Minimally Invasive Surgery With Thrombolysis for Intracerebral Hemorrhage Evacuation: Bayesian Reanalysis of a Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Bayesian analysis of randomized controlled trials (RCTs) can extend the value of trial data beyond interpretations based on conventional p value-based binary cutoffs. We conducted an exploratory post hoc Bayesian reanalysis of the minimally invasive surgery with thrombolysis for intracerebral hemorrhage (ICH) evacuation (MISTIE-3) trial and derived probabilities of potential intervention effect on functional and survival outcomes. METHODS: MISTIE-3 was a multicenter phase 3 RCT designed to evaluate the efficacy and safety of the MISTIE intervention. Five hundred and six adults (18 years or older) with spontaneous, nontraumatic, supratentorial ICH of ≥30 mL were randomized to receive either the MISTIE intervention (n = 255) or standard medical care (n = 251). We provide Bayesian-derived estimates of the effect of the MISTIE intervention on achieving a good 365-day modified Rankin Scale score (mRS score 0-3) as relative risk (RR) and absolute risk difference (ARD), and the probabilities that these treatment effects are greater than prespecified thresholds. We used 2 sets of prior distributions: (1) reference priors, including minimally informative, enthusiastic, and skeptical priors, and (2) data-derived prior distribution, using a hierarchical random effects model. We additionally evaluated the potential effects of the MISTIE intervention on 180-day and 30-day mRS and 365-, 180-, and 30-day mortality using data-derived priors. RESULTS: The Bayesian-derived probability that MISTIE intervention has any beneficial effect (RR >1) on achieving a good 365-day mRS score was 70% using minimally informative prior, 87% with enthusiastic prior, 68% with skeptical prior, and 73% with data-derived prior. However, these probabilities were ≤55% for RR >1.10 and 0% for RR >1.52 across a range of priors. The probabilities of achieving RR >1 for 180- and 30-day mRS scores are 65% and 80%, respectively. Furthermore, the probabilities of achieving RR <1 for 365-, 180-, and 30-day mortality are 93%, 98%, and 99%, respectively. DISCUSSION: Our exploratory analyses indicate that across a range of priors, the Bayesian-derived probability of MISTIE intervention having any beneficial effect on 365-day mRS for patients with ICH is between 68% and 87%. These analyses do not change the frequentist-based interpretation of the trial. However, unlike the frequentist p values, which indirectly evaluate treatment effects and only provide an arbitrary binary cutoff (such as 0.05), the Bayesian framework directly estimates the probabilities of potential treatment effects. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov/ct2/show/NCT01827046. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that minimally invasive surgery (MIS) + recombinant tissue plasminogen activator (rt-PA) does not significantly improve functional outcome in patients with ICH. However, this study lacks the precision to exclude a potential benefit of MIS + rt-PA.

A Neuro-Informatics Pipeline for Cerebrovascular Disease: Research Registry Development.

BACKGROUND: Although stroke is well recognized as a critical disease, treatment options are often limited. Inpatient stroke encounters carry critical information regarding the mechanisms of stroke and patient outcomes; however, these data are typically formatted to support administrative functions instead of research. To support improvements in the care of patients with stroke, a substantive research data platform is needed. OBJECTIVE: To advance a stroke-oriented learning health care system, we sought to establish a comprehensive research repository of stroke data using the Houston Methodist electronic health record (EHR) system. METHODS: Dedicated processes were developed to import EHR data of patients with primary acute ischemic stroke, intracerebral hemorrhage (ICH), transient ischemic attack, and subarachnoid hemorrhage under a review board-approved protocol. Relevant patients were identified from discharge diagnosis codes and assigned registry patient identification numbers. For identified patients, extract, transform, and load processes imported EHR data of primary cerebrovascular disease admissions and available data from any previous or subsequent admissions. Data were loaded into patient-focused SQL objects to enable cross-sectional and longitudinal analyses. Primary data domains (admission details, comorbidities, laboratory data, medications, imaging data, and discharge characteristics) were loaded into separate relational tables unified by patient and encounter identification numbers. Computed tomography, magnetic resonance, and angiography images were retrieved. Imaging data from patients with ICH were assessed for hemorrhage characteristics and cerebral small vessel disease markers. Patient information needed to interface with other local and national databases was retained. Prospective patient outreach was established, with patients contacted via telephone to assess functional outcomes 30, 90, 180, and 365 days after discharge. Dashboards were constructed to provide investigators with data summaries to support access. RESULTS: The Registry of Neurological Endpoint Assessments among Patients with Ischemic and Hemorrhagic Stroke (REINAH) database was constructed as a series of relational category-specific SQL objects. Encounter summaries and dashboards were constructed to draw from these objects, providing visual data summaries for investigators seeking to build studies based on REINAH data. As of June 2022, the database contains 18,061 total patients, including 1809 (10.02%) with ICH, 13,444 (74.43%) with acute ischemic stroke, 1221 (6.76%) with subarachnoid hemorrhage, and 3165 (17.52%) with transient ischemic attack. Depending on the cohort, imaging data from computed tomography are available for 85.83% (1048/1221) to 98.4% (1780/1809) of patients, with magnetic resonance imaging available for 27.85% (340/1221) to 85.54% (11,500/13,444) of patients. Outcome assessment has successfully contacted 56.1% (240/428) of patients after ICH, with 71.3% (171/240) of responders providing consent for assessment. Responders reported a median modified Rankin Scale score of 3 at 90 days after discharge. CONCLUSIONS: A highly curated and clinically focused research platform for stroke data will establish a foundation for future research that may fundamentally improve poststroke patient care and outcomes.

Seasonal variation in the incidence of primary intracerebral hemorrhage: a 16-year nationwide analysis.

Introduction: Data on nationwide trends and seasonal variations in the incidence of Intracerebral Hemorrhage (ICH) in the United States (US) are lacking. Methods: We used the Nationwide Inpatient Sample (2004-2019) and Census Bureau data to calculate the quarterly (Q1:January-March; Q2:April-June; Q3:July-September; Q4:October-December) incidence rates (IR) of adult (≥18 years) ICH hospitalizations, aggregated across Q1-Q4 and Q2-Q3. We report adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) for differences in the quarterly incidence of ICH, as compared to acute ischemic stroke (AIS), between Q1Q4 and Q2Q3 using a multivariable Poisson regression model. We additionally performed stratified analyses across the four US regions. Results: Among 822,143 (49.0% female) ICH and 6,266,234 (51.9% female) AIS hospitalizations, the average quarterly crude IR of ICH was consistently higher in Q1Q4 compared to Q2Q3 (5.6 vs. 5.2 per 100,000) (aIRR, CI: 1.09, 1.08-1.11)-this pattern was similar across all four US regions. However, a similar variation pattern was not observed for AIS incidence. The incidence (aIRR, CI) of both ICH (1.01, 1.00-1.02) and AIS (1.03, 1.02-1.03) is rising. Conclusion: Unlike AIS, ICH incidence is consistently higher in colder quarters, underscoring the need for evaluation and prevention of factors driving seasonal variations in ICH incidence.

Lifelong cerebrovascular disease burden among CADASIL patients: analysis from a global health research network.

Introduction: Data reporting on patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) within the United States population is limited. We sought to evaluate the overt cerebrovascular disease burden among patients with CADASIL. Methods: Harmonized electronic medical records were extracted from the TriNetX global health research network. CADASIL patients were identified using diagnostic codes and those with/without history of documented stroke sub-types (ischemic stroke [IS], intracerebral hemorrhage [ICH], subarachnoid hemorrhage [SAH] and transient ischemic attack [TIA]) were compared. Adjusted odds ratios (OR) and 95% confidence intervals (CI) of stroke incidence and mortality associated with sex were computed. Results: Between September 2018 and April 2020, 914 CADASIL patients were identified (median [IQR] age: 60 [50-69], 61.3% females); of whom 596 (65.2%) had documented cerebrovascular events (i.e., CADASIL-Stroke patients). Among CADASIL-Stroke patients, 89.4% experienced an IS, co-existing with TIAs in 27.7% and hemorrhagic strokes in 6.2%; initial stroke events occurred ≤65 years of age in 71% of patients. CADASIL-Stroke patients (vs. CADASIL-non-Stroke) had higher cardiovascular and neurological (migraines, cognitive impairment, epilepsy/seizures, mood disorders) burden. In age- and comorbidity-adjusted models, males had higher associated risk of stroke onset (OR: 1.37, CI: 1.01-1.86). Mortality risk was higher for males (OR: 2.72, CI: 1.53-4.84). Discussion: Early screening and targeted treatment strategies are warranted to help CADASIL patients with symptom management and risk mitigation.

Stroke severity mediates the effect of socioeconomic disadvantage on poor outcomes among patients with intracerebral hemorrhage.

Background: Socioeconomic deprivation drives poor functional outcomes after intracerebral hemorrhage (ICH). Stroke severity and background cerebral small vessel disease (CSVD) burden have each been linked to socioeconomic status and independently contribute to worse outcomes after ICH, providing distinct, plausible pathways for the effects of deprivation. We investigate whether admission stroke severity or cerebral small vessel disease (CSVD) mediates the effect of socioeconomic deprivation on 90-day functional outcomes. Methods: Electronic medical record data, including demographics, treatments, comorbidities, and physiological data, were analyzed. CSVD burden was graded from 0 to 4, with severe CSVD categorized as ≥3. High deprivation was assessed for patients in the top 30% of state-level area deprivation index scores. Severe disability or death was defined as a 90-day modified Rankin Scale score of 4-6. Stroke severity (NIH stroke scale (NIHSS)) was classified as: none (0), minor (1-4), moderate (5-15), moderate-severe (16-20), and severe (21+). Univariate and multivariate associations with severe disability or death were determined, with mediation evaluated through structural equation modelling. Results: A total of 677 patients were included (46.8% female; 43.9% White, 27.0% Black, 20.7% Hispanic, 6.1% Asian, 2.4% Other). In univariable modelling, high deprivation (odds ratio: 1.54; 95% confidence interval: [1.06-2.23]; p = 0.024), severe CSVD (2.14 [1.42-3.21]; p < 0.001), moderate (8.03 [2.76-17.15]; p < 0.001), moderate-severe (32.79 [11.52-93.29]; p < 0.001), and severe stroke (104.19 [37.66-288.12]; p < 0.001) were associated with severe disability or death. In multivariable modelling, severe CSVD (3.42 [1.75-6.69]; p < 0.001) and moderate (5.84 [2.27-15.01], p < 0.001), moderate-severe (27.59 [7.34-103.69], p < 0.001), and severe stroke (36.41 [9.90-133.85]; p < 0.001) independently increased odds of severe disability or death; high deprivation did not. Stroke severity mediated 94.1% of deprivation's effect on severe disability or death (p = 0.005), while CSVD accounted for 4.9% (p = 0.524). Conclusion: CSVD contributed to poor functional outcome independent of socioeconomic deprivation, while stroke severity mediated the effects of deprivation. Improving awareness and trust among disadvantaged communities may reduce admission stroke severity and improve outcomes.

Geographic Disparities in Case Fatality and Discharge Disposition Among Patients With Primary Intracerebral Hemorrhage.

Background We evaluate nationwide trends and urban-rural disparities in case fatality (in-hospital mortality) and discharge dispositions among patients with primary intracerebral hemorrhage (ICH). Methods and Results In this repeated cross-sectional study, we identified adult patients (≥18 years of age) with primary ICH from the National Inpatient Sample (2004-2018). Using a series of survey design Poisson regression models, with hospital location-time interaction, we report the adjusted risk ratio (aRR), 95% CI, and average marginal effect (AME) for factors associated with ICH case fatality and discharge dispositions. We performed a stratified analysis of each model among patients with extreme loss of function and minor to major loss of function. We identified 908 557 primary ICH hospitalizations (overall mean age [SD], 69.0 [15.0] years; 445 301 [49.0%] women; 49 884 [5.5%] rural ICH hospitalizations). The crude ICH case fatality rate was 25.3% (urban hospitals: 24.9%, rural hospitals:32.5%). Urban (versus rural) hospital patients had a lower likelihood of ICH case fatality (aRR, 0.86 [95% CI, 0.83-0.89]). ICH case fatality is declining over time; however, it is declining faster in urban hospitals (AME, -0.049 [95% CI, -0.051 to -0.047]) compared with rural hospitals (AME, -0.034 [95% CI, -0.040 to -0.027]). Conversely, home discharge is increasing significantly among urban hospitals (AME, 0.011 [95% CI, 0.008-0.014]) but not significantly changing in rural hospitals (AME, -0.001 [95% CI, -0.010 to 0.007]). Among patients with extreme loss of function, hospital location was not significantly associated with ICH case fatality or home discharge. Conclusions Improving access to neurocritical care resources, particularly in resource-limited communities, may reduce the ICH outcomes disparity gap.

Real-world effectiveness of COVID-19 vaccines and anti-SARS-CoV-2 monoclonal antibodies against postacute sequelae of SARS-CoV-2: analysis of a COVID-19 observational registry for a diverse US metropolitan population.

OBJECTIVES: We evaluated the effectiveness of COVID-19 vaccines and monoclonal antibodies (mAbs) against postacute sequelae of SARS-CoV-2 infection (PASC). DESIGN AND SETTING: A retrospective cohort study using a COVID-19 specific, electronic medical record-based surveillance and outcomes registry from an eight-hospital tertiary hospital system in the Houston metropolitan area. Analyses were replicated across a global research network database. PARTICIPANTS: We identified adult (≥18) patients with PASC. PASC was defined as experiencing constitutional (palpitations, malaise/fatigue, headache) or systemic (sleep disorder, shortness of breath, mood/anxiety disorders, cough and cognitive impairment) symptoms beyond the 28-day postinfection period. STATISTICAL ANALYSIS: We fit multivariable logistic regression models and report estimated likelihood of PASC associated with vaccination or mAb treatment as adjusted ORs with 95% CIs. RESULTS: Primary analyses included 53 239 subjects (54.9% female), of whom 5929, 11.1% (95% CI 10.9% to 11.4%), experienced PASC. Both vaccinated breakthrough cases (vs unvaccinated) and mAb-treated patients (vs untreated) had lower likelihoods for developing PASC, aOR (95% CI): 0.58 (0.52-0.66), and 0.77 (0.69-0.86), respectively. Vaccination was associated with decreased odds of developing all constitutional and systemic symptoms except for taste and smell changes. For all symptoms, vaccination was associated with lower likelihood of experiencing PASC compared with mAb treatment. Replication analysis found identical frequency of PASC (11.2%, 95% CI 11.1 to 11.3) and similar protective effects against PASC for the COVID-19 vaccine: 0.25 (0.21-0.30) and mAb treatment: 0.62 (0.59-0.66). CONCLUSION: Although both COVID-19 vaccines and mAbs decreased the likelihood of PASC, vaccination remains the most effective tool for the prevention of long-term consequences of COVID-19.

Extraction of Radiological Characteristics From Free-Text Imaging Reports Using Natural Language Processing Among Patients With Ischemic and Hemorrhagic Stroke: Algorithm Development and Validation.

BACKGROUND: Neuroimaging is the gold-standard diagnostic modality for all patients suspected of stroke. However, the unstructured nature of imaging reports remains a major challenge to extracting useful information from electronic health records systems. Despite the increasing adoption of natural language processing (NLP) for radiology reports, information extraction for many stroke imaging features has not been systematically evaluated. OBJECTIVE: In this study, we propose an NLP pipeline, which adopts the state-of-the-art ClinicalBERT model with domain-specific pretraining and task-oriented fine-tuning to extract 13 stroke features from head computed tomography imaging notes. METHODS: We used the model to generate structured data sets with information on the presence or absence of common stroke features for 24,924 patients with strokes. We compared the survival characteristics of patients with and without features of severe stroke (eg, midline shift, perihematomal edema, or mass effect) using the Kaplan-Meier curve and log-rank tests. RESULTS: Pretrained on 82,073 head computed tomography notes with 13.7 million words and fine-tuned on 200 annotated notes, our HeadCT_BERT model achieved an average area under receiver operating characteristic curve of 0.9831, F1-score of 0.8683, and accuracy of 97%. Among patients with acute ischemic stroke, admissions with any severe stroke feature in initial imaging notes were associated with a lower probability of survival (P<.001). CONCLUSIONS: Our proposed NLP pipeline achieved high performance and has the potential to improve medical research and patient safety.

A Contemporary Review of Epidemiology, Risk Factors, Etiology, and Outcomes of Premature Stroke.

PURPOSE OF REVIEW: Recent data identifies increases in young ischemic and hemorrhagic strokes. We provide a contemporary overview of current literature on stroke among young patients or premature stroke along with directions for future investigation. RECENT FINDINGS: Strokes in the young are highly heterogenous and often cryptogenic. Sex distribution and risk factors shift from women among the youngest age groups (< 35) to men over the age of 45, with a coinciding rise in traditional vascular risk factors. Incidence is higher in minority and socioeconomically disadvantaged populations, and the impact of stroke among these communities may be exaggerated by disparities in symptom recognition and access to care. Special diagnostic work-up may be needed, and a lower threshold for diagnosis is warranted as potential misdiagnosis is a concern and may preclude necessary triage and management. Although "premature strokes" form a relatively small proportion of total incidence, they vary greatly across subgroups and present an outsized impact on quality of life and productivity.

COVID-19 associated disruptions in routine health care of people with mild cognitive impairment or dementia.

Introduction: We report the COVID-19 pandemic's impact on health-care use disruption among people with mild cognitive impairment or Alzheimer's disease and related dementia (MCI/ADRD). Methods: We compared the pandemic-period health-care use between MCI/ADRD and matched non-MCI/ADRD patients. Using 4-year pre-pandemic data, we modeled three health-care use types (inpatient, outpatient, emergency encounters) to predict pandemic-period use, disaggregated for lockdown and post-lockdown periods. Observed health-care use was compared to the predicted. Proportional differences (confidence intervals) are reported. Results: Both MCI/ADRD and non-MCI/ADRD patients (n = 5479 each) experienced pandemic-related health-care use disruptions, which were significantly larger for the MCI/ADRD group for outpatient, -13.2% (-16.2%, -10.2%), and inpatient encounters, -12.8% (-18.4%, -7.3%). Large health-care disruptions during lockdown were similar for both groups. However, post-lockdown outpatient, -14.4% (-17.3%, -11.5%), and inpatient, -15.2% (-21.0%, -9.5%), disruptions were significantly greater for MCI/ADRD patients. Conclusion: MCI/ADRD patients experienced greater and sustained pandemic-related health-care use disruptions, highlighting the need for robust strategies to sustain their essential health care during pandemic-like catastrophes.

Sex differences in post-stroke cognitive decline: A population-based longitudinal study of nationally representative data.

BACKGROUND: Sex differences in post-stroke cognitive decline have not been systematically evaluated in a nationally representative cohort. We use a quasi-experimental design to investigate sex differences in rate of post-stroke cognitive decline. METHODS: Utilizing the event study design, we use the Health and Retirement Study (HRS) data (1996-2016) to evaluate the differences (percentage points [95% Confidence interval]) in the rate of change in cognitive function, measured using the modified version of the Telephone Interview for Cognitive Status (TICS-m) score, before and after incident stroke, and among patients with and without incident stroke. We estimated this event study model for the overall study population and separately fit the same model for male and female participants. RESULTS: Of 25,872 HRS participants included in our study, 14,459 (55.9%) were females with an overall mean age (SD) of 61.2 (9.3) years. Overall, 2,911 (11.3%) participants reported experiencing incident stroke. Participants with incident stroke (vs. no stroke) had lower baseline TICS-m score (15.6 vs. 16.1). Among participants with incident stroke, the mean pre-stroke TICS-m score was higher than the mean post-stroke TICS-m score (14.9 vs. 12.7). Event study revealed a significant short-term acceleration of cognitive decline for the overall population (4.2 [1.7-6.6] percentage points, p value = 0.001) and among female participants (5.0 [1.7-8.3] percentage points, p value = 0.003). We, however, found no evidence of long-term acceleration of cognitive decline after stroke. Moreover, among males, incident stroke was not associated with significant changes in rate of post-stroke cognitive decline. CONCLUSION: Females, in contrast to males, experience post-stroke cognitive deficits, particularly during early post-stroke period. Identifying the sex-specific stroke characteristics contributing to differences in post stroke cognitive decline may inform future strategies for reducing the burden of post-stroke cognitive impairment and dementia.

Contemporary Trends in the Nationwide Incidence of Primary Intracerebral Hemorrhage.

BACKGROUND: We report contemporary trends in nationwide incidence of intracerebral hemorrhage (ICH) across demographic and regional strata over a 15-year period. METHODS: Utilizing the Nationwide Inpatient Sample (2004-2018) and US Census Bureau data, we calculated ICH incidence rates for age, race/ethnicity, sex, and hospital region sub-cohorts across 5 consecutive 3-year periods (2004-2006 to 2016-2018). We fit Poisson and log binomial regression models to evaluate demographic and regional differences in ICH incidence and trends in prevalence of hypertension and past/current anticoagulant use among hospitalized ICH patients. RESULTS: Overall, the annual incidence rate (95% CI) of ICH per 100 000 was 23.15 (23.10-23.20). The 3-year incidence of ICH (per 100 000) increased from 62.79 in 2004 to 2006 to 78.86 in 2016 to 2018 (adjusted incidence rate ratio, CI: 1.11 [1.02-1.20]), coinciding with increased 3-year prevalence of hypertension and anticoagulant use among hospitalized ICH patients (adjusted risk ratio, CI: hypertension-1.16 [1.15-1.17]; anticoagulant use-2.30 [2.14-2.47]). We found a significant age-time interaction, whereby ICH incidence increased significantly faster among those aged 18 to 44 years (adjusted incidence rate ratio, CI: 1.10 [1.05-1.14]) and 45 to 64 years (adjusted incidence rate ratio, CI: 1.08 [1.03-1.13]), relative to those aged ≥75 years. CONCLUSIONS: Rising ICH incidence among young and middle-aged Americans warrants ICH prevention strategies targeting these economically productive age groups.

Investigation of endophenotype potential of decreased fractional anisotropy in pediatric bipolar disorder patients and unrelated offspring of bipolar disorder patients.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder associated with structural and functional brain abnormalities, some of which have been found in unaffected relatives as well. In this study, we examined the potential role of decreased fractional anisotropy (FA) as a BD endophenotype, in adolescents at high risk for BD. METHODS: We included 15 offspring of patients with BD, 16 pediatric BD patients, and 16 matched controls. Diffusion weighted scans were obtained on a 3T scanner using an echo-planar sequence. Scans were segmented using FreeSurfer. RESULTS: Our results showed significantly decreased FA in six brain areas of offspring group; left superior temporal gyrus (LSTG; P < .0001), left transverse temporal gyrus (LTTG; P = .002), left banks of the superior temporal sulcus (LBSTS; P = .002), left anterior cingulum (LAC; P = .003), right temporal pole (RTP; P = .004) and left frontal pole (LFP; P = .017). On analysis, LSTG, LAC, and RTP demonstrated a potential to be an endophenotype when comparing all three groups. FA values in three regions, LBSTS, LTTG, and LFP were increased only in controls. CONCLUSION: Our findings point at decreased FA as a possible endophenotype for BD, as they were found in children of patients with BD. Most of these areas were previously found to have morphological and functional changes in adult and pediatric BD, and are thought to play important roles in affected domains of functioning. Prospective follow up studies should be performed to detect reliability of decreased FA as an endophenotype and effects of treatment on FA.

Correlations between peripheral levels of inflammatory mediators and frontolimbic structures in bipolar disorder: an exploratory analysis.

BACKGROUND: Altered peripheral immune/inflammatory system and brain volumetric changes have been implicated in the pathophysiology of bipolar disorder (BD). This study aimed to evaluate how peripheral levels of cytokines are related to volumetric brain changes in euthymic patients with BD. METHODS: Euthymic patients with BD (n = 21) and healthy controls (n = 22) were enrolled in this exploratory study. Blood samples were collected on the same day of clinical assessment and neuroimaging. Cytokines were measured through cytometric bead array method. Neuroimaging data were acquired using a sagittal three-dimensional magnetic resonance imaging T1-weighted fast field echo sequence and was processed using FreeSurfer. RESULTS: Compared to controls, BD patients had significantly lower volumes in the cingulate, medial-orbitofrontal (MOF) and parahippocampal regions. We found a negative correlation between right MOF volume and interferon-gamma levels (ß = -0.431, P = .049) and a positive correlation between interleukin-10 levels and left posterior cingulate volume (ß = 0.457, P = .048). CONCLUSION: Our results support the involvement of inflammatory pathways in structural brain changes in BD.

Evidence of altered metabolism of cellular membranes in bipolar disorder comorbid with post-traumatic stress disorder.

In proton magnetic resonance spectroscopy (¹H MRS) studies, aberrant levels of choline-containing compounds that include glycerophosphocholine plus phosphocholine (GPC+PC), can signify alterations in the metabolism of cellular membrane phospholipids (MPLs) from a healthy baseline. In a recent ¹H MRS study, we reported increased GPC+PC in cortical and subcortical areas of adult patients with bipolar disorder I (BP-I). Post-traumatic stress disorder (PTSD) can worsen the severity of BP-I, but it is unclear whether the effect of a PTSD comorbidity in BP-I is associated with altered MPL metabolism. The purpose of this study was to re-investigate the ¹H MRS data to determine whether the regional extent of elevated GPC+PC was greater in BP-I patients with PTSD (BP-I/wPTSD) compared to BP-I without comorbid PTSD (BP-I/woPTSD) patients and healthy controls. GPC+PC levels from four brain areas [the anterior cingulate cortex (ACC), anterior-dorsal ACC, caudate, and putamen] were measured in 14 BP-I/wPTSD, 36 BP-I/woPTSD, and 44 healthy controls using a multi-voxel 1H MRS approach on a 3 Tesla system with high spatial resolution and absolute quantification. Results show a significant increase in GPC+PC levels from the caudate and putamen of BP-I/wPTSD patients compared to healthy controls (P<0.05) and in the putamen compared to BP-I/woPTSD patients (P<0.05). These findings are consistent with evidence of elevated degradation of MPLs in the neuropil that is more pronounced in BP-I patients with comorbid PTSD.

Altered neurochemistry in the anterior white matter of bipolar children and adolescents: a multivoxel 1H MRS study.

Abnormalities within frontal lobe gray and white matter of bipolar disorder (BD) patients have been consistently reported in adult and pediatric studies, yet little is known about the neurochemistry of the anterior white matter (AWM) in pediatric BD and how medication status may affect it. The present cross-sectional 3T 1H MRS study is the first to use a multivoxel approach to study the AWM of BD youth. Absolute metabolite levels from four bilateral AWM voxels were collected from 49 subjects between the ages of 8 and 18 (25 healthy controls (HC); 24 BD) and quantified. Our study found BD subjects to have lower levels of N-acetylaspartate (NAA) and glycerophosphocholine plus phosphocholine (GPC + PC), metabolites that are markers of neuronal viability and phospholipid metabolism and have also been implicated in adult BD. Further analysis indicated that the observed patterns were mostly driven by BD subjects who were medicated at the time of scanning and had an ADHD diagnosis. Although limited by possible confounding effects of mood state, medication, and other mood comorbidities, these findings serve as evidence of altered neurochemistry in BD youth that is sensitive to medication status and ADHD comorbidity.

Eotaxin-1/CCL11 correlates with left superior temporal gyrus in bipolar disorder: A preliminary report suggesting accelerated brain aging.

BACKGROUND: Neuropsychiatric disorders have been linked to immune mechanisms. Altered peripheral levels of eotaxin-1/CCL11; a cytokine implicated in allergic reactions and aging process; have been reported in bipolar disorder (BD). Several brain areas, especially the temporal lobe, seem to display volume loss and accelerated aging in BD. This study aimed at exploring potential associations between eotaxins and brain volumes in patients with BD compared to controls. METHODS: Twenty-two euthymic patients with BD and 22 controls were enrolled in this study. Serum levels of eotaxin-1/CCL11, eotaxin-2/CCL24 and eotaxin-3/CCL26 were determined alongside brain volumes. RESULTS: There were no differences in the levels of eotaxins between patients and controls. A negative correlation was found between eotaxin-1/CCL11 levels and left-hemisphere's superior-temporal volume only in BD patients, which persisted with covariate adjusted model. CONCLUSION: This study corroborates the emerging evidence of association between inflammation and brain volumes in BD. Our preliminary results also support the hypothesis of a possible role of eotaxin-1/CCL11 in accelerated brain aging in BD.

Stress, inflammation and hippocampal subfields in depression: A 7 Tesla MRI Study.

Experiencing stressful events throughout one's life, particularly childhood trauma, increases the likelihood of being diagnosed with Major Depressive Disorder (MDD). Raised levels of cortisol, and markers of inflammation such as Interleukin (IL-6) and C-reactive protein (CRP), have been linked to both early life stress and MDD. We aimed to explore the biological stress signatures of early stress and MDD on hippocampal sub regional volumes using 7 Tesla MRI imaging. A cohort of 71 MDD patients was compared against 46 age and sex-matched healthy volunteers. MDD subjects had higher averages of IL-6 and CRP levels. These differences were significant for IL-6 levels and trended for CRP. There were no significant group differences in any of the hippocampal subfields or global hippocampal volumes; further, there were no hippocampal subfield differences between MDD subjects with high levels of our biological stress measures and MDDs with normal levels.

Measures of possible allostatic load in comorbid cocaine and alcohol use disorder: Brain white matter integrity, telomere length, and anti-saccade performance.

Chronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM), telomere length, and impulsivity/attentional bias were obtained. WM (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by the telomere to single copy gene (T/S) ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2 = 0.56 and 0.51, both p < .005) but not years of alcohol use. CUD/AUD subjects showed more anti-saccade errors (p < .01), greater attentional bias scores (p < .001), and higher HDDM drift rates on cocaine-cue trials (Bayesian probability CUD/AUD > control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of WM as measured by RD (model R2 = 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load.