Key-Chung Park

Regional white matter hyperintensities in normal aging, single domain amnestic mild cognitive impairment, and mild Alzheimer’s disease

Few studies have examined white matter hyperintensities (WMH) along the cognitive continuum between single-domain amnestic mild cognitive impairment (sd-aMCI) and Alzheimers disease (AD). The aims of our study were to explore relationships between the extent and location of WMH and disease severity along the cognitive continuum and to determine whether differences in the distribution of WMH could be predictive of specific patterns of cognitive impairment. We compared cognitive function, vascular risk factors, and regional (frontal lobe, parieto-occipital [PO] lobe, temporal lobe, periventricular [PV] white matter and deep white matter) WMH volume in 37 patients with mild AD, 23 patients with sd-aMCI, and 24 age-matched and education-matched normal controls. A quantitative volumetric method was applied to measure WMH burden. Total and regional WMH burdens, except for those in the temporal lobe, were significantly correlated with age (p<0.01). We found a trend toward increasing WMH volume with disease severity, higher in AD than in sd-aMCI and lowest in the controls. Total WMH volume was associated with the global cognitive test score. In multiple linear regression analysis, PV WMH volume, but not deep WMH volume, strongly predicted performances on the Controlled Oral Word Association test and the Color Word Stroop test after adjusting for important demographic variables. Only PO WMH volume was a significant predictor of a cognitive test score when frontal and temporal WMH volumes were simultaneously entered into the regression model. The extent and distribution of WMH, especially in the PV and PO regions, were associated with disease severity and reduced cognition.

Relationship between clinical course and Diffusion-weighted MRI findings in sporadic Creutzfeldt-Jakob Disease

The aim of this study was to investigate the relationship between clinical course and diffusion-weighted MRI (DWI) findings in sporadic Creutzfeldt-Jakob Disease (sCJD). We reviewed clinical records and MRI examination in nine probable sCJD. According to hyperintense signal distribution on DWI, the patients were classified into two groups with cortical ribbon plus basal ganglia hyperintensity (6/9) and with only increased cortical signals (3/9). Clinical features including quadriparesis (3/6), akinetic mutism (2/6), and dysphasia (2/6), which were usually observed in the more advanced stage of CJD, were noted only in patients with cortical ribbon plus basal ganglia hyperintensity at the time of initial DWI examination. The patients with the cortical plus basal ganglia hyperintensity (6.4±1.7 weeks) had a shorter interval from symptom onset to akinetic mutism than those with only cortical ribbon hyperintensity (26.0±22.5 weeks) (p=0.02). These findings suggest that DWI may predict the clinical course of CJD.

Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia

The hexanucleotide repeat expansion (GGGGCC) in chromosome 9 open-reading frame 72 (C9orf72) and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes are known to be associated with the main causes of familial or sporadic amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in Western populations. These genetic abnormalities have rarely been studied in Asian FTD populations. We investigated the frequencies of mutations in MAPT and GRN and the C9orf72 abnormal expansion in 75 Korean FTD patients. Two novel missense variants of unknown significance in the MAPT and GRN were detected in each gene. However, neither abnormal C9orf72 expansion nor pathogenic MAPT or GRN mutation was found. Our findings indicate that MAPT, GRN, and C9orf72 mutations are rare causes of FTD in Korean patients.

Executive dysfunction associated with stroke in the posterior cerebral artery territory

Cognitive decline following posterior cerebral artery infarction (PCAI) is associated with lesions in the occipital lobe that extend into the parahippocampus or the splenium. We investigated patterns of neuropsychological deficits, including those causing executive dysfunction, associated with isolated lesions of the occipital lobe and with extensive lesions of the occipital lobe that extended into the splenium or the posterior ventral temporal lobes including the parahippocampus and fusiform gyrus. Eleven patients with unilateral PCAI involving the cerebral cortex and one patient with an occipital hemorrhage were selected for inclusion in this study. The mean age of the patients was 68.50 ± 7.94 years and their mean level of education was 8.58 ± 4.12 years. Four patients had isolated occipital lobe lesions and eight had lesions in either the splenium or the posterior ventral temporal lobe in addition to the occipital lobe. Whereas three of four patients with isolated occipital lobe lesions had left-sided lesions, only three of the eight patients with extended occipital lesions had left-sided lesions. The patients underwent a standardized battery of neuropsychological tests. The patients with occipital injuries in addition to splenial or posterior ventral temporal lobe injuries demonstrated performance decline across diverse cognitive domains, including memory (eight of eight), visuospatial function (eight of eight), executive function (seven of eight), language-related function (four of eight) and attention (one of eight). In contrast, memory impairment (three of four patients) was the only area in which patients with isolated occipital lobe lesions demonstrated decline in performance. Our findings suggest that strokes in the territory of the posterior cerebral artery are frequently associated with executive dysfunction. Injuries involving the splenium or posterior ventral temporal lobe in addition to the occipital lobe lead to more diverse neuropsychological impairments than do isolated occipital lobe injuries alone.

Amnesic syndrome in a mammillothalamic tract infarction.

It is controversial whether isolated lesions of mammillothalamic tract (MTT) produce significant amnesia. Since the MTT is small and adjacent to several important structures for memory, amnesia associated with isolated MTT infarction has been rarely reported. We report a patient who developed amnesia following an infarction of the left MTT that spared adjacent memory-related structures including the anterior thalamic nucleus. The patients memory deficit was characterized by a severe anterograde encoding deficit and retrograde amnesia with a temporal gradient. In contrast, he did not show either frontal executive dysfunction or personality change that is frequently recognized in the anterior or medial thalamic lesion. We postulate that an amnesic syndrome can develop following discrete lesions of the MTT.

Apelin is transcriptionally regulated by ER stress-induced ATF4 expression via a p38 MAPK-dependent pathway

Apelin, which is an endogenous ligand for the orphan G-protein-coupled receptor APJ, was reported to be up-regulated by hypoxia-inducible factor 1-α (HIF1-α) in hypoxia- and insulin-treated cell systems. However, a negative transcriptional regulator of apelin has not yet been identified. In this study, we showed that apelin is down-regulated by ATF4 via the pro-apoptotic p38 MAPK pathway under endoplasmic reticulum (ER) stress. First, we analyzed the human apelin promoter to characterize the effects of ER stress on apelin expression in hepatocytes. Treatment with thapsigargin, an inducer of ER stress, and over-expression of ATF4 decreased apelin expression in hepatocytes. This work identified an ATF4-responsive region within the apelin promoter. Interestingly, ATF4-mediated repression of apelin was dependent upon the N-terminal domain of ATF4. C/EBP-β knockdown experiments suggest that C/EBP-β, which acts as an ATF4 binding partner, is critical for the ER stress-induced down-regulation of apelin. We also demonstrated that ATF4 regulates apelin gene expression via p38 pathways. Ectopic expression of constitutively active MKK6, an upstream kinase of p38, suggested that activation of the p38 pathway is sufficient to induce ATF4-mediated repression of apelin. Moreover, apelin enhanced cell migration in a wound healing assay in a p38 MAPK-dependent manner. Furthermore, analysis of caspase-3 activation indicated that ATF4 knockdown up-regulated apelin expression, leading to the inability of MKK6 (CA) to exert pro-apoptotic effects. Taken together, our results suggest that ATF4-mediated repression of apelin contributes substantially to the pro-apoptotic effects of p38.

A Case of Herpes Zoster Ophthalmicus with Isolated Trochlear Nerve Involvement

Background Herpes zoster ophthalmicus (HZO) can involve the oculomotor nerve; however, isolated trochlear nerve palsy has rarely been reported. Case Report An 83-year-old man who suffered from HZO in the right frontal area and scalp subsequently developed vertical diplopia and severe pain. Cerebrospinal fluid examination and brain MRI revealed no abnormalities. Isolated right trochlear nerve palsy was diagnosed based on the findings of neuro-ophthalmological tests. Conclusions Isolated trochlear nerve involvement associated with HZO is very rare and may be easily overlooked. Physicians should carefully examine oculomotor involvement in HZO.

Sleep Disturbances and Predictive Factors in Caregivers of Patients with Mild Cognitive Impairment and Dementia

Background and Purpose We examined the characteristics of sleep disturbances and sleep patterns in the caregivers of patients with amnestic mild cognitive impairment (aMCI) and dementia. Methods We prospectively studied 132 patients (60 with aMCI and 72 with dementia) and their caregivers, and 52 noncaregiver controls. All caregivers and controls completed several sleep questionnaires, including the Pittsburgh Sleep Quality Index (PSQI). The patients were administered neuropsychological tests and the neuropsychiatric inventory to evaluate their behavioral and neuropsychiatric symptoms of dementia (BPSD). Results The PSQI global score was 6.25±3.88 (mean±SD) for the dementia caregivers and 5.47±3.53 for the aMCI caregivers. The Insomnia Severity Index (ISI) and short form of the Geriatric Depression Scale (GDS-S) predicted higher PSQI global scores in aMCI caregivers, and higher scores for the ISI, Epworth Sleepiness Scale (ESS), and GDS-S in dementia caregivers. BPSD, including not only agitation, depression, and appetite change in dementia patients, but also depression, apathy, and disinhibition in aMCI patients, was related to impaired sleep quality of caregivers, but nighttime behavior was not. Age and gender were not risk factors for disturbed sleep quality. Conclusions Dementia and aMCI caregivers exhibit impaired quality of sleep versus non-caregivers. ISI, GDS-S, and ESS scores are strong indicators of poor sleep in dementia caregivers. In addition, some BPSD and parts of the neuropsychological tests may be predictive factors of sleep disturbance in dementia caregivers.

Transcortical sensory aphasia following a left frontal lobe infarction probably due to anomalously represented language areas

A 57-year-old right-handed man presented with speech disturbance 1 day prior to his admission. The standardized aphasia test batteries showed transcortical sensory aphasia. MRI revealed a left frontal and insular infarct. Positron emission tomography scans also revealed a glucose hypometabolism in the same region as the infarcted area on MRI. Repeated aphasia testing showed that his aphasia only partially improved.

Takayasu’s disease presenting with atherothrombotic ischaemic stroke

Takayasu’s arteritis is a chronic inflammatory disease of the aorta and its main branches, and a well known cause of stroke. Pathogenesis of ischaemic stroke has been attributed to intracranial vasculitic involvement or emboli from either stenoocclusive extracranial vessels or cardiac disease such as aortic regurgitation. We present a patient with Takayasu’s arteritis and recurrent cerebral infarctions associated with intracranial atherosclerosis. We postulate that the intracranial atherosclerotic process is an important mechanism in Takayasu’s arteritis-related ischaemic stroke.