ARTICLE IN BRIEF
Using diffusion tensor imaging, the researchers found that elevated blood pressure correlated with greater evidence of white matter damage, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibers that project from the thalamus to the superior frontal gyrus. The article highlights commentary on this and other recent papers that make the case for an association between high blood pressure and other cerebrovascular risk factors and white matter damage.
High blood pressure, besides promoting cardiovascular disease, also appears to damage myelin in the brain starting in middle age, according to a new study published online Nov. 2 before the December print edition of The Lancet Neurology. However, the mechanism causing the damage remains obscure.
The paper found a linear association between systolic blood pressure and white-matter damage in 579 people with a mean age of 39.2 years — members of the third generation of participants in the longitudinal Framingham Heart Study.
Using diffusion tensor imaging (DTI), the researchers found that elevated blood pressure correlated with greater evidence of white matter damage, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibers that project from the thalamus to the superior frontal gyrus. Elevated blood pressure also was strongly associated with reduced gray-matter volumes, especially in Brodmann's area 48 on the medial surface of the temporal lobe, and Brodmann's area 21 of the middle temporal gyrus.
The results from DTI studies, capable of detecting even subtle changes in myelin, suggest that brain injury from elevated blood pressure begins well before signs of overt atherosclerosis appear. The study was funded by the NIH and its institutes, including the National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.
“We're showing brain damage in people you wouldn't expect to show brain changes due to hypertension,” said lead author Charles DeCarli, MD, professor of neurology at the University of California, Davis, who holds the Victor and Genevieve Orsi chair in Alzheimer's research. “Some are only 40 years old. This is the youngest age group in which such brain injury has been detected. This moves the impact of hypertension on the brain forward by at least 20 years.”
THE CASE FOR ‘LEUKOARAIOSIS’
Dr. DeCarli became interested in how vascular disease affects the brain 25 years ago while at the NIH's Laboratory of Neurosciences — the section on brain aging and dementia. A 1987 paper by Vladimir Hachinski, MD, now a professor in the department of clinical neurological sciences at Western University in London, Ontario, introduced the word “leukoaraiosis,” which refers to hyperintensities on MRIs that increase with age. [Dr. Hachinski also serves on the editorial advisory board of Neurology Today.] Three studies last summer in Neurology linked leukoaraiosis to cognitive decline, and the European LADIS (Leukoaraiosis And DISability) study, started in 2001, has found that white matter changes, once thought to be benign aspects of aging, strongly predict cognitive and motor decline.
DTI detects white matter damage long before leukoaraiosis becomes visible on conventional MRI. “DTI is a much more sensitive method for examining white matter microstructure,” Dr. DeCarli said. “But we don't know what's causing the damage. It could be altered blood flow; it could be inflammation; it could be circulating chemicals in blood related to hypertension that we don't know anything about yet. It's not simply the amplitude of the blood pressure causing the damage. There are probably other things going on.”
The authors of The Lancet Neurology paper acknowledge that they cannot explain the vulnerability of specific white matter tracts to elevated blood pressure, or the reductions in gray-matter volume. They call for a longitudinal study to determine how the subtle white matter changes they have detected progress.
WHAT IS CAUSING THE MYELIN DAMAGE?
The myelin damage could be caused by something that drives hypertension, such as the signaling proteins involved in the renin-angiotensin system, which regulates blood pressure and fluid balance, according to George Bartzokis, MD, a professor in the department of psychiatry at the David Geffen School of Medicine at the University of California, Los Angeles.
“Your renin-angiotensin system not only operates within your vessels to affect blood pressure; it also operates within your organs, including your brain, and is basically an inflammatory system,” said Dr. Bartzokis, whose research has linked the production, maintenance, and deterioration of myelin to an array of disorders. “The high blood pressure is telling you that your renin-angiotensin system is hyperactive, and you probably have inflammation in your organs. Many of the medications we have are either inhibitors or blockers of the renin-angiotensin system.”
Dr. Bartzokis pointed to a pair of recent papers by Juan M. Saavedra, MD, a senior investigator with the NIH, suggesting that angiotensin II AT1 receptor blockers (ARBs), commonly used to treat hypertension, diabetes, and stroke, also counteract brain inflammation. In the November issue of the journal Clinical Science, Dr. Saavedra reported that animal studies suggest that ARBs “ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury.” In the July issue of Cell and Molecular Neurobiology he proposed three possible mechanisms for the effectiveness of ARBs: their ability to reduce inflammatory factor production in peripheral organs; their effectiveness at reducing inflammatory cascades in the brain; and their direct anti-inflammatory effects on endothelial cells, microglia, and neurons.
Dr. Bartzokis found The Lancet Neurology paper fascinating because it detects a regionally specific vulnerability of anterior white matter tracts to increased systolic blood pressure, as well as a generalized atrophy of gray matter. He suspects that degradation of late-developing myelin plays a role in both.
“Most people think of white matter and gray matter as separate tissues,” he said. “But gray matter is full of myelin; it's just not as pure as in white matter. Gray matter, especially in humans, is very well myelinated, particularly in middle-aged people, which is the population they studied.”
Also, the late-myelinating regions in the anterior frontal lobe are particularly vulnerable. “You can have the appearance of gray matter reduction because you're losing some of the myelin in the gray matter, plus some myelin in the late-myelinating subcortical regions,” Dr. Bartzokis said.
MYELIN, ONLY A PART OF THE STORY
A paper in the April edition of Neuropsychologia studied 72 adults ages 19-77, and determined that elevated systolic blood pressure explained some of the age-related reductions in white matter, but only in carriers of the apolipoprotein E4 (APOE4) allele, a major genetic risk factor for Alzheimer's disease.
“Thus, even in healthy older carriers of the APOE4 allele, a clinically unremarkable increase in vascular risk may be associated with reduced frontal volumes and impaired cognitive functions,” the authors wrote.
Therefore, as important as myelin is to cognitive function, it probably does not explain entirely the results reported in The Lancet Neurology, said Naftali Raz, PhD, the corresponding author of the Neuropsychologia paper.
“Because myelin is produced and lost and produced again throughout the life span, studying changes in energetics underlying this metabolically expensive process may hold a great promise,” said Dr. Raz, associate director for the Lifespan Cognitive Neuroscience program at Wayne State University's Institute of Gerontology. “Genetic contributions to vascular risk may play an important role in moderating the effect of blood pressure on the brain. It was a bit disappointing that the authors of The Lancet Neurology paper did not examine the possible effect of APOE4 allele in conjunction with systolic blood pressure.”
Earlier studies have shown that frontal white matter bears the brunt of aging and vascular risk effects, according to Dr. Raz. “On the other hand, we and others have found the hippocampus especially vulnerable to the influence of hypertension,” he said. “And in a small longitudinal study we observed that hypertensive individuals show a wider spread of brain changes in comparison to people who remained healthy.”
Protecting brain myelin from the damage caused by elevated systolic blood pressure involves more than lowering blood pressure, according to a paper in the May issue of the Journal of Human Hypertension. The authors found that reductions of gray matter volume were not halted in 41 hypertensive patients despite a year of successful treatment.
“We know that the brain is very effective at regulating blood pressure, so when blood pressure increases, that regulation is not able to overcome it,” said lead author J. Richard Jennings, PhD, a professor in the departments of psychiatry and psychology at the University of Pittsburgh School of Medicine.
In a 2009 paper in NeuroImage that anticipated the results in The Lancet Neurology, Dr. Jennings and a postdoctoral student, Ydwine Zanstra, reported that “early stage hypertension is associated with cognitive deficits, altered cerebral blood flow support for cognitive processing, and decreased grey matter in specific cortical regions.” They also found that controlling hypertension with medication was less successful in patients who displayed premature brain aging, and failed to reverse the progression and structural changes within the cerebral cortex.
“As for the basic mechanism — whether it has to do with the angiotensin system or the sympathetic nerve system — I don't think we know at this point,” Dr. Jennings told Neurology Today. “I think it's fair to say we're still struggling with the complexity of the brain, and what these things mean for hypertension.”
ELEVATED LIPOPROTEIN AND WHITE MATTER DAMAGE
Elevated low-density lipoprotein (LDL) cholesterol may also compromise the structural integrity of white matter, according to a paper published earlier this year in the journal Human Brain Mapping.
DTI studies of 125 adults, ages 43-87, found a correlation between elevated LDL and decreased white-matter integrity in right frontal and temporal regions, the superior longitudinal fasciculus, and the internal and external capsules.
The compromised regions were found even among the 88 percent who had LDL levels below 130 mg/dL, the cutoff for mildly high. Also, the associations between LDL and white matter decline persisted even after controlling for age and gender, and did not change significantly with the use of lipid-lowering medication. They proposed that the relationship between LDL and brain tissue microstructure suggests the presence of previously undetected “subclinical risk” that could contribute to cognitive decline later in life.
“We don't know if it's myelin damage per se,” said lead author David H. Salat, PhD, assistant professor in radiology at Harvard Medical School, and assistant neuroscientist at Massachusetts General Hospital. “And we don't know what drives the regional nature of effects. It suggests to us that there are a variety of factors that contribute to the general neural environment of an individual, and given that cholesterol is a risk factor for vascular conditions, we think that may be related to the blood flow mechanisms that might play a role in these effects.”
Another 2012 paper by Dr. Salat and colleagues at the Neuroimaging Research for Veterans Center and the Geriatric Research Education and Clinical Center in Boston — published in the journal Neuroimage — reported an association between elevated blood pressure and a decline in regional white matter integrity in 128 adults ages 43-87. The association persisted even after controlling for age, white matter lesions, and the use of hypertensive medication.
Like the authors of The Lancet Neurology paper, Dr. Salat and his co-authors suspect something besides arterial pressure accounts for the decline found in white matter integrity among those prone to hypertension.
“We looked at pre-hypertensive individuals — people who have a degree of risk that typically is not managed,” Dr. Salat said. “We were surprised to find these associations between blood pressure and brain health exist even in this subclinical population.”
FOR FURTHER READING:
• Williams VJ, Leritz EC, Salat DH, et al. Inter-individual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults. Human Brain Mapp 2012; E-pub 2012 Mar 22.
• Salat DH, Williams VJ, Milberg WP, et al. Inter-individual variation in blood pressure is associated with regional white matter integrity in generally healthy older adults. Neuroimage 2012; 59(1):181–192.E-pub 2011 Jul 23.
Visit the Neurology Today archive of articles on high blood pressure and other metabolic/cerebrovascular risk factors for Alzheimer's disease and other CNS disorders: http://bit.ly/11r68Rw.
FOR FURTHER READING:
• Maillard P, Seshadri S, DeCarli C, et al. Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: A cross-sectional study. Lancet Neurol 2012;11(12):1039–1047; E-pub 2012 Nov. 2.
• Silbert LC, Dodge HH, Kaye JA, et al. Trajectory of white matter hyperintensity burden preceding mild cognitive impairment. Neurology 2012; 79(8):741–747.
• Zhuang L, Sachdev PS, Wen W, et al. Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. Neurology 2012; 79(8):748–854.
• Price CC, Mitchell SM, Libon DJ, et al. MRI-leukoaraiosis thresholds and the phenotypic expression of dementia. Neurology 2012; 79(8):734–740.
• Poggesi A, Pantoni L, et al, for the LADIS Study Group. 2001–2011: A Decade of the LADIS (Leukoaraiosis And DISability) Study: What have we learned about white matter changes and small-vessel disease? Cerebrovas Dis 2011;32:577–588.
• Saavedra JM. Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders. Clin Sci 2012;123:567–590.
• Saavedra JM. Angiotensin II AT1 Receptor blockers ameliorate inflammatory stress: A beneficial effect for the treatment of brain disorders. Cell Mol Neurobiol 2012; 32(5):667–681.
• Bender AR, Raz N. Age-related differences in memory and executive functions in healthy Apo 4 carriers: The contribution of individual differences in prefrontal volumes and systolic blood pressure. Neuropsychologia 2012;50:704–714.
• Jennings JR, Mendelson DN, Aizenstein H, et al. Regional grey matter shrinks in hypertensive individuals despite successful lowering of blood pressure. J Hum Hypertens 2012;26(5):295–305.
• Jennings JR, Zanstra Y. Is the brain the essential in hypertension? NeuroImage 2009;47:914–921.