Simon Kang Seng Ting

Absence of A673T amyloid-β precursor protein variant in alzheimer's disease and other neurological diseases

The rare variant A673T in the amyloid-β precursor protein (APP) gene has been shown to reduce the risk of cognitive impairment. We genotyped the variant in 8721 Asian individuals comprising 552 with Alzheimers disease and vascular dementia, 790 with Parkinsons disease, and 7379 controls. The A673T variant was absent in all of the subjects. Our finding suggests that the A673T protective variant is not relevant in our Asian population. Studies in other ethnic populations would clarify whether this variant is specific to specific races/ethnicities.

Higher Peripheral TREM2 mRNA Levels Relate to Cognitive Deficits and Hippocampal Atrophy in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment

BACKGROUND Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimers disease (AD) risk. Recent studies have reported inconsistent peripheral TREM2 mRNA expression levels and relationship with cognitive scores in AD and mild cognitive impairment (MCI). Additionally, no study has examined the association of peripheral TREM2 levels with neuroimaging measures in AD and MCI. OBJECTIVE To determine peripheral TREM2 mRNA levels in AD, amnestic MCI (aMCI) and healthy controls, and the association with cognitive performance and brain structural changes. METHODS We measured peripheral TREM2 mRNA levels in 80 AD, 30 aMCI, and 86 healthy controls using real time polymerase chain reaction. TREM2 levels were correlated with various cognitive performance and brain volumes, correcting for APOE4 status. RESULTS TREM2 mRNA levels were significantly higher in AD compared to controls and aMCI. Levels did not differ between aMCI and controls. Corrected for APOE4, higher TREM2 levels correlated with lower Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and episodic memory scores, and lower total grey matter and right hippocampal volumes. Whole-brain voxel-based morphometry analysis found negative association between TREM2 mRNA levels and grey matter volumes in temporal, parietal and frontal regions. AD subjects with MoCA scores ≤20 had higher TREM2 levels correlating with smaller total grey matter, left hippocampal and right hippocampal volumes. CONCLUSION Peripheral TREM2 mRNA levels are higher in AD and are associated with AD-related cognitive deficits and hippocampal atrophy. Our findings suggest that TREM2 may be a potential non-invasive peripheral biomarker for AD diagnosis.

Early detection of dementia in multilingual populations: Visual Cognitive Assessment Test (VCAT)

Background Early diagnosis of cognitive impairment allows timely intervention with pharmacological and non-pharmacological measures. However, current cognitive evaluation tools do not cater for multilingual populations. Objective To develop and validate a visual-based cognitive evaluation tool, the Visual Cognitive Assessment Test (VCAT), which can be administered to multilingual populations without the need for translation or adaptation. Method We designed a battery of tests to evaluate the domains of memory, executive function, visuospatial function, language and attention. Pilot testing of individual test items, followed by test refinement and development of a field version was performed. We subsequently validated VCAT for the diagnosis of mild cognitive impairment (MCI) and mild Alzheimers disease (AD). Diagnostic performance was assessed by the area under the curve (AUC), sensitivity (Se) and specificity (Sp). Results VCAT was validated in a sample of 206 participants. The sample comprised 53.9% males; mean age (SD) was 67.8 (8.86) years; mean years of education was 10.5(6.0). AUC of VCAT for detection of cognitive impairment was found to be 93.3 (95% CI 90.1 to 96.4). Also, the Se and Sp of VCAT for the diagnosis of cognitive impairment (MCI and mild AD) were 85.6% and 81.1%, respectively. VCATs diagnostic Se and Sp comparable to those of the Montreal Cognitive Assessment in the same cohort. Mean time-to-complete VCAT was 15.7±7.3 min. Conclusions The VCAT has good Se and Sp for the diagnosis of MCI and mild AD. The visual-based test paradigm allows easy application to multilingual populations without the need for translation or adaptation.

A Novel PSEN1 Mutation (I238M) associated with Early-Onset Alzheimer's Disease in an African-American Woman

Mutations in PSEN1 are the most common cause of autosomal dominant familial Alzheimers disease (FAD). We describe an African-American woman with a family history consistent with FAD who began to experience cognitive decline at age 50. Her clinical presentation, MRI, FDG-PET, and PIB-PET scan findings were consistent with AD and she was found to have a novel I238M substitution in PSEN1. As this mutation caused increased production of Aβ42 in an in vitro assay, was not present in two population databases, and is conserved across species, it is likely to be pathogenic for FAD.

Dissociative semantic breakdown in Alzheimer's disease: evidence from multiple category fluency test.

BACKGROUND Category-specific semantic dissociation particularly in terms of biological and non-biological dichotomy has been described in Alzheimers disease (AD). We re-examine above finding by performing multiple superordinate category verbal fluency test in AD patients. METHOD We analyze the baseline neuropsychological assessment performance of food and animal fluency test of AD patients from a tertiary hospital that collected prospectively over 5 years period and correlation was calculated by Kappa test. The analysis is stratified according to literacy level (primary: 0-6 years education and secondary: >6 years education) and disease severity (MMSE score: mild 19-24, moderate 13-18 and severe <13). RESULT A total of 296 AD patients were analyzed and only fair to moderate agreement between food and animal category fluency test was found especially in the mild AD cases (primary: kappa 0.42; secondary: kappa 0.40). Kappa agreement level increases when disease progress especially in the secondary education group. Food category, which is a more relevant semantic knowledge to Singapore population, is generally more affected. Higher educated subjects appeared to have less semantic dissociation effect when disease progress. CONCLUSION Despite less primed in daily life, biological category of semantic knowledge appears to be affected less during AD process in highly urbanized Singapore society. Brain appears to have special protective mechanism towards living things. However, education level seems have a modulation effect towards the biological protective mechanism.

Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer’s disease

Psychosis is common in Alzheimer’s disease (AD). However, studies on neuropathology in vascular etiology contributing to psychosis in AD is lacking to date. The aim of this study was to investigate neuropathological vascular related changes in Alzheimer’s disease with psychosis. Data of patients with AD from the National Alzheimer’s Coordinating Center between 2005 to September 2013 was accessed and reviewed. Presence of psychosis was determined based on Neuropsychiatric Inventory Questionnaire taken from the last visit within one year prior to death, and patients were divided into psychosis positive and negative group. Comparison of clinical details and neuropathological vascular changes between the groups was performed using Wilcoxon rank sum test and Chi-square/ Fisher’s exact test. Significant variables were further included in a multivariate logistic model. Overall, 145 patients was included. Of these, 50 patients were psychosis positive. Presence of one or more cortical microinfarcts and moderate to severe arteriosclerosis was found to be positively associated with psychosis. Our results suggest vascular changes correlate with psychosis in Alzheimer’s disease.

Short duration repetitive transcranial magnetic stimulation for tinnitus treatment: A prospective Asian study

BACKGROUND Tinnitus is a subjective auditory perception of sounds or noise not triggered by external auditory stimuli. To date, treatment in severe cases is generally unsatisfactory. Characteristic functional brain imaging changes associated with tinnitus include hyperactivity encompassing both the primary auditory cortex (AC) and the secondary or associative cortex. Brief repetitive transcranial magnetic stimulation (rTMS) trains applied to the scalp overlying the hyperactive left AC is known to produce moderate tinnitus attenuation. OBJECTIVE Although Western studies have documented the value of rTMS in tinnitus treatment, we evaluate the efficacy of a short duration rTMS protocol for the first time in the Asian setting. METHOD Consecutive patients were recruited at our tinnitus clinic. Detailed history, examination, audiogram and baseline tinnitus scales were recorded. RTMS consisted of 1000 pulses/day at 1 Hz and 110% of the motor threshold, for five consecutive days over the left temporoparietal cortex. Tinnitus ratings were determined weekly for 4 weeks after rTMS. RESULT Fifteen patients completed the trial; none experienced significant side effects. Repeated measures ANOVA showed significant linear decrease in Tinnitus Handicap Inventory (THI) scores over the time period (F((1,14))=4.7, p=0.04). However, none of the other parameters (severity, annoyance, effect on lifestyle and overall impression: visual analogue scale) showed beneficial outcomes. CONCLUSIONS Our findings point to a positive effect of short duration rTMS in tinnitus treatment using the THI. However, no significant benefits were demonstrated for other subjective patient ratings. Although well tolerated and convenient, short duration rTMS may prove inadequate for modulating maladaptive plastic changes at the cortical level, and our results suggest the need for delivery of more stimuli. Future studies will utilize at least 2000 pulses/day, in line with previous experience in Western settings.

A Rare Cause of Cerebellar Ataxia Syndrome: Superficial Siderosis of Central Nervous System

PURPOSE To describe and emphasize importance of recognizing superficial siderosis (SS) of the central nervous system (CNS) when assessing cerebellar ataxia syndrome CASE REPORT Superficial siderosis (SS) of the central nervous system (CNS) is a rare disorder that results from chronic hemosiderin deposition in the subpial layers of the brain and the spinal cord. Although recurrent bleeding in the subarachnoid space is the most likely explanation, a definite history of subarachnoid hemorrhage (SAH) is often lacking. Among the clinical presentations described in the literature include sensorineural deafness, dementia, anosmia, pyramidal tract signs and cerebellar ataxia. However, due to its rarity, SS remains one of the least considered differential diagnosis in patients with sporadic ataxia syndrome. We describe a case of progressive gait imbalance that was initially misdiagnosed for several years until a brain MRI study showed evidence of diffuse hemosiderin deposition suggestive of SS of CNS. CONCLUSION MR brain with gradient-echo T2-weightd images should be included in all MR studies carried out to investigate the etiology of cerebellar ataxia to allow early diagnosis and prompt intervention for SS.

Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement.

To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found. In 45 subjects screened for C9orf72 repeat expansions, no pathogenic expansion (≥30 repeats) was identified, but there was a higher proportion of intermediate length (≥10-29 repeats) alleles in patients compared with controls (8/90 alleles, 8.9% vs. 9/164 alleles, 5.5%). Overall, we detected a mutation rate of 7.7% (4/52 patients) in our cohort. Given recent findings of enrichment of rare TREM2 variants (including R47C) in Alzheimers disease, it is notable that we detected a homozygous TREM2 R47C carrier presenting with an FTD rather than an Alzheimers disease phenotype.

Characteristics of number transcoding errors of Chinese- versus English-speaking Alzheimer's disease patients

ABSTRACT Number processing disorder is an acquired deficit in mathematical skills commonly observed in Alzheimer’s disease (AD), usually as a consequence of neurological dysfunction. Common impairments include syntactic errors (800012 instead of 8012) and intrusion errors (8 thousand and 12 instead of eight thousand and twelve) in number transcoding tasks. This study aimed to understand the characterization of AD-related number processing disorder within an alphabetic language (English) and ideographical language (Chinese), and to investigate the differences between alphabetic and ideographic language processing. Chinese-speaking AD patients were hypothesized to make significantly more intrusion errors than English-speaking ones, due to the ideographical nature of both Chinese characters and Arabic numbers. A simplified number transcoding test derived from EC301 battery was administered to AD patients. Chinese-speaking AD patients made significantly more intrusion errors (p = 0.001) than English speakers. This demonstrates that number processing in an alphabetic language such as English does not function in the same manner as in Chinese. The impaired inhibition capability likely contributes to such observations due to its competitive lexical representation in brain for Chinese speakers.