Shahul Hameed

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.

Treatment outcome correlates with knowledge of disease in hemifacial spasm.

OBJECTIVES Hemifacial spasm (HFS), a potentially disabling facial condition affects quality of life (QOL) and botulinum toxin is an effective treatment. No studies have examined whether a better level of knowledge of the disease would lead to an improved quality of life and treatment response in HFS. We examined the relationship between knowledge of disease with improvement in QOL following botulinum toxin treatment in HFS patients. PATIENTS AND METHODS A total of 106 HFS patients (mean age of 56.8+/-9.9 years) were prospectively included. A baseline knowledge questionnaire and a validated disease-specific quality of life scale (HFS-7) were administered before and after botulinum toxin treatment. RESULTS A better educational level was an independent predictor of high knowledge of HFS (p=0.02). Multivariate analysis using improvement in HFS-7 (total and subscore) as outcomes, and adjusting for age, gender, education, severity and duration of HFS, showed that high knowledge was predictive of a bigger improvement in HFS-7 total (p=0.03) and HFS-7 subscore (p=0.03). CONCLUSIONS HFS patients with high knowledge of disease reported better improvement in QOL following botulinum toxin treatment. Better educational efforts will augment current medical and surgical treatments in improving QOL in HFS. Our findings could potentially be extended to many other medical conditions.

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.

Cost Related to Dementia in the Young and the Impact of Etiological Subtype on Cost

BACKGROUND Young onset dementia (YOD) presents in individuals who are economically productive and socially active. While the cost related to dementia in the elderly has been widely studied, the cost related to YOD is largely unknown. OBJECTIVE To study the economic burden of community dwelling YOD in relation to late onset dementia (LOD) and cost of YOD based on etiology. METHODS In this prospective cross-sectional study of 255 patients attending a tertiary neurology center, data on economic burden, clinical features, and caregiver burden were collected using structured financial questionnaire, standard cognitive and neuropsychiatric measures, and Zarit caregiver burden scale. Cost components were grouped into those relating to direct medical costs, direct non-medical costs, and those related to indirect costs. Cost was also categorized based on etiology of YOD. RESULTS The mean age at symptom onset in the YOD and LOD cohort was 57.0 (SD 5.1) and 75.0 (SD 5.9) years, respectively. The median annual cost for patients with YOD was almost twice that of LOD (USD 15,815 versus USD 8,396). Indirect cost contributed heavily to cost related to YOD. Even when grouped by dementia etiology, YOD patients with Alzheimers disease, frontotemporal dementia (FTD), and vascular dementia had higher cost compared to their elderly counterparts. Young onset FTD had the highest cost. 43.2% of YOD reported loss of employment due to dementia, which was significantly higher than that in LOD (2.4%). CONCLUSION Patients with YOD have a high economic burden. Young patients with FTD have the highest cost followed by vascular dementia and Alzheimers disease.

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.

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.

Digit span: a comparison of Chinese versus alphabetic language speakers in dysexecutive dementia patients

Objective: To study the language effect in digit span performance of dysexecutive dementia patients from a multilingual society. Background: Literature raises concern of cross language discrepancies in the performance of digit span. To date, the cross language effect has not been examined among patients who suffer neurodegenerative disease from a multi-lingual society. We hypothesize that performance on the forward digit span (FDS) task is language dependent and not associated with executive function. Methods: A total of 121 Chinese and non-Chinese speaking patients (English and Malay) with dementia and executive dysfunction completed the working memory task from Wechsler Memory Scale-Revised (WMS-R) edition. Logistic regression was performed to identify differences in performance on this task between these two groups. Results: Chinese speakers were found to perform significantly better on the FDS when compared to non-Chinese speakers. There was no difference in performance of visual memory span between the groups. Conclusions: Consistent with pervious findings, FDS is independent of executive function. It indicates a need to validate the performance on the digit span task among different languages within a population from the same social background. Disclosure: Dr. Ting has nothing to disclose. Dr. Hameed has nothing to disclose. Dr. Tan has nothing to disclose. Dr. Gabriel has nothing to disclose. Dr. Doshi has nothing to disclose.

THE ROLE OF COMPREHENSIVE INVESTIGATION IN THE DIAGNOSTIC WORK-UP OF YOUNGER PATIENTS WITH COGNITIVE IMPAIRMENT

and adjusted for age. WM tracks that significantly correlated with EYO were further evaluated with pathological biomarkers (cerebrospinal fluid (CSF) amyloid and tau). Results:Significant changes in mean diffusivity and radial diffusivity were seen within parietal and frontal regions for MC CDR>0 compared to other groups (Fig1). Within the MC group, three WM tracks were significantly associated with EYO: forceps major (FMaj), cingulum, and posterior corpus callosum (PCC). Initial decline in WM for MC and NC occur around 10 years prior to EYO. A significant interaction was observed for mutation status and EYO in the cingulum. CSF amyloid correlated with average mean fractional anisotropy (FA; p1⁄40.02) but not with any specific WM track. CSF T-tau correlated with FA for the PCC (p1⁄40.04) and FMaj (p1⁄40.001). Conclusions: This data reveals that WM integrity in ADAD is most strongly affected in posterior/parietal white matter with more advanced disease. These changes suggest that structural decline may initiate just before EYO that associates with the underlying pathology.