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Background: To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N‐acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. Methods: Eighteen healthy Japanese participants (7 males/11 females) aged 20–30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase‐2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N‐acetylaspartate N‐acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1H‐MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two‐way repeated‐measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within‐ and between‐subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). Results: Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. Conclusions: Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are atypical parkinsonisms (APs) that are classified as tauopathies. Patients with these APs may present with similar early clinical manifestations to Parkinson's disease (PD), but they prove unresponsive to anti‐parkinsonian medications. Objective: The main objective of this meta‐analysis was to compare first‐ and second‐generation tau PET tracer efficacy in patients with the APs to identify potential diagnostic biomarkers. Methods: PubMed and Web of Science were searched between January 1, 1999 and December 31, 2022. We included case–control studies that were published in English and report tau PET tracer binding as mean ± SD in at least one region of interest (ROI). Differences in tau PET binding values were meta‐analyzed using random‐effects meta‐analytic models and subgroup analyses based on ROIs in the statistical programming language R (version 4.2.1). Results: Overall, 29 studies with 665 patients were included in the final review. [18F]PI‐2620 outperformed first‐generation tracers when comparing PSP‐HC (g = −1.68, 95% CI: −2.05 to −1.30) and CBD‐HC (g = −1.37, 95% CI: −2.25 to −0.49). When comparing PSP‐PD, the first‐generation tracer, [18F]AV‐1451, presented with higher binding to PSP patients (g = −0.80, 95% CI: −1.24 to −0.35). Conclusions: Our results demonstrate the efficacy of [18F]PI‐2620 PET in imaging AP‐tau. These findings contribute towards identifying a diagnostic imaging biomarker for patients with APs. The main limitation of this study was the heterogeneity of the results. Future studies should conduct AP‐PD comparisons with second‐generation tracers to confirm the preliminary results found here. [ABSTRACT FROM AUTHOR]

Background: Interventions to prevent cognitive decline and dementia in high‐risk populations such as those with remitted Major Depressive Disorder (rMDD) or Mild Cognitive Impairment (MCI) are urgently needed. Method: PACt‐MD was a double‐blind randomized trial conducted between 2015 and 2022 comparing cognitive remediation (CR) plus transcranial Direct Current Stimulation (tDCS) vs. sham‐CR+sham‐tDCS delivered 5 days/week for 8 weeks followed by 5‐day semi‐annual boosters and at‐home daily CR, in participants with rMDD or MCI. Participants were assessed at baseline, week‐8, and yearly. The hypotheses were that compared to sham+sham, CR+tDCS would: slow cognitive decline (H1); reduce progression to MCI or dementia (H2); and acutely improve cognition (H3). The primary outcome composite score was calculated when at least half of the tests for at least four of six cognitive domains were completed. Due to COVID‐19, some participants did not complete enough tests and a second composite score using all available data was generated. Result: 375 participants were randomized (Active: N = 188, Mean Age = 72.1 ± 6.3; Sham: N = 187, Mean Age = 72.3 ± 6.4) and received at least one intervention session. Over up to six years, there was no time‐by‐treatment interaction using the primary composite score but there was using the all‐data score. Change in composite score differed between the two intervention groups for the primary and all‐data scores for all years except for year‐6 primary score. The year‐5 adjusted z‐score difference was ‐0.15 (95%CI [‐0.29, ‐0.005]) for the primary and ‐0.21 (95%CI [‐0.34, ‐0.067]) for all‐data score (Fig.1). Comparing active vs. sham at 8‐week (H3), the adjusted z‐score difference was ‐0.06 (95%CI: [‐0.12, 0.005]; p = 0.072); and for progression (H2), HR was 0.66 (95%CI [0.40, 1.08] p = 0.101) in a stratified Cox model. In a preplanned secondary analysis of domain scores, there was a time‐by‐treatment interaction for verbal memory with a year‐5 adjusted z‐score difference of ‐0.30 (95%CI [‐0.53, ‐0.074]) (Fig.2) but not the other domains. In another preplanned secondary analysis, the model with a randomization diagnosis‐by‐time‐by‐treatment was different from the model without this three‐way interaction (p = 0.012; Fig.3). Conclusion: CR+tDCS may be effective in slowing cognitive decline (particularly verbal memory) in older patients with rMDD or MCI. [ABSTRACT FROM AUTHOR]

Aim: Validating the vulnerabilities and pathologies underlying treatment‐resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS. Methods: We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first‐line antipsychotics (FL‐Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ‐Resp) and 22 FL‐ and clozapine‐resistant patients (patients with ultratreatment‐resistant schizophrenia [URS]). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis. Results: Both CLZ‐Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [gH] = 0.75; P = 0.013, gH = 0.96) and FL‐Resp (P = 0.007, gH = 1.00; P = 0.002, gH = 1.31) in the left medial parietal cortex (Lt‐MPC). In addition, both CLZ‐Resp and URS had lower SA in the Lt‐MPC than FL‐Resp (P < 0.001, gH = 1.22; P < 0.001, gH = 1.75). LGI and SA were positively correlated in non‐TRS (FL‐Resp) (ρ = 0.64, P = 0.008) and TRS (CLZ‐Resp + URS) (ρ = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non‐TRS versus TRS with LGI and SA in the Lt‐MPC were 0.79 and 0.85, respectively. SA in the Lt‐MPC was inversely correlated with negative symptoms (ρ = −0.40, P = 0.018) and clozapine plasma levels (ρ = −0.35, P = 0.042) in TRS. Conclusion: LGI and SA in the Lt‐MPC, a functional hub in the default‐mode network, were abnormally reduced in TRS compared with non‐TRS. Thus, altered LGI and SA in the Lt‐MPC might be structural features associated with genetic vulnerability to TRS. [ABSTRACT FROM AUTHOR]

Background: Gamma‐Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment‐resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy (1H‐MRS), and clozapine response in patients with TRS. Methods: This study enrolled patients with TRS who did not respond to clozapine (ultra‐resistant schizophrenia: URS) and who responded to clozapine (non‐URS), patients with schizophrenia who responded to first‐line antipsychotics (first‐line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1H‐MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups. Results: A total of 98 participants (URS: n = 22; non‐URS: n = 25; FLR: n = 16; HCs: n = 35) completed the study. We found overall group differences in MCC GABA levels (F(3,86) = 3.25, P = 0.04). Specifically, patients with URS showed higher GABA levels compared to those with non‐URS (F(1,52) = 8.40, P = 0.03, Cohen's d = 0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group. Conclusion: Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance. [ABSTRACT FROM AUTHOR]

Objective: Clozapine is presently the sole antipsychotic with an indication for treatment‐resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine‐induced weight gain. Methods: We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes. Results: Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine‐only group at 6 months (clozapine+metformin: −0.15 kg [SE = 1.08] vs. clozapine‐only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: −0.67 kg, SE = 1.22 vs. clozapine‐only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only. Conclusion: In this large retrospective naturalistic cohort study, co‐prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine‐induced weight gain; larger randomized controlled trials are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Aims: Develop a robust and user‐friendly software tool for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone, in order to facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. Methods: Previously developed population pharmacokinetic models for olanzapine and risperidone were combined with a pharmacodynamic model for D2 RO and implemented in the R programming language. Maximum a posteriori Bayesian estimation was used to provide predictions of plasma concentration and RO based on sparse concentration sampling. These predictions were then compared to observed plasma concentration and RO. Results: The average (standard deviation) response times of the tools, defined as the time required for the application to predict parameter values and display the output, were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (95% confidence interval) of predicted vs. observed concentrations were 3.73 ng/mL (−2.42–9.87) and 10.816 ng/mL (6.71–14.93) for olanzapine, and 0.46 ng/mL (−4.56–5.47) and 6.68 ng/mL (3.57–9.78) for risperidone and its active metabolite (9‐OH risperidone). Mean error and root mean squared error of RO were −1.47% (−4.65–1.69) and 5.80% (3.89–7.72) for olanzapine and −0.91% (−7.68–5.85) and 8.87% (4.56–13.17) for risperidone. Conclusion: Our monitoring software predicts concentration–time profiles and the corresponding D2 RO from sparsely sampled concentration measurements in an accessible and accurate form. [ABSTRACT FROM AUTHOR]

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: 0.75–5.44), SAT (MD = 24.29 cm2; 95% CI: 2.97–45.61) and VAT (MD = 33.73 cm2, 95% CI: 4.19–63.27) compared to healthy controls. AP treatment was found to increase SAT (MD = 31.98 cm2; 95% CI: 11.33–52.64) and VAT (MD = 16.30 cm2; 95% CI: 8.17–24.44) with no effect on %BF. However, change in %BF was higher for AP‐free/AP‐naïve 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‐naïve 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. [ABSTRACT FROM AUTHOR]

Background: Emotion dysregulation was studied as a potential risk marker for Alzheimer's disease (AD) by assessing emotional memory in high AD‐risk groups characterized by the presence of mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) and by evaluating the relationship between emotional memory and in vivo cerebral amyloid‐β deposition. Method: 435 participants enrolled in the PACt‐MD clinical trial of cognitive remediation plus transcranial direct current stimulation were evaluated at baseline. The sample included 127 older adults with amnestic mild cognitive impairment (aMCI), 51 non‐amnestic MCI (naMCI), 60 rMDD without MCI, 81 rMDD+aMCI, 42 rMDD+naMCI, and 74 cognitively unimpaired older adults (CU). Diagnoses were established during a consensus conference based on psychiatric, medical, and neuropsychological assessment. Emotional memory was assessed by evaluating immediate and short‐term delayed recall of 15 personality adjectives (5 each of positive, negative and neutral words) from the Emotional Verbal Learning Test (Mah et al., 2017, American Journal of Geriatric Psychiatry, 25:1160). A subset (N = 167) completed a Positron Emission Tomography (PET) scan with carbon‐11 Pittsburgh Compound B ([11C] PIB). Valence and diagnostic group effects on recall were assessed using mixed ANOVA. Regression modelling assessed the association between emotional memory bias and amyloid‐β burden. Result: Relative to CU, both aMCI and rMDD+aMCI groups showed enhanced memory for negative words at immediate recall, which persisted after short delay in the aMCI group only (F(1, 339) = 2.66, p =.048; Figure 1). Enhanced memory for negative words at short delay was predictive of in vivo cerebral amyloid‐β deposition (standardized beta =.117, t = 1.84, p =.067), over and above the contributions of age, sex, Apolipoprotein E genotype, depression diagnosis and symptoms, and long delayed verbal recall (F(4,154) = 25.8, p<.001, R2 =.41; Figure 2). Conclusion: The association between enhanced memory for negative personality adjectives and aMCI replicates earlier work in single‐domain aMCI (Mah et al., 2017) and suggests that aMCI is characterized by a negativity bias in memory. These findings, taken together with the relationship between a negativity bias in memory and amyloid‐β burden, suggest that emotion dysregulation, in the form of enhanced memory for negative information, is a potential marker of AD risk. [ABSTRACT FROM AUTHOR]

Background: Behavioral and psychological symptoms in dementia (BPSD) are highly prevalent in patients with Alzheimer's dementia (AD). We examined sex differences in the frequency and severity of BPSD in patients with advanced AD residing in long term care or admitted to inpatient psychiatric units. Also, sex differences in the frequency and severity of BPSD symptom clusters were explored. Method: We analyzed data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201). BPSD was assessed with the Neuropsychiatric Inventory Clinician rating scale. Chi‐squared tests and Mann‐Whitney U tests were used to determine sex differences in frequency and severity of BPSD, respectively. Bonferroni correction was used for multiple comparisons. Generalized linear models were performed to examine effect of sex on severity of BPSD while controlling for age and residence. BPSD symptom clusters were defined as: (1) psychosis (hallucinations and delusions), (2) emotional distress (depression and anxiety), and (3) agitation (agitation, aggression, irritability, aberrant motor behavior, and aberrant vocalizations). Result: 194 participants (99 female, 95 male) were included. Females had higher frequency of delusions (X2(N = 176) = 8.47, p =.004) and males had higher frequency of sleep disturbances (X2(N = 176) = 9.89, p =.002). Further, females had greater severity of delusions (N = 176, U = 2976, p =.001), and sleep disturbances (N = 176, U = 2950, p =.002). In generalized linear models, sex was associated with severity of delusions (Wald X2 = 3.97, N = 176, p =.046), but not with sleep disturbances. Examination of clusters revealed that females had higher frequency of psychosis (X2(N = 176) = 4.25, p =.039). Conclusion: We observed sex differences in the frequency and severity of specific BPSD. Future studies should aim to understand potential mechanisms underlying these differences, and to study their relevance for screening, and individualized management of BPSD. [ABSTRACT FROM AUTHOR]

Background: Inflammatory activation and increased immune response to lipopolysaccharide (LPS, a cell wall component of gut bacteria) is observed in both depression and cognitive decline. Depression is associated with accelerated cognitive decline, and persistent inflammatory activation may link depression and cognitive decline in later life. We determined if LPS is associated with inflammatory activation and cerebral deposition of amyloid‐beta (Abeta) in older adults with Mild Cognitive Impairment (MCI) and/or remitted Major Depressive Disorder (rMDD). Method: Serum samples of LPS, LPS‐binding protein (LBP, which enhances the inflammatory response to LPS), and inflammatory markers (Interleukin 6 [Il‐6], C‐reactive protein [CRP], Monocyte Chemoattractant Protein 1 [MCP‐1]) were measured using ELISA. Abeta deposition was measured using PET neuroimaging using [11C]‐PIB radiotracer. Global amyloid burden was calculated using a composite Standardized Uptake Value Ratio (SUVR) score with the cerebellar cortex as the reference region. Multivariable linear regression analyses, adjusting for significant demographic and genetic variables, were conducted to determine if LPS, LBP, inflammatory biomarkers, MCI and rMDD were independently associated with global cerebral deposition of Abeta. Result: Among 155 study participants (79 with MCI only, 54 with both MCI and rMDD, 22 with rMDD only) we found a median Abeta SUVR of 1.41 (IQR 0.57). There was no significant association between LPS (beta ‐1.28, 95% CI ‐11.69, 9.13, p = 0.8) or LBP (beta ‐0.02, 95% CI ‐0.05, 0.006, p = 0.12) and global deposition of Abeta, following adjustment for age, sex, and APOE genotype. LBP was positively correlated with inflammatory biomarkers: CRP (r = 0.49, p < 0.001) and IL‐6 (r = 0.21, p = 0.01) but no inflammatory biomarker was significantly associated with Abeta deposition. Having a history of rMDD (beta ‐0.09, 95% CI ‐0.26, 0.08, p = 0.28) or MCI alone (beta ‐0.11, 95% CI ‐0.47, 0.049, p = 0.11) was not associated with deposition of Abeta. Conclusion: In this cross‐sectional analysis, we did not find an association between LPS/LBP, immune biomarkers, remitted MDD and global deposition of Abeta. Future analyses should examine the longitudinal relationships between peripheral and central biomarkers of immune activation with cerebral Abeta deposition in patients and controls. [ABSTRACT FROM AUTHOR]

Background and Purpose: Amyloid deposition, tau neurofibrillary tangles, and cerebrovascular dysfunction are important pathophysiologic features in Alzheimer's disease. Pittsburgh compound B ([11 C]-PIB) is a positron emission tomography (PET) radiotracer used to quantify amyloid deposition in vivo. In addition, certain models of [11 C]-PIB delivery reflect cerebral blood flow rather than amyloid plaques. As cerebral blood flow and perfusion deficits are associated with white matter pathology, we hypothesized that [11 C]-PIB delivery in white matter regions may reflect white matter integrity.Methods: We obtained [11 C]-PIB-PET scans and quantified white matter hyperintensities and global fractional anisotropy on magnetic resonance images as biomarkers of white matter pathology in 34 older participants with mild cognitive impairment with or without a history of major depressive disorder. We analyzed the [11 C]-PIB time-activity curve data with models associated with cerebral blood flow: the early maximum standard uptake value and the relative delivery parameter R1. We used a global white matter region of interest.Results: Both of the partial-volume corrected PET parameters were correlated with white matter hyperintensities and fractional anisotropy.Conclusion: Future studies are warranted to explore whether [11 C]-PIB PET is a "triple biomarker" that may provide information about amyloid deposition, cerebral blood flow, and white matter pathology. [ABSTRACT FROM AUTHOR]

The radiotracers [11C]‐raclopride and [11C]‐(+)‐PHNO are commonly used to measure differences in amphetamine‐induced dopamine release between healthy persons and persons with neuropsychiatric diseases. As an agonist radiotracer, [11C]‐(+)‐PHNO should theoretically be roughly 2.7 times more sensitive to displacement by endogenous dopamine than [11C]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 [11C]‐raclopride binding in the caudate. Thus, it is unclear whether the preponderance of evidence supports the theory that [11C]‐(+)‐PHNO is more sensitive to displacement by amphetamine in humans than [11C]‐raclopride. In order to clarify these issues, we conducted a comparative meta‐analysis summarizing the effects of amphetamine on [11C]‐raclopride and [11C]‐(+)‐PHNO binding in healthy humans. Our analysis indicates that amphetamine given at 0.3 mg/kg, p.o. does not reliably reduce [11C]‐raclopride binding in the caudate. Second, the greater sensitivity of [11C]‐(+)‐PHNO is evidenced at 0.5 mg/kg, p.o., but not at lower doses of amphetamine. Third, our analysis suggests that [11C]‐(+)‐PHNO may be roughly 1.5 to 2.5 times more sensitive to displacement by amphetamine than [11C]‐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, [11C]‐raclopride studies should employ at least n = 34 participants per group, while [11C]‐(+)‐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. [ABSTRACT FROM AUTHOR]

Aim: It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods: This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6‐week double‐blind, placebo‐controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results: Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2:.51,.42 and.55,.54, respectively). Conclusion: Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity. [ABSTRACT FROM AUTHOR]

Impaired illness awareness or not accepting that one has hypertension (HTN) may be an important predictor of treatment adherence and optimal blood pressure control. The purpose of this study was to perform a systematic review of available instruments to evaluate HTN awareness, and subsequently present a novel scale that measures the core domains of subjective illness awareness in HTN. Based on the absence of any validated HTN specific measure identified through our review, the Blood Pressure Awareness and Insight Scale (BASIS) was developed (www.illnessawarenessscales.com). An online survey platform was used to collect data on 100 participants. BASIS showed good concurrent (r(98) = .65, P < 0.001) and discriminant validity, internal consistency (Cronbach's α = .75), and 1-month test-retest reliability (ICC = 0.77). BASIS is a comprehensive, easy-to-use instrument specifically designed to measure subjective HTN awareness. BASIS may be used in research studies and clinical practice to assess the impact of HTN awareness on treatment adherence and clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D2/3 receptor (D2/3 R) blockade by antipsychotics.Methods: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D2/3 R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate.Results: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: β = -.38, t = -2.48, P = .01; left: β = -.31, t = -2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (β = -.43, t = -0.26, P = .03).Conclusion: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3 R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are common during the course of neurocognitive disorders. NPS have been previously reported in early and late stages of Alzheimer's Disease. However, our understanding of NPS in high‐risk states for dementia such as mild cognitive impairment (MCI) and major depressive disorder (MDD) is poor. The purpose of this study was to compare the frequency and factor structure of neuropsychiatric symptoms among individuals with Mild Cognitive Impairment (MCI), Major Depressive Disorder (MDD) in remission, and comorbid MCI and MDD (in remission) (MCI‐D). Method: We used baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt‐MD) study, a multicenter trial across five academic sites in Toronto, Canada (clinical trial No. NCT0238667). We used ANOVA or χ2‐test to compare frequency of NPS across groups. We used factor analysis of Neuropsychiatric Inventory Questionnaire (NPI‐Q) items in the three groups. Result: We included 374 participants with a mean age of 72.0 years (SD = 6.3). In the overall sample, at least one NPS was present in 64.2% participants, and 36.1% had at least moderate severity NPS (36.1%). Depression (54%, χ2 < 0.001) and apathy (28.7%, χ2 = 0.002) were more prevalent in the MCI‐D group as compared to MCI and MDD groups. In factor analysis, NPS grouped differently in MCI, MDD, and MCI‐D groups. A "psychotic" subgroup emerged among MCI and MCI‐D, but not in MDD. Night‐time behaviors and disinhibition grouped differently across all three groups. Conclusion: Prevalence of NPS seems higher in persons with MCI‐D as compared to those with only MCI or MDD. The factor structure of NPS differed between MCI, MDD, and MCI‐D groups. Future studies should investigate the association of NPS factors with cognition, function, and illness biomarkers. [ABSTRACT FROM AUTHOR]

Background: Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in patients with dementia during the course of the disease. Among BPSD symptoms, agitation and aggression are a source of distress for both the patients and their caregivers. In this study, we investigated the impact of agitation and aggression on Quality of Life (QoL) of patients with dementia living in long‐term care homes or admitted to psychiatric inpatient units. Method: Data were obtained from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study, a multisite trial conducted in Canada. Agitation and aggression were assessed with the Cohen‐Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory Clinician rating scale (NPI‐C); QoL with the informant‐rated Alzheimer's Disease Related Quality of Life (ADRQL) tool; stage of dementia with the Functional Assessment Staging Tool (FAST); and burden of physical illness with the Cumulative Illness Rating Scale‐Geriatric (CIRS‐G). Regressions were performed to investigate the associations between agitation or aggression and QoL controlling for demographic factors, FAST score, and CIRS‐G score. Result: 179 participants were included (52.5% female; mean (SD) age = 80.79 (9.45) years. The ADRQL score was correlated with: (1) CMAI total frequency score (Pearson's r = ‐.333, p<.001); (2) NPI‐C agitation score (Pearson's r = ‐.209, p =.005); and (3) NPI‐C aggression score (Pearson's r = ‐.300, p<.001). The associations remained significant for the CMAI total frequency score (β = ‐.235, SE B = 0.054, p<.001), and NPI‐C agitation and aggression composite score (β = ‐.288, SE B = 1.254, p<.001) after controlling for age, sex, current residence, FAST score and CIRS‐G score. Conclusion: QoL is related to agitation and aggression in patients with dementia. The relationship is independent of demographic factors, stage of dementia, and burden of comorbid physical illness. This suggests that better management of agitation and aggression may be an important factor in improving QoL in patients with dementia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Differences in regional brain volumes as a function of family history (FH) of alcohol use disorder (AUD) have been reported, and it has been suggested that these differences might index genetic risk for AUD. However, results have been inconsistent. The aims of the current study were (i) to provide an updated descriptive review of the existing literature and (ii) to examine the association of FH with indices of subcortical volumes and cortical thickness in a sample of youth recruited based on FH status. Methods: To address aim 1, a literature search located 15 published studies comprising 1,735 participants. Studies were characterized according to population, analytic methods, regions of interest, and primary findings. To address the second aim, we examined volumetric and cortical thickness in a sample of 69 youth (mean age = 19.71 years, SD = 0.79) recruited based on FH status and matched on drinking variables. Associations of sex and alcohol use with volumetric outcomes were also examined. Results: Our descriptive review revealed an inconsistent pattern of results with respect to the presence, direction, and regional specificity of volumetric differences across FH groups. The most consistent finding, significantly smaller amygdala volumes in FH+ participants, was not replicated in all studies. In the current sample of youth, measures of subcortical volumes and cortical thickness did not significantly differ as a function of FH, sex, or their interaction. Conclusions: Evidence for FH group differences in regional brain volumes is inconsistent, and the current study failed to detect any group differences. Further research is needed to confirm the reproducibility of FH group differences and implications for AUD risk. Neuroimaging studies have reported differences in brain structure as a function of family history (FH) of alcohol use disorder. This descriptive literature review revealed an inconsistent pattern of findings with respect to the presence, direction, and regional specificity of volumetric differences between FH groups. Additionally, in the present sample of youth recruited based on FH status, measures of subcortical volumes and cortical thickness did not differ across FH groups. Further research is needed to confirm FH differences in structural outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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 38:5519-5534, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [11C]-(+)-PHNO tracer at baseline (before prazosin), at steady state, and after a wash out period. Prazosin administration was associated with an increase of [11C]-(+)-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. [ABSTRACT FROM AUTHOR]

Endogenous dopamine (DA) levels at dopamine D2/3 receptors (D2/3R) have been quantified in the living human brain using the agonist radiotracer [11C]-(+)-PHNO. As an agonist radiotracer, [11C]-(+)-PHNO is more sensitive to endogenous DA levels than antagonist radiotracers. We sought to determine the proportion of the variance in baseline [11C]-(+)-PHNO binding to D2/3Rs which can be accounted for by variation in endogenous DA levels. This was done by computing the Pearson's coefficient for the correlation between baseline binding potential (BPND) and the change in BPND after acute DA depletion, using previously published data. All correlations were inverse, and the proportion of the variance in baseline [11C]-(+)-PHNO BPND that can be accounted for by variation in endogenous DA levels across the striatal subregions ranged from 42-59%. These results indicate that lower baseline values of [11C]-(+)-PHNO BPND reflect greater stimulation by endogenous DA. To further validate this interpretation, we sought to examine whether these data could be used to estimate the dissociation constant (Kd) of DA at D2/3R. In line with previous in vitro work, we estimated the in vivo Kd of DA to be around 20 nM. In summary, the agonist radiotracer [11C]-(+)-PHNO can detect the impact of endogenous DA levels at D2/3R in the living human brain from a single baseline scan, and may be more sensitive to this impact than other commonly employed radiotracers. [ABSTRACT FROM AUTHOR]

Background: Theta phase‐gamma amplitude coupling (TGC) is a neurophysiological mechanism that underlies working memory (WM)1. WM is also associated with demographic, clinical, genetic and neuroimaging measures. However, the relative contributions of TGC and these measures to WM, and the relationship between TGC and these measures, remains unclear. We examined the relative contributions of TGC and these measures to WM performance in a group of participants at‐risk for Alzheimer's dementia. Method: Older participants (age=71.2±6.0, N = 206) with Mild Cognitive Impairment (MCI), Major Depressive Disorder (MDD), or MCI+MDD completed clinical assessment, N‐back WM task with EEG to measure TGC, genetic testing, PET with [11C]‐Pittsburgh Compound B ([11C]‐PIB PET) and brain 3T MRI. Linear regressions were used to assess the relationships among 2‐back WM performance; demographic and clinical variables; TGC; ApoE4 carrier status; total beta‐amyloid SUVR ([11C]‐PIB PET); and regional cortical thickness, subcortical volumes, and white matter fractional anisotropy (MRI). Result: 2‐back WM performance was associated with age and TGC after controlling for all other measures (Age: β=‐0.253; p=0.039, TGC: β=0.300; p=0.005). TGC was not associated with any other measures after correction for multiple comparisons. Conclusion: TGC predicts WM performance in contrast to demographic, clinical, genetic, and PET and MRI imaging measures. Our findings underline the strong association between WM and TGC, a dynamic time‐based neurophysiological measure that is capturing a functional process which may not be captured by these static measures. Future studies could explore other dynamic measures with other imaging modalities and their relationships with TGC or other neurophysiological measures. 1. Rajji, T.K., et al., Ordering Information in Working Memory and Modulation of Gamma by Theta Oscillations in Humans. Cerebral Cortex, 2017. 27(2): p. 1482‐1490. [ABSTRACT FROM AUTHOR]

Impaired illness awareness or anosognosia is a common, but poorly understood feature of schizophrenia that contributes to medication nonadherence and poor treatment outcomes. Here we present a functional imaging study to measure brain activity at the moment of illness denial. To accomplish this, participants with schizophrenia ( n = 18) with varying degrees of illness awareness were confronted with their illness beliefs while undergoing functional MRI. To link structure with function, we explored the relationships among impaired illness awareness and brain activity during the illness denial task with cortical thickness. Impaired illness awareness was associated with increased brain activity in the left temporoparieto-occipital junction (TPO) and left medial prefrontal cortex (mPFC) at the moment of illness denial. Brain activity in the left mPFC appeared to be a function of participants' degree of self-reflectiveness, while the activity in the left TPO was associated with cortical thinning in this region and more specific to illness denial. Participants with impaired illness awareness had slower response times to illness related stimuli than those with good illness awareness. Increased left hemisphere brain activity in association with illness denial is consistent with the literature in other neuropsychiatric conditions attributing anosognosia or impaired illness awareness to left hemisphere dominance. The TPO and mPFC may represent putative targets for noninvasive treatment interventions, such as transcranial magnetic or direct current stimulation. Hum Brain Mapp, 36:391-414, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Theta‐gamma coupling (TGC) is an electroencephalography (EEG) marker of working memory and depends on robust synaptic plasticity within the recurrent prefrontal cortical networks (Rajji et al. 2017, Buszaski et al. 2012). ApoE4 allele has deleterious effects on synaptic plasticity (Teter et al. 2004). Thus, the primary objective of this analysis is to determine whether there is a relationship between ApoE4 genotype and TGC during the performance of a working memory task (N‐back). Method: We used baseline data from a large Alzheimer's dementia prevention trial. Participants were diagnosed with Mild Cognitive Impairment (MCI), past history of Major Depressive Disorder (MDD), or both (MCI+MDD) and had completed N‐back‐EEG and ApoE genotyping. TGC was measured across right and left frontal electrodes. Participants were grouped based on E4 presence (ApoE2/E3 or ApoE3/E3 [noncarriers] vs. ApoE3/E4 or ApoE4/E4 [carriers]). Result: We included 248 participants (MCI= 125; MDD= 44, MCI+MDD= 79; 153 females/95 males). There were 182 ApoE4 noncarriers (age= 71±6.5; Theta power= 16,290±14,764; Gamma power= 5793±5663; TGC= 0.00251±0.00227; PiB frontal amyloid=1.4371±0.32) and 66 noncarriers (age=71±5.0; Theta power= 17,235±14,312; Gamma power= 6473±5287; TGC= 0.002184±0.001622; PiB frontal amyloid= 2.09±0.78). Multiple linear regression results show that ApoE4 carriers had reduced TGC (β= 0.205, p= 0.042, Cohen's d= 0.28) after controlling for age, sex, diagnosis, theta power, gamma power, and PiB frontal amyloid. Gamma power was also a significant predictor of TGC. Conclusion: Our results suggest that presence of ApoE4 allele contributes to the modulation of TGC during a working memory task. As ApoE impacts synaptic plasticity, our findings suggest that synaptic plasticity or other ApoE‐related mechanisms underlie TGC. Rajji, T.K., et al., Ordering Information in Working Memory and Modulation of Gamma by Theta Oscillations in Humans. Cerebral Cortex, 2017. 27(2): p. 1482‐1490. Buzsaki, G. and X.J. Wang, Mechanisms of Gamma Oscillations, in Annual Review of Neuroscience, Vol 35, S.E. Hyman, Editor. 2012. p. 203‐225. Teter, B., ApoE‐dependent plasticity in Alzheimer's disease. Journal of Molecular Neuroscience, 2004. 23(3): p. 167‐179. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < 0.002) for five participants with SD. The 2-6-month interval revealed a late increase in normalized metabolic activity in the left insula (p < 0.013), right insula (p < 0.009), and left anterior cingulate (p < 0.005). The right anterior cingulate showed both an initial increase and a delayed further increase (2-6 months, p < 0.016). FBI scores worsened by 43.3%. One participant with SD opted not to continue memantine beyond 2 months yet showed similar FDG-PET increases.Conclusions: Increases in normalized cortical metabolic activity in salience network hubs were sustained in SD over a 6-month period. Because one participant without medication also showed these changes, further investigation is recommended through a double-blind, placebo-controlled study with FDG-PET as an outcome measure. [ABSTRACT FROM AUTHOR]

Objective: We explored whether prior findings of reduction in serotonin 2A receptor (5-HT(2A) R) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods: We derived 5-HT(2A) R nondisplaceable binding potentials (BP(ND) ) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results: The 5-HT(2A) R BP(ND) s decreased with age, a relationship best described by an exponential-decay regression. The BP(ND) s were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions: These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects. [ABSTRACT FROM AUTHOR]

Objective We explored whether prior findings of reduction in serotonin 2A receptor (5-HT2AR) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods We derived 5-HT2AR nondisplaceable binding potentials (BPND) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results The 5-HT2AR BPNDs decreased with age, a relationship best described by an exponential-decay regression. The BPNDs were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The D2 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. [11C]-(+)-PHNO is a PET D2 agonist radioligand and therefore provides a preferential measure of the D2high receptors. In contrast, [11C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D2 high- and low-affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [11C]-(+)-PHNO and [11C]raclopride in volunteers using a within-subject design. Both radioligands accumulated in brain areas rich in D2/D3-receptors. However, [11C]-(+)-PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [11C]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 [11C]raclopride, equal in the ventral-striatum (3.4 vs. 3.3), and higher in the globus pallidus for [11C]-(+)-PHNO (1.8 vs. 3.3). Moreover [11C]-(+)-PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [11C]-(+)-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 D3-over-D2 with [11C]-(+)-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. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that patients with Alzheimer's disease (AD) present with deficits in neuroplasticity of their dorsolateral prefrontal cortex (DLPFC); and decreased N‐acetyl aspartate (NAA) and increased myo‐inositol (mI) concentrations in the cingulate cortex and hippocampus. In this study, we examined the relationship between these metabolites and neuroplasticity in the DLPFC of patients with AD and healthy older adults. Method: Patients meeting the core clinical criteria for probable AD and older healthy controls (HC) were recruited. Left DLPFC plasticity was assessed using paired associative stimulation (PAS) combined with EEG. NAA and mI concentrations were assessed in the DLPFC using 3T proton Magnetic Resonance Spectroscopy (point‐resolved spectroscopy, echo time = 35 ms). Result: 48 AD participants (mean (SD) age: 75.4 (6.9) years; mean (SD) Mini Mental State Examination (MMSE) score (SD): 23.1 (3.1)) were compared with 27 HC (mean (SD) age: 72.3 (7.0) years; mean (SD) MMSE: 29.5 (0.6)): participants with AD had impaired DLPFC plasticity (t = 2.8, df = 69, p = 0.006) and decreased NAA concentration in the DLPFC (t = 2.4, df = 64, p = 0.02). In the combined group of AD and HC participants, after correcting for multiple comparisons, mI concentration in the DLPFC was negatively correlated with DLPFC plasticity (Pearson's r = ‐ 0.4, n = 62, p corrected = 0.002). Conclusion: Deficits in neuroplasticity in the DLPFC of patients with AD are associated with abnormalities of a metabolite indicative of neuronal injury. These findings advance our understanding of potential mechanisms underlying deficits in DLPFC plasticity in AD. [ABSTRACT FROM AUTHOR]

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 [11C]‐(+)‐PHNO has been observed in a retina‐like region of interest (ROI) in humans. Here, we attempted to quantify [11C]‐(+)‐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 [11C]‐(+)‐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 [11C]‐(+)‐PHNO into a retina‐like ROI in humans can be quantified using both arterial blood sampling (VT) and simplified reference tissue methods (BPND). [ABSTRACT FROM AUTHOR]