ß-Amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy.

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)-like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini-Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [(11)C]Pittsburgh Compound B to measure brain amyloid deposition as well as three-dimensional T1-weighted MRI. Gray-matter volumes (GMVs) were estimated by voxel-based morphometry. Volumes-of-interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid-positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid-negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid-positive DLB/PDD and AD groups and by 10% in the amyloid-negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD-like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD-like atrophy in DLB/PDD patients with amyloid deposition.

Differential effects of acute exercise on emotional memory in men and women.

Exercise may change emotional memory, which is associated with the induction of mental disorders such as depression and anxiety. This effect of exercise may be influenced by exercise-induced cortisol release. Depending on sex, cortisol exerts differential effects on emotional memory consolidation. However, whether acute exercise and exercise-induced cortisol release have sex-dependent effects on emotional memory has not been established. Therefore, first, we aimed to determine the effects of acute exercise on emotional memory, separately for men and women, in a within-subjects design. Second, we aimed to examine whether the effects of acute exercise on emotional memory are related to the effects of exercise-induced cortisol release, separately for men and women. Sixteen healthy men and 15 healthy women were presented with positive and negative emotional images, followed by either rest or a vigorous-intensity cycling exercise condition using a within-subjects design on separate days. Salivary cortisol was measured before presenting the emotional images presentation and 20 min after each intervention. Emotional memory was assessed two days later. Vigorous-intensity exercise decreased emotional memory in women, whereas there was no change in men after rest or exercise. Cortisol levels increased after exercise intervention in both men and women, although there was no association between cortisol levels and emotional memory. These findings demonstrate that the effect of a single bout of vigorous-intensity exercise on emotional memory differs between men and women and is associated with decreased emotional memory in women.

The development and validation of an emotional vulnerability scale for university students.

This study developed an emotional vulnerability scale and examined its reliability and validity with a sample of university students. In health psychology, a measurement of emotional pain ("hurt feelings") can contribute to the prevention and improvement of physical and mental health problems in daily life. We collected data from 361 Japanese university students (186 men and 175 women; mean age = 19.6 ± 0.98 years). From preliminary interviews with 20 participants, 42 semantic units were extracted. For scale development, a questionnaire survey was conducted using the 42 extracted categories, and exploratory and confirmatory factor analyses were performed. Four factors (16 items) emerged, which were both reliable and valid: (1) "vulnerability toward criticism or denial," (2) "vulnerability toward worsening relationships," (3) "vulnerability toward interpersonal discord," and (4) "vulnerability toward procrastination and emotional avoidance." This scale can be useful to understand vulnerability in everyday situations and grasp the vulnerable conditions experienced by individuals. This can help prevent stress responses (such as depression and sadness) and mental health problems, which are valuable contributions to health psychology.

High Organization-Based Self-Esteem Is Associated With Lower Risk of Depressive Symptoms Among University Athletes.

As depressive symptoms can impair athletes' healthy competitive life and lead to a decline in performance, it is necessary to identify and prevent these symptoms. Organization-based self-esteem is one of the factors that influence the mental health of the members of an organization. It has been found that employees with high organization-based self-esteem have good mental health. However, the relationship between organization-based self-esteem and mental health has not yet been investigated in athletes. Therefore, we aimed to develop an organization-based self-esteem scale for university athletes (Study I) and investigate the relationship between organization-based self-esteem and depressive symptoms (Study II). Study I included subsample A: 210 university athletes (average age 19.6 ± 0.64 years) and subsample B: 371 university athletes (average age 19.4 ± 0.90), who responded to the newly developed Organization-Based Self-Esteem Scale for University Athletes (OBSE-UA), the Rosenberg Self-Esteem Scale, and the Sports Commitment Scale. To confirm the reliability of the developed scale, 2 weeks later they responded to the OBSE-UA again. In Study II, the participants were 232 university athletes (average age 19.5 ± 1.10 years), who completed the OBSE-UA developed in Study I and the Self-Rating Depression Scale. In Study I, we extracted a one-factor structure with six items for the OBSE-UA using exploratory and confirmatory factor analysis. Sufficient validity and reliability were confirmed by examining the relationship between organization-based self-esteem and sports commitment scale and retest methods, respectively. In Study II, athletes with high organization-based self-esteem showed a 0.33 time lower risk of experiencing depressive symptoms, compared to athletes with low organization-based self-esteem.

Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia.

Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.

PET study of brain acetylcholinesterase in cerebellar degenerative disorders.

To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.

Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. OBJECTIVE: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. METHODS: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. RESULTS: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. CONCLUSION: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

Association between physical restraint and drug-induced liver injury.

OBJECTIVE: As animal models have suggested enhancement of xenobiotic-induced hepatotoxicity due to restraint stress, a case-control study was undertaken to investigate the effects of physical restraint on the development of drug-induced liver injury (DILI) in a psychiatric intensive care unit. METHOD: Demographic and clinical characteristics were compared between restrained patients (n = 106) and nonrestrained patients (n = 528) admitted to the psychiatric intensive care unit during a 4-year period from January 2003 to December 2006. RESULTS: Rates of DILI differed significantly between restrained patients (8.5%) and nonrestrained patients (1.9%; odds ratio 4.81, p = 0.0016), although no initial differences were seen in medical and psychiatric conditions. No differences in mean number of drugs were identified. The rate of patients who received antipsychotics was higher in the restrained group than in the nonrestrained group, whereas the rate of patients who received antidepressants was higher in the nonrestrained group than in the restrained group. CONCLUSIONS: Despite methodological limitations imposed by the retrospective design, a conservative claim can be made that physical restraint might represent a risk for DILI. This observation deserves confirmation in a prospective study.

An easy Z-score imaging system for discrimination between very early Alzheimer's disease and controls using brain perfusion SPECT in a multicentre study.

BACKGROUND AND AIM: In Alzheimer's disease (AD), regional cerebral blood flow (rCBF) in the posterior cingulate gyrus and precuneus has been reported to decrease even at a very early stage. We performed a multicentre SPECT study to evaluate the discrimination ability of an easy Z-score imaging system (eZIS) by detecting an rCBF decrease in this area with a common normal database between very early AD patients at the stage of mild cognitive impairment and age-matched healthy volunteers. METHODS: Brain perfusion SPECT images of 40 Alzheimer's disease patients and 40 healthy volunteers were acquired from four gamma camera systems in different institutions. Systematic differences of SPECT images between different gamma cameras were corrected using conversion maps calculated from the SPECT images of the same brain phantom. Ten observers with various degrees of expertise graded eZIS results for receiver operating characteristic (ROC) curves. ROC curves for a positive Z-score in the volume of interest (VOI) of the posterior cingulate gyrus and precuneus were also analysed. RESULTS: An area under the ROC curve value (AZ) for ten observers showed the highest value of 0.866 on average with the smallest standard deviation of 0.027 in the condition of the lower threshold of a Z-score map of 2 without superimposition of VOI. Automated analysis of a Z-score in the VOI showed an AZ value of 0.895. CONCLUSION: Since the degree of expertise of the observers with respect to reading eZIS did not influence the performance and an eZIS can use a common normal database by converting site-specific SPECT data to the core data, the eZIS was considered to be very useful for diagnosing early AD in routine studies in many institutions.

Benefits of use, and tolerance of, medium-chain triglyceride medical food in the management of Japanese patients with Alzheimer's disease: a prospective, open-label pilot study.

OBJECTIVES: This is the first clinical trial of this type in Japan, designed to analyze two important aspects of Alzheimer's disease (AD) management using medium-chain triglycerides. Axona was administered for 3 months (40 g of powder containing 20 g of caprylic triglycerides). We used an indurating, four-step dose-titration method (from 10 to 40 g per day) for 7 days before the trial, and examined the tolerance and adverse effects of this intervention. We also investigated its effect on cognitive function in mild-to-moderate AD patients. PATIENTS AND METHODS: This was a clinical intervention in 22 Japanese patients with sporadic AD at a mild-to-moderate stage (ten females, 12 males), mean age (± standard deviation) 63.9 (±8.5) years, Mini-Mental State Examination (MMSE) score, 10-25, seven patients were ApoE4-positive. During Axona administration, we examined changes in cognitive function by obtaining MMSE and AD assessment-scale scores. Intolerance and serum ketone concentrations were also examined. RESULTS: The tolerance of Axona was good, without severe gastrointestinal adverse effects. Axona did not improve cognitive function in our sample of AD patients, even in those patients without the ApoE4 allele. However, some ApoE4-negative patients with baseline MMSE score ≥14 showed improvement in their cognitive functions. CONCLUSION: The modified dose-titration method, starting with a low dose of Axona, decreased gastrointestinal adverse effects in Japanese patients. Axona might be effective for some relatively mildly affected patients with AD (with cognitive function MMSE score of ≥14 and lacking the ApoE4 allele).

Estimation of plasma IC50 of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) and PET.

Donepezil hydrochloride is a potent and selective inhibitor for brain acetylcholinesterase (AChE) and is currently used worldwide for the treatment of Alzheimer's disease. Until now, there is no in vivo study on the relation between the plasma concentration and the brain AChE inhibition. The purpose of this study was to estimate in vivo plasma IC(50) of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[(11)C]methylpiperidin-4-yl acetate, which is an acetylcholine analog recently developed by us for quantifying in vivo brain AChE activity. PET scans with donepezil at two doses, 100 microg/kg (donepezil-1; N=5) or 250 microg/kg (donepezil-2; N=5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N=10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.2+/-2.9 ng/ml (donepezil-1) and 44.0+/-5.0 ng/ml (donepezil-2), and the mean AChE inhibitions in four neocortical regions as evaluated by PET were also dose-dependent, 27% (donepezil-1) and 53% (donepezil-2). In IC(50) estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC(50) values (estimate+/-SE) were 42+/-9.0 (ng/ml; donepezil-1), 34+/-3.2 (donepezil-2), and 37+/-4.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.

Evaluation of simplified kinetic analyses for measurement of brain acetylcholinesterase activity using N-[11C]Methylpiperidin-4-yl propionate and positron emission tomography.

The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.

A simple method for the detection of abnormal brain regions in Alzheimer's disease patients using [11C]MP4A: comparison with [123I]IMP SPECT.

We have developed a radiolabeled lipophilic acetylcholine analogue, N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) to measure brain acetylcholinesterase (AChE) activity by positron emission tomography (PET) in vivo. Aiming to develop a new SPECT tracer similar to MP4A, we first proposed a simple method for diagnosing Alzheimer's disease (AD) using [11C]MP4A PET. We performed [11C]MP4A PET and N-isopropyl [123I]iodoamphetamine ([123I]IMP) SPECT in 13 patients with AD and in 17 normal controls (NC). We calculated the ratio of radioactivity of the cortical region of interest (ROI) to that of the cerebellum measured with [11C]MP4A PET (MP4A ratio) and the ratio of regional cerebral blood flow (rCBF) to that of the cerebellum measured with [123I]IMP SPECT (IMP ratio). Eleven cortical ROIs were placed in the frontal, sensorimotor, temporal, parietal, and occipital cortices in both hemispheres and in the posterior cingulate cortex, and z-score was calculated in each ROI in patients with AD compared with NC. When the z-score was 2 or more in a ROI, it was defined as a positive ROI. When a patient had 3 or more positive ROIs, the patient was diagnosed as having AD. The reduction in the MP4A ratio was greater than that in the IMP ratio in all cortical ROIs except for in the right parietal cortex and cingulate cortex in patients with AD. MP4A ratio method showed 92% sensitivity and the IMP ratio method 69% sensitivity for the diagnosis of AD. These results encourage us to develop a new SPECT tracer similar to MP4A for the diagnosis of AD.

Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography.

OBJECTIVES: Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain. METHODS: N-[C] methylpiperidin-4-yl acetate ([C]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model. RESULTS: Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL. CONCLUSIONS: Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.

Maximal response to electroconvulsive therapy for the treatment of catatonic symptoms.

OBJECTIVES: Because the number of medical lawsuits has recently increased in Japan, doses of medication above the upper limits have recently been avoided, even when treating catatonic patients. We treated catatonic symptoms with drugs within the upper limit of dosage and electroconvulsive therapy (ECT) to determine the maximal response. METHODS: We examined 50 consecutive patients with catatonic symptoms admitted to a university hospital during a 32-month period who were treated with either drugs within the upper limit or ECT. RESULTS: Response rates were as follows: ECT, 100%; chlorpromazine, 68%; risperidone, 26%; haloperidol, 16%; and benzodiazepines, 2%. CONCLUSIONS: The findings indicated that ECT is the treatment of choice for catatonic symptoms.

A quantitative near-infrared spectroscopy study: a decrease in cerebral hemoglobin oxygenation in Alzheimer's disease and mild cognitive impairment.

A newly developed quantitative near-infrared spectroscopy (NIRS) system was used to measure changes in cortical hemoglobin oxygenation during the Verbal Fluency Task in 32 healthy controls, 15 subjects with mild cognitive impairment (MCI), and 15 patients with Alzheimer's disease (AD). The amplitude of changes in the waveform, which was quantitatively calculated by a signal processing method, was significantly lower in the frontal, and the bilateral parietal areas in the AD group, whereas that in the MCI group was significantly lower only in the right parietal area. The NIRS system may be a potential tool for the primary screening of AD.