Statins and cognition in late-life bipolar disorder.

OBJECTIVES: Recent data suggests that statins have positive effects on cognition in older adults. Studies in patients with mood disorders have found contradicting positive and negative effects of statins on mood and cognition, with limited data in bipolar disorder (BD). The objective of this study was to assess the association between statin use and cognition in older adults with BD. METHODS: In a cross-sectional sample of 143 euthymic older adults with BD (age ≥ 50), statin users (n = 48) and nonusers (n = 95) were compared for cognitive outcomes: Global and cognitive domain z-scores were calculated from detailed neuropsychological batteries using normative data from healthy comparators (n = 87). RESULTS: The sample had a mean age of 64.3 (±8.9) years, 65.0% were female, with an average of 15.1 (±2.79) years of education. Statin users did not differ from nonusers on global (-0.60 [±0.69] vs -0.49 [±0.68], t[127] = 0.80, P = .42) or individual cognitive domains z-score. CONCLUSIONS: In older patients with BD, statin use is not independently associated with cognitive impairment. This suggests that in older BD patients, the cognitive dysfunction associated with BD trumps the potential cognitive benefit that is associated with statins in older adults without a psychiatric disorder. Further, statins do not seem to exacerbate this cognitive dysfunction. Future longitudinal studies are needed to confirm these findings.

Allostatic load but not medical burden predicts memory performance in late-life bipolar disorder.

OBJECTIVE: Older patients with bipolar disorder (BD) present with variable degrees of cognitive impairment. Over time, stress, mood episodes, and comorbidities increase the body's allostatic load. We assessed the extent to which allostatic load vs more traditional measures of medical burden account for the heterogeneity in cognition in this population. METHODS: Thirty-five older euthymic patients with BD and 30 age-equated, gender-equated, and education-equated comparison participants were administered a comprehensive assessment including a neuropsychological battery, and 9 physiological measures to determine allostatic load. The relationship among allostatic load, medical burden, and cognition was assessed. RESULTS: Compared with the mentally healthy comparators, patients were impaired globally, and in 4 cognitive domains-information-processing speed / executive functioning, delayed memory, language, and visuomotor ability, and presented with greater medical burden but not a different allostatic load. Allostatic load, but not medical burden, was associated with delayed memory performance both in a correlational analysis and in a multivariate regression analysis. CONCLUSION: Euthymic older patients with BD are impaired on several cognitive domains and have high medical burden. Their memory performance is more strongly associated with allostatic load than with traditional measures of medical burden. These findings need to be replicated and extended longitudinally.

Oligodendrocyte genes, white matter tract integrity, and cognition in schizophrenia.

Oligodendrocyte genes and white matter tracts have been implicated in the pathophysiology of schizophrenia and may play an important etiopathogenic role in cognitive dysfunction in schizophrenia. The objective of the present study in 60 chronic schizophrenia patients individually matched to 60 healthy controls was to determine whether 1) white matter tract integrity influences cognitive performance, 2) oligodendrocyte gene variants influence white matter tract integrity and cognitive performance, and 3) effects of oligodendrocyte gene variants on cognitive performance are mediated via white matter tract integrity. We used the partial least-squares multivariate approach to ascertain relationships among oligodendrocyte gene variants, integrity of cortico-cortical and subcortico-cortical white matter tracts, and cognitive performance. Robust relationships among oligodendrocyte gene variants, white matter tract integrity, and cognitive performance were found in both patients and controls. We also showed that effects of gene variants on cognitive performance were mediated by the integrity of white matter tracts. Our results were strengthened by bioinformatic analyses of gene variant function. To our knowledge, this is the first study that has brought together these lines of investigation in the same population and highlights the importance of the oligodendrocyte/white matter pathway in schizophrenia, particularly as it pertains to cognitive function.

Cognitive performance of individuals with schizophrenia across seven decades: a study using the MATRICS consensus cognitive battery.

OBJECTIVES: The objectives of this study were to determine the effect of aging, schizophrenia, and their interaction on cognitive function. DESIGN: Cross-sectional controlled study. SETTING: Community living. PARTICIPANTS: A total of 235 subjects with schizophrenia age 19-79 and 333 comparison subjects age 20-81. MEASUREMENTS: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). RESULTS: Older age was associated with poorer performance on 9 of 10 MCCB tests in both subjects with schizophrenia and comparison subjects. Subjects with schizophrenia were impaired relative to comparison subjects on each of the 10 tests. However, there was no interaction between aging and schizophrenia on any test. Essentially the same results were observed when analyzing performance on the seven MCCB cognitive domains and MCCB global composite score. CONCLUSIONS: Consistent with other reports, schizophrenia appears to be a disorder marked by generalized cognitive dysfunction. However, the rate of cognitive decline appears to be similar to that observed in healthy comparison subjects. They do not experience acceleration in cognitive aging, which supports the hypothesis that schizophrenia is a syndrome of premature aging. Longitudinal studies including very old patients are needed to confirm and extend these findings.

Diffusion tensor tractography findings in schizophrenia across the adult lifespan.

In healthy adult individuals, late life is a dynamic time of change with respect to the microstructural integrity of white matter tracts. Yet, elderly individuals are generally excluded from diffusion tensor imaging studies in schizophrenia. Therefore, we examined microstructural integrity of frontotemporal and interhemispheric white matter tracts in schizophrenia across the adult lifespan. Diffusion tensor imaging data from 25 younger schizophrenic patients (< or = 55 years), 25 younger controls, 25 older schizophrenic patients (> or = 56 years) and 25 older controls were analysed. Patients with schizophrenia in each group were individually matched to controls. Whole-brain tractography and clustering segmentation were employed to isolate white matter tracts. Groups were compared using repeated measures analysis of variance with 12 within-group measures of fractional anisotropy: (left and right) uncinate fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, inferior occipito-frontal fasciculus, cingulum bundle, and genu and splenium of the corpus callosum. For each white matter tract, fractional anisotropy was then regressed against age in patients and controls, and correlation coefficients compared. The main effect of group (F(3,92) = 12.2, P < 0.001), and group by tract interactions (F(26,832) = 1.68, P = 0.018) were evident for fractional anisotropy values. Younger patients had significantly lower fractional anisotropy than younger controls (Bonferroni-corrected alpha = 0.0042) in the left uncinate fasciculus (t(48) = 3.7, P = 0.001) and right cingulum bundle (t(48) = 3.6, P = 0.001), with considerable effect size, but the older groups did not differ. Schizophrenic patients did not demonstrate accelerated age-related decline compared with healthy controls in any white matter tract. To our knowledge, this is the first study to examine the microstructural integrity of frontotemporal white matter tracts across the adult lifespan in schizophrenia. The left uncinate fasciculus and right cingulum bundle are disrupted in younger chronic patients with schizophrenia compared with matched controls, suggesting that these white matter tracts are related to frontotemporal disconnectivity. The absence of accelerated age-related decline, or differences between older community-dwelling patients and controls, suggests that these patients may possess resilience to white matter disruption.

Early Psychosis Intervention-Spreading Evidence-based Treatment (EPI-SET): protocol for an effectiveness-implementation study of a structured model of care for psychosis in youth and emerging adults.

INTRODUCTION: While early psychosis intervention (EPI) has proliferated in recent years amid evidence of its effectiveness, programmes often struggle to deliver consistent, recovery-based care. NAVIGATE is a manualised model of EPI with demonstrated effectiveness consisting of four components: individualised medication management, individual resiliency training, supported employment and education and family education. We aim to implement NAVIGATE in geographically diverse EPI programmes in Ontario, Canada, evaluating implementation and its effect on fidelity to the EPI model, as well as individual-level outcomes (patient/family member-reported and interviewer-rated), system-level outcomes (captured in provincial administrative databases) and engagement of participants with lived experience. METHODS AND ANALYSIS: This is a multisite, non-randomised pragmatic hybrid effectiveness-implementation type III mixed methods study coordinated at the Centre for Addiction and Mental Health (CAMH) in Toronto. Implementation is supported by the Provincial System Support Program, a CAMH-based programme with provincial offices across Ontario, and Extension of Community Healthcare Outcomes Ontario Mental Health at CAMH and the University of Toronto. The primary outcome is fidelity to the EPI model as measured using the First Episode Psychosis Services-Fidelity Scale. Four hundred participants in the EPI programmes will be recruited and followed using both individual-level assessments and health administrative data for 2 years following NAVIGATE initiation. People with lived experience will be engaged in all aspects of the project, including through youth and family advisory committees. ETHICS AND DISSEMINATION: Research ethics board approval has been obtained from CAMH and institutions overseeing the local EPI programmes. Study findings will be reported in scientific journal articles and shared with key stakeholders including youth, family members, programme staff and policymakers. TRIAL REGISTRATION NUMBER: NCT03919760; Pre-results.

The MMSE is not an adequate screening cognitive instrument in studies of late-life depression.

BACKGROUND: The Mini Mental State Examination (MMSE) is frequently used to assess cognition in studies of late-life depression (LLD). However, its sensitivity and specificity in this population are largely unknown. We undertook an analysis of subjects with LLD and hypothesized that: (1) at the traditional cutoff of 24, the MMSE would have low sensitivity in the detection of cognitive impairment; (2) increasing the cutoff score would improve this sensitivity at the expense of a minimal reduction in specificity. METHODS: We analyzed the MMSE scores of 447 non-demented subjects with LLD using the Dementia Rating Scale (DRS) as the gold standard for cognitive function. RESULTS: Using the DRS raw total cutoff of 132 as the "gold standard", the MMSE at a cutoff of 24 has a sensitivity of 8.0% and a specificity of 99.4% in detecting "cognitively impaired" depressed elders. A receiver operating characteristic curve demonstrates that with an MMSE cutoff of 27 instead of 24, its sensitivity more than quadruples and increases to 37.5% while its specificity decreases minimally from 99.4% to 91.3%. CONCLUSIONS: In our sample almost all of those classified as cognitively impaired by the DRS are mislabelled as "cognitively intact" by the MMSE. By using a higher cutoff score, the sensitivity can be increased with a minimal reduction in specificity. Our findings have significant implications for those who study or treat persons with LLD or other neuropsychiatric disorders.

The impact of aging, cognition, and symptoms on functional competence in individuals with schizophrenia across the lifespan.

OBJECTIVE: Life expectancy in individuals with schizophrenia continues to increase. It is not clear whether cognitive deficits associated with schizophrenia remain as strong predictors of function in older and younger individuals. Thus, we assessed the relationship between cognition and functional competence in individuals with schizophrenia across 7 decades of life. METHODS: We analyzed data obtained in 232 community-dwelling participants with schizophrenia (age range: 19-79 years). Cognition was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. Functional competence was assessed using the UCSD Performance-based Skills Assessment, which includes measures of Comprehension and Planning of Recreational Activities Skills, Financial Skills, Communication Skills, Transportation Skills, and Household Management Skills. To assess the effects of Global Cognition on functional competence, we performed hierarchical multivariate linear or logistic regression analyses controlling for age, education, gender, and negative symptoms. RESULTS: Participants' mean age was 49.1 (SD = 13.2, range = 19-79 years), 161 (69%) were male, and 55 (24%) were aged ≥60. Global Cognition was a predictor of Comprehension and Planning Skills (Exp(ß) = 1.048), Financial Skills (Exp(ß) = 1.104), Communication Skills (ΔR (2) = .31) and Transportation Skills (Exp(ß) = 1.066), but not Household Management Skills after adjusting for age, education, gender, and negative symptoms of schizophrenia. CONCLUSION: Cognition remains a strong predictor of functional competence across the lifespan. These findings suggest that treating cognitive impairment associated with schizophrenia could improve individuals' function independent of their age.

Cognition, function, and disability in patients with schizophrenia: a review of longitudinal studies.

This paper aims to review longitudinal studies assessing the impact of cognition on function in patients with schizophrenia. PubMed and Scholars Portal were searched using search terms related to schizophrenia, cognition, function, and longitudinal studies. Some functional abilities have been studied more than others. Some studies suggest that the impact of cognition on function depends on the severity of baseline cognitive deficits. Other studies suggest that the impact of cognition on function depend on what phase of the illness the patient is in or what stage in that particular function the patient is involved in. Finally, few studies assessed interactions between cognition and other aspects of schizophrenia in predicting function, such as functional capacity, insight, motivation, and negative symptoms. More longitudinal and comprehensive studies are needed. A focus on community living is of high public significance as patients with schizophrenia continue to grow old. Future studies should also focus on the longitudinal interactions between cognition and other dimensions of schizophrenia as well as on the biological factors that underlie these interactions.

Cet article vise à examiner les études longitudinales évaluant l'effet de la cognition sur la fonction des patients souffrant de schizophrénie. Des recherches ont été effectuées dans PubMed et Scholars Portal à l'aide de mots clés liés à la schizophrénie, la cognition, la fonction, et les études longitudinales. Certaines capacités fonctionnelles ont été étudiées plus que d'autres. Des études suggèrent que l'effet de la cognition sur la fonction dépend de la gravité des déficits cognitifs au départ. D'autres études font valoir que l'effet de la cognition sur la fonction dépend de la phase de la maladie ou du stade de cette fonction où se situe le patient. Enfin, peu d'études ont évalué les interactions entre cognition et autres aspects de la schizophrénie pour prédire la fonction, comme la capacité fonctionnelle, l'intuition, la motivation, et les symptômes négatifs. Il faut plus d'études longitudinales et exhaustives. Mettre l'accent sur la vie dans la communauté est d'une grande importance publique car les patients souffrant de schizophrénie continuent de vieillir. Les futures études devraient aussi se pencher sur les interactions longitudinales entre la cognition et d'autres dimensions de la schizophrénie, ainsi que sur les facteurs biologiques qui sous-tendent ces interactions.

Age-related decline in white matter tract integrity and cognitive performance: a DTI tractography and structural equation modeling study.

Age-related decline in microstructural integrity of certain white matter tracts may explain cognitive decline associated with normal aging. Whole brain tractography and a clustering segmentation in 48 healthy individuals across the adult lifespan were used to examine: interhemispheric (corpus callosum), intrahemispheric association (cingulum, uncinate, arcuate, inferior longitudinal, inferior occipitofrontal), and projection (corticospinal) fibers. Principal components analysis reduced cognitive tests into 6 meaningful factors: (1) memory and executive function; (2) visuomotor dexterity; (3) motor speed; (4) attention and working memory; (5) set-shifting/flexibility; and (6) visuospatial construction. Using theory-based structural equation modeling, relationships among age, white matter tract integrity, and cognitive performance were investigated. Parsimonious model fit demonstrated relationships where decline in white matter integrity may explain age-related decline in cognitive performance: inferior longitudinal fasciculus (ILF) with visuomotor dexterity; the inferior occipitofrontal fasciculus with visuospatial construction; and posterior fibers (i.e., splenium) of the corpus callosum with memory and executive function. Our findings suggest that decline in the microstructural integrity of white matter fibers can account for cognitive decline in normal aging.

Cholinergic pathways and cognition in patients with schizophrenia: a pilot study.

BACKGROUND: Cognitive deficits are core features in schizophrenia. Disruption in cholinergic neurotransmission has been associated with executive dysfunction in animals and humans. The objective of this study was to evaluate the impact of compromised cholinergic pathways on executive versus non-executive cognitive functions of patients with schizophrenia. METHODS: 62 patients with schizophrenia and 62 age- and sex-matched non-psychiatric control subjects ("controls") were assessed and compared using: clinical measures, cognitive measures of global cognition, executive function, and memory; and an MRI-based visual rating scale that assesses damage strategically localized within the cholinergic pathways. RESULTS: 11 of the 62 patients with schizophrenia (17.7%) and 6 of the 62 controls (9.7%) had compromised cholinergic pathways. These proportions were not statistically significant. Patients and controls with compromised cholinergic pathways were more impaired on measures related to executive function than patients or controls without compromised pathways. CONCLUSIONS: Patients with schizophrenia have worse executive function than controls. Compromised cholinergic pathways appear to worsen the executive dysfunction observed in schizophrenia. If these preliminary findings are replicated, they could lead to the identification of a subgroup of patients with schizophrenia who could specifically benefit from interventions enhancing cholinergic neurotransmission.

The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease.

CONTEXT: The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the BDNF gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which BDNF gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder. OBJECTIVE: To determine whether the BDNF Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance. DESIGN: A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING: University hospital. PARTICIPANTS: A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES: The BDNF Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated. RESULTS: The BDNF Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility. CONCLUSIONS: The BDNF gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD.

The ZNF804A gene: characterization of a novel neural risk mechanism for the major psychoses.

Schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant's potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant ('A' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder.

Differentiating the cognitive profile of schizophrenia from that of Alzheimer disease and depression in late life.

BACKGROUND: To compare the cognitive profile of older patients with schizophrenia to those with other neuropsychiatric disorders assessed in a hospital-based memory clinic. METHODS: Demographic, clinical, and cognitive data of all patients referred to the memory clinic at the Centre for Addiction and Mental Health between April 1, 2006 and August 15, 2008 were reviewed. We then identified four groups of older patients with: (1) late-life schizophrenia (LLS) and no dementia or depression (DEP); (2) Alzheimer's disease (AD); (3) DEP and no dementia or LLS; (4) normal cognition (NC) and no DEP or LLS. RESULTS: The four groups did not differ in demographic data except that patients with AD were about 12 years older than those with LLS. However, they differed on cognitive tests even after controlling for age. Patients with LLS were impaired on most cognitive tests in comparison with patients with NC but not on recalling newly learned verbal information at a short delay. They experienced equivalent performance on learning new verbal information in comparison with patients with AD, but better performance on all other tests of memory, including the ability to recall newly learned verbal information. Finally, they were more impaired than patients with DEP in overall memory. CONCLUSIONS: Patients with LLS have a different cognitive profile than patients with AD or DEP. Particularly, memory impairment in LLS seems to be more pronounced in learning than recall. These findings suggest that cognitive and psychosocial interventions designed to compensate for learning deficits may be beneficial in LLS.