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Primary angiitis of central nervous system (PACNS) is a rare idiopathic vasculitis that typically involves small arteries. An 18-year-old woman was operated on for resection of a ruptured aneurysm in a cerebral artery. Multiple aneurysms of cerebral arteries had been detected by neuroimaging examinations since the age of 12, and she had been administered drugs following a diagnosis of PACNS since the age of 15. The resected aneurysm was a ruptured saccular aneurysm occurring in a medium-sized artery. Histologically, necrotizing arteritis of the polyarteritis nodosa (PAN) type was noted in the aneurysmal wall. It consisted of an admixture of acute and healing stages. In the acute stage, fibrinoid necrosis in the intima and media and intense inflammatory cell infiltrate in the entire wall were present. The inflammatory cells mainly consisted of lymphocytes, including plasma cells, neutrophils, and macrophages. In the healing stage, disappearance of fibrinoid necrosis, fibrosis in the intima and media, and scarce inflammatory cells were noted. The acute stage was mainly present near the ruptured site. From these findings, the aneurysm was considered to have been caused by necrotizing arteritis of the PAN type. Although saccular aneurysmal formation in a medium-sized artery is rare in PACNS, an understanding of aneurysms produced by necrotizing arteritis of the PAN type offers useful information for the diagnosis and treatment of PACNS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Spontaneous intracerebral hemorrhage (SICH) remains a devastating form of stroke. Prior use of antiplatelets or warfarin before SICH is associated with poor outcomes, but the effects of direct oral anticoagulants (DOACs) remain unclear. This study aimed to clarify trends in prior antithrombotic use and to assess the associations between prior use of antithrombotics and in-hospital mortality using a multicenter prospective registry in Japan. In total, 1085 patients were analyzed. Prior antithrombotic medication included antiplatelets in 14.2%, oral anticoagulants in 8.1%, and both in 1.8%. Prior warfarin use was significantly associated with in-hospital mortality (odds ratio [OR] 5.50, 95% confidence interval [CI] 1.30-23.26, P < 0.05) compared to no prior antithrombotic use. No such association was evident between prior DOAC use and no prior antithrombotic use (OR 1.34, 95% CI 0.44-4.05, P = 0.606). Concomitant use of antiplatelets and warfarin further increased the in-hospital mortality rate (37.5%) compared to warfarin alone (17.2%), but no such association was found for antiplatelets plus DOACs (8.3%) compared to DOACs alone (11.9%). Prior use of warfarin remains an independent risk factor for in-hospital mortality after SICH in the era of DOACs. Further strategies are warranted to reduce SICH among patients receiving oral anticoagulants and to prevent serious outcomes., (© 2024. The Author(s).)

This study investigated prognostic factors in elderly patients (80 years and older) undergoing mechanical thrombectomy (MT) for anterior circulation large vessel occlusion (LVO) in acute stroke treatment. Of 59 cases, 47.5% achieved a favorable outcome (mRS ≤ 3) at three months, with a mortality rate of 20.3%. Factors associated with better outcomes included younger age, lower admission National Institute of Health Stroke Scale (NIHSS) scores, lower N-terminal pro-brain natriuretic peptide (NT-proBNP) and D-dimer levels, the presence of the first pass effect (FPE), and successful recanalization. However, logistic regression showed that only lower admission NIHSS scores were significantly correlated with favorable outcomes. In addition, this study suggests that lower admission NT-proBNP and D-dimer levels could potentially serve as prognostic indicators for elderly LVO patients undergoing MT., Competing Interests: The authors declare no conflict of interest.

Background: Twisted carotid bifurcation (TCB) is a well-known anatomical variation of the carotid bifurcation in patients undergoing carotid endarterectomy. However, few investigations of TCB have focused on patients without internal carotid artery (ICA) stenosis. This study was performed to analyze the characteristics of TCB in patients with ICA stenosis and other diverse pathologies., Methods: All conventional cerebral angiographies performed in our institute for any reason from January 2012 to December 2018 were reviewed. The patients were divided into two groups, the TCB group and the anatomically normal non-TCB group, and the basic characteristics of the groups were analyzed., Results: Both sides of the carotid bifurcation were clearly visualized in 457 patients. TCB was found in 89 of 457 patients (19.5%); among these 89 patients, 74 (83.1%) had TCB only on the right side, 8 (9.0%) only on the left side, and 7 (7.9%) bilaterally. TCB was found more frequently on the right than left [81 (17.7%) and 15 (3.3%), respectively, on each of the 457 sides (p < 0.0001)]. TCB was significantly more frequent in older patients (p = 0.02), female patients (p < 0.001), and patients with ICA stenosis or occlusion at the bifurcation (p = 0.005). The prevalence of TCB was 19.5%, and 84.4% of cases were on the right side in patients with diverse pathologies., Conclusions: Older patients, female patients, and patients with ICA stenosis or occlusion are more prone to have TCB., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

A 48-year-old man hospitalized for subarachnoid hemorrhage harbored a ruptured aneurysm arising from an anomalous hyperplastic anterior choroidal artery. Endovascular treatment was performed and the aneurysm was successfully embolized with neck remnant. The anterior choroidal artery is a very important artery supplying critical brain structures in the treatment of intracranial vascular disease. Anomalous hyperplastic anterior choroidal artery is rare, so the embryological perspective is important for its recognition in surgical procedures.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis and profoundly impacted acute treatment delivery. This study conducted long-term evaluations of the impact of the pandemic on acute stroke management., Methods: Data from a university-owned medical facility in Tokyo, Japan, were retrospectively analyzed. The number of hospital admissions for stroke and time metrics in the management of patients with acute ischemic stroke were evaluated. A year-over-year comparison was conducted using data from April 2019 to December 2021 to assess the impact of the pandemic., Results: The year-over-year comparison demonstrated that the number of admissions of patients with stroke and patients who underwent magnetic resonance imaging (MRI), intravenous recombinant tissue plasminogen activator (rt-PA), and thrombectomy during the pandemic remained comparable to the pre-COVID data. However, we found a decrease in the number of admissions of patients with stroke alerts and stroke when hospital cluster infection occurred at this facility and when the region hosted the Tokyo Olympics games during the surge of infection. The door-to-computed tomography time in 2021 was affected. This is plausibly due to the reorganization of in-hospital stroke care pathways after hospital cluster infection. However, no significant difference was observed in the onset-to-door, door-to-MRI, door-to-needle, or door-to-groin puncture times., Conclusions: We did not observe long-term detrimental effects of the pandemic at this site. Prevention of hospital cluster infections remains critical to provide safe and timely acute stroke management during the pandemic., (© 2022. The Author(s).)

Introduction: Early restoration of blood flow in stroke patients can be achieved by reducing the door-to-computed tomography (DTC) time. Previous research has proposed several methods to reduce the DTC time, but the implementation costs limit its transferability. This study aimed to propose a novel, simple, and low-cost method for reducing the DTC time by providing feedback on each patient's DTC time to a small group of medical workers and physicians., Methods: A field experiment was conducted for 233 days, and the DTC time of 249 patients with stroke symptoms who were transported via ambulance to a medium-sized university hospital in Japan within 24 h after stroke onset was obtained. The first and second feedback reports on the 59th day and 154th day, respectively, were provided at the beginning of the field experiment. Using the data collected during the first 58 days as baseline data, the baseline data were compared with the post-intervention data. As part of the intervention, feedback on the DTC time for each patient was provided to six medical workers and physicians during regular meetings. The primary outcome was a continuous measure of DTC time (in min). The feedback effect hypothesis was formulated prior to data collection., Results: In a sample of 68 patients at baseline, the mean DTC time was 18.16 min with a standard deviation of 7.38 min. As a result of the two feedback reports, in the sample with outliers, the mean and standard deviation decreased to 15.64 min and 5.97 min, respectively. The difference in means was 2.51 min (p = 0.021 in t tests). Results of the test of the equality of the standard deviations suggested that the two standard deviations were not equal (p = 0.065)., Conclusions: The low-cost interventions successfully reduced both the mean DTC time and variation, suggesting an improvement in the quality and consistency of medical services. The result of our fine-grained analysis with a field-experiment design supports the role of feedback in achieving early treatment as suggested in the Target: Stroke initiative., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

An intracranial collision tumor is a rare lesion composed of two histologically different neoplasms in the same anatomic location. Even more rare is the collision tumor of a solitary fibrous tumor/hemangiopericytoma (SFT/HPC) and meningioma. The patient was a 46-year-old woman who had a 40 × 35 × 30-mm mass in the vermis of the cerebellum. Histologically, the mass consisted of two different components. One component showed the morphology of meningioma (World Health Organization (WHO) grade I), and the other component exhibited small round cell proliferation with hypercellular density, which was revealed to be SFT/HPC (WHO grade III) based on STAT6 immunohistochemistry. STAT6 showed completely different immunohistochemistry results in these two components (nuclear-negative in meningioma and nuclear-positive in SFT/HPC). Since these two neoplasms are associated with different prognoses, they should be distinguished from each other. When meningioma and an SFT/HPC-like lesion are identified morphologically, it is important to recognize the presence of such a collision tumor composed of meningioma and SFT/HPC, and identify the SFT/HPC component by employing STAT6 immunohistochemistry., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: The internal carotid artery is normally positioned posterolateral to the external carotid artery at the carotid bifurcation. An anatomic variation with the internal carotid artery positioned medial to the external carotid artery, the so-called twisted carotid bifurcation (TCB), is sometimes encountered in patients undergoing carotid endarterectomy (CEA). Little is known about the TCB or the implications for CEA., Objective: The present study investigated the demographics and surgical results of our patients with TCB who underwent CEA, and demonstrates the surgery in a video clip., Methods: Eleven of our series of 73 consecutive CEA patients (15.1%) had a TCB (TCB group). The basic surgical method was the same for both the TCB and non-TCB groups., Results: The patient demographics were almost identical between the 2 groups. No significant difference was observed in the degree of stenosis, the duration of operation, or the surgery-related complications between the 2 groups. However, 9 of 11 cases were right-sided in the TCB group; the only significant difference between the groups., Conclusions: CEA for TCB can be safely performed by extension of the normal procedure, but with more meticulous preoperative assessment and gentle maneuvers. The reason for the right-side dominance is still unknown. Further investigation is needed of this anatomic entity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Safe and appropriate harvesting of the donor scalp vessel is the first key procedure in any type of bypass surgery., Objective: To use the so-called bipolar cutting method to harvest donor arteries, in which the donor arteries are skeletonized with bipolar cautery. The surgical procedure and the preparation of the equipment of the bipolar cutting method are described. The surgical results and histological assessment are presented., Methods: The bipolar generator was set at 50 Malis units in the coagulation mode. Under the surgical microscope, the surrounding tissue of the donor artery was divided and coagulated with the bipolar forceps. The donor artery was completely skeletonized to provide adequate length. After the recipient artery was chosen and the anastomosis site was decided, the distal end of the donor artery was cut to the appropriate length. The remnant fragment of the donor artery was histologically investigated for any damage to the arterial wall. The specimen was cut longitudinally to observe the entire length of the arterial wall and stained with hematoxylin and eosin and elastica van Gieson., Results: A total of 30 bypass surgeries were performed and 38 histological specimens were obtained between February 2015 and June 2016. The success rate of the bypass was 96%. No arterial wall damage such as thermal injury or dissection of the wall was recognized in any of the specimens., Conclusion: The bipolar cutting method is a useful and safe method for harvesting donor scalp artery., (Copyright © 2017 by the Congress of Neurological Surgeons)

OBJECT Although cerebral vasospasm (CV) is one of the most important predictors for the outcome in patients with subarachnoid hemorrhage (SAH), no treatment has yet been established for this condition. This study investigated the efficacy of continuous direct infusion of magnesium sulfate (MgSO4) solution into the intrathecal cistern in patients with an aneurysmal SAH. METHODS An SAH caused by a ruptured aneurysm was identified on CT scans within 72 hours after SAH onset. All patients were treated by surgical clipping and randomized into 2 groups: a control group of patients undergoing a standard treatment and a magnesium (Mg) group of patients additionally undergoing continuous infusion of 5 mmol/L MgSO4 solution for 14 days. The Mg(2+) concentrations in serum and CSF were recorded daily. Neurological examinations were performed by intensive care clinicians. Delayed cerebral ischemia was monitored by CT or MRI. To assess the effect of the Mg treatment on CV, the CVs were graded on the basis of the relative degree of constriction visible on cerebral angiograms taken on Day 10 after the SAH, and transcranial Doppler ultrasonography was performed daily to measure blood flow velocity in the middle cerebral artery (MCA). Neurological outcomes and mortality rates were evaluated with the Glasgow Outcome Scale and modified Rankin Scale at 3 months after SAH onset. RESULTS Seventy-three patients admitted during the period of April 2008 to March 2013 were eligible and enrolled in this study. Three patients were excluded because of violation of protocol requirements. The 2 groups did not significantly differ in age, sex, World Federation of Neurosurgical Societies grade, or Fisher grade. In the Mg group, the Mg(2+) concentration in CSF gradually increased from Day 4 after initiation of the continuous MgSO4 intrathecal administration. No such increase was observed in the control group. No significant changes in the serum Mg(2+) levels were observed for 14 days, and no cardiovascular complications such as bradycardia or hypotension were observed in any of the patients. However, bradypnea was noted among patients in the Mg group. The Mg group had a significantly better CV grade than the control group (p < 0.05). Compared with the patients in the Mg group, those in the control group had a significantly elevated blood flow velocity in the MCA. Both groups were similar in the incidences of cerebral infarction, and the 2 groups also did not significantly differ in clinical outcomes. CONCLUSIONS Continuous cisternal irrigation with MgSO4 solution starting on Day 4 and continuing to Day 14 significantly inhibited CV in patients with aneurysmal SAH without severe cardiovascular complications. However, this improvement in CV neither reduced the incidence of delayed cerebral ischemia nor improved the functional outcomes in patients with SAH.

A 68-year-old man experienced a right caudate haemorrhage with intraventricular haemorrhage. Although a subarachnoid haemorrhage was not shown clearly, our investigation demonstrated an aneurysm-like vascular pouch located in the anomalous vessel arising from the A2 segment of the right anterior cerebral artery. Rupture of the vascular pouch was considered to be the cause of the caudate haemorrhage. Neck clipping was performed. In intraoperative observation, the anomalous vessel was diagnosed as a right accessory middle cerebral artery. Histopathology of the saccular wall showed only an adventitia and a fibrin layer, indicating a pseudoaneurysm. We routinely perform detailed vascular evaluation for any cerebrovascular disease. A meticulous vascular survey makes it possible to obtain valuable clues in cases such as caudate haemorrhage due to pseudoaneurysm of the accessory middle cerebral artery, leading to prevention of rebleeding., (2015 BMJ Publishing Group Ltd.)

Purpose: To investigate the length variation of the posterior auricular artery and propose a novel classification of the posterior auricular artery based on angiographical appearance., Patients and Methods: A series of 234 consecutive patients who had undergone conventional cerebral angiography was analyzed. The posterior auricular artery was examined on the lateral projection of the external carotid or common carotid arteriography. The posterior auricular artery was classified into four groups by length, using the external auditory canal and the top of the helix as radiographical landmarks. Our proposed classification is as follows: Type A, posterior auricular artery terminates between its origin and the center of the external auditory canal; Type B, posterior auricular artery terminates between the center of the external auditory canal and the top of the helix; Type C, posterior auricular artery terminates between the top of the helix and the vertex; and Type D, posterior auricular artery reaches up to the vertex., Results: A total of 424 (right, 214; left, 210) posterior auricular arteries were analyzed in 111 men and 123 women aged 11 to 91 years (mean, 61.0 years) examined for aneurysms in 78 cases, occlusive vascular diseases in 56, intracranial hemorrhages in 41, tumors in 35, and others in 24. Types A, B, C, and D were found in 15.1%, 34.9%, 48.8%, and 1.2% of the patients, respectively., Conclusion: A novel classification of the posterior auricular artery identifies four types based on its length on cerebral angiography.

The posterior auricular artery (PAA) is one of the branches of the external carotid artery, but is usually too small for use as a donor artery for middle cerebral artery (MCA) territory revascularization. An extremely unusual case of PAA-MCA anastomosis was performed in a patient requiring MCA territory revascularization because the superficial temporal artery (STA) parietal branch was absent and the PAA was large enough. A 65-year-old man developed mild motor weakness in the right extremities caused by multiple small infarctions. Single photon emission computed tomography (CT) revealed deterioration of the vascular reserve capacity in the left MCA area. Cerebral angiography showed severe stenosis in the C2 portion of the left internal carotid artery, absence of the parietal branch of the left STA, and a well-developed PAA extending to the parietal area. The patient underwent STA (frontal branch)-MCA and PAA-MCA double anastomosis, and has suffered no stroke or transient ischemic attack. The STA with no bifurcation is known as a rare variation. The PAA also occurs with size variations but well-developed PAA is thought to be extremely rare. PAA can be used as a donor artery for MCA territory revascularization if the vessel size is suitable. Preoperative evaluation of the anatomy is mandatory for harvesting the arteries.

Introduction: Spinal subarachnoid hemorrhage has many causes including trauma, vascular malformations, aneurysms, spinal cord tumors, coagulation abnormalities, use of anticoagulants, systemic lupus erythematosus, or Behçet's disease. We report on a rare case of a spontaneous spinal subarachnoid hemorrhage after severe coughing of unknown origin. To the best of our knowledge, this is the first report of spontaneous spinal subarachnoid hemorrhage after severe coughing., Case Presentation: A 66-year-old Japanese woman initially complained of headache with severe back pain after severe coughing. She was referred to our neurology department 6 days after her first visit to our hospital. No neurological deficits were revealed except for meningism. Computed tomography of her head revealed no abnormality. A lumbar puncture showed bloody cerebrospinal fluid with xanthochromia. Cerebral angiography revealed no abnormality. Magnetic resonance imaging of her lumbar spine revealed subarachnoid hemorrhage. Spinal angiography revealed no abnormality. The diagnosis of spontaneous spinal subarachnoid hemorrhage was made. She recovered with conservative treatment and her neurological status was normal 2 years after the onset., Conclusions: Spontaneous spinal subarachnoid hemorrhage could be caused by rapid changes in intrathoracic and intra-abdominal pressure. Spontaneous subarachnoid hemorrhage should be considered when sudden back pain associated with severe headache develops. Even though emergent surgical decompression is necessary when the neurological state progressively deteriorates, conservative treatment with close monitoring of the symptoms can be recommended for patients with a stable neurological status.

Introduction: [(18)F]FP-TZTP is an M2 muscarinic subtype selective receptor-binding radiotracer used in vivo to image human and nonhuman primate brain following both bolus injection and infusion. In order to carry out repeated studies in rodents, the techniques developed for primates must be transferred to rodents with the same precision. This includes obtaining a metabolite-corrected input function., Methods: We compared bolus injection with constant infusion in rats that were awake or under isoflurane anesthesia. Brain-plasma and brain-blood distribution ratios were calculated by dividing brain (18)F concentrations, determined in vivo by positron emission tomography imaging with the Advanced Technology Laboratory Animal Scanner, ex vivo by direct counting in excised brain tissue or by quantitative autoradiography by the plasma or whole blood concentrations that had been corrected for metabolite contents., Results: Blood volume constraints prevented adequate blood sampling to define a precise input function after bolus injection, thus preventing full kinetic analysis. Constant infusion, however, required fewer blood samples to define the input function, allowing calculation of distribution ratios, but complete equilibrium between plasma and tissue had not yet been reached after 120 min., Conclusion: Our results showed that the blood clearance and metabolism were too rapid to obtain a reproducible input function after bolus injection. The equilibrium distribution ratios did not lead to precise biochemical parameters, but the constant infusion was more suitable in that distribution ratios between tissue and plasma were statistically more precise. Constant infusion is the better approach for studying [(18)F]FP-TZTP by small animal imaging., (Published by Elsevier Inc.)

Giant intracranial aneurysm is a life-threatening lesion and treatment of the aneurysm could be hazardous and complex. This study describes direct surgical treatment of giant middle cerebral artery (MCA) aneurysms using microvascular reconstruction techniques in 13 patients treated between 2006 and 2009. In all 13 patients, superficial temporal artery (STA)-MCA (M(2)) anastomosis was performed as a precaution prior to attacking the aneurysm. During surgery, microvascular reconstruction of incorporative arteries was additionally performed if the aneurysm was removed. Direct neck clipping was performed in four patients, trapping and removal of the aneurysm in one, and removal of the aneurysm with vascular reconstruction of the MCA in eight patients. Minor ischemic complications due to perforator ischemia were recognized in 6 patients, and 10 patients achieved functionally favorable outcomes (modified Rankin scale score 0 or 1). In direct surgery for giant MCA aneurysm, precautionary STA-M(2) bypass could provide appropriate surgical strategies tailored to individual cases, including direct clipping and removal of the aneurysm with or without vascular reconstruction. Microvascular reconstruction techniques are essential for complete cure of giant MCA aneurysms.

Background and Importance: A nonbifurcating cervical carotid artery is an extremely rare type of carotid artery anomaly. We present a patient with a nonbifurcating cervical carotid artery and a large aneurysm of the cavernous internal carotid artery (ICA). The patient was successfully treated with combined microsurgical and endovascular techniques. We describe this case with reference to the relevant literature., Clinical Presentation: A 66-year-old woman with progressive left external ocular movement dysfunction was found to have a large left cavernous ICA aneurysm. Serial magnetic resonance angiography revealed progressive growth of the lesion. In addition, conventional angiography showed a nonbifurcating cervical carotid artery and a persistent primitive trigeminal artery. The aneurysm was found unsuitable for direct surgery because of its size and location and for endovascular intervention because of extreme tortuosity of both carotid and right vertebral arteries. Surgery was performed in 2 stages. First, we performed an extracranial-intracranial high-flow bypass using radial artery graft, followed by proximal occlusion of the carotid artery. As the second stage, the patient underwent intravascular parent artery occlusion via the radial artery graft bypass to approach the intracranial carotid artery. The carotid artery was successfully coil embolized, and the aneurysm was undetectable on a postprocedure angiogram. Serial follow-up magnetic resonance imaging revealed thrombosis of the aneurysm., Conclusion: We report a rare case that involves the novel use of the radial artery graft bypass as an approach for parent vessel occlusion.

A 47-year-old man presented with a rare case of dural cavernous hemangioma of the cerebellar falx incidentally detected as a mass lesion in the posterior cranial fossa. Neurological examination revealed no deficits or physical symptoms. Computed tomography demonstrated a well-demarcated hyperdense mass, with no calcification, in the cerebellar vallecula. Magnetic resonance imaging showed the extra-axial mass as homogeneously isointense on T(1)-weighted images, and hyperintense on T(2)-weighted images, compared to the adjacent cerebellar parenchyma that had no hypointense halo. The cerebellar vermis was slightly compressed ventrally, the adjacent brain parenchyma was not swollen, and there was no evidence of hydrocephalus. The mass and the attached cerebellar falx were homogeneously enhanced by contrast medium. The dural enhancement was considered a dural tail. No other intracranial vascular malformations were found. The preoperative diagnosis was posterior cranial fossa meningioma attached to the cerebellar falx. Median suboccipital craniotomy exposed the reddish mass attached to the cerebellar falx. The arachnoid plane was well preserved. Total en bloc resection was performed with minimal blood loss. The postoperative course was unremarkable. The resected mass had a reddish-brown mulberry appearance, with spongy cross section with multiple blood-filled spaces. Histological examination identified dilated blood-containing channels lined with flattened endothelium and separated by fibrous tissue, but no luminal thrombus or hemorrhage. The histological diagnosis was dural cavernous hemangioma of the cerebellar falx. Preoperative radiosurgery or embolization is recommended for most of the dural cavernous hemangiomas, but surgery for the present dural cavernous hemangioma of the cerebellar falx was performed safely.

High-sensitivity and high-resolution LC/MS instrumentation has been applied in positron emission tomography (PET) radiopharmaceutical development to provide quantitative measurement of the mass of radiotracers extracted from tissues of rats. We employed the highly sensitive Waters Q-TOF premier MS coupled with an Acquity UPLC system to demonstrate that LC-MS can generate ex vivo biodistribution data for PET 5-HT(1A) ligand FPWAY without the need to radiolabel. For the biodistribution studies, we injected rats with [(18)F]FPWAY containing various amounts of nonradioactive FPWAY. At the end of the allotted time, the animals were killed and six regions of brain and plasma from each animal were processed for quantitative measurement of parent compound concentration by LC-MS. These data were then converted to the differential uptake ratio DUR (%ID/g*body weight/100) and the brain tissue-specific binding ratio to allow direct comparison with data obtained by gamma counting of the coinjected radioactive [(18)F]FPWAY. The DUR and the brain tissue-specific binding ratio calculated using the LC-MS method were highly correlated to the values obtained by standard radioactivity measurements of [(18)F]FPWAY. In conclusion, there was significant concordance between the LC/MS and radioactivity method in determination of DUR and the specific binding ratio in the rat brain. This concordance indicated that high-sensitivity LC/MS is an indispensable tool in evaluating the quantity of administered chemical in tissue as part of the development of new molecular imaging probes.

Purpose: To determine whether brain and plasma equilibrium of a proposed PET tracer for 5-HT(1A), [(18)F]FPWAY, can be achieved in a sufficiently short time for practical use of the brain to plasma equilibrium distribution ratio (DR) to monitor receptor availability with and without isoflurane anesthesia., Methods: Awake (n=4) and isoflurane-anesthetized (n=4) rats were administered a continuous 60 min intravenous infusion of [(18)F]FPWAY with timed arterial blood sampling. Brains of the isoflurane-anesthetized rats were scanned with the ATLAS small animal PET scanner; awake rats were not. All rats were killed at 60 min and scanned postmortem for 15 min, followed by brain slicing for autoradiography. Several regions of interest (ROIs) were defined in the PET images as well as in the autoradiographic images. Regional DRs were calculated as total activity in the brain ROI divided by plasma [(18)F]FPWAY activity., Results: DRs in the anesthetized animals were constant between 30 and 60 min, indicating that near equilibrium between brain and plasma had been achieved by approximately 30 min. DRs determined from postmortem PET data were higher in the isoflurane-anesthetized rats by 24% (not significant) and 33% (p=0.065) in whole brain and hippocampus, respectively. DRs determined from autoradiographic data were greater in isoflurane-anesthetized rats in medial hippocampus, lateral hippocampus, and cerebellum by 33% (p=0.054), 63% (p<0.01), and 32% (p<0.05), respectively., Conclusion: [(18)F]FPWAY could be an appropriate ligand for monitoring changes in receptor availability in the serotonergic system using a bolus/infusion paradigm. One possible explanation for higher DRs in anesthetized rats may be a reduction in endogenous 5-HT secretion under isoflurane anesthesia.

Unlabelled: We determined an operational value for the lumped constant to be used in measurements of the local rate of cerebral glucose use (lCMR(glc)) with FDG in normal adult male rats., Methods: The standard quantitative autoradiographic method was used with 2-deoxy-d-(14)C-glucose ((14)C-DG) and with (14)C-FDG in awake normal adult male rats. Timed arterial blood samples were drawn for 45 min after the bolus and assayed for plasma glucose and (14)C concentrations. At the end of the 45-min experimental period, the rats were killed, and their brains were removed and divided in half sagittally. One hemisphere was immediately frozen and assayed for local (14)C concentrations by quantitative autoradiography; the other was weighed, homogenized in t-octylphenoxypolyethoxyethanol solution, and assayed for (14)C concentrations in the whole brain by liquid scintillation counting. Paired rats (3 pairs), one in each pair receiving (14)C-DG and the other receiving (14)C-FDG, were studied in parallel on the same day. Additional unpaired animals (n = 8) were studied with either (14)C-DG or (14)C-FDG but not in parallel on the same day. To calculate the lCMR(glc) in rats studied with (14)C-FDG, the rate constants for (14)C-FDG were estimated from the (14)C-DG values determined for rats and the (14)C-FDG/(14)C-DG ratios determined for humans. In all of the rats studied with either (14)C-DG or (14)C-FDG, the lCMR(glc) was first calculated in 12 representative brain structures with the lumped constant of 0.48 previously determined for (14)C-DG in rats. The ratio of the lCMR(glc) thus determined with (14)C-FDG to that determined with (14)C-DG for each structure was then multiplied by the lumped constant for (14)C-DG to estimate the lumped constant for (14)C-FDG. The lCMR(glc) and the lumped constant for FDG in the brain as a whole were similarly estimated from the tracer concentrations in the brain homogenates., Results: The mean values for the lumped constant for FDG were found to be 0.71 and 0.70 in the autoradiographic assays and the assays with brain homogenates, respectively., Conclusion: The appropriate value for the lumped constant to be used in determinations of the lCMR(glc) in normal adult male rat studies with (18)F-FDG and small-animal PET scanners is 0.71.

[(18)F]FCWAY and [(18)F]FPWAY, analogues of the high affinity 5-HT(1A) receptor (5-HT(1A)R) antagonist WAY100635, were evaluated in rodents as potential radiopharmaceuticals for determining 5-HT(1A)R density and changes in receptor occupancy due to changes in endogenous serotonin (5-HT) levels. The in vivo hippocampus specific binding ratio [(hippocampus(uptake)/cerebellum(uptake))-1] of [(18)F]FPWAY was decreased to 32% of the ratio of [(18)F]FCWAY, indicating that [(18)F]FPWAY has lower affinity than [(18)F]FCWAY. The 5-HT(1A)R selectivity of [(18)F]FPWAY was confirmed using ex vivo autoradiography studies with 5-HT(1A)R knockout, heterozygous, and wildtype mice.Pre- or post-treatment of awake rodents in tissue dissection studies with paroxetine had no effect on hippocampal binding of [(18)F]FCWAY or [(18)F]FPWAY compared to controls, indicating neither tracer was sensitive to changes in endogenous 5-HT. In mouse ex vivo autoradiography studies in which awake mice were treated with fenfluramine following the [(18)F]FPWAY, a significant decrease was not observed in the hippocampus specific binding ratios. In rat dissection studies with fenfluramine administered following [(18)F]FPWAY or [(18)F]FBWAY ([(18)F]-MPPF) in awake or urethane-anesthetized rats, no significant differences in the specific binding ratios of the hippocampus were observed compared to their respective controls. [(18)F]FPWAY and [(18)F]FBWAY uptakes in all brain regions were increased variably in the anesthetized group (with the greatest increase in the hippocampus) vs. the awake group, but were decreased in the fenfluramine-treated anesthetized group vs. the anesthetized group. These data are best explained by changes in blood flow caused by urethane and fenfluramine, which varies from region to region in the brain.