White matter hyperintensities contribute to early cortical thinning in addition to tau in aging.

Cortical thinning related to periventricular and deep white matter hyperintensities

To the Editor: The recent article by DeCarli et al1 addresses a somewhat neglected aspect of white matter hyperintensities (WMH), the significance of their anatomical location. The authors argue that the commonly accepted categorization into deep (DWMH) and periventricular (PVWMH) WMH is arbitrary, because the 2 are very highly correlated, and a spatial analysis does not reveal distinct populations. We think that this conclusion is premature, because the categorization depends on a number of factors. The first limitation of their analysis is that they examined individuals in their 70s who presented to a specialty clinic, suggesting that the white matter lesions in their sample were at an advanced stage. If an analogy is drawn from cerebral atrophy in dementia, regional differences in atrophy that are present in the different subtypes of dementia become less prominent in the later stages. In our study of WMH in middle age (60 to 64 years), the correlation of DWMH and PVWMH was much lower ( r =0.621; …

Cerebrovascular disease is a common comorbidity in older adults, typically assessed in terms of white matter hyperintensities (WMHs) on MRI. While it is well known that WMHs exacerbate cognitive symptoms, the exact relation of WMHs with cognitive performance and other degenerative diseases is unknown. Furthermore, based on location, WMHs are often classified into periventricular and deep WMHs and are believed to have different pathological origins. Whether the two types of WMHs influence cognition differently is unclear. Using regression models, we assessed the independent association of these two types of WMHs with cognitive performance in two separate studies focused on distinct degenerative diseases, early Alzheimer's (mild cognitive impairment), and Parkinson's disease. We further tested if the two types of WMHs were differentially associated with reduced cortical cerebral blood flow (CBF) as measured by arterial spin labeling and increased mean diffusivity (MD, a marker of tissue injury) as measured by diffusion imaging. Our approach revealed that both deep and periventricular WMHs were associated with poor performance on tests of global cognition (Montreal cognitive Assessment, MoCA), task processing (Trail making test), and category fluency in the study of mild cognitive impairment. They were associated with poor performance in global cognition (MoCA) and category fluency in the Parkinson's disease study. Of note, more associations were detected between cognitive performance and deep WMHs than between cognitive performance and periventricular WMHs. Mechanistically, both deep and periventricular WMHs were associated with increased MD. Both deep and periventricular WMHs were also associated with reduced CBF in the gray matter.

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White matter hyperintensities are characteristic of old age and identifiable on FLAIR and T2-weighted MR imaging. They are typically separated into periventricular or deep categories. It is unclear whether the innermost segment of periventricular white matter hyperintensities is truly abnormal or is imaging artifacts. We used FLAIR MR imaging from 665 community-dwelling subjects 72-73 years of age without dementia. Periventricular white matter hyperintensities were visually allocated into 4 categories: 1) thin white line; 2) thick rim; 3) penetrating toward or confluent with deep white matter hyperintensities; and 4) diffuse ill-defined, labeled as "subtle extended periventricular white matter hyperintensities." We measured the maximum intensity and width of the periventricular white matter hyperintensities, mapped all white matter hyperintensities in 3D, and investigated associations between each category and hypertension, stroke, diabetes, hypercholesterolemia, cardiovascular disease, and total white matter hyperintensity volume. The intensity patterns and morphologic features were different for each periventricular white matter hyperintensity category. Both the widths (r = 0.61, P < .001) and intensities (r = 0.51, P < .001) correlated with total white matter hyperintensity volume and with each other (r = 0.55, P < .001) for all categories with the exception of subtle extended periventricular white matter hyperintensities, largely characterized by evidence of erratic, ill-defined, and fragmented pale white matter hyperintensities (width: r = 0.02, P = .11; intensity: r = 0.02, P = .84). The prevalence of hypertension, hypercholesterolemia, and neuroradiologic evidence of stroke increased from periventricular white matter hyperintensity categories 1 to 3. The mean periventricular white matter hyperintensity width was significantly larger in subjects with hypertension (mean difference = 0.5 mm, P = .029) or evidence of stroke (mean difference = 1 mm, P < .001). 3D mapping revealed that periventricular white matter hyperintensities were discontinuous with deep white matter hyperintensities in all categories, except only in particular regions in brains with category 3. Periventricular white matter hyperintensity intensity levels, distribution, and association with risk factors and disease suggest that in old age, these are true tissue abnormalities and therefore should not be dismissed as artifacts. Dichotomizing periventricular and deep white matter hyperintensities by continuity from the ventricle edge toward the deep white matter is possible.

Objective To investigate the correlation between white matter hyperintensities(WMH)and hyperintense vessel sign(HVS)on fluid-attenuated inversion recovery(FLAIR)magnetic resonance imaging(MRI)in old adults and to explore the risk factors and pathogeneses of WMH. Methods We retrospectively collected imaging and clinical data of patients who had received both head and neck CTA and brain MRI within one month at our hospital from 2013 to 2016.The Fazekas visual scale was used to evaluate periventricular white matter hyperintensity(PWMH)and deep white matter hyperintensity(DWMH)in each brain hemisphere.According to the presence or absence of HVS in a cerebral hemisphere, patients were assigned into an HVS-positive group or an HVS-negative group.Clinical data, PWMH, and DWMH differences were compared between the two groups. Results A total of 271 patients(542 cerebral hemispheres)were included in this study.HVS-positive imaging occurred in 79(14.6%)cerebral hemispheres and negative imaging was observed in 463(85.4%)cerebral hemispheres.There was a significant difference between the HVS-positive and negative groups in the ipsilateral CIA stenosis(χ2=126.840, P<0.01). The incidence of ipsilateral severe carotid artery stenosis in the HVS-positive group was 62.0%(49/79), which was significantly higher than 9.9%(46/463)in the HVS-negative group.The incidence of moderate-severe DWMH was 65.8%(52/79)in the HVS-positive group, which was higher than 34.8%(161/463)in the negative group(χ2=34.962, P<0.01). Nevertheless, the incidences of moderate-severe PWMH in the two groups were 65.8%(52/79)and 55.5%(257/463), respectively, without a significant difference between them(χ2=6.944, P=0.074). After adjusting for age, gender, ipsilateral ICA stenosis, hypertension, diabetes, etc.multivariate analysis suggested that HVS-positive imaging was still an independent risk factor for DWMH(OR=2.653, 95%CI: 1.489-4.726, P=0.001). Conclusions HVS-positive imaging is an independent risk factor for DWMH in the elderly, but no clear correlation with PWMH is found.It suggests that hypoperfusion is a possible mechanism for the development of DWMH in the elderly. Key words: White matter hyperintensities; Hyperintense vessel sign; Internal carotid artery stenosis; Fluid-attenuated inversion recovery; Magnetic resonance imaging

White matter hyperintensities (WMHs) are established structural imaging markers of cerebral small vessel disease. The pathophysiologic condition of brain tissue varies over the core, the vicinity, and the subtypes of WMH and cannot be interpreted from conventional magnetic resonance imaging. We aim to improve our pathophysiologic understanding of WMHs and the adjacently injured normal-appearing white matter in terms of microstructural and microvascular alterations using quantitative magnetic resonance imaging in patients with sporadic and genetic cerebral small vessel disease. Structural T2-weighted imaging, multishell diffusion imaging, and dynamic contrast-enhanced magnetic resonance imaging were performed at 3T in 44 participants with sporadic cerebral small vessel disease and 32 participants with monogenic cerebral small vessel disease (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; 59±12 years, 41 males) between June 2017 and May 2020 as part of the prospective, multicenter (Edinburgh, the United Kingdom; Maastricht, the Netherlands; and Munich, Germany), observational INVESTIGATE-SVDs study (Imaging Neurovascular, Endothelial and Structural Integrity in Preparation to Treat Small Vessel Diseases). The mean diffusivity, free water content, and perfusion (all derived from multishell diffusion imaging), as well as the blood-brain barrier leakage and plasma volume fraction (derived from dynamic contrast-enhanced magnetic resonance imaging), were compared between deep and periventricular WMH types using paired t tests. Additional spatial analyses were performed inside and outside the WMH types to determine the internal heterogeneity and the extent of the penumbras, that is, adjacent white matter at risk for conversion to WMH. Periventricular WMH had higher mean diffusivity, higher free water content, and more plasma volume compared with deep WMH (P<0.001, P=0.01, and P<0.001, respectively). No differences were observed in perfusion (P=0.94) and blood-brain barrier leakage (P=0.65) between periventricular and deep WMHs. The spatial analyses inside WMH and the adjacent white matter revealed a gradual gradient in white matter microstructure, free water content, perfusion, and plasma volume but not in blood-brain barrier leakage. We showed different pathophysiological heterogeneity of the 2 WMH types. Periventricular WMHs display more severe damage and fluid accumulation compared with deep WMH, whereas deep WMHs reflect stronger hypoperfusion in the lesion's core. URL: https://www.isrctn.com; Unique identifier: ISRCTN10514229.

Introduction: White Matter Hyperintensities (WMH) have been implicated as a risk factor for motor and cognitive decline, dementia and stroke. A standard for use in clinical settings is needed to identify which cases are advanced or meet thresholds with implications for degree of impairment. The system of Fazekas is a promising candidate due to its simplicity and strong correlation with outcomes. The original Fazekas categorized deep and periventricular WMH separately. Advanced periventricular and deep WMH were later shown to have equivalent pathology and etiology. Subsequent work by De Carli showed the classification of deep and periventricular WMH on axial images to be arbitrary and suggested a common etiology for lesser degrees of WMH as well. We therefore adapted the Fazekas criteria to consider deep and periventricular WMH jointly. Questions persist about low reproducibility of grading systems. In a preliminary analysis we found frequent disagreement classifying lesions less than 3mm in diameter and decided to incorporate this threshold into our criteria to determine the effect on reproducibility and correlation of our final model with automated volumes. Hypothesis: Modification of the Fazekas grading system to consider deep and periventricular WMH jointly is less arbitrary. Simple modifications of such a system will result in a high degree of reproducibility and high correlation with automated WMH volumes. Methods: Axial 3T FLAIR MR images of the brain were obtained from community dwelling subjects. Grading measurements were applied to diameter of deep WMH and thickness of periventricular WMH. The initial system defined Grade 0 as no WMH, Grade 1 as &lt; 10mm, Grade 2 as &gt;=10mm but &lt;20mm and Grade 3 as &gt;=20mm. 52 studies were read separately by 2 reviewers. We then revised grade 0 to include intensities &lt; 3mm and grade 1 as &gt;=3mm but &lt;10mm. 40 additional studies were then read and level of agreement was re-assessed. 563 studies were read for correlation with automated volumes. Results: After modifications, inter-rater agreement for Fazekas white matter score increased from 72% to 89% with kappa increased from 0.45 to 0.78. There was good correlation of grade and automated volume (ANOVA R-Square: 0.52 P &lt;.0001). Conclusion: Advances in understanding of White Matter Hyperintensities suggest periventricular and deep lesions should be rated jointly. This modification was applied to the Fazekas system with excellent reproducibility after implementation of a 3mm size threshold as well as high agreement with automated volumes ammong community dwelling subjects.

MRI segmentation and mapping techniques were used to assess evidence in support of categorical distinctions between periventricular white matter hyperintensities (PVWMH) and deep WMH (DWMH). Qualitative MRI studies generally identify 2 categories of WMH on the basis of anatomical localization. Separate pathophysiologies and behavioral consequences are often attributed to these 2 classes of WMH. However, evidence to support these empirical distinctions has not been rigorously sought. MRI analysis of 55 subjects included quantification of WMH volume, mapping onto a common anatomical image, and spatial localization of each WMH voxel. WMH locations were then divided into PVWMH and DWMH on the basis of distance from the lateral ventricles and correlations, with total WMH volume determined. Periventricular distance histograms of WMH voxels were also calculated. PVWMH and DWMH were highly correlated with total WMH (R2>0.95) and with each other (R2>0.87). Mapping of all WMH revealed smooth expansion from around central cerebrospinal fluid spaces into more distal cerebral white matter with increasing WMH volume. PVWMH, DWMH, and total WMH are highly correlated with each other. Moreover, spatial analysis failed to identify distinct subpopulations for PVWMH and DWMH. These results suggest that categorical distinctions between PVWMH and DWMH may be arbitrary, and conclusions regarding individual relationships between causal factors or behavior for PVWMH and DWMH may more accurately reflect total WMH volume relationships.

Topography of cortical thinning associated with white matter hyperintensities in Parkinson's disease.

<i>Stroke</i> : Highlights of Selected Articles

Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups. To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups. This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights-Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020. Total and regional WMH volumes. The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome. In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P < .001), paracentral (P < .001), and pars triangularis (P = .02) cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit (right caudal middle frontal cortex: standardized β = 0.129; unstandardized b = 0.335; 95% CI, 0.055 to 0.616; P = .01; left entorhinal cortex: β = 0.119; b = 0.290; 95% CI, 0.018 to 0.563; P = .03). The association of total WMH with thinning in the right caudal middle frontal and right paracentral cortex was greater in non-Hispanic Black participants compared with White participants (right caudal middle frontal cortex: β = -0.222; b = -0.059; 95% CI, -0.114 to -0.004; P = .03; right paracentral cortex: β = -0.346; b = -0.155; 95% CI, -0.244 to -0.066; P = .001). The association of parietal WMH with cortical thinning of the right rostral middle frontal, right pars triangularis, and right paracentral cortices was also stronger among non-Hispanic Black participants compared with White participants (right rostral middle frontal cortex: β = -0.252; b = -0.202; 95% CI, -0.349 to -0.055; P = .007; right pars triangularis cortex: β = -0.327; b = -0.253; 95% CI, -0.393 to -0.113; P < .001; right paracentral cortex: β = -0.263; b = -0.337; 95% CI, -0.567 to -0.107; P = .004). In this study, small vessel cerebrovascular disease, operationalized as WMH, was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults. Cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.

Association of white matter hyperintensity accumulation with domain-specific cognitive decline: a population-based cohort study

Objective: To investigate the value of intravoxel incoherent motion diffusion weighted imaging (IVIM DWI) in evaluating microstructure changes in elderly white matter hyperintensities (WMH) patients and to analyze the correlation between IVIM parameters and severity grading and cognitive scores. Methods: Sixty-two WMH patients in Zhejiang Hospital were collected from December 2014 to March 2018 and underwent conventional magnetic resonance (MR) plain scan and diffusion weighted imaging with different b values. The age was 60-92(74±10) years with 37 males, 25 females. The severity of WMH was assessed by T(2) fluid attenuated inversion recovery (FLAIR) sequence and Fazekas score,which were divided into two subgroups. Slow diffusion coefficient (D), fast diffusion coefficient (D(*)) and perfusion fraction (f) from IVIM parameters of double exponential model were compared between regions of WMH (deep WMH (DWMH) and periventricular WMH (PWMH)) and surrounding normal white matter (NWM).The Shapiro-Wilk test was used for normality tests, Kruskal-Wallis tests and Dwass-Steel-Critchlow-Fligner (DSCF) procedure were used for the comparison among these parameters. Furthermore, Wilcoxon two-sample test was used for the comparisons between different severity. Pearson correlation analysis was performed to determine whether these D, D(*), f values were correlated with the mini mental state examination (MMSE) scores. Results: D(D)WMH (0.83(0.72,0.99)×10(-3) mm(2)/s), D(PWMH)((1.13±0.25)×10(-3) mm(2)/s) were significantly higher than D(NWM) ((0.71±0.05)×10(-3) mm(2)/s)(P<0.01). f (DWMH) ((8.94%(7.46%,11.67%)), f (PWMH)(8.34%(6.73%,9.96%)) were significantly higher than f (NWM)(6.71%±1.72%)(P<0.01).D in DWMH were significantly lower than that in PWMH(P<0.01), there's no statistically difference between other groups. D in severe WMH (both DWMH and PWMH) were significantly higher than that in mild WMH (P=0.000 1, P=0.04). Only f in PWMH were positively associated with the MMSE scores (r=0.326 5,P<0.05). Conclusions: IVIM DWI can noninvasively assess the variation of microstructure diffusion and perfusion in WMH in one sequence,which may objectively reflect the severity of these lesions. This method has important clinical significance for better assessment and management of this disease.

We sought to determine the underlying pathophysiology relating white matter hyperintensities to chronic aphasia severity. We hypothesized that: (i) white matter hyperintensities are associated with damage to fibres of any length, but to a higher percentage of long-range compared to mid- and short-range intracerebral white matter fibres; and (ii) the number of long-range fibres mediates the relationship between white matter hyperintensities and chronic post-stroke aphasia severity. We measured the severity of periventricular and deep white matter hyperintensities and calculated the number and percentages of short-, mid- and long-range white matter fibres in 48 individuals with chronic post-stroke aphasia. Correlation and mediation analyses were performed to assess the relationship between white matter hyperintensities, connectome fibre-length measures and aphasia severity as measured with the aphasia quotient of the Western Aphasia Battery-Revised (WAB-AQ). We found that more severe periventricular and deep white matter hyperintensities correlated with a lower proportion of long-range fibres (r = -0.423, P = 0.003 and r = -0.315, P = 0.029, respectively), counterbalanced by a higher proportion of short-range fibres (r = 0.427, P = 0.002 and r = 0.285, P = 0.050, respectively). More severe periventricular white matter hyperintensities also correlated with a lower proportion of mid-range fibres (r = -0.334, P = 0.020), while deep white matter hyperintensities did not correlate with mid-range fibres (r = -0.169, P = 0.250). Mediation analyses revealed: (i) a significant total effect of periventricular white matter hyperintensities on WAB-AQ (standardized beta = -0.348, P = 0.008); (ii) a non-significant direct effect of periventricular white matter hyperintensities on WAB-AQ (P > 0.05); (iii) significant indirect effects of more severe periventricular white matter hyperintensities on worse aphasia severity mediated in parallel by fewer long-range fibres (effect = -6.23, bootstrapping: standard error = 2.64, 95%CI: -11.82 to -1.56) and more short-range fibres (effect = 4.50, bootstrapping: standard error = 2.59, 95%CI: 0.16 to 10.29). We conclude that small vessel brain disease seems to affect chronic aphasia severity through a change of the proportions of long- and short-range fibres. This observation provides insight into the pathophysiology of small vessel brain disease, and its relationship with brain health and chronic aphasia severity.