A 12-year comparison of patients with Alzheimer's dementia with their informants in eight Asian countries.

BACKGROUND: The number of patients with Alzheimer's disease (AD) has increased dramatically in Asia. OBJECTIVE: To update the demographic characteristics of patients with AD and their informants in eight Asian countries and compare them from 12 years prior. METHODS: The A1-A3 components of the Uniform Dataset (UDS), version 3.0, were administered in Taiwan, Beijing, Hong Kong, Korea, Japan, Philippines, Thailand, and Indonesia. Data were compared with patients with AD in the first registration using the UDS version 1.0 from 2010-2014 in the same regions. RESULTS: A total of 1885 patients with AD and their informants were recruited from 2022 to 2024 and were compared with 2042 patients recruited a decade prior. Each country had its own unique characteristics that changed between both eras. The mean age of the patients and informants was 79.8±8.2 years and 56.5±12.1 years, respectively. Compared with the first registration, the patients were older (79.8 vs 79.0, p=0.002) and had worse global function (mean CDR-SB scores 6.1 vs 5.8, p<0.001); more informants were children (56 % vs. 48 %, p<0.001), and their frequency of in-person visits increased significantly if not living together. A total of 11 %, 4.5 %, 11 %, and 0.4 % of the patients had a reported history of cognitive impairment in their mothers, fathers, siblings, and children, respectively; all percentages, except children, increased significantly over the past decade. CONCLUSION: The present study reports the heterogeneous characteristics of patients with AD and their informants in Asian countries, and the distinct changes in the past decade. The differences in dementia evaluation and care between developing and developed countries warrant further investigation.

Cognitive performance in patients with neuromyelitis optica: clinical and imaging characteristics.

This study aimed to identify the prevalence, clinical and radiographic characteristics, and risk factors for cognitive dysfunction in patients with Neuromyelitis optica spectrum disorder (NMOSD). Eighty-three participants who were diagnosed with NMOSD were recruited. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). The mean age of the patients was 47.78 ± 13.14 years, with an average of 12.05 ± 4.62 years of formal education. The majority (54%) exhibited cognitive impairment, defined by a MoCA score < 25 (mean: 22.96 ± 3.82). Disease severity (evaluated by the Expanded Disability Status Scale) and lower formal education levels were associated with cognitive impairment (p = 0.011 and < 0.001, respectively). The annualized relapse rate, disease duration, and AQP4 antibody status were not associated with cognitive impairment. Interestingly, informant-reported cognitive decline was associated with poorer cognitive performance (p = 0.027). Radiographic findings of lesion location and severity were associated with MoCA-assessed cognitive performance, particularly for lesions in the right parietal lobes (p = 0.023). Hippocampal atrophy was negatively correlated with FAB scores. In conclusion, approximately half of the Thai patients with NMOSD exhibited cognitive impairment, which was associated with age, formal education level, disease severity, relative perception, and specific radiological findings. Further studies incorporating comprehensive neuropsychological tests and subjective cognitive complaints are warranted.

Feature-Based Classification of Mild Cognitive Impairment and Alzheimer's Disease Based on Optical Coherence Tomographic Angiographic Image.

Alzheimer's disease is a type of neurodegenerative disorder that is characterized by the progressive degeneration of brain cells, leading to cognitive decline and memory loss. It is the most common cause of dementia and affects millions of people worldwide. While there is currently no cure for Alzheimer's disease, early detection and treatment can help to slow the progression of symptoms and improve quality of life. This research presents a diagnostic tool for classifying mild cognitive impairment and Alzheimer's diseases using feature-based machine learning applied to optical coherence tomographic angiography images (OCT-A). Several features are extracted from the OCT-A image, including vessel density in five sectors, the area of the foveal avascular zone, retinal thickness, and novel features based on the histogram of the range-filtered OCT-A image. To ensure effectiveness for a diverse population, a large local database for our study was collected. The promising results of our study, with the best accuracy of 92.17,% will provide an efficient diagnostic tool for early detection of Alzheimer's disease.

A Framework for Best Practices and Readiness in the Advent of Anti-Amyloid Therapy for Early Alzheimer's Disease in Asia.

Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer's disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients.

Subjective cognitive complaints and objective cognitive impairment in patients suspected of obstructive sleep apnea who underwent polysomnography.

OBJECTIVES: Obstructive sleep apnea (OSA) is linked to cognitive impairment. We aimed to investigate subjective cognitive complaints (SCCs) and objective cognitive scores and their relation to polysomnography (PSG) parameters in patients suspected of having OSA. METHODS: A prospective cohort cross-sectional study was conducted at Siriraj Hospital. Patients suspected of OSA who were scheduled for PSG were recruited. Cognition was assessed using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT). The Memory Index Score (MIS) was calculated from the MoCA. Subjective cognitive complaint presence was assessed through direct questioning of patients and by employing the Cognitive Change Index rated by self or informants (CCI-I). Patients with severe dementia were excluded. RESULTS: Among 258 patients (mean age 61.46 ± 7.05 years, 51.2% female), the mean MoCA score was 23.89 ± 3.89. Based on PSG results, patients were categorized into groups as follows: those without OSA or with mild OSA (combined total of 20.1%), moderate OSA (28.3%), or severe OSA (51.6%). Cognitive Change Index rated by self and CCI-I scores correlated significantly (r = 0.238, p = 0.019) but not with the MoCA score or CTT time. Objective cognitive scores were associated with PSG parameters: total sleep time (TST), sleep onset latency, wake after sleep onset, sleep stages, mean O2 saturation, and time spent with SaO2 below 90% (all p < 0.05). Subjective cognitive scores were not associated with PSG parameters, except CCI-I with TST. Participants with objective cognitive impairment had lower education, higher body mass index, more comorbidities, and lower SCC percentage (all p < 0.05). Patients with moderate to severe OSA had a higher proportion of objective cognitive impairment (64.1%) but a lower incidence of SCC (38.3%) than patients with no OSA or mild OSA. Thirty patients with severe OSA and cognitive impairment received continuous positive airway pressure (CPAP) treatment for a mean of 12.2 months. These patients showed MoCA and MIS improvement, but no significant changes were observed in their CTT and Cognitive Change Index scores. CONCLUSIONS: Most patients with OSA had objective cognitive impairment, but SCC was less frequent in patients with more severe OSA. Several PSG parameters correlated with cognitive scores but not with subjective cognitive scores. Patients with severe OSA may benefit cognitively from CPAP treatment.

Clinical presentations and treatment outcomes of Hashimoto encephalopathy at Siriraj Hospital - Thailand's largest national tertiary referral center.

BACKGROUND: Hashimoto encephalopathy has multiple clinical presentations, and other than the presence of thyroid antibody, laboratory and imaging investigations are all non-specific. Data specific to the clinical presentations and treatment outcomes of patients with Hashimoto encephalopathy in Thailand remain scarce. OBJECTIVES: To retrospectively investigate the clinical presentations and treatment outcomes of patients with Hashimoto encephalopathy at Siriraj Hospital. METHODS: Patients who presented with acute encephalopathy at our center during July 2012-March 2017 were evaluated for eligibility. The inclusion criteria were positive anti-thyroperoxidase (anti-TPO) or anti-thyroglobulin (anti-Tg) in serum with negative neuronal antibody in serum or cerebral spinal fluid (CSF). Clinical presentations, symptom duration, laboratory results of thyroid status and thyroid autoantibody, CSF study, and clinical outcomes were collected. RESULTS: Of the 204 patients who presented with encephalopathy, 31 (15.2%) were positive for the anti-TPO or anti-Tg antibody. Of those, 13 patients met the diagnostic criteria for Hashimoto encephalopathy. Clinical presentations included cognitive impairment (76.9%), clouding of consciousness (46.2%), and behavior change (30.8%). The neuropsychiatric presentations were visual hallucination (30.8%), auditory hallucination (15.4%), delusion (7.7%), and mood disturbance (23.1%). Other clinical presentations included seizure (38.5%), abnormal movement (23.1%), sleep disturbance (38.5%), ataxia (46.2%), stroke-like episode (15.4%), and fever (15.4%). Most patients (76.9%) had onset within < 3 months. Regarding outcomes, 1 patient who did not receive corticosteroid died from status epilepticus and septic shock. Among the 12 patients who received corticosteroid, 9 (75%) had marked improvement, 1 (8.3%) had slight improvement, and 2 (16.6%) had no clinical improvement. Seven patients (53.9%) had normal thyroid function, 4 patients (30.8%) had subclinical hypothyroidism, and 2 patients (15.4%) had subclinical hyperthyroidism. CONCLUSIONS: The results of this study revealed cognitive impairment, neuropsychiatric symptoms, seizure, ataxia, and sleep disturbance to be common manifestations of Hashimoto encephalopathy. This condition should always be considered in individuals with subacute onset of unexplained cognitive impairment or cerebellar ataxia. Laboratory and neuroimaging investigations were all found to be nonspecific in Hashimoto encephalopathy. Most patients responded well to treatment, so clinical suspicion and early diagnosis and treatment will lead to improved patient outcomes.

Quantitative gait analysis in mild cognitive impairment, dementia, and cognitively intact individuals: a cross-sectional case-control study.

BACKGROUND: Cognitive age-related decline is linked to dementia development and gait has been proposed to measure the change in brain function. This study aimed to investigate if spatiotemporal gait variables could be used to differentiate between the three cognitive status groups. METHODS: Ninety-three older adults were screened and classified into three groups; mild cognitive impairment (MCI) (n = 32), dementia (n = 31), and a cognitively intact (n = 30). Spatiotemporal gait variables were assessed under single- and dual-tasks using an objective platform system. Effects of cognitive status and walking task were analyzed using a two-way ANCOVA. Sub-comparisons for between- and within-group were performed by one-way ANCOVA and Paired t-tests. Area Under the Curve (AUC) of Receiver Operating Characteristics (ROC) was used to discriminate between three groups on gait variables. RESULTS: There were significant effects (P < 0.05) of cognitive status during both single and dual-task walking in several variables between the MCI and dementia and between dementia and cognitively intact groups, while no difference was seen between the MCI and cognitively intact groups. A large differentiation effect between the groups was found for step length, stride length, and gait speed during both conditions of walking. CONCLUSIONS: Spatiotemporal gait variables showed discriminative ability between dementia and cognitively intact groups in both single and dual-tasks. This suggests that gait could potentially be used as a clinical differentiation marker for individuals with cognitive problems.

Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia.

PURPOSE: This study aimed to evaluate the influence of genetic polymorphisms of drug-metabolizing enzyme genes, transporter gene, pathological gene (APOE), and non-genetic factors on therapeutic outcomes as well as steady-state plasma concentrations (Cpss) of galantamine in Thai patients with mixed dementia. METHODS: Fifty-one Thai patients with mixed dementia who received galantamine for at least 6 months were recruited. CYP2D6, CYP3A5, and ABCB1 polymorphisms were detected by TaqMan® Genotyping Assay. UGT1A1 and APOE polymorphism was detected by direct Sanger sequencing technique and restriction fragment length polymorphism technique. Cpss of galantamine was measured by ultra-performance liquid chromatography. Associations of genetic and non-genetic factors with Cpss and clinical outcomes (change in cognitive function as measured by the Thai Mental State Examination (ΔTMSE) scores) were determined by using univariate and multivariate analysis. RESULTS: The multivariate regression model revealed that patients who carried one or more detrimental allelic variant (CYP2D6, CYP3A5, and UGT1A1) showed a tendency toward a higher galantamine adjusted Cpss (B = 34.559, 95% CI = 0.741-68.377, p value = 0.045). Logistic regression analysis also revealed CYP2D6*10 carriers were significantly associated with higher ΔTMSE (B = 5.227, 95% CI = 2.395-8.060, p value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level can attenuate therapeutic outcomes of galantamine. CONCLUSION: Pharmacokinetic-related genes including CYP2D6*10 and UGT1A1 mutant alleles were significantly associated with galantamine adjusted Cpss and cognitive function. Determination of Cpss and genotype could be an adjunct examination to provide further explanation in interindividual variability of galantamine therapeutic outcome.

High burden of cerebral white matter lesion in 9 Asian cities.

Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited (n = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer's disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies.

Accuracy of Support-Vector Machines for Diagnosis of Alzheimer's Disease, Using Volume of Brain Obtained by Structural MRI at Siriraj Hospital.

Background: The determination of brain volumes using visual ratings is associated with an inherently low accuracy for the diagnosis of Alzheimer's disease (AD). A support-vector machine (SVM) is one of the machine learning techniques, which may be utilized as a classifier for various classification problems. This study exploratorily investigated the accuracy of SVM classification models for AD subjects using brain volume and various clinical data as features. Methods: The study was designed as a retrospective chart review. A total of 201 eligible subjects were recruited from the Memory Clinic at Siriraj Hospital, Thailand. Eighteen cases were excluded due to incomplete MRI data. Subjects were randomly assigned to a training group (AD = 46, normal = 46) and testing group (AD = 45, normal = 46) for SVM modeling and validation, respectively. The results in terms of accuracy and a receiver operating characteristic curve analysis are reported. Results: The highest accuracy for brain volumetry (62.64%) was found using the hippocampus as a single feature. A combination of clinical parameters as features provided accuracy ranging between 83 and 90%. However, a combination of brain volumetry and clinical parameters as features to the SVM models did not improve the accuracy of the result. Conclusions: In our study, the use of brain volumetry as SVM features provided low classification accuracy with the highest accuracy of 62.64% using the hippocampus volume alone. In contrast, the use of clinical parameters [Thai mental state examination score, controlled oral word association tests (animals; and letters K, S, and P), learning memory, clock-drawing test, and construction-praxis] as features for SVM models provided good accuracy between 83 and 90%.

Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus.

BACKGROUND: Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761® , is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits. AIMS: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI. MATERIALS & METHODS: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option. RESULTS: EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals. DISCUSSION: EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD. CONCLUSION: As an expert group, we suggest it is clinically appropriate to incorporate EGb 761® as part of the multidomain intervention for MCI.

Action observation combined with gait training to improve gait and cognition in elderly with mild cognitive impairment A randomized controlled trial.

Owing to advancement of medical technology and current knowledge, the population has a longer life expectancy, leading to an increase in the proportion of elderly. OBJECTIVE: The study aimed to investigate the effect of action observation (AO) combined with gait training on gait and cognition in elderly with mild cognitive impairment (MCI). METHODS: Thirty-three participants were randomly allocated to action observation with gait training (AOGT), gait training (GT), and control (CT) groups. The AOGT and GT groups received a program of observation and gait training protocol with the same total duration of 65 min for 12 sessions. For the observation, the AGOT group watched a video of normal gait movement, while the GT group watched an abstract picture and the CT group received no training program. All participants were assessed for gait parameters during single- and dual-tasks using an electronic gait mat system and were assessed for cognitive level using the Montreal Cognitive Assessment (MoCA) at baseline, after training and at 1-month follow-up. RESULTS: The results showed that the AOGT group had significant improvements in gait speeds during single- and dual-tasks, as well as better MoCA score, while the GT group had significant improvement only in gait speed. CONCLUSION: The adjunct treatment of AO with gait training provides greater benefits for both gait and cognitive performances in elderly with MCI.

Com o avanço da tecnologia médica e do conhecimento atual, a população tem uma expectativa de vida mais longa, levando a um aumento na proporção de idosos. OBJETIVO: O estudo teve como objetivo investigar o efeito da observação de ação (AO) combinada com o treinamento da marcha na marcha e cognição em idosos com comprometimento cognitivo leve (CCL). MÉTODOS: Trinta e três participantes foram alocados aleatoriamente para observação de ação com grupos de treinamento de marcha (AOGT), treinamento de marcha (GT) e controle (CT). Os grupos AOGT e GT receberam um programa de observação e protocolo de treinamento de marcha com a mesma duração total de 65 minutos por 12 sessões. Na observação, o grupo AGOT assistiu a um vídeo de movimento normal da marcha, enquanto o grupo GT assistiu a uma figura abstrata e o grupo CT não recebeu nenhum programa de treinamento. Todos os participantes foram avaliados quanto aos parâmetros da marcha durante tarefas simples e duplas, utilizando um sistema eletrônico de esteira da marcha e avaliados quanto ao nível cognitivo, utilizando a Avaliação Cognitiva de Montreal (MoCA) na linha de base, após o treinamento e 1 mês de acompanhamento. RESULTADOS: Os resultados mostraram que o grupo AOGT apresentou melhorias significativas nas velocidades da marcha durante tarefas simples e duplas, além do escore MoCA, enquanto o grupo GT teve melhora significativa apenas na velocidade da marcha. CONCLUSÃO: O tratamento adjunto da AO com o treinamento da marcha proporciona maiores benefícios tanto do desempenho da marcha quanto do desempenho cognitivo em idosos com CCL.

Action observation combined with gait training to improve gait and cognition in elderly with mild cognitive impairment A randomized controlled trial / Observação da ação e treinamento da marcha para melhorar a marcha e a cognição em idosos com comprometimento cognitivo leve: um estudo controlado randomizado

Abstract. Owing to advancement of medical technology and current knowledge, the population has a longer life expectancy, leading to an increase in the proportion of elderly. Objective: The study aimed to investigate the effect of action observation (AO) combined with gait training on gait and cognition in elderly with mild cognitive impairment (MCI). Methods: Thirty-three participants were randomly allocated to action observation with gait training (AOGT), gait training (GT), and control (CT) groups. The AOGT and GT groups received a program of observation and gait training protocol with the same total duration of 65 min for 12 sessions. For the observation, the AGOT group watched a video of normal gait movement, while the GT group watched an abstract picture and the CT group received no training program. All participants were assessed for gait parameters during single- and dual-tasks using an electronic gait mat system and were assessed for cognitive level using the Montreal Cognitive Assessment (MoCA) at baseline, after training and at 1-month follow-up. Results: The results showed that the AOGT group had significant improvements in gait speeds during single- and dual-tasks, as well as better MoCA score, while the GT group had significant improvement only in gait speed. Conclusion: The adjunct treatment of AO with gait training provides greater benefits for both gait and cognitive performances in elderly with MCI.

Resumo. Com o avanço da tecnologia médica e do conhecimento atual, a população tem uma expectativa de vida mais longa, levando a um aumento na proporção de idosos. Objetivo: O estudo teve como objetivo investigar o efeito da observação de ação (AO) combinada com o treinamento da marcha na marcha e cognição em idosos com comprometimento cognitivo leve (CCL). Métodos: Trinta e três participantes foram alocados aleatoriamente para observação de ação com grupos de treinamento de marcha (AOGT), treinamento de marcha (GT) e controle (CT). Os grupos AOGT e GT receberam um programa de observação e protocolo de treinamento de marcha com a mesma duração total de 65 minutos por 12 sessões. Na observação, o grupo AGOT assistiu a um vídeo de movimento normal da marcha, enquanto o grupo GT assistiu a uma figura abstrata e o grupo CT não recebeu nenhum programa de treinamento. Todos os participantes foram avaliados quanto aos parâmetros da marcha durante tarefas simples e duplas, utilizando um sistema eletrônico de esteira da marcha e avaliados quanto ao nível cognitivo, utilizando a Avaliação Cognitiva de Montreal (MoCA) na linha de base, após o treinamento e 1 mês de acompanhamento. Resultados: Os resultados mostraram que o grupo AOGT apresentou melhorias significativas nas velocidades da marcha durante tarefas simples e duplas, além do escore MoCA, enquanto o grupo GT teve melhora significativa apenas na velocidade da marcha. Conclusão: O tratamento adjunto da AO com o treinamento da marcha proporciona maiores benefícios tanto do desempenho da marcha quanto do desempenho cognitivo em idosos com CCL.

Role of Fluid Biomarkers and PET Imaging in Early Diagnosis and its Clinical Implication in the Management of Alzheimer's Disease.

Clinical diagnosis of Alzheimer's disease (AD) is based on symptoms; however, the challenge is to diagnose AD at the preclinical stage with the application of biomarkers and initiate early treatment (still not widely available). Currently, cerebrospinal fluid (CSF) amyloid-ß 42 (Aß42) and tau are used in the clinical diagnosis of AD; nevertheless, blood biomarkers (Aß42 and tau) are less predictive. Amyloid-positron emission tomography (PET) imaging is an advancement in technology that uses approved radioactive diagnostic agents (florbetapir, flutemetamol, or florbetaben) to estimate Aß neuritic plaque density in adults with cognitive impairment evaluated for AD and other causes of cognitive decline. There is no cure for AD to date-the disease progression cannot be stopped or reversed; approved pharmacological agents (donepezil, galantamine, and rivastigmine; memantine) provide symptomatic treatment. However, the disease-modifying therapies are promising; aducanumab and CAD106 are in phase III trials for the early stages of AD. In conclusion, core CSF biomarkers reflect pathophysiology of AD in the early and late stages; the application of approved radiotracers have potential in amyloid-PET brain imaging to detect early AD.

Pathogenic PSEN1 Glu184Gly Mutation in a Family from Thailand with Probable Autosomal Dominant Early Onset Alzheimer's Disease.

A pathogenic mutation in PSEN1 p.Glu184Gly was discovered in a Thai family with early onset Alzheimer's disease (EOAD) as the first case in Asia. Proband patient presented memory impairment and anxiety at the age of 41 years. Family history was positive, since several family members were also diagnosed with dementia (father and grandfather). MRI in the patient revealed global cortical atrophy without specific lesions or lacuna infarctions. Extensive genetic profiling for 50 neurodegenerative disease related genes was performed by next generation sequencing (NGS) on the patient. PSEN1 Glu184Gly was previously reported in French families with frontal variant Alzheimer's disease (AD). Interestingly, this mutation is located near the splicing site and could possibly result in abnormal cleavage of PSEN1 transcript. Furthermore, 3D models from protein structural predictions revealed significant structural changes, since glycine may result in increased flexibility of TM-III helix. Inter/intra-helical interactions could also be altered. In the future, functional studies should be performed to verify the probable role PSEN1 Glu184Gly in amyloid beta processing and pathogenicity.

Influence of CYP2D6, CYP3A5, ABCB1, APOE polymorphisms and nongenetic factors on donepezil treatment in patients with Alzheimer's disease and vascular dementia.

PURPOSE: This study aims to evaluate the influence of genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and APOE genes and nongenetic factors on steady-state plasma concentrations (Cpss) of donepezil and therapeutic outcomes in Thai patients with Alzheimer's disease (AD) and vascular dementia (VAD). PATIENTS AND METHODS: Eighty-five dementia patients who received donepezil for at least six months were recruited. CYP2D6, CYP3A5, ABCB1, and APOE polymorphisms were genotyped. Cpss of donepezil was measured. Association of genetic and non-genetic factors with Cpss and clinical outcomes of donepezil (cognitive function as measured by the Thai Mental State Examination score; TMSE) were determined by using univariate and multivariate analysis. RESULTS: Both univariate and multiple linear regression analysis indicated that only CYP2D6*10 allele was associated with higher Cpss (p-value =0.029 and B =0.478, p-value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE (p-value =0.010 and B =4.527, p-value =0.001) and ΔTMSE (p-value =0.023 and B =4.107, p-value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil (p-value =0.007 and B =0.511, p-value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =-2.719, p-value =0.013 and ΔTMSE: B =-2.348, p-value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of CYP3A5*3, ABCB1 3435C>T or ABCB1 1236C>T, and APOE ε4 genotypes with Cpss or clinical outcomes of donepezil was found in this study. CONCLUSION: Our results suggests that CYP2D6*10 strongly influences Cpss and there is a trend toward better outcomes of donepezil in patients with AD. Nongenetic factors including concomitant drugs treatment might alter Cpss of donepezil or clinical outcomes.

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer's Disease.

Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer's disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders' genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area.

Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761®.

BACKGROUND: The Ginkgo biloba special extract, EGb 761® has been widely used in the treatment of neuropsychiatric disorders, including Alzheimer's disease (AD). METHODS: To guide clinical practice in the Asian region, the Asian Clinical Expert Group on Neurocognitive Disorders compiled evidence-based consensus recommendations regarding the use of EGb 761® in neurocognitive disorders with/without cerebrovascular disease. RESULTS: Key randomized trials and robust meta-analyses have demonstrated significant improvement in cognitive function, neuropsychiatric symptoms, activities of daily living (ADL) and quality of life with EGb 761® versus placebo in patients with mild-to-moderate dementia. In those with mild cognitive impairment (MCI), EGb 761® has also demonstrated significant symptomatic improvement versus placebo. World Federation of Societies of Biological Psychiatry guidelines list EGb 761® with the same strength of evidence as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists e.g. memantine (Grade 3 recommendation; Level B evidence). Only EGb 761® had Level B evidence in improving cognition, behaviour, and ADL in both AD and vascular dementia patients. Safety analyses show EGb 761® to have a positive risk-benefit profile. While concerns have been raised regarding a possible increased bleeding risk, several randomized trials and two meta-analyses have not supported this association. CONCLUSIONS: The Expert Group foresee an important role for EGb 761® , used alone or as an add-on therapy, in the treatment of MCI and dementias, particularly when patients do not derive benefit from acetylcholinesterase inhibitors or NMDA antagonists. EGb 761® should be used in alignment with local clinical practice guidelines.

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

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.