Hae Ri Na

Effect of ApoE Genotype on Response to Donepezil in Patients with Alzheimer’s Disease

Background/Aims: The possible influence of apolipoprotein E (ApoE) genotype on the response to acetylcholinesterase inhibitor therapy in patients with Alzheimer’s disease (AD) remains a matter of controversy. In order to address this issue, we investigated the effects of ApoE genotype on the clinical response to donepezil in patients with mild to moderate AD. Methods: An open study was carried out in 51 patients with probable AD who were treated with 5–10 mg of donepezil per day for 48 weeks. Results: Eighteen (35.3%) of the 51 patients had 1 or 2 ApoE Ε4 alleles. ApoE Ε4 carriers with AD showed a mean 1.1-point increase from the baseline score of 23.9 on the 70-point Alzheimer’s Disease Assessment Scale-Cognitive Component at 48 weeks, while the ApoE Ε4 noncarrier group showed a 3.1-point increase from the baseline score of 22.5 (p = 0.03). The ApoE Ε4 carrier group exhibited a mean 0.13-point worsening from the baseline score of 0.97 on the Korean Instrumental Activities of Daily Living at 48 weeks, while the ApoE Ε4 noncarrier group exhibited a 0.17-point worsening from the baseline score of 0.64 (p = 0.05). Conclusion: AD patients who carry the ApoE Ε4 allele may respond more favorably to donepezil than Ε4 noncarriers.

Fibrinogen gamma-A chain precursor in CSF: a candidate biomarker for Alzheimer's disease

BackgroundCerebrospinal fluid (CSF) may be valuable for exploring protein markers for the diagnosis of Alzheimers disease (AD). The prospect of early detection and treatment, to slow progression, holds hope for aging populations with increased average lifespan. The aim of the present study was to investigate candidate CSF biological markers in patients with mild cognitive impairment (MCI) and AD and compare them with age-matched normal control subjects.MethodsWe applied proteomics approaches to analyze CSF samples derived from 27 patients with AD, 3 subjects with MCI and 30 controls. The AD group was subdivided into three groups by clinical severity according to clinical dementia rating (CDR), a well known clinical scale for dementia.ResultsWe demonstrated an elevated level of fibrinogen gamma-A chain precursor protein in CSF from patients with mild cognitive impairment and AD compared to the age-matched normal subjects. Moreover, its expression was more prominent in the AD group than in the MCI and correlated with disease severity and progression. In contrast, fibrinogen gamma-A chain precursor protein was detected very low in the age-matched normal group.ConclusionThese findings suggest that the CSF level of fibrinogen gamma-A chain precursor may be a candidate biomarker for AD.

Both plasma retinol-binding protein and haptoglobin precursor allele 1 in CSF: Candidate biomarkers for the progression of normal to mild cognitive impairment to Alzheimer's disease

Cerebrospinal fluid (CSF) may be of valuable for exploring protein markers for the diagnosis of Alzheimers disease (AD). The prospect of early detection and treatment, to slow progression, holds hope for aging populations with increased average lifespan. The aim of the present study was to investigate candidate CSF biological markers in patients with mild cognitive impairment (MCI) and AD and compare them with age-matched normal control subjects. In this report, we applied proteomics approaches to analyze 60 CSF samples derived from patients with neurodegenerative diseases such as MCI and AD. We classified patients by three groups: normal controls without cognitive dysfunction, MCI and AD. The AD group was subdivided into three groups by clinical severity according to clinical dementia rating (CDR), a well known clinical scale for dementia. We demonstrated a gradual decrease or absent of plasma retinol-binding protein (RBP) and haptoglobin precursor allele 1 in CSF from patients with MCI and AD compared to the age-matched normal subjects. Moreover, expression levels of both RBP and haptoglobin precursor allele 1 were observed to be very high in age-matched normal subjects. In contrast, the RBP and haptoglobin precursor allele 1 were much decreased in the MCI group; those expressions were more weak or absent in AD group, and correlated with disease severity and progression. These findings suggest that the CSF levels of both RBP and haptoglobin precursor allele 1 may be candidate biomarkers for the progression of normal to MCI to AD.

Urinary incontinence in patients with Alzheimer's disease: Relationship between symptom status and urodynamic diagnoses

To assess factors associated with detrusor overactivity in urinary incontinence patients with Alzheimers disease, and to determine the correlation between the degree of Alzheimers disease and the presence of detrusor overactivity.

Periventricular white matter hyperintensities and the risk of dementia: a CREDOS study.

BACKGROUND Cerebral white matter hyperintensities (WMH) are prevalent incident findings on brain MRI scans among elderly people and have been consistently implicated in cognitive dysfunction. However, differential roles of WMH by region in cognitive function are still unclear. The aim of this study was to ascertain the differential role of regional WMH in predicting progression from mild cognitive impairment (MCI) to different subtypes of dementia. METHODS Participants were recruited from the Clinical Research Center for Dementia of South Korea (CREDOS) study. A total of 622 participants with MCI diagnoses at baseline and follow-up evaluations were included for the analysis. Initial MRI scans were rated for WMH on a visual rating scale developed for the CREDOS. Differential effects of regional WMH in predicting incident dementia were evaluated using the Cox proportional hazards model. RESULTS Of the 622 participants with MCI at baseline, 139 patients (22.3%) converted to all-cause dementia over a median of 14.3 (range 6.0-36.5) months. Severe periventricular WMH (PWMH) predicted incident all-cause dementia (Hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.43-3.43) and Alzheimers disease (AD) (HR 1.86; 95% CI 1.12-3.07). Subcortical vascular dementia (SVD) was predicted by both PWMH (HR 16.14; 95% CI 1.97-132.06) and DWMH (HR 8.77; 95% CI 1.77-43.49) in more severe form (≥ 10 mm). CONCLUSIONS WMH differentially predict dementia by region and severity. Our findings suggest that PWMH may play an independent role in the pathogenesis of dementia, especially in AD.

Effects of lacunar infarctions on cognitive impairment in patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background and Purpose Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. Although previous studies have shown an association between lacunar infarction and cognitive impairment, the relationship between MRI parameters and cognition remains unclear. In this study we investigated the influence of MRI parameters on cognitive impairment in CADASIL. Methods We applied a prospective protocol to 40 patients. MRI analysis included the normalized volume of white-matter hyperintensities (nWMHs), number of lacunes, and number of cerebral microbleeds. Cognition was assessed with the aid of psychometric tests [Mini-Mental State Examination (MMSE), Alzheimers Disease Assessment Scale-cognition (ADAS-cog), Trail-Making Test, and Stroop interference (Stroop IF)]. Results A multivariate regression analysis revealed that the total number of lacunes influenced the performance in the MMSE, ADAS-cog, and Stroop IF, while nWMHs had a strong univariate association with ADAS-cog and Stroop IF scores. However, this association disappeared in the multivariate analysis. Conclusions These findings demonstrate that the number of lacunes is the main predictive factor of cognitive impairment in CADASIL.

Response to rivastigmine transdermal patch or memantine plus rivastigmine patch is affected by apolipoprotein E genotype in Alzheimer patients.

Background/Aims: The apolipoprotein E (APOE) genotype in response to pharmacological treatments in patients with Alzheimer’s disease (AD) remains a matter of controversy. This analysis investigated the effect of the APOE genotype on the clinical response to rivastigmine transdermal patch monotherapy or memantine plus rivastigmine patch in patients with mild to moderate AD. Methods: Two hundred and six (n = 206) patients with probable AD and Mini-Mental State Examination (MMSE) scores of 10–20 were randomized to rivastigmine patch monotherapy or memantine plus rivastigmine patch for 24 weeks. Of the 206 patients with probable AD, 146 patients who consented to genetic testing for APOE were included and assessed for this subgroup study. Results: There were no significant differences on MMSE, NPI, ADAS-cog, ADCS-ADL, CDR-SB, NPI and FAB between rivastigmine patch monotherapy and memantine plus rivastigmine patch according to the APOE genotype. However, patients with moderately severe AD (MMSE ≤15) who were APOE ε4 carriers showed higher responder rates on ADCS-ADL with memantine plus rivastigmine patch compared to rivastigmine patch monotherapy. Conclusion: Moderately severe AD patients with the APOE ε4 allele may respond more favorably to memantine plus rivastigmine patch than ε4 noncarriers.

Cognitive Profiles and Neuropsychiatric Symptoms in Korean Early-Onset Alzheimer's Disease Patients: A CREDOS Study

BACKGROUND & OBJECTIVE Early-onset Alzheimers disease (EOAD, onset age < 65 years) may differ from late-onset Alzheimers disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD. METHODS Through propensity score matching, a total of 435 patients with EOAD and a total of 435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging. RESULTS Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE ε4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype. CONCLUSION Our results suggested that EOAD may be an important phenotype, fronto-parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients.

Group- and Home-Based Cognitive Intervention for Patients with Mild Cognitive Impairment: A Randomized Controlled Trial.

Background: We examined the efficacy of group-based cognitive intervention (GCI) and home-based cognitive intervention (HCI) in amnestic mild cognitive impairment (aMCI) and intervention effects on serum brain-derived neurotrophic factor (BDNF). Methods: In this randomized and rater-blinded trial, 293 patients with aMCI from 18 nationwide hospitals were randomized: 96 to the GCI group, 98 to the HCI group and 99 to the control group. For 12 weeks, subjects receiving GCI participated twice per week in group sessions led by trained instructors, and those receiving HCI completed homework materials 5 days per week. They were assessed at baseline, postintervention (PI) and at the 6-month follow-up after the intervention. The primary endpoint was the change from baseline to PI in the modified Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-Cog). Results: In comparison to the controls (a 0.8-point decrease), the subjects receiving GCI (a 2.3-point decrease, p = 0.01) or HCI (a 2.5-point decrease, p = 0.02) showed significant improvements in the modified ADAS-Cog at PI, respectively. By the 6-month follow-up, those receiving GCI or HCI had better scores in the modified ADAS-Cog than the controls. The changes in BDNF levels significantly correlated with the changes in the modified ADAS-Cog in the GCI (r = -0.29, p = 0.02 at PI) and HCI (r = -0.27, p = 0.03 at 6-month follow-up) groups, respectively. Conclusions: The GCI and HCI resulted in cognitive improvements in aMCI. An enhanced brain plasticity may be a component of the mechanism underpinning the cognitive improvements associated with the cognitive interventions.

Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVE We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients. METHODS The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimers disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value. RESULTS Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD. CONCLUSIONS Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.