Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer's disease

Vo Van Giau,1,* Vorapun Senanarong,2,* Eva Bagyinszky,1 Chanin Limwongse,2 Seong Soo A An,1 SangYun Kim3 1Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Seongnam, South Korea; 2Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 3Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea *These authors contributed equally to this work Introduction: Early-onset Alzheimer’s disease (AD) accounts for than less 1% of all AD cases, with large variation in the reported genetic contributions of known dementia genes. Mutations in the amyloid precursor protein (APP) gene were the first to be recognized as the cause of AD. Methods: Here, a male patient with probable early-onset AD at the age of 55 years from Thailand was investigated by next-generation sequencing. Results: A novel mutation in exon 14 of APP (c.1810C>T, p.V604M) was found. He initially illustrated the clinical manifestations of progressive nonfluent aphasia in 2011. However, he was finally diagnosed with AD presenting logopenic aphasia in 2013. The follow-up magnetic resonance imaging scan showed progression of hippocampal trophy compared with the initial image. A 3D protein structure model revealed that V604M exchange could result in significant changes in the APP protein due to the increased hydrophobicity of methionine in the helix, which could result in altering of the APP functions. Conclusion: Additional studies to characterize APP p.V604M are necessary to further understand the effects of this mutation. Keywords: APP, Alzheimer’s disease, Thailand, V604

Alzheimer’s Disease Dementia as the Diagnosis Best Supported by the Cerebrospinal Fluid Biomarkers: Difference in Cut-Off Levels from Thai Experience

Objectives. To determine how beta-amyloid 1-42 (Aβ 1-42), total tau (tTau), and phosphorylated tau (pTau) levels in CSF behave in a cohort of Thai patients from the Memory Clinic in Bangkok, Thailand. Methods. During 2009–2011, twenty eight subjects from the memory clinic at Siriraj Hospital had CSF analysis for AD biomarkers. Aβ 1-42, tTau, and pTau (at amino acid 181) were measured in CSF by ELISA technique. Results. Mean of Thai mental state examination (TMSE) of 28 Thai cohort was 16.48 (6.63). Fourteen had AD, ten had non-AD dementia, and four non-cases were those with subjective memory complaint (SMC) without dementia. Mean CSF Aβ 1-42, tTau, ptau (181), and pTau/Aβ 1-42 in the AD group were 241.36 (60.14) pg/mL, 222.79 (212.24) pg/mL, 40.79 (27.84) pg/mL, and 0.18 (0.12) accordingly. Mean CSF Aβ 1-42, tTau, pTau (181), and pTau/Aβ 1-42 in the non-AD dementia group were 430.40 (125.18) pg/mL, 349.30 (692.16) pg/mL, 36.80 (14.90) pg/mL, and 0.09 (0.04) accordingly. Mean CSF Aβ 1-42, tTau, pTau (181), and pTau/Aβ 1-42 in the non-cases with SMC without dementia were 499.75 (93.44) pg/mL, 137.25 (62.74) pg/mL, 31.75 (17.48) pg/mL, and 0.06 (0.02). There is significant difference (P<0.05) among the 3 groups in CSF Aβ 1-42 and pTau/Aβ 1-42. We propose mean + 1.5 SD of CSF Aβ 1-42 in AD group (331.57 pg/mL) to be the cut-off point in Thai subjects. Conclusion. There are significant different in CSF Aβ 1-42 and CSF p-tau/Aβ 1-42 among those with AD, non-AD dementia and non cases with SMC without dementia in Thai cohort. Cut-off point of CSF Aβ 1-42 of 331.57 pg/mL is suggested in Thai study

Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson&rsquo;s disease dementia

Nagaendran Kandiah,1,2 Ming-Chyi Pai,3,4 Vorapun Senanarong,5 Irene Looi,6,7 Encarnita Ampil,8 Kyung Won Park,9 Ananda Krishna Karanam,10 Stephen Christopher11 1Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, 2Duke-NUS, Graduate Medical School, Singapore; 3Division of Behavioral Neurology, Department of Neurology, 4Alzheimer&rsquo;s Disease Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 5Division of Neurology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 6Clinical Research Centre, 7Department of Medicine, Hospital Seberang Jaya, Penang, Malaysia; 8Department of Neurology and Psychiatry, Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines; 9Department of Neurology and Cognitive Disorders and Dementia Center, Institute of Convergence Bio-Health, Dong-A University College of Medicine, Busan, Republic of Korea; 10Novartis Healthcare Private Limited, Hyderabad, India; 11Novartis (Singapore) Pte. Ltd., Singapore Abstract: Several studies have demonstrated clinical benefits of sustained cholinesterase inhibition with rivastigmine in Alzheimer&rsquo;s disease (AD) and Parkinson&rsquo;s disease dementia (PDD). Unlike donepezil and galantamine that selectively inhibit acetylcholinesterase (AChE; EC 3.1.1.7), rivastigmine is a unique cholinesterase inhibitor with both AChE and butyrylcholinesterase (BuChE; EC 3.1.1.8) inhibitory activity. Rivastigmine is also available as transdermal patch that has been approved by the US Food and Drug Administration for the treatment of mild, moderate, and severe AD as well as mild-to-moderate PDD. In this review, we explore the role of BuChE inhibition in addition to AChE inhibition with rivastigmine in the outcomes of cognition, global function, behavioral symptoms, and activities of daily living. Additionally, we review the evidence supporting the use of dual AChE-BuChE inhibitory activity of rivastigmine as a therapeutic strategy in the treatment of neurological disorders, with a focus on the role of rivastigmine in subcortical dementias such as vascular dementia (VaD) and PDD. Toward this objective, we performed a literature search in PubMed and Ovid with limits to articles published in the English language before June 2016. The available evidence from the literature suggests that the dual inhibition of AChE and BuChE may afford additional therapeutic potential of rivastigmine in subcortical dementias (subcortical VaD and PDD) with benefits on cognition and behavioral symptoms. Rivastigmine was found to specifically benefit executive dysfunction frequently observed in subcortical dementias; however, large randomized clinical studies are warranted to support these observations. Keywords: acetylcholinesterase, BuChE genotype, butyrylcholinesterase, Parkinson&rsquo;s disease dementia, rivastigmine, subcortical vascular dementi

The dementia and disability project in Thai elderly: rational, design, methodology and early results

<p>Abstract</p> <p>Background</p> <p>A strong inverse relationship of functional limitation and socioeconomic status has been established in western ageing society. Functional limitation can be related to chronic diseases, disuse, cognitive decline, and ageing. Among chronic diseases in the Thai population, cerebrovascular diseases, diabetes, and arthritis are common. These factors are known to contribute to disability and poor quality of life in the elder population. Neuropsychiatric problems, cognitive decline, dementia, and cultural issues in elderly people also can alter the quality of life of the elderly.</p> <p>Methods</p> <p>The Dementia and Disability Project in Thai Elderly (DDP) aims at comprehensively assessing community dwelling Thai elderly to understand the relationship between disability and motor function, neuropsychiatric symptoms, cognitive function, and chronic diseases. The DDP is the first study to look at the prevalence and etiology of dementia and of mild cognitive impairment (MCI) in Thai elders and to explore the relationship of cognition, disability, small vessel diseases and cortical degeneration with neuroimaging in Thai elderly people. 1998 Thai elders were screened in 2004–2006 and diagnosed as having MCI or dementia. 223 elders with MCI or dementia and cognitively normal elderly had brain magnetic resonance imaging (MRI) or at baseline. 319 elders from the 3 groups had blood tests to investigate the risks and possible etiologies of dementia including genotyping at baseline.</p> <p>Results</p> <p>The mean age of elders in this study is 69.51(SD=6.71, min=60, max=95) years. 689(34.9%) are men and 1284(65.1%) are women. Mean body weight was 58.36(SD=11.20) kgs. The regression model reveals that performance on gait and balance and serum triglyceride predicts activity of daily living performance (adjusted r² = 0.280, f=2.644, p=0.003). The majority of abnormal gait in Thai elders was lower level gait disturbance. Only 1.5% (29/1952) had highest level gait disorders. 39.5% of 1964 subjects were free of chronic diseases. Treatment gap (indicating those who have untreated or inadequate treatment) of diabetes mellitus and hypertension in Thai elders in this study was 37% and 55.5% respectively. 62.6% of Thai elders have ApoE3E3 allele. Prevalence of positive ApoE4 gene in this study is 22.85%. 38.6% of Thai elders who had MRI brain study have moderate to severe white matter lesions.</p> <p>Conclusion</p> <p>The large and comprehensive set of measurements in DDP allows a wide-ranging explanation of the functional and clinical features to be investigated in relation to white matter lesions or cortical atrophy of the brain in Thai elderly population. An almost 2 year follow up was made available to those with MCI and dementia and some of the cognitively normal elderly. The longitudinal design will provide great understanding of the possible contributors to disability in the elderly and to the progression of cognitive decline in Thai elders.</p

Analysis of the effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer's disease

Background: Alzheimer's disease ( AD) is a progressive neurodegenerative disorder and delaying disease worsening is a relevant treatment outcome. Methods: Data from 6 randomized, double-blind, placebo-controlled, 6-month studies were pooled and a subgroup of patients ( 867 on placebo, 959 on memantine) with moderate to severe AD ( MiniMental State Examination &lt; 20) was analyzed. 'Any clinical worsening' was defined as a decline on the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) or the Severe Impairment Battery ( SIB) and on the Clinician's Interview-Based Impression of Change Plus Caregiver In put (CIBIC-plus) and the Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL), and 'marked clinical worsening' as 6 4 points decline on the ADAS-cog or 6 5 points on the SIB and decline on the CIBIC-plus and the ADCS-ADL. Results: More placebo-treated than memantine-treated patients showed any clinical worsening ( 28 vs. 18%; p &lt; 0.001), and 21% placebo-treated patients compared to 11% memantine-treated patients had marked clinical worsening ( p &lt; 0.001). Conclusion: In this population of moderate and severe AD patients, treatment with memantine was associated with reducing worsening of clinical symptoms in AD during the 6-month study period. Copyright (c) 2007 S. Karger AG, Base