Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD.

Psychometric properties of the AIR Self-Determination Scale: the Chinese version (AIR SDS-C) for Chinese people with intellectual disabilities.

BACKGROUND: The construct of self-determination has received considerable attention in the international field of intellectual disabilities (ID). Recently, there has been a rapid development of this construct in Chinese societies including Hong Kong. However, there is no locally validated instrument to measure self-determination in people with ID. This article explains the validation process of the AIR Self-Determination Scale - Chinese version (AIR SDS-C) adapted from the 24-item AIR Self-Determination Scale, developed by Wolman and his colleagues, which is used in school setting. METHODS: People with mild/moderate ID aged 15 years or above were recruited from special schools and social services units in different regions of Hong Kong. Factor analysis and reliability tests were conducted. RESULTS: Data for a total of 356 participants were used for the analysis. A confirmatory factor analysis was performed to test the factorial construct, and Mplus 7.0 was used for the analysis. The factor structure proposed in the original English version was supported by the data, and all factor loadings were between 0.42 and 0.76. The whole scale achieved good reliability (Cronbach's α = 0.88 and ω = 0.90). CONCLUSIONS: The AIR SDS-C appears to be a valid and reliable scale. This study examined adult groups as well as student groups. The application of the scale can thus be extended to a wider population. The implications for theory building and practice are discussed.

Marital satisfaction of Chinese mothers of children with autism and intellectual disabilities in Hong Kong.

BACKGROUND: Previous research showed an association among perceived stigma, perceived caregiving burden and marital satisfaction of mothers. However, little is known about their relationship among mothers of young children with disabilities in the Chinese context. The mediating role of perceived caregiving burden between perceived stigma and marital satisfaction was seldom explored. Hence, the present study aims to investigate the relationship between perceived stigma, perceived caregiving burden and marital satisfaction of Chinese mothers of children with intellectual disabilities or autism spectrum disorders in Hong Kong. METHODS: A cross-sectional survey using convenience sampling was conducted with mothers of pre-school children with disabilities aged from 2 to 6. A total of 160 completed questionnaires were collected from five special child care centres in Hong Kong. RESULTS: The findings in the hierarchical regression analyses showed that perceived stigma and perceived caregiving burden were significant predictors of mothers' marital satisfaction. Perceived burden, including perceived social burden, emotional burden and developmental burden but excluding time-dependence and physical burden, were found to be significant mediators between perceived stigma and marital satisfaction. CONCLUSION: To address the negative consequences brought on by stigma, measures can be taken to prevent stigmatisation and minimise the harmful effects. To alleviate mothers' perceived burden, Acceptance and Commitment Therapy, mutual support groups and psycho-educational and skills training programmes can be conducted for the mothers.

Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography.

OBJECTIVE: To examine the association between regional brain uptake of a novel amyloid positron emission tomography (PET) tracer florbetapir F 18 ([(18)F]-AV-45) and cognitive performance in a pilot study. DESIGN: Cross-sectional comparison of [(18)F]-AV-45 in AD patients versus controls. SETTING: Three specialty memory clinics. PARTICIPANTS: Eleven participants with probable Alzheimer disease (AD) by NINDS/ADRDA criteria and 15 healthy comparison (HC) participants. MEASUREMENTS: Participants underwent PET imaging following a 370 MBq (10 mCi) intravenous administration of [(18)F]-AV-45. Regional/cerebellar standardized uptake value ratios (SUVRs) were calculated. Cognition was assessed using Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Wechsler Logical Memory IA (immediate recall) test (LMIA), and verbal category fluency. RESULTS: Greater [(18)F]-AV-45 SUVR was associated with poorer performance on all cognitive tests. In the HC group, occipital, parietal, precuneus, temporal, and cortical average SUVR was associated with greater ADAS-Cog, and greater anterior cingulate SUVR was associated with lower LMIA. Two HC participants had [(18)F]-AV-45 cortical/cerebellar SUVR greater than 1.5, one of whom had deficits in episodic recall and on follow-up met criteria for amnestic mild cognitive impairment. CONCLUSION: [(18)F]-AV-45 SUVR in several brain regions was associated with worse global cognitive performance particularly in HC, suggesting its potential as a marker of preclinical AD.

The maintenance effect of cognitive-behavioural treatment groups for the Chinese parents of children with intellectual disabilities in Melbourne, Australia: a 6-month follow-up study.

BACKGROUND: Caring for a child with intellectual disability can be stressful. No data on the longer-term effects of cognitive-behavioural treatment (CBT) on parents from a Chinese-speaking background who have children with intellectual disabilities are available in the literature. This study attempted to fill this research gap by examining the maintenance effect of CBT among the Chinese parents of such children in Melbourne, Australia. METHOD: Thirty-nine participants took part in our CBT groups and attended follow-up meetings. A questionnaire comprising four instruments, the Parenting Stress Index (PS) - Parent Domain, General Health Questionnaire-12 (GHQ-12), Abbreviated Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-18) and Dysfunctional Attitude Scale (DAS), was administered to the participants at the pre- and post-test stage and at the 6-month follow-up. RESULTS: One-way repeated-measures analyses of variance revealed significant time and group effects in the PS (F(2,27) = 16.93, P < 0.001), Q-LES-Q-18 (F(2,27) = 15.98, P < 0.001), GHQ-12 (F(2,27) = 81.93, P < 0.001) and DAS (F(2,27) = 15.50, P < 0.001) scores at the three measurement times. The participants continued to maintain significant improvements in mental health and quality of life and declines in the severity of parenting stress and dysfunctional attitudes at the 6-month follow-up. Effect size analyses revealed mostly large differences in the foregoing measurements (Cohen's d = 0.76-2.18) between the pre-test and 6-month follow-up. Employing a cut-off score of 3/4 in the GHQ-12 to identify at-risk and not-at-risk cases, approximately 90.5% of the participants could be classified as not-at-risk at the follow-up. Lastly, regression analyses showed that changes in DAS scores significantly predicted changes in the GHQ-12 and Q-LES-Q-18 scores at the follow-up. CONCLUSIONS: This study provides preliminary evidence of the 6-month maintenance effect of CBT groups for the Melbourne-resident Chinese parents of children with intellectual disabilities.

Initial validation of the Chinese Quality of Life Questionnaire-Intellectual Disabilities (CQOL-ID): a cultural perspective.

BACKGROUND: In the field of intellectual disabilities (ID), the quality of life concept has been developing rapidly in Chinese societies including Hong Kong, mainland China and Taiwan. However, there is a lack of locally validated instruments to measure the quality of life of people with ID. The study reported in this paper attempted to validate the Chinese Quality of Life Questionnaire - Intellectual Disabilities adapted from the Quality of Life Questionnaire developed by Schalock & Keith. METHODS: People with mild/moderate ID aged 15 years or above were recruited from special schools, skills centres, community service units and residential units in different regions of Hong Kong. A number of procedures were followed including reliability tests, factor analysis, content validity and construct validity. RESULTS: A total of 359 participants were recruited for the study. Factor analysis was conducted according to the rotated component matrix method, in which 23 items were extracted from the original 40-item version of the Quality of Life Questionnaire and three domains (renamed satisfaction, competence and daily choice making/interpersonal relations) were observed. The items in each domain were shown to have factor loadings ranging from 0.42 to 0.90. Construct validity tests indicated the positive nature of the relationship between earnings, and that self-determination and social interaction increase with more independent living environments and less segregated work environments achieving higher scores (P<0.000, P<0.01 and P<0.05 respectively). The scale also achieved a good degree of reliability (Cronbach's α=0.79). CONCLUSIONS: Initial validity tests indicated that the Chinese Quality of Life Questionnaire - Intellectual Disabilities may be a useful instrument for measuring the quality of life of Chinese people with ID. Cultural issues are discussed and recommendations for future research and service development are made.

Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain.

D2 dopamine and S2 serotonin receptors were imaged and measured in healthy human subjects by positron emission tomography after intravenous injection of 11C-labeled 3-N-methylspiperone. Levels of receptor in the caudate nucleus, putamen, and frontal cerebral cortex declined over the age span studied (19 to 73 years). The decline in D2 receptor in males was different from that in females.

Imaging dopamine receptors in the human brain by positron tomography.

Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-[11C]methylspiperone, which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in humans.

Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics.

In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.

Bayesian hierarchical modeling of receptor occupancy in PET trials.

Receptor occupancy (RO) PET is a non-invasive way to determine drug on target. Given the complexity of procedures, long acquisition times, and high cost, ligand displacement imaging trials often have a limited size and produce sparse RO results over the time course of the blocking drug. To take the best advantage of the available data, we propose a Bayesian hierarchical model to analyze RO as a function of the displacing drug. The model has three components: the first estimates RO using brain regional time-radioactivity concentrations, the second shapes the pharmacokinetic profile of the blocking drug, and the last relates PK to RO. Compared to standard 2-steps RO estimation methods, our Bayesian approach quantifies the variability of the individual RO measures. The model has also useful prediction capabilities: to quantify brain RO for dosage regimens of the drug that were not tested in the experiment. This permits the optimal dose selection of neuroscience drugs at a limited cost. We illustrate the method in the prediction of RO after multiple dosing from a single-dose trial.

Enhancing staff attitudes, knowledge and skills in supporting the self-determination of adults with intellectual disability in residential settings in Hong Kong: a pretest-posttest comparison group design.

BACKGROUND: The ecological perspective recognizes the critical role that is played by rehabilitation personnel in helping people with intellectual disability (ID) to exercise self-determination, particularly in residential settings. In Hong Kong, the authors developed the first staff training programme of its kind to strengthen the competence of personnel in this area. The purpose of this study was to examine the effectiveness of staff training in enhancing residential staff's attitudes, knowledge and facilitation skills in assisting residents with ID to exercise self-determination. METHODS: A pretest-posttest comparison group design was adopted. Thirty-two participants in an experimental group attended a six-session staff training programme. A 34-item self-constructed scale was designed and used for measuring the effectiveness of the staff training. RESULTS: The results showed that the experimental group achieved statistically significant positive changes in all domains, whereas no significant changes were found in the comparison group. CONCLUSIONS: The findings provided initial evidence of the effectiveness of staff training that uses an interactional attitude-knowledge-skills model for Chinese rehabilitation personnel. The factors that contributed to its effectiveness were discussed and recommendations for future research were made.

Unexpected thymic hyperplasia in transgenic mice harboring a neuronal promoter fused with simian virus 40 large T antigen.

The hypothalamic peptide growth hormone-releasing factor (GRF) regulates the secretion and production of growth hormone from the anterior pituitary (M. C. Gelato and G. R. Merriam, Annu. Rev. Physiol. 48:569-591). To study GRF gene regulation, transgenic mice were generated that harbor the human GRF promoter fused to the coding sequences from the simian virus 40 early region. These mice had normal hypothalamic functions but unexpectedly suffered from severe thymic hyperplasia. Immunohistochemical analysis revealed that large T antigen was expressed in the thymic epithelial cells. These cells have endocrine properties and are known to produce thymic hormones [corrected]. The thymic hyperplasia was the apparent consequence of inappropriate production of T-cell maturation factors by epithelial cells and could involve increased self renewal of apparently normal T stem cells in the thymus.

In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder.

BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.

Cocaine-induced reduction of glucose utilization in human brain. A study using positron emission tomography and [fluorine 18]-fluorodeoxyglucose.

We examined the effects of cocaine hydrochloride (40 mg intravenously) on regional cerebral metabolic rates for glucose and on subjective self-reports of eight polydrug abusers in a double-blind, placebo-controlled, crossover study. The regional cerebral metabolic rate for glucose was measured by the [fluorine 18]-fluorodeoxyglucose method, using positron emission tomography. With eyes covered, subjects listened to a tape that presented white noise, "beep" prompts, and questions about subjective effects of cocaine or saline. Cocaine produced euphoria and reduced glucose utilization globally (mean reduction, 14%). Twenty-six of 29 brain regions (all neocortical areas, basal ganglia, portions of the hippocampal formation, thalamus, and midbrain) showed significant decrements (5% to 26%) in the regional cerebral metabolic rate for glucose. No significant effects of cocaine were observed in the pons, the cerebellar cortex, or the vermis. Right-greater-than-left hemispheric asymmetry of regional cerebral metabolic rates for glucose occurred in the lateral thalamus. The findings demonstrate that reduced cerebral metabolism is associated with cocaine-induced euphoria.

Morphine-induced metabolic changes in human brain. Studies with positron emission tomography and [fluorine 18]fluorodeoxyglucose.

Morphine sulfate effects (30 mg, intramuscularly) on cerebral glucose utilization and subjective self-reports were examined in 12 polydrug abusers by positron emission tomography and [fluorine 18]fluorodeoxyglucose in a double-blind placebo-controlled crossover study. During testing, subjects sat with eyes covered, listening to white noise and "beep" prompts. Morphine significantly reduced glucose utilization by 10% in whole brain and by about 5% to 15% in telencephalic areas and the cerebellar cortex, assuming no contribution of hypercapnia. When the contribution of PaCO2 (45 minutes after morphine was administered) was partialled out, significant morphine-induced reductions persisted in whole brain and six cortical areas. Irrespective of morphine, left-greater-than-right asymmetry occurred in the temporal cortex, and an interaction between hemisphere and drug was noted in the postcentral gyrus. In most cases, effects on glucose utilization were not significantly related to measures of euphoria.

Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Quantification of neuroreceptors in living human brain. v. endogenous neurotransmitter inhibition of haloperidol binding in psychosis.

The half-inhibition concentration (IC50) of a drug indicates its ability to inhibit the binding of other ligands of a receptor. The authors used positron emission tomography to test the hypothesis that haloperidol's IC50 toward the binding of tracer N-[11C]methylspiperone ([11C]NMSP) in brain must be increased in patients in whom more dopamine is bound to receptors than in healthy volunteers. The IC50 of haloperidol was significantly elevated from 1.5 nmol/L in healthy volunteers and patients with bipolar disease without psychosis to 4.5 nmol/L in patients with schizophrenia or bipolar disease with psychosis. The higher IC50 values in psychosis are consistent with an 8-fold increased binding of dopamine and a 16-fold elevated concentration of synaptic dopamine in psychosis. At the 80% haloperidol blockade of the receptors, the calculated amount of neurotransmitter bound in the patients with psychosis declined to twice the value estimated in the nonpsychotic subjects, that is, 5 pmol cm(-3).

Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands.

A first step in the quantification of receptor density in the living human brain is the measurement of the binding of a labeled ligand to the receptor in question. In the present study, we determined the rate of binding of 11C-labeled N-methylspiperone (NMSP) to the D2 dopamine receptor in 11 normal volunteers, using a three-compartment model to relate the time integral of the measured plasma concentration to the distribution of the tracer in the caudate nucleus. The plasma concentrations of NMSP were separated from the contaminating metabolites by the ratio of radioactivities in cerebellum and blood plasma. Plasma concentrations calculated in this way agreed with plasma concentrations determined by HPLC. The rate of binding of labeled NMSP to its receptors (k3) was defined as the product of the bimolecular association rate (kon) and the quantity of available receptors (B'max) and calculated as the ratio between the steady-state rate of accumulation and the volume of distribution of labeled NMSP in the caudate nucleus. The average value of k3 in the 11 normal volunteers was 0.065 min-1. The fractional clearance of labeled NMSP from the caudate nucleus (k2) was 0.070 min-1 and thus close to the value of k3. We also examined several indexes of binding based on ratios between different regions in brain. The indexes required that binding be negligible compared to the efflux of labeled NMSP (i.e., k2 much greater than k3) and therefore yielded incorrectly low values of k3. Thus, the only accurate approach used measured plasma concentrations to estimate transfer constants at steady state and yielded the absolute rate of binding k3. The approach is applicable to other irreversibly bound ligands.