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White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responsesHyperintense lesions are frequently identified in T2-weighted magnetic resonance images (MRI) in the ageing brain. The pathological correlate and pathogenesis of white matter lesions (WML) remain unclear, and it is uncertain whether pathology and pathogenesis differ in periventricular lesions (PVL) compared with deep subcortical lesions (DSCL). Therefore we characterized astrocytic, microglial and oligodendrocyte responses in PVL and DSCL and compared them with control white matter using immunohistochemistry. Both PVL and DSCL were associated with severe myelin loss and increased microglia (P = 0.069 and P < 0.001), compared with nonlesional aged brain. Clasmatodendritic astroglia, immunoreactive for the serum protein fibrinogen, were present in 67% of PVL examined and 42% of DSCL. Compared with control and DSCL cases, more MAP-2 +13 positive remyelinating oligodendrocytes (P = 0.003 and P = 0.035) and platelet-derived growth factor alpha receptor positive reactive astrocytes (P < 0.001) were present in the perilesional white matter of PVL. In addition to a role for hypoperfusion, our data suggest that dysfunction of the blood-brain barrier may also contribute to the pathogenesis of a proportion of cerebral WML associated with ageing, and that attempts at remyelination are only associated with PVL and not DSCL.

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White matter lesions (WML) on magnetic resonance imaging (MRI) brain scans are associated with ageing. They are unrelated to specific disorders, and their impact on cognitive and other brain functions is poorly characterized. Pathological studies often omit systematic survey of WML because of the need to study multiple full coronal tissue blocks, and uncertainty over the significance of lesions identified in periventricular and deep subcortical regions. Post-mortem MRI provides a means of mapping WML but the sensitivity and specificity of the method are unresolved. In this study post-mortem MRI of WML in fixed brain slices was compared with pathology in 33 brains donated to the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). This study shows that MRI detection of WML was less sensitive than pathology: periventricaular lesions (PVL) sensitivity = 95% (87-99%), specificity = 71% (44-90%); deep subcortical lesions (DSCL) sensitivity = 86% (79-93%), specificity = 80% (72-88%). False negative MRI was associated with milder pathology, but lesions detected by myelin attenuation alone showed both microglial and endothelial activation. Therefore post-mortem MRI of formalin-fixed brain slices is a reliable method to obtain systematic data on the severity and distribution of cerebral white matter disease, and appears to detect those WML most likely to have clinical impact.

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.

Vascular endothelial growth factor (VEGF) prolongs survival in the mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS), whereas dysregulation of VEGF through deletion of its hypoxia-regulatory element causes motor neuron degeneration in mice. We investigated the expression of VEGF and its major agonist receptors in the normal central nervous system and in patients with ALS. Immunohistochemistry demonstrated similar expression patterns of VEGF and VEGF receptor 2 (VEGFR2) in the spinal cord with finely punctate staining of the neuropil and strong expression in anterior horn cells (AHCs). Granular staining on the surface of some AHCs, similar to that seen with synaptic markers, suggested synaptic labeling. VEGFR2 staining was reduced in the neuropil of ALS cases (p=0.018) associated with a reduction of synaptophysin but not SNAP25 expression. A greater proportion of AHCs in ALS cases showed low expression of VEGF (p=0.006) and VEGFR2 (p=0.009) compared with controls. Expression of VEGF and VEGFR2 was confirmed by Western blotting and quantitative reverse transcriptase-polymerase chain reaction (QPCR). The similar expression patterns of VEGF and VEGFR2 suggests autocrine/paracrine effects on spinal motor neurons, and the reduction in their expression seen in ALS cases would support the hypothesis that, as in mouse models of the disease, reduced VEGF signaling may play a role in the pathogenesis of ALS.

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