Permutations of cerebrovascular pathologies in older adults with and without diabetes.

Permutations of cerebrovascular pathologies (CVP) in persons with diabetes mellitus (DM) have not been comprehensively investigated. Here, we examine diverse postmortem CVP outcomes, including permutations of single or mixed CVP, in 2163 older adults with or without DM who were followed in longitudinal studies of aging. Annual clinical evaluations included data to classify DM status by medical history (DM diagnosis), direct medication inspection (anti-diabetic therapy), and hemoglobin A1C level (≥6.

Association of late-life variability in hemoglobin A1C with postmortem neuropathologies.

Introduction: To study the relationship of late-life hemoglobin A1C (A1C) with postmortem neuropathology in older adults with and without diabetes mellitus (DM).

Methods: A total of 990 participants from five cohort studies of aging and dementia with at least two annually-collected A1C measures, who had autopsy. Neuropathologic evaluations documented cerebrovascular disease, Alzheimer's disease (AD), and other pathologies.

Review of Associations of Diabetes and Insulin Resistance With Brain Health in Three Harmonised Cohort Studies of Ageing and Dementia.

Diabetes increases the risk of dementia, and insulin resistance (IR) has emerged as a potential unifying feature. Here, we review published findings over the past 2 decades on the relation of diabetes and IR to brain health, including those related to cognition and neuropathology, in the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study (ROS/MAP/MARS), three harmonised cohort studies of ageing and dementia at the Rush Alzheimer's Disease Center (RADC). A wide range of participant data, including information on medical conditions such as diabetes and neuropsychological tests, as well as other clinical and laboratory-based data collected annually.

Brain phosphoproteomic analysis identifies diabetes-related substrates in Alzheimer's disease pathology in older adults.

Introduction: Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored.

Associations of renin-angiotensin system inhibitor use with brain insulin signaling and neuropathology.

Objective: To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology.

Methods: Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations.

Profiles of Lifestyle Health Behaviors and Postmortem Dementia-Related Neuropathology.

High engagement in lifestyle health behaviors appears to be protective against cognitive decline in aging. We investigated the association between patterns of modifiable lifestyle health behaviors and common brain neuropathologies of dementia as a possible mechanism. We examined 555 decedents from the Rush Memory and Aging Project, free of dementia at their initial concurrent report of lifestyle health behaviors of interest (physical, social, and cognitive activities, and healthy diet), and who underwent a postmortem neuropathology evaluation.

Understanding central nervous system fluid networks: Historical perspectives and a revised model for clinical neurofluid imaging.

The central nervous system (CNS) lacks traditionally defined lymphatic vasculature. However, CNS tissues and barriers compartmentalize the brain, spinal cord, and adjacent spaces, facilitating the transmittal of fluids, metabolic wastes, immune cells, and vital signals, while more conventional lymphatic pathways in the meninges, cervicofacial and paraspinal regions transmit efflux fluid and molecules to peripheral lymph and lymph nodes. Thus, a unique and highly organized fluid circulation network encompassing intraparenchymal, subarachnoid, dural, and extradural segments functions in unison to maintain CNS homeostasis.

Associations of Serum Insulin and Related Measures With Neuropathology and Cognition in Older Persons With and Without Diabetes.

Objective: To examine associations of serum insulin and related measures with neuropathology and cognition in older persons.

Methods: We studied 192 older persons (96 with diabetes and 96 without, matched by sex and balanced by age-at-death, education, and postmortem interval) from a community-based, clinical-pathologic study of aging, with annual evaluations including neuropsychological testing (summarized into global cognition and 5 cognitive domains) and postmortem autopsy. We assessed serum insulin, glucose, leptin, adiponectin, hemoglobin A1C, advanced glycation-end products (AGEs), and receptors for advanced glycation-end products, and calculated the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and adiponectin-to-leptin ratio.

Giant Arachnoid Granulations: A Systematic Literature Review.

Giant arachnoid granulations (GAGs) are minimally investigated. Here, we systematically review the available data in published reports to better understand their etiologies, nomenclature, and clinical significance. In the literature, 195 GAGs have been documented in 169 persons of varied ages (range, 0.

Giant Arachnoid Granulations: Diagnostic Workup and Characterization in Three Symptomatic Adults.

Giant arachnoid granulations (GAGs) are poorly investigated. Here, we document clinical findings associated with five new GAGs and illustrate the anatomical composition of these structures as well as diagnostic considerations in three symptomatic adults. The GAGs ranged from 1.

Ultrasound-mediated blood-brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer's disease.

Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer's disease (AD).

Methods: At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles.

The Vascular-Immune Hypothesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating and irreversible neurodegenerative disorder with unknown etiology. While its cause is unclear, a number of theories have been proposed to explain the pathogenesis of AD. In large part, these have centered around potential causes for intracerebral accumulation of beta-amyloid (βA) and tau aggregates.

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma.

Arachnoid granulations (AG) are poorly investigated. Historical reports suggest that they regulate brain volume by passively transporting cerebrospinal fluid (CSF) into dural venous sinuses. Here, we studied the microstructure of cerebral AG in humans with the aim of understanding their roles in physiology.

Neuropathology of the Common Forms of Dementia.

Dementias encompass a range of debilitating neurologic conditions. Here, we summarize the neuropathology of common forms of dementia, focusing on Alzheimer disease (AD) and related dementias. AD is part of a spectrum of neurodegenerative diseases that consists of various protein inclusions (ie, proteinopathies) but other brain abnormalities are also related to dementia.

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer's disease.

Perivascular spaces (PVS) drain brain waste metabolites, but their specific flow paths are debated. Meningeal pia mater reportedly forms the outermost boundary that confines flow around blood vessels. Yet, we show that pia is perforated and permissive to PVS fluid flow.

Association of Traumatic Brain Injury With and Without Loss of Consciousness With Neuropathologic Outcomes in Community-Dwelling Older Persons.

Importance: A history of traumatic brain injury (TBI) has been considered a risk factor for Alzheimer dementia. However, the specific association of TBI, even without loss of consciousness (LOC), with pathologic findings that underlie Alzheimer dementia, including Alzheimer disease (AD), non-AD neurodegenerative, and vascular pathologic findings, remains unclear.

Objective: To examine the association between TBI with and without LOC and neuropathologic findings in community-based cohorts.

Cerebrospinal fluid is a significant fluid source for anoxic cerebral oedema.

Cerebral oedema develops after anoxic brain injury. In two models of asphyxial and asystolic cardiac arrest without resuscitation, we found that oedema develops shortly after anoxia secondary to terminal depolarizations and the abnormal entry of CSF. Oedema severity correlated with the availability of CSF with the age-dependent increase in CSF volume worsening the severity of oedema.

What is 'Alzheimer's disease'? The neuropathological heterogeneity of clinically defined Alzheimer's dementia.

Purpose Of Review: Beta-amyloid with paired helical filaments (PHF)-tau neurofibrillary tangles define hallmark Alzheimer's disease neuropathologic changes (AD-NC). Yet persons with Alzheimer's dementia, defined broadly as an amnestic multidomain progressive dementia, often exhibit postmortem evidence of other neuropathologies including other neurodegenerative (Lewy body disease and transactive response DNA-binding protein disease) and vascular-related brain lesions. Clinicopathologic and epidemiologic analyses demonstrate the significance of these substrates, as coinciding neuropathologies mitigate the threshold for diagnosis of Alzheimer's dementia.

Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease.

Background Opening of the blood-brain barrier (BBB) induced with MRI-guided focused ultrasound has been shown in experimental animal models to reduce amyloid-β plaque burden, improve memory performance, and facilitate delivery of therapeutic agents to the brain. However, physiologic effects of this procedure in humans with Alzheimer disease (AD) require further investigation. Purpose To assess imaging effects of focused ultrasound-induced BBB opening in the hippocampus of human participants with early AD and to evaluate fluid flow patterns after BBB opening by using serial contrast-enhanced MRI.

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

Background And Purpose: Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults.

Cerebrospinal fluid influx drives acute ischemic tissue swelling.

Stroke affects millions each year. Poststroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment.

Intrathrombus polymer coating deposition: a pilot study of 91 patients undergoing endovascular therapy for acute large vessel stroke. Part I: Histologic frequency.

Background: Polymer coating embolism due to vascular medical device use is an increasingly recognized iatrogenic complication. This phenomenon has been linked with various adverse effects including neuroinflammation, acute ischemic stroke, cerebral hemorrhage, and death. Notably, procedure- and device-specific risks of this complication are poorly investigated.

Hydrophilic Polymer Embolism: Implications for Manufacturing, Regulation, and Postmarket Surveillance of Coated Intravascular Medical Devices.

Hydrophilic polymers are ubiquitously applied as surface coatings on catheters and intravascular medical technologies. Recent clinical literature has heightened awareness on the complication of hydrophilic polymer embolism, the phenomenon wherein polymer coating layers separate from catheter and device surfaces, and may be affiliated with a range of unanticipated adverse reactions. Significant system barriers have limited and delayed reporting on this iatrogenic complication, the full effects of which remain underrecognized by healthcare providers and manufacturers of various branded devices.

Expanding the neurodevelopmental phenotype of PURA syndrome.

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals.