomarkers were found to be similar to those found in Alzheimer's disease, with a decreased concentration of Abeta42 and an increased concentration of pTau181 (tTau).

Serial Positron Emission Tomography Findings and Neuropsychological Assessments in Limbic Encephalitis

OBJECTIVE: Limbic encephalitis (LE) is characterized by rapid development of impaired cognitive function, seizure and psychiatric symptoms. Brain 18fluoro labelled deoxyglucose (18FDG)-positron emission tomography (PET) typically showed glucose hypermetabolism in the temporomesial region in the acute stage. Although several studies about brain 18FDG-PET in LE have been reported, serial 18FDG-PET findings during the course of the disease are limited. The purpose of this study is to analyze serial 18FDG-PET findings in LE and to compare them with the results of neuropsychological test. METHODS: We studied prospectively two patients diagnosed as LE using clinical criteria. They underwent serial brain magnetic resonance imaging (MRI) and 18FDG-PET scans. They also received detailed neuropsychological tests. RESULTS: Initial 18FDG-PET presented glucose hypermetabolism in unilateral temporomesial region without obvious abnormalities in brain MRI. Follow-up 18FDG-PET images obtained three month later displayed hypometabolism in both temporomesial region. Correspondingly, neuropsychological studies revealed prominent visuospatial and verbal memory deficits. CONCLUSION: The initial 18FDG-PET was very sensitive in visualizing the disease process compared with MRI and suggesting more markedly functional impairment than structural damage in early stage of LE. This was well correlated with cognitive dysfunction measured by neuropsychological test such as anterograde episodic memory loss involving both verbal and non-verbal materials.