Julia Kim

Hippocampal and Clinical Trajectories of Mild Cognitive Impairment with Suspected Non-Alzheimer's Disease Pathology

Suspected non-Alzheimers disease pathology (SNAP) characterizes individuals showing neurodegeneration (e.g., hypometabolism) without amyloid-β (Aβ). Findings from previous studies regarding clinical and structural trajectories of SNAP are inconsistent. Using data from the Alzheimers Disease Neuroimaging Initiative, patients with amnestic mild cognitive impairment (MCI) were categorized into four groups: amyloid positive with hypometabolism (Aβ+ND+), amyloid only (Aβ+ND-), neither amyloid nor hypometabolism (Aβ-ND-), and SNAP (Aβ-ND+). Aβ+ND+(n = 33), Aβ+ND-(n = 32), and Aβ-ND-(n = 36) were matched to SNAP for age, gender, apolipoprotein E4 (apoE4) genotype, and scores on the Montreal Cognitive Assessment. Elderly controls (n = 40) were also matched to SNAP for age, gender, and apoE4 genotype. Longitudinal changes were compared across groups in terms of hippocampal volume, clinical symptoms, daily functioning, and cognitive functioning over a 2-year period. At baseline, no difference in cognition and functioning was observed between SNAP and Aβ+groups. SNAP showed worse clinical symptoms and impaired functioning at baseline compared to Aβ-ND-and controls. Two years of follow-up showed no differences in hippocampal volume changes between SNAP and any of the comparison groups. SNAP showed worse functional deterioration in comparison to Aβ-ND-and controls. However, Aβ+ND+ showed more severe changes in clinical symptoms in comparison to SNAP. Thus, patients with MCI and SNAP showed 1) more severe functional deterioration compared to Aβ-ND-and controls, 2) no differences with Aβ+ND-, and 3) less cognitive deterioration than Aβ+ND+. Future studies should investigate what causes SNAP, which is different from typical AD pathology and biomarker cascades.

The effects of illness severity, cognition, and estimated antipsychotic dopamine receptor occupancy on insight into the illness in schizophrenia: An analysis of clinical antipsychotic trials of intervention effectiveness (CATIE) data

Background: The relationship between dopamine D2 receptor (D2R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses. Aim and methods: We investigated the influence of estimated D2R (Est.D2R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18−62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D2R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIAs relationship to illness severity, cognition, and Est.D2R. Results: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D2R did not predict IIA, and Est.D2R did not serve either a moderating or mediating role in both regression and path analyses. Conclusions: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D2R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late‐life schizophrenia (i.e. ≥60years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity. HIGHLIGHTSIllness severity was predictive of impaired illness awareness (IIA)Cognition, antipsychotic dopamine receptor occupancy (Est.D2R), and premorbid IQ did not predict IIAEst.D2R did not mediate or moderate the relationshipsIIA is a function of illness severity in adult patients with schizophrenia

S175. AMOTIVATION IS ASSOCIATED WITH SMALLER VENTRAL STRIATUM VOLUMES IN OLDER PATIENTS WITH SCHIZOPHRENIA

Abstract Background 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 (D2/3R) 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 D2/3R 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). Discussion We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit.

S16. GLUTAMATERGIC NEUROMETABOLITE LEVELS IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA: A CROSS-SECTIONAL 3T PROTON MRS STUDY

Abstract Background In terms of response to antipsychotic treatment, patients with schizophrenia can be classified into three groups; (1) treatment-resistant patients who are clozapine (CLZ)-resistant (ultra treatment-resistant schizophrenia [UTRS]), (2) treatment-resistant patients who are CLZ-responsive (TRS), and (3) patients who respond to non-CLZ antipsychotics (treatment non-resistant schizophrenia [TnRS]). The aim of this study was to examine glutamatergic neurometabolite levels in these three patient groups, along with healthy controls (HCs), using proton magnetic resonance spectroscopy (1H-MRS). Methods Glutamate (Glu) and glutamate+glutamine (Glx) levels were assessed in the associative striatum (Str), anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) using 3T 1H-MRS (PRESS, TE=35ms). Neurometabolite levels were corrected for cerebrospinal fluid proportion. Results A total of 100 participants (26 UTRS, 27 TRS, 21 TnRS, and 26 HCs) were included in this study. Patients with UTRS showed higher Glx levels in the ACC compared to HCs (p=0.038). When patients with UTRS and TRS were combined into one group, this subset of patients showed higher Glu and Glx levels in the ACC compared to HCs (p=0.028 and p=0.023, respectively). There were no significant group differences in the Str or DLPFC. Discussion Previous findings reporting higher glutamatergic levels in the ACC of patients with TRS may be mainly influenced by patients with CLZ non-responder. Higher ACC glutamatergic neurometabolite level may be a biological trait of resistance to the first-line antipsychotic treatment that is retained even after CLZ administration.

F178. NEUROANATOMICAL PROFILES OF TREATMENT-RESISTANCE IN PATIENTS WITH SCHIZOPHRENIA

Abstract Background About 20 to 35% of patients with schizophrenia show partial or no response to standard first-line antipsychotic treatment and are thus believed to have treatment-resistant schizophrenia (TRS). Notably, the antipsychotic clozapine (CLZ) has been reported to have superior efficacy compared to other agents for the treatment of TRS. However, a subset of patients still do not respond to CLZ treatment and are thus considered to have ultra-treatment-resistant schizophrenia (UTRS). Overall, the pathophysiology associated with UTRS appears to be different than TRS, yet both remain elusive. In light of the unknown factors underlying UTRS and TRS, along with the widely reported structural alterations that exist in patients with schizophrenia, our study aimed to examine subcortical structure volumes and cortical thickness in patients with UTRS, patients with TRS responding to CLZ (henceforth, TRS), patients responding to a first-line antipsychotic (treatment non-resistant schizophrenia (TnRS)), and healthy controls (HC). We hypothesized that deficits in subcortical structure volumes and cortical thickness would exist within the UTRS group compared to other groups. Methods As of December 2017, the sample consisted of a total of 94 participants, including 24 patients with UTRS, 24 patients with TRS, 21 patients with TnRS, and 25 HCs. Participants underwent a 3-dimensional T1-weighted scan in a 3T MRI machine. The MAGeT-Brain segmentation algorithm was used to acquire volumes of the thalamus, striatum, globus pallidus, hippocampus, and amygdala. Cortical thickness was estimated using the CIVET processing pipeline. Total brain volume was obtained using the BEaST method. Group comparisons were performed using analyses of covariance and post-hoc comparisons. Results Group volumetric differences were identified bilaterally within the thalamus, striatum, and globus pallidus (p<0.01). Post-hoc investigations revealed that bilateral thalamic volumes were smaller in the UTRS group compared to the HC group (p<0.01), bilateral striatal volumes were larger in the TnRS group compared to the UTRS and HC groups (p<0.01), and bilateral globus pallidus volumes were larger in the TnRS group compared to the HC group (p<0.01). No differences in hippocampal, amygdala, or total brain volume were observed. At a 5% false discovery rate, widespread cortical thinning was identified in both the UTRS and TRS groups compared to the TnRS and HC groups; this effect was stronger and more diffuse in the UTRS group. Discussion Our findings suggest that thalamic volume deficits might be a distinct feature of UTRS. Contrastingly, striatal and globus pallidus volume enlargement may be associated with first-line antipsychotic response or treatment. Cortical thinning is apparent in both the UTRS and TRS groups. In many cases, structural compromise appears to follow a continuum of response, whereby deficits are most severe in UTRS patients, followed by TRS patients, who are followed by TnRS patients and HCs.

Striatal neurometabolite levels in patients with schizophrenia undergoing long-term antipsychotic treatment: A proton magnetic resonance spectroscopy and reliability study

Previous proton magnetic resonance spectroscopy (1H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla 1H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the 1H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired 1H-MRS acquisitions: average = 90.33; range = 7-306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576-0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naïve first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication.

The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: A systematic review

Approximately one-third of patients with schizophrenia have treatment-resistant schizophrenia (TR-SCZ), which is a condition characterized by suboptimal response to antipsychotics other than clozapine. Importantly, treatment with clozapine-the only antipsychotic with an indication for TR-SCZ-is often delayed, which could contribute to negative outcomes. Given that the specific impact of delay in clozapine initiation is not well understood, we aimed to conduct a systematic search of the Ovid Medline® database to identify English language publications exploring the impact of delay in clozapine initiation on treatment outcomes in patients with TR-SCZ. Additionally, clinico-demographic factors associated with clozapine delay were examined. Our search identified four retrospective studies that showed an association between longer delay in clozapine initiation and poorer treatment outcomes, even after including covariates, such as age, sex, and duration of illness. In addition, we found six studies that showed an association between age and clozapine delay, but results with regard to other clinico-demographic variables were inconsistent. Overall, the available literature reveals a possible link between delay in clozapine use and poorer treatment outcomes in patients with TR-SCZ. However, given the relatively small number of studies on this clinically important topic, future research is warranted to draw more definitive conclusions.

Neurometabolite levels in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis of 1H-MRS studies

Background: Studies using proton magnetic resonance spectroscopy (1H‐MRS) have reported altered neurometabolite levels in patients with schizophrenia. However, results are possibly confounded by the influence of antipsychotic (AP). Thus, this meta‐analysis aimed to examine neurometabolite levels in AP‐naïve/free patients with schizophrenia. Methods: A literature search was conducted using Embase, Medline, and PsycINFO to identify studies that compared neurometabolite levels in AP‐naïve/free patients with schizophrenia to healthy controls (HCs). Eight neurometabolites (glutamate, glutamine, glutamate + glutamine, N‐acetylaspartate [NAA], choline, creatine, myo‐inositol, and &ggr;‐Aminobutyric acid [GABA]) and seven regions of interest (ROI; medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter, occipital lobe, basal ganglia, hippocampus/medial temporal lobe, and thalamus) were examined. Results: Twenty‐one studies (N = 1281) were included in the analysis. The results showed lower thalamic NAA levels (3 studies, n = 174, effect size = −0.56, P = 0.0005) in the patient group. No group differences were identified for other neurometabolites. Conclusions: Our findings suggest that impaired neuronal integrity in the thalamus may be a potential trait maker in the early stages of schizophrenia. HighlightsAntipsychotics may be a confounding factor of 1H‐MRS studies.This is the meta‐analysis of 1H‐MRS studies focusing on unmedicated schizophrenia.This study replicated the finding of lower NAA levels in the Thalamus.Impaired thalamic neuronal integrity may be a trait maker in early schizophrenia.

Reprint of OASIS – Obesity Awareness and Insight Scale

AIMS Impaired illness awareness or not accepting that one has obesity is an understudied phenomenon that may negatively influence treatment adherence and clinical outcomes. The purpose of this study was to perform a systematic review of available measures of obesity awareness, and subsequently develop and validate a novel scale that measures the core domains of obesity awareness. METHODS A systematic review of the literature revealed no illness specific measure of subjective obesity awareness. As such, we designed the Obesity Awareness and Insight Scale (OASIS) to assess the following core domains of illness awareness: General Illness Awareness, Symptom Attribution, Awareness of Need for Treatment and the Negative Consequences attributable to the illness (www.illnessawarenessscales.com). Participants (n=100) were recruited from an online survey platform to assess the psychometric properties of OASIS. RESULTS The OASIS demonstrated strong internal consistency (Cronbachs alpha=0.89), convergent (r(98)=0.65, p<0.001) and discriminant validity, and test-retest reliability (intra-class correlation=0.76). An exploratory factor analysis of OASIS revealed a single latent component. CONCLUSIONS OASIS is an obesity-specific instrument that comprehensively measures subjective obesity awareness. OASIS can be used in epidemiological studies, intervention trials, and clinical practice to assess the impact of obesity awareness on treatment adherence and outcomes.

OASIS: The Obesity Awareness and Insight Scale

Aims Impaired illness awareness or not accepting that one has obesity is an understudied phenomenon that may negatively influence treatment adherence and clinical outcomes. The purpose of this study was to perform a systematic review of available measures of obesity awareness, and subsequently develop and validate a novel scale that measures the core domains of obesity awareness. Methods A systematic review of the literature revealed no illness specific measure of subjective obesity awareness. As such, we designed the Obesity Awareness and Insight Scale (OASIS) to assess the following core domains of illness awareness: General Illness Awareness,, Symptom Attribution,, Awareness of Need for Treatment and the Negative Consequences attributable to the illness (www.illnessawarenessscales.com). Participants (n=100) were recruited from an online survey platform to assess the psychometric properties of OASIS. Results The OASIS demonstrated strong internal consistency (Cronbachs alpha=0.89), convergent (r(98)=0.65, p<0.001) and discriminant validity, and test-retest reliability (intra-class correlation=0.76). An exploratory factor analysis of OASIS revealed a single latent component. Conclusions OASIS is an obesity-specific instrument that comprehensively measures subjective obesity awareness. OASIS can be used in epidemiological studies, intervention trials and clinical practice to assess the impact of obesity awareness on treatment adherence and outcomes.