Age-related changes in normal-appearing brain tissue and white matter hyperintensities: more of the same or something else?
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BACKGROUND AND PURPOSE: Cerebral white matter (WM) hyperintensities are a frequent finding in elderly people, and lowering of cerebral magnetization transfer ratio (MTR) has been observed. The aim of this study was to assess the relationship between age-related WM hyperintensities and MTR changes in the brain. METHODS: We performed MR imaging in a group of young subjects, a group of elderly individuals with minimal WM hyperintensities, and a group of elderly individuals with abundant WM hyperintensities. In addition, we performed volumetric MTR analysis of the whole brain and of the normal-appearing WM (NAWM) in these groups. RESULTS: Volumetric MTR parameters differed between elderly and young patients. Mean MTR ± standard error of the mean (SEM) was 34.0% ± 0.12% in the young, 33.0% ± 0.08% in the elderly with minimal WM hyperintensities, 32.8% ± 0.09%) in the group with abundant WM hyperintensities. Peak height (number of voxels ± SEM) was 122 ± 1.2 in the young, 99 ± 1.5 in the elderly with minimal WM hyperintensities, and 98 ± 1.6 in the group with abundant WM hyperintensities. Mean MTR of NAWM was lower in the elderly compared with the young (36.7% ± 0.12%) but did not differ between subjects with minimal (36.0% ± 0.11%) and those with abundant WM hyperintensities (35.9% ± 0.13%). CONCLUSION: Our results show that aging gives rise to changes in normal-appearing brain tissue. These changes, which can be detected on magnetization transfer imaging, seem to have no relationship with age-related WM hyperintensities and might have a different etiology.Keywords:
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Conventional MRI can reveal decreases in brain volumes with aging but fails to provide information about the underlying microstructural modifications. Magnetization transfer (MT) and diffusion tensor (DT) MRI can in part overcome these limitations.To investigate the influence of aging on conventional and MT and DT MRI-derived measurements in brain white (WM) and gray (GM) matter.Dual-echo, T1-weighted, MT and DT MR images of the brain were obtained in 89 healthy subjects (age range 11 to 76 years). Normalized GM and WM volumes were measured and MT ratio (MTR) and mean diffusivity (MD) histograms produced for both tissue compartments.Normalized brain (r = -0.78), GM (r = -0.75), and WM (r = -0.34) volumes and the number of brain T2 hyperintensities (r = 0.49) were correlated with age. Additionally, all GM MT- and DT-derived parameters also correlated with age (r values ranging from 0.28 to 0.64), whereas only the peak height (ph) of the normal-appearing (NA) WM MD histogram did so (r = -0.34). After correcting for the number of T2 hyperintensities, gender, and the corresponding normalized tissue volumes, only the correlations between age and GM average MD (r = 0.24), GM-MD-ph (r = -0.37), and NAWM-MD-ph (r = -0.29) remained significant. A multivariate regression analysis including both brain tissues variables retained the GM volume (beta = -0.18, SE = 0.02, p < 0.001) and the GM average MD (beta = 45, SE = 19, p = 0.02) as independent predictors of subject's age.Brain white matter and gray matter have different vulnerabilities to aging. Microstructural imaging is important to achieve a complete picture of the complex changes occurring in the aging brain.
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Background Changes in the cerebral hemispheric white matter are detected with increasing frequency by CT and MRI among persons older than 60 years. The pathogenesis, clinical significance, and morphological substrate of these changes are incompletely understood. Patients who have such neuroimaging abnormalities are sometimes diagnosed with “Binswanger’s disease,” an eponym that has generated much confusion because of its imprecise meaning. The objectives of this study were to determine whether the term Binswanger’s disease merits acceptance as a distinct clinicopathologic entity, to deduce the clinical significance of these white matter abnormalities from the analysis of appropriate publications, and to evaluate studies that correlate in vivo changes in the cerebral white matter with pathological features. Summary of Review We evaluated Binswanger’s original case description and, after conducting a Medline search, reviewed more than 160 publications, mostly in the English language, on the subject of white matter abnormalities detectable by currently used neuroimaging methods (ie, leukoaraiosis). Conclusions Binswanger’s original description appears to be insufficient for the purpose of defining a new nosological entity. After evaluating the vaguely outlined pathological correlates described in a few of these subcortical cerebral leukoencephalopathies, we conclude that the clinical significance of leukoaraiosis remains incompletely defined. However, its frequency increases with age independent of other risk factors, and in nondemented subjects leukoaraiosis is associated with deficits in selected cognitive functions. Moreover, leukoaraiosis correlates with an increased risk for the subsequent development of strokes. We make specific suggestions for future studies that may help to clarify this topic.
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The severity of tissue changes associated with incidental white matter hyperintensities (WMH) in the elderly cannot be sufficiently determined by conventional MRI. We, therefore, performed a regional analysis of the magnetization transfer ratio (MTR) maps obtained on a 1.5 T scanner from 198 neurologically asymptomatic participants of the Austrian Stroke Prevention Study (mean age 70, age range 52-87 years) in regard to WMH and predefined areas of normal appearing brain tissue. Fluid attenuated inversion recovery MRI was used to grade lesion severity and for lesion volume measurements. The MTR of WMH was always significantly lower than that of normal appearing white matter (NAWM) with an overall relative reduction of approximately 10% and decreased significantly with increasing scores of WMH severity (P = 0.02) and WMH volume (r = -0.24, P = 0.0016). NAWM MTR was not different between subjects with very few and extensive WMH and the WMH volume was associated with NAWM MTR of the frontal lobes only. Concerning a possible impact on cerebral functioning the MTR of the frontal NAWM was significantly associated with fine motor dexterity (P = 0.04) but not with cognitive performance. A significant decline of the MTR with aging was seen in both NAWM and cortex but not in WMH. We conclude that MTR measurements can serve to quantify WMH associated tissue damage. It is predominantly focal, relatively mild, increases with lesion size and may have remote effects on the frontal white matter.
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BACKGROUND AND PURPOSE:
Reductions in magnetization transfer ratio have been associated with brain microstructural damage. We aim to compare magnetization transfer ratio in global and regional GM and WM between individuals with Alzheimer disease and healthy control participants to analyze the relationship between magnetization transfer ratio and cognitive functioning in Alzheimer disease.MATERIALS AND METHODS:
In this prospective study, participants with Alzheimer disease and a group of age-matched healthy control participants underwent clinical examinations and 3T MR imaging. Magnetization transfer ratios were determined in the cortex, AD-signature regions, normal-appearing WM, and WM hyperintensities.RESULTS:
Seventy-seven study participants (mean age ± SD, 72 ± 8 years; 47 female) and 77 age-matched healthy control participants (mean age ± SD, 72 ± 8 years; 44 female) were evaluated. Magnetization transfer ratio values were lower in patients with Alzheimer disease than in healthy control participants in all investigated regions. When adjusting for atrophy and extent of WM hyperintensities, significant differences were seen in the global cortex (OR = 0.47; 95% CI: 0.22, 0.97; P = .04), in Alzheimer disease–signature regions (OR = 0.31; 95% CI: 0.14, 0.67; P = .003), in normal-appearing WM (OR = 0.59; 95% CI: 0.39, 0.88; P = .01), and in WM hyperintensities (OR = 0.18; 95% CI: 0.09, 0.33; P ≤ .001). The magnetization transfer ratio in these regions was an independent determinant of AD. When correcting for atrophy and WM hyperintensity extent, lower GM magnetization transfer ratios were associated with poorer global cognition, language function, and constructional praxis.CONCLUSIONS:
Alzheimer disease is associated with magnetization transfer ratio reductions in GM and WM regions of the brain. Lower magnetization transfer ratios in the entire cortex and AD-signature regions contribute to cognitive impairment independent of brain atrophy and WM damage.Magnetization transfer
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Regional Brain Changes in Aging Healthy Adults: General Trends, Individual Differences and Modifiers
Brain aging research relies mostly on cross-sectional studies, which infer true changes from age differences. We present longitudinal measures of five-year change in the regional brain volumes in healthy adults. Average and individual differences in volume changes and the effects of age, sex and hypertension were assessed with latent difference score modeling. The caudate, the cerebellum, the hippocampus and the association cortices shrunk substantially. There was minimal change in the entorhinal and none in the primary visual cortex. Longitudinal measures of shrinkage exceeded cross-sectional estimates. All regions except the inferior parietal lobule showed individual differences in change. Shrinkage of the cerebellum decreased from young to middle adulthood, and increased from middle adulthood to old age. Shrinkage of the hippocampus, the entorhinal cortices, the inferior temporal cortex and the prefrontal white matter increased with age. Moreover, shrinkage in the hippocampus and the cerebellum accelerated with age. In the hippocampus, both linear and quadratic trends in incremental age-related shrinkage were limited to the hypertensive participants. Individual differences in shrinkage correlated across some regions, suggesting common causes. No sex differences in age trends except for the caudate were observed. We found no evidence of neuroprotective effects of larger brain size or educational attainment.
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Objective: White matter hyperintensities (WMH) are commonly seen on neuroimaging scans, but their underlying histopathologic substrate is unclear. The aim of this work was to establish the pathologic correlates of WMH in unselected elderly cases using two study designs. To avoid potential bias from comparisons of different anatomic regions, study 1 compared, region-by-region, the severity of WMH determined in vivo with measures of each of the major white matter (WM) components. Study 2 compared the histopathology of WMH with normal WM. Methods: Study 1: The periventricular and deep WM regions of three lobes in 23 brains with in vivo MRI scans were investigated using histologic and immunohistochemical stains. The severity of each pathologic measure was correlated with WMH severity determined using the Scheltens scale. Study 2: Lesioned and nonlesioned areas identified by postmortem MRI in the frontal WM of 20 brains were examined histologically and immunohistochemically. Results: No single pathologic variable correlated with the severity of WMH; however, a multiple stepwise regression analysis revealed that vascular integrity predicted total Scheltens score (β = −0.53, p = 0.01). Comparison of lesioned and nonlesioned areas demonstrated that vascular integrity was reduced in WMH [t(18) = 3.79, p = 0.001]. Blood–brain barrier integrity was also found to be reduced in WMH [t(5) = −5.31, p = 0.003]. Conclusions: White matter hyperintensities (WMH) involve a loss of vascular integrity, confirming the vascular origin of these lesions. This damage to the vasculature may in turn impair blood–brain barrier integrity and be one mechanism by which WMH evolve.
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Abstract The purpose of this study was to assess whether structural brain damage as detected by volumetric magnetization transfer imaging (MTI) is present in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and, if so, whether these abnormalities are global in character or restricted to the temporal lobe. Volumetric MTI analysis of the whole brain and temporal and frontal lobes was performed in 25 patients with probable AD, in 13 patients with MCI, and in 28 controls. Magnetization transfer ratio (MTR) histograms were produced, from which we derived measures for structural brain damage and atrophy. The peak heights of the MTR histograms of MCI and AD patients were lower than those of controls for the whole brain and temporal and frontal lobes, reflecting structural brain damage. AD patients had more atrophy than controls in all regions that were studied. MCI patients differed from controls for temporal lobe atrophy only. Volumetric MTI demonstrates structural changes that are related to cognitive decline in large parts of the brain of AD patients. Moreover, structural changes also were observed in MCI patients, indicating that widespread brain damage can be demonstrated before patients are clinically demented.
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PURPOSE: Our aim was to assess whether presumed histologic heterogeneity of age-related white matter hyperintensities (WMH) is reflected in quantitative magnetization transfer imaging measures. MATERIALS AND METHODS: From a group of patients participating in a double-blind placebo-controlled multicenter study on the effect of pravastatin (PROSPER), we selected 56 subjects with WMH. WMH were classified as periventricular WMH (PVWMH) and deep WMH (DWMH). PVWMH were subclassified as irregular or smooth, depending on the aspect of their border. Signal intensity of WMH on T1-weighted images was scored as iso- or hypointense. The mean magnetization transfer ratio (MTR) value of different types of WMH was assessed and compared. As a control group, we selected 19 subjects with no or limited WMH. RESULTS: Mean (SE) MTR of PVWMH (frontal, 31.2% [0.2%]; occipital, 32.2% [0.2%]) was lower than that of DWMH (33.7% [0.5%]). The mean MTR of frontal PVWMH (31.2% [0.2%]) was lower than that of occipital PVWMH (32.2% [0.2%]). Compared with occipital PVWMH, frontal PVWMH more often had a smooth lining (72% frontal versus 8% occipital) and an area with low signal intensity on T1-weighted images (76% frontal versus 35% occipital). MTR did not differ between smooth (31.1% [0.3%]) and irregular (31.6% [0.5%]) PVWMH. CONCLUSION: Age-related WMH are heterogeneous, despite their similar appearance on T2-weighted images. By taking into account heterogeneity of age-related WMH, both in terms of etiology and in terms of severity of tissue destruction, one may obtain better understanding on the causes and consequences of these lesions.
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In subjects with subcortical ischemic vascular dementia (SIVD), tissue vacuolization, myelin pallor, and demyelination have been found on pathologic examination of white matter signal hyperintensities (WMSH). Magnetization transfer ratio (MTR) values provide a potential measure of compromised white matter integrity. The purpose of this study was to determine if there were differences in MTR of WMSH between subjects with SIVD and cognitively normal healthy control subjects.Fifteen subjects with SIVD and 16 control subjects of comparable age and sex were studied. MTR images were coregistered to MR images segmented into tissue classes (gray matter, white matter, CSF, WMSH, and lacunar infarcts). MTR of WMSH was compared across groups and examined by WMSH location, size, and total burden.WMSH burden was greater in SIVD patients than in control subjects (2.4% vs 0.67%). MTR of WMSH did not differ between groups, but MTR of periventricular WMSH was lower in SIVD patients than in control subjects (37.6% vs 39.4%). Even after accounting for covariant effects of lesion burden, there was still a trend toward reduced periventricular WMSH MTR in the group with dementia. There was no correlation between WMSH MTR and WMSH lesion size.These findings are consistent with observations that pathologic changes in vascular dementia are most severe in the periventricular white matter and suggest that insight into the pathophysiology of SIVD might be gleaned from studies of the periventricular region.
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