Spatial Distribution of White-Matter Hyperintensities in Alzheimer Disease, Cerebral Amyloid Angiopathy, and Healthy Aging

Boston University, Boston, Massachusetts, United States
Stroke (Impact Factor: 5.72). 05/2008; 39(4):1127-33. DOI: 10.1161/STROKEAHA.107.497438
Source: PubMed


White-matter hyperintensities (WMHs) detected by magnetic resonance imaging are thought to represent the effects of cerebral small-vessel disease and neurodegenerative changes. We sought to determine whether the spatial distribution of WMHs discriminates between different disease groups and healthy aging individuals and whether these distributions are related to local cerebral perfusion patterns.
We examined the pattern of WMHs by T2/fluid-attenuated inversion recovery-weighted magnetic resonance imaging in 3 groups of subjects: cerebral amyloid angiopathy (n=32), Alzheimer disease or mild cognitive impairment (n=41), and healthy aging (n=29). WMH frequency maps were calculated for each group, and spatial distributions were compared by voxel-wise logistic regression. WMHs were also analyzed as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography atlas.
Although WMH volume was greater in cerebral amyloid angiopathy and Alzheimer disease/mild cognitive impairment than in healthy aging, there was no consistent difference in the spatial distributions when controlling for total WMH volume. Hyperintensities were most frequent in the deep periventricular WM in all 3 groups. A strong inverse correlation between hyperintensity frequency and normal perfusion was demonstrated in all groups, demonstrating that WMHs were most common in regions of relatively lower normal cerebral perfusion.
WMHs show a common distribution pattern and predilection for cerebral WM regions with lower atlas-derived perfusion, regardless of the underlying diagnosis. These data suggest that across diverse disease processes, WM injury may occur in a pattern that reflects underlying tissue properties, such as relative perfusion.

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    • "White matter abnormalities are a common pathological feature of the ageing brain and are closely linked with cognitive impairment particularly a reduction in the speed of information processing (O`Sullivan et al., 2001; Charlton et al., 2006; Grieve et al., 2007; Kennedy and Raz, 2009, Bolandzadeh et al., 2012). Chronic cerebral hypoperfusion is closely associated with white matter alterations in ageing and in disease (Kalaria, 1996; Tang et al., 1997; de Leeuw et al., 2000; Farkas and Luiten, 2001; Fernando et al. 2006; Holland et al. 2008; De Carli, 2013). To experimentally study the association between reductions in the cerebral blood supply and white matter pathology, animal models of chronic cerebral hypoperfusion have been developed initially in the rat and recently in the mouse. "
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    ABSTRACT: White matter abnormalities due to age- related cerebrovascular alterations is a common pathological hallmark associated with functional impairment in the elderly which has been modeled in chronically hypoperfused mice. 5-Methylcytosine (5mC) and its oxidized derivative 5-hydroxymethylcytosine (5hmC) are DNA modifications that have been recently linked with age-related neurodegeneration and cerebrovascular pathology. Here we conducted a pilot investigation of whether chronic cerebral hypoperfusion might affect genomic distribution of these modifications and/ or a Ten- Eleven Translocation protein 2 (TET2) which catalyses hydroxymethylation in white and grey matter regions of this animal model. Immunohistochemical evaluation of sham and chronically hypoperfused mice a month after surgery revealed significant (p<0.05) increases in the proportion of 5hmC positive cells, Iba1 positive inflammatory microglia, and NG2 positive oligodendroglial progenitors in the hypoperfused corpus callosum. In the same white matter tract there was an absence of hypoperfusion- induced alterations in the proportion of 5mC, TET2 positive cells and CC1 positive mature oligodrendrocytes. Correlation analysis across animals within both treatment groups demonstrated a significant association of the elevated 5hmC levels with increases in the proportion of inflammatory microglia only (p=0.01) in the corpus callosum. In vitro studies revealed that 5hmC is lost during oligodendroglial maturation but not microglial activation. Additionally, TET1, TET2, and TET3 protein levels showed dynamic alterations during oligodendroglial development and following oxidative stress in vitro. Our study suggests that 5hmC exhibits white matter tract and cell type specific dynamics following chronic cerebral hypoperfusion in mice.
    Brain Research 10/2014; 1592. DOI:10.1016/j.brainres.2014.09.060 · 2.84 Impact Factor
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    • "However, despite this molecular relationship , CAA is a different entity from AD as less than 50% of CAA cases meet the pathologic criteria for AD and >75% of patients with AD have mild or no CAA at all (Vinters, 1987; Ellis et al., 1996). Cerebral amyloid angiopathy-related impairments in cerebral perfusion may be responsible for subcortical WMLs and microscopic damage seen in the disease (Gurol et al., 2006; Holland et al., 2008; Viswanathan et al., 2008). Some studies have suggested that advanced CAA is associated with a larger burden "
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    ABSTRACT: The association between cerebral small vessel disease (SVD) - in the form of white matter lesions, infarctions, and hemorrhages - with vascular cognitive impairment (VCI), has mostly been deduced from observational studies. Pathological conditions affecting the small vessels of the brain and leading to SVD have suggested plausible molecular mechanisms involved in vascular damage and their impact on brain function. However, much still needs to be clarified in understanding the pathophysiology of VCI, the role of neurodegenerative processes such as Alzheimer's disease, and the impact of aging itself. In addition, both genetic predispositions and environmental exposures may potentiate the development of SVD and interact with normal aging to impact cognitive function and require further study. Advances in technology, in the analysis of genetic and epigenetic data, neuroimaging such as magnetic resonance imaging, and new biomarkers will help to clarify the complex factors leading to SVD and the expression of VCI.
    Frontiers in Aging Neuroscience 03/2014; 6:24. DOI:10.3389/fnagi.2014.00024 · 4.00 Impact Factor
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    • "Cerebral WML segmentation and intensity thresholding were performed on 1.5T coronal 5 mm FLAIR images using the MRIcron software with a modification (see later) of the method used in Gurol et al. [18]. The segmentation method involves an initial rough manual demarcation of WML, separating them from noncerebral regions and septum pellucidum, as in Holland et al. [31], within the same intensity span, followed by an intensity threshold set to separate WML from adjacent tissue types. In the Gothenburg MCI cohort, artifactual image intensity differences between slices and between series (using the same FLAIR sequence) were common. "
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    ABSTRACT: Age-related white matter lesions (WML) are a risk factor for stroke, cognitive decline, and dementia. Different requirements are imposed on methods for the assessment of WML in clinical settings and for research purposes, but reliability analysis is of major importance. In this study, WML assessment with three different methods was evaluated. In the Gothenburg mild cognitive impairment study, MRI scans from 152 participants were used to assess WML with the Fazekas visual rating scale on T2 images, a manual volumetric method on FLAIR images, and FreeSurfer volumetry on T1 images. Reliability was acceptable for all three methods. For low WML volumes (2/3 of the patients), reliability was overall lower and nonsignificant for the manual volumetric method. Unreliability in the assessment of patients with low WML with manual volumetry may mainly be due to intensity variation in the FLAIR sequence used; hence, intensity standardization and normalization methods must be used for more accurate assessments. The FreeSurfer segmentations resulted in smaller WML volumes than the volumes acquired with the manual method and showed deviations from visible hypointensities in the T1 images, which quite likely reduces validity.
    Journal of aging research 01/2013; 2013(59):198471. DOI:10.1155/2013/198471
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