Advancing clinical trial readiness in white matter disease and related dementias: key steps for future research progress.

White matter disease, a broad-spectrum term that covers various types of white matter lesions and degeneration, is strongly related to age-related neurodegenerative disorders including Alzheimer's disease (AD), and vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's related dementias (ADRD). There is no specific treatment for white matter disease. Therefore, basic research and clinical studies are essential for future outcomes.

Loss of Sarm1 Mitigates Axonal Degeneration and Promotes Neuronal Repair After Ischemic Stroke.

Axonal degeneration is a core feature of ischemic brain injury that limits functional recovery (1). The pro-degenerative molecule Sarm1 is required for Wallerian axon degeneration after traumatic and chemotoxic nerve injuries (2), however it is unclear if a similar mechanism mediates axonal degradation after ischemic injury. Here we show that loss of Sarm1 results in profound attenuation of axonal degeneration after focal ischemia to the subcortical white matter.

Suboptimal medication possession ratio is associated with recurrent ischemic stroke in a veteran population.

Objectives: Recurrent stroke results in higher disability and mortality but might be mitigated through interventions that improve medication adherence. The medication possession ratio (MPR) is an objective proxy for adherence that may provide an individualized risk assessment for recurrent stroke.

Methods: This is a retrospective, longitudinal cohort study of patients with recent ischemic stroke or TIA referred to a Veterans Affairs vascular neurology outpatient clinic between 2010 and 2016.

White matter free water mediates the associations between placental growth factor, white matter hyperintensities, and cognitive status.

Introduction: Placental growth factor (PlGF) may regulate cerebrovascular permeability. We hypothesized that white matter interstitial fluid accumulation, estimated via magnetic resonance imaging (MRI) free water (FW), would explain the associations between elevated PlGF, white matter hyperintensities (WMH), and cognitive impairment.

Methods: MarkVCID consortium participants ≥55 years old with plasma PlGF and brain MRI were included.

Vascular Neurology Considerations for Antiamyloid Immunotherapy: A Science Advisory From the American Heart Association.

Antibodies directed at the amyloid-β peptide offer the prospect of disease-modifying therapy for early-stage Alzheimer disease but also carry the risk of brain edema or bleeding events, collectively designated amyloid-related imaging abnormalities. Introduction of the antiamyloid immunotherapies into practice is therefore likely to present a new set of questions for clinicians treating patients with cerebrovascular disease: Which manifestations of cerebrovascular disease should preclude, or permit, antibody treatment? Is it safe to prescribe amyloid immunotherapies to individuals who require antithrombotic treatment, or to administer thrombolysis to antibody-treated individuals with acute stroke? How should severe amyloid-related imaging abnormalities be managed? This science advisory summarizes the data and key considerations to guide these challenging decisions as the medical community collects further data and experience with these groundbreaking agents.

Development and Validation of a Flow-Dependent Endothelialized 3D Model of Intracranial Atherosclerotic Disease.

Intracranial atherosclerotic disease (ICAD) is a major cause of stroke globally, with mechanisms presumed to be shared with atherosclerosis in other vascular regions. Due to the scarcity of relevant animal models, testing biological hypotheses specific to ICAD is challenging. We developed a workflow to create patient-specific models of the middle cerebral artery (MCA) from neuroimaging studies, such as CT angiography.

Arterial Lesion Location and Outcomes of Intracranial Atherosclerotic Disease.

Intracranial atherosclerosis is a leading cause of stroke with a high recurrence rate despite treatment. Numerous factors are proposed to influence stroke recurrence due to intracranial atherosclerosis including lesion eccentricity, plaque characteristics, and computational fluid dynamic metrics, such as wall shear stress. An overlooked variable that intrinsically relates to intracranial atherosclerosis is the location of the arterial segment where the lesion occurs.

Recent Translational Research Models of Intracranial Atherosclerotic Disease.

Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke worldwide. However, research on the pathophysiology of ICAD is scarce due to the relative inaccessibility of histology samples and the lack of comprehensive experimental models. As a result, much of the current understanding of ICAD relies on research on extracranial atherosclerosis.

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

Background: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort.

Methods: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean -score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5).

Simultaneous isolation of intact brain cells and cell-specific extracellular vesicles from cryopreserved Alzheimer's disease cortex.

Background: The neuronal and gliaI populations within the brain are tightly interwoven, making isolation and study of large populations of a single cell type from brain tissue a major technical challenge. Concurrently, cell-type specific extracellular vesicles (EVs) hold enormous diagnostic and therapeutic potential in neurodegenerative disorders including Alzheimer's disease (AD).

New Method: Postmortem AD cortical samples were thawed and gently dissociated.

Late-Onset COL4A1 Mutation with Recurrent Ischemic and Hemorrhagic Strokes.

Introduction: Mutations in type IV collagen gene COL4A1 are identified as a cause of autosomal dominant cerebrovascular disease. We report an unusual late-onset presentation.

Case Report: A 64-year-old male was found to have an ischemic stroke and diffuse white matter changes.

Alterations in oligodendrocyte transcriptional networks reveal region-specific vulnerabilities to neurological disease.

Neurological disease is characterized the by dysfunction of specific neuroanatomical regions. To determine whether region-specific vulnerabilities have a transcriptional basis at cell-type-specific resolution, we analyzed gene expression in mouse oligodendrocytes across various brain regions. Oligodendrocyte transcriptomes cluster in an anatomical arrangement along the rostrocaudal axis.

Placental growth factor as a sensitive biomarker for vascular cognitive impairment.

Introduction: High-performing biomarkers measuring the vascular contributions to cognitive impairment and dementia are lacking.

Methods: Using a multi-site observational cohort study design, we examined the diagnostic accuracy of plasma placental growth factor (PlGF) within the MarkVCID Consortium (n = 335; CDR 0-1). Subjects underwent clinical evaluation, cognitive testing, MRI, and blood sampling as defined by Consortium protocols.

IL-17/CXCL5 signaling within the oligovascular niche mediates human and mouse white matter injury.

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO).

P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells.

Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo.

Regional Cerebral Small Vessel Disease (rCSVD) Score: A clinical MRI grading system validated in a stroke cohort.

Background: Current methods for quantitative assessment of cerebral small vessel disease (CSVD) ignore critical aspects of the disease, namely lesion type and regionality. We developed and tested a new scoring system for CSVD, "regional Cerebral Small Vessel Disease" (rCSVD) based on regional assessment of magnetic resonance imaging (MRI) features.

Methods: 141 patients were retrospectively included with a derivation cohort of 46 consecutive brain MRI exams and a validation cohort of 95 patients with known cerebrovascular disease.

Temporal Patterning of Neurofilament Light as a Blood-Based Biomarker for Stroke: A Systematic Review and Meta-Analysis.

Damage to axons is a core feature of ischemic stroke and cerebrovascular disease. The burden of axonal injury is correlated with the acute clinical deficits, the underlying burden of ischemic brain injury, the prognosis of recovery, and may be a meaningful therapeutic target for brain repair. Neurofilament light chain (NfL) has been identified as a blood-based biomarker that reflects neuroaxonal damage resulting from stroke.

Post-Stroke Cognitive Impairment and Dementia.

Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID.

Inflammation and the Link to Vascular Brain Health: Timing Is Brain.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the COVID-19 pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke.

Plasma amyloid beta, neurofilament light chain, and total tau in the Systolic Blood Pressure Intervention Trial (SPRINT).

Introduction: Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non-disease-specific neurodegeneration.

Methods: We examined the effect of intensive (< 120 mm Hg) versus standard (< 140 mm Hg) BP control on longitudinal changes in plasma amyloid beta (Aβ) and Aβ , total tau, and neurofilament light chain (NfL) in a subgroup of participants from the Systolic Blood Pressure Intervention Trial (N = 517).

Heterogeneity between proximal and distal aspects of occlusive thrombi on pretreatment imaging in acute ischemic stroke.

Background: The potential heterogeneity in occlusive thrombi caused by in situ propagation by secondary thrombosis after embolic occlusion could obscure the characteristics of original thrombi, preventing the clarification of a specific thrombus signature for the etiology of ischemic stroke. We aimed to investigate the heterogeneity of occlusive thrombi by pretreatment imaging.

Methods: Among consecutive stroke patients with acute embolic anterior circulation large vessel occlusion treated with thrombectomy, we retrospectively reviewed 104 patients with visible occlusive thrombi on pretreatment non-contrast computed tomography admitted from January 2015 to December 2018.

Elevated complement mediator levels in endothelial-derived plasma exosomes implicate endothelial innate inflammation in diminished brain function of aging humans.

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling.