COVID-19 olfactory dysfunction: associations between coping, quality of life, and mental health.

BACKGROUND: Persistent olfactory dysfunction (OD) is a common symptom following SARS-CoV-2 infection that can greatly impact quality of life (QoL). Because coping strategies have been shown to moderate the effect of disease symptoms on functional and affective outcomes, this study aims to determine whether specific coping strategies are associated with and moderate QoL outcomes. METHODOLOGY: Participants with prior SARS-CoV-2 infection underwent psychophysical olfactory testing with Sniffin' Sticks and completed questionnaires to elicit subjective olfactory function, coping strategies, olfactory-specific QoL, general QoL, and mental health. RESULTS: There were 93 participants included in the study. Olfactory specific QoL scores were significantly worse among individuals with subjective and psychophysically measured OD compared to those with subjective and psychophysically confirmed normosmia. Olfactory-specific QoL, general QoL, and anxiety symptom scores were positively correlated with avoidant and disengagement coping among individuals with subjective and psychophysically measured OD. Depression symptom scores were positively correlated with avoidant and disengagement coping and negatively correlated with approach and engagement coping. There were no significant moderating effects on the association between olfactory performance and QoL or mental health screening assessment. CONCLUSIONS: Approach and engagement coping mechanisms are associated with improved depression, whereas avoidant and disengagement coping tracks with worse QoL and mental health screening assessment, offering an opportunity to counsel patients accordingly.

APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms.

The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

Computerized Cognitive Training in Mild Cognitive Impairment: Findings in African Americans and Caucasians.

BACKGROUND: African Americans with MCI may be at increased risk for dementia compared to Caucasians. The effect of race on the efficacy of cognitive training in MCI is unclear. METHODS: We used data from a two-site, 78-week randomized trial of MCI comparing intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles to examine the effect of race on outcomes. The study outcomes were changes from baseline in cognitive and functional scales as well as MRI-measured changes in hippocampal volume and cortical thickness. Analyses used linear models adjusted for baseline scores. This was an exploratory study. RESULTS: A total of 105 subjects were included comprising 81 whites (77.1%) and 24 African Americans (22.8%). The effect of race on the change from baseline in ADAS-Cog-11 was not significant. The effect of race on change from baseline to week 78 in the Functional Activities Questionnaire (FAQ) was significant with African American participants' FAQ scores showing greater improvements at weeks 52 and 78 (P = 0.009, P = 0.0002, respectively) than white subjects. Within the CCT cohort, FAQ scores for African American participants showed greater improvement between baseline and week 78, compared to white participants randomized to CCT (P = 0.006). There was no effect of race on the UPSA. There was no effect of race on hippocampal or cortical thickness outcomes. CONCLUSIONS: Our preliminary findings suggest that web-based cognitive training programs may benefit African Americans with MCI at least as much as Caucasians, and highlight the need to further study underrepresented minorities in AD prevention trials. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.).

Expectancy Does Not Predict 18-month Treatment Outcomes with Cognitive Training in Mild Cognitive Impairment.

BACKGROUND: Computerized cognitive training (CCT) has emerged as a potential treatment option for mild cognitive impairment (MCI). It remains unclear whether CCT's effect is driven in part by expectancy of improvement. OBJECTIVES: This study aimed to determine factors associated with therapeutic expectancy and the influence of therapeutic expectancy on treatment effects in a randomized clinical trial of CCT versus crossword puzzle training (CPT) for older adults with MCI. DESIGN: Randomized clinical trial of CCT vs CPT with 78-week follow-up. SETTING: Two-site study - New York State Psychiatric Institute and Duke University Medical Center. PARTICIPANTS: 107 patients with MCI. INTERVENTION: 12 weeks of intensive training with CCT or CPT with follow-up booster training over 78 weeks. MEASUREMENTS: Patients rated their expectancies for CCT and CPT prior to randomization. RESULTS: Patients reported greater expectancy for CCT than CPT. Lower patient expectancy was associated with lower global cognition at baseline and older age. Expectancy did not differ by sex or race. There was no association between expectancy and measures of everyday functioning, hippocampus volume, or apolipoprotein E genotype. Expectancy was not associated with change in measures of global cognition, everyday functioning, and hippocampus volume from baseline to week 78, nor did expectancy interact with treatment condition. CONCLUSIONS: While greater cognitive impairment and increased age was associated with low expectancy of improvement, expectancy was not associated with the likelihood of response to treatment with CPT or CCT.

Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype.

Alzheimer's disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.

Development of an UPSA Short Form for Use in Longitudinal Studies in the Early Alzheimer's Disease Spectrum.

BACKGROUND: In individuals with only mild or very mild cognitive attenuations (i.e., so-called pre-clinical AD), performance-based measures of function may be superior to informant-based measures because of increased sensitivity, greater reliability, and fewer ceiling effects. OBJECTIVE: We sought to determine if a performance-based measure of everyday function would demonstrate adequate psychometric properties and validity in the context of serial assessment over a one-year period in patients with Mild Cognitive Impairment (MCI) and early stage Alzheimer's disease (AD). DESIGN: Participants were assessed with the performance-based measure at baseline, six weeks, and one year. SETTING: A specialized center for the assessment and treatment of AD. PARTICIPANTS: Three groups of subjects participated: a healthy subjects (HS) older cognitively intact group (N=43), an MCI group (N=20), and an AD group (N=26). MEASUREMENTS: A three subtest short form of the UCSD Performance-Based Skills Assessment (UPSA) (called the UPSA-3) was the measure of interest. It consisted of the Communication, Planning, and Finance subtests. RESULTS: Mixed model repeated measures were used to assess performance over time. Large group effects were present (HS>MCI>AD). Additionally, the AD and MCI groups demonstrated declines over one year, while the HS group remained stable (group x time interaction p=.11). The MCI/AD group demonstrated adequate test-retest reliability and did not demonstrate ceiling or floor effects. CONCLUSION: Our data indicate that the UPSA-3 is suitable for clinical trials in that it has adequate ecological coverage and reasonable psychometric properties, and perhaps most importantly, demonstrates validity in serial assessments.

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality.

Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.

Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test.

Recent physiological and cognitive studies of schizophrenia have implicated dysfunction of prefrontal cortex as a possible explanation for some of the disabling intellectual and social aspects of the disorder. To investigate the potential reversibility of cognitive deficits and the role of state variables, eg, attention and motivation, three groups of patients with schizophrenia were administered the Wisconsin Card Sorting Test on six consecutive occasions. Two of the groups received incremental information on how to do the test, including explicit card-by-card instruction. The third group served as a control. Regardless of the degree of instruction, patients who could not do the test could not learn it. The deficit did not appear generalized, as patients were able to learn word lists on the Selective Reminding memory test and were not globally demented on the Mini-Mental State Examination. These data suggest that prefrontal-type cognitive deficits in schizophrenia may be more profound than is generally appreciated.

Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia.

BACKGROUND: Impaired Wisconsin Card Sorting Test (WCST) performance has been one critical piece of evidence suggesting frontal lobe dysfunction in schizophrenia. However, the specific cognitive processes underlying impaired performance have not been identified. Impaired WCST performance in schizophrenia might in part reflect a fundamental working memory deficit. METHODS: We examined the performance of 30 normal subjects and 36 patients with schizophrenia on a neuropsychological battery including a novel measure of working memory-letter-number (LN) span. RESULTS: Patients with schizophrenia were impaired on LN span performance, which was also highly correlated with WCST performance (r = 0.74). Between-group WCST differences were eliminated when we covaried LN span. Regression analyses suggested that LN span performance predicted the WCST category achieved score, whereas measures of set shifting, verbal fluency, and attention were predictive of perseveration. CONCLUSION: Working memory may be a critical determinant of one aspect of WCST performance in schizophrenia.

The hippocampus and parahippocampus in schizophrenia, suicide, and control brains.

Recent postmortem studies in schizophrenia have shown abnormalities in medial temporal lobe structures, including the hippocampus and parahippocampus. We tried to replicate previous studies and to explore the specificity of this finding to schizophrenia. The anterior hippocampus and parahippocampal cortex were evaluated for area and shape in postmortem tissue from 12 schizophrenic, 17 nonschizophrenic suicide, and 10 nonpsychiatric control brains. No significant differences were found in hippocampal area, but the parahippocampal cortex was significantly smaller in the schizophrenic group than in the control group. When parahippocampi from right and left sides were analyzed separately, both the suicide and schizophrenic groups had smaller parahippocampi on the right side than did the controls [corrected]. The suicide group exhibited greater parahippocampal areas in the left than in the right tissue samples within the group, while such a difference did not exist in the schizophrenic or control groups. This study demonstrated changes in temporal lobe structures in both schizophrenic and nonschizophrenic suicide groups.

Schizophrenia and temporal lobe epilepsy. A neuropsychological analysis.

BACKGROUND: Recent neuroimaging studies have reported structural abnormalities of mesial temporal lobe structures in schizophrenia. This study compared the neuropsychological performance of patients with schizophrenia with patients with either left or right temporal lobe epilepsy to determine if lateralized, developmental temporal lobe dysfunction provides a model of the cognitive impairments observed in schizophrenia. METHODS: A total 66 patients with schizophrenia and 101 patients with medically intractable focal temporal lobe epilepsy (48 left temporal, 53 right temporal) received a comprehensive neuropsychological battery. RESULTS: The three groups did not differ on age, years of education, or Full-Scale IQ. However, clear differences were noted in performance profiles. Patients with schizophrenia scored significantly higher than either epilepsy group on a measure of word reading thought to reflect premorbid competence. Patients with schizophrenia demonstrated greater attentional impairment and motor slowing than either epilepsy group. The patients with schizophrenia had superior semantic knowledge and verbal memory compared with the left temporal lobe group. On the Wisconsin Card Sorting Test the patients with schizophrenia obtained significantly fewer categories than either temporal lobe group, but were not significantly more perseverative. CONCLUSIONS: Data suggest lateralized temporal lobe dysfunction does not provide an adequate model of the cognitive impairments seen in schizophrenia. The disorders seem to follow different developmental paths: In early-onset epilepsy, the acquisition of cognitive skills and academic knowledge is compromised, while in schizophrenia cognitive functions are lost. Extratemporal pathologic features, most likely of the frontal lobe, are implicated in the cognitive dysfunction of schizophrenia.

Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect.

BACKGROUND: Although intellectual and neurocognitive deficits accompany schizophrenia, there are inconsistencies in the literature concerning issues of intellectual decline, premorbid deficits, a modal deficit pattern, and preserved abilities. METHODS: A battery of neuropsychological tests was administered once to 117 consecutively admitted patients with chronic schizophrenia and a group of 27 healthy control subjects to examine patterns of premorbid and current intellect (measured by means of reading scores and IQ, respectively) and the attendant cognitive profiles in schizophrenia using classification methods based on clinically derived (IQ levels) and atheoretical (cluster) techniques. RESULTS: Sixty patients (51%) with schizophrenia who displayed a general intellectual decline of 10 points or greater from estimated premorbid levels also exhibited deficits of executive function, memory, and attention. Twenty-eight patients (23%) with consistently low estimated premorbid intellect and current intellectual levels who displayed no evidence of IQ decline exhibited language and visual processing deficits in addition to deficits present in the intellectually declining group. The remaining 29 patients (25%) who displayed average estimated premorbid intellectual levels did not show IQ decline and exhibited a cognitive profile similar to normal, with the exception of executive function and attention impairment. Atheoretical analyses support the findings from clinically derived subgroups. CONCLUSIONS: These results suggest that IQ decline, although modal in schizophrenia, is not universally characteristic and that executive function and attention deficits may be core features of schizophrenia, independent of IQ variations.

Neuropsychological assessment of monozygotic twins discordant for schizophrenia.

A comparison of monozygotic twins discordant for schizophrenia controls for genetic variance and reduces variance due to environmental circumstances, thus serving to highlight differences due to phenotypic-related variables. In this study, we assessed 16 such twin pairs on a wide range of neuropsychological tests. The affected twins tended to perform worse than their unaffected counterparts on most of the tests. Deficits were especially severe on tests of vigilance, memory, and concept formation, suggesting that dysfunction is greatest in the frontotemporal cortex. While manifest symptoms were not highly associated with neuropsychological scores, global level of functioning was. To address the issue of genetic liability, we also compared the sample of discordant unaffected twins with a sample of seven pairs of normal monozygotic twins. No significant differences between the groups were found for any neuropsychological test. In fact, the results suggest that neuropsychological dysfunction is a consistent feature of schizophrenia and that it is related primarily to the clinical disease process and not to genetic or nonspecific environmental factors.

Visuospatial working memory in patients with schizophrenia.

Recent investigations have documented abnormalities in working memory related processes in schizophrenics on tasks assessing the central executive component of this cognitive model. This preliminary study investigated the function of another component of the working memory system, the visuospatial scratch pad in schizophrenia. The "scratch pad's" passive visual store--responsible for the temporary retention of visual material--was assessed via a computerized spatial delayed response task, whereas its active spatial rehearsal subsystem--specialized for retaining the temporal properties--was explored through visual block span. To assess elemental visual spatial abilities we used the Judgment of Line Orientation test. Thirty-two schizophrenics and 27 controls were tested. Although we discovered the basic perceptual abilities of patients to be intact, we determined that whenever memory was necessitated on spatial tasks, patients demonstrated marked deficits. This pattern of cognitive dysfunction is consistent with impairments in a neural network involving prefrontal and/or posterior brain regions in schizophrenia.

Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers.

BACKGROUND: The N-methyl-D-aspartate receptor antagonist, ketamine, produces a clinical syndrome of thought disorder, perceptual distortion, and cognitive impairment. METHODS: We have administered ketamine to healthy volunteers to characterize the formal thought disorder and specific memory dysfunction associated with ketamine. Ten healthy volunteers underwent a double-blind, placebo-controlled, ketamine infusion (0.12 mg/kg bolus and 0.65 mg/kg/hour). Thought disorder was evaluated with the Scale for the Assessment of Thought, Language and Communication. Cognitive testing involved working and semantic memory tasks. RESULTS: Ketamine produced a formal thought disorder, as well as impairments in working and semantic memory. The degree of ketamine-induced thought disorder significantly correlated with ketamine-induced decreases in working memory and did not correlate with ketamine-induced impairments in semantic memory. CONCLUSIONS: This study characterizes the formal thought disorder associated with ketamine and may suggest that ketamine-induced deficits in working memory are associated with ketamine-induced thought disorder.

Lack of a bimodal distribution of ventricular size in schizophrenia: a Gaussian mixture analysis of 1056 cases and controls.

The finding of clinical and laboratory differences between schizophrenic patients with large and small cerebral ventricles has led to the widespread assumption that large ventricles are a marker that characterizes a subgroup of patients with schizophrenia. We reviewed all published English language ventricle-to-brain ratio (VBR) studies in which individual data points were available (schizophrenics: n = 691, medical controls; n = 205, normal volunteers: n = 160). Using a univariate normal mixture model to examine the distribution of ventricular size in each group, we found no evidence of a mixture of Gaussian distributions (i.e., "bimodality") within any of the three groups. The same analysis was then performed on the combined sample of schizophrenic patients and normal and medical controls, respectively. In each case the improvement in fit of a mixture of normal distributions compared to a single component normal distribution was significant. The data do not support the notion that ventricular enlargement is a discontinuous marker of a subtype of schizophrenia.

Computed tomography measurements of brain density in Schizophrenia.

Although previous studies have reported differences in computed tomography (CT) scan attenuation values between patients with schizophrenia and controls, interpretation of these findings has been hindered by methodological shortcomings such as the failure to control for head size, scanner calibration differences, and other confounding variables. In the present study of CT attenuation values in multiple brain regions in 20 patients with chronic schizophrenia and an equal number of age- and sex-matched normal subjects we controlled for head size and normalized the attenuation values for each scan to an internal standard. No significant differences emerged between the patients with schizophrenia and the controls. However, in the controls only, the mean density of white matter in the left frontal area was significantly higher (t = -2.83, p = 0.01) than that in the right. The results, although possibly suggestive of deviant lateralization in schizophrenia, raise questions about the sensitivity and validity of regional CT attenuation values in detecting subtle anatomic abnormalities in patients with this illness.

Neuropsychological performance of monozygotic twins discordant for bipolar disorder.

BACKGROUND: A paradigm that involves cognitive assessment of monozygotic (MZ) twins discordant for a neuropsychiatric disorder (here bipolar illness) allows for the examination of both disease-specific impairments (in the comparison of affected to unaffected twins) and risk factors (in the comparison of unaffected twins to normal twins). METHODS: Neuropsychological functions were evaluated in seven MZ twin pairs discordant for bipolar illness and seven pairs of normal MZ twins in an attempt to highlight cognitive abilities associated with manifestations of disease and genetic risk factors. At the time of testing, 3 of the affected twins were euthymic, 2 had depressive symptoms, and 2 had manic symptoms; all were receiving medication. All twins receive neuropsychological tests to evaluate intelligence, attention, visuospatial skills, language, learning and memory, and problem solving. RESULTS: Statistical analyses revealed that the affected twins were significantly impaired as compared to the unaffected (and normal) twins on some measures of visuospatial functioning and some verbal memory measures. In contrast to a sample of MZ twins discordant for schizophrenia studied previously, the cognitive impairments we observed in bipolar twins were mild in nature and fairly circumscribed. The unaffected twins performed significantly worse than normal controls on a Brown-Petersen memory task, verbal list learning, and overall Wechsler Memory Quotient. CONCLUSIONS: These data suggest that while some visuospatial deficits and verbal memory deficits may be features of bipolar disorder related to disease parameters, mild attenuations in overall memory or retrieval function may be related to genetic factors associated with the illness.

Tardive dyskinesia: neuropsychological, computerized tomographic, and psychiatric symptom findings.

Prior studies have suggested that schizophrenic patients with tardive dyskinesia (TD) have an unusual incidence of cognitive impairment, structural brain abnormalities, and negative symptoms. Twenty-seven schizophrenic patients with TD and an equal number of age-, gender-, and education-matched schizophrenic controls were studied. Each patient received neuropsychological testing, psychiatric symptom ratings, and most had cerebral computed tomography (CT) scans. Patients with TD significantly differed from controls on only 1 of 23, cognitive measures, and the overall group performance profiles were highly similar. No differences were observed on symptom ratings. Patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls. These data fail to support an association of TD with global measures of "organicity." Abnormal movements may result from specific dysfunction within the more purely motor circuits of the basal ganglia without compromising other neural systems involved in cognitive processing.