Journal of Cerebral Blood Flow & Metabolism最新文献

Longitudinal in vivo imaging studies characterizing subarachnoid hemorrhage (SAH)-induced large artery vasospasm (LAV) in mice are lacking. We developed a SAH-scoring system to assess SAH severity in mice using micro CT and longitudinally analysed LAV by intravenous digital subtraction angiography (i.v. DSA). Thirty female C57Bl/6J-mice (7 sham, 23 SAH) were implanted with central venous ports for repetitive contrast agent administration. SAH was induced by filament perforation. LAV was assessed up to 14 days after induction of SAH by i.v. DSA. SAH-score and neuroscore showed a highly significant positive correlation (r_sp = 0.803, p < 0.001). SAH-score and survival showed a negative significant correlation (r_sp = -0.71, p < 0.001). LAV peaked between days 3-5 and normalized on days 7-15. Most severe LAV was observed in the internal carotid (Δ_max = 30.5%, p < 0.001), anterior cerebral (Δ_max = 21.2%, p = 0.014), middle cerebral (Δ_max = 28.16%, p < 0.001) and basilar artery (Δ_max = 23.49%, p < 0.001). Cerebral perfusion on day 5 correlated negatively with survival time (r_Pe = -0.54, p = 0.04). Arterial diameter of the left MCA correlated negatively with cerebral perfusion on day 3 (r_Pe = -0.72, p = 0.005). In addition, pseudoaneurysms arising from the filament perforation site were visualized in three mice using i.v. DSA. Thus, micro-CT and DSA are valuable tools to assess SAH severity and to longitudinally monitor LAV in living mice.

The metabotropic glutamate receptor 5 (mGluR5) is a promising treatment target for psychiatric disorders due to its modulatory effects on glutamate transmission. Using [¹¹C]ABP688, we previously showed that the rapidly acting antidepressant ketamine decreases mGluR5 availability. The mGluR5 radioligand [¹⁸F]FPEB offers key advantages over [¹¹C]ABP688; however, its suitability for drug challenge studies is unknown. We evaluated whether [¹⁸F]FPEB can be used to capture ketamine-induced effects on mGluR5. Seven healthy subjects participated in three [¹⁸F]FPEB scans: a baseline, a same-day post-ketamine, and a 24-h post-ketamine scan. The outcome measure was V_T/f_P, obtained using a two-tissue compartment model and a metabolite-corrected arterial input function. Dissociative symptoms, heart rate and blood pressure increased following ketamine infusion. [¹⁸F]FPEB V_T/f_P decreased by 9% across the cortex after ketamine infusion, with minimal difference between baseline and 24-h scans. Compared to our previous work using [¹¹C]ABP688, the magnitude of the ketamine-induced change in mGluR5 was smaller using [¹⁸F]FPEB; however, effect sizes were similar for the same-day post-ketamine vs. baseline scan (Cohen's d = 0.75 for [¹⁸F]FPEB and 0.88 for [¹¹C]ABP688). [¹⁸F]FPEB is therefore able to capture some of the effects of ketamine on mGluR5, but [¹¹C]ABP688 appears to be more suitable in drug challenge paradigms designed to probe glutamate transmission.

Vascular dysfunction is correlated to the incidence and severity of Alzheimer's disease. In a mouse model of Alzheimer's disease (APP/PS1) using in vivo, time-lapse, multiphoton microscopy, we found that occlusions of the microvasculature alter amyloid-beta (Aβ) plaques. We used several models of vascular injury that varied in severity. Femtosecond laser-induced occlusions in single capillaries generated a transient increase in small, cell-sized, Aβ deposits visualized with methoxy-X04, a label of fibrillar Aβ. After occlusions of penetrating arterioles, some plaques changed morphology, while others disappeared, and some new plaques appeared within a week after the lesion. Antibody labeling of Aβ revealed a transient increase in non-fibrillar Aβ one day after the occlusion that coincided with the disappearance of methoxy-X04-labeled plaques. Four days after the lesion, anti-Aβ labeling decreased and only remained in patches unlabeled by methoxy-X04 near microglia. Histology in two additional models, sparse embolic occlusions from intracarotid injections of beads and infarction from photothrombosis, demonstrated increased labeling intensity in plaques after injury. These results suggest that microvascular lesions can alter the deposition and clearance of Aβ and confirm that Aβ plaques are dynamic structures, complicating the interpretation of plaque burden as a marker of Alzheimer's disease progression.

Diffuse correlation spectroscopy (DCS) can non-invasively and continuously asses regional cerebral blood flow (rCBF) at the cot-side by measuring a blood flow index (BFI) in non-traditional units of cm²/s. We have validated DCS against positron emission tomography using ¹⁵O-labeled water (¹⁵O-water PET) in a piglet model allowing us to derive a conversion formula for BFI to rCBF in conventional units (ml/100g/min). Neonatal piglets were continuously monitored by the BabyLux device integrating DCS and time resolved near infrared spectroscopy (TRS) while acquiring ¹⁵O-water PET scans at baseline, after injection of acetazolamide and during induced hypoxic episodes. BFI by DCS was highly correlated with rCBF (R = 0.94, p < 0.001) by PET. A scaling factor of 0.89 (limits of agreement for individual measurement: 0.56, 1.39)×10⁹× (ml/100g/min)/(cm²/s) was used to derive baseline rCBF from baseline BFI measurements of another group of piglets and of healthy newborn infants showing an agreement with expected values. These results pave the way towards non-invasive, cot-side absolute CBF measurements by DCS on neonates.