CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia.

PURPOSE: Donepezil, a drug frequently used to treat dementia, is mainly metabolized by cytochrome P450 2D6 (CYP2D6). This study investigated the relationships between CYP2D6 genotype and activity scores as well as predicted phenotype of plasma donepezil concentrations in 86 Thai dementia participants. MATERIALS AND METHODS: CYP2D6 was genotyped using bead-chip technology (Luminex xTAG® v.3). Steady-state trough plasma donepezil concentrations were measured using high-performance liquid chromatography. RESULTS: Sixteen genotypes were found but the most frequent genotypes detected among our participants were CYP2D6*10/*10 (27.9%) and *1/*10 (26.7%). One-third of the participants had an activity score of 1.25 which predicted that they were normal metabolizers. The overall median (interquartile range) of plasma donepezil concentration was 51.20 (32.59-87.24) ng/mL. Normal metabolizers (NMs) had lower plasma donepezil concentrations compared to intermediate metabolizers (IMs) (41.15 (28.44-67.65) ng/mL vs 61.95 (35.25-97.00) ng/mL). Multivariate analysis showed that CYP2D6 activity score (r2 = 0.50) and the predicted phenotype (independent of dose) could predict the plasma donepezil concentration (r2 = 0.49). CONCLUSION: Plasma donepezil concentration in NMs was lower compared to IMs. Additional studies with larger sample size and use of next-generation sequencing as well as its outcomes are warranted to confirm the benefit of using pharmacogenetic-guided treatment for donepezil.

Early prediction of donepezil cognitive response in Alzheimer's disease by brain perfusion single photon emission tomography.

Currently, there is no effective means to evaluate donepezil response. We evaluated brain perfusion change at 4 h after donepezil administration (4 h DNPZ) to predict cognitive responses after 6 months of medication. CERAD neuropsychological assessment battery was used to define cognitive response at 6 months. We compared 4 h DNPZ to baseline single photon emission tomography (SPECT) by statistical parametric mapping to identify perfusion changes in responders (N = 16) and non-responders (N = 7). In responders, there were significant relatively increase in perfusion in left parietal lobe (BA39, 7, 1), right superior frontal gyrus (BA6) and right middle occipital gyrus (BA39). In the non-responders, perfusion was relatively increase in the left parietal lobe (BA39) only. In an explorative analysis, we found a significant correlation between perfusion changes in right BA6 and CERAD score changes at 6 months. Different SPECT perfusion changes at 4 h after donepezil administration were demonstrated in the group of responders and non-responders with potential correlation with CERAD score change. Thus, 4 h DNPZ brain perfusion SPECT can be used to predict donepezil response at 6 months.

Peripheral Blood Biomarkers Coupled with the Apolipoprotein E4 Genotype Are Strongly Associated with Semantic and Episodic Memory Impairments in Elderly Subjects with Amnestic Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The Apolipoprotein E4 (ApoE4) genotype is strongly associated with Alzheimer's disease (AD), although the presence of the ApoE4 allele alone is not sufficient to explain AD. The pathophysiology of amnestic mild cognitive impairment (aMCI) remains unclear. OBJECTIVE: This study aims to examine associations between peripheral blood biomarkers coupled with ApoE4 and episodic and semantic memory. METHODS: The CERAD battery was completed and various biomarkers were assayed in 60 subjects with aMCI, 60 with AD, and 62 healthy controls. RESULTS: Deficits in semantic and episodic memory were significantly predicted by anion gap and bicarbonate, albumin, and glucose coupled with ApoE4. Furthermore, these peripheral biomarkers interacted with ApoE to predict greater memory impairments. CONCLUSIONS: Peripheral blood biomarkers may interact with pathways related to ApoE4 to predict greater semantic and episodic memory impairments, thus contributing to the pathophysiology of aMCI and AD. Our data suggest that the transition from aMCI to AD could at least in some cases be associated with significant interactions between ApoE4 and those peripheral blood biomarkers.

Validation of the Thai version of the short Boston Naming Test (T-BNT) in patients with Alzheimer's dementia and mild cognitive impairment: clinical and biomarker correlates.

OBJECTIVES: Impairments in the Boston Naming Test (BNT), which measures confrontational word retrieval, frequently accompanies Alzheimer's dementia (AD) and may predict a more rapid progression of illness. This study aims to validate the Thai version of the 15-item BNT (T-BNT) in participants with AD and amnestic mild cognitive impairment (aMCI) and to externally validate the T-BNT using clinical and biomarker measurements. METHODS: This cross-sectional study recruited patients with AD, diagnosed according to NINCDS-ADRDA criteria (n = 60), aMCI, diagnosed using the Petersen criteria (n = 60), and healthy controls (n = 62). We examined the internal consistency, concurrent and discriminant reliability of the T-BNT. We also assessed the Mini Mental State Examination (MMSE), the Verbal Fluency Test (VFT) and the Word List Memory (WLM) tests and measured apolipoprotein E polymorphism and serum levels of folic acid, high-density lipoprotein cholesterol (HDL) and triglycerides. RESULTS: This study validated a 10-item T-BNT (10T-BNT), which yielded good internal consistency (0.92), a one-factor unidimensional structure, and adequate concurrent and discriminant validity. Lower scores on the 10T-BNT highly significantly predict AD, but not aMCI, and are positively associated with VFT and WLM test scores. Furthermore, lowered 10T-BNT scores are significantly associated with the ApoE4 allele, lower folate levels and an increased triglyceride/HDL-cholesterol ratio. CONCLUSIONS: This study validated the 10T-BNT and the total score on this scale is strongly associated with AD, impairments in semantic and episodic memory and biomarkers, which are known to modify memory via different mechanisms.

Characteristics of Mild Cognitive Impairment Using the Thai Version of the Consortium to Establish a Registry for Alzheimer's Disease Tests: A Multivariate and Machine Learning Study.

BACKGROUND: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) developed a neuropsychological battery (CERAD-NP) to screen patients with Alzheimer's dementia. Mild cognitive impairment (MCI) has received attention as a pre-dementia stage. OBJECTIVES: To delineate the CERAD-NP features of MCI and their clinical utility to externally validate MCI diagnosis. METHODS: The study included 60 patients with MCI, diagnosed using the Clinical Dementia Rating, and 63 normal controls. Data were analysed employing receiver operating characteristic analysis, Linear Support Vector Machine, Random Forest, Adaptive Boosting, Neural Network models, and t-distributed stochastic neighbour embedding (t-SNE). RESULTS: MCI patients were best discriminated from normal controls using a combination of Wordlist Recall, Wordlist Memory, and Verbal Fluency Test. Machine learning showed that the CERAD features learned from MCI patients and controls were not strongly predictive of the diagnosis (maximal cross-validation 77.2%), whilst t-SNE showed that there is a considerable overlap between MCI and controls. CONCLUSIONS: The most important features of the CERAD-NP differentiating MCI from normal controls indicate impairments in episodic and semantic memory and recall. While these features significantly discriminate MCI patients from normal controls, the tests are not predictive of MCI.

In Thai Nationals, the ApoE4 Allele Affects Multiple Domains of Neuropsychological, Biobehavioral, and Social Functioning Thereby Contributing to Alzheimer's Disorder, while the ApoE3 Allele Protects Against Neuropsychiatric Symptoms and Psychosocial Deficits.

The apolipoprotein E epsilon 4 (ApoE4) allele is the strongest genetic risk factor for Alzheimer's disorder (AD) and is associated with semantic and episodic memory deficits. The aim of this study was to examine the associations between ApoE alleles (E2, E3, E4) and genotypes and neuropsychological tests, behavioral functions, and dementia symptoms as assessed using Consortium to Establish a Registry for Alzheimer's Disease (CERAD). This study included 60 patients with Alzheimer's disorder (AD), 60 with mild cognitive disorder (MCI), and 62 normal volunteers. ApoE4 carriers and individuals with E3/E4 and E4/E4 genotypes show an increased incidence of AD, but not MCI. ApoE4 carriers and especially E4/E4 homozygotes show a worse outcome on the CERAD total score, Blessed Dementia Scale, and Short Blessed Test and lower scores on the Verbal Fluency Test, Boston Naming Test, Constructional Praxis Recall, and Word List Memory, Recall, and Recognition. ApoE4 carriers and E4/E3 heterozygotes show higher scores on the Clock Drawing Test. ApoE4 carriers show a worse outcome on the CERAD clinical history scores of memory, language, personality, ADL, orientation, and social skills, while allele AopE3 carriers show better scores on activities of daily living (ADL) and social skills. ApoE3 carriers show lower total weighted, irritability/aggression, and behavioral dysregulation scores on the Behavior Rating Scale for Dementia. The results show that in Thai individuals, the presence of ApoE4 allele is accompanied by a multifarious decline in neurocognitive functions and behavioral features and that ApoE3 may convey protection against neuropsychiatric symptoms and a decline in social skills. ApoE4 and especially the E4/E4 genotype may affect multiple domains of cognitive, biobehavioral, and social functioning thereby contributing to AD phenomenology.