Is the Association Between Education and Cognitive Resilience Modified by Brain Weight and Cortical Atrophy?

Introduction: Some individuals are able to avoid reaching the threshold for clinical dementia despite the presence of Alzheimer neuropathology. This disparity between the neuropathologic and clinical symptoms required for a diagnosis of AD is often attributed to cognitive resilience, defined in the current study as the combined influence of brain reserve and cognitive reserve. This study assessed how educational attainment (a common measure of cognitive reserve), as well as brain weight and cortical atrophy (measures of brain reserve), may influence the outcome of cognitive resilience independently or through interactions with each other. Methods: Analyses were based on the Nun Study, a longitudinal study of aging in 678 participants aged 75+ years at baseline. Educational attainment data were available through convent archives while brain weight and cortical atrophy data were collected through post mortem autopsies. Alzheimer neuropathology was assessed through post mortem autopsies and was defined using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) and National Institute on Aging and Reagan Institute (NIA-RI) neuropathologic criteria. Finally, dementia status was determined through annual cognitive testing using DSM-IV criteria. Logistic regression analyses were conducted to assess all associations between exposures (educational attainment, brain weight and cortical atrophy) and the outcome (cognitive resilience), controlling for participant age at the time of death and the presence of apolipoprotein E-ε4. Results: Higher educational attainment and brain weight, and the absence of cortical atrophy were all positively associated with cognitive resilience defined using both CERAD and NIA-RI neuropathologic criteria. However, the negative association between cortical atrophy and cognitive resilience was significant only when brain weights were high. When brain weight and educational attainment were assessed in the same models, the influence of educational attainment fell below statistical significance. Finally, when educational attainment was assessed in models stratified by cortical atrophy status, it remained significant only in the presence of mild atrophy. Discussion: It was hypothesized that higher educational attainment, higher brain weight and the absence of cortical atrophy would all be positively associated with cognitive resilience. These hypotheses were supported by findings in the study. Further, it was hypothesized that the impacts of mild atrophy would be more significant among individuals with lower brain weights than among those with higher brain weights, as higher brain weight would act as a buffer against mild atrophy. However, findings were contrary to this hypothesis, with results suggesting that atrophy was only significant when brain weights were high. This non-significant effect is likely partially related to low statistical power in the low brain weight strata. However, this result may additionally be the result of a floor effect whereby low brain weight depletes brain reserve to such an extent that further loss in tissue (through cortical atrophy) is unlikely to result in further impairment. Finally, it was hypothesized that educational attainment would be most strongly associated with cognitive resilience when brain reserve was low (i.e., in the presence of cortical atrophy or low brain weight). This hypothesis was partially supported by findings indicating that when mild atrophy was present, low educational attainment was associated with reduced odds of resilience. Overall, it appears that cognitive reserve factors (educational attainment) are important in reducing the clinical symptoms of AD in late life; however, these positive effects were only found when threats to brain reserve (cortical atrophy, low brain weight) were absent or of mild severity. Conclusion: Higher levels of education can improve cognitive reserve and help reduce the risk of dementia symptoms despite AD brain changes. These benefits are only realized, however, when low brain weight and cortical atrophy are avoided. This study and future efforts aimed at better understanding how late-life cognitive resilience is influenced by factors from across the lifespan could inform applications of cognitive resilience theory to clinical and community settings with the goal of offsetting the devastating impacts of AD

Deviant cortical sulcation related to schizophrenia and cognitive deficits in the second trimester

Aberrant cortical development, inferred from cortical folding, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the timing of the prenatal insult linked to schizophrenia and the cognitive impairment seen in this illness. Anatomical MRI scans from 68 patients with schizophrenia and 72 controls were used to evaluate the sulcal depth of five major invariable primary sulci representing lobar development (calcarine sulcus, superior temporal sulcus, superior frontal sulcus, intraparietal sulcus and inferior frontal sulcus) with formation representing the distinct developmental periods. A repeated-measure ANOVA with five sulci and two hemispheres as the within-subject factors and gender, age and intracranial volume as covariates revealed a significant effect of diagnosis (F[1,134] = 14.8, p = 0.0002). Control subjects had deeper bilateral superior temporal, right inferior frontal and left calcarine sulci. A deeper superior frontal sulcus predicted better cognitive scores among patients. Our results suggest that the gestational disruption underlying schizophrenia is likely to predate, if not coincide with the appearance of calcarine sulcus (early second trimester). Nevertheless, the burden of cognitive deficits may relate specifically to the aberrant superior frontal development apparent in late second trimester

Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate

Early response to antipsychotic medications is one of the most important determinants of later symptomatic and functional outcomes in psychosis. Glutathione and glutamate have emerged as promising therapeutic targets for patients demonstrating inadequate response to dopamine-blocking antipsychotics. Nevertheless, the role of these neurochemicals in the mechanism of early antipsychotic response remains poorly understood. Using a longitudinal design and ultrahigh field 7-T magnetic resonance spectroscopy (MRS) protocol in 53 subjects, we report the association between dorsal anterior cingulate cortex glutamate and glutathione, with time to treatment response in drug naive (34.6% of the sample) or minimally medicated first episode patients with schizophreniform disorder, schizophrenia, and schizoaffective disorder. Time to response was defined as the number of weeks required to reach a 50% reduction in the PANSS-8 scores. Higher glutathione was associated with shorter time to response (F = 4.86, P = 0.017), while higher glutamate was associated with more severe functional impairment (F = 5.33, P = 0.008). There were no significant differences between patients and controls on measures of glutamate or glutathione. For the first time, we have demonstrated an association between higher glutathione and favorable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis

Progressive changes in descriptive discourse in First Episode Schizophrenia: a longitudinal computational semantics study

Computational semantics, a branch of computational linguistics, involves automated meaning analysis that relies on how words occur together in natural language. This offers a promising tool to study schizophrenia. At present, we do not know if these word-level choices in speech are sensitive to the illness stage (i.e., acute untreated vs. stable established state), track cognitive deficits in major domains (e.g., cognitive control, processing speed) or relate to established dimensions of formal thought disorder. In this study, we collected samples of descriptive discourse in patients experiencing an untreated first episode of schizophrenia and healthy control subjects (246 samples of 1-minute speech; n = 82, FES = 46, HC = 36) and used a co-occurrence based vector embedding of words to quantify semantic similarity in speech. We obtained six-month follow-up data in a subsample (99 speech samples, n = 33, FES = 20, HC = 13). At baseline, semantic similarity was evidently higher in patients compared to healthy individuals, especially when social functioning was impaired; but this was not related to the severity of clinically ascertained thought disorder in patients. Across the study sample, higher semantic similarity at baseline was related to poorer Stroop performance and processing speed. Over time, while semantic similarity was stable in healthy subjects, it increased in patients, especially when they had an increasing burden of negative symptoms. Disruptions in word-level choices made by patients with schizophrenia during short 1-min descriptions are sensitive to interindividual differences in cognitive and social functioning at first presentation and persist over the early course of the illness

Widespread cortical thinning, excessive glutamate and impaired linguistic functioning in schizophrenia: A cluster analytic approach

Introduction: Symptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structure, is suspected in schizophrenia, we aimed to first seek patient subgroups with different neurobiological signatures and then quantify linguistic indices that capture the symptoms of “negative formal thought disorder” (i.e., fluency, cohesion, and complexity of language production). Methods: Atlas-based cortical thickness values (obtained with a 7T MRI scanner) of 66 patients with first-episode psychosis and 36 healthy controls were analyzed with hierarchical clustering algorithms to produce neuroanatomical subtypes. We then examined the generated subtypes and investigated the quantitative differences in MRS-based glutamate levels [in the dorsal anterior cingulate cortex (dACC)] as well as in three aspects of language production features: fluency, syntactic complexity, and lexical cohesion. Results: Two neuroanatomical subtypes among patients were observed, one with near-normal cortical thickness patterns while the other with widespread cortical thinning. Compared to the subgroup of patients with relatively normal cortical thickness patterns, the subgroup with widespread cortical thinning was older, with higher glutamate concentration in dACC and produced speech with reduced mean length of T-units (complexity) and lower repeats of content words (lexical cohesion), despite being equally fluent (number of words). Conclusion: We characterized a patient subgroup with thinner cortex in first-episode psychosis. This subgroup, identifiable through macroscopic changes, is also distinguishable in terms of neurochemistry (frontal glutamate) and language behavior (complexity and cohesion of speech). This study supports the hypothesis that glutamate-mediated cortical thinning may contribute to a phenotype that is detectable using the tools of computational linguistics in schizophrenia

Glutamate and Dysconnection in the Salience Network: Neurochemical, Effective Connectivity, and Computational Evidence in Schizophrenia

Background: Functional dysconnection in schizophrenia is underwritten by a pathophysiology of the glutamate neurotransmission that affects the excitation-inhibition balance in key nodes of the salience network. Physiologically, this manifests as aberrant effective connectivity in intrinsic connections involving inhibitory interneurons. In computational terms, this produces a pathology of evidence accumulation and ensuing inference in the brain. Finally, the pathophysiology and aberrant inference would partially account for the psychopathology of schizophrenia as measured in terms of symptoms and signs. We refer to this formulation as the 3-level hypothesis. Methods: We tested the hypothesis in core nodes of the salience network (the dorsal anterior cingulate cortex [dACC] and the anterior insula) of 20 patients with first-episode psychosis and 20 healthy control subjects. We established 3-way correlations between the magnetic resonance spectroscopy measures of glutamate, effective connectivity of resting-state functional magnetic resonance imaging, and correlations between measures of this connectivity and estimates of precision (inherent in evidence accumulation in the Stroop task) and psychopathology. Results: Glutamate concentration in the dACC was associated with higher and lower inhibitory connectivity in the dACC and in the anterior insula, respectively. Crucially, glutamate concentration correlated negatively with the inhibitory influence on the excitatory neuronal population in the dACC of subjects with first-episode psychosis. Furthermore, aberrant computational parameters of the Stroop task performance were associated with aberrant inhibitory connections. Finally, the strength of connections from the dACC to the anterior insula correlated negatively with severity of social withdrawal. Conclusions: These findings support a link between glutamate-mediated cortical disinhibition, effective-connectivity deficits, and computational performance in psychosis

Microstructural imaging and transcriptomics of the basal forebrain in first-episode psychosis

Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, \u3c2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n = 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (p \u3e 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia

Prognostic indicators of functional outcome in first episode psychosis: Linguistic, Anatomical, and Metabolic Predictors of Early Social and Vocational Outcome

A significant cause of disease related burden in schizophrenia relates to reductions in social and occupational functioning. Thus, understanding the variables that are associated with good versus poor functional prognosis is key to improving overall patient outcomes. This dissertation assessed the associations between baseline variables and later occupational and social deficits in the first year of treatment. In chapter 1, we used automated linguistic analysis software programs to determine if elements of speech production were aberrant in patients versus healthy controls. These features were then entered into a prototypical constraint-based algorithm to identify any dependencies with vocational inactivity (NEET), or scores on the Social and Occupational Functioning Assessment Scale (SOFAS). Only reduced speech (lower total words spoken) explained worsened occupational and community functioning. In chapter 2 we assessed whether baseline cortical thickness or local gyrification index (LGI) were associated with baseline clinical severity and later social and vocational status. We identified increased gyrification in frontal and parietal regions to be associated with increased symptom burden at baseline, as well as with a higher status of vocational inactivity following treatment. Finally, we assessed whether central anti-oxidant tone measured in-vivo was associated with better social and vocational outcomes, revealing an association between higher glutathione levels at baseline and improved functional outcomes in the first year of treatment. By elucidating these mechanisms within early psychosis samples, clinicians may be able to augment standard treatment paradigms to improve outcomes among patients at risk of poor treatment response

Deviant cortical sulcation related to schizophrenia and cognitive deficits in the second trimester

Aberrant cortical development, inferred from cortical folding, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the timing of the prenatal insult linked to schizophrenia and the cognitive impairment seen in this illness

Linguistic determinants of formal thought disorder in first episode psychosis

Aim: Thought disorder is a core feature of schizophrenia but assessment of disordered thinking is challenging, which may contribute to the paucity of mechanistic understanding of disorganization in early psychosis. We studied the use of linguistic connectives in relation to clinically quantified dimensions of thought disorder using automated speech analysis in untreated, first episode psychosis (FEPs) and healthy controls (HCs). Methods: 39 treatment-naïve, actively psychotic FEPs and 23 group matched HCs were recruited. Three one-minute speech samples were induced in response to photographs from the Thematic Apperception Test and speech was analysed using COH-METRIX software. Five connectives variables from the Coh-Metrix software were reduced using principle component analysis, resulting in two linguistic connectives factors. Thought disorder was assessed using the Thought Language Index (TLI) and the PANSS-8. Results: Connective factors predicted disorganization, but not impoverishment suggesting aberrant use of connectives is specific to positive thought disorder. An independent t test comparing low and high disorganization FEPs showed higher load of acausal temporal connectives in high disorganization FEPs compared to low disorganization FEPs (mean [SD] in high vs low disorganization FEPs = 0.64 (1.1) vs -0.37 (1.02); t = 2.91, P =.006). Acausal-temporal connectives were not correlated with severity of symptoms or cognition suggesting connective use is a specific index of disorganized thinking rather than overall illness status. Conclusions: Clinical assessment of disorganization in psychosis is likely linked to the aberrant use of connectives resulting in an intuitive sense of incoherence. In early psychosis, thought disorder may be reliably quantifiable using automated syntax analysis