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ARTICLES: K. Park, N. Yasuda, S. Toyonaga, S. M. Yamada, H. Nakabayashi, M. Nakasato, T. Nakagomi, E. Tsubosaki, and K. Shimizu Significant association between leukoaraiosis and metabolic syndrome in healthy subjects Neurology 2007; 69: 974-978 [Abstract] [Full text] [PDF]

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Significant association between leukoaraiosis and metabolic syndrome in healthy subjects

R. N. Kaveer Nandigam, M.D   (27 December 2007)

Reply from the authors

Kaechang Park, MD, Nobufumi Yasuda, MD   (27 December 2007)

Significant association between leukoaraiosis and metabolic syndrome in healthy subjects 27 December 2007
R. N. Kaveer Nandigam, M.D, MGH Stroke Centre and Dept. of Neurology, Massachusetts General Hospital 175 Cambridge St, Suite 300, Boston, MA 02114 Send Correspondence to journal: Re: Significant association between leukoaraiosis and metabolic syndrome in healthy subjects rnandigam{at}partners.org R. N. Kaveer Nandigam, M.D	I read with interest the article by Park et al. who reported an association between leukoaraiosis (LA) and metabolic syndrome (MetS). [1] Ultrastructural analysis of white matter (WM) using electron microscope in patients with LA identified microvascular wall pathology in the form of massive fibrohyalinosis. This ultrastructural degeneration of the cerebral WM microvessels revealed a clear association with the peripheral atherosclerosis.[2] MetS, which is defined by a cluster of risk factors for peripheral atherosclerosis, appears to be a logical extension that shows a significant association with LA and is not surprising. However, as noted in the accompanying editorial, [3] the odds of MetS being present were similar across all grades of LA severity, with no statistical evidence of a dose effect and absence of higher prevalence of MetS in those with severe LA compared with mild LA. In an autopsy study on brains from subjects with LA, Moody et al. quantified the local WM afferent cerebral microvascular density with nonsubjective, automated reproducible morphometric analysis. The authors found a significantly decreased vascular density not only in the LA lesions, but also in the healthy appearing WM and cortex, compared to age-matched subjects without LA.[4] Based on this finding, they concluded that LA is a generalized cerebrovascular disease affecting the entire brain. It is feasible that the underlying microvascular disease responsible for LA impacts the entire brain at the same time, but the threshold to develop the radiological LA lesions, characterized histopathologically by demyelination, apoptosis of oligodendrogliocytes, gliosis and regressive astrocytic changes, differs among different regions of WM. These are dictated by the susceptibility of the ultracellular structures, mitochondria in particular, to chronic cerebral hypoperfusion and the consequent activation of excitotoxic pathways at the ultracellular level. Certain regions such as periventricular WM may therefore show these lesions early, possibly due to lower threshold compared to other regions such as subcortical WM. The progression of LA lesions may not entirely be the result of progression of underlying microvascular pathology, but an arguable consequence of a particular WM region reaching the threshold to develop new radiological LA lesions. In theory, this would explain the puzzling finding in this study that MetS was significantly associated with both minimal (LA in periventricular regions) and advanced (LA in other subcortical regions) LA with similar odds. [1] References 1. Park K, Yasuda N, Toyonaga S, et al. Significant association between leukoaraiosis and metabolic syndrome in healthy subjects. Neurology 2007;69:974-978. 2. Farkas E, de Vos RA, Donka G, Jansen Steur EN, Mihaly A, Luiten PG. Age-related microvascular degeneration in the human cerebral periventricular white matter. Acta Neuropathol (Berl) 2006;111:150-157. 3. Furie KL, Smith EE. Metabolic syndrome: A target for preventing leukoaraiosis and age-related dementia? Neurology 2007;69:951-952. 4. Moody DM, Thore CR, Anstrom JA, Challa VR, Langefeld CD, Brown WR. Quantification of afferent vessels shows reduced brain vascular density in subjects with leukoaraiosis. Radiology 2004;233:883-890. Disclosure: The author reports no conflicts of interest.
Reply from the authors 27 December 2007
Kaechang Park, MD, Department of Neurology, Medical School, Kochi University Kohasu, Okohcho, Nankokushi, Kochi, 783-8505, Japan, Nobufumi Yasuda, MD Send Correspondence to journal: Re: Reply from the authors park{at}kochi-u.ac.jp Kaechang Park, MD, et al.	We thank Dr. Nandigam for his interest in our article. He describes the possibility of different radiological occurrences of leukoaraiosis (LA) according to white matter regions (periventricular or subcortical) when metabolic syndrome (MetS) was associated with generalized cerebrovascular damages. We similarly speculated on this possibility. In our study, more than the half of minimal LA were punctations in subcortical regions. It is possible that in subcortical regions, the radiological LA might not reflect progression of pathological LA from a punctate to a confluent lesion. A new classification of LA may be necessary to describe the association with MetS, especially in the range of minimal LA. Single or multiple punctations in the subcortical region and thickness of Cap in the periventricular regions may be useful for the detailed classification. The influence of MetS upon LA progression was not adequately analyzed because the assessment of the duration of morbidity with MetS was not considered. The answer to the puzzling finding of similar odds between advanced and minimal LA in association with MetS should be explored by a longitudinal study. Disclosure: The authors report no conflicts of interest.