Summary The term cerebral small vessel disease refers to a group of pathological processes with various aetiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms. The consequences of small vessel disease on the brain parenchyma are mainly lesions located in the subcortical structures such as lacunar infarcts, white matter lesions, large haemorrhages, and microbleeds. Because lacunar infarcts and white matter lesions are easily detected by neuroimaging, whereas small vessels are not, the term small vessel disease is frequently used to describe the parenchyma lesions rather than the underlying small vessel alterations. This classification, however, restricts the definition of small vessel disease to ischaemic lesions and might be misleading. Small vessel disease has an important role in cerebrovascular disease and is a leading cause of cognitive decline and functional loss in the elderly. Small vessel disease should be a main target for preventive and treatment strategies, but all types of presentation and complications should be taken into account.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(10)70104-6.pdf

Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges.

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.

/pdf/heterogeneity-of-small-vessel-disease-a-systematic-review-of-3x3id0hun1.pdf

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

There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer’s disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood–brain barrier, and reduces the brain’s repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.

/pdf/the-overlap-between-neurodegenerative-and-vascular-factors-53adutgkg6.pdf

The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia

Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses.

Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic white matter disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular disease, which is epidemic in our aging population.

Understanding White Matter Disease. Imaging-Pathological Correlations in Vascular Cognitive Impairment

White matter lesions (WML), a common feature in brain ageing, are classified as periventricular (PVL) or deep subcortical (DSCL), depending on their anatomical location. Microglial activation is implicated in a number of neurodegenerative diseases, but the microglial response in WML is poorly characterized and its role in pathogenesis unknown. We have characterized the microglial response in WML and control white matter using immunohistochemistry to markers of microglial activation and of proliferation. WML of brains from an unbiased population-based autopsy cohort (Medical Research Council's Cognitive Function and Ageing Study) were identified by post mortem magnetic resonance imaging and sampled for histology. PVL contain significantly more activated microglia, expressing major histocompatibility complex (MHC) class II and the costimulatory molecules B7-2 and CD40, than either control white matter (WM) or DSCL. Furthermore, we show that significantly more microglia express the replication licensing protein minichromosome maintenance protein 2 within PVL, suggesting this is a more proliferation-permissive environment than DSCL. Although microglial activation occurs in both PVL and DSCL, our findings suggest a difference in pathogenesis between these lesion-types: the ramified, activated microglia associated with PVL may reflect immune activation resulting from disruption of the blood brain barrier, while the microglia within DSCL may reflect an innate, amoeboid phagocytic phenotype. We also show that microglia in control WM from lesional cases express significantly more MHC II than control WM from nonlesional ageing brain, suggesting that WML occur in a 'field-effect' of abnormal WM.

Microglial activation in white matter lesions and nonlesional white matter of ageing brains.

Microglial activation in white matter of the ageing brain

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Microglial activation in white matter lesions and nonlesional white matter of ageing brains.

Microglial activation in white matter of the ageing brain