Il Han Choo

Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease

Objectives: The current model of Alzheimer disease (AD) stipulates that brain amyloidosis biomarkers turn abnormal earliest, followed by cortical hypometabolism, and finally brain atrophy ones. The aim of this study is to provide clinical evidence of the model in patients with mild cognitive impairment (MCI). Methods: A total of 73 patients with MCI from 3 European memory clinics were included. Brain amyloidosis was assessed by CSF Aβ42 concentration, cortical metabolism by an index of temporoparietal hypometabolism on FDG-PET, and brain atrophy by automated hippocampal volume. Patients were divided into groups based on biomarker positivity: 1) Aβ42− FDG-PET− Hippo−, 2) Aβ42+ FDG-PET− Hippo−, 3) Aβ42 + FDG-PET + Hippo−, 4) Aβ42 + FDG-PET+ Hippo+, and 5) any other combination not in line with the model. Measures of validity were prevalence of group 5, increasing incidence of progression to dementia with increasing biological severity, and decreasing conversion time. Results: When patients with MCI underwent clinical follow-up, 29 progressed to dementia, while 44 remained stable. A total of 26% of patients were in group 5. Incident dementia was increasing with greater biological severity in groups 1 to 5 from 4% to 27%, 64%, and 100% (p for trend < 0.0001), and occurred increasingly earlier (p for trend = 0.024). Conclusions: The core biomarker pattern is in line with the current pathophysiologic model of AD. Fully normal and fully abnormal pattern is associated with exceptional and universal development of dementia. Cases not in line might be due to atypical neurobiology or inaccurate thresholds for biomarker (ab)normality.

Mild cognitive impairment with suspected nonamyloid pathology (SNAP) Prediction of progression

Objectives: The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non–Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI). Methods: We measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [18F]-fluorodeoxyglucose–PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A− and N+/N− based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A−N+ cases. Results: The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A−N−, A+N−, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N− and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A−N−, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N− patients did not (hazard ratio = 1.13, p = 0.771). In A+N− and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073). Conclusions: Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.

Prediction of AD dementia by biomarkers following the NIA-AA and IWG diagnostic criteria in MCI patients from three European memory clinics.

Proposed diagnostic criteria (international working group and National Institute on Aging and Alzheimers Association) for Alzheimers disease (AD) include markers of amyloidosis (abnormal cerebrospinal fluid [CSF] amyloid beta [Aβ]42) and neurodegeneration (hippocampal atrophy, temporo‐parietal hypometabolism on [18F]‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET), and abnormal CSF tau). We aim to compare the accuracy of these biomarkers, individually and in combination, in predicting AD among mild cognitive impairment (MCI) patients.

Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression

5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1-8 showed the best binding affinity with a Ki value of 8.69nM and it was verified as a novel antagonist according to functional assays. The compound 1-8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1-8 exhibited an antidepressant effect at a dose of 25mg/kg in the forced swimming test in mice and showed a U-shaped dose-response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone.

Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson’s disease

In Parkinsons disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinsons disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinsons disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.

Aryl Biphenyl-3-ylmethylpiperazines as 5-HT7 Receptor Antagonists

The 5‐HT7 receptor (5‐HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5‐HT7R antagonist SB‐269970 exhibited antidepressant‐like activity, whereas systemic administration of the 5‐HT7R agonist AS‐19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5‐HT7R antagonists or agonists, aryl biphenyl‐3‐ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5‐HT7R. Among the synthesized compounds, 1‐([2′‐methoxy‐(1,1′‐biphenyl)‐3‐yl]methyl)‐4‐(2‐methoxyphenyl)piperazine (28) was the best binder to the 5‐HT7R (pKi=7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5‐HT7R over other serotonin receptor subtypes, such as 5‐HT1R, 5‐HT2R, 5‐HT3R, and 5‐HT6R. In a molecular modeling study, the 2‐methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.

Factors Associated with Health-Related Quality of Life Among Overweight and Obese Korean Women

Health-related quality of life (HRQOL) tends to be lower among individuals who are overweight and obese than those of normal weight, and women may be more vulnerable to lower HRQOL associated with obesity than men. Identifying factors associated with HRQOL may be crucial for improving HRQOL for overweight/obese women. We aimed to determine the factors associated with obesity-specific HRQOL among overweight/obese Korean women. A cross-sectional study was conducted with 125 women aged 20–64 years, who comprised a baseline sample in the Community-based Heart and Weight Management Trial. The data were collected from September 2010 to November 2011. The Weight Efficacy Lifestyle, Beck Depression Inventory-II, Interpersonal Social Evaluation List, and Impact of Weight on Quality of Life (IWQOL)–Lite scales were used to measure self-efficacy for weight control, depressive symptoms, social support, and HRQOL, respectively. Increased body mass index, lower self-efficacy for weight control, and higher levels of depressive symptoms were significantly associated with greater impairment in total IWQOL in the regression models. However, social support was not significantly associated with IWQOL. Along with weight loss strategies, other strategies for improving self-efficacy and alleviating depressive symptoms may be essential for improving HRQOL among overweight and obese women.

Novel thienopyrimidinones as mGluR1 antagonists

There has been much attention to discover mGluR1 antagonists for treating various central nervous system diseases such as seizures and neuropathic pain. Thienopyrimidinone derivatives were designed, synthesized, and biologically evaluated against mGluR1. Among the synthesized compounds, 3-(4-methoxyphenyl)-7-(o-tolyl)thienopyrimidin-4-one 30 exhibited the most potent inhibitory activity with an IC50 value of 45xa0nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC50xa0=xa09.87xa0μM), good profiles to CYP isozymes, and a good pharmacokinetic profile. Overall, the compound 30 was identified as a selective mGluR1 antagonist with a good pharmacokinetic profile, which is probably devoid of cardiac side effect and drug-drug interactions. Therefore, the compound 30 can be expected to be broadly used as mGluR1 antagonistic chemical probe in inxa0vitro and inxa0vivo study for investigating CNS diseases.

Psychiatric Symptoms in Temporal Lobe Epilepsy with Left Mesial Hippocampal Sclerosis

A 16-year-old woman was referred to us for depression and persistent suicidal and homicidal ideation. From 2010, the patient visited a neurologist due to recurrent grand mal epilepsy, auditory and visual hallucinations, episodic memory loss, and persistent depression. Upon admission, it was revealed through clinical history taking that she had suffered from chronic bullying from same-sex peers and sexual abuse, twice, from an adult male in the neighborhood when she was 10 years old. A brain magnetic resonance imaging study showed left mesial hippocampal sclerosis. The patient exhibited improvement of her psychiatric symptoms after treatment with a combination of fluoxetine (30 mg) and aripiprazole (10 mg). Children and adolescents with epilepsy experience conflicts in the family, challenges at school, stigma, and psychosocial limitations or deprivations due to their comorbid psychiatric symptoms and hence, psychiatric evaluation and early intervention is important when treating these patients.

Structural MRI and amyloid PET imaging for prediction of conversion to Alzheimer’s disease in patients with mild cognitive impairment: A meta-analysis

each population separately. Results: Figure 1 shows 12 transverse slices of the average WMH maps for the entire PREVENT-AD and ADC populations overlapped on the ADNI template. Conclusions:WMHs have been observed in normal control subjects at risk of AD as well as NC/MCI/AD population. WMHs occur more often in the periventricular areas especially adjacent to the horns of the lateral ventricles and less often in the other areas. The difference between the two maps suggests that WMHs are more extensive in AD populations than in healthy controls at risk of AD, especially in regions such as parietal lobe suggesting the probability of an inhomogeneous spread of the WMHs in different regions. (Funding: CIHR MOP-111169, P30 AG010129, Pfizer Canada, FRQ-S, and Douglas Hospital Research Centre.)