Daniel Todd Laskowitz

INTRODUCTION: Whether APOE ε4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown. METHODS: In Framingham Heart Study Offspring participants, we related antecedent echocardiographic remodeling (Examinations 4–6) to repeated brain MRI, and cardiac magnetic resonance phenotypes to regional cortical morphometry, testing cardiac × APOE ε4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen. RESULTS: APOE ε4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion (β=−0.00858, P=1.45×10⁻⁴, q=0.0023; N=1,305; 3,787 MRI observations), the only FDR-significant result of 16 longitudinal tests, including with participant-specific MRI-time slopes (q=0.034); it weakened when intracranial volume × MRI time was modeled. Four regional ventricular cardiac × APOE ε4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE ε4-dependent association with left middle-occipital cortical-thickness variability (whole-brain q=0.017; permutation P=0.041) that persisted after ventricular adjustment. Cardiac phenotypes and trajectories showed no FDR-significant APOE ε4-dependent associations with plasma Aβ42/40, p-tau181, GFAP, or NfL, and adjustment for these biomarkers changed the regional interactions by at most 3.2%. Allen Human Brain Atlas data showed cholesterol-biosynthesis enrichment in the right superior frontal cortex, implicated by the LV end-systolic volume interaction, but without convergent pathway evidence. DISCUSSION: APOE ε4 modified atrial–brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed. Highlights: APOE ε4 modified how left atrial remodeling related to later brain ventricle growth. It was the only FDR-significant result of 16 tests and persisted with random slopes. In ε4 carriers, larger LA volume tracked lower occipital thickness variability. This atrial–cortical association was independent of LV mass and ejection fraction. Exploratory: HbA1c related to LV end-diastolic volume differently by APOE ε4 status.

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Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with significant neurological morbidity. In current practice, there are limited pharmacological interventions to reduce the neurologic and functional deficits after SAH. The current study tests a novel therapy designed to reduce neuroinflammatory responses and improve functional outcomes in a clinically relevant murine model of SAH. The effect of MW189, an anti-inflammatory small molecule investigational drug, was tested in a murine model of SAH induced by endovascular filament perforation. Male C57BL/6 J mice (10-12 weeks old) were treated with MW189 at a dose of 5 mg/kg in 100 µl 0.9% NaCl or vehicle delivered by intraperitoneal injection at 30 min post-SAH and every 12 h (q12h) for 7 days. Functional outcomes, including Rotarod latency, neuroseverity score, and gait performance were assessed, as well as the effect of treatment on histological evidence of microgliosis, using unbiased stereological measurements with TMEM119 immunohistochemistry. To assess sex effects, functional outcomes were determined in a separate cohort of female mice using the same SAH induction/treatment paradigm. In male mice, treatment with MW189 was associated with durable functional improvements during the 35-day testing period, including improvements in Rotarod latency, neuroseverity score, CatWalk gait speed, and shortened run duration. MW189 treatment reduced microglial activation as assessed by TMEM119 staining. In female animals, there was overall increased mortality following SAH induction, but MW189 treatment was associated with increased survival compared with vehicle treatment, significant improvements in Rotarod latency and CatWalk run duration, and trends toward improvement in CatWalk speed and neuroseverity score. Treatment with MW189 was associated with durable functional improvement in a murine model of SAH. MW189-treated mice also showed a reduction in microgliosis and several proinflammatory proteins consistent with an anti-inflammatory mechanism of action.

Traumatic brain injury (TBI) presents a major biomedical challenge due to its complex biomechanics and the heterogeneous cellular responses it elicits, including neuronal death, glial activation, and blood–brain barrier disruption. Traditional in vitro models, including 2D neuronal cultures, brain slices and transwell systems, have provided valuable insights into molecular and cellular biology but remain limited by their lack of human-specific architecture, vascularization, and neurovascular interactions. The purpose of this review is to systematically examine advances in in vitro TBI modeling, with particular attention to studies leveraging human induced pluripotent stem cell (iPSC)-derived neural and vascular tissues, organoids, hydrogel scaffolds, microfluidic platforms, and mechanical injury. We highlight how the integration of neurovascular unit (NVU) components has improved the physiological and functional relevance of these models. Finally, we identify key limitations, including variability in organoid maturation, incomplete vascularization, and lack of methodological standardization, and outline future directions for improving translational fidelity. Therefore, this review contributes to a critical evaluation of emerging technologies and their potential to advance neurotrauma research and therapeutic discovery.

Intracerebral hemorrhage (ICH) remains the least treatable form of stroke, with inflammation implicated as a major pathophysiological feature. Hence, this study sought to associate serum proteins and hormones associated with inflammation and ICH outcomes. Patients presenting to Duke University Hospital with computed tomography-verified spontaneous, supratentorial, non-traumatic ICH within 24 h of symptom onset were prospectively recruited. In this pilot study, equal numbers of men and women and Black and White individuals were included and matched by a 6-month modified Rankin Score (mRS). The primary analyses were the correlation of L-ratios (LR; Log2(Day 2/Day 1 concentrations)) of serum gonadal hormones and neuroinflammatory proteins with mRS > 3 at 6 months. A total of 40 participants were included in this pilot study. LRs were significantly higher for C-reactive protein (CRP; p = 0.013) and lower for interleukin-6 (IL-6; p = 0.026) and surfactant protein-D (p = 0.036) in participants with unfavorable outcomes at 6 months after ICH. Further, higher CRP (p = 0.02) and lower IL-6 (p = 0.035) and surfactant protein-D (p = 0.041) LRs were associated with mRS > 3 at 6 months after ICH in multiple logistic regression analyses, adjusted for race and sex. The relationship amongst gonadal hormones, neuroinflammatory proteins, and ICH outcome is complex. In this pilot study, unfavorable outcomes after ICH may have been associated with selected inflammatory biomarkers. A larger scale study is warranted to define interactions between hormones, proteins, and their effects on ICH outcomes.

Background/Objectives: Traumatic brain injury (TBI) is a complex condition and a leading cause of injury-related disability and death, with significant impacts on patient outcomes. Extracranial organ involvement plays a critical role in the outcome of patients following TBI. Method: This review aims to provide a comprehensive overview of the pathophysiology, clinical presentation, and challenges in diagnosing patients with autonomic dysfunction after TBI. The databases used in this review include PubMed/MEDLINE, Cochrane Central Register, and Scopus. Results: Of 172 articles identified for screening, 98 were ultimately included in the review. Conclusion: This review summarized the current evidence on the pathophysiology, clinical presentation, and diagnosis of early autonomic dysfunction. It also emphasizes the effects of autonomic dysfunction on end-organ damage. These insights aim to guide clinicians and researchers toward improving the care for and understanding of autonomic dysfunction in TBI patients, while underscoring the need for further research in this area.

Aneurysmal subarachnoid hemorrhage (aSAH) may be associated with cerebral vasospasm, which can lead to delayed cerebral ischemia, infarction, and worsened functional outcomes. The delayed nature of cerebral ischemia secondary to SAH-related vasculopathy presents a window of opportunity for the evaluation of well-tolerated neuroprotective agents administered soon after ictus. Secondary ischemic injury in SAH is associated with increased extracellular glutamate, which can overactivate NMDA receptors (NMDARs), thereby triggering NMDAR-mediated cellular damage. In this study, we have evaluated the effect of the pH-sensitive GluN2B-selective NMDAR inhibitor, NP10679, on neurologic impairment after SAH. This compound demonstrates a selective increase in potency at the acidic extracellular pH levels that occur in the setting of ischemia. We found that NP10679 produced durable improvement of behavioral deficits in a well-characterized murine model of SAH, and these effects were greater than those produced by nimodipine alone, the current standard of care. In addition, we observed an unexpected reduction in SAH-induced luminal narrowing of the middle cerebral artery. Neither nimodipine nor NP10679 alter each other9s pharmacokinetic profile, suggesting no obvious drug-drug interactions. Based on allometric scaling of both toxicological and efficacy data, the therapeutic margin in man should be at least 2. These results further demonstrate the utility of pH-dependent neuroprotective agents and GluN2B-selective NMDAR inhibitors as potential therapeutic strategies for the treatment of aSAH. Significance Statement This report describes the properties and utility of the GluN2B-selective pH-sensitive NMDA receptor inhibitor, NP10679, in a well-characterized rodent model of subarachnoid hemorrhage. We show that the administration of NP10679 improves long-term neurological function following subarachnoid hemorrhage, and that in rats there are no drug-drug interactions between NP10679 and nimodipine, the standard of care for this indication.

The disruption of the blood–brain barrier (BBB) in Alzheimer’s Disease (AD) is largely influenced by amyloid beta (Aβ). In this study, we developed a high-throughput microfluidic BBB model devoid of a physical membrane, featuring endothelial cells interacting with an extracellular matrix (ECM). This paper focuses on the impact of varying concentrations of Aβ_1–42 oligomers on BBB dysfunction by treating them in the luminal. Our findings reveal a pronounced accumulation of Aβ_1–42 oligomers at the BBB, resulting in the disruption of tight junctions and subsequent leakage evidenced by a barrier integrity assay. Additionally, cytotoxicity assessments indicate a concentration-dependent increase in cell death in response to Aβ_1–42 oligomers (LC50 ~ 1 µM). This study underscores the utility of our membrane-free vascular chip in elucidating the dysfunction induced by Aβ with respect to the BBB.

Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (–2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.

Acute traumatic spinal cord injury (SCI) can be a devastating and costly event for individuals, their families, and the health system as a whole. Prognosis is heavily dependent on the physical extent of the injury and the severity of neurological dysfunction. If not treated urgently, individuals can suffer exacerbated secondary injury cascades that may increase tissue injury and limit recovery. Initial recognition and rapid treatment of acute SCI are vital to limiting secondary injury, reducing morbidity, and providing the best chance of functional recovery. This article aims to review the pathophysiology of SCI and the most up-to-date management of the acute traumatic SCI, specifically examining the modern approaches to surgical treatments along with the ethical limitations of research in this field.