Alida A. Gouw

Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations

Background White matter hyperintensities (WMH), lacunes and microbleeds are regarded as typical MRI expressions of cerebral small vessel disease (SVD) and they are highly prevalent in the elderly. However, clinical expression of MRI defined SVD is generally moderate and heterogeneous. By reviewing studies that directly correlated postmortem MRI and histopathology, this paper aimed to characterise the pathological substrates of SVD in order to create more understanding as to its heterogeneous clinical manifestation. Summary Postmortem studies showed that WMH are also heterogeneous in terms of histopathology. Damage to the tissue ranges from slight disentanglement of the matrix to varying degrees of myelin and axonal loss. Glial cell responses include astrocytic reactions—for example, astrogliosis and clasmatodendrosis—as well as loss of oligodendrocytes and distinct microglial responses. Lipohyalinosis, arteriosclerosis, vessel wall leakage and collagen deposition in venular walls are recognised microvascular changes. Suggested pathogenetic mechanisms are ischaemia/hypoxia, hypoperfusion due to altered cerebrovascular autoregulation, blood–brain barrier leakage, inflammation, degeneration and amyloid angiopathy. Only a few postmortem MRI studies have addressed lacunes and microbleeds to date. Cortical microinfarcts and changes in the normal appearing white matter are ‘invisible’ on conventional MRI but are nevertheless expected to contribute substantially to clinical symptoms. Conclusion Pathological substrates of WMH are heterogeneous in nature and severity, which may partly explain the weak clinicoradiological associations found in SVD. Lacunes and microbleeds have been relatively understudied and need to be further investigated. Future studies should also take into account ‘MRI invisible’ SVD features and consider the use of, for example, quantitative MRI techniques, to increase the sensitivity of MRI for these abnormalities and study their effects on clinical functioning.

Progression of White Matter Hyperintensities and Incidence of New Lacunes Over a 3-Year Period The Leukoaraiosis and Disability Study

Background and Purpose— We studied the natural course of white matter hyperintensities (WMH) and lacunes, the main MRI representatives of small vessel disease, over time and evaluated possible predictors for their development. Methods— Baseline and repeat MRI (3-year follow-up) were collected within the multicenter, multinational Leukoaraiosis and Disability study (n=396). Baseline WMH were scored on MRI by the Fazekas scale and the Scheltens scale. WMH progression was assessed using the modified Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Baseline and new lacunes were counted per region. WMH and lacunes at baseline and vascular risk factors were evaluated as predictors of WMH progression and new lacunes. Results— WMH progressed (mean±SD=1.9±1.8) mostly in the subcortical white matter, where WMH was also most prevalent at baseline. The majority of new lacunes, which were found in 19% of the subjects (maximum=9), also appeared in the subcortical white matter, mainly of the frontal lobes, whereas most baseline lacunes were located in the basal ganglia. Baseline WMH and lacunes predicted both WMH progression and new lacunes. Furthermore, previous stroke, diabetes, and blood glucose were risk factors for WMH progression. Male sex, hypertension, systolic blood pressure, previous stroke, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes. Conclusion— WMH and lacunes progressed over time, predominantly in the subcortical white matter. Progression was observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, the presence of vascular risk factors at baseline predicted WMH progression and new lacunes over a 3-year period.

Heterogeneity of white matter hyperintensities in Alzheimer's disease: post-mortem quantitative MRI and neuropathology

White matter hyperintensities (WMH) are frequently seen on T(2)-weighted MRI scans of elderly subjects with and without Alzheimers disease. WMH are only weakly and inconsistently associated with cognitive decline, which may be explained by heterogeneity of the underlying neuropathological substrates. The use of quantitative MRI could increase specificity for these neuropathological changes. We assessed whether post-mortem quantitative MRI is able to reflect differences in neuropathological correlates of WMH in tissue samples obtained post-mortem from Alzheimers disease patients and from non-demented elderly. Thirty-three formalin-fixed, coronal brain slices from 11 Alzheimers disease patients (mean age: 83 +/- 10 years, eight females) and 15 slices from seven non-demented controls (mean age: 78 +/- 10 years, four females) with WMH were scanned at 1.5 T using qualitative (fluid-attenuated inversion recovery, FLAIR) and quantitative MRI [diffusion tensor imaging (DTI) including estimation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA), and T(1)-relaxation time mapping based on flip-angle array). A total of 104 regions of interest were defined on FLAIR images in WMH and normal appearing white matter (NAWM). Neuropathological examination included (semi-)quantitative assessment of axonal density (Bodian), myelin density (LFB), astrogliosis (GFAP) and microglial activation (HLA-DR). Patient groups (Alzheimers disease versus controls) and tissue types (WMH versus NAWM) were compared with respect to QMRI and neuropathological measures. Overall, Alzheimers disease patients had significantly lower FA (P < 0.01) and higher T(1)-values than controls (P = 0.04). WMH showed lower FA (P < 0.01) and higher T(1)-values (P < 0.001) than NAWM in both patient groups. A significant interaction between patient group and tissue type was found for the T(1) measurements, indicating that the difference in T(1)-relaxation time between NAWM and WMH was larger in Alzheimers disease patients than in non-demented controls. All neuropathological measures showed differences between WMH and NAWM, although the difference in microglial activation was specific for Alzheimers disease. Multivariate regression models revealed that in Alzheimers disease, axonal density was an independent determinant of FA, whereas T(1) was independently determined by axonal and myelin density and microglial activation. Quantitative MRI techniques reveal differences in WMH between Alzheimers disease and non-demented elderly, and are able to reflect the severity of the neuropathological changes involved.

Venous Drainage in Perimesencephalic Hemorrhage

Background and Purpose— In perimesencephalic nonaneurysmal hemorrhage (PMH), subarachnoid blood accumulates around the midbrain. Clinical and radiological characteristics suggest a venous origin of PMH. We compared the venous drainage of the midbrain between patients with PMH and aneurysmal subarachnoid hemorrhage (aSAH) by means of computed tomography angiography (CTA). Methods— CTAs of 55 PMH patients and 42 aSAH patients with a posterior circulation aneurysm were reviewed. Venous drainage was classified into: (1) normal continuous: the basal vein of Rosenthal is continuous with the deep middle cerebral vein and drains mainly to the vein of Galen (VG); (2) normal discontinuous: drainage anterior to uncal veins and posterior to VG; and (3) primitive variant: drainage to other veins than VG. Additionally, we compared in PMH patients the side of the primitive variant and side of the bleeding. Results— A primitive variant was present on one or both hemispheres in 53% of PMH patients with PMH (95% CI, 40% to 65%) and in 19% of aSAH patients (95% CI, 10% to 33%). In all 16 PMH patients with a unilateral primitive drainage, blood was seen on the side of the primitive drainage (100%; 95% CI, 81% to 100%); blood was never found mainly on the side with normal drainage. Conclusions— Patients with PMH have a primitive venous drainage directly into dural sinuses instead of via the vein of Galen more often than do controls. Moreover, the side of the perimesencephalic hemorrhage relates to the side of the primitive drainage. These results further support a venous origin of PMH.

Brain magnetic resonance imaging abnormalities in patients with heart failure

Although heart failure (HF) is a common cardiovascular disorder, to date little research has been conducted into possible associations between HF and structural abnormalities of the brain.

Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study

BackgroundWhite matter hyperintensities (WMH) on MRI are associated with disorders of gait and balance and with cognitive impairment. The most suitable method to assess WMH in relation to the clinical evaluation of disturbances in these areas has not yet been established.AimTo compare a simple visual rating scale, a detailed visual rating scale and volumetric assessment of WMH with respect to their associations with clinical measures of physical performance and cognition.MethodsData were drawn from the multicentre, multinational LADIS study. Data of 574 subjects were available. MRI analysis included assessment of WMH using the simple Fazekas scale, the more complex Scheltens scale and a semi-automated volumetric method. Disturbances of gait and balance and general cognitive function were assessed using the Short Physical Performance Battery (SPPB) and the Mini Mental State Examination (MMSE), respectively.ResultsIrrespective of the method of measuring WMH, subjects with disturbances of gait and balance (SPPB≤10) had more WMH than subjects with normal physical performance. Subjects with mild cognitive deficits (MMSE≤25) had more WMH than subjects with normal cognition. Correlations between clinical measures and WMH were equal across methods of WMH measurement (SPPB: Spearman r=−0.22, −0.25, −0.26, all p<0.001; MMSE: Spearman r=−0.11, −0.10, −0.09, all p<0.05, for Fazekas scale, Scheltens scale and volumetry, respectively). These associations remained significant and comparable after correcting for age, gender and education in multivariate linear regression analyses.ConclusionSimple and complex measures of WMH yield comparable associations with measures of physical performance and cognition. This suggests that a simple visual rating scale may be sufficient, when analyzing relationships between clinical parameters and WMH in a clinical setting.

Diffusion-Weighted Imaging and Cognition in the Leukoariosis and Disability in the Elderly Study

Background and Purpose— The mechanisms by which leukoariosis impacts on clinical and cognitive functions are not yet fully understood. We hypothesized that ultrastructural abnormalities of the normal-appearing brain tissue (NABT) assessed by diffusion-weighted imaging played a major and independent role. Methods— In addition to a comprehensive clinical, neuropsychologic, and imaging work-up, diffusion-weighted imaging was performed in 340 participants of the multicenter leukoariosis and disability study examining the impact of white matter hyperintensities (WMH) on 65- to 85-year old individuals without previous disability. WMH severity was rated according to the Fazekas score. Multivariate regression analysis served to assess correlations of histogram metrics of the apparent diffusion coefficient (ADC) of whole-brain tissue, NABT, and of the mean ADC of WMH with cognitive functions. Results— Increasing WMH scores were associated with a higher frequency of hypertension, a greater WMH volume, more brain atrophy, worse overall cognitive performance, and changes in ADC. We found strong associations between the peak height of the ADC histogram of whole-brain tissue and NABT with memory performance, executive dysfunction, and speed, which remained after adjustment for WMH lesion volume and brain atrophy and were consistent among centers. No such association was seen with the mean ADC of WMH. Conclusions— Ultrastructural abnormalities of NABT increase with WMH severity and have a strong and independent effect on cognitive functions, whereas diffusion-weighted imaging metrics within WMH have no direct impact. This should be considered when defining outcome measures for trials that attempt to ameliorate the consequences of WMH progression.

MRI-Defined Subcortical Ischemic Vascular Disease: Baseline Clinical and Neuropsychological Findings

Background: Subcortical ischemic vascular disease (SIVD) is a common, but often overlooked cause of vascular cognitive impairment. Diagnostic research criteria for SIVD are based on magnetic resonance imaging (MRI) findings including substantial white matter lesions (WML) and multiple lacunar infarcts. Empirical studies validating these imaging criteria are still few. The purpose of the study was to describe the clinical and cognitive characteristics of the MRI-defined SIVD in a mixed sample of functionally independent elderly subjects with WML. Methods: The subjects of the Leukoaraiosis and Disability (LADIS) study, aged 65–84 years, underwent comprehensive clinical and neuropsychological examinations, and brain MRI at the baseline assessment. The subjects meeting the SIVD imaging criteria (n = 89) were compared to the other subjects of the sample (n = 524). Results: SIVD was associated with lower education, hypertension and, independently, with obesity. The subjects with SIVD had more often motor impairment, a history of falls, and subtle impairment in activities of daily living, but they did not differ for depressive symptoms. SIVD subjects performed significantly inferiorly in tests of global cognitive function, psychomotor speed, attention and executive functions, verbal fluency, and working memory. Conclusion: In this population of nondisabled older adults with WML, SIVD was related to specific clinical and functional characteristics. Neuropsychological features included psychomotor slowing as well as deficits in attention and executive functions.

Assessing mental flexibility: neuroanatomical and neuropsychological correlates of the trail making test in elderly people

The Trail Making Test part B (TMT-B) is highly sensitive to age-related changes in the brain and cognitive function. However, the precise contribution of periventricular hyperintensities (PVH), deep white matter hyperintensities (DWMH), and medial temporal lobe atrophy (MTA) to task performance remains unspecified. Similarly, diminished performance may be due to deficient flexibility functions, but also to other age-related cognitive decline (e.g., mental slowing). The aim of the present study was to determine neuroanatomical (PVH, DWMH, MTA) and neuropsychological (working memory, executive function, speed and attention, episodic memory) predictors of TMT-B performance in elderly people. Results showed that MTA was the strongest predictor of TMT-B performance. The predictive value of the neuropsychological scores differed among the various TMT-B variables. For example, all neuropsychological domains predicted the TMT-B total completion time, whereas only executive function predicted the ratio score (TMT-B/A). We conclude that MTA is a very important predictor of TMT-B performance in elderly people. Furthermore, multiple cognitive functions are involved in TMT-B performance and a mild decline in any of these functions may result in diminished TMT-B performance. Therefore it is crucial to use the ratio score when one wishes to examine executive function ability.

On the Etiology of Incident Brain Lacunes Longitudinal Observations From the LADIS Study

Background and Purpose— We investigated regional differences in MRI characteristics and risk factor profiles of incident lacunes over a 3-year period. Methods— Baseline and 3-year follow-up MRI were collected within the LADIS study (n=358). Incident lacunes were characterized with respect to brain region, their appearance within pre-existent white matter hyperintensities (WMH), surrounding WMH size, and risk factors. Results— 106 incident lacunes were observed in 62 patients (58 subcortical white matter [WM], 35 basal ganglia, and 13 infratentorial). Incident subcortical WM lacunes occurred more often within preexisting WMH (P=0.01) and were mostly accompanied by new and expanded WMH (P<0.001), compared to incident basal ganglia and infratentorial lacunes. Risk factors for incident subcortical WM lacunes were history of hypertension and stroke, whereas atrial fibrillation predicted incident basal ganglia/infratentorial lacunes. Conclusion— Differences in relation to WMH and risk factor profiles may suggest that incident lacunes in the subcortical WM have a different pathogenesis than those in the basal ganglia and infratentorial region.