Search

Background: Frontotemporal dementia (FTD) syndrome is a genetically heterogeneous group of diseases. Pathogenic variants in the chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) genes are mainly associated with genetic FTD in Caucasian populations. Objective: To understand the genetic background of Korean patients with FTD syndrome. Methods: We searched for pathogenic variants of 52 genes related to FTD, amyotrophic lateral sclerosis, familial Alzheimer’s disease, and other dementias, and hexanucleotide repeats of the C9orf72 gene in 72 Korean patients with FTD using whole exome sequencing and the repeat-primed polymerase chain reaction, respectively. Results: One likely pathogenic variant, p.G706R of MAPT, in a patient with behavioral variant FTD (bvFTD) and 13 variants of uncertain significance (VUSs) in nine patients with FTD were identified. Of these VUSs, M232R of the PRNP gene, whose role in pathogenicity is controversial, was also found in two patients with bvFTD. Conclusions: These results indicate that known pathogenic variants of the three main FTD genes (MAPT, GRN, and C9orf72) in Western countries are rare in Korean FTD patients.

Background Telomeres are repetitive DNA sequences of TTAGGG at the ends of chromosomes. Many studies have shown that telomere shortening is associated with aging-related diseases, such as cardiovascular diseases, hypertension, diabetes, cancer, and various neurodegenerative diseases, including Alzheimer's disease, vascular dementia, Parkinson's disease, and dementia with Lewy bodies. However, changes in telomere length (TL) in patients with frontotemporal dementia (FTD) syndrome are unclear. Accordingly, in this study, we assessed TL in blood samples from patients with FTD syndrome. Methods Absolute TL was measured in peripheral blood leukocytes from 53 patients with FTD syndromes (25 with behavioral variant FTD, 19 with semantic variant primary progressive aphasia [PPA], six with nonfluent/agrammatic variant PPA, and three with amyotrophic lateral sclerosis [ALS] plus) and 28 cognitively unimpaired (CU) controls using terminal restriction fragment analysis. Results TL was significantly longer in the FTD group than in the CU group. All FTD subtypes had significantly longer TL than controls. There were no significant differences in TL among FTD syndromes. No significant correlations were found between TL and demographic factors in the FTD group. Conclusions Longer telomeres were associated with FTD syndrome, consistent with a recent report demonstrating that longer telomeres are related to ALS. Therefore, our results may support a shared biology between FTD and ALS. More studies with larger sample sizes are needed.

We investigated the survival time of each clinical syndrome of frontotemporal dementia (FTD) and the impacts of behavioral and motor features on survival of FTD. A total of 216 patients with FTD [82 behavioral variant FTD (bvFTD), 78 semantic variant primary progressive aphasia (svPPA), 43 non-fluent/agrammatic variant PPA (nfvPPA), 13 FTD-motor neuron disease (MND)] were enrolled from 16 centers across Korea. Behaviors and parkinsonism were assessed using the Frontal Behavioral Inventory and Unified Parkinson’s Disease Rating Scale Part III, respectively. The Kaplan–Meier method was used for the survival analysis and the Cox proportional hazards model was applied for analysis of the effect of behavioral and motor symptoms on survival, after controlling vascular risk factors and cancer. An overall median survival of FTD was 12.1 years. The survival time from onset was shortest for FTD-MND and longest for svPPA. The median survival time of patients with bvFTD was unavailable but likely comparable to that of patients with nfvPPA. In the bvFTD group, negative behavioral symptoms and akinetic rigidity were significantly associated with survival. In the nfvPPA group, the presence of dysarthria had a negative impact on survival. These findings provide useful information to clinicians planning for care.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Background: The K variant of butyrylcholinesterase (BCHE-K) exhibits a reduced acetylcholine-hydrolyzing capacity; so the clinical response to rivastigmine may differ in Alzheimer's disease (AD) patients with the BCHE-K gene. Objective: To investigate the clinical response to rivastigmine transdermal patch monotherapy or memantine plus rivastigmine transdermal patch therapy in AD patients based on the BCHE-K gene. Methods: A total of 146 probable AD patients consented to genetic testing for butyrylcholinesterase and underwent the final efficacy evaluations. Responders were defined as patients with an equal or better score on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 16 weeks compared to their baseline score. Results:BCHE-K carriers showed a lower responder rate on the ADAS-cog than non-carriers (38.2 vs. 61.7%, p = 0.02), and this trend was evident in AD patients with apolipoprotein E I 4 (35 vs. 60.7%, p = 0.001). The presence of the BCHE-K allele predicted a worse response on the ADAS-cog (odds ratio 0.35, 95% confidence interval 0.14-0.87), after adjusting for demographic and baseline cognitive and functional variables. Conclusion: The BCHE-K genotype may be related to a poor cognitive response to rivastigmine patch or memantine add-on therapy, especially in the presence of apolipoprotein E I 4. i 2014 S. Karger AG, Basel

To identify pathogenic variants in 107 Korean patients with sporadic frontotemporal dementia (FTD), 46 genes related to FTD, amyotrophic lateral sclerosis, and other dementias were screened by next-generation sequencing. Hexanucleotide repeats in C9orf72 gene were also tested by repeat-primed polymerase chain reaction. Next-generation sequencing revealed one known pathogenic variant (c.708+1G>A) in the GRN gene in a patient with behavioral variant FTD (bvFTD). In addition, a novel in-frame deletion (c.2675_2683del) in the CSF1R gene was identified in a patient with bvFTD who had severe bifrontal atrophy with frontal subcortical white matter changes. Novel compound heterozygous variants in the AARS2 gene, c.1040+1G>A and c.636G>A (p.Met212Ile), were found in a patient with bvFTD. Forty-six variants of uncertain significance were detected in other patients. None of the patients had expanded hexanucleotide repeats in C9orf72. These results show that pathogenic variants of known FTD genes are rare in Korean FTD patients but the CSF1R and AARS2 genes should be screened for a genetic diagnosis of FTD or other dementias.

Background: Mild cognitive impairment (MCI) is a heterogeneous condition with a variety of clinical outcomes, the presence of which correlates with risk of Alzheimer’s disease as well as pre-clinical stages of other dementia subtypes. The aims of this study were to assess the specific patterns of cognitive profiles and to identify changes from baseline to 24 weeks in patients with MCI using detailed neuropsychological testing. Methods: We consecutively recruited 120 MCI patients at baseline according to the Petersen’s clinical diagnostic criteria, who were admitted to the Dementia and Memory Clinics. We analyzed patients who fulfilled both inclusion and exclusion criteria for MCI and classified them into four subtypes according to deficits in major cognitive domains; amnestic MCI single domain (aMCI-s), amnestic multiple domain MCI (aMCI-m), non-amnestic single domain MCI (naMCI-s) and non-amnestic multiple domain MCI (naMCI-m). Four groups of MCI were evaluated by a detailed neuropsychological battery test. Results: 83 patients with MCI at the 24-week follow-up were classified into four subtypes. The most frequent subtype was amnestic multi-domain MCI, with the frequency of MCI subtypes as follows: aMCI-s (n = 21, 25.3%), aMCI-m (n = 53, 63.9%), naMCI-s (n = 5, 6.0%) and naMCI-m (n = 4, 4.8%). In the major cognitive items of the SNSB-D, there were significant changes between the initial and follow-up tests in the domains of language, memory and the fron-tal/executive function (p < 0.05), except for attention, in all MCI patient subtypes. At 24-weeks follow-up, the conversion rate to Alzheimer’s disease was 2.4% (n = 2) from a subtype of amnestic multi-domain MCI. Conclusions: Our study revealed the most frequent subtype of MCI to be multiple domain amnestic MCI, with this subtype having a higher tendency of conversion to Alzheimer’s disease.

Patients with left unilateral neglect misbisect lines toward the right. To discriminate between contralesional unawareness and ipsilesional hyperattention hypotheses for this ipsilesional bias, we performed the line quadrisection test on 18 patients with and 25 without neglect, and 24 normal controls. Overall the patients with neglect were unbiased when performing the left quadrisection task, but erred rightward on the right quadrisection task. These results suggest that the ipsilesional bisection errors produced by patients with neglect are primarily influenced by ipsilesional hyperattention rather than contralesional unawareness. However, further analyses showed heterogeneity of performance in left quadrisection, which can be explained by multiple factors that include the top down attention to left space associated with left quadrisection, the orienting to the salience of the line's left end, and distorted mental representation, in addition to ipsilesional hyperattention.

Patients often demonstrate attentional and action-intentional biases in both the transverse and coronal planes. In addition, when making forelimb movements in the transverse plane, normal participants also have spatial and magnitude asymmetries, but forelimb spatial asymmetries have not been studied in coronal space. Thus, to learn if when normal people make vertical movements they have right–left spatial and magnitude biases, seventeen healthy, blindfolded volunteers had their hands (holding pens) placed vertically in their midsagittal plane, 10 inches apart, on pieces of paper positioned above, below, and at eye-level. Participants were asked to move their hands together vertically and meet in the middle. Participants demonstrated less angular deviation in the below-eye condition than in the other spatial conditions, when moving down than up, and with their right than left hand. Movements toward eye level from upper or lower space were also more accurate than movements in the other directions. Independent of hand, lines were longer with downward than upward movements and the right hand moved more distance than the left. These attentional-intentional asymmetries may be related to gravitational force, hand-hemispheric dominance, and spatial “where” asymmetries; however, the mechanisms accounting for these asymmetries must be ascertained by future research. (JINS, 2011, 17, 732–739)

Background/Aims: The possible influence of apolipoprotein E (ApoE) genotype on the response to acetylcholinesterase inhibitor therapy in patients with Alzheimer’s disease (AD) remains a matter of controversy. In order to address this issue, we investigated the effects of ApoE genotype on the clinical response to donepezil in patients with mild to moderate AD. Methods: An open study was carried out in 51 patients with probable AD who were treated with 5–10 mg of donepezil per day for 48 weeks. Results: Eighteen (35.3%) of the 51 patients had 1 or 2 ApoE Ε4 alleles. ApoE Ε4 carriers with AD showed a mean 1.1-point increase from the baseline score of 23.9 on the 70-point Alzheimer’s Disease Assessment Scale-Cognitive Component at 48 weeks, while the ApoE Ε4 noncarrier group showed a 3.1-point increase from the baseline score of 22.5 (p = 0.03). The ApoE Ε4 carrier group exhibited a mean 0.13-point worsening from the baseline score of 0.97 on the Korean Instrumental Activities of Daily Living at 48 weeks, while the ApoE Ε4 noncarrier group exhibited a 0.17-point worsening from the baseline score of 0.64 (p = 0.05). Conclusion: AD patients who carry the ApoE Ε4 allele may respond more favorably to donepezil than Ε4 noncarriers.

We investigated whether the perception or production of a given line length in normal subjects varies according to where in peripersonal space the line is perceived or produced. We also investigated the influence of the direction of movement used to make the line. In Experiment 1, blindfolded normal subjects were asked to estimate distances while the examiner moved the subject's hand in proximal (medial) or distal (lateral) space, moving centripetally or centrifugally. The subjects showed a spatial effect, perceiving the same length as shorter in proximal space than distal space. This result could be related to either a proximal spatial attentional bias or an anisometric representation of spatial distances. In Experiment 2, we attempted to dissociate these hypotheses by studying blindfolded normal subjects, who were requested to produce horizontal lines of a given length (100 or 200 mm) in proximal versus distal peripersonal space using centripetal or centrifugal movements. Centrifugal movements in proximal space were the longest; centrifugal movements in distal space were the shortest; in between were the proximal centripetal and distal centripetal movements which did not differ from each other. These results suggest that in peripersonal space the perception of length in normal subjects is most consistent with anisometric mental representation where the size of mental representations of length units decreases as a function of the distance from the subject's midsagittal plane. Length production, however, may depend on an interaction of the anisometric mental representation and the premotor/intentional factors. (JINS, 2004, 10, 913–919.)

Acute mountain sickness (AMS) occurs commonly in hikers who are rapidly exposed to high altitude environments. Despite the numerous reports of AMS, few studies have reported pallidal lesions associated with altitude sickness. A previously healthy 49-yr-old Korean patient, after ascent to 4,700 m, suffered symptoms consistent with AMS. After returning home, the patient showed changes in personality characterized by abulia, indifference, and indecisiveness. T2 weighted brain magnetic resonance imaging showed high signal lesions involving bilateral globus pallidus. Our case suggests that globus pallidus injury should be included in the differential diagnosis of patients with personality or cognitive change after recovery from AMS.

The objective of this study was to investigate the relationship between neurologic signs and cognitive dysfunction in subcortical ischemic vascular dementia (SIVD). 121 patients with SIVD were recruited from multiple nationwide hospitals. The patients’ neurologic signs were evaluated using the Focal Neurologic Sign Score (FNSS). The FNSS scores did not correlate with the composite neuropsychology scores and Korean Mini-Mental State Examination scores. The FNSS scores correlated with the letter fluency and Rey–Osterrieth Complex Figure (ROCF) copy scores. Using a multivariate regression analysis controlled for age, sex, and educational level, the FNSS scores had a significant relationship with the letter fluency test scores (R 2 = 0.08, β = −2.28, p = 0.02) and ROCF copy scores (R 2 = 0.08, β = −0.42, p = 0.03). These findings suggest that the neurologic signs in patients with SIVD do not correlate with global cognitive functions; however, these signs do correlate with executive dysfunction in these patients.

randomized to receive either Vitamin E 800 IU vitamin C 200 mg alpha lipoic acid 600 mg/day; coenzyme Q 2400 mg per day (800mg 3 times per day), or placebo, for 16 weeks. CSF and plasma were obtained at baseline and after 16 weeks of treatment. Physical examination, blood tests and adverse event reports were used to monitor safety. The MMSE and ADCS-ADL were administered at baseline and week 16. CSF levels of A-beta42, tau and P-tau181 were measured by multiplex assays. F2-isoprostanes are measured by LC-MS methods. Clinical and CSF data were compared between groups using ANCOVA models. Results: 78 subjects with AD (50% women) were randomized. Study medications were well-tolerated, without differences in adverse events between groups. 74 subjects completed treatment and had successful serial lumbar punctures. At baseline, means (SD) were: age 72.8 (9.1), MMSE 22.9 (3.7); these did not differ between treatment arms. CSF levels of A-beta42, tau and P-tau-181 did not differ between treatment arms at baseline. Changes in CSF levels of A-beta42, tau and P-tau181 from baseline to week 16 did not differ between either treatment arm and placebo. Measurements of F2-isoprostanes are in progress. Conclusions: Treatment with a cytosolic antioxidant combination or with CoQ did not alter CSF biomarkers related to A-beta or tau in AD. The supplements, at the doses used, did not appear to influence AD pathologic processes in the brain sufficiently to alter CSF biomarkers. Supported by NIA grant AG10483.

The possible influence of apolipoprotein E (ApoE) genotype on the response to acetylcholinesterase inhibitor therapy in patients with Alzheimer's disease (AD) remains a matter of controversy. In order to address this issue, we investigated the effects of ApoE genotype on the clinical response to donepezil in patients with mild to moderate AD.An open study was carried out in 51 patients with probable AD who were treated with 5-10 mg of donepezil per day for 48 weeks.Eighteen (35.3%) of the 51 patients had 1 or 2 ApoE epsilon4 alleles. ApoE epsilon4 carriers with AD showed a mean 1.1-point increase from the baseline score of 23.9 on the 70-point Alzheimer's Disease Assessment Scale-Cognitive Component at 48 weeks, while the ApoE epsilon4 noncarrier group showed a 3.1-point increase from the baseline score of 22.5 (p = 0.03). The ApoE epsilon4 carrier group exhibited a mean 0.13-point worsening from the baseline score of 0.97 on the Korean Instrumental Activities of Daily Living at 48 weeks, while the ApoE epsilon4 noncarrier group exhibited a 0.17-point worsening from the baseline score of 0.64 (p = 0.05).AD patients who carry the ApoE epsilon4 allele may respond more favorably to donepezil than epsilon4 noncarriers.

We report a 62-year-old man with non-convulsive status epilepticus (NCSE) presenting as a progressive aphasia that developed insidiously over 5 weeks. On video-EEG monitoring, aggravation of the aphasia coincided with occurrence of seizure activities arising from the left fronto-temporal area. Brain MRI was noncontributory but a fluorodeoxyglucose-PET scan revealed a hypometabolism in the left anterior temporal area. Following anticonvulsant treatment, aphasia recovered gradually over several weeks despite prompt resolution of epileptic discharges on EEG. Our patient’s findings, gradual onset of isolated aphasia with gradual resolution after initiation of treatment, may differ from previously reported cases with aphasic status epilepticus because their aphasia showed abrupt onset and rapid resolution with anticonvulsant medication.

Background Patients' tendency to draw near or into the target when copying figures, a phenomenon termed closing-in , has been previously described. That the closing-in could occur when copying hand gestures has also been noted. Objectives To study a patient with corticobasal degeneration to quantify his manual approach behavior and to test a possible working memory hypothesis. Methods The subject of this study is a patient with severe ideomotor apraxia from probable corticobasal degeneration. Fluorine 18–labeled deoxyglucose–positron emission tomographic findings revealed a hypometabolism involving the bilateral parietotemporal and the right frontal lobes. When asked to copy an examiner's (J.C.K.) hand gesture, the patient approached, touched, or grasped the examiner's hand, a behavior mostly consistent with the closing-in behavior previously proposed. To investigate the frequency and severity of closing-in, the patient was asked to copy 20 meaningless hand gestures (10 simple and 10 complex). Copying the 20 hand gestures was performed with either the left or the right hand while the patient was seated opposite the examiner (across condition) or on the same side of the examiner (lateral condition). Results Of the 80 trials, closing-in occurred in 43 (53.8%) (35 with approaching, 6 with touching, and 2 with grasping). The closing-in was more frequent and more severe when gesturing with the left than the right hand, but it did not differ between the lateral and across conditions and between simple and complex gestures. Conclusions Corticobasal degeneration might be associated with aberrant manual approach behavior. Although our results do not support the working memory hypothesis, frontal dysfunction might have led to a loss of voluntary control of ontologically primitive propensity to move the forelimb in the direction to which one attends.

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.

Korean written language is composed of ideogram (Hanja) and phonogram (Hangul), as Japanese consists of Kanji (ideogram) and Kana (phonogram). Dissociation between ideogram and phonogram impairment after brain injury has been reported in Japanese, but few in Korean. We report a 64-yr-old right-handed man who showed alexia with agraphia in Hanja but preserved Hangul reading and writing after a left posterior inferior temporal lobe infarction. Interestingly, the patient was an expert in Hanja; he had been a Hanja calligrapher over 40 yr. However, when presented with 65 basic Chinese letters that are taught in elementary school, his responses were slow both in reading (6.3 sec/letter) and writing (8.8 sec/letter). The rate of correct response was 81.5% (53 out of 65 letters) both in reading and writing. The patient's performances were beyond mean-2SD of those of six age-, sex-, and education-matched controls who correctly read 64.7 out of 65 and wrote 62.5 out of 65 letters with a much shorter reaction time (1.3 sec/letter for reading and 4.0 sec/letter for writing). These findings support the notion that ideogram and phonogram can be mediated in different brain regions and Hanja alexia with agraphia in Korean patients can be associated with a left posterior inferior temporal lesion.