Abstract Background Neuromelanin (NM) is a byproduct of monoamine metabolism, including that of dopamine. NM-sensitive Magnetic Resonance Imaging (NM-MRI) sequences enable the in vivo quantification of NM levels in the substantia nigra (SN). The NM-MRI signal is considered a surrogate marker for the integrity of SN dopamine neurons and, consequently, striatal dopaminergic functioning. Elevated striatal dopamine synthesis is associated with patients responsive to first-line antipsychotics (FLR) in schizophrenia, while normal striatal dopamine synthesis is implicated in the pathophysiology of treatment-resistant schizophrenia (TRS). Clozapine is the only antipsychotic currently approved for TRS. However, no studies have yet explored the relationship between SN accumulations, as measured by NM-MRI, and clozapine response in TRS patients. Aims & Objectives The study aims to investigate differences in dopaminergic activities among schizophrenia patients based on their treatment response, using NM-MRI. Methods The study enrolled TRS patients who either did not respond to clozapine (ultra-resistant schizophrenia [URS]) or did respond (non-URS), along with FLR patients and healthy controls (HCs). TRS was defined as resistance to at least two first-line antipsychotics and ongoing clozapine treatment at the time of the study. SN-NM levels were measured using 3T-MRI. The Contrast Ratio (CR) was calculated as the relative signal intensity difference between the SN and the crus cerebri. SN-CR values were compared between groups, controlling for age and sex. Associations between SN-CR and symptom severity scores were also explored within patient groups. Results A total of 78 participants (URS: n=16; non-URS: n=16; FLR: n=20; HCs: n=26) completed the study. Overall group differences in SN-CR values were significant (F(3,72)=3.80, η2=0.21, p=0.001). Specifically, URS patients (Cohen’ s d=0.86, p=0.049) and FLR patients (Cohen’ s d=1.27, p<0.0001) exhibited higher SN-CR values compared to HCs. No associations were found between SN-CR values and symptom severity scores within each group or the entire patient cohort. Discussion & Conclusion This study is the first to assess a proxy measure of mesostriatal dopamine function in schizophrenia patients, stratified by treatment responsiveness, using NM-MRI. We observed elevated SN-NM contrast in URS and FLR patients compared to HCs, and levels similar to HCs in non-URS patients. Longitudinal studies are warranted to determine whether SN-NM levels can serve as a reliable biomarker for predicting treatment response in schizophrenia.

Adherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed an Integrated Care Pathway (ICP) that standardized behavioral and pharmacological interventions for agitation in dementia, and evaluated it against treatment-as-usual (TAU). The two primary hypotheses were that, compared to TAU, the ICP would result in (1) lower agitation and (2) lower rates of polypharmacy at study end. The Sta ndardizing Care for N europsychiatric Symptoms and Quality of Life in Dementia (StaN) trial ( ClinicalTrials.gov # NCT03672201) was conducted at five academically affiliated inpatient units (Inpatient) and seven long-term-care homes (LTCHs). Participants with agitation related to Alzheimer’s dementia were randomized 1:1 to receive the ICP or TAU for 12 weeks. Primary outcomes were: (1) Cohen Mansfield Agitation Inventory (CMAI) completed at weeks 3, 8, and 12 (primary), and (2) polypharmacy defined as using more than one psychotropic medication assessed at weeks 1, 3, 4, 6, 8, 10, and 12 (primary) post-randomization. Linear mixed effect models and generalized estimating equations were used to test our hypotheses controlling for age, gender, and stage of dementia. The study was powered for Inpatient and LTCH settings separately. 185 participants were randomized: 93 in Inpatient (46 ICP: 47 TAU; females = 32 (34.4%); mean (standard deviation [SD]) age = 75.0 (8.4) years), and 92 in LTCH (46 ICP: 46 TAU; women = 63 (68.5%); mean (SD) age = 85.9 (7.6) years). There were no significant time*group interactions for the CMAI scores for Inpatient (F 4, 297.9 = 0.8, p = 0.53) or LTCH (F 4, 297.3 = 1.1, p = 0.36) and no significant differences at week-12 (Inpatient: ICP-TAU adjusted difference = 0.025; 95% Confidence Interval (CI): -0.410, 0.460; LTCH: ICP-TAU adjusted difference = -0.214; 95%CI: -0.699, 0.270). However, there were significant time*group interactions for polypharmacy for both Inpatient (χ 2 7 = 18.6, p = 0.01) and LTCH (Χ 2 7 = 22.9, p = 0.002). Differences were not significant at week-12 (Inpatient: ICP-TAU adjusted difference = 0.15; 95%CI: -0.11, 0.40; LTCH: ICP-TAU adjusted difference = 0.33; 95%CI: -0.06, 0.72), the ICP group had lower rates of polypharmacy than TAU group at weeks 3, 4, and 6 on Inpatient, and week 3 in LTCH. Standardizing care for agitation in dementia may result in less polypharmacy without affecting efficacy. Future studies should assess the ICP in broader community and outpatient settings.

Importance:Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. Objective:To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. Design, Setting, and Participants:This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. Interventions:CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. Main Outcomes and Measures:The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Results:Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. Conclusions and Relevance:The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. Trial Registration:ClinicalTrials.gov Identifier: NCT02386670.

Neuromelanin (NM), a byproduct of monoamine metabolism, reflects dopamine and norepinephrine activity in the brain. NM-sensitive MRI sequences enable in vivo quantification of NM levels in the substantia nigra (SN) and locus coeruleus (LC), which correspond to dopamine and norepinephrine neuron activity, respectively. Striatal dopamine dysfunction is a hallmark of schizophrenia: increased striatal dopamine synthesis has been associated with responsiveness to first-line antipsychotics (first-line responders [FLR]), whereas normal striatal dopamine synthesis characterizes treatment-resistant schizophrenia (TRS). Clozapine is the only approved treatment for TRS; however, its relationship with NM-MRI-derived dopamine markers remains unexplored. Additionally, norepinephrine dysregulation, originating in the LC, has been implicated in delusions and cognitive impairments in schizophrenia, yet its role in treatment response remains unvalidated using NM-MRI. This study aims to elucidate the relationship between NM accumulation and treatment responsiveness in schizophrenia. Specifically, we sought to: We conducted a cross-sectional study involving four groups: URS (n = 16), non-URS (n = 16), FLR (n = 20), and HCs (n = 26). NM-MRI was used to measure NM signals in the SN and LC, quantified as contrast ratios (CR). Group comparisons were performed, controlling for age and sex, with Benjamini–Hochberg correction applied for multiple comparisons. Associations between CR and clinical characteristics were also analyzed. Of the 78 participants, two (1 URS, 1 FLR) were excluded due to insufficient data quality. Significant group differences were observed in CR for both the SN and LC (SN: F(3,70) = 4.45, η² = 0.16, p = 0.01; LC: F(3,70) = 2.87, η² = 0.11, p = 0.04). In the SN, both URS (Cohen’s d = 1.01, p = 0.01) and FLR (Cohen’s d = 0.94, p = 0.01) showed elevated CR compared to HCs. In the LC, URS demonstrated higher CR than FLR (Cohen’s d = 0.99, p = 0.04). No significant associations were found between CR and clinical characteristics or symptom severity. This study highlighted distinct dopaminergic and noradrenergic activity patterns in schizophrenia subgroups. Elevated dopaminergic activity (SN CR) was observed in both URS and FLR, whereas heightened noradrenergic activity (LC CR) differentiated URS from FLR. These findings suggest NM-MRI’s potential in predicting treatment response in schizophrenia, underscoring the need for longitudinal studies to establish its clinical utility.

BACKGROUND AND HYPOTHESIS Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. STUDY DESIGN In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. STUDY RESULTS SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009). CONCLUSIONS The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.

Introduction: Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders. However, the differences in presentation of NPS in high-risk states for dementia such as mild neurocognitive disorder (Mild NCD) and remitted major depressive disorder (rMDD) remain unclear. The purpose of this study was to compare the frequency and factor structure of NPS in Mild NCD, rMDD, and Mild NCD with rMDD (Mild NCD-rMDD). METHODS:We analyzed baseline data from the multicenter Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression trial (NCT0238667). NPS were assessed using the Neuropsychiatric Inventory Questionnaire in those with Mild NCD, rMDD, and Mild NCD-rMDD. We compared the NPS frequency and factor structure across the three groups. RESULTS:Among 374 participants with a mean (SD) age = 72.0 (6.3) years, the overall frequency of any NPS was highest in Mild NCD-rMDD (75.9%), as compared to Mild NCD (63.5%) or rMDD (55.7%) groups (p = 0.014). Depression/dysphoria was the most common NPS in all three groups. In factor analyses, NPS grouped into four factor structures in all three groups, but the composition of factors of individual symptoms (delusions, motor disturbances, nighttime behaviors, anxiety, and apathy) were different. CONCLUSION:NPS are common in high-risk states of dementia, and the frequency of NPS is higher in Mild NCD-rMDD as compared to only Mild NCD or rMDD. Further, there are key differences in presentation of NPS in Mild NCD, rMDD, and Mild NCD-rMDD. Future studies should investigate the relevance of these differences for cognition, function, and disease biomarkers. .

Impaired insight into illness occurs in up to 98% of patients with schizophrenia, depending on the stage of illness, and leads to negative clinical outcomes. Previous neuroimaging studies suggest that impaired insight in patients with schizophrenia may be related to structural and functional anomalies in frontoparietal brain regions. To date, limited studies have investigated the association between regional cerebral blood flow (CBF) and impaired insight in schizophrenia. Therefore, we sought to investigate the relationship between regional CBF, as measured by arterial spin labeling (ASL), and impaired insight in participants with schizophrenia. A total of 32 participants were included in the analysis. Impaired insight in patients with schizophrenia was measured using the VAGUS, Self-report (VAGUS-SR). Resting-state regional CBF was measured using pseudo-continuous ASL (pCASL) and extracted using SPM12 and REX toolbox. Whole brain analysis found that impaired insight was associated with higher regional CBF in the right angular gyrus, left supramarginal gyrus, and right superior frontal region when controlling for age, gender, smoking status, and illness severity. The results indicate that impaired insight in schizophrenia is related to regional CBF in frontoparietal areas. These neuroimaging findings can serve as therapeutic targets for intervention, such as with non-invasive brain stimulation.

OBJECTIVE:Relapse prevention is a major goal of schizophrenia treatment. However, there is no standard definition of relapse. To address this, the authors reviewed recent approaches and developed consensus criteria to operationally define relapse. METHODS:To evaluate current criteria, a systematic review was performed of randomized controlled trials of relapse conducted from 2012 to 2024. To develop consensus criteria, the authors used a multiphase Delphi approach involving over 100 experts from 37 countries, including people with lived experience of relapse. RESULTS:The review showed only two pairs of studies that used the same criteria. Clinical judgment alone was sufficient to define relapse in 85% of studies, and 58% used relative symptom change. The recommended criteria cover the pre-baseline, baseline, and relapse components with optimum and minimum criteria and provide a reporting checklist. The recommendations include using standardized, validated measures that can be applied across settings, and using absolute symptom change. The authors also identify criteria that should not be used and make reporting recommendations, including for specific symptom domains (positive, negative, or cognitive) and across symptom domains, hospitalization, home treatment, and risky, violent, or suicidal behavior. CONCLUSIONS:There are limitations and heterogeneity in current definitions of relapse, which limit study comparisons, potentially bias meta-analyses, and question the validity of some studies. Adopting the consensus recommendations for a standardized approach should improve the validity and reliability of study outcomes, facilitate cross-study comparisons, and also standardize research into risk factors for relapse.

Abstract Background Approximately 30% of patients with schizophrenia (SZ) do not respond to antipsychotic treatment. Although abnormalities of the dopamine (DA) function are implicated in the pathophysiology of SZ, reports on striatal DA function and treatment responsiveness are inconsistent.The striatum is modified by dopamine released from the substantia nigra (SN). Neuromelanin (NM) is a product of monoamine metabolism including DA. NM-sensitive MRI sequences allow in vivo quantification of NM levels in the SN. NM-MRI signal is thought to serve as a biomarker for SN DA neuron integrity, and in turn, striatal DA functioning. A recent meta-analysis (1) reported that NM levels were higher in patients with SZ than healthy controls (HCs), but no studies have reported on the relationship between NM levels and treatment responsiveness in this population. Aims The purpose of this study was to investigate the relationship between midbrain DA function and treatment responsiveness in patients with schizophrenia. Methods This study was approved by the Ethics Committee of Keio University School of Medicine and Komagino Hospital (approval numbers: 20170313, 20230003). We recruited patients with treatment- resistant schizophrenia (TRS) and patients with non-TRS from Komagino Hospital (Tokyo, Japan). We used a 3T GE MRI with a 8-channel head coil and applied NM sensitive MRI (2D GRE MT, TR=260ms) to measure NM signals in the SN. We also evaluated the severity of symptoms using the Positive and Negative Symptom Scale (PANSS). First, we conducted an analysis of covariance to compare the levels of NM signals between the TRS and non-TRS groups controlling for age and sex as covariates. Subsequently, we performed correlation analyses to explore relationships between severity of symptoms and NM signals. Results Forty-nine participants (TRS: n=17; non-TRS: n=21) completed the study. Overall group differences were found in contrast-to-noise ratio (CNR)-NM ((F(1, 34)=3.04, p=0.082, Adjusted R2=23.9%)). Specifically, the TRS group showed higher CNR-NM compared to the non-TRS group (p =0.03, Cohen’ s d=2.46). Correlations were not found between CNR-NM and age or between CNR-NM and PANSS scores in each group. In the whole patient group, CNR-NM was higher in women (t (36) = 2.5, p = 0.017) and associated with PANSS positive scores (r=0.45, p=0.005). Conclusion The present study demonstrated elevated SN DA function in TRS compared to non-TRS. PET studies have shown inconsistent relationships between treatment response and striatal DA function. Further research is needed to examine the relationship between antipsychotic treatment response and dopamine function in the nigrostriatal pathway of schizophrenia. References (1)Ueno, F. et al. (2022) 'Neuromelanin accumulation in patients with schizophrenia: A systematic review and meta-analysis,' Neuroscience &Biobehavioral Reviews, 132, pp. 1205–1213. https://doi.org/10.1016/j.neubiorev.2021.10.028.

Abstract Background Conventional caloric vestibular stimulation (CVS), which involves the irrigation of cold or warm water into the external ear canal induces a temperature gradient across the semicircular canals of the vestibular apparatus stimulating the vestibular nerve and eliciting the vestibulo-ocular reflex. It is commonly used in both otolaryngology to assess vestibular function and neurology to test brain stem function. In schizophrenia, there is no conclusive link between psychopathology and vestibular dysfunction. Initial data from another CVS study by our group suggests that individuals with schizophrenia may have greater reactivity to body temperature (37° C) CVS, as measured by the peak slow phase velocity of the resulting nystagmus (PSPV), than would be expected for healthy participants1. However, we are unaware of any studies that have investigated the differential effects of CVS temperature gradients on individuals with schizophrenia versus healthy control participants. Aim & Objective In the current study we aimed to examine if individuals with schizophrenia have greater reactivity to caloric vestibular stimulation than healthy control (HC) participants. Methods Patients with schizophrenia and HC participants received three conditions bilaterally: (1) body temperature (37° C) CVS; (2) warm CVS (44° C), and (3) cold CVS (30° C). All conditions were performed by an audiologist. The physiological response of vestibular stimulation was assessed with videonystagmography, which provides a measure of the intensity of the nystagmus via PSPV. Independent sample t-tests were conducted to compare vestibular reactivity (i.e., nystagmus) between patients and HC participants for each CVS condition. Results A total of 20 patients (mean age 39.2, SD=12.6, 25% female) and 20 HC participants (mean age 37.9, SD=13.1; 25% female) completed the study. There was no statistically significant difference between patients and HC participants in body temperature, warm or cold CVS (p>0.05). Discussion & Conclusion In schizophrenia, there is no conclusive link between psychopathology and vestibular dysfunction, and we are not aware of any data that exists on the range of responses to CVS in persons with schizophrenia. We did not find any differences in vestibular reactivity between patients with schizophrenia and HC participants in response to CVS. References Gerretsen, P.et al.(2017) ‘Vestibular stimulation improves insight into illness in schizophrenia spectrum disorders’, Psychiatry Research, 251, pp. 333–341. doi:10.1016/j.psychres.2017.02.020.

Objective: The pathophysiological mechanisms influencing psychosis spectrum disorders are largely unknown. The glymphatic system, which is a brain waste clearance pathway, has recently been implicated in its pathophysiology and has also been shown to be disrupted in various neurodegenerative and vascular diseases. Initial studies examining the glymphatic system in psychosis spectrum disorders have reported disruptions, but the findings have been confounded by medication effects as they included antipsychotic-treated patients. In this study, we used diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) as a technique to measure the functionality of the glymphatic system in a sample of antipsychotic-minimally exposed patients with psychosis spectrum disorders and healthy controls. Methods: The study included 13 antipsychotic-minimally exposed (2 weeks antipsychotic exposure in the past 3 months/lifetime) patients with psychosis spectrum disorders and 114 healthy controls. We quantified water diffusion metrics along the x-, y-, and z-axes in both projection and association fibres to derive the DTI-ALPS index, a proxy for glymphatic activity. Between-group differences were analyzed using two-way ANCOVA controlling for age and sex. Partial correlations were used to assess the association between the ALPS index and clinical variables. Results: Analyses revealed that antipsychotic-minimally exposed psychosis spectrum disorder patients had a lower DTI-ALPS index value than healthy controls in both hemispheres and the whole brain (all P < 0.005). Significant differences were also observed between the x and y projections/associations between patients and healthy controls (P < 0.001). Furthermore, we did not find any significant correlations (all P > 0.05) between the DTI-ALPS index with age, body mass index, symptomatology, and metabolic parameters. Conclusion: This study shows that the glymphatic system is dysregulated in antipsychotic-minimally exposed patients with psychosis spectrum disorders. Understanding the mechanisms that influence the glymphatic system may help to understand the pathophysiology of psychosis spectrum disorders as proper waste clearance is needed for normal brain functioning.

INTRODUCTION: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 AD living in long-term care homes or admitted to inpatient psychiatric units. METHODS:Data were obtained from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201). BPSD were assessed using the Neuropsychiatric Inventory-Clinician rating scale (NPI-C), and symptom clusters were clustered as follows: (1) psychosis (hallucinations and delusions), (2) emotional distress cluster A (depression and anxiety), (3) emotional distress cluster B (depression, anxiety, and apathy), and (4) agitation (agitation, aggression, irritability, aberrant motor behavior, and aberrant vocalizations). Sex differences in frequency and severity of individual BPSD and clusters were compared using chi-square and Mann-Whitney U tests and generalized linear models while controlling for age and place of residence. RESULTS:Females had higher frequency (males = 21.7% vs. females = 42.9%, χ2 = 8.83, N = 174, p = 0.003) and greater severity of delusions (mean [SD] males = 51.87 [44.15], mean [SD] females = 67.93 [70.53], U = 2,924, N = 174, p = 0.002). Males had higher frequency (males = 51.8% vs. females = 27.5%, χ2 = 10.80, N = 174, p = 0.001) and greater severity of sleep disorders (mean [SD] males = 2.94 [4.21], mean [SD] females = 1.76 [3.92], U = 2,885.50, N = 174, p = 0.002). After controlling for age and residence, sex differences remained significant for delusions (Wald χ2 = 3.97, N = 176, p = 0.046), but not for sleep disorders. There were no sex differences in the frequency or severity of any BPSD clusters. CONCLUSIONS: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 in screening, and for individualized sex-specific management of BPSD.

The [18F]SynVest-1 radiotracer targets the synaptic vesicle glycoprotein 2A (SV2A) and is a proxy of presynaptic density. Parkinson's disease is associated with synaptic dysfunction. Here we investigated synaptic density via the [18F]SynVest-1 radiotracer in people with PD compared with healthy controls, with reference to how it compares to the previous SV2A radiotracer, [11C]UCB-J. Ten Parkinson's patients and 12 healthy subjects underwent a [18F]SynVest-1 PET scan. We compared non-displaceable binding potential via voxel-wise and volume of interest analysis to investigate group differences. Volume-of-interest-analyses reported lower non-displaceable binding potential in key a priori regions associated with Parkinson's disease, namely the substantia nigra and caudate nucleus (P < 0.05). Follow-up exploratory volume-of-interest-analyses reported widespread reduction in non-displaceable binding potential within all brain lobes, cerebellum, hippocampus, thalamus and insula; however, these findings did not survive correction for multiple comparisons (P < 0.004). In addition, voxel-wise analyses with family-wise error correction, highlighted significantly lower non-displaceable binding potential in the PD cohort within the putamen and cerebellum. We did not observe any relationships between clinical metrics and non-displaceable binding potential. The results are in line with differences observed using the [11C]UCB-J radiotracer. The [18F]SynVest-1 radiotracer confirmed lower synaptic density in the Parkinson's disease cohort and adds to the growing evidence of synaptic dysfunction in Parkinson's disease pathology.

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that delivers a constant low electric current through electrodes placed on the scalp. A significant amount of research has explored the clinical potential of tDCS in psychiatric disorders. However, the mechanism of tDCS’ behavioural effects remains largely unknown. Cerebral blood flow (CBF) is a surrogate marker of neural activity and has been used as an index of brain dysfunction in various psychiatric disorders. Studies have shown that single-session tDCS can modulate regional CBF in humans, however, these results as yet have not been systematically reviewed. The primary objective of this systematic review and meta-analysis was to evaluate the immediate effects of single-session tDCS on regional CBF. A literature search of English language publications in humans was conducted through Ovid database using Medline, Embase, and PsycINFO (last search in August 2023). The following search terms were used: (transcranial direct current stimulation or tDCS) and (cerebral blood flow or cerebrovascular circulation). Studies that reported sufficient data for calculating the pooled effect size of regional CBF change from baseline to immediately post-tDCS were included. The analysis was separated by anodal, cathodal, and sham stimulation. The search identified 188 English language publications. Four papers were deemed eligible for the analysis, while two of them were based on the same sample. Studies varied in terms of tDCS montage, stimulation protocol, and population studied. The meta-analysis found a decrease in regional CBF following single-session cathodal tDCS stimulation (n = 34) and no effect of single-session anodal (n = 58) or sham tDCS (n = 52). However, increased regional CBF following anodal tDCS was significantly associated with older age, sex (

Abstract Background Growing research shows abnormal brain structure and connectivity in patients with treatment-resistant schizophrenia (TRS) compared to first-line-responders (TxR) and healthy-controls (HC). While differences are documented as early as first-episode-psychosis (FEP), standard measures of structure and connectivity including thickness, volume, functional connectivity, and diffusion, show susceptibility to antipsychotic treatment and interpatient heterogeneity that limit their clinical and research use for TRS. In this regard, Intrinsic-Cortical-Curvature (ICC), a highly sensitive neurodevelopmental measure of both structure and connectivity, associated with the position and spread of functional activity areas, may provide a novel approach for the assessment and differentiation of TRS. Indeed, preliminary studies have not only linked elevations of ICC with TRS-like traits in FEP, including worsening cognition at follow-ups and reduced response to treatment, but methodology comparison studies have also proven ICC to be especially sensitive to schizophrenia differences compared to more common extrinsic gyrification measures. Despite this evidence, due to the previous complexity and computational demands required for ICC quantification, ICC research in schizophrenia and TRS remains scarce. Aim Our goal was to investigate whether differences in ICC between TRS, TxR and HC exist, their association to symptomology, and susceptibility to antipsychotic treatment, as a possible marker for treatment-resistance. Methods ICC was assessed from brain imaging data acquired using 3T high resolution magnetic resonance imaging (MRI). Regions of interest associated with TRS literature were processed, including the bilateral anterior-cingulate-cortices (ACC), dorsolateral-prefrontal- cortices (DLPFC), temporal-cortices, and parietal-cortices of TxR=38, TRS (clozapine-resistant ClzR- =30, clozapine-responders ClzR+=37), and HC=52. Positive, negative, and cognitive symptom severity was assessed (PANSS, MMSE, EXIT), along with chlorpromazine-equivalence (APT) and nicotine-use (NIC) to assess possible interactions. Results ICC elevations were observed in temporal-cortices of ClzR- and ClzR+ compared to HC (p=0.001), and DLPFC of ClzR- compared to TxR and HC (p<0.001). ICC elevations correlated with reduced cognition (p<0.007) and negative symptomology (p=0.036) in ClzR-. LH- temporal and parietal-cortices correlated with reduced cognition in ClzR+ (p=0.018) and TxR (p=0.008), respectively. No ICC/APT/NIC interactions were found (p>0.092). Conclusion Results show elevations of ICC in patients with TRS, particularly in regions associated with glutamatergic dysregulation. Elevations of ICC were also associated with reduced cognition, primarily in ClzR-. Considering ICC was not associated with APT or NIC, future research may prove ICC a resilient marker associated with TRS abnormalities.

Emerging evidence demonstrates that insulin has a modulating effect on metabolic and cognitive function in the brain, highlighting the potential role of aberrant brain insulin signaling in the pathogenesis of various neuropsychiatric illnesses. Neuroimaging paradigms using intranasal insulin (INI) as a pharmacological challenge have allowed us to study the effects of insulin in the human brain. In this scoping review, we conducted a systematic database search to identify relevant research studies that employed an INI-based neuroimaging assay of brain insulin signaling. Thirty-six studies met inclusion criteria for this review. INI was found to significantly modulate activity and cerebral blood flow in brain regions related to homeostatic/hedonic control of food intake, as well as cognition. This review highlights the putative role of insulin signaling in the brain and the potential therapeutic value of INI in patients with mental health, addiction, and co-morbid metabolic disorders.

Commonly used screening measures of cognitive function such as the Montreal Cognitive Assessment (MoCA) are not sensitive to assess cognitive function among individuals with severe cognitive impairment due to floor effect. The Severe Cognitive Impairment Rating Scale (SCIRS) was designed to assess cognitive function in those with severe cognitive impairment, however, psychometric properties of its English version have not been reported. Using the existing data from StaN and tTED studies, floor and ceiling effects (percentage of minimal or maximal scores) of SCIRS and MoCA were examined, and the association between SCIRS and MoCA was evaluated. Data from 141 participants (mean age = 78.7, 56% females) who completed either the SCIRS (n = 122) or MoCA (n = 80) were collected (n = 61 completed both). There was robust association between SCIRS and MoCA, supporting criterion validity of the SCIRS as a measure of cognitive function. SCIRS had a lower floor effect (13.1% minimal scores) as compared to the MoCA (27.5% minimal scores). Out of 22 participants with minimal scores on the MoCA, 16 participants completed the SCIRS with mean score of 9.8 (SD = 7.5). SCIRS appears to be a valid measure of cognitive function, showing better variance among individuals with severe cognitive impairment, as compared to MoCA.

INTRODUCTION:Excessive alcohol use (EAU) elevates the risk of dementia through various mechanisms, yet its impact on the behavioural and psychological symptoms of dementia (BPSDs) remains uncertain. METHODS:In this exploratory cross-sectional analysis of baseline data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201), we included individuals with Alzheimer's disease and related dementias requiring BPSD treatment. We compared demographic characteristics and presentation of BPSDs (using the total and domain scores on the Neuropsychiatric Inventory-Clinician) in those with and without a lifetime history of EAU. RESULTS:Among 193 participants [mean (SD) age: 80.6 (9.7) years, male: 48.4%], those in the EAU group (n = 17) and in the comparator group (n = 176) had severe and comparable cognitive impairment, with a median Functional Assessment Staging Tool for Dementia score of 6e. Participants with EAU were significantly younger than comparators [mean age (SD): 72.9 (7.1) years vs. 81.4 (9.5) years] (t = -3.678, df = 181, P < .001), and were more frequently male (76.5% [13 of 17] vs. 46.6% [82 of 176]; P = .036). In a sensitivity analysis, there were no differences in the Neuropsychiatric Inventory-Clinician total or individual domain scores between those with EAU and a subsample of those without EAU matched for age, sex, and recruitment site. CONCLUSION:This exploratory study found that among individuals with Alzheimer's disease and related dementias and BPSDs, lifetime history of EAU is more frequent in younger males. Future studies may further examine the impact of EAU in individuals with BPSDs.