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(Stroke. 2004;35:2756.)
© 2004 American Heart Association, Inc.

Letters to the Editor

White Matter Hyperintensities: Pearls and Pitfalls in Interpretation of MRI Abnormalities

Vinod K. Gupta, MD

Dubai Police Medical Services, Dubai, United Arab Emirates

To the Editor:

Atwood et al acknowledge that the pathophysiology of white matter hyperintensities (WMH) is uncertain and underscore the possibility of ischemic etiology, especially in the elderly.¹ These authors regard WMH as an excellent marker of brain aging and emphasize their heritability in patients with negative correlation with cerebrovascular brain injury.

WMH are neither age-specific nor generally heritable, having been found in both sexes in hypertensive encephalopathy, puerperal eclampsia, migraine, and therapy with cyclosporin, interferon-, and tacrolimus.^2,3 Kruit and coworkers found WMH in MRI only in women migraine patients,² which likely reflects an investigational artifact. Atwood et al did not exclude hypertensive and migraine patients from their analysis, which prominently confounds their interpretation of WMH as indicative of brain aging.

An important pathophysiological clue to the nature of WMH is offered by the characteristic difference in the distribution of infarcts and deep WMH in migraine patients. Predominantly posterior circulation territory (PCT) migrainous infarcts in contrast to anterior circulation infarcts in embolic or atherosclerotic thrombotic strokes in general are likely related to rheological factors. Anatomical vulnerability of the posterior cerebral artery renders it particularly susceptible to vasospastic influences in migraine patients.⁴ The rare occurrence of neuroanatomically nonlateralizing—in relation to headache or aura—PCT infarcts in younger migraine sufferers might represent an uncommon complication of an adaptive vasospasm that rarely reduces perfusion critically in a particularly labile region.⁴

Diffuse nonlateralizing distribution of deep WMH unaffected by triptan use² indicates that WMH do not reflect the outcome of vasospastic ischemia. Also, local changes during migraine attacks, eg, excessive neuronal activation or excitotoxicity,² should logically manifest lateralizing WMH. Deep WMH, in contrast to infarcts, likely resolve totally along with resolution of symptoms and signs after treatment of hypertension or withdrawal (or reduction of dose) of immunosuppressive agents.³ Vasogenic cerebal edema probably underlies WMH in hypertensive encephalopathy; breakdown of the blood–brain barrier has been shown in human and in rat models.³ Attack-related, inconsistently-lateralized, and prolonged (>48 hours) hyperperfusion prevails in the cerebral cortex, thalamus, and basal ganglia in migraine.⁵ In direct contrast to infarcts, WMH probably result from intense but self-limited cerebral hyperperfusion. I propose that WMH are markers of transient breakdown of the blood–brain barrier rather than aging.

The heritability of WMH volumes is an intriguing feature.¹ The decline in heritability estimates after age 60¹ indicates the nongenetic nature of this observation. Another indicator of the nongenetic nature of WMH is the absence of correlation with aging in women despite higher heritability. Migraine is more prevalent in women than in men, from approximately age 14.⁶ Breakdown of the aging-marker hypothesis for WMH in women may relate to migraine headaches. Finally, heritability of WMH may relate more to heritability of hypertension or migraine or both. In the absence of any link to cerebrovascular disease, the menopause probably has no independent bearing on WMH. Spontaneous resolution likely underlies significantly smaller WMH volumes at younger age, especially in women,¹ in which cohort the highest prevalence of migraine can be expected. These authors also hope to establish a genetic link between WMH and silent brain infarctions.¹ Unless the resolution or otherwise of WMH is established prospectively, it is premature to link this MRI finding with cerebrovascular ischemic disease. Cross-sectional studies of WMH cannot establish vascular-related genetic influences, as has been suggested.¹ Assumption of the genetic model for WMH¹ is probably incorrect.

References

1. Atwood LD, Wolf PA, Heard-Costa NL, Massaro JM, Beiser A, D’Agostino RB, DeCarli C. Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke. 2004; 35: 1609–1613.[Abstract/Free Full Text]
2. Kruit MC, van Buchem MA, Hofman PA, Bakkers JTN, Terwindt GM, Ferrari MD, Launer LJ. Migraine as a risk factor for subclinical brain lesions. JAMA. 2004; 291: 427–434.[Abstract/Free Full Text]
3. Donnan GA. Posterior leucoencephalopathy syndrome. Lancet. 1996; 347: 988.[Medline] [Order article via Infotrieve]
4. Gupta VK. Regional cerebral blood flow patterns in migraine: what is the contribution to insight into disease mechanisms? Eur J Neurol. 1995; 2: 586–587.
5. Kobari M, Meyer JS, Ichijo M, Imai A, Oravez WT. Hyperperfusion of cerebral cortex, thalamus and basal ganglia during spontaneously occurring migraine headaches. Headache. 1989; 29: 282–289.[CrossRef][Medline] [Order article via Infotrieve]
6. Ziegler DK. Headache. Public health problem. Neurol Clin. 1990; 8: 781–791.[Medline] [Order article via Infotrieve]

Response:

Charles DeCarli, MD

Alzheimer’s Disease Center and Imaging of Dementia and Aging Laboratory, Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, California

Larry D. Atwood, PhD Philip A. Wolf, MD

Department of Neurology, Boston University, Boston, Massachusetts

In his letter to the editor, Dr Gupta argues that white matter hyperintensities (WMH) are neither age-specific nor heritable. As evidence in support of this argument, he expands on an already lengthy list of causes for WMH in order to underscore the nonspecific nature of these phenomena. He then focuses on the distribution of WMH in migraine patients to support his hypothesis that WMH represent transient breakdown of the blood–brain barrier rather than the aging process per se. Finally, Dr Gupta concludes that our data do not support the heritability of WMH.

In response to his observations that WMH should be considered nonspecific, we agree completely. Many diseases lead to WMH. We must note, however, that most of the causes identified by Dr Gupta are extremely rare in a community-based population such as the Framingham Heart Study, suggesting that the overall influence of these diseases is likely to be extremely low. Regarding his hypothesis that WMH reflect a breakdown of the blood–brain barrier, there is ample evidence to support this, particularly in multiple sclerosis; but again, the prevalence of this disease in a healthy population is so low as to be negligible, and all known subjects with multiple sclerosis or other neurological diseases affecting white matter were systematically excluded. Dr Gupta does note that transient breakdown of the blood–brain barrier may be common to migraine, but this would not explain our findings as migraine declines in prevalence with advancing age. In addition, we note that age-related increases in WMH volume are one of the most consistent findings in studies that limit analysis to extremely healthy individuals.^1–4 From these data, we conclude that age, in fact, does relate to WMH volumes for the general population. In the manuscript, however, we do caution that age-related cardiovascular diseases such as systolic hypertension are also likely to contribute to the extent of WMH,⁵ leading us to suggest that WMH may serve as a phenotypic marker for both aging and disease.

Dr Gupta also argues that our data do not conclusively show heritability of WMH. As evidence for this, he notes the decline in heritability after age 60. He further concludes that our data state that there is no correlation with age and WMH among women. Regarding the decline in heritability seen with advancing aging, it is important understand that this was a family-based study. With advancing age, individuals are less likely to have informative family members to estimate heritability, leading to the possibility of spurious findings such as that seen with the oldest woman of this study. In fact, other than this anomaly, the heritability estimates were remarkably consistent at about 0.60 across both age and gender differences. Dr Gupta’s second argument for heritability reflects an apparent misunderstanding of the data. Age was not a significant covariate for the heritability estimates in women, but the correlation between age and WMH was high (r=0.50) and nearly identical for men and women.

We appreciate Dr Gupta’s critical review of our manuscript, but continue to believe that WMH lesions are strongly heritable. We also continue to believe that this heritability probably reflects both the processes of aging and concurrent disease and hope that WMH will serve as a new phenotype to explore the genetics of both processes.⁶

References

1. DeCarli C, Murphy DG, Tranh M, Grady CL, Haxby JV, Gillette JA, Salerno JA, Gonzales-Aviles A, Horwitz B, Rapoport SI, et al. The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults. Neurology. 1995; 45: 2077–2084.[Abstract]
2. Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO. A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol. 1994; 51: 874–887.[Abstract]
3. Jernigan TL, Archibald SL, Fennema-Notestine C, Gamst AC, Stout JC, Bonner J, Hesselink JR. Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging. 2001; 22: 581–594.[CrossRef][Medline] [Order article via Infotrieve]
4. Coffey CE, Wilkinson WE, Parashos IA, Soady SA, Sullivan RJ, Patterson LJ, Figiel GS, Webb MC, Spritzer CE, Djang WT. Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging. Neurology. 1992; 42 (3 Pt 1): 527–536.[Abstract/Free Full Text]
5. Vasan RS, Beiser A, Seshadri S, Larson MG, Kannel WB, D’Agostino RB, Levy D. Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA. 2002; 287: 1003–1010.[Abstract/Free Full Text]
6. Turner ST, Jack CR, Fornage M, Mosley TH, Boerwinkle E, de Andrade M. Heritability of leukoaraiosis in hypertensive sibships. Hypertension. 2004; 43: 483–487.[Abstract/Free Full Text]

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