Pandemic of the Aging Society — Sporadic Cerebral Small Vessel Disease
Introduction
With the global population aging, the prevalence of age-related sporadic cerebral small vessel disease (CSVD) is on the rise. This condition, often asymptomatic or presenting with subtle changes in mental and motor functions, is increasingly recognized as a significant health concern. The widespread use of advanced brain magnetic resonance imaging (MRI) has enhanced our understanding of CSVD’s in vivo evolution, its impact on the brain, associated risk factors, and the mechanisms behind its clinical manifestations. This article aims to provide a comprehensive overview of the pathophysiology, risk factors, biomarkers, and clinical spectrum of sporadic CSVD.
Pathology and Pathophysiology
Anatomy
Cerebral small vessels include intracranial perforating arteries originating from major cerebral arteries, basilar/vertebral arteries, and superficial leptomeningeal pial vessels. These vessels branch into smaller arteries and arterioles, eventually forming a dense capillary network that reaches nearly every neuron in the brain. The capillaries, with their single-layered endothelial walls, form the blood-brain barrier (BBB), surrounded by pericytes, astrocytes, neurons, and extracellular components that constitute the neurovascular units (NVU).
Small Vessel Changes
Autopsy studies reveal that affected cerebral arterioles in CSVD patients exhibit loss of smooth muscle cells, subintimal deposits of fibrinoid or hyaline material, and thickening of the vessel wall, leading to luminal narrowing and sometimes occlusion. Venules may show excessive collagen deposits, particularly around periventricular regions, causing luminal narrowing or occlusion. Capillary density loss is also observed.
Brain Parenchymal Changes
CSVD-related brain parenchymal changes include infarcts (microinfarcts and lacunes), hemorrhages (microbleeds and intracerebral hemorrhages), enlarged perivascular spaces (ePVS), and white matter changes (WMC). WMC, often seen as white matter hyperintensities (WMH) on MRI, are typically patchy or confluent and located in periventricular regions. Microscopically, WMC involve swollen myelin sheaths, loss of axons and oligodendrocytes, astrocytic gliosis, and zones of rarefaction or cavitation.
Early hypotheses suggested that arteriosclerotic occlusion leads to lacunar infarcts, while luminal narrowing causes partial ischemia, resulting in WMC. Recent evidence points to endothelial dysfunction, BBB breakdown, and NVU disintegration as key contributors to CSVD-related brain changes. These processes, along with impaired vasodilatory response, inflammation, increased vascular pulsatility, and impaired cerebral autoregulation, lead to white and grey matter atrophy, resulting in overall brain shrinkage.
Risk Factors
Sporadic CSVD is believed to result from an interplay of aging, vascular risk factors (especially hypertension and smoking), and genetic susceptibility. Hypertension is strongly associated with WMH, though this association weakens with age. Diabetes is linked mainly to lacunes, while hyperlipidemia may be associated with microatheroma-related lacunar infarcts. Genetic factors, such as mutations in HTRA1, FOXC/FOXF2, and COL4A1/COL4A2, increase susceptibility to CSVD. Ethnic differences, such as higher WMH prevalence in Chinese compared to Caucasians, suggest genetic and environmental influences.
In Vivo Detection
Direct visualization of cerebral small vessels in vivo is challenging due to their small size. Advanced imaging techniques, such as 7.0-Tesla MR angiography and three-dimensional rotational angiography, offer better visualization of perforators and arterioles. Transcranial Doppler ultrasound (TCD) and retinal imaging provide indirect assessments of cerebral small vessel changes. TCD-derived pulsatility index (PI) reflects vascular resistance and correlates with MRI markers of CSVD and cognitive performance. Retinal imaging, sharing anatomical similarities with cerebral vessels, shows associations between retinal vessel calibers and CSVD markers.
Conventional MRI and CT are used to assess CSVD-related brain parenchymal changes, including recent small subcortical infarcts, lacunes, WMH, ePVS, cerebral microbleeds, and brain atrophy. Advanced MRI techniques, such as diffusion tensor imaging (DTI) and functional MRI, reveal white matter microstructural changes and brain network connectivity alterations. Dynamic contrast-enhanced MRI and translocator protein PET imaging capture BBB leakage and neuroinflammation, respectively. Potential cerebrospinal fluid (CSF) and blood-based biomarkers, such as elevated CSF/blood albumin ratio and altered matrix metalloproteinases, reflect key pathophysiological processes in CSVD.
Clinical Manifestations
Stroke
CSVD commonly presents as stroke, including lacunar stroke or deep intracerebral hemorrhage (ICH). Transient ischemic attacks (TIA) with mild, non-specific symptoms may precede more severe episodes. Lacunar infarcts can cause pure motor or sensory stroke, ataxic hemiparesis, dysarthria-clumsy hand syndrome, hemiballismus, chorea, athetosis, vertigo, and Parkinsonism. Cognitive decline may occur immediately after a stroke if the lesion involves strategic sites, such as the left caudate, pallidum, or white matter tracts. Cerebral microbleeds are associated with a high risk of ICH, and subclinical CSVD increases the risk of stroke and mortality.
Cognitive Impairment
Even without overt stroke, CSVD can cause varying degrees of cognitive impairment, from subtle deficits to dementia. The cognitive impairment associated with CSVD is typically of the “subcortical” type, characterized by slow processing speed, executive dysfunction, and reduced attention span. Memory problems in CSVD often improve with cueing, and recognition tasks are performed better than free recall. The severity of cognitive impairment correlates with the extent of CSVD markers, disruption of white matter integrity, BBB leakage, and concurrent brain atrophy. CSVD also increases the risk of dementia in patients with Alzheimer’s disease (AD) and accelerates cognitive decline in AD patients.
Behavioral and Other Manifestations
Apathy and depression are common behavioral disturbances in CSVD, mediated by frontal-subcortical regions. These disturbances are associated with increased disability and mortality in stroke patients. Other behavioral issues, such as emotional lability, disinhibition, agitation, aberrant motor behavior, and sleep disturbance, may also occur. CSVD-related Parkinsonism typically involves the lower body and shows minimal response to levodopa. Urinary incontinence, often seen in advanced CSVD, is linked to frontal subcortical tract damage. Severe CSVD can lead to pseudobulbar palsy, characterized by dysarthria, dysphagia, and reduced facial and tongue movements.
Conclusion
Sporadic cerebral small vessel disease (CSVD) is a significant health concern in aging populations, contributing to stroke, cognitive impairment, and behavioral disturbances. Advances in neuroimaging have enhanced our understanding of CSVD’s pathophysiology, risk factors, and clinical manifestations. Addressing CSVD requires a comprehensive approach, including early detection, management of vascular risk factors, and development of targeted therapies. Given its resemblance to the COVID-19 pandemic in its impact on older adults, CSVD warrants increased attention and research efforts to mitigate its burden on society.
doi.org/10.1097/CM9.0000000000001320
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