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.