Vascular Inflammation in Aging and Neurodegeneration

Editors

Donghui Zhu

Stony Brook University

Axel Montagne

University of Edinburgh

Zhen Zhao

University of Southern California

Impact

Review

11 August 2022

The role of neutrophils in the dysfunction of central nervous system barriers

Bruno Santos-Lima

, 3 more and

Gabriela Constantin

Leukocyte migration into the central nervous system (CNS) represents a central process in the development of neurological diseases with a detrimental inflammatory component. Infiltrating neutrophils have been detected inside the brain of patients with several neuroinflammatory disorders, including stroke, multiple sclerosis and Alzheimer’s disease. During inflammatory responses, these highly reactive innate immune cells can rapidly extravasate and release a plethora of pro-inflammatory and cytotoxic factors, potentially inducing significant collateral tissue damage. Indeed, several studies have shown that neutrophils promote blood-brain barrier damage and increased vascular permeability during neuroinflammatory diseases. Recent studies have shown that neutrophils migrate into the meninges and choroid plexus, suggesting these cells can also damage the blood-cerebrospinal fluid barrier (BCSFB). In this review, we discuss the emerging role of neutrophils in the dysfunction of brain barriers across different neuroinflammatory conditions and describe the molecular basis and cellular interplays involved in neutrophil-mediated injury of the CNS borders.

10,156 views

32 citations

Receiver operating characteristic curve (ROC) analyses of the stress hyperglycemia ratio (SHR), admission fasting plasma glucose (FPG), and admission random plasma glucose (RPG) for the prediction of outcomes. Training dataset: (A) moderate-to-severe cerebral edema (CED), (B) 90-day poor functional outcome, and (C) 90-day death. Validation dataset: (D) moderate-to-severe CED, (E) 90-day poor functional outcome, and (F) 90-day death.

Original Research

01 September 2022

The stress hyperglycemia ratio is associated with the development of cerebral edema and poor functional outcome in patients with acute cerebral infarction

Yilun Deng

, 6 more and

Ming Liu

3,454 views

17 citations

Review

28 April 2022

Pathophysiological Mechanisms Underlying Idiopathic Normal Pressure Hydrocephalus: A Review of Recent Insights

Phillip A. Bonney

, 10 more and

Darrin J. Lee

The pathophysiologic mechanisms underpinning idiopathic normal pressure hydrocephalus (iNPH), a clinically diagnosed dementia-causing disorder, continue to be explored. An increasing body of evidence implicates multiple systems in the pathogenesis of this condition, though a unifying causative etiology remains elusive. Increased knowledge of the aberrations involved has shed light on the iNPH phenotype and has helped to guide prognostication for treatment with cerebrospinal fluid diversion. In this review, we highlight the central role of the cerebrovasculature in pathogenesis, from hydrocephalus formation to cerebral blood flow derangements, blood-brain barrier breakdown, and glymphatic pathway dysfunction. We offer potential avenues for increasing our understanding of how this disease occurs.

11,413 views

22 citations

T cell aging. (A) With age, thymic output drastically decreases and the naïve T cell compartment is maintained by homeostatic proliferation. (B) Naïve CD4+ T cells slightly decrease in absolute number with age; while naïve CD8+ T cells drastically decrease with age. (C) The number of T cell receptors—also called the T cell repertoire—declines with age, while clonal sizes increase with age. This process is called T cell receptor contraction. (D) T effector memory CD45 RA (TEMRA) cells; exhausted T cells expressing PD-1, TIM-3, and LAG-3; and senescent T cells accumulating with age.

Mini Review

12 April 2022

Ryu Watanabe

and

Motomu Hashimoto

7,883 views

17 citations

Mini Review

10 March 2022

Microvascular Changes in Parkinson’s Disease- Focus on the Neurovascular Unit

Gesine Paul

and

Osama F. Elabi

Vascular alterations emerge as a common denominator for several neurodegenerative diseases. In Parkinson’s disease (PD), a number of observations have been made suggesting that the occurrence of vascular pathology is an important pathophysiological aspect of the disease. Specifically, pathological activation of pericytes, blood-brain barrier (BBB) disruption, pathological angiogenesis and vascular regression have been reported. This review summarizes the current evidence for the different vascular alterations in patients with PD and in animal models of PD. We suggest a possible sequence of vascular pathology in PD ranging from early pericyte activation and BBB leakage to an attempt for compensatory angiogenesis and finally vascular rarefication. We highlight different pathogenetic mechanisms that play a role in these vascular alterations including perivascular inflammation and concomitant metabolic disease. Awareness of the contribution of vascular events to the pathogenesis of PD may allow the identification of targets to modulate those mechanisms. In particular the BBB has for decades only been viewed as an obstacle for drug delivery, however, preservation of its integrity and/or modulation of the signaling at this interface between the blood and the brain may prove to be a new avenue to take in order to develop disease-modifying strategies for neurodegenerative disorders.

10,711 views

47 citations

Schematic representation of vascular calcifications along the central nervous system (CNS) vascular network. Cellular and structural diversity of the vascular network along the arterio-venous axis (A). In arteries, lumen forming endothelial cells (EC) are separated from circumferentially wrapped vascular smooth muscle cells (VSMC) by a basement membrane (BM). Capillary endothelial cells are covered by pericytes (PC) with a prominent cell body and slender processes with which they share the basement membrane and are in direct contact. Capillaries transition into veins which have an incomplete mural cell coverage. The entire vasculature is covered by astrocyte end-feet and occasionally innervated by nerve fibers. Between VSMC layer and astrocyte end-feet reside perivascular fibroblasts (PVF) and perivascular macrophages (PVM). Arterial calcifications can be intimal (B), resulting from atherosclerotic plaque in the lumen, as well as medial (C), due to phenotypic alterations of VSMCs leading to mineralization of extracellular matrix. It is not known to what extent PVM and PVF become modified and contribute to the pathophysiology. Capillary calcifications (D) are characterized by the appearance of mineralized “beads” on the capillary wall, which protrude into brain parenchyma. While it is known that capillary calcifications elicit strong glial reactions, changes in pericytes and endothelial cells in calcified capillaries are poorly understood. Calcifications are depicted as yellow spheres or polygons. BM, basement membrane; CAA, calcification-associated astrocyte; CAM, calcification-associated microglia; EC, endothelium; PVF, perivascular fibroblast; PVM, perivascular macrophage; VSMC, vascular smooth muscle cell.

Review

02 March 2022

The Interplay Between Brain Vascular Calcification and Microglia

Upasana Maheshwari

, 2 more and

Annika Keller

Vascular calcifications are characterized by the ectopic deposition of calcium and phosphate in the vascular lumen or wall. They are a common finding in computed tomography scans or during autopsy and are often directly related to a pathological condition. While the pathogenesis and functional consequences of vascular calcifications have been intensively studied in some peripheral organs, vascular calcification, and its pathogenesis in the central nervous system is poorly characterized and understood. Here, we review the occurrence of vessel calcifications in the brain in the context of aging and various brain diseases. We discuss the pathomechanism of brain vascular calcification in primary familial brain calcification as an example of brain vessel calcification. A particular focus is the response of microglia to the vessel calcification in the brain and their role in the clearance of calcifications.

13,929 views

18 citations

Original Research

30 November 2021

The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study

Jaime Ramos-Cejudo

, 15 more and

Ricardo S. Osorio

4,960 views

28 citations

Review

08 September 2021

Vascular Dementia and Underlying Sex Differences

Firoz Akhter

, 3 more and

Donghui Zhu

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer’s disease (AD); where Alzheimer’s accounts for 60–70% of cases of dementia and VaD accounts for 20% of all dementia cases. VaD is defined as a reduced or lack of blood flow to the brain that causes dementia. VaD is also known occasionally as vascular contributions to cognitive impairment and dementia (VCID) or multi-infarct dementia (MID). VCID is the condition arising from stroke and other vascular brain injuries that cause significant changes to memory, thinking, and behavior, and VaD is the most severe stage while MID is produced by the synergistic effects caused by multiple mini strokes in the brain irrespective of specific location or volume. There are also subtle differences in the presentation of VaD in males and females, but they are often overlooked. Since 1672 when the first case of VaD was reported until now, sex and gender differences have had little to no research done when it comes to the umbrella term of dementia in general. This review summarizes the fundamentals of VaD followed by a focus on the differences between sex and gender when an individual is diagnosed. In addition, we provide critical evidence concerning sex and gender differences with a few of the main risk factors of VaD including pre-existing health conditions and family history, gene variants, aging, hormone fluctuations, and environmental risk factors. Additionally, the pharmaceutical treatments and possible mitigation of risk factors is explored.

14,540 views

55 citations