Leukoaraiosis: A Hidden Cause Of Brain Aging

As imaging techniques evolve, we are able to understand more about the workings of our brain. One of the most alarming discoveries has been the existence of ominous changes found in the brains of more than 60% of people in late middle age and beyond²—changes that were once thought to be simply “age spots” on the brain, but have now taken center stage in the battle against age-related cognitive decline.

Officially known as “leukoaraiosis,” or “white matter hyperintensities,” these tiny spots appear bright white on magnetic resonance imaging (MRI) scans. Scientists are only now coming to grips with the fact that these innocent-appearing spots carry grave implications for cognition, memory, personality, and even gait and balance changes as we age.^3,4

Fortunately, as we learn more about leukoaraiosis, we’re finding clues to its causes and, therefore, intriguing hints about how we might slow its progress or even prevent it entirely, thereby preserving our cherished brain function well into advanced age.

What Is Leukoaraiosis?

Leukoaraiosis, a small vessel disease, refers to the appearance on CT or MRI scans of damage in the white matter regions of the brain.⁵

Leukoaraiosis is a common finding in stroke patients. Leukoaraiosis appears to be an independent predictor of stroke outcomes. Evidence from neuroimaging indicates that some leukoaraiosis is caused by white matter infarcts, which may be particularly frequent in patients with aggressive small vessel disease.

Much of the brain’s total volume is composed of white matter, which runs like tracts of communications cables throughout the brain, connecting different regions so that they can coordinate and optimize the essential exchange of information.

Damage to white matter, then, is likely to result in impairment of brain functions that require complex interactions between regions. Such interactions include the so-called “executive functions” such as memory processing, decision-making, and priority-setting, as well as more basic functions like motor coordination, balance, and maintaining a normal gait.^5,6

The damage that produces leukoaraiosis appears to result from poor blood flow through the smallest arteries and capillaries in the brain (as opposed to “large vessel disease” involving bigger arteries). Small vessel disease caused by insufficient blood flow (hypoperfusion) usually produces few specific symptoms.⁵

But that does not mean that leukoaraiosis is benign, as was originally thought. It represents regions of the brain that are not getting enough blood—and hence, not enough oxygen and nutrients.^5,6

It was not until powerful imaging techniques such as MRI were developed that we had any way of detecting small vessel disease as it formed and progressed.⁴ Thanks to MRI and other advanced technology, however, we can now watch as leukoaraiosis forms, the hallmark of small vessel disease. On such scans, leukoaraiosis shows up as bright white regions (“unidentified bright objects”) scattered through white matter areas of the brain.^1,5 Each region of leukoaraiosis represents real brain damage, even though it is often undetected by victims or health care providers.

And even though early and limited leukoaraiosis typically produces no specific symptoms, the more leukoaraiosis you have, the poorer your function on tests of memory, cognition, gait, and balance—reflecting the damage to those white matter communications channels.^6,7 Over time, leukoaraiosis may produce slowed thinking, forgetfulness, disorientation, perseveration (inability to get off of one subject), depression, and many other problems.⁵

The white matter hyperintensities characteristic of leukoaraiosis have now been found in at least 40 to 50% of apparently healthy adults over age 50, and some reports estimate as high as 95%.^5,6 Though several different possible explanations for the cause of leukoaraiosis exist, we still don’t know exactly what causes the lesions seen in leukoaraiosis, in part because the symptoms of the condition are so non-specific.^6,8,9

What Causes Leukoaraiosis?

Like so many age-related, chronic conditions, leukoaraiosis appears to have multiple causes, but these differ somewhat from the typical risk factors for larger-vessel diseases of the kinds that cause stroke and heart attacks.^6,8-10

Hypertension is a leading risk factor for leukoaraiosis, and the small vessel disease it represents.^6,11,12People who have hypertension are up to 14 times as likely to develop leukoaraiosis than those who do not.^13,14 That differs from large vessel disease of the kind that typically causes overt strokes, in which atherosclerosis is the greatest risk factor.⁹

Research shows that having high blood pressure, particularly ongoing hypertension occurring over time, is a strong predictor of having more severe leukoaraiosis, and of its progression over time; people with the highest cumulative blood pressure across 5 visits had twice the risk of leukoaraiosis progression, compared to those with lower blood pressures.¹⁵

Reduced cerebral blood flow is increasingly being recognized as a cause of leukoaraiosis. People with leukoaraiosis were found to have just 39.7% of the volume of blood flow in affected regions of their brains compared with those having normal appearing white matter.¹⁶ And the ability of the brain’s smaller blood vessels to react to changes in blood flow is also reduced to about 53% of normal in leukoaraiosis patients.²Some of this loss of blood flow may be related to the age-related twisting of smaller arteries, which creates increased resistance and hence lower flow.¹⁷ Finally, arterial stiffening of larger arteries, a consequence of long-term endothelial dysfunction, creates increased pulse waves in smaller arteries that feed the brain, again resulting in periods of very low blood flow.¹⁸

Homocystelne, a byproduct of protein metabolism, is known to be involved in dysfunction of the endothelium, the ultra-thin lining layer of small blood vessels and capillaries, and endothelial dysfunction in turn is related to poor blood flow in small vessels, leading to leukoaraiosis.^19-23 High homocysteine levels increase the risk of developing leukoaraiosis, with changes detectable as early as middle age.^24-28

Platelets are the tiny blood components responsible for forming clots; treatments aimed at keeping platelets in check have been successful at preventing large vessel diseases including strokes and heart attacks.²⁹ But platelet characteristics also affect risk factors for developing leukoaraiosis; those with larger, “stickier” platelets have at least a 60% increase in the risk of developing the brain abnormality.³⁰

Sleep-disordered breathing , which includes the common malady known as obstructive sleep apnea, increases your risk for high blood pressure (the more severe the breathing problem, the higher the risk of hypertension), and hence, the risk of leukoaraiosis.³¹ Fortunately, various non-invasive interventions, such as continuous positive airway pressure (CPAP), have been shown to correct sleep-disordered breathing and lower blood pressure, thereby probably reducing your risk for leukoaraiosis.³¹ Anyone with high blood pressure should, therefore, be evaluated for a sleep-related breathing disorder.

Other risk factors for leukoaraiosis are being discovered; some of the most prominent of these are diabetes (types I or II),^32,33 high levels of inflammation,³⁴ the metabolic syndrome^35-38, mitochondrial dysfunction³⁹, and smoking.⁴⁰ Note that all of these factors are known contributors to endothelial dysfunction. Table 1 shows the main risk factors for the small blood vessel disease that produces leukoaraiosis as cited in a recent review.⁵

What Are The Consequences Of Leukoaraiosis?

The white matter damage that shows up as leukoaraiosis produces no symptoms until it is relatively widespread, and even then symptoms emerge only very slowly over time, and are often confused with “just getting older.”⁶ But studies show that, even in non-disabled older adults, leukoaraiosis on MRI scans is significantly associated with subtle neurological changes that can be detected on a simple physical exam: gait and stance abnormalities, abnormal reflexes, and slowing of small precise movements like finger-tapping.⁴¹

And, when symptoms do arise, leukoaraiosis produces a number of concerning findings.^6,42

Cognitive decline across many different kinds of function is one of the most widely recognized consequences of leukoaraiosis.^6,43,44 As one would expect, based on the involvement of white matter communications channels, leukoaraiosis mainly affects executive functioning (planning, prioritizing, risk assessment, etc.), processing speed, and attention, all of which depend on rapid and accurate exchange of information throughout the brain.⁶

A telling study was conducted at the Mayo Clinic and published late in 2012.⁷ Researchers studied a group of apparently cognitively healthy elderly people with and without significant areas of leukoaraiosis, comparing specific regions of brain activation using a functional MRI scanner. Such scans “light up” in brain regions that are activated by specific tasks. The participants with leukoaraiosis had reduced brain activation in all areas associated with certain forms of decision-making.⁷

These changes in cognition and executive function appear to produce some very worrisome outcomes, since they occur in people who typically continue to function and operate independently in society. Leukoaraiosis has been found to be associated, for example, with the risk of being involved in serious traffic crashes. People with large or multiple areas of leukoaraiosis have a two-to-three-fold increase in having crashes, especially deadly crossroad crashes.⁴⁵