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.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).

A 44-year-old Caucasian man presented with seizures and cognitive impairment. He had marked retinal drusen, and MR brain scan showed features of cerebral small vessel disease; he was diagnosed with a leukoencephalopathy of uncertain cause. He died at the age of 46 years and postmortem brain examination showed widespread small vessel changes described as a vasculopathy of unknown cause. Seven years postmortem, whole-genome sequencing identified a homozygous nonsense HTRA1 mutation (p.Arg302Ter), giving a retrospective diagnosis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.

Encephalopathy in a Large Cohort of British Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients.

Background and Purpose- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke usually presenting with migraine with aura, lacunar infarcts, and cognitive impairment. Acute encephalopathy is a less recognized presentation of the disease. Methods- Data collected prospectively from 340 consecutively recruited symptomatic patients with diagnosis of CADASIL seen in a British National CADASIL clinic was retrospectively reviewed and original clinical records and imaging obtained. An encephalopathic event was defined as an acute event of an altered state of consciousness in a patient with CADASIL, manifesting with signs of brain dysfunction, which warranted hospital admission in the absence of any other cause. Clinical characteristics, risk factors, and outcome of encephalopathic presentations were studied. Results- A total of 35 of 340 (10.3%) participants had a history of 50 encephalopathic events which was the first hospital presentation of CADASIL in 33 (94.3%) patients. Most commonly reported features during episodes were visual hallucinations (44%), seizures (22%), and focal neurological deficits (60%).Complete recovery within 3 months was reported in 48(96%) episodes. In 62% of episodes, there was a history of migraine or migraine aura directly preceding the encephalopathy. In 2 out of 15 cases where magnetic resonance imaging during episodes was available, unilateral focal cortical swelling was seen. A past history of migraine was independently associated with encephalopathy (odds ratio=12.3 [95% CI, 1.6-93.7]; P=0.015). Conclusions- In up to 10% of CADASIL patients, a reversible encephalopathy is the first presentation leading to diagnosis. The strong association with migraine suggests a shared pathogenesis. Focal cortical swelling may be seen on magnetic resonance imaging during the acute episode.

Recent advances in the management of symptomatic vertebral artery stenosis.

PURPOSE OF REVIEW: Vertebrobasilar stenosis accounts for 20% of posterior circulation strokes and is associated with high risk of early stroke recurrence. We review data from randomized controlled trials examining whether stenting may reduce this risk, including the recently published Vertebral Artery Ischaemia Stenting Trial (VIST). RECENT FINDINGS: VIST and VAST (Vertebral Artery Stenting Trial), having recruited both intracranial and extracranial vertebral stenosis and showed a low rate of perioperative stroke for extracranial (0 and 2%, respectively), but a higher rate for intracranial stenosis (15 and 22%, respectively). In VIST, the primary endpoint of stroke occurred in five patients in the stent group vs. 12 in the medical group (hazard ratio 0.40; 95% confidence interval 0.14-1.13, P = 0.08), although when days from last symptoms were adjusted for, the hazard ratio was 0.34 (95% confidence interval 0.12-0.98; P = 0.046). SAMMPRIS (Stenting and Aggressive Medical Management for the Prevention of Recurrent Stroke in Intracranial Stenosis) recruited only intracranial vertebral stenosis and showed a better outcome with intensive medical therapy than stenting. SUMMARY: Stenting of extracranial stenosis can be performed with a low operative risk. VIST suggests it may reduce longer term stroke risk, but this needs confirming in larger trials. For intracranial stenosis, due to a higher operative risk, current evidence favours medical treatment. SAMMPRIS have emphasized the need for intensive medical therapy whether or not stenting is performed.

False-Positive Metastatic Bone Disease on FDG PET/CT Due to Multilevel Tophaceous Gout of the Spine.

ABSTRACT: A 74-year-old woman was referred for 18 F-FDG PET/CT for the evaluation of incidental CT finding of expansile destruction of left L4/5 facet joint with associated soft tissue mass concerning for a metastatic deposit. The FDG PET/CT revealed variable abnormally increased FDG activity involving multiple facet joints in all regions of the spine with corresponding expansile "punched-out" lytic lesions with sclerotic rims and overhanging margins on CT, raising the possibility of inflammatory polyarthropathy, including gout, as a differential diagnosis. Dual-energy CT of lumbar spine and CT-guided biopsy and culture of the left L4/5 facet joint demonstrated the presence of urate crystal deposition with no evidence of malignancy or infection, confirming the diagnosis of multilevel tophaceous gout of the spine.