Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(10)

Published: May 14, 2024

Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% ischemic strokes the vast majority spontaneous intracerebral hemorrhage is also most important vascular contributor dementia. Despite its high prevalence potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview recent advances in this field. We summarize data highlighting remarkable continuum between monogenic multifactorial cSVDs involving NOTCH3, HTRA1, COL4A1/A2 genes. Taking vessel-centric view, discuss possible cause-and-effect relationships risk factors, structural functional changes, manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction rightly considered central feature cSVD, contributions smooth muscle cells, pericytes, other cells warrant continued investigation.

Language: Английский

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Impact of arterial stiffness on cerebrovascular function: a review of evidence from humans and preclinical models

AJP Heart and Circulatory Physiology, Journal Year: 2024, Volume and Issue: 326(3), P. H689 - H704

Published: Jan. 12, 2024

With advancing age, the cerebral vasculature becomes dysfunctional, and this dysfunction is associated with cognitive decline. However, initiating cause of these age-related cerebrovascular impairments remains incompletely understood. A characteristic feature aging increase in stiffness large elastic arteries. This arterial elevated pulse pressure blood flow pulsatility vasculature. Evidence from both humans rodents supports that increases artery are impairments. These impacts on function wide-ranging include reductions global regional flow, small vessel disease, endothelial cell dysfunction, impaired perivascular clearance. Furthermore, recent findings suggest relationship between may be influenced by genetics, specifically

Language: Английский

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The Indissociable Triad: Vascular Impairment, Muscle Atrophy, and Cognitive Decline

Published: Aug. 12, 2024

The triad of vascular impairment, muscle atrophy, and cognitive decline represents critical age-related conditions that significantly impact health. Vascular impairment disrupts blood flow, precipitating mass reduction seen in sarcopenia the neuronal functions characteristic neurodegeneration. Our limited understanding intricate relationships within this hinders accurate diagnosis effective treatment strategies. This review ana-lyzes interrelated mechanisms contribute to these conditions, with a specific focus on ox-idative stress, chronic inflammation, impaired nutrient delivery. aim is understand common pathways involved suggest comprehensive therapeutic approaches. dysfunctions hinder circulation transportation nutrients, resulting sar-copenia characterized by atrophy weakness. dysfunction have negative physical function quality life. Neurodegenerative diseases exhibit comparable pathophysiological affect motor functions. Preventive approaches encompass lifestyle adjustments, addressing oxidative in-flammation, integrated therapies improving muscular well-being. Better links can refine strategies yield better patient out-comes. study emphasizes complex interplay between dysfunction, de-generation, decline, highlighting necessity for multidisciplinary ap-proaches. Advances domain promise improved diagnostic accuracy, more thera-peutic options, enhanced preventive measures, all contributing higher life elderly population.

Language: Английский

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Monogenic causes of cerebral small vessel disease- models for vascular cognitive impairment and dementia?

Current Opinion in Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Purpose of review Recent advancements in molecular biomarkers and therapeutic options for Alzheimer's disease have brought into focus the need greater progress second most common cause dementia, vascular cognitive impairment dementia (VCID). We examine how study monogenic causes VCID has contributed to understanding its pathophysiology potential biomarker treatment research. findings It is widely accepted that conditions which disrupt cerebral small vessels contribute pathologies including stroke microbleeds, ultimately leading dementia. Among these are a range vessel diseases (SVDs) such as CADASIL, CARASIL, Fabry COL4A-related disorders. Summary This indicates importance furthering research SVDs order gain insight pathomechanisms more broadly. Monogenic easier model than sporadic can serve guide identifying diagnosis, monitoring intervention outcomes.

Language: Английский

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Microenvironmental determinants of endothelial cell heterogeneity

Nature Reviews Molecular Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Language: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

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Resilience to diabetic retinopathy

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 101, P. 101271 - 101271

Published: May 11, 2024

Chronic elevation of blood glucose at first causes relatively minor changes to the neural and vascular components retina. As duration hyperglycemia persists, nature extent damage increases becomes readily detectable. While this second, overt manifestation diabetic retinopathy (DR) has been studied extensively, what prevents maximal from very start remains largely unexplored. Recent studies indicate that diabetes (DM) engages mitochondria-based defense during retinopathy-resistant phase, thereby enables retina remain healthy in face hyperglycemia. Such resilience is transient, its deterioration results progressive accumulation retinal damage. The concepts co-emerge with these discoveries set stage for novel intellectual therapeutic opportunities within DR field. Identification biomarkers mediators protection DM-mediated will enable development resilience-based therapies indefinitely delay onset DR.

Language: Английский

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Sensorineural hearing loss and cognitive impairment: three hypotheses

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: Feb. 28, 2024

Sensorineural hearing loss (SNHL) is a category of that often leads to difficulty in understanding speech and other sounds. Auditory system dysfunction, including deafness auditory trauma, results cognitive deficits via neuroplasticity. Cognitive impairment (CI) refers an abnormality the brain’s higher intellectual processes related learning, memory, thinking judgment can lead severe learning memory deficits. Studies have established strong correlation between SNHL CI, but it remains unclear how contributes CI. The purpose this article describe three hypotheses regarding relationship, mainstream load hypothesis, co-morbidity sensory deprivation as well latest research progress each hypothesis.

Language: Английский

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Vascular Impairment, Muscle Atrophy, and Cognitive Decline: Critical Age-Related Conditions

Biomedicines, Journal Year: 2024, Volume and Issue: 12(9), P. 2096 - 2096

Published: Sept. 13, 2024

The triad of vascular impairment, muscle atrophy, and cognitive decline represents critical age-related conditions that significantly impact health. Vascular impairment disrupts blood flow, precipitating the mass reduction seen in sarcopenia neuronal function characteristic neurodegeneration. Our limited understanding intricate relationships within this hinders accurate diagnosis effective treatment strategies. This review analyzes interrelated mechanisms contribute to these conditions, with a specific focus on oxidative stress, chronic inflammation, impaired nutrient delivery. aim is understand common pathways involved suggest comprehensive therapeutic approaches. dysfunctions hinder circulation transportation nutrients, resulting characterized by atrophy weakness. dysfunction have negative physical quality life. Neurodegenerative diseases exhibit comparable pathophysiological affect motor functions. Preventive approaches encompass lifestyle adjustments, addressing integrated therapies improving muscular well-being. Better links can refine strategies yield better patient outcomes. study emphasizes complex interplay between dysfunction, degeneration, decline, highlighting necessity for multidisciplinary Advances domain promise improved diagnostic accuracy, more options, enhanced preventive measures, all contributing higher life elderly population.

Language: Английский

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The pathobiology of neurovascular aging

Neuron, Journal Year: 2025, Volume and Issue: 113(1), P. 49 - 70

Published: Jan. 1, 2025

Language: Английский

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