[(11)C]TASP457, a novel PET ligand for histamine H3 receptors in human brain.

PURPOSE: The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [(11)C]TASP0410457 ([(11)C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain. METHODS: Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [(11)C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme. RESULTS: [(11)C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 - 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm(3) in the pallidum, 9 - 14 in the basal ganglia, 6 - 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [(11)C]TASP457 was 6.9 µSv/MBq. CONCLUSION: [(11)C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.

[Adult-onset nemaline myopathy with distal muscle atrophy--case report].

We report the case of a 35-year-old male who started gradually developing gait difficulty and atrophy in the distal extremities at the age of 20. In addition to the motor symptoms, skeletal abnormalities such as high-arched palate and pes cavus were also noted. Muscle biopsy revealed numerous nemaline rods and type I atrophy--the pathologic hallmarks of congenital forms of adult nemaline myopathy (ANM). To elucidate the distribution of affected muscles in ANM, we reviewed 61 case reports of ANM and classified these cases into the 3 subcategories proposed by Suzuki et al., as follous: (1) congenital adult-aggravation form, (2) congenital adult-onset form, and (3) non-congenital adult-onset form. Our review suggested that the proximal muscles were predominantly affected both in patients with the congenital adult-onset form and in those with the non-congenital adult-onset form, whereas the distal muscles were affected in approximately half of the patients with the congenital adult-aggravation form. Therefore, on the basis of the characteristic muscle pathology and skeletal deformities observed, we concluded that this patient corresponded to the congenital form of ANM with skeletal abnormalities. A unique feature of this case was the relatively late onset. Therefore, we propose that ANM should be considered as a possible diagnosis for patients with adult-onset distal myopathy, particularly for those with skeletal abnormalities.

Polymyositis with atypical pathological features associated with thymic carcinoma.

A 66-year-old man was admitted for progressive proximal weakness and myalgia in his shoulder girdles without skin lesions. A muscle biopsy showed infiltration of inflammatory cells, degeneration of muscle fibers, and perifascicular atrophy. Remarkably, MHC-I antigen was expressed in the muscle membrane and most of the inflammatory cells were CD8-positive, suggesting that class-I antigen-dependent cytotoxic T-cells played a crucial role in the muscle pathology, which supported a diagnosis of polymyositis rather than dermatomyositis. Magnetic resonance imaging of his chest revealed two mediastinal tumors, which were extirpated and diagnosed as thymic carcinoma. The muscle weakness was completely recovered after the operation and subsequent administration of oral prednisolone. Postoperative clinical improvement and decline of serum creatinine kinase suggested a paraneoplastic nature of the polymyositis in this patient.

Evaluation of autonomic malfunction in idiopathic normal pressure hydrocephalus.

OBJECTIVE: The autonomic nervous system plays an important role in urinary disturbance which is one of the main symptoms of idiopathic normal pressure hydrocephalus (iNPH); thus, the focus of the present study was to identify the autonomic function parameters that would be useful as clinical indicators of iNPH. METHODS: The subjects consisted of 18 iNPH patients (group N) and 31 normal controls (group C). Before and after a lumbar puncture test, they were examined for CVR-R and total heart rate. A power spectral analysis of R-R interval variability of their 24-hour Holter ECGs was also done. High frequency (HF) was an indicator of parasympathetic activity, while the low to high frequency ratio (L/H) was used as an indicator of sympathetic activity. Urinary incontinence was evaluated using the overactive bladder symptom score (OABSS) questionnaire and bladder capacity. Correlations between the above indicators and clinical indicators of iNPH, such as the mini-mental state examination and the Evans index, were examined. RESULTS: The HF values (ms(2)) were 190.3 in group C and 237.2 in group N; the difference was statistically significant. In group N, the HF value after the lumbar puncture test was lower (160.3) than the value before the lumbar puncture test, confirming that the increased parasympathetic state returned to a near normal level after CSF drainage. A significant positive correlation was noted only between the pre-lumbar puncture HF value and the OABSS. CONCLUSION: iNPH is associated with increased parasympathetic activity, and the lumbar puncture test and shunt surgery may correct this autonomic imbalance to near normal levels.

[Case of baroreflex failure after bilateral revascularization of the cervical carotid artery].

We report a patient of baroreflex failure two years after bilateral cervical internal carotid artery (ICA) revascularization. A 76-year-old hypertensive man was admitted to our hospital after suffering multiple syncopal events for the past 2 years prior to admission. He received bilateral surgical and endovascular revascularization for stenotic lesions of the ICA orifices 4 years ago. Intervention consisted of carotid endarterectomy and carotid stenting for the right and left ICAs, respectively. Head T2-weighted magnetic resonance images demonstrated multiple high intensity signals in the basal ganglia bilaterally. To investigate his autonomic function, head-up tilt test, 24-hour ambulatory blood pressure measurements, and Valsalva's maneuver were performed. The patient demonstrated marked orthostatic hypotension without increment of heart rate, increased variability of blood pressure and abnormal hypertensive surges in a single 24 hour period, and abnormal response of heart rate during Valsalva's maneuver. These findings were indicative of impaired baroreflex-mediated vasomotor and heart rate control. Other examinations involving hematological analysis, cardiac function assessment, and scintigraphy for pheochromocytoma were within normal limits except for a marked increase in plasma norepinephrine during hypertensive surge. We therefore considered that he had baroreflex failure resulting from previous bilateral ICA orifice revascularization. The patient was given diazepam during hospitalization. After then, his blood pressure stabilized somewhat and syncopal attacks were controlled. Our case suggests that patients, who undergo bilateral ICA orifice revascularization and present with syncopal attacks, should be considered baroreflex failure even if the patient is post-operative several years. Long-term follow up should therefore be necessitated in patients who undergo bilateral carotid revascularization.

Anaplastic astrocytoma presenting as reversible posterior leukoencephalopathy syndrome.

We report a 60-year-old man with grade III astrocytoma, who presented with status epilepticus. The initial MRI did not demonstrate typical findings of an astrocytoma but rather showed reversible posterior leukoencephalopathy syndrome (RPLS). N-Isopropil-p-[I] iodoamphetamine single photon emission computed tomography (SPECT) demonstrated hyperperfusion in this area. A brain tumor should be considered and the patient carefully followed by MRI, even if the MRI white matter lesion pattern suggests RPLS. This is especially relevant in the presence of atypical findings for RPLS on SPECT.