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PubMed1992

Effect of instructional cues on schizophrenic patients' performance on the Wisconsin Card Sorting Test.

OBJECTIVE: Schizophrenic patients are particularly deficient on measures of executive functioning, notably the Wisconsin Card Sorting Test. This study was conducted to determine the efficacy of a cuing strategy in facilitating performance on this cognitive measure of the integrity of prefrontal brain structures and functioning. METHOD: Twenty-four schizophrenic inpatients and 24 demographically matched inpatients with mood disorders were administered the Wisconsin Card Sorting Test either with instructional cues at the beginning of the task or with the standard administration procedure. RESULTS: There was a significant benefit of cues for the patients with affective disorders as well as for the schizophrenic patients. The schizophrenic subjects in the uncued condition maintained poor but stable performance throughout the course of the task. CONCLUSIONS: The study suggests that the deficit in executive functioning of schizophrenic patients may lie in the formation of concepts, not in their application.

Adolescent↗

PubMed1995

Regional cerebral blood flow measured by 99mTc-HMPAO SPECT differs in subgroups of Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous entity. Identifying AD subtypes might have impact in patients' response to different treatment strategies. We designed a study to examine regional cerebral blood flow (rCBF) in AD subtypes. To identify AD subtypes, we performed a cluster analysis including performance on memory, language, visuospatial, praxic, and executive functions. The rCBF measured by 99mTc-HMPAO SPECT was referred to the cerebellum. We examined 35 patients fulfilling the NINCDS-ADRDA criteria of probable AD and 13 age and sex-matched healthy cognitively intact controls. AD patients were at the early stage of the disease, their mean Mini-Mental Status (MMS) score (S.D.) was 22.5 (3.6). The cluster analysis revealed two AD subgroups: AD1 (N = 12) and AD2 (N = 23). The subgroups did not differ in age, sex, or global clinical severity as assessed by MMS and Brief Cognitive Rating Scale (BCRS). Both subgroups had equally impaired memory. The AD2 group was inferior to the AD1 group on verbal, visuospatial, praxic, and executive functions. The AD1 group showed reduced rCBF ratios in the temporal and parietal cortices and the amygdala compared to controls. The AD2 group differed from controls in the rCBF ratios of frontal, temporal, parietal, occipital, basal ganglia, and amygdaloid regions bilateral and from AD1 in the rCBF ratios of frontal and temporal cortices. In AD patients, the rCBF ratios did not correlate with MMS or BCRS scores. In contrast, several significant correlations were found between decreases rCBF ratios and impairment of memory and other cognitive functions. In conclusion, a cluster analysis on neuropsychological test performance identified two AD subgroups that differed on the neuropsychological profile and on the rCBF in spite of similar global clinical severity.

Aged↗

PubMed1996

Frontal/executive impairments in schizophrenia.

A study of frontal/executive impairments in schizophrenia is reported. Schizophrenia patients and controls were not significantly different with respect to age, sex, and premorbid IQ. The schizophrenia group demonstrated significant impairments in cognitive flexibility and forward planning, replicating results from a 1990 study by Morice. Impairment prevalence figures of 65 and 76 percent for cognitive flexibility and forward planning, respectively, were demonstrated. Several tests for short-term memory were administered. Schizophrenia patients were not found to be impaired on tests of simple, or primary, short-term memory as measured by Digits Span Forward and Words Span Forward, but they were found to be significantly impaired compared with controls on two tests of working memory, Alphabet Span and Sentence Span. Using a cutoff derived from the mean score for the controls, 65 percent of schizophrenia patients proved to be impaired on Sentence Span. A total of 16 (94%) were impaired on one or more of the three tests of executive functioning used. The effects of IQ on test results were examined, and impairment of cognitive flexibility and forward planning seemed to occur regardless of whether premorbid IQ had been preserved or had deteriorated. However, working memory impairments occurred in the subgroup of schizophrenia patients demonstrating a substantial fall in IQ from premorbid levels. The ability to process increasingly complex information was addressed by a more detailed examination of the Tower of London results. There were no differences in performance between groups for the first three levels of complexity (1-3 moves), but significant, and increasing, differences emerged for the last three levels (4-6 moves). These results were taken to support the hypothesis that schizophrenia represents a loss of, or a failure to acquire, the ability to process complex information. Impairments of executive functions that could affect complex information processing could have implications for schizophrenia rehabilitation.

Adult↗

PubMed2026

Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.

Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL/6J mice. Volume electron microscopy of the mPFC revealed age-related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria-targeted antioxidant MitoQ improved attentional set-shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.

Animals↗

PubMed2024

Free-water: A promising structural biomarker for cognitive decline in aging and mild cognitive impairment.

Diffusion MRI derived free-water (FW) metrics show promise in predicting cognitive impairment and decline in aging and Alzheimer's disease (AD). FW is sensitive to subtle changes in brain microstructure, so it is possible these measures may be more sensitive than traditional structural neuroimaging biomarkers. In this study, we examined the associations among FW metrics (measured in the hippocampus and two AD signature meta-ROIs) with cognitive performance, and compared FW findings to those from more traditional neuroimaging biomarkers of AD. We leveraged data from a longitudinal cohort (nparticipants = 296, nobservations = 870, age at baseline: 73 ± 7 years, 40% mild cognitive impairment [MCI]) of older adults who underwent serial neuropsychological assessment (episodic memory, information processing speed, executive function, language, and visuospatial skills) and brain MRI over a maximum of four time points, including baseline (n = 284), 18-month (n = 246), 3-year (n = 215), and 5-year (n = 125) visits. The mean follow-up period was 2.8 ± 1.3 years. Structural MRI was used to quantify hippocampal volume, in addition to Schwarz and McEvoy AD Signatures. FW and FW-corrected fractional anisotropy (FAFWcorr) were quantified in the hippocampus (hippocampal FW) and the AD signature areas (SchwarzFW, McEvoyFW) from diffusion-weighted (dMRI) images using bi-tensor modeling (FW elimination and mapping method). Linear regression assessed the association of each biomarker with baseline cognitive performance. Additionally, linear mixed-effects regression assessed the association between baseline biomarker values and longitudinal cognitive performance. A subsequent competitive model analysis was conducted on both baseline and longitudinal data to determine how much additional variance in cognitive performance was explained by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein-ε4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. All analyses were corrected for multiple comparisons using an FDR procedure. Cross-sectional results indicate that hippocampal volume, hippocampal FW, Schwarz and McEvoy AD Signatures, and the SchwarzFW and McEvoyFW metrics are all significantly associated with memory performance. Baseline competitive model analyses showed that the McEvoy AD Signature and SchwarzFW explain the most unique variance beyond covariates for memory (ΔRadj 2 = 3.47 ± 1.65%) and executive function (ΔRadj 2 = 2.43 ± 1.63%), respectively. Longitudinal models revealed that hippocampal FW explained substantial unique variance for memory performance (ΔRadj 2 = 8.13 ± 1.25%), and outperformed all other biomarkers examined in predicting memory decline (pFDR = 1.95 x 10-11). This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.

Alzheimer’s disease (AD)↗

PubMedDate not supplied

[Deficits in memory retrieval: an argument in favor of frontal subcortical dysfunction in depression].

UNLABELLED: While numerous studies have objective quantitative and qualitative deficits of memory in depressed patients, the mechanisms of these impairments are not well established. The study reported here was designed to assess encoding and retrieval processes in depression and to define the specific nature of memory failure associated with this disorder. METHODS: Ten inpatients with major depression responding to DSM III-R criteria and ten normal controls were included in this study. All subjects were assessed with a neuropsychological battery including: a) subtests of Weschsler memory scale (digit span, logical memory); b) verbal fluency (letter); c) two tasks assessing executive functions (cognitive estimate, Nelson's test); d) two explicit tasks of verbal learning (California Verbal Learning Test and Grober & Buschke's procedure) which measure memory performance in various conditions of encoding (incidental vs controlled) and of recollection (free recall, cued recall and recognition). Severity of depression was assessed with the MADRS and the Retardation Rating Scale for Depression. RESULTS: Although there was no difference between patients and controls on digit span and logical memory tasks, depressed patients exhibited a deficit in verbal learning with CVLT and Grober & Buschke's procedure. On California Verbal Learning Test, depressive subjects performed poorly in free recall and demonstrated poor consistency. Patients show free recall improvement across trials 1 or 5 and this learning effect didn't differ from controls. Score of patients and controls on cued recall and recognition were at the same level. Grober & Buschke's procedure confirmed these results. Despite a control of encoding processes during the initial presentation of the words, free recall measure revealed significant difference between groups. Like controls, patients recalled almost all items when semantic cues was provided and their recognition results showed a ceiling effect. Consistency indexes of free recall and cued recall differed significantly between groups. Verbal fluency and frontal tasks didn't allow to distinguish the depressive patients from controls. DISCUSSION: Depressive subjects exhibited a deficit in free recall and poor consistency while cued recall and recognition were normal. Patient's results in free recall are characterized by difficulties in planning and in maintaining retrieval strategies. These findings suggest that memory failure in depression could reflect an impairment in retrieval processes depending on executive functions controlled by the subcortical structures.

Adult↗

PubMedDate not supplied

Assessing cognitive function: a guide to neuropsychological testing.

Neuropsychology is a discipline that studies brain-behavior relations through laboratory testing of behavior. Neuropsychologists develop a comprehensive clinical description of the person's cognitive processes and their implications for everyday behavior. Nurses can use the results of neuropsychological assessments as an objective source of information when planning care for clients who are cognitively impaired. This article provides an introduction to neuropsychology as a discipline, to its tests, and to its methods of assessment and interpretation. Two standard test batteries, the Halstead-Reitan Battery and the Luria-Nebraska Neuropsychological Battery, are described. Special tests for many cognitive functions--such as attention, executive functions, sensation and perception, motor performance, memory, language, and intelligence--also are described.

Adult↗

PubMed1984

Performance and its measurement.

Performance involves numerous sub-functions, and cannot be treated as a unit. Several attempts have been made to separate functions impaired by different classes of drug: for example, high (monitoring) vs lower (performing) levels of function, early (perceptual) vs later (motor) functions, and strategic vs executive functions. The practical implications are that one cannot predict effects of a drug from a single performance test. One must either simulate the practical situation exactly, or use a battery of analytical tests to form a profile of effects. The latter is the policy urged in this paper.

Amphetamine↗

PubMed1971

[The executive--a functional dental chair].

Explore the source record for details and available documents.

Dental Equipment↗

PubMed2025

Impact of Chewing Behavior Change on Cognition and Cerebral Hemodynamics.

BACKGROUND: Impaired chewing ability is a recognized risk factor for cognitive decline in older adults, potentially due to reduced neural stimulation in cognition-related brain regions. While short-term studies have demonstrated transient increases in neural activity from chewing, the sustained cognitive and neurophysiological effects of encouraging thorough chewing habits in daily life remain unclear. OBJECTIVE: This randomized controlled trial investigated whether promoting thorough chewing during meals could improve cognitive function and cerebral hemodynamics in older adults. METHODS: Fifty participants aged 65 y or older were randomly assigned to either a 1-mo intervention group, which used a wearable device to monitor and increase chewing strokes during meals, or a control group that maintained usual chewing habits. Chewing behavior, cognitive performance (including memory and executive function via the color Stroop test), and cerebral hemodynamics in the dorsolateral prefrontal cortex (DLPFC) were measured at baseline and after 1 mo. Statistical analyses included t tests, chi-square tests, 2-way analysis of variance with post hoc tests, Pearson correlations, and generalized linear models to evaluate group differences and associations between chewing and cognitive outcomes. RESULTS: Significant time-by-group interactions were observed for memory, F(1, 48) = 6.24, P = 0.043, and hemodynamic responses in the left DLPFC, F(1, 48) = 6.19, P = 0.013. The intervention group showed increased chewing frequency (P = 0.017), improved memory performance, and reduced left DLPFC responses compared with controls. Chewing frequency was positively correlated with Stroop test scores (r = 0.53, P = 0.010) and negatively with hemodynamic changes in the left DLPFC (r = -0.30, P = 0.040). Although improvements in other cognitive outcomes and hemodynamic measures favored the intervention group, these differences did not reach statistical significance. CONCLUSIONS: Promoting intentional chewing habits for 1 mo may enhance memory-related cognitive performance and neural efficiency in the DLPFC during working memory tasks in older adults. This nonpharmacologic, low-burden strategy warrants further research with longer interventions to support cognitive health and dementia prevention. TRIAL REGISTRATION ID: UMIN000044280Knowledge Transfer Statement:This study demonstrates that promoting thorough chewing habits in older adults can improve memory and enhance neural efficiency in the brain. Encouraging intentional mastication is a simple, nonpharmacologic approach that may help maintain cognitive health and prevent dementia, providing a practical strategy for clinicians and policymakers to support healthy aging.

Humans↗

PubMed2026

Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.

Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.

Amyotrophic Lateral Sclerosis↗

PubMed1996

Assessing declarative memory in schizophrenia using Wisconsin Card Sorting Test stimuli: the Paired Associate Recognition Test.

The Paired Associate Recognition Test (PART) was developed to measure declarative memory using Wisconsin Card Sorting Test (WCST) stimuli, so that both tasks could be administered during functional neuroimaging to differentiate memory and executive function, and associated frontal and temporal lobe activation in schizophrenia. The current study was designed to compare PART and WCST performance in schizophrenic patients and to examine effects of medication and symptomatology. The PART, WCST, and standard declarative memory tasks were administered to 30 chronic schizophrenic patients and 30 matched healthy control subjects. Supporting task validity was the finding that patients were equally impaired on the PART and the WCST. Neuroleptics did not appear to affect performance. The effect of anticholinergic medication correlated negatively with WCST performance in a small subsample. Severity of schizophrenia-specific symptoms measured at intake on the Brief Psychiatric Rating Scale correlated negatively with performance on the WCST. These results support the application of the PART and WCST in future functional neuroimaging studies.

Adult↗

PubMed1993

A meta-analysis of the relative sensitivity of neuropsychological screening tests.

The National Institute of Mental Health recently formed a committee of experts which published a proposal for a lengthy neuropsychological test battery judged most apt to detect diffuse brain damage while covering a wide range of cognitive abilities. The purposes of the present study were (1) to assemble empirical evidence of the existence of statistically significantly sensitive screening tests across an equivalently wide range of functional domains, and (2) to present this evidence systematically, in such a manner as to help clinicians select subsets of screening tests manifesting greatest sensitivity to diffuse brain damage. It was found that in certain functional domains (speed of processing, problem solving, executive functions), marked differences in sensitivity occurred. Brief tests just as sensitive as time-consuming tests were also identified. The reader is cautioned about possible extraneous sources of the differences obtained (test and group selection bias, test reliability, test difficulty, procedural effects, Type I error). Nevertheless, it was concluded that a brief highly sensitive and functionally wide-ranging neuropsychological test battery for screening cases of putative diffuse brain dysfunction can be assembled.

Attention↗

PubMed2026

Subacute and long-term changes in cognitive functioning after administration of classic psychedelics, MDMA and ketamine: A systematic review of clinical and preclinical evidence.

Psychedelic agents induce a window of heightened neuroplasticity that extends beyond acute intoxication, during which neural circuits are more amenable to change. This period may facilitate changes in cognition relevant to the treatment of psychiatric disorders. This systematic review synthesised clinical and preclinical evidence of subacute and long-term (≥1 day) effects of classic and non-classic psychedelics on cognition. MEDLINE, EMBASE, APA PsycInfo and Web of Science were searched to identify human and animal studies investigating psychedelics and cognition (executive function, attention, decision-making). Sixty-seven (47 clinical, 20 preclinical) articles met inclusion criteria. Psilocybin demonstrated the most consistent evidence of subacute and longer-term cognitive improvement, particularly in cognitive flexibility and attention. Ketamine showed enhancement across cognitive domains, although findings were heterogeneous. LSD and DMT showed no consistent subacute changes, while MDMA was associated with transient cognitive impairments that resolved within days. Risk of bias assessments revealed selective outcome reporting, poor reporting of missing data and inadequate methodological detail, limiting the confidence of findings. Current evidence provides preliminary support for subacute changes in cognition following administration of select psychedelic agents. Cognitive improvements were more frequently seen in psychiatric populations than healthy subjects, which may reflect a remediation of existing cognitive deficit rather than enhancement above normal functioning. Adequately powered, controlled studies with standardised reporting of cognitive outcomes are required to determine the magnitude, durability and clinical relevance of psychedelic-associated cognitive change.

Hallucinogens↗

PubMed2026

Game changer? Cognitive-motor effects of VR exergaming compared to video-based training.

BACKGROUND/OBJECTIVE: Virtual reality (VR) exergaming enhances several cognitive domains through multisensory engagement. Acute cognitive benefits of VR are established, but evidence for direct comparisons with non-immersive controls is limited. This study aimed to determine whether VR exercise provides additional cognitive and cognitive-motor benefits beyond a matched non-immersive active stick-fight video (SFV) intervention, and whether effects persist after training. METHODS: In this randomized quasi-experimental study, N = 55 healthy adults (VR: n = 30; SFV: n = 25; 25.5 ± 7.1 years; 41.8% female) completed an 8-week program (2 × 30 min/week), of VR or SFV matched in movement patterns, frequency, intensity and duration. Measurements included reaction time (RT), Stroop Test (versions 1-3), Letter Cancellation Test (LCT), Trail Making Test (TMT), Trail Walking Test (TWT) and Fitts task (difficulty level 1-4). Data were analyzed using mixed-design ANOVAs. RESULTS: Improvements were observed in Stroop reading (F(1,53) = 14.84, p < .001, η2 = 0.219), Stroop inhibition (F(1,53) = 10.99, p = .002, η2 = 0.172), and LCT (F(1,53) = 4.57, p = .037, η2 = 0.079). A time × group interaction was found for TMT (F(1,53) = 6.55, p = .031, η2 = 0.110), indicating greater changes following VR training. Both groups improved cognitive-motor performance (TWT: F(1,25) = 55.32, p < .001, η2 = 0.689; Fitts3: F(1,53) = 44.97, p < .001, η2 = 0.459), with greater gains for VR in Fitts3 (p = .006). CONCLUSION(S): Eight weeks of VR and SFV enhanced cognitive and cognitive-motor performance. VR provided domain-specific advantages in executive function, but these effects were not uniformly persistent. SFV sustained more improvements in real-world-relevant cognitive-motor tasks.

Humans↗

PubMed2025

Genetic and epigenetic changes to the glucocorticoid receptor gene (NR3C1) and cognition in major depressive disorder.

INTRODUCTION: Many studies have found that hypothalamic-pituitary-adrenal (HPA) axis abnormalities are related to the pathophysiology of major depressive disorder (MDD) and cognitive functioning. Our aim was to assess the influence of genetic polymorphisms and methylation levels in three different promoter regions throughout the glucocorticoid receptor (GR) gene NR3C1 on cognitive performance in MDD. Plausible interactions with childhood adversity and mediation relationships between genetic and epigenetic variables were explored. MATERIALS AND METHODS: The sample included a total of 64 MDD patients and 82 healthy controls. Child maltreatment and neurocognitive performance were assessed in all participants. HPA negative feedback was analyzed using the dexamethasone suppression test after the administration of 0.25mg of dexamethasone. A total of 23 single-nucleotide polymorphisms were genotyped, and methylation levels at several CpGs in exons 1D, 1F and 1H of the GR gene were measured. RESULTS: Results show that, beyond the influence of other covariables, NR3C1 single-nucleotide polymorphisms and methylation levels predicted performance in executive functioning and working memory tasks. No significant interactions or mediation relationships were detected. CONCLUSIONS: Results suggest that genetic variations and epigenetic regulation of the GR gene are relevant factors influencing cognitive performance in MDD and could emerge as significant biomarkers and therapeutic targets in mood disorders and other stress-related disorders.

Humans↗

PubMed2026

Post-intervention effectiveness of a computerized personalized cognitive stimulation program adapted according to cognitive reserve in older adults without cognitive impairment in Primary Care: A randomized clinical trial.

BACKGROUND: Cognitive reserve may influence responsiveness to cognitive interventions, yet it is rarely used to tailor computerized stimulation. OBJECTIVE: To evaluate the effectiveness of a computerized cognitive stimulation program personalized according to cognitive reserve on cognition, reserve-related activities, and digital competence in community-dwelling older adults without cognitive impairment in Primary Care. METHODS: In this randomized clinical trial, 102 adults aged ≥65 years with normal cognitive performance were recruited from three primary care centers in Zaragoza, Spain, and stratified by cognitive reserve level before random allocation to intervention or control. The intervention comprised digital literacy sessions followed by 8 weeks of home-based computerized cognitive stimulation tailored to participants' cognitive reserve profiles and life history. Controls received a single group-based health education session focused on maintaining everyday cognitive activity. Outcomes were assessed at baseline and post-intervention using global cognition (MEC-35), the Cognitive Reserve Questionnaire, the Mobile Device Proficiency Questionnaire-16, and domain-specific neuropsychological tests. A total of 100 participants completed the final evaluation and were included in complete-case analyses. RESULTS: Compared with controls, the intervention group showed greater adjusted post-intervention improvements in global cognition (MEC-35 between-group difference: 1.8 points) and several cognitive measures, including temporal orientation, calculation, attention, praxis, verbal fluency, processing speed, executive functions, and verbal learning. CRQ scores and digital competence also improved, with small-to-large effect sizes. CONCLUSIONS: A computerized cognitive stimulation program adapted according to cognitive reserve appears feasible in Primary Care and may improve cognition, engagement in reserve-related activities, and digital competence in older adults without cognitive impairment.

Humans↗

PubMed2026

Distinct contributions of schizophrenia and neurotransmitter pathway genetic liability to neurocognition and antipsychotic efficacy in drug-naïve first-episode schizophrenia.

The genetic mechanisms underlying heterogeneity in symptom presentation and antipsychotic response in schizophrenia remain unclear, limiting the development of personalized treatment. We integrated genome-wide schizophrenia polygenic risk scores (SZ-PRS) and pathway-specific PRSs (pPRSs) for four major neurotransmitter systems to examine their associations with clinical phenotypes across the course of illness. Primary analyses were conducted in 394 drug-naïve, first-episode patients from the Chinese First-Episode Schizophrenia Trial (CNFEST) to investigate associations with baseline symptom severity, neurocognitive impairment, and longitudinal treatment response. The CNFEST cohort included 52-week longitudinal assessments of symptoms and neurocognition using the Positive and Negative Syndrome Scale and a modified version of the MATRICS Consensus Cognitive Battery. An independent case-control cohort evaluated associations with schizophrenia diagnosis, while a cohort of 514 healthy adults assessed whether PRS-cognition associations are specific to schizophrenia. Higher SZ-PRS predicted schizophrenia diagnosis (OR = 2.28, Pfdr = 0.003) and poorer baseline executive function (β = -0.44, Pfdr = 0.006) and working memory (β = -0.49, Pfdr = 0.018), but these associations were absent in healthy adults. In contrast, pPRSs showed weaker associations with diagnosis and baseline cognition but were more informative for treatment outcomes: higher serotonin-pPRS predicted greater improvement in depressive symptoms (Pfdr = 0.023-0.032), and higher GABA-pPRS predicted greater improvement in overall symptoms (Pfdr = 0.038-0.043) during weeks 4-24. Exploratory drug-specific analyses further suggested that treatment response varied across antipsychotics and was differentially associated with pPRSs. These findings demonstrate that genome-wide and pathway-specific PRSs contribute distinctly to schizophrenia phenotypes, supporting their integration for personalized stratification and treatment.

Humans↗