Cerebral White Matter Lesions as a Clinically Relevant Intermediate Target of Cerebrovascular Prevention

Dementia is a devastating condition for the patient and family members and is associated with millions of dollars in health care costs. The number of persons with dementia increases with the aging of the population and its prevention is warranted in both human and economic terms. Prospective cohort studies have shown that increased blood pressure (BP) is associated with an increased risk of dementia, but it is still a matter of debate how BP shapes the trajectory to dementia and the pathological substrate of hypertension‐induced cognitive decline.

Hypertension causes changes in the cerebral vasculature that affect both large and small vessels. Macrovascular atherosclerotic disease causes brain infarcts that can be either silent or clinically evident as stroke. The microvascular disease results in chronic ischemic changes affecting, to a large extent, the white matter (also known as white matter lesions [WMLs] or leukoaraiosis). The outcome of single or multiple events is a stepwise progression to multi‐infarct dementia, while the outcome of chronic microvascular damage is a continuous progression from mild cognitive impairment to overt vascular dementia.1 Microvascular disease causes basal ganglia dysfunction and cortical deafferentation. These processes cause a subtype of vascular dementia, the subcortical syndrome, particularly related to hypertension and to cardiovascular risk factors, characterized by impairment of executive function and attention.2 The vascular alterations also disrupt cerebral blood flow autoregulation and make the brain more susceptible to hypoperfusion during occasional or chronic hypotension that may be caused by inappropriate antihypertensive therapy. Finally, vascular lesions also have a permissive effect on the clinical expression of neurodegenerative dementia of the Alzheimer type.3

White matter changes (WMCs) and WMLs are frequent but nonspecific neuroradiological findings, appearing as hyperintensities on T2‐weighted imaging. Certain WMCs could be detected in up to 90% of neurologically symptom‐free elderly people by magnetic resonance imaging (MRI) and even in about 20% by cranial computer tomography, yielding the term “incidental” or age‐related WMCs.4 The current gold standard for diagnosis of WMLs includes various MRI sequences, such as T1, T2, proton density, or fluid‐attenuated inversion recovery (FLAIR).5

Pathological examination of WMLs reveals a spectrum of changes ranging from myelin pallor, enlarged perivascular spaces, tissue infarction, gliosis, and axonal loss. As these lesions become more confluent, there is complete loss of the entire nerve fiber. Perivascular infiltration of foam cells, and proinflammatory mediators including apolipoprotein E, α₂‐macroglobulin, and immunoglobulin G, have also been described, as have reactive astrocytosis and microglial activation. Other evidence also points to a loss of integrity of small vessel endothelium or the blood‐brain barrier. Venous collagenosis has also been observed in areas of WMLs. Alteration of RNA transcription may occur in multiple genes that are involved in immune regulation, cell cycle, apoptosis, and proteolysis, and highlight the complexity of this phenotype.6

WMLs on MRI are important for diagnosing vascular dementia, relevant for cognitive function, and are significantly associated with arterial hypertension.2 WMLs also have important cognitive consequences in the normal aging population. Important noncognitive consequences of WMLs include minor motor deficits (ie, gait disorder, imbalance, urinary frequency) that may impair quality of life and cause depression.7

WMLs may progress over time, although predictors and rates of progression in different patients remain to be clarified. Individuals with more extensive white matter changes manifest a faster rate of progression of dementia, and hypertension is a predictor of WML progression.2 Quantification of WMLs is reliable and magnetic resonance techniques with analyses of WMLs can be used in large‐scale trials. A sample size of only 50 patients with confluent lesions is required per treatment arm to demonstrate a 40% change in the rate of disease progression over a 3‐year period.2

Wang and coworkers8 demonstrated that both high and low pulse pressure (PP) predict cognitive decline in stroke/transient ischemic attack patients with confluent WMCs over 18‐month follow‐up.

Other investigators have examined the effect of PP and central hemodynamics on cerebral structure and cognition. Marked stiffening of the aorta was associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage, and lower scores in various cognitive domains.9 WMLs have been correlated with systolic pressure and arterial stiffness measured by pulse wave velocity in the central vasculature.10 PP elevation was associated with increased cerebrospinal fluid P‐tau and decreased Aβ_1–42 in cognitively normal older adults, suggesting that pulsatile hemodynamics favor amyloidosis and tau‐related neurodegeneration.11 Higher central systolic pressure and higher central PP were associated with poorer processing speed, Stroop processing, and recognition memory.12 Higher brachial systolic pressure and brachial PP were associated with poorer Stroop processing.12 Wider PP was associated with increased risk of dementia, and diastolic BP showed a U‐shaped relationship with incident dementia in patients taking antihypertensive treatment (ie, increased risk of dementia at both low and high diastolic pressure under treatment).13 On the other hand, lower carotid artery stiffness in endurance‐trained adults was associated with better neuropsychological outcome and greater occipitoparietal perfusion.14 Elderly patients with high intracranial pulsatility displayed smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain.15

All these data are consistent with a hemodynamic and structural effect of hypertension, PP, and aortic stiffness on the cerebral vasculature and cognitive function. However, the study by Wang and colleagues adds new information by showing that reduced PP is also associated with cognitive deterioration.8 Reduced PP could be caused by increased arterial distensibility, low systolic BP, and low cardiac output, as well as increased diastolic pressure. Increased arterial distensibility and increased diastolic pressure without concomitant systolic hypertension are unlikely. Therefore, low PP may indicate decreased blood ejection and stroke volume that reduce cerebral blood flow and contribute to cognitive decline. In fact, heart failure, AF, and orthostatic hypotension are related to WMCs and cognitive decline.16 Furthermore, short‐term BP reduction may affect attention and executive function that is related to small vessel disease.17

The study by Wang and colleagues also confirms that it is possible to document short‐term cognitive deterioration in a relatively small number of patients, if they are carefully selected on the basis of WMLs, reliable markers of microvascular damage, and relevant intermediate targets in hypertension.8 Therefore, this study design should be kept in mind when planning future investigations on the prevention of dementia.

The clinical consequence of these data is that careful BP control, avoiding hypotension, is mandatory in stroke patients to prevent cognitive decline, a long‐term complication of cerebrovascular diseases.