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Objective Although a relationship between schizophrenia (SCZ), antipsychotic (AP) medication, and metabolic dysregulation is now well established, the effect of adiposity is less well understood. By synthesizing findings from imaging techniques that measure adiposity, our systematic review and meta-analysis (PROSPERO CRD42020192977) aims to determine the adiposity-related effects of illness and treatment in this patient population. Methods We searched MEDLINE, EMBASE, PsychINFO and Scopus for all relevant case-control and prospective longitudinal studies from inception until February 2021. Measures of adiposity including percent body fat (%BF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed as primary outcomes. Results Our search identified 29 articles that used imaging methods to quantify adiposity among patients with SCZ spectrum disorders. Analyses revealed that patients have greater %BF (mean difference (MD) = 3.09%; 95%CI: 0.75 to 5.44), SAT (MD = 24.29 cm2 ; 95%CI: 2.97 to 45.61) and VAT (MD = 33.73 cm2 , 95%CI: 4.19 to 63.27) compared to healthy controls. AP treatment was found to increase SAT (MD = 31.98 cm2 ; 95%CI: 11.33 to 52.64) and VAT (MD = 16.30 cm2 ; 95%CI: 8.17 to 24.44) with no effect on %BF. However, change in %BF was higher for AP-free/AP-naive patients compared to treated patients. Conclusion Our findings indicate that patients with SCZ spectrum disorders have greater adiposity than healthy controls, which is increased by AP treatment. Young, AP-naive patients may be particularly susceptible to this effect. Future studies should explore the effect of specific APs on adiposity and its relation to overall metabolic health.

Aim Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. Methods A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. Results There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (β = 0.721, P = 0.019; F1, 8 = 8.67, adjusted R2 = 0.46). Conclusions The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347-351.

The radiotracers [11 C]-raclopride and [11 C]-(+)-PHNO are commonly used to measure differences in amphetamine-induced dopamine release between healthy persons and persons with neuropsychiatric diseases. As an agonist radiotracer, [11 C]-(+)-PHNO should theoretically be roughly 2.7 times more sensitive to displacement by endogenous dopamine than [11 C]raclopride. To date, only one study has been published comparing the sensitivity of these two radiotracers to amphetamine-induced dopamine release in healthy persons. Unfortunately, conflicting findings in the literature suggests that the dose of amphetamine they employed (0.3 mg/kg, p.o.) may not reliably reduce [11 C]-raclopride binding in the caudate. Thus, it is unclear whether the preponderance of evidence supports the theory that [11 C]-(+)-PHNO is more sensitive to displacement by amphetamine in humans than [11 C]-raclopride. In order to clarify these issues, we conducted a comparative meta-analysis summarizing the effects of amphetamine on [11 C]-raclopride and [11 C]-(+)-PHNO binding in healthy humans. Our analysis indicates that amphetamine given at 0.3 mg/kg, p.o. does not reliably reduce [11 C]-raclopride binding in the caudate. Second, the greater sensitivity of [11 C]-(+)-PHNO is evidenced at 0.5 mg/kg, p.o., but not at lower doses of amphetamine. Third, our analysis suggests that [11 C]-(+)-PHNO may be roughly 1.5 to 2.5 times more sensitive to displacement by amphetamine than [11 C]-raclopride in healthy persons. We recommend that future displacement studies with these radiotracers employ 0.5 mg/kg, p.o. of amphetamine with a dose, post-scan interval of at least 3 hr. Using this dose of amphetamine, [11 C]-raclopride studies should employ at least n = 34 participants per group, while [11 C]-(+)-PHNO studies should employ at least n = 6 participants per group, in order to be sufficiently powered (80%) to detect changes in radiotracer binding within the caudate.

Impulsivity is considered a vulnerability trait for addiction. Recently, we found trait non-planning impulsiveness measured with the Karolinska Scales of Personality was negatively correlated with dopamine D2/3 receptor availability in the ventral striatum of healthy humans. While also observed in rodents, human studies have failed to find this association with other measures of trait impulsivity. We explored whether another rodent finding, reduced ventral striatum volume with greater impulsivity, could also be observed in humans using this scale. Non-planning impulsiveness was measured in 52 healthy subjects (21 female; mean age: 33.06 ± 9.69) using the Karolinska Scales of Personality. Striatal subregion volumes, including the globus pallidus, were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Although failing to support our a priori hypothesis, there was a significant sex interaction in the post-commissural putamen with impulsiveness. Exploratory analyses revealed impulsiveness was negatively correlated with post-commissural putamen volumes in males, but positively correlated in females. We replicated this finding in males in an increased sample (including all 52 previous subjects) who provided impulsiveness measured by the Temperament and Character Inventory (n = 73; 32 female; mean age: 33.48 ± 9.75). These correlations by sex were statistically different from one another, the main finding with the Kasolinksa Scales of Personality surviving correction for multiple comparisons. While impulsivity may be related to reduced ventral striatal D2/3 receptors across sexes, males but not females may show significant reductions in post-commissural putamen volume. These findings have important implications for understanding biological markers underlying sex differences in drug addiction vulnerability.

Background Abnormalities in dopamine (DA) and brain morphology are observed in several neuropsychiatric disorders. However, it is not fully understood how these abnormalities may relate to one another. For such in vivo findings to be used as biomarkers for neuropsychiatric disease, it must be understood how variability in DA relates to brain structure under healthy conditions. We explored how the availability of striatal DA D2/3 receptors (D2/3R) is related to the volume of subcortical brain structures in a sample of healthy humans. Differences in D2/3R availability measured with an antagonist radiotracer ([11C]-raclopride) versus an agonist radiotracer ([11C]-(+)-PHNO) were examined. Methods Data from 62 subjects scanned with [11C]-raclopride (mean age = 38.98 ± 14.45; 23 female) and 68 subjects scanned with [11C]-(+)-PHNO (mean age = 38.54 ± 14.59; 25 female) were used. Subcortical volumes were extracted from T1-weighted images using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Partial correlations were used controlling for age, gender, and total brain volume. Results For [11C]-(+)-PHNO, ventral caudate volumes were positively correlated with BPND in the dorsal caudate and globus pallidus (GP). Ventral striatum (VS) volumes were positively correlated with BPND in the VS. With [11C]-raclopride, BPND in the VS was negatively correlated with subiculum volume of the hippocampus. Moreover, BPND in the GP was negatively correlated with the volume of the lateral posterior nucleus of the thalamus. Conclusion Findings are purely exploratory and presented corrected and uncorrected for multiple comparisons. We hope they will help inform the interpretation of future PET studies where concurrent changes in D2/3R and brain morphology are observed. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

The neurotransmitter dopamine is present in the retina and is involved in several modulatory functions. Unlike in rodents, dopamine D3 receptors are expressed in the retina of humans. Recently, uptake of the D3 receptor-preferring radiotracer [11 C]-(+)-PHNO has been observed in a retina-like region of interest (ROI) in humans. Here, we attempted to quantify [11 C]-(+)-PHNO uptake into this ROI using an independent sample, employing an extended scan acquisition time (120 min) and arterial kinetic modeling. Data from 14 healthy controls were analyzed (Mean Age: 38.41 ± 9.55, 3 female), 8 of which provided arterial line input function data (Mean Age: 41.07 ± 7.82, 3 female). Using Ichise's multilinear analysis (MA1) method, it was possible to quantify the volume of distribution (VT ) of [11 C]-(+)-PHNO in this retina-like region (Mean VT = 13.56 ± 3.52; Mean χ2 = 2.08 ± 2.20). Notably, the shape of the time activity curve resembled closely that of the globus pallidus. Moreover, the VT values in the retina correlated well with binding potential (BPND ) values calculated using the simplified reference tissue model (Mean BPND = 2.11 ± .94; Mean χ2 = 5.76 ± 2.56), employing the cerebellum as the reference region (r = .76, r2 = .58). In summary, we provide evidence that the in vivo uptake of [11 C]-(+)-PHNO into a retina-like ROI in humans can be quantified using both arterial blood sampling (VT ) and simplified reference tissue methods (BPND ).

Objective This study sought to determine psychosocial and clinico-demographic factors related to each symptomatic cluster (i.e., aggressiveness, psychosis, apathy/eating problems, and emotion/disinhibition) of neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD) needing interventional treatment against their agitation or psychotic symptoms. These clusters were classified from 12 Neuropsychiatric Inventory (NPI) subscores in our previous study using the Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer's Disease (CATIE-AD) dataset. Methods Based on clinical data from 421 AD outpatients with agitation or psychotic symptoms needed interventional treatment enrolled in the CATIE-AD, we conducted logistic regression analyses to examine the relationships between each symptomatic cluster and three psychosocial (marital status, residence, and caregivers' burden) and nine clinico-demographic (age, gender, education year, general cognition, activity of daily living [ADL], general medical health, race, and intake of anti-dementia drugs or psychotropics) factors. Results While no factor contributed to aggressiveness, psychosis was associated with several clinico-demographic factors: female gender, non-Caucasian race, and lower cognitive function. Apathy/eating problems was associated with more severe caregiver burden, living in one's own home, lower ADL level, and male gender, while emotion/disinhibition was predicted by more severe caregiver burden, lower education level, not-married status, and younger age. Conclusions Among the four NPS clusters, apathy/eating problems and emotion/disinhibition were associated with psychosocial as well as clinico-demographic factors in AD patients with psychotic symptoms or agitation needed interventional treatment.

Background Pittsburgh compound B ([11C]-PIB) identifies amyloid-β (Aβ) deposition in vivo. Asymptomatic Aβ deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aβ deposition. Objective Comparison of Aβ deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia. Methods Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff. Results The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD. Conclusions Aβ deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit Aβ deposition. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives Impaired insight into illness is a prevalent feature of schizophrenia, which negatively influences treatment adherence and clinical outcomes. Little is known about the effects of aging on insight impairment. We aimed to review the available research literature on the effects of aging on insight into illness in schizophrenia, in relation to positive, negative, and cognitive symptoms. Ultimately, we propose a trajectory of insight in schizophrenia across the lifespan. Method A systematic Medline® literature search was conducted, searching for English language studies describing the relationship of insight into illness in schizophrenia with aging. Results We identified 62 studies. Insight impairment is associated with illness severity, premorbid intellectual function (i.e. IQ), executive function, and memory. Insight impairment improves modestly during midlife, worsening again in late life. It tends to fluctuate with each episode of psychosis, likely in relation to worsening positive symptoms that improve with antipsychotic treatment. The relationship between insight impairment and cognitive dysfunction appears to attenuate with age, while the relationship with lower premorbid intellectual function is preserved. The association between impaired insight and negative symptoms is unclear. Conclusions The available literature suggests that the course of insight impairment follows a U-shaped curve, where insight impairment is severe during the first episode of psychosis, modestly improves over midlife, and declines again in late life. Future studies are required to investigate the trajectory of insight into illness and its core domains across the lifespan from prodromal phase to late life. Copyright © 2014 John Wiley & Sons, Ltd.

Objectives To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open-label study of memantine in frontotemporal dementia (FTD). Methods We repeated fluorodeoxyglucose positron emission tomography (FDG-PET) after 6 months of drug use and subjected the data to Statistical Parametrical Mapping (SPM) analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI) and the PET signal. Results Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia (SD). The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p

Introduction: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia. Methods: Both voxel‐based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation‐based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates. Results: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe (t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex (t = 5.80, P = 0.003) and parietal lobe (t = 4.3, P = 0.050) using the deformation‐based approach. Trend level associations were identified in the right medial prefrontal cortex (t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume (r = 0.401, P < 0.01) and illness severity (r = 0.559, P < 0.01). Conclusion: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume‐based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.

The D(2) receptors exist in either the high‐ or low‐affinity state with respect to agonists, and while agonists bind preferentially to the high‐affinity state, antagonists do not distinguish between the two states. [(11)C]‐(+)‐PHNO is a PET D(2) agonist radioligand and therefore provides a preferential measure of the D(2) (high) receptors. In contrast, [(11)C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D(2) high‐ and low‐affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [(11)C]‐(+)‐PHNO and [(11)C]raclopride in volunteers using a within‐subject design. Both radioligands accumulated in brain areas rich in D(2)/D(3)‐receptors. However, [(11)C]‐(+)‐PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [(11)C]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [(11)C]raclopride, equal in the ventral‐striatum (3.4 vs. 3.3), and higher in the globus pallidus for [(11)C]‐(+)‐PHNO (1.8 vs. 3.3). Moreover [(11)C]‐(+)‐PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [(11)C]‐(+)‐PHNO in the globus pallidus and ventral‐striatum could be the presence of a greater proportion of high‐ vs. low‐affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D(3)‐over‐D(2) with [(11)C]‐(+)‐PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease. Hum Brain Mapp 2008. © 2007 Wiley‐Liss, Inc.

Interest in a role for norepinephrine (NE) in substance use disorders has increased over recent years. In particular, its interaction with dopamine (DA) is of importance. In this study, positron emission tomography (PET) was used to explore the impact of prazosin (an alpha 1 NE antagonist) on DA levels. Healthy volunteers were administered prazosin for approximately 4 weeks at the daily dose of 15 mg to reach steady state. Participants were scanned with PET imaging and the [11 C]-(+)-PHNO tracer at baseline (before prazosin), at steady state, and after a wash out period. Prazosin administration was associated with an increase of [11 C]-(+)-PHNO binding potential in the dorsal caudate relative to baseline, which corresponds to a decrease in DA levels. This study is the first to demonstrate interactions between DA and NE in healthy humans.