Neurohistopathological findings of the brain parenchyma after long-term deep brain stimulation: Case series and systematic literature review.

Introduction: Efficacy of deep brain stimulation (DBS) is established for several movement and psychiatric disorders. However, the mechanism of action and local tissue changes are incompletely described. We describe neurohistopathological findings of 9 patients who underwent DBS for parkinsonism and performed a systematic literature review on postmortem pathologic reports post-DBS.

Elevated serum neurologic biomarker profiles after cardiac arrest in a porcine model.

Introduction: Swine exhibit cerebral cortex mitochondrial dysfunction and neuropathologic injury after hypoxic cardiac arrest treated with hemodynamic-directed CPR (HD-CPR) despite normal Cerebral Performance Category scores. We analyzed the temporal evolution of plasma protein biomarkers of brain injury and inflammatory cytokines, as well as cerebral cortical mitochondrial injury and neuropathology for five days following pediatric asphyxia-associated cardiac arrest treated with HD-CPR.

Methods: One-month-old swine underwent asphyxia associated cardiac arrest, 10-20 min of HD-CPR (goal SBP 90 mmHg, coronary perfusion pressure 20 mmHg), and randomization to post-ROSC survival duration (24, 48, 72, 96, 120 h; n = 3 per group) with standardized post-resuscitation care.

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer's disease.

Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 25-80 years old without a known history of dementia, and its prevalence was comparable to the locus coeruleus (LC).

Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations.

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted.

Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest.

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage.

Normoxic Management during Cardiopulmonary Bypass Does Not Reduce Cerebral Mitochondrial Dysfunction in Neonatal Swine.

Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury.

Early Impairment of Cerebral Bioenergetics After Cardiopulmonary Bypass in Neonatal Swine.

We previously demonstrated cerebral mitochondrial dysfunction in neonatal swine immediately following a period of full-flow cardiopulmonary bypass (CPB). The extent to which this dysfunction persists in the postoperative period and its correlation with other markers of cerebral bioenergetic failure and injury is unknown. We utilized a neonatal swine model to investigate the early evolution of mitochondrial function and cerebral bioenergetic failure after CPB.

Repetitive head impacts induce neuronal loss and neuroinflammation in young athletes.

Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Further, the symptoms endorsed by young individuals with early disease are not fully explained by the extent of p-tau deposition, severely hampering development of therapeutic interventions.

Determinants of astrocytic pathology in stem cell models of primary tauopathies.

Astrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). In all of these diseases, astrocytic tau consists mostly of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in CTE. Even the rare astrocytic tau aggregates seen in Pick's disease appear to contain both 3R and 4R tau.

Determinants of Astrocytic Pathology in Stem Cell Models of Primary Tauopathies.

Astrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). In all cases, astrocytic tau consists exclusively of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in CTE. The reasons for this and the mechanisms by which astrocytic tau aggregates form remain unclear.

Alcohol inhibits sociability via serotonin inputs to the nucleus accumbens.

Social interaction is a core component of motivational behavior that is perturbed across multiple neuropsychiatric disorders, including alcohol use disorder (AUD). Positive social bonds are neuroprotective and enhance recovery from stress, so reduced social interaction in AUD may delay recovery and lead to alcohol relapse. We report that chronic intermittent ethanol (CIE) induces social avoidance in a sex-dependent manner and is associated with hyperactivity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN).

Alcohol inhibits sociability via serotonin inputs to the nucleus accumbens.

Social interaction is a core component of motivational behavior that is perturbed across multiple neuropsychiatric disorders, including alcohol use disorder (AUD). Positive social bonds are neuroprotective and enhance recovery from stress, so reduced social interaction in AUD may delay recovery and lead to alcohol relapse. We report that chronic intermittent ethanol (CIE) induces social avoidance in a sex-dependent manner and is associated with hyperactivity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN).

Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer's disease.

Alzheimer's disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in the brainstem, but a causal relationship has not been firmly established. This is due in part to a dearth of animal models that recapitulate early AD neuropathology and symptoms.

Characterization of the Tau Interactome in Human Brain Reveals Isoform-Dependent Interaction with 14-3-3 Family Proteins.

Despite exhibiting tau phosphorylation similar to Alzheimer's disease (AD), the human fetal brain is remarkably resilient to tau aggregation and toxicity. To identify potential mechanisms for this resilience, we used co-immunoprecipitation (co-IP) with mass spectrometry to characterize the tau interactome in human fetal, adult, and Alzheimer's disease brains. We found significant differences between the tau interactome in fetal and AD brain tissue, with little difference between adult and AD, although these findings are limited by the low throughput and small sample size of these experiments.

Thioflavin S Staining and Amyloid Formation Are Unique to Mixed Tauopathies.

Tau phosphorylation, aggregation, and toxicity are the main drivers of neurodegeneration in multiple tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau. Although aggregation and amyloid formation are often assumed to be synonymous, the ability of tau aggregates in different diseases to form amyloids in vivo has not been systematically studied. We used the amyloid dye Thioflavin S to look at tau aggregates in mixed tauopathies such as AD and primary age-related tauopathy, as well as pure 3R or 4R tauopathies such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration.

Pediatric Extracorporeal Cardiopulmonary Resuscitation: Development of a Porcine Model and the Influence of Cardiopulmonary Resuscitation Duration on Brain Injury.

Background The primary objective was to develop a porcine model of prolonged (30 or 60 minutes) pediatric cardiopulmonary resuscitation (CPR) followed by 22- to 24-hour survival with extracorporeal life support, and secondarily to evaluate differences in neurologic injury. Methods and Results Ten-kilogram, 4-week-old female piglets were used. First, model development established the technique (n=8).

Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome.

Neuroinflammation is one of the main mechanisms leading to neuronal death and dysfunction in neurodegenerative diseases. The role of microglia as primary mediators of inflammation is unclear in Leigh syndrome (LS) patients. This study aims to elucidate the role of microglia in LS progression by a detailed multipronged analysis of LS neuropathology, mouse and human induced pluripotent stem cells models of Leigh syndrome.

Human Brainstem and Cerebellum Atlas: Chemoarchitecture and Cytoarchitecture Paired to MRI.

Lesion localization is the basis for understanding neurologic disease, which is predicated on neuroanatomical knowledge carefully cataloged from histology and imaging atlases. However, it is often difficult to correlate clinical images of brainstem injury obtained by MRI scans with the details of human brainstem neuroanatomy represented in atlases, which are mostly based on cytoarchitecture using Nissl stain or a single histochemical stain, and usually do not include the cerebellum. Here, we report a high-resolution (200 μm) 7T MRI of a cadaveric male human brainstem and cerebellum paired with detailed, coregistered histology (at 2 μm single-cell resolution) of the immunohistochemically stained cholinergic, serotonergic, and catecholaminergic (dopaminergic, noradrenergic, and adrenergic) neurons, in relationship to each other and to the cerebellum.

Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.

Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication.