Association of Radiation Dose to the Amygdala-Orbitofrontal Network with Emotion Recognition Task Performance in Patients with Low-Grade and Benign Brain Tumors.

BACKGROUND: Although data are limited, difficulty in social cognition occurs in up to 83% of patients with brain tumors. It is unknown whether cranial radiation therapy (RT) dose to the amygdala-orbitofrontal network can impact social cognition. METHODS: We prospectively enrolled 51 patients with low-grade and benign brain tumors planned for cranial RT. We assessed longitudinal changes on an emotion recognition task (ERT) that measures the ability to recognize emotional states by displaying faces expressing six basic emotions and their association with the RT dose to the amygdala-orbitofrontal network. ERT outcomes included the median time to choose a response (ERTOMDRT) or correct response (ERTOMDCRT) and total correct responses (ERTHH). RESULTS: The RT dose to the amygdala-orbitofrontal network was significantly associated with longer median response times on the ERT. Increases in median response times occurred at lower doses than decreases in total correct responses. The medial orbitofrontal cortex was the most important variable on regression trees predicting change in the ERTOMDCRT. DISCUSSION: This is, to our knowledge, the first study to show that off-target RT dose to the amygdala-orbitofrontal network is associated with performance on a social cognition task, a facet of cognition that has previously not been mechanistically studied after cranial RT.

The phenotype of delirium based on a close reading of diagnostic criteria.

OBJECTIVE: Although delirium is well known to acute care clinicians, the features required for its diagnosis and how to understand and operationalize them remain sticking points in the field. To clarify the delirium phenotype, we present a close reading of past and current sets of delirium diagnostic criteria. METHODS: We first differentiate the delirium syndrome (i.e., features evaluated at bedside) from additional criteria required for diagnosis. Next, we align related features across diagnostic systems and examine them in context to determine intent. Where criteria are ambiguous, we review common delirium instruments to illustrate how they have been interpreted. RESULTS: An acute disturbance in attention is universally attested across diagnostic systems. A second core feature denotes confusion and has been included across systems as disturbance in awareness, impaired consciousness, and thought disorganization. This feature may be better understood as a disturbance in thought clarity and operationalized in terms of neuropsychological domains thereby clearly linking it to global neurocognitive disturbance. Altered level of activity describes a third core feature, including motor and sleep/wake cycle disturbances. Excluding stupor (wherein mental content cannot be assessed due to reduced arousal) from delirium, as in DSM-5-TR, is appropriate for a psychiatric diagnosis, but the brain injury exclusion in ICD-11 is unjustified. CONCLUSIONS: The delirium phenotype involves a disturbance in attention, qualitative thought clarity, and quantitative activity level, including in relation to expected sleep/wake cycles. Future diagnostic systems should include a severity threshold and specify that delirium diagnosis refers to a 24-h period.

Longitudinal Effects of Combination Antiretroviral Therapy on Cognition and Neuroimaging Biomarkers in Treatment-Naive People With HIV.

BACKGROUND AND OBJECTIVES: While combination antiretroviral therapy (cART) has dramatically increased the life expectancy of people with HIV (PWH), nearly 50% develop HIV-associated neurocognitive disorders. This may be due to previously uncontrolled HIV viral replication, immune activation maintained by residual viral replication or activation from other sources, or cART-associated neurotoxicity. The aim of this study was to determine the effect of cART on cognition and neuroimaging biomarkers in PWH before and after initiation of cART compared with that in HIV-negative controls (HCs) and HIV elite controllers (ECs) who remain untreated. METHODS: We recruited 3 groups of participants from the University of Rochester, McGovern Medical School, and SUNY Upstate Medical University: (1) ART treatment-naive PWH; (2) age-matched HCs; and (3) ECs. Participants underwent brain MRI and clinical and neuropsychological assessments at baseline, 1 year, and 2 years. PWH were also assessed 12 weeks after initiating cART. Volumetric analysis and fractal dimensionality (FD) were calculated for cortical and subcortical regions. Mixed effect regressions examined the effect of group and imaging variables on cognition. RESULTS: We enrolled 47 PWH, 58 HCs, and 10 ECs. At baseline, PWH had worse cognition and lower cortical volumes than HCs. Cognition improved after initiation of cART and remained stable over time. Greater cortical thickness was associated with better cognition at baseline; greater FD of parietal, temporal, and occipital lobes was associated with better cognition at baseline and longitudinally. At baseline, ECs had worse cognition, lower cortical thickness, and lower FD in all 4 lobes and caudate than PWH and HCs. Greater cortical thickness, hippocampal volumes, and FD of frontal, temporal, and occipital lobes were associated with better cognition longitudinally. DISCUSSION: Initiation of cART in PWH is associated with improvement in brain structure and cognition. However, significant differences persist over time when compared with HCs. Similar trends in ECs suggest that results are due to HIV infection rather than treatment. Stronger associations between cognition and FD suggest this imaging metric may be a more sensitive marker of neuronal injury than cortical thickness and volumetric measures.

Fixel-Based Analysis and Free Water Corrected DTI Evaluation of HIV-Associated Neurocognitive Disorders.

Background: White matter (WM) damage is a consistent finding in HIV-infected (HIV+) individuals. Previous studies have evaluated WM fiber tract-specific brain regions in HIV-associated neurocognitive disorders (HAND) using diffusion tensor imaging (DTI). However, DTI might lack an accurate biological interpretation, and the technique suffers from several limitations. Fixel-based analysis (FBA) and free water corrected DTI (fwcDTI) have recently emerged as useful techniques to quantify abnormalities in WM. Here, we sought to evaluate FBA and fwcDTI metrics between HIV+ and healthy controls (HIV-) individuals. Using machine learning classifiers, we compared the specificity of both FBA and fwcDTI metrics in their ability to distinguish between individuals with and without cognitive impairment in HIV+ individuals. Methods: Forty-two HIV+ and 52 HIV- participants underwent MRI exam, clinical, and neuropsychological assessments. FBA metrics included fiber density (FD), fiber bundle cross section (FC), and fiber density and cross section (FDC). We also obtained fwcDTI metrics such as fractional anisotropy (FAT) and mean diffusivity (MDT). Tract-based spatial statistics (TBSS) was performed on FAT and MDT. We evaluated the correlations between MRI metrics with cognitive performance and blood markers, such as neurofilament light chain (NfL), and Tau protein. Four different binary classifiers were used to show the specificity of the MRI metrics for classifying cognitive impairment in HIV+ individuals. Results: Whole-brain FBA showed significant reductions (up to 15%) in various fiber bundles, specifically the cerebral peduncle, posterior limb of internal capsule, middle cerebellar peduncle, and superior corona radiata. TBSS of fwcDTI metrics revealed decreased FAT in HIV+ individuals compared to HIV- individuals in areas consistent with those observed in FBA, but these were not significant. Machine learning classifiers were consistently better able to distinguish between cognitively normal patients and those with cognitive impairment when using fixel-based metrics as input features as compared to fwcDTI metrics. Conclusion: Our findings lend support that FBA may serve as a potential in vivo biomarker for evaluating and monitoring axonal degeneration in HIV+ patients at risk for neurocognitive impairment.

Neurophysiological biomarkers to optimize deep brain stimulation in movement disorders.

Intraoperative neurophysiological information could increase accuracy of surgical deep brain stimulation (DBS) lead placement. Subsequently, DBS therapy could be optimized by specifically targeting pathological activity. In Parkinson's disease, local field potentials (LFPs) excessively synchronized in the beta band (13-35 Hz) correlate with akinetic-rigid symptoms and their response to DBS therapy, particularly low beta band suppression (13-20 Hz) and high frequency gamma facilitation (35-250 Hz). In dystonia, LFPs abnormally synchronize in the theta/alpha (4-13 Hz), beta and gamma (60-90 Hz) bands. Phasic dystonic symptoms and their response to DBS correlate with changes in theta/alpha synchronization. In essential tremor, LFPs excessively synchronize in the theta/alpha and beta bands. Adaptive DBS systems will individualize pathological characteristics of neurophysiological signals to automatically deliver therapeutic DBS pulses of specific spatial and temporal parameters.

Mitochondrial toxicity before and after combination antiretroviral therapy, a Magnetic Resonance Spectroscopy study.

The aim of this study was to quantify, via Magnetic Resonance Spectroscopy (MRS), the effect of combination antiretroviral therapy (cART) on brain metabolites and characterize any possible associations between changes in metabolites, age, blood biomarkers of neuronal damage, functional connectivity and cognitive performance. As cART has dramatically increased the life expectancy of HIV-infected (HIV + ) individuals and unmasked an increase in HIV-associated neurocognitive disorders, it is still not clear whether cART neurotoxicity contributes to these disorders. We hypothesized a bimodal effect, with early cART treatment of HIV infection decreasing inflammation as measured by MRS metabolites and improving cognitive performance, and chronic exposure to cART contributing to persistence of cognitive impairment via its effect on mitochondrial function. Basal ganglia metabolites, functional connectivity, cognitive scores, as well as plasma levels of neurofilament light chain (NfL) and tau protein were measured before and after 12 weeks, 1 year and 2 years of cART in a cohort of 50 cART-naïve HIV + subjects and 72 age matched HIV- healthy controls. Glutamate (Glu) levels were lower in the cART naïve patients than in healthy controls and were inversely correlated with plasma levels of NfL. There were no other significant metabolite differences between HIV + and uninfected individuals. Treatment improved Glu levels in HIV+, however, no associations were found between Glu, functional connectivity and cognitive performance. Stable brain metabolites and plasma levels of NfL and Tau over two-years of follow-ups suggest there are no signs of cART neurotoxicity in this relatively young cohort of HIV + individuals.

A longitudinal analysis of brain extracellular free water in HIV infected individuals.

Initiation of combination antiretroviral therapy (cART) reduces inflammation in HIV-infected (HIV+) individuals. Recent studies demonstrated that diffusion MRI based extracellular free water (FW) modeling can be sensitive to neuroinflammation. Here, we investigate the FW in HIV-infection, its temporal evolution, and its association with blood markers, and cognitive scores. Using 96 age-matched participants, we found that FW was significantly elevated in grey and white matter in cART-naïve HIV+ compared to HIV-uninfected (HIV-) individuals at baseline. These increased FW values positively correlated with neurofilament light chain (NfL) and negatively correlated with CD4 counts. FW in grey and white matter, as well as NfL decreased in the HIV+ after 12 weeks of cART treatment. No significant FW differences were noted between the HIV+ and HIV- cohorts at 1 and 2-year follow-up. Results suggest that FW elevation in cART-naïve HIV+ participants is likely due to neuroinflammation. The correlation between FW and NfL, and the improvement in both FW and NfL after 12 weeks of cART treatment further reinforces this conclusion. The longer follow-up at 1 and 2 years suggests that cART helped control neuroinflammation as inferred by FW. Therefore, FW could be used as a biomarker to monitor HIV-associated neuroinflammation.

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium.

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

Cognitive, Psychiatric, and Quality of Life Outcomes in Adult Survivors of Extracorporeal Membrane Oxygenation Therapy: A Scoping Review of the Literature.

OBJECTIVES: To perform a scoping literature review of cognitive, psychiatric, and quality of life outcomes in adults undergoing extracorporeal membrane oxygenation for any indication. DATA SOURCES: We searched PubMed, EMBASE, Cochrane Library, Web of Science, CINAHL, and PsycINFO from inception to June 2019. STUDY SELECTION: Observational studies, clinical trials, qualitative studies, and case series with at least 10 adult subjects were included for analysis. Outcomes of interest consisted of general or domain-specific cognition, psychiatric illness, and quality of life measures that included both mental and physical health. DATA EXTRACTION: Study selection, data quality assessment, and interpretation of results were performed by two independent investigators in accordance with the PRISMA statement. DATA SYNTHESIS: Twenty-two articles were included in this review. Six described cognitive outcomes, 12 described psychiatric outcomes of which two were qualitative studies, and 16 described quality of life outcomes. Cognitive impairment was detected in varying degrees in every study that measured it. Three studies examined neuroimaging results and found neurologic injury to be more frequent in venoarterial versus venovenous extracorporeal membrane oxygenation, but described a variable correlation with cognitive impairment. Rates of depression, anxiety, and post-traumatic stress disorder were similar to other critically ill populations and were related to physical disability after extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation survivors' physical quality of life was worse than population norms but tended to improve with time, while mental quality of life did not differ significantly from the general population. Most studies did not include matched controls and instead compared outcomes to previously published values. CONCLUSIONS: Extracorporeal membrane oxygenation survivors experience cognitive impairment, psychiatric morbidity, and worse quality of life compared with the general population and similar to other survivors of critical illness. Physical disability in extracorporeal membrane oxygenation patients plays a significant role in psychiatric morbidity. However, it remains unclear if structural brain injury plays a role in these outcomes and whether extracorporeal membrane oxygenation causes secondary brain injury.

Cognitive function in patients with chronic lymphocytic leukemia: a cross-sectional study examining effects of disease and treatment.

Cancer-related cognitive impairment (CRCI) has not been objectively assessed in chronic lymphocytic leukemia (CLL). It is currently unclear how much of CRCI is attributable to disease, treatment, or both. We used CLL as a novel model to study the differential roles of disease and treatment in CRCI. One hundred and fifty CLL patients (100 treatment-naïve and 50 chemotherapy-treated) including 84 patients with higher-risk of CLL progression completed objective neuropsychological tests. Sociodemographic-adjusted linear regression models examined cognitive outcomes in relation to risk and treatment. Higher-risk patients recalled two fewer words on a memory task (ß = -1.8, 95%CI -3.3,-0.3) and took 15 s longer on an executive function task (ß = 15.4, 95%CI 3.1, 27.6) than lower-risk patients, independent of treatment. Treated patients reported greater cognitive difficulties than treatment-naive patients (ß = -6.1, 95%CI -10.1, -2.2) but did not perform worse on objective measures. Higher-risk patients experienced impairments in executive function and memory suggesting that disease biology contributes to CRCI independent of treatment.

Pathomechanisms of HIV-Associated Cerebral Small Vessel Disease: A Comprehensive Clinical and Neuroimaging Protocol and Analysis Pipeline.

Rationale: We provide an in-depth description of a comprehensive clinical, immunological, and neuroimaging study that includes a full image processing pipeline. This approach, although implemented in HIV infected individuals, can be used in the general population to assess cerebrovascular health. Aims: In this longitudinal study, we seek to determine the effects of neuroinflammation due to HIV-1 infection on the pathomechanisms of cerebral small vessel disease (CSVD). The study focuses on the interaction of activated platelets, pro-inflammatory monocytes and endothelial cells and their impact on the neurovascular unit. The effects on the neurovascular unit are evaluated by a novel combination of imaging biomarkers. Sample Size: We will enroll 110 HIV-infected individuals on stable combination anti-retroviral therapy for at least three months and an equal number of age-matched controls. We anticipate a drop-out rate of 20%. Methods and Design: Subjects are followed for three years and evaluated by flow cytometric analysis of whole blood (to measure platelet activation, platelet monocyte complexes, and markers of monocyte activation), neuropsychological testing, and brain MRI at the baseline, 18- and 36-month time points. MRI imaging follows the recommended clinical small vessel imaging standards and adds several advanced sequences to obtain quantitative assessments of brain tissues including white matter microstructure, tissue susceptibility, and blood perfusion. Discussion: The study provides further understanding of the underlying mechanisms of CSVD in chronic inflammatory disorders such as HIV infection. The longitudinal study design and comprehensive approach allows the investigation of quantitative changes in imaging metrics and their impact on cognitive performance.

Cognition and mood in perimenopause: a systematic review and meta-analysis.

OBJECTIVE: It is suggested that declines in estrogen around menopause are associated with declines in cognitive functioning as well as increased risk of depressive symptoms and depressive disorders. Existing studies of objective cognitive function and mood have differed in the criteria used to stage the menopausal transition and in the outcome measures used. The purpose of this review was to synthesize the existing studies of the relationship between menopausal stage and neuropsychological performance and depression. DESIGN: A search of the literature of observational studies was performed using PubMed. Four cross-sectional studies on menopausal transition stage and cognitive function and four longitudinal studies on menopausal transition stage and risk of depression, as measured by symptom inventories and structured clinical interviews, were selected. For the cognitive outcomes, fixed effects models were used to estimate overall standardized effect sizes. For the depression outcomes, the results of group comparisons were summarized using the log odds ratio and its estimated standard error. RESULTS: Postmenopausal women performed significantly worse than pre- and perimenopausal women on delayed verbal memory tasks, and significantly worse than perimenopausal women on phonemic verbal fluency tasks. Peri- and postmenopausal women were at significantly increased risk of depression, as measured by standard symptom inventories and structured clinical interviews, than premenopausal women. CONCLUSIONS: The menopausal transition is a time of increased vulnerability to cognitive declines and increased risk of depressive symptoms and depressive disorders. However, these results cannot necessarily be generalized beyond the studies included in this review. This article is part of a Special Issue entitled 'Menopause'.

Cognition in perimenopause: the effect of transition stage.

OBJECTIVE: The aims of this cross-sectional study were to determine if cognitive function differs across stages of reproductive aging and to evaluate whether hormones or menopausal symptoms predict cognition in perimenopause. We hypothesized that women in late menopausal transition and early postmenopause would perform more poorly than those in the late reproductive stage on attention and verbal memory tasks, and that estradiol, depressive symptoms, anxiety symptoms, hot flashes, and sleep disturbance would predict cognitive performance on those tasks. METHODS: One hundred seventeen middle-aged women enrolled in the Rochester Investigation of Cognition Across Menopause were categorized into late reproductive stage (n = 34), early menopausal transition stage (n = 28), late menopausal transition stage (n = 41), or early postmenopause stage (n = 14) according to criteria from the Stages of Reproductive Aging Workshop +10. We administered a neuropsychological battery assessing six domains of cognition, assessed menopausal symptoms, and measured serum levels of estradiol and follicle-stimulating hormone. Multivariate regressions were conducted to determine the impact of menopausal stage and symptoms on cognition. RESULTS: Women in the first year of postmenopause performed significantly worse than women in the late reproductive and late menopausal transition stages on measures of verbal learning, verbal memory, and motor function. They also performed significantly worse than women in the late menopausal transition stage on attention/working memory tasks. CONCLUSIONS: Cognitive function does not change linearly across perimenopause. Decreases in attention/working memory, verbal learning, verbal memory, and fine motor speed may be most evident in the first year after the final menstrual period.

Reconciling subjective memory complaints with objective memory performance in the menopausal transition.

OBJECTIVE: The overall aim of this study was to examine the relationship between subjective memory complaints and objective cognitive performance in perimenopausal women. The specific aims were to determine (1) if subjective complaints of memory problems relate to objective performance on memory tests, (2) if subjective complaints of memory problems relate to other domains of cognitive function, and (3) if subjective memory complaints relate to other noncognitive factors, such as depression, anxiety, and sleep quality. METHODS: Seventy-five perimenopausal women completed a comprehensive neuropsychological battery, which included measures of attention, working memory, verbal memory, verbal fluency, visuospatial skill, and fine motor dexterity; completed self-report inventories of their perceived memory and menopausal symptoms; and provided serum levels of estradiol and follicle-stimulating hormone. RESULTS: Memory complaints were not associated with verbal learning or verbal memory but were associated with working memory and complex attention/vigilance. Memory complaints were also associated with symptoms of depression, anxiety, somatic complaints, and sleep disturbance. Regression analyses revealed that memory complaints were best predicted by depressive symptoms, somatic complaints, and working memory performance. CONCLUSIONS: Memory complaints in the menopausal transition may reflect true difficulties with attentionally mediated cognitive processes. Memory complaints may also be associated with other menopausal-related symptoms.