Distinct Neural Correlates of Executive Function by Amyloid Positivity and Associations with Clinical Progression in Mild Cognitive Impairment.

PURPOSE: This study aimed to identify the neural basis of executive function (EF) in amnestic mild cognitive impairment (aMCI) according to beta-amyloid (Aß) positivity. Furthermore, we explored if the identified brain areas could serve as predictors for clinical progression. MATERIALS AND METHODS: We included individuals with aMCI using data from [18F]-florbetapir-positron emission tomography (PET), fluorodeoxyglucose-PET, and EF scores, as well as follow-up clinical severity scores at 1 and 5 years from baseline from the Alzheimer's Disease Neuroimaging Initiative database. The correlations between EF score and regional cerebral glucose metabolism (rCMglc) were analyzed separately for aMCI with low Aß burden (aMCI Aß-, n=230) and aMCI with high Aß burden (aMCI Aß+, n=268). Multiple linear regression analysis was conducted to investigate the associations between rCMglc and clinical progression. RESULTS: Longitudinal courses differed between aMCI Aß- and aMCI Aß+ groups. On average, aMCI Aß- subjects maintained their level of clinical severity, whereas aMCI Aß+ subjects showed progression. EF impairment in aMCI Aß- was related to the anterior cingulate cortex (ACC), whereas that in aMCI Aß+ was related to Alzheimer's Disease-vulnerable brain regions. ACC and the posterior cingulate cortex were associated with clinical progression in aMCI Aß- and aMCI Aß+, respectively. CONCLUSION: Our findings suggest that although MCI subjects showed similar behavioral phenotypes at the time of diagnosis, EF and further progression were associated with different brain regions according to Aß burden. Clarification of the etiologies and nature of EF impairment in aMCI are critical for disease prognosis and management.

Topographical APOE ɛ4 Genotype Influence on Cerebral Metabolism in the Continuum of Alzheimer's Disease: Amyloid Burden Adjusted Analysis.

BACKGROUND: APOE ɛ4 contributes to Alzheimer's disease (AD) pathogenesis by amyloid-beta (Aß)-dependent and Aß-independent processes. OBJECTIVE: We investigated the APOE ɛ4 influence on regional cerebral glucose metabolism (rCMglc) in the continuum of AD after Aß adjustment. METHODS: We included 318 cognitively normal (CN) elderly, 498 mild cognitive impairment (MCI), and 178 AD from the Alzheimer's Disease Neuroimaging Initiative database. They had [18F] florbetapir positron emission tomography (PET) and [18F] fluorodeoxyglucose (FDG)-PET conducted within 3 months of a clinical and cognitive assessment visit and APOE genotype. At first, the rCMglc differences between APOE ɛ4 carriers (ɛ4+) and non-carriers (ɛ4-) were estimated on a voxel-based analysis using a 'two-sample t-test' design. In the second analysis, Aß was added as covariate. RESULTS: In CN, ɛ4+ showed reduced rCMglc compared to ɛ4-in the bilateral frontal, temporal, and the left parietal regions. In MCI, ɛ4+ showed reduced rCMglc compared to ɛ4- in the bilateral posterior parietal, temporal, and left frontal regions. In AD, ɛ4+ showed reduced rCMglc in the left hippocampus, right insular, and right temporal gyrus. However, after Aß adjustment, the significant differences in the temporal regions were absent in CN and MCI, and none of the areas detected as significant in the first analysis were statistically significant in AD. CONCLUSIONS: Our study demonstrated that Aß-independent APOE ɛ4 influence on rCMglc is limited to the parietal and frontal, but not temporal lobes. These results suggest that APOE ɛ4 may predispose for regional vulnerability according to Aß-independent and Aß-dependent processes.

Direct vascular actions of quercetin in aorta from renal hypertensive rats.

BACKGROUND: Chronic treatment with the dietary flavonoid quercetin is known to lower blood pressure and restore endothelial dysfunction in animal models of hypertension. This study investigated the direct effects of quercetin on vascular response in chronic 2-kidney, 1-clip (2K1C) renal hypertensive rats. The effects of antioxidant vitamin ascorbic acid on the vasoreactivity were also examined. METHODS: 2K1C renal hypertension was induced by clipping the left renal artery; age-matched rats that received sham treatment served as controls. Thoracic aortae were mounted in tissue baths for the measurement of isometric tension. RESULTS: Relaxant responses to acetylcholine were significantly attenuated in 2K1C rats in comparison with sham rats. Quercetin or ascorbic acid augmented acetylcholine-induced relaxation in 2K1C rats, whereas no significant differences were noted in sham rats. The relaxation response to sodium nitroprusside was comparable between 2K1C and sham rats, and sodium nitroprusside-induced relaxation was not altered by quercetin or ascorbic acid in either group. The contractile response to phenylephrine was significantly enhanced in 2K1C rats compared with sham rats. Phenylephrine-induced contraction was inhibited by pretreatment with quercetin or ascorbic acid in 2K1C rats, whereas neither chemical affected responses in sham rats. N(w)-nitro-L-arginine methyl ester markedly augmented the contractile response to phenylephrine in sham rats, whereas no significant differences were observed in 2K1C rats. Quercetin or ascorbic acid did not affect phenylephrine-induced contraction in the presence of N(w)-nitro-L-arginine methyl ester in either 2K1C or sham rats. CONCLUSION: Acute exposure to quercetin appears to improve endothelium-dependent relaxation and inhibit the contractile response, similar to the effect of ascorbic acid in 2K1C hypertension. These results partially explain the vascular beneficial effects of quercetin in renal hypertension.

Independent and Interactive Influences of the APOE Genotype and Beta-Amyloid Burden on Cognitive Function in Mild Cognitive Impairment.

This study aimed to investigate the independent and interactive influences of apolipoprotein E (APOE) ε4 and beta-amyloid (Aß) on multiple cognitive domains in a large group of cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Participants were included if clinical and cognitive assessments, amyloid imaging, and APOE genotype were all available from the Alzheimer's Disease Neuroimaging Initiative database (CN = 324, MCI = 502, AD = 182). Individuals with one or two copies of ε4 were designated as APOE ε4 carriers (ε4+); individuals with no ε4 were designated as APOE ε4 non-carriers (ε4-). Based on mean florbetapir standard uptake value ratios, participants were classified as Aß burden-positive (Aß+) or Aß burden-negative (Aß-). In MCI, APOE ε4 effects were predominantly observed on frontal executive function, with ε4+ participants exhibiting poorer performances; Aß positivity had no influence on this effect. Aß effects were observed on global cognition, memory, and visuospatial ability, with Aß+ participants exhibiting poorer performances. Measures of frontal executive function were not influenced by Aß. Interactive effects of APOE ε4+ and Aß were observed on global cognition and verbal recognition memory. Aß, not APOE ε4+, influenced clinical severity and functional status. The influences of APOE ε4+ and Aß on cognitive function were minimal in CN and AD. In conclusion, we provide further evidence of both independent and interactive influences of APOE ε4+ and Aß on cognitive function in MCI, with APOE ε4+ and Aß showing dissociable effects on executive and non-executive functions, respectively.

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.

Do benzodiazepines extend the duration of follow-up treatment in patients with bipolar disorder?

INTRODUCTION: In patients with bipolar disorder, relapse and recurrence from the premature discontinuation of pharmacotherapy are serious clinical problems. Thus, clinicians must make every effort to ensure the sufficient duration of continual treatment even after the remission of acute episodes. Here, we examine whether there is any association between benzodiazepine (BZD) use and the duration of follow-up treatment in patients with bipolar disorder. METHODS: The medical records of 70 bipolar patients hospitalized in a university hospital psychiatry ward were reviewed. Selected demographic and clinical variables, such as extent of BZD use and the total duration of outpatient follow-up treatment, were compared. RESULTS: The duration of maintenance treatment at the outpatient department differed significantly between patients who were or were not given BZDs during admission (571 vs. 179 days) and after discharge (836 vs. 154 days). The variables that differed significantly between patients who received follow-up treatment for 6 or more months and those who did not was the number of days of BZD administration during admission (11 vs. 5 days) and after discharge (280 vs. 7 days), and years of education (11 vs. 13 years). CONCLUSION: In the present study, BZDs are suggested as a possible adjunctive therapy for extending follow-up and thus preventing recurrence in patients with bipolar disorder.