Pathologic subtyping of Alzheimer's disease brain tissue reveals disease heterogeneity.

In recent years, multiple groups have shown that what is currently thought of as "Alzheimer's Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 pathologic variables recorded on 666 AD brain autopsies to better define how co-pathologies and ethnicity relate to established AD subtypes.

Bridging the gap: Multi-omics profiling of brain tissue in Alzheimer's disease and older controls in multi-ethnic populations.

Introduction: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD.

Methods: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors.

The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors.

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations.

Introduction: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD.

Methods: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors.

Clonal CD8 T Cells Accumulate in the Leptomeninges and Communicate with Microglia in Human Neurodegeneration.

Murine studies have highlighted a crucial role for immune cells in the meninges in surveilling the central nervous system (CNS) and influencing neuroinflammation. However, how meningeal immunity is altered in human neurodegeneration and its effects on CNS inflammation is understudied. We performed the first single-cell analysis of the transcriptomes and T cell receptor (TCR) repertoire of 104,635 immune cells from 55 postmortem human brain and leptomeningeal tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease.

Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration.

Recent murine studies have highlighted a crucial role for the meninges in surveilling the central nervous system (CNS) and influencing CNS inflammation. However, how meningeal immunity is altered in human neurodegeneration and its potential effects on neuroinflammation is understudied. In the present study, we performed single-cell analysis of the transcriptomes and T cell receptor repertoire of 72,576 immune cells from 36 postmortem human brain and leptomeninges tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease.

Gastrointestinal bleeding in a patient with a continuous-flow biventricular assist device.

The association between continuous-flow left ventricular assist devices (CF-LVADs) and gastrointestinal (GI) bleeding from angiodysplasia is well recognized. However, the association between continuous-flow biventricular assist devices (CF-BIVADs) and bleeding angiodysplasia is less understood. We report a case of GI bleeding from a patient with a CF-BIVAD.

Damage to Arousal-Promoting Brainstem Neurons with Traumatic Brain Injury.

Study Objectives: Coma and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI.

Methods: Postmortem examination of 8 TBI patients and 10 controls.

Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area.

Study Objectives: To examine the integrity of sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients.

Methods: Postmortem examination of five narcolepsy and eight control brains.

Results: VLPO galanin neuron count did not differ between narcolepsy patients (11,151 ± 3,656) and controls (13,526 ± 9,544).

Damage to histaminergic tuberomammillary neurons and other hypothalamic neurons with traumatic brain injury.

The need for increased sleep after traumatic brain injury is a common and disabling complaint, yet its etiology is unknown. Previous studies have demonstrated diffuse damage to various hypothalamic systems, but the integrity of the histaminergic tuberomammillary nucleus, a major arousal-promoting system located in the posterior hypothalamus, has never been examined in head trauma patients. Here, we demonstrate that severe head trauma is associated with a marked loss (41%) of histaminergic neurons.

Increase of histaminergic tuberomammillary neurons in narcolepsy.

Objective: Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy.

Diagnostic yield of stereotactic needle-biopsies of sub-cubic centimeter intracranial lesions.

Background: Stereotactic brain biopsies are widely used for establishing the diagnosis of intracranial lesions. Here we examine whether stereotactic biopsy of smaller brain lesions, defined for this study as being less than 1 cubic centimeter (1 cc) in volume, are associated with lowered diagnostic yield.

Methods: We conducted a retrospective analysis of 267 consecutive patients who underwent stereotactic brain biopsy between 2007 and 2011.

Illusion of stroke: intravascular lymphomatosis.

We describe an unusual case of cerebral intravascular lymphomatosis wherein the patient presented with multiple embolic strokes predominantly in the posterior circulation. Using this case as an illustration, we review the literature of this malignancy, which consists of extranodal diffuse large B-cell lymphoma. For patients with recurrent stroke-like events without cardiac risk factors, the accurate diagnosis requires a high index of suspicion by the neurologist and a brain biopsy specimen demonstrating lymphoma cells within the lumen of cerebral blood vessels.

Polyradiculopathies from schwannomatosis.

We describe a case of schwannomatosis presenting as radicular pain and numbness in multiple radicular nerve distributions. There were multiple peripheral nerve tumors detected by magnetic resonance imaging (MRI) at the left vestibular nerve, cauda equina, right radial nerve, thoracic paraspinal nerve, and brachial plexi. Several resected tumors have features of schwannomas, including hypercellular Antoni A areas, hypocellular Antoni B areas, Verocay bodies, and hyalinized blood vessels.

A pregnant female with a large intracranial mass: Reviewing the evidence to obtain management guidelines for intracranial meningiomas during pregnancy.

Introduction: Non-obstetric surgery for intracranial meningioma is uncommon during pregnancy and poses significant risks to both the mother and the fetus. We present a case of a parturient that presented with acute mental status changes and we illustrate the decision making process that resulted in a best-possible outcome.

Case Description: A woman at 29-week gestation presented with acute language and speech deficits and deteriorating mental status after 2 weeks of headache.

Post-transcriptional regulation of O(6)-methylguanine-DNA methyltransferase MGMT in glioblastomas.

Background: The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) confers therapeutic resistance to DNA alkylating agents, including temozolomide. It is largely believed that MGMT promoter methylation is associated with down regulation of MGMT transcription and corresponding protein expression, thereby predisposing tumor cells to the toxic effect of temozolomide. Here we rigorously examined this underlying assumption.

Sources of error in neuropathology intraoperative diagnosis.

Objective: The goal of this study was to optimize intraoperative neuropathology consultations by studying trends and sources of diagnostic error. We hypothesized that errors in intraoperative diagnoses would have sampling, technical, and interpretive sources. The study also audited diagnostic strengths, weaknesses and trends associated with increasing experience.