Microglial activation and blood-brain barrier permeability in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying pathogenesis is poorly understood, but both neuroinflammation and increased blood-brain barrier permeability have been hypothesized to play a role, and preclinical studies suggest the two processes may be linked. We used PET magnetic resonance to simultaneously measure microglial activation using the translocator protein radioligand 11C-PK11195, and blood-brain barrier permeability using dynamic contrast enhanced MRI. A case control design was used with two disease groups with sporadic SVD (n = 20), monogenic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL), and normal controls (n = 20) were studied. Hotspots of increased glial activation and blood-brain barrier permeability were identified as values greater than the 95th percentile of the distribution in controls. In sporadic SVD there was an increase in the volume of hotspots of both 11C-PK11195 binding (P = 0.003) and blood-brain barrier permeability (P = 0.007) in the normal appearing white matter, in addition to increased mean blood-brain barrier permeability (P < 0.001). In CADASIL no increase in blood-brain barrier permeability was detected; there was a non-significant trend to increased 11C-PK11195 binding (P = 0.073). Hotspots of 11C-PK11195 binding and blood-brain barrier permeability were not spatially related. A panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured in each participant; principal component analysis was performed and the first component related to blood-brain barrier permeability and microglial activation. Within the sporadic SVD group both hotspot and mean volume blood-brain barrier permeability values in the normal appearing white matter were associated with dimension 1 (ß = 0.829, P = 0.017, and ß = 0.976, P = 0.003, respectively). There was no association with 11C-PK11195 binding. No associations with blood markers were found in the CADASIL group. In conclusion, in sporadic SVD both microglial activation and increased blood-brain barrier permeability occur, but these are spatially distinct processes. No evidence of increased blood-brain barrier permeability was found in CADASIL.

Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab.

The magnetization transfer ratio reflects the integrity of tissue structure, including myelination and axonal density. Mean magnetization transfer ratio fell in 18 untreated patients with multiple sclerosis both in normal appearing grey (-0.25 pu/year, p < 0.001) and white matter (-0.12 pu/year, p = 0.004). Conversely, mean magnetization transfer ratio was stable in 20 alemtuzumab-treated patients (grey matter: -0.01 pu/year, p = 0.87; white matter: -0.02 pu/year, p = 0.51). The gradient difference in grey matter was 0.25 pu/year (p < 0.001) after age-adjustment. These data suggest that in multiple sclerosis alemtuzumab protects against tissue damage in normal-appearing grey matter, perhaps by preventing new lesion formation.

Longitudinal evaluation of clinically early relapsing-remitting multiple sclerosis with diffusion tensor imaging.

Diffusion tensor imaging (DTI) parameters such as mean diffusivity (MD) and fractional anisotropy (FA) assess aspects of structural integrity within tissue. In relapsing-remitting (RR) multiple sclerosis (MS), abnormalities in normal appearing brain tissue (NABT) have been shown cross-sectionally. The evolution of these abnormalities over time is unclear. We present a longitudinal study investigating early RR MS subjects. The aims were to determine DTI changes over two years and assess the potential of DTI as a longitudinal quantitative marker at this stage of MS. Fifteen controls and 28 patients with RR MS (median disease duration 1.9 years; median EDSS 1.5) had DTI yearly for two years. NABT and whole brain tissue (NABT plus lesions) FA and MD histograms analysed. At baseline, differences in FA were noted between patients and controls (mean [p = 0.042] and peak height [p = 0.008]), while at two years differences in MD were observed (mean [p = 0.008] and peak location [p = 0.024]). However there were no significant DTI differences in longitudinal rates of change between patients and cohorts. In conclusion, although subtle NABT abnormalities were detected in early RR MS, the absence of longitudinal change suggests a limited role for global DTI assessment of NABT in following the early disease course.