William M. Feinberg Award for Excellence in Clinical Stroke: Big Pictures and Small Vessels.
William M. Feinberg Award for Excellence in Clinical Stroke: Big Pictures and Small Vessels.
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William M. Feinberg 临床中风卓越奖：大图片和小血管。
DOI：
10.1161/strokeaha.117.017246
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发表时间：
2017
期刊：
影响因子：
8.3
通讯作者：
Greenberg,StevenM
中科院分区：
文献类型：
--
作者：
Greenberg,StevenM
CAA contributions to VCID are harder to detect than its contributions to intracerebral hemorrhage, but—like small vessel disease–related brain injury in general—may represent the greater public health impact. ROS-MAP reported moderate–severe CAA in nearly one fifth of autopsied brain, where it is associated with reduced perceptual speed and episodic memory independently of AD pathology, age, sex, education, cerebral infarcts, and Lewy bodies. 17 Further analysis showed CAA severity associated with faster trajectories of cognitive decline over a mean 7.1 years before death, again remaining independent in models controlling for age, sex, education, AD, macroscopic infarcts, and Lewy bodies. 18 The high prevalence of advanced CAA and its independent contribution to worse cognition suggests that the scale of CAA-related cognitive impairment is truly population wide. Although the relationship between CAA and cognitive impairment appears clear, the mechanism by which vascular amyloid actually causes reduced cognition is anything but. The list of potential suspects is long: advanced CAA is associated with microbleeds, 19 microinfarcts, 20, 21 greater volume of white matter T2 hyperintensity, 22 altered structural network connectivity, 23 reduced cortical thickness, 24 increased amyloid labeling, 25, 26 and impaired vascular reactivity to physiological stimulation. 27, 28 Which of these markers represent mechanisms that directly contribute to worse cognitive performance? Which are just innocent bystanders, markers of advanced CAA without direct contribution to brain dysfunction? The questions are more than academic, as they govern the choice of treatment, outcome marker, and patient selection criteria for clinical trials aimed at slowing or stopping the key steps in the pathogenesis of CAA-related VCID. Definitive answers remain challenging, but a few tentative conclusions can be drawn from CAA. First, microinfarcts are numerous29, 30 and drastically undercounted by in vivo magnetic resonance imaging, which demonstrates only a small proportion of microinfarcts detectable by very high-resolution postmortem magnetic resonance imaging or histopathologic sectioning. 21 Estimates of total microinfarct burden throughout the brain based on histological sectioning30 or incidence of small diffusion-restricted lesions31 are in the hundreds or thousands, suggesting that these lesions might be numerous enough to have a substantial impact on brain connectivity. Second, the closest correlation with clinical performance—processing speed, executive function, and gait velocity in particular—appears to come from measures of structural network connectivity analyzed by diffusion tensor imaging magnetic resonance imaging. Diffusion tensor imaging studies in CAA have quantified structural connectivity by the graph theory parameter network efficiency, 23 but similarly strong correlations with cognitive performance in other small vessel diseases have been demonstrated using the alternative parameter of the peak width of the mean diffusivity histogram of skeletonized white matter. 32 Both studies suggest that diffusion tensor imaging–based measures of white matter integrity may be important and useful summary markers of the cumulative effects of multiple types of small brain injuries on overall neurological function. Finally, analyses of families carrying an early-onset CAA amyloid precursor protein mutation indicate that altered vascular reactivity occurs early in the disease. The amplitude of the functional magnetic resonance imaging response to visual stimulation is reduced not only in symptomatic carriers who had already suffered CAA-related …
