Recent advances in mechanistic,therapeutic,and diagnostic research of cerebrovascular diseases: updates from brain & BrainPET 2022

Abstract

Cerebrovascular dysfunction and diseases are major causes of mortality, morbidity, and poor quality of patient life. Despite the enormous socioeconomic burden imposed by these conditions, therapeutic options remain scarce. However, rigorous preclinical and clinical research has augmented our mechanistic understanding of cerebrovascular diseases and underlying pathophysiological processes, and there is some optimism that novel therapeutic strategies may be developed in the next decade. This special collection comprises preclinical and clinical studies from investigators who presented their work at the Brain & BrainPET 2022 conference. It highlights recent research on cerebrovascular disease mechanisms, diagnosis, and treatments. A focus is set on cerebroprotective strategies during acute and chronic cerebral ischemia and predicting stroke risk and unfavorable outcomes. The special collection also sheds light on emerging novel treatment targets and management strategies in the pursuit of better clinical outcomes for patients with cerebrovascular diseases.

Cerebrovascular dysfunction and related diseases, such as ischemic stroke, hemorrhagic stroke, and vascular cognitive impairment, severely impact patients’ daily living and pose a substantial medical and socioeconomic burden. Indeed, stroke and cognitive impairment caused by cerebrovascular or neurodegenerative pathologies are the major contributors to neurological disability-adjusted life-years (DALYs) worldwide. ¹ Their impact is considered to even increase in the future, particularly due to rapidly aging populations. Although effective and widely available treatments for cerebrovascular diseases remain rare, recent mechanistic research has provided a much better understanding of underlying pathophysiological processes, which may lead to the development of novel therapeutic strategies. Therefore, this special collection was organized to present progress in the research on the mechanisms, diagnosis, and treatments of cerebrovascular dysfunction and disease. The special collection compiles preclinical and clinical studies, most of which were presented during the Brain & BrainPET 2022 conference in Glasgow. It features 12 publications including five clinical studies and two reviews. A primary focus is on cerebroprotective strategies against acute or chronic brain ischemia and predicting stroke risk and unfavorable outcomes.

Ischemic stroke is a leading cause of functional disability, cognitive dysfunction, and death. Recanalization strategies are the only available causative therapeutic options but are limited by several contraindications and short therapeutic windows. ² It is believed that cerebroprotective strategies used in the context of recanalization and not primarily as stand-alone treatments may improve long-term functional outcomes in stroke patients. ³

During the acute phase after cerebral ischemic and reperfusion injury, Qu and colleagues evaluated the effect of nicotinamide adenine dinucleotide (NAD⁺) precursors on neurological outcome three days after transient middle cerebral artery occlusion (tMCAO). ⁴ They found that NAD⁺ precursor treatment after reperfusion significantly improved stroke outcomes, but pretreatment for three days before tMCAO enlarged infarct volume and exacerbated neurological deficits. The authors attributed these diametric results to the increased expression of metabolic regulators including sirtuin-1 and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) after only a single NAD⁺ precursor treatment. Multiple administration in pretreatment paradigm did not cause such effects. Although this phenomenon requires further clarification, the widespread use of NAD⁺ precursors as a nutritional supplement may be a concern.

During the late phase of ischemic brain injury, cognitive dysfunction can frequently occur and worsen patients’ life quality. For example, post-stroke dementia, an important form of vascular cognitive impairment (VCI), ⁵ is a feared yet incompletely understood stroke sequela. Basak et al. investigated the hypothesis that amyloid β (Aβ) deposits contribute to post-stroke cognitive impairment. Increased levels of soluble Aβ40 and Aβ42 and upregulated activity of Aβ-producing β-site amyloid precursor protein cleaving enzyme 1 (BACE1) were detected in the ipsilateral hippocampus seven days after tMCAO. A BACE1 inhibitor ⁶ restored synaptic plasticity and prevented cognitive decline, suggesting that applying BACE1 inhibitors could improve cognitive outcomes after stroke. ⁷

Neuroinflammation is increasingly recognized as a critical mediator of functional decline, which can be affected by both peripheral and local inflammation. ⁸ Zhang et al. described myeloid immune cell infiltration, increased proinflammatory signaling, extensive and widespread white matter damage, and motor deficits in the germinal matrix hemorrhage (GMH) model, ⁹ which is a significant complication in prematurity. Li et al. focused on neuroinflammatory aspects, briefly discussing the dual actions of the stress-associated activating transcription factor 3 (Atf3) in neuroinflammatory responses after brain injury. Atf3 exerts deleterious proinflammatory activities but also mitigates neuronal apoptosis. Thus, future research must investigate the exact regulatory functions of Atf3 in both acute and late stages of brain injury to establish the potential role of Atf3 as a biomarker or therapeutic target. ¹⁰

In addition to acute ischemic stroke, long-term subcortical ischemic vascular dementia (SIVD) is also discussed in the special collection. As another common subtype of VCI which can be caused by chronic cerebral hypoperfusion, SIVD is mechanistically different from post-stroke dementia. Bilateral carotid artery stenosis (BCAS) by micro-coils is a common rodent SIVD model.^11,12 Ishikawa et al. reviewed studies using the BCAS model and highlighted primary pathological mechanisms of white matter (WM) damage including chronic hypoperfusion, microvascular injury, oxidative stress, blood-brain barrier dysfunction, and neuroinflammation. ¹³ This may pave the way to novel treatment strategies for SIVD. In a recent BCAS study, He and colleagues showed that the antidiabetic metformin reduced WM lesions and cognitive dysfunction by ameliorating oligodendrocyte precursor cell (OPC) dysfunction. Metformin could also promote oligodendroglial maturation. ¹⁴

The special collection also contains several clinical studies predicting stroke risk and unfavorable outcomes. Through Mendelian randomization, He et al. investigated the relationship between genetically predicted metabolic syndrome, its components, and stroke risk. Among other findings, they confirmed that genetically predicted metabolic syndrome, waist circumference, hypertension, and triglycerides are associated with an increased risk of large artery stroke. ¹⁵ Their observations highlight the importance of early metabolic syndrome management for stroke prevention.

A retrospective clinical study by Konduri et al. investigated the effects of intravenous thrombolysis (IVT) by alteplase on late ischemic lesion growth. ¹⁶ While alteplase doubtlessly has considerable benefits in acute ischemic stroke treatment, neurotoxic and lesion-promoting aspects have also been discussed, suggesting a potential link to incompletely understood subacute lesion growth. Konduri et al. investigated 116 patients from the MR CLEAN-NO trial, 63 of whom received IVT and 53 were treated by endovascular thrombectomy. No association between IVT and subacute lesion growth could be established by analyzing CT scans performed 24 hours and one week following stroke and thrombolysis.

Li and colleagues focused on unfavorable venous outflow (UVO) in ischemic stroke, as VO is related to cerebral edema and poor functional outcomes.^17,18 They retrospectively investigated 102 stroke patients with large vessel occlusion who underwent reperfusion therapy, revealing that microvascular dysfunction as measured by extravascular-extracellular volume fraction and poor arterial collateral filling could independently predict UVO. ¹⁹ Their results suggest that microvascular dysfunction may be a UVO cause.

Cao et al. reported urea removal index and hemoglobin levels were suitable predictors of cerebral atrophy in maintenance-hemodialysis patients. ²⁰

Although the clinical studies presented in this special collection provided intriguing new insights into mechanisms of cerebrovascular diseases and related diagnostic and therapeutic opportunities, prospective investigations in multi-center studies with larger cohort sizes will be needed to verify reported findings.

The application of arterial spin labeling (ASL), which is increasingly used to quantitatively assess cerebral blood flow (CBF) in cognitive impairment and other neurovascular diseases, ²¹ is also covered in this collection. Zhao and colleagues utilized ASL to examine hemodynamics in 52 Moyamoya patients. They detected improved cerebrovascular reserve after revascularization surgery and showed that ASL could effectively examine vascular hemodynamics in Moyamoya. ²²

Singh et al. assessed the effect of methylene blue, a drug with potential neuroprotective and antioxidant effects, on brain perfusion and metabolism in healthy humans and rats using ASL and blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI). Unexpectedly, they observed reduced CBF and cerebral metabolic rate of oxygen. They assume that these findings, consistent between species and dose-dependent, may be related to the relatively high doses of methylene blue used. ²³

In summary, the findings presented in this special collection may pave the way toward novel diagnostic and treatment strategies for cerebrovascular diseases. Nevertheless, these interesting contributions represent small steps toward clinical application, and some findings still await verification in large-scale clinical studies.