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In addition to Alzheimer's disease (AD), the hippocampus is now known to be affected in variants of frontotemporal degeneration (FTD). In semantic variant primary progressive aphasia (svPPA), characterized by language impairments, hippocampal atrophy is greater in the left hemisphere. Nonverbal impairments (e.g., visual object recognition) are prominent in the right temporal variant of FTD (rtvFTD), and hippocampal atrophy may be greater in the right hemisphere. In this study we examined the hypothesis that leftward hippocampal asymmetry (predicted in svPPA) would be associated with selective verbal memory impairments (with relative preservation of visual memory), while rightward asymmetry (predicted in rtvFTD) would be associated with the opposite pattern (greater visual memory impairment). In contrast, we predicted that controls and individuals in the amnestic mild cognitive impairment stage of AD (aMCI), both of whom were expected to show symmetrical hippocampal volumes, would show roughly equivalent scores in verbal and visual memory. Participants completed delayed recall tests with words and geometric shapes, and hippocampal volumes were assessed with MRI. The aMCI sample showed symmetrical hippocampal atrophy, and similar degree of verbal and visual memory impairment. The svPPA sample showed greater left hippocampal atrophy and verbal memory impairment, while rtvFTD showed greater right hippocampal atrophy and visual memory impairment. Greater asymmetry in hippocampal volumes was associated with larger differences between verbal and visual memory in the FTD samples. Unlike AD, asymmetry is a core feature of brain-memory relationships in temporal variants of FTD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hurley, Lapin, Jones, Crawford, Leverenz, Bonner-Jackson and Pillai.)

Objective: Quantify cognitive deficits in patients with postacute sequelae of COVID-19 (PASC) and identify key variables related to cognitive impairment in PASC., Method: Patients with polymerase chain reaction-confirmed COVID-19 underwent a comprehensive neuropsychological evaluation. The comparison group included patients without neurological disorders determined by the neuropsychologist to be cognitively intact. Cognitive impairment was defined as impairment (Composite T ≤35) in 1 of 6 cognitive domains. The PASC group was split into impaired or intact based on the above criteria. Multivariable logistic regression models assessed predictors including demographics, COVID-19 severity, clinical characteristics, and mood., Results: There were 210 patients with PASC, predominantly female (73.3%, P < .001), without other demographic differences when compared with 369 normal controls. Patients with PASC were more likely to have cognitive impairment (odds ratio 3.61; 95% confidence interval, 2.36-5.54; P < .001) compared with controls, with significantly lower scores in domains of memory, language, processing speed, visuospatial function, executive function (P < .001), and higher depressive (P = .004) and anxiety symptoms (P = .003). Patients with PASC who demonstrated cognitive impairment (n = 93) had higher body mass index compared with those with PASC without cognitive impairment (n = 117), without differences in other predictors., Conclusion: Patients with PASC are almost 4 times more likely to evidence cognitive dysfunction compared with normal controls. Forty-four percent of patients with PASC demonstrated cognitive deficits about 7 months from infection. Estimated premorbid intelligence significantly correlated with impairment. Higher body mass index was the only metric shown to differentiate those with PASC and cognitive impairment from those with PASC who were cognitively intact., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: A subset of individuals with coronavirus disease 2019 (COVID-19) appears to develop persisting cognitive and medical symptoms. Research in the acute stages of illness, generally utilizing cognitive screening measures or case reports, suggests presence of deficits in attention and executive function. This observational study investigated cognitive functioning among individuals with persistent cognitive complaints about 5.5 months after COVID-19 infection., Methods: Patients with polymerase chain reaction confirmed COVID-19 and persistent cognitive complaints underwent comprehensive in-person neuropsychological evaluations. Patients with prior neurological disorders were excluded. When diagnosed, 40% required hospitalization, 15% were in an intensive care unit, 10% needed mechanical ventilation, and 10% experienced delirium., Results: This sample was predominately women (90%), White non-Hispanic (70%), with average education of 15 years. Mild cognitive deficits were seen on tests involving attention and processing speed or executive function. Seventy percent of patients were diagnosed with a mood disorder prior to COVID-19 infection. At the time of testing, 35%-40% endorsed moderate to severe mood symptoms and 85% noted significant fatigue as measured by the Fatigue Severity Scale., Conclusions: The pattern of cognitive deficits, although mild, is consistent with prior research at the acute stage of the illness. These findings suggest that psychological factors and other persisting symptoms (e.g., sleep, fatigue) may play a significant role in subjective cognitive complaints in patients with persisting complaints post COVID-19 who did not require intensive treatment. These patients would likely benefit from resources to manage persisting or new mood symptoms and compensatory strategies for the cognitive inefficiencies they experience., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP)., Methods: A retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer's Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score ≤ 1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ε4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups., Results: One thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ε4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7-2.14, p = 0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47-0.96, p = 0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ε4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02-110.62, p < 0.0001], while no difference was noted for initial executive/attention symptoms. Among LRP, the odds of APOE ε4 on amnestic symptom was not significant; however, the interaction effect evaluating the difference in odds ratios of amnestic symptom between ADP and LRP groups also did not reach statistical significance., Conclusions: The odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ε4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ε4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ε4 carriers. This supports the hypothesis that APOE ε4 differentially impacts initial cognitive symptoms together with underlying neuropathology.

Objective: To determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration., Methods: A longitudinal study of MCI-AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty-three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform. Inflammatory analytes that predict clinical progression on Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Mini Mental State Exam scores were assessed in multivariate regression models. To provide context, key analyte results in ADNI were compared against biomarkers of neurodegeneration, hippocampal volume, and CSF neurofilament light (NfL), in receiver operating characteristic (ROC) analyses evaluating highest quartile of CDR-SB change over two years (≥3 points)., Results: Cerebrospinal fluid inflammatory analytes in relation to cognitive decline were best described by gene ontology terms, natural killer cell chemotaxis, and endothelial cell apoptotic process and in plasma, extracellular matrix organization, blood coagulation, and fibrin clot formation described the analytes. CSF CCL2 was most robust in predicting rate of cognitive change and analytes that correlated to CCL2 suggest IL-10 pathway dysregulation. The ROC curves for ≥3 points change in CDR-SB over 2 years when comparing baseline hippocampal volume, CSF NfL, and CCL2 were not significantly different., Interpretation: Baseline levels of immune cell chemotactic cytokine CCL2 in the CSF and IL-10 pathway dysregulation impact longitudinal cognitive and functional decline in MCI-AD. CCL2's utility appears comparable to biomarkers of neurodegeneration in predicting rapid decline., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer's disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels., Objective: We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD., Methods: Retrospective comparative case study of 97 patients evaluated in a memory clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOEɛ4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates., Results: Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOEɛ4, MoCA, and CSF Aβ42. Logopenic AD had higher t-tau and p-tau levels compared to other variants., Conclusions: Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant.

Purpose: To investigate outer retinal parameters among patients with various chronic neurodegenerative disorders by using spectral-domain coherence tomography (OCT) in a prospective cross-sectional cohort study., Methods: A total of 132 participants were enrolled following a comprehensive diagnostic evaluation with neurologic, neuropsychology, and magnetic resonance imaging volumetric evaluations. Participants were 50 years or older, either diagnosed with Alzheimer's disease (AD) dementia, amnestic mild cognitive impairment (MCI), non-AD dementia, Parkinson's disease (PD), or age- and sex-matched controls. All participants underwent a macular cube scan for both eyes by using the Cirrus 4000 HD-OCT (Zeiss, Oberkochen, Germany). The OCT image with the best quality was selected for further analysis. Outer retinal parameters including ellipsoid zone mapping and outer nuclear layer metrics were evaluated with a novel software platform., Results: One hundred twenty-four eyes of 124 participants with AD dementia (24 eyes), amnestic MCI (22 eyes), non-AD dementia (20 eyes), PD (22 eyes), and age- and sex-matched controls (36 eyes) were included in the analysis. Eight eyes were excluded either due to the presence of macular disease or poor quality of the OCT image. The mean ages of participants were 65.9 ± 8.9 years. The outer retinal thickness measures did not show any statistical significance between the groups. However, ellipsoid zone to retinal pigment epithelium volume correlated with cognitive testing scores in all study participants., Conclusions: There were no identifiable differences in the outer retinal metrics across neurodegenerative disease groups and controls. The relationship between the degree of cognitive impairment and ellipsoid zone to retinal pigment epithelium volume warrants further study.

Background: How accurate are mild cognitive impairment (MCI) patients in assessing their cognitive and functional deficit is often unclear to the clinician. The accuracy of patient self-appraisal in Parkinson's disease-MCI (PD-MCI) has received less attention than amnestic MCI (a-MCI) often associated with Alzheimer's disease. We evaluated if PD-MCI patients demonstrate accurate self-appraisal of their cognitive deficits compared to patients with amnestic a-MCI or non-amnestic MCI (na-MCI)., Methods: This cross-sectional cohort study included, 30 PD-MCI, 33 a-MCI, and 17 na-MCI patients. Self-appraisal was assessed by comparing responses of caregivers and patients on a validated self-rating questionnaire of cognitive and functional impairments. All patients completed a full neuropsychological evaluation and depression screening measure. Univariate ANOVA, regression, and correlational analyses were employed to identify group differences in self-appraisal scores and relationships between cognitive and functional impairment, depression measures, and self-appraisal scores., Results: Self-appraisal scores for PD-MCI did not differ significantly from a-MCI and na-MCI. In the PD-MCI group, higher depression scores were associated with lower self-appraisal scores (i.e, patients assessed cognition as worse than caregivers). In a stepwise regression model with self-appraisal scores as the dependent variable, only the depression score was significant predictor among PD-MCI and accounted for 50% of the variance., Conclusions: Our findings suggest that impaired patient self-appraisal is equally likely to occur in PD-MCI as in a-MCI and na-MCI patients. Among PD-MCI, depression was the strongest predictor of impaired patient self-appraisal. Impaired insight into cognitive impairment and depression should be considered in both care and research with PD patients.

Objectives: Diffusivity in white-matter tracts is abnormal throughout the brain in cross-sectional studies of prodromal Huntington's disease. To date, longitudinal changes have not been observed. The present study investigated cross-sectional and longitudinal changes in white-matter diffusivity in relationship to the phase of prodromal Huntington's progression, and compared them with changes in brain volumes and clinical variables that track disease progression., Methods: Diffusion MRI profiles were studied for 2 years in 37 gene-negative controls and 64 prodromal Huntington's disease participants in varied phases of disease progression. To estimate the relative importance of diffusivity metrics in the prodromal phase, group effects were rank ordered relative to those obtained from analyses of brain volumes, motor, cognitive, and sensory variables., Results: First, at baseline diffusivity was abnormal throughout all tracts, especially as individuals approached a manifest Huntington's disease diagnosis. Baseline diffusivity metrics in 6 tracts and basal ganglia volumes best distinguished among the groups. Second, group differences in longitudinal change in diffusivity were localized to the superior fronto-occipital fasciculus, most prominently in individuals closer to a diagnosis. Group differences were also observed in longitudinal changes of most brain volumes, but not clinical variables. Last, increases in motor symptoms across time were associated with greater changes in the superior fronto-occipital fasciculus diffusivity and corpus callosum, cerebrospinal fluid, and lateral ventricle volumes., Conclusions: These novel findings provide new insights into changes within 2 years in different facets of brain structure and their clinical relevance to changes in symptomatology that is decisive for a manifest Huntington's diagnosis. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL) thickness, and macular volume (MV) utilizing spectral domain optical coherence tomography (SD-OCT) were compared among patients with Alzheimer's disease (AD) dementia, non-Alzheimer's disease (non-AD) dementia, amnestic mild cognitive impairment (aMCI), Parkinson's disease (PD), and age- and sex-matched controls in a cross-sectional cohort study. A total of 116 participants were diagnosed and evaluated (21 AD, 20 aMCI, 20 non-AD, 20 PD, and 34 controls) after comprehensive neurological, neuropsychology, and magnetic resonance imaging (MRI) volumetric evaluations. Retinal nerve fiber layer thickness, GCL thickness, and MV were measured. Analysis of variance models were used to compare groups on MRI volumetric measures, cognitive test results, and SD-OCT measures. Associations between SD-OCT measures and other measures were performed using mixed-effect models. Spectral domain optical coherence tomography analysis of retinal markers, including RNFL thickness, GCL thickness, and MV, did not differ between amnestic MCI, AD dementia, PD, non-AD, dementia, and age- and sex-matched controls in a well-characterized patient cohort., (© The Author(s) 2016.)

Aims: We examined the effect of vascular or Lewy body co-pathologies in subjects with autopsy-confirmed Alzheimer's disease (AD) on the rate of cognitive and functional decline and transition to dementia., Methods: In an autopsy sample of prospectively characterized subjects from the National Alzheimer's Coordinating Center database, neuropathology diagnosis was used to define the groups of pure AD (pAD, n = 84), mixed vascular and AD (ADV, n = 54), and mixed Lewy body disease and AD (ADLBD, n = 31). Subjects had an initial Clinical Dementia Rating-Global (CDR-G) score <1, Mini-Mental State Examination ≥15, a final visit CDR-G >1, ≥3 evaluations, and Braak tangle stage ≥III. We compared the rate of cognitive and functional decline between the groups., Results: The rate of functional and cognitive decline was lower for ADV, and ADV patients had less severe deficits on CDR-G and the CDR-Sum of Boxes scores at the last visit than pAD and ADLBD patients. No significant differences were noted between ADLBD and pAD patients. After controlling for age at death, the odds of reaching CDR ≥1 at the last visit were lower in the ADV subjects compared to the pAD subjects., Conclusions: The mean rate of functional and cognitive decline among ADV subjects was slower than among either pAD or ADLBD patients. Vascular pathology did not increase the odds of attaining CDR ≥1 when occurring with AD in this national cohort., (© 2016 S. Karger AG, Basel.)

Introduction: Better characterization of the relationship between episodic memory and hippocampal volumes is crucial in early detection of neurodegenerative disease. We examined these relationships in a memory clinic population., Methods: Participants (n = 226) underwent structural magnetic resonance imaging and tests of verbal (Hopkins Verbal Learning Test-Revised, HVLT-R) and non-verbal (Brief Visuospatial Memory Test-Revised, BVMT-R) memory. Correlational analyses were performed, and analyses on clinical subgroups (i.e., amnestic Mild Cognitive Impairment, non-amnestic Mild Cognitive Impairment, probable Alzheimer's disease, intact memory) were conducted., Results: Positive associations were identified between bilateral hippocampal volumes and both memory measures, and BVMT-R learning slope was more strongly positively associated with hippocampal volumes than HVLT-R learning slope. Amnestic Mild Cognitive Impairment (aMCI) participants showed specific positive associations between BVMT-R performance and hippocampal volumes bilaterally. Additionally, analyses of the aMCI group showed trend-level evidence of material-specific lateralization, such that retention of verbal information was positively associated with left hippocampal volume, whereas learning curve and retention of non-verbal information was positively associated with right hippocampal volume., Conclusions: Findings support the link between episodic memory and hippocampal volumes in a memory clinic population. Non-verbal memory measures also may have higher diagnostic value, particularly in individuals at elevated risk for Alzheimer's disease.

Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer's disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65-85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Detecting and monitoring early cognitive impairment in Alzheimer's disease (AD) is a significant need in the field of AD therapeutics. Successful AD clinical trial designs have to overcome challenges related to the subtle nature of early cognitive changes. Continuous unobtrusive assessments using Information and Communication Technology (ICT) devices to capture markers of intra-individual change over time to assess cognitive and functional disability therefore offers significant benefits. We review the literature and provide an overview on randomized clinical trials in AD that use intelligent systems to monitor functional decline, as well as strengths, weaknesses, and future directions for the use of ICTs in a new generation of AD clinical trials.

Background: There is heterogeneity in the pattern of early cognitive deficits in Alzheimer's disease (AD). However, whether the severity of initial cognitive deficits relates to different clinical trajectories of AD progression is unclear., Objective: To determine if deficits in specific cognitive domains at the initial visit relate to the rate of progression in clinical trajectories of AD dementia., Methods: 68 subjects from the National Alzheimer's Coordinating Center database who had autopsy-confirmed AD as the primary diagnosis and at least 3 serial assessments a year apart, with a Mini-Mental State Examination (MMSE) score >15 and a Clinical Dementia Rating Scale-Global (CDR-G) score ≤1 at the initial visit were included. A mixed regression model was used to examine the association between initial neuropsychological performance and rate of change on the MMSE and CDR Sum of Boxes., Results: Preservation of working memory, but not episodic memory, in the mild cognitive impairment and early dementia stages of AD relates to slower rate of functional decline., Discussion: These findings are relevant for estimating the rate of decline in AD clinical trials and in counseling patients and families. Improving working memory performance as a possible avenue to decrease the rate of functional decline in AD dementia warrants closer investigation., (© 2014 S. Karger AG, Basel.)

Huntington disease (HD) is associated with decline in cognition and progressive morphological changes in brain structures. Cognitive reserve may represent a mechanism by which disease-related decline may be delayed or slowed. The current study examined the relationship between cognitive reserve and longitudinal change in cognitive functioning and brain volumes among prodromal (gene expansion-positive) HD individuals. Participants were genetically confirmed individuals with prodromal HD enrolled in the PREDICT-HD study. Cognitive reserve was computed as the composite of performance on a lexical task estimating premorbid intellectual level, occupational status, and years of education. Linear mixed effects regression (LMER) was used to examine longitudinal changes on four cognitive measures and three brain volumes over approximately 6 years. Higher cognitive reserve was significantly associated with a slower rate of change on one cognitive measure (Trail Making Test, Part B) and slower rate of volume loss in two brain structures (caudate, putamen) for those estimated to be closest to motor disease onset. This relationship was not observed among those estimated to be further from motor disease onset. Our findings demonstrate a relationship between cognitive reserve and both a measure of executive functioning and integrity of certain brain structures in prodromal HD individuals.

Background: Recent work has demonstrated the potentially protective effects of the apolipoprotein E (APOE) ε2 allele on cognitive functioning in individuals at risk for developing Alzheimer disease. However, little is known regarding the effect of ε2 genotype on rate of change in daily functioning over time. The aim of the current study was to examine the relationship between APOE genotype and change over time in ability to perform daily activities., Methods: We examined the relationship between APOE genotype and change in the ability to perform activities of daily living at 12- and 24-month intervals in 225 healthy comparison subjects, 381 individuals with amnestic mild cognitive impairment, and 189 individuals with Alzheimer disease who were enrolled in the Alzheimer's Disease Neuroimaging Initiative study. Neuropsychological measures were also collected at each follow-up., Results: Overall, individuals with at least one APOE-ε2 allele showed less functional decline over time and better performance on neuropsychological measures than those without an ε2 allele, even after controlling for potential confounders. When diagnostic groups were examined individually, presence of the ε2 allele continued to be associated with slower functional decline, although the relationship was no longer statistically significant in most cases, likely due to reduced statistical power., Conclusions: Our findings suggest that the APOE-ε2 allele provides a buffer against significant changes in daily functioning over time and is associated with better neuropsychological performance across a number of measures.

Individuals with schizophrenia demonstrate episodic memory (EM) deficits and abnormal EM-related brain activity. Experimental encoding manipulations significantly benefit memory performance in schizophrenia, suggesting that a strategic processing deficit may contribute to memory impairment. However, few studies have investigated the combined effects of encoding and retrieval strategies on EM in schizophrenia. The current study examined the impact of encoding and retrieval strategies on associative memory and brain activity in schizophrenia. We also assessed the role of verbal processing ability in response to strategic memory interventions in schizophrenia. Behavioral and functional neuroimaging data were collected from 23 participants with schizophrenia and 24 comparison subjects while performing associative memory encoding and recall tasks. Behaviorally, both schizophrenia participants and controls benefited from memory strategies and showed significant associations between verbal processing ability and recall. Additionally, among schizophrenia participants, encoding strategy use was associated with enhanced brain activity in multiple brain areas. Schizophrenia participants also demonstrated significant associations between verbal processing ability and encoding-related brain activity in prefrontal cortex. Findings suggest that memory performance and brain activity in schizophrenia can be enhanced via strategic manipulations, and individual differences in cognitive abilities in schizophrenia can affect behavioral and neurobiological responses to strategic memory interventions.

Objective: This research addresses the following questions: what is the prevalence and severity of first-rank symptoms (FRS) during an extended period of time in patients with schizophrenia and bipolar disorder with psychosis? Are the specific FRS listed in Diagnostic and Statistical Manual of Mental Disorders DSM, Third Edition, Revised/Fourth Edition Criterion A for schizophrenia diagnosis (a voice keeping a running commentary or voices conversing) more prevalent and severe in patients with schizophrenia than bipolar disorder with psychosis? Lastly, do FRS at index hospitalization in patients with schizophrenia predict the absence of later recovery?, Methods: This research follows a sample of patients with psychotic disorders who were evaluated at index hospitalization and then prospectively followed-up at 6 evaluations during next 20 years (n = 86). All patients were evaluated as part of a prospective research study designed to measure multiple factors of phenomenology, severity of illness, course of illness, prognosis, and global outcome., Results: First-rank symptoms are not exclusive to schizophrenia; they also occur in some bipolar patients. However, they are more frequent and more severe in patients with schizophrenia than bipolar disorder. Schizophrenia patients with FRS during the acute phase are more likely to have poorer long-term outcome than schizophrenia patients who do not have FRS during the acute phase., Conclusions: Our results indicate FRS at the acute phase are not a clinicopathologic correlate specific to schizophrenia. However, the presence and severity of any FRS and specifically of the 2 FRS associated with Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised/Fourth Edition Criterion A are more prevalent and more severe in patients with schizophrenia than patients with bipolar disorder., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Individuals with schizophrenia have relative deficits in cognition, although little is known regarding the course of such deficits across the life span and at various stages of the illness. Furthermore, the relationship between psychosis and cognition has not been adequately explored to this point. Prospective, longitudinal, multi-assessment studies of the same patients across time are rare in the field and provide a unique opportunity to examine long-term changes in cognition among individuals with schizophrenia. As part of The Chicago Follow-up Study, we prospectively assessed 244 psychiatric inpatients, including individuals with schizophrenia, other psychotic disorders, and nonpsychotic depression. Assessments were conducted 7 times (once at index hospitalization and then 6 times subsequently for the next 20 years) to provide longitudinal data about cognition and symptoms, with a focus on 2 aspects of cognition: processing speed and the ability to access general knowledge. The Digit Symbol-Coding and Information subtests from the Wechsler Adult Intelligence scale were used to measure the 2 cognitive domains at each assessment. At all 7 assessments, individuals with schizophrenia performed more poorly than the other diagnostic groups on the 2 cognitive measures. However, after the acute phase (index hospitalization), individuals with schizophrenia demonstrated significant improvements in cognition and did not show evidence of cognitive decline over the remaining 6 assessments spanning 20 years. Our data support the presence of relative cognitive impairment in schizophrenia, as well as a pattern of stability in some cognitive areas after the acute phase. In addition, we find evidence for an association between relative cognitive impairment and psychosis., (Copyright 2010 Elsevier Inc. All rights reserved.)

Individuals with schizophrenia demonstrate behavioral and neurobiological deficits in episodic memory. However, recent work suggests that episodic memory deficits in schizophrenia may be mitigated through specific encoding strategies. The current study directly compared brain activity and memory performance associated with two different verbal encoding orientations in the same group of schizophrenia participants, in order to more fully characterize the role of strategy in memory processing in this population. Participants included 18 individuals with schizophrenia and 15 healthy comparison participants. Participants encoded words under two conditions during separate fMRI scanning runs. During Incidental encoding, participants were required to make abstract/concrete judgments for each word. During Intentional encoding, participants were instructed to memorize each word for a later memory test. Free recall and a recognition task (utilizing the Remember/Know paradigm) were performed outside of the scanner. Consistent with prior work, schizophrenia participants recognized more words encoded Incidentally than Intentionally, although free recall remained substantially impaired. Schizophrenia participants were also less likely to give Remember judgments for old words and more likely to give Guess judgments for both old and new words. When functional magnetic resonance imaging data were examined, we found that Incidental encoding was associated with substantially fewer between-group differences (Control>Schizophrenia) than Intentional encoding. Furthermore, schizophrenia participants exhibited intact activity during encoding of items that were subsequently retrieved. Our results suggest that use of an Incidental encoding strategy improved recognition memory among individuals with schizophrenia and resulted in a pattern of encoding-related brain activity that was more similar to that seen in control participants. However, we found that Incidental encoding did not improve free recall in schizophrenia participants and abnormal brain activity in some regions was observed, despite improvements in recognition memory.

Background: First-degree relatives of individuals with schizophrenia show cognitive impairments that are similar to but less severe than their ill relatives. We have shown that memory impairments can be improved and prefrontal cortical (PFC) activity increased in individuals with schizophrenia by providing beneficial encoding strategies. The current study used a similar paradigm to determine whether siblings of individuals with schizophrenia (SIBs) also show increases in brain activity when presented with beneficial encoding strategies., Methods: Twenty-one SIBs and 38 siblings of healthy comparison subjects underwent functional magnetic resonance imaging scans while engaged in deep (abstract/concrete judgments) and shallow (orthographic judgments) encoding. Subjects were then given a recognition memory test., Results: The groups did not differ on encoding or recognition accuracy, and the SIBs benefited from deep encoding to a similar degree as control subjects. The SIBs showed deep encoding-related activity in a number of PFC regions typically activated during semantic processing. However, SIBs showed more activity than control subjects in three subregions of PFC (left BA 44 & BA 47 bilaterally)., Conclusions: Siblings of individuals with schizophrenia benefit from supportive verbal encoding conditions. Like individuals with schizophrenia, SIBs also show increased task-related activity in a larger number of PFC subregions than control subjects during deep verbal encoding.

Background: Recent work suggests that episodic memory deficits in schizophrenia may be related to disturbances of encoding or retrieval. Schizophrenia patients appear to benefit from instruction in episodic memory strategies. We tested the hypothesis that providing effective encoding strategies to schizophrenia patients enhances encoding-related brain activity and recognition performance., Methods: Seventeen schizophrenia patients and 26 healthy comparison subjects underwent functional magnetic resonance imaging scans while performing incidental encoding tasks of words and faces. Subjects were required to make either deep (abstract/concrete) or shallow (alphabetization) judgments for words and deep (gender) judgments for faces, followed by subsequent recognition tests., Results: Schizophrenia and comparison subjects recognized significantly more words encoded deeply than shallowly, activated regions in inferior frontal cortex (Brodmann area 45/47) typically associated with deep and successful encoding of words, and showed greater left frontal activation for the processing of words compared with faces. However, during deep encoding and material-specific processing (words vs. faces), participants with schizophrenia activated regions not activated by control subjects, including several in prefrontal cortex., Conclusions: Our findings suggest that a deficit in use of effective strategies influences episodic memory performance in schizophrenia and that abnormalities in functional brain activation persist even when such strategies are applied.

Background: Mismatch negativity (MMN) is an event-related brain potential that is sensitive to stimulus deviation from a repetitive pattern. The MMN is thought primarily to reflect the activity of sensory memory, with, at most, moderate influences of higher-level cognitive processes, such as attention. The MMN is reported to be reduced in patients with chronic schizophrenia. However, it is unknown whether MMN is reduced in patients with first-episode schizophrenia (at first hospitalization)., Methods: Subject groups comprised patients with chronic schizophrenia (n = 16) and older control subjects (n = 13), and patients with first-episode schizophrenia (n = 21) and younger control subjects (n = 27). The MMN was visualized by subtracting the averaged event-related brain potential to standard tones (1 kHz [95% of all tones]) from the event-related brain potential to pitch-deviant tones (1.2 kHz [5% of all tones]). The MMN voltage was the mean voltage from 100 to 200 milliseconds., Results: Pitch-deviant MMN was reduced by approximately 47% in patients with chronic illness along the sagittal midline relative to controls. The MMN was not reduced in patients with first-episode schizophrenia. All 4 groups showed approximately 64% larger MMN to pitch-deviant tones over the right hemisphere compared with the left hemisphere., Conclusions: The pitch-deviant MMN reductions present in patients with chronic schizophrenia are not present at first hospitalization. The sensory, echoic memory functions indexed by MMN seem unaffected early in the schizophrenia disease process. Reductions in MMN amplitude may develop over time and index the progression of the disorder, although that can only be definitively determined by longitudinal assessments.