Hippocampal resting-state connectivity is associated with posterior-cortical cognitive impairment in Parkinson's disease.

AIM: Frontal and posterior-cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior-cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: K-means cluster analysis delineated subtypes (cognitively intact, frontal, posterior-cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N = 42) and 20 healthy controls (HCs) underwent rs-fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior-cortical, cognitively intact, and HC participants using seed-based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. RESULTS: The posterior-cortical subtype (N = 19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N = 11) group, p-false discovery rate (FDR) = .01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N = 20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p-FDR = .01). CONCLUSION: Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior-cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted.

Characterization of de novo Dementia with Lewy Body with different duration of rapid eye movement sleep behavior disorder.

BACKGROUND: Cognitive disorder, parkinsonism, autonomic dysfunction (AuD) and rapid eye movement sleep behavior disorder (RBD) can occur prior to or simultaneously with Dementia with Lewy Body (DLB) onset. RBD is generally linked with progressive neurodegenerative traits. However, associations between RBD with DLB, RBD without DLB, and RBD duration effects on DLB symptoms remain unclear. OBJECTIVES: To examine DLB symptom frequency and subtypes in RBD, and explore the effects of different RBD onset times on symptoms in de novo DLB patients. METHODS: In this multicenter investigation, we consecutively recruited 271 de novo DLB patients. All had standardized clinical and comprehensive neuropsychological evaluations. Subgroup analyses, performed based on the duration of RBD confirmed by polysomnography before the DLB diagnosis, we compared the proportion of patients with cognitive impairment, parkinsonism, and AuD features between groups. RESULTS: Parkinsonism and AuD incidences were significantly elevated in DLB patients with RBD when compared with patients without RBD. Subgroup analyses indicated no significant differences in parkinsonism between DLB patients who developed RBD ≥10 years prior to the DLB diagnosis and DLB patients without RBD. The incidence of non-tremor-predominant parkinsonism and AuD was significantly higher in DLB patients whose RBD duration before the DLB diagnosis was <10 years when compared with DLB patients without RBD. CONCLUSIONS: We identified significant symptom and phenotypic variability between DLB patients with and without RBD. Also, different RBD duration effects before the DLB diagnosis had a significant impact on symptomatic phenotypes, suggesting the existence of a slowly progressive DLB neurodegenerative subtype.

Cognitive dysfunction in de novo Parkinson disease: Remitting vs. progressive cognitive impairment.

INTRODUCTION: Parkinson's disease (PD) exhibits divergent cognitive trajectories; however, the factors contributing to these variations remain elusive. This study aimed to examine the clinical features of patients with different long-term cognitive trajectories in de novo PD over a five-year follow-up. METHODS: We analyzed 258 patients who completed every annual evaluation for five years. According to the Montreal Cognitive Assessment (MoCA) scores, we classified patients into three groups: cognitively normal (n = 118, CN), remitting MoCA decline (n = 74, RMD), and progressive MoCA decline (n = 66, PMD). RESULTS: The RMD group was associated with lower olfactory scores (Odds Ratio (OR) = 0.958, p = 0.040), whereas PMD was associated with higher depression scores (OR = 1.158, p = 0.045), probable RBD (OR = 3.169, p = 0.002), older age (OR = 1.132, p < 0.001) and lower educational attainment (OR = 0.828, p = 0.004). PMD had higher neurofilament light chain protein values than CN and RMD (p = 0.006, 0.015, respectively). Longitudinally, PMD showed a greater decline in all cognitive scores and hippocampus volumes (p = 0.004). Meanwhile, RMD exhibited intermediate cognitive and volumetric trajectories between CN and PMD and displayed worse score changes in memory tasks than CN. CONCLUSIONS: While PMD exhibited known risk factors for cognitive impairment, along with worse cognitive performance and hippocampal volume decline, RMD displayed baseline lower olfactory scores and intermediate cognitive and hippocampal volume decline between the two groups. These findings suggest individuals in RMD may still be at risk for cognitive deficits. However, further long-term follow-up data are needed to unravel the determinants and dynamics of cognitive functions.

Shared Proteins and Pathways of Cardiovascular and Cognitive Diseases: Relation to Vascular Cognitive Impairment.

One of the primary goals of systems medicine is the detection of putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular cognitive impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular cognitive genes and proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.

Schizotypy Moderates the Relationship Between Sleep Quality and Social Cognition.

ABSTRACT: Poor sleep quality has been tied to worse social cognition. Social cognitive deficits have been noted in those with high schizotypy. Yet, no study has assessed whether schizotypy moderates the relationship between sleep quality and social cognition, which may be vital to our understanding of contributors to social functioning. We conducted a cross-sectional analysis of associations of sleep quality and social cognition, with potential moderation by schizotypy. Participants ( n = 906) completed self-report measures of schizotypy, sleep quality, and social cognition. Levels of schizotypy significantly moderated some of the relationships between sleep and social cognition. For participants low in total or interpersonal schizotypy, worse sleep quality was associated with worse theory of mind scores. For participants low in total, disorganized, or cognitive perceptual schizotypy, worse sleep quality was associated with worse self-reported cognitive empathy. For those high in these facets of schizotypy, worse sleep quality was associated with better self-reported cognitive empathy. These results suggest that the individual facets of schizotypy provide additional information and, therefore, are important to assess when examining social cognition and sleep.

High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis.

BACKGROUND: Uric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients. METHODS: We enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007-2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT). RESULTS: Out of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (µmol/L; ALS-INT, 289.7 ± 75.5 µmol/L; ALS-FTD, 271.8 ± 74.9 µmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01-1.43; p = 0.038) in binary logistic regression. CONCLUSIONS: We found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.

Protecting the Brain While Healing Hearts: The Protective Role of Cognitive Reserve in Cardiac Surgery.

OBJECTIVE: One of the most significant complications following coronary artery bypass grafting (CABG) is postoperative cognitive decline (POCD). CABG patients frequently experience considerable postoperative cognitive dysfunction (POCD), including decline in attention, orientation, memory, judgment, and social functioning. DESIGN: These negative effects may potentially be resolved by a protective factor, cognitive reserve (CR) that has been considered to function as a buffer against the consequences of neuropathology. SETTING: We explored the frequency of POCD and CR in coronary artery disease patients undergoing CABG. We hypothesized that high levels of CR would protect against POCD after cardiac surgery. PARTICIPANTS: We assessed 101 patients before surgery, and 4 months after cardiopulmonary bypass surgery with the use of extracorporeal circulation. MEASUREMENTS: Measures of cognitive functions, CR, anxiety, and depression were included in the assessment. RESULTS: Each patient was placed in the high (n = 50) or low CR (n = 51) group, based on median split. Chi-square tests effect showed that patients with low CR were more likely to a great extend to demonstrate postsurgical cognitive decline in attention, memory, visuospatial perception and executive functions than patients with high CR upon postsurgery neuropsychological assessment. CONCLUSIONS: Our results suggest that CR can forecast neuropsychological outcomes of cardiac surgery, recognizing the patients with low CR and help them to participate to interventions programs that could slow cognitive aging or reduce the risk of dementia and enhance their overall postsurgical functional outcome.

Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Cognitive function in amyotrophic lateral sclerosis: a cross-sectional and prospective pragmatic clinical study with review of the literature.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) can present with either bulbar or spinal symptoms, and in some cases, both types of symptoms may be present. In addition, cognitive impairment has been observed in ALS. The study aimed to evaluate the frontal and general cognitive performance in ALS not only cross-sectionally but also longitudinally. METHODS AND MATERIALS: The Frontal Assessment Battery (FAB) and the Montreal Cognitive Assessment (MoCA) were employed to assess cognitive function in 52 adults with ALS and 52 cognitively healthy individuals. The statistical analyses encompassed the Pearson Chi square test, the Skillings-Mack test, the Spearman's rank correlation coefficient, and the Proportional Odds Logistic Regression Model (POLR). RESULTS: Cross-sectionally, lower cognitive performance was associated with ALS diagnosis, older age, and motor functional decline. The cognitive impairment of individuals with bulbar and spinal-bulbar symptoms showed faster deterioration compared to those with spinal symptoms. The spinal subgroup consistently performed worst in delayed recall and attention, while the spinal-bulbar and bulbar subgroups exhibited inferior scores in delayed recall, attention, visuospatial skills, orientation, and verbal fluency. CONCLUSION: The incorporation of cognitive screening in the diagnostic workup of ALS may be beneficial, as early detection can enhance symptom management and improve the quality of life for both individuals with ALS and their care partners.

Unmet needs in epileptic encephalopathy with spike-and-wave activation in sleep: A systematic review.

INTRODUCTION: Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS), also referred to as electrical status epilepticus during sleep (ESES) or epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS or EE-CSWS), is a spectrum of rare childhood epileptic encephalopathies that can lead to long-term cognitive impairment. Despite the importance of early diagnosis and intervention for D/EE-SWAS, there is a paucity of well-controlled clinical trial data to inform treatment, and no approved treatments are available. To assess correlations between diagnosis, treatment, and outcomes in D/EE-SWAS, we carried out a systematic review of the literature. METHODS: In August 2020, we conducted comprehensive database searches using search terms including "electrical status epilepticus," "ESES," "CSWS," and "Landau-Kleffner syndrome." Two or more independent reviewers screened titles, abstracts, and full-text articles for those that met the following criteria: prospective studies (randomized controlled trials [RCTs] or open-label trials), retrospective studies (drug evaluations or observational studies/chart reviews), and case series with ≥ 10 participants. Both interventional and non-interventional studies were included (i.e., drug intervention was not an inclusion criterion). Articles published before 2012, review articles, animal studies, and studies of surgical or dietary interventions were excluded. Standardized data extraction templates were used to capture data on study design, patient characteristics, interventions, and outcomes from each of the selected publications. Study quality was assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale (NOS) or the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for retrospective, observational studies. RESULTS: A total of 34 studies were included for full data extraction, most of which were uncontrolled and observational. Interpretation of study outcomes was limited by small study populations, variability in inclusion criteria, and inconsistency in methods of assessment and reporting of outcomes, which resulted in large heterogeneity in patients and their presenting symptoms. Despite these limitations, some patterns could be discerned. Several studies found that longer duration of ESES and younger age at onset were correlated with more severe language and cognitive deficits. In addition, several studies reported an association between improvement in cognitive outcomes and reduction in electroencephalogram (EEG) abnormalities and/or seizure frequency. In the 16 prospective or retrospective studies that evaluated drug treatments (e.g., antiseizure medications, corticosteroids, and high-dose diazepam), there was some improvement in EEG, seizure, and/or cognitive outcomes, although the specific outcomes and rates of improvement reported varied from study to study. CONCLUSION: Long-term cognitive deficits remain common in D/EE-SWAS, and data gaps exist in the literature that preclude an evidence-based approach to managing this complex epilepsy indication. Early intervention with more effective medications is needed to optimize long-term outcomes. Sufficiently powered, randomized, double-blind, controlled trials with standardized methods and predefined primary and secondary outcomes are needed.

Driving Impairment Among Older Adults.

This JAMA Patient Page describes risk factors for driving impairment among older adults, such as medical conditions and medications, and ways to mitigate driving impairment.

Molecular mechanism of cognitive impairment associated with Parkinson's disease: A stroke perspective.

Parkinson's disease (PD) is a common neurological illness that causes several motor and non-motor symptoms, most characteristically limb tremors and bradykinesia. PD is a slowly worsening disease that arises due to progressive neurodegeneration of specific areas of the brain, especially the substantia nigra of the midbrain. Even though PD has continuously been linked to a higher mortality risk in numerous epidemiologic studies, there have been significant discoveries regarding the connection between PD and stroke. The incidence of strokes such as cerebral infarction and hemorrhage is substantially associated with the development of PD. Moreover, cognitive impairments, primarily dementia, have been associated with stroke and PD. However, the underlying molecular mechanism of this phenomenon is still obscure. This concise review focuses on the relationship between stroke and PD, emphasizing the molecular mechanism of cognition deficit and memory loss evident in PD and stroke. Furthermore, we are also highlighting some potential drug molecules that can target both PD and stroke.

COVID-19 in Relation to Alzheimer's Disease: Mendelian Randomization Analyses Add to Multiple Lines of Evidence.

The potential link between COVID-19 and Alzheimer's disease (AD) has been an intriguing topic in the global pandemic. Whether the susceptibility and severity of COVID-19 affects the onset and progression of AD is of great concern. Clinical studies suggested an increased risk of AD occurrence or cognitive deficit after COVID-19. Basic research found that severe COVID-19 induced changes resembling AD. Evidence synthesis should always take into account diverse study designs, both traditional and novel. The recent study by Ding et al. aimed to investigate the association of COVID-19 with AD using a non-overlapping two-sample Mendelian randomization analysis.

Similarities in cognitive impairment between recent- onset and chronic schizophrenia patients: a consideration for the neurodevelopmental hypothesis.

Impairment in attention, memory, processing speed and executive functions have been described in patients with schizophrenia. Such impairments can be observed in early stages of the disease and in chronic patients; discrepancy in findings regarding the cognitive deficits at different stages of the illness keeps the debate about schizophrenia as a neurodegenerative condition which courses with continuous deterioration, or if deficits remain stable, as the neurodevelopmental hypothesis suggests.

Motoric Cognitive Risk and Incident Dementia in Older Adults.

Importance: Motoric cognitive risk (MCR) is a novel predementia syndrome; however, whether it can estimate dementia in a nationwide population or has additive estimation validity over cognitive or motoric components alone remains unknown. Objective: To examine whether modified MCR, which incorporates the timed-up-and-go and one-leg-standing tests, improves estimation validity for incident dementia over using cognitive or motoric components alone. Design, Setting, and Participants: This nationwide cohort study evaluated data from individuals aged 66 years who participated in the National Screening Program for Transitional Ages in Korea from January 1, 2009, to December 31, 2013, and examined the association between MCR and incident dementia using Cox proportional hazards regression analysis. Data were collected from the index date (the date on which the participant had the screening) until dementia onset, death, or the end of the follow-up period, whichever came first. The 2 subtypes were defined as subjective cognitive declines with timed-up-and-go impairment or one-leg-standing impairment. The data set was generated with permission from the Korean National Health Insurance Service, and data analysis was conducted from August 2, 2021, to January 31, 2022. Individuals diagnosed with dementia or psychotic disorders or those who had a documented history of dementia medication use before the index date were excluded. Main Outcomes and Measures: The main outcome was incidence of dementia, defined as an individual receiving their first dementia medication with the relevant International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes after the index date. Results: Among the 1 137 530 participants (53.7% women), 15 380 (1.4%) met the MCR criteria for the timed-up-and-go subtype, and 32 910 (2.9%) met the criteria for the one-leg-standing subtype. The mean (SD) follow-up period was 7.02 (1.38) years. Participants with MCR demonstrated an approximately 2-fold higher risk of incident dementia than those without MCR (timed-up-and-go subtype, adjusted hazard ratio, 2.03; 95% CI, 1.94-2.13; one-leg-standing subtype, adjusted hazard ratio, 2.05; 95% CI, 1.98-2.12). Conclusions and Relevance: In this cohort study of participants aged 66 years of the National Screening Program for Transitional Ages, modified motoric cognitive risk had higher adjusted hazard ratios of incident dementia than individual cognitive or motoric components. Motoric cognitive risk may be a practical screening tool for estimating dementia among individuals in their mid-60s ; however, further investigation of the clinical and neurobiological aspects is necessary.

Serotonin Degeneration and Amyloid-ß Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits.

BACKGROUND: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-ß (Aß). OBJECTIVE: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aß in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aß to cognitive deficits. METHODS: Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aß, structural magnetic resonance imaging and neuropsychological assessments. RESULTS: Lower cortical, striatal, and limbic 5-HTT and higher cortical Aß was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A ß was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aß, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. CONCLUSIONS: These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

Exercise as an add-on treatment in individuals with schizophrenia: Results from a large multicenter randomized controlled trial.

Current treatment methods do not achieve recovery for most individuals with schizophrenia, and symptoms such as negative symptoms and cognitive deficits often persist. Aerobic endurance training has been suggested as a potential add-on treatment targeting both physical and mental health. We performed a large-scale multicenter, rater-blind, parallel-group randomized controlled clinical trial in individuals with stable schizophrenia. Participants underwent a professionally supervised six-month training comprising either aerobic endurance training (AET) or flexibility, strengthening, and balance training (FSBT, control group), follow-up was another six months. The primary endpoint was all-cause discontinuation (ACD); secondary endpoints included effects on psychopathology, cognition, functioning, and cardiovascular risk. In total, 180 participants were randomized. AET was not superior to FSBT in ACD and most secondary outcomes, with dropout rates of 59.55% and 57.14% in the six-month active phase, respectively. However, both groups showed significant improvements in positive, general, and total symptoms, levels of functioning and in cognitive performance. A higher training frequency additionally promoted further memory domains. Participants with higher baseline cognitive abilities were more likely to respond to the interventions. Our results support integrating exercise into schizophrenia treatment, while future studies should aim to develop personalized training recommendations to maximize exercise-induced benefits.

Incident sarcopenia in hospitalized older people: A systematic review.

Hospitalization has been associated with the development of sarcopenia. This study aimed to examine the new incidences of hospital sarcopenia, associated risk factors and health outcomes, as defined by internationally recognized diagnostic criteria in hospitalized older people. Pre-defined search terms were run through five databases. Six studies that assessed sarcopenia on two separate time points during hospitalization on older inpatients were included. Prevalence of sarcopenia varied from 14.1% to 55% depending on diagnostic criteria and cut-off points used. New sarcopenia occurred between 12% to 38.7% patients following hospitalization. Risk factors were older age, longer duration of bed rest, lower baseline body mass index, cognitive impairment and activities of daily living disability. None of the studies reported health outcomes associated with newly developed sarcopenia in hospital.

The relationship between negative symptoms and MATRICS neurocognitive domains: A meta-analysis and systematic review.

BACKGROUND: Negative symptoms (NS) are a core symptom domain in schizophrenia spectrum disorders and are associated with poorer social and vocational functioning, and with increased likelihood and durations of hospital admission. NS are not well understood, limiting available interventions. However, numerous studies have reported associations between neurocognitive domains and NS severity. Thus, one promising area in understanding NS is in relation to neurocognition. Currently, the specificity of the relationship between NS and neurocognition is unknown, meaning that there is no consensus regarding which neurocognitive domain is most strongly associated with NS. There is a need to systematically examine the relationship between NS and various neurocognitive domains within study samples. METHODS: A systematic search of Ovid PsycINFO, Ovid MEDLINE and Web of Science was performed for articles published since 2004 (year of MATRICS Consensus publication). Inclusion criteria were: 1) individuals with schizophrenia spectrum disorders, first episode psychosis or clinical high risk 2) assessed all six MATRICS neurocognitive domains (processing speed, attention, working memory, verbal learning & memory, visual learning & memory, reasoning & problem solving), 3) reported correlations between all six MATRICS neurocognitive domains and global NS. A three-level random effects hierarchical meta-analysis was performed to assess the relationship between NS (global, expressive, and experiential dimensions) and the six MATRICS neurocognitive domains. RESULTS: 21 studies were included in the review (n = 3619). All MATRICS neurocognitive domains had small significant correlations with global NS (r = -0.16 to -0.20, p < 0.0001). This relationship was significantly moderated by diagnosis and the moderating effect of sex/ gender trended on significance. Analysis of a subset of the studies revealed that MATRICS neurocognitive domains also had small significant correlations with the two NS dimensions, expressive and experiential. Correlations were stronger with the expressive NS dimension. CONCLUSIONS: This review is novel in assessing the relationship between multiple neurocognitive domains and NS within the same sample, by synthesizing close to two decades of research. Our results suggest that there is a non-specific relationship between neurocognition and NS, and that expressive NS may have a stronger relationship with neurocognitive functioning-based on the MATRICS classification of neurocognition and the neurocognitive assessments used in the included studies. This has implications on our understanding of NS and neurocognition, as well as their treatments. As we gain better understanding of the directionality of the NS-cognition relationship, it could suggest that NS, particularly in the expressive domain, could be improved by targeting cognition globally or that neurocognitive treatments could be more effective if NS are addressed first. Further implications of these results are discussed.