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A 21-nucleotide duplication in one allele ofSNCAwas identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). Both wild-type α-synuclein and its insertion mutant containing seven additional residues (MAAAEKT) after residue 22 were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA type I and type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. Our findings provide insight into a likely mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.

REM sleep behavior disorder (RBD) is known to be observed more frequently in patients with an α-synucleinopathy such as Parkinson’s disease (PD) than in the general population. The precise prevalence of RBD in Japanese PD patients is not known. Therefore, we investigated the prevalence and the clinical characteristics of patients with RBD in a large population of Japanese patients with PD. We investigated various clinical features and employed the Japanese version of the RBD screening questionnaire on 469 non-demented Japanese PD patients in this multicenter study. Probable or possible RBD was detected in 146 patients (31.1%) and was significantly associated with longer PD duration, higher Hoehn and Yahr stage, higher Unified Parkinson’s Disease Rating Scale part III subscale (7 items), more motor fluctuations, and a higher levodopa-equivalent daily dose (p

Objective: The aim of this work was to investigate the prevalence of camptocormia and the clinical characteristics of patients with camptocormia in a large population of PD patients. Background: Although camptocormia has been recognized as a prominent phenomenon in PD, the previous epidemiological reports were limited, especially in terms of sample size. Methods: We evaluated 531 PD patients (disease duration: 7.0 ± 5.5 years, mean ± standard deviation). We examined their clinical features and the prevalence of camptocormia. Results: Camptocormia was detected in 22 patients (4.1%) and found in patients who were older and had more severe motor symptoms and a higher levodopa (L-dopa) dose (P < 0.05), compared to the patients without camptocormia. Patients with camptocormia showed significantly higher frequencies of autonomic symptoms, such as constipation and urinary incontinence (P < 0.05). Conclusions: Camptocormia is uncommon in PD and is associated with disease severity, higher L-dopa dose and higher frequencies of autonomic symptoms. © 2011 Movement Disorder Society

A 46-year-old woman developed painful dysesthesia in her extremities and ataxic gait. She was diagnosed with Sjogren's syndrome, and her condition was diagnosed as sensory ataxic and painful neuropathy. Intravenous immunoglobulin therapy alleviated the ataxia and severe pain in her extremities. When she was 61-years-old, she developed dysphagia and dyspnea. Laryngoscopy showed tactile anesthesia on the epiglottis, indicating paresis of the superior laryngeal nerve. We considered that the primary cause of dysphagia was paresis of the internal branch of the superior laryngeal nerve, and carried out tracheostomy and high-dose intravenous methylprednisolone therapy (1 g/day × 3 days). Her dysphagia and aspiration gradually improved without following oral steroid therapy. Our case is the first report of the internal branch of superior laryngeal nerve paresis as a possible cause of dysphagia and aspiration in a patient with Sjogren's syndrome. Additional cases of Sjogren's syndrome with dysphagia should be investigated to confirm our findings.

A 44-year-old Japanese man with elevated growth hormone levels and gradual deterioration of mental and renal function was admitted to the hospital. With his deteriorated general condition and renal failure, the patient developed pulmonary thromboembolism and died of respiratory failure. Autopsy examination was conducted, which revealed abnormal accumulation or intracytoplasmic storage of lipid-rich material in the small blood vessels, kidney, heart, and nervous system. After postmortem pathologic studies, including light-microscopic histochemistry, electron microscopy, and biochemical analysis of the stored lipid contents, a final diagnosis of Fabry disease was made. Histopathologic examination revealed a unique vasculopathy characterized by the presence of abnormal intracytoplasmic lipid inclusions and vascular remodeling. With regard to the clinical presentation of acromegaly, hyperplasia but not adenomatous transformation of the acidophils of the anterior pituitary gland with immunohistochemical detection of growth hormone within the cells was noted. In this case, the complication of acromegaly with hyperplasia of the acidophilic cells of the anterior pituitary gland and the unique vasculopathy causing significant organ failure, mainly of the kidney, heart, and central nervous systems, possibly as a result of microcirculatory failure, are considered to be not incidental findings but to be intimately involved in the pathogenesis of Farby disease.

A Japanese male developed gradual loss of spontaneous speech at age 60. Three years later meaningful speech had deteriorated to the point that it had become restricted to monotonous utterances. Neuropsychological examination at age 62 showed that he had severe non-fluent aphasia. A brain MRI demonstrated mild cortical atrophy with ischemic lesions in the cerebral white matter. He was diagnosed as having primary progressive aphasia. At age 63, he was admitted to the hospital to reevaluate the neurological condition. Neurologic examination showed severe non-fluent aphasia, hyperreflexia, snout and sucking reflexes. No alien hand was observed. He was able to walk, dress, wash himself and use chopsticks as well as name real objects. At age 65, 99Tc-hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO-SPECT) revealed diffuse cerebral hypoperfusion that was particularly prominent in the left frontal lobe. An MRI showed progressive cortical atrophy with the definite atrophy of the left paracentral gyrus. The hippocampal formation and putamen were also atrophic. He died of pneumonia at age 67. The brain weighed 810 g with atrophy of the frontal lobe, globus pallidus, enlargement of the lateral ventricles and depigmentation of the substantia nigra. Microscopic examination showed severe neuronal loss and gliosis in the cerebral cortex, globus pallidus interna and substantia nigra. Ballooned neurons were observed in the cerebral cortex. Gallyas-Braak method revealed numerous astrocytic plaques and argentophilic threads in the cerebrum. Clinical diagnosis of corticobasal degeneration sometimes is difficult in individuals with atypical clinical presentations. More exact clinical and radiological criteria may warrant a diagnosis of corticobasal degeneration.

The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclel; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by alpha-synuclein antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of alpha-Synuclein, beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and Neurofilament-M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.

Epidemiological evidence has demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) may lower the risk of developing Alzheimer's disease (AD). Cyclooxygenase (COX)-2, a target enzyme of NSAIDs which is involved in inflammatory reactions as well as physiological brain functions, has been found to be upregulated in AD brains. In the present study, we used immunohistochemistry to determine the localization and the cellular type of the COX-2-expressing cells as well as the spatial relationship between these cells and the characteristic β-amyloid (Aβ 1–42 )-immunopositive senile plaques (SP) or tau-positive neurofibrillary tangles (NFT) which are found in the brains of patients with a Presenilin-1 gene mutation. Numerous Aβ 1–42 -positive SP were detected throughout the brains. COX-2 immunoreactivity was present between SP mainly in pyramidal neurons in the cerebral cortex and the hippocampal formation. COX-2 was also found in small round cells in close association with SP. The COX-2-positive neurons were most dense in the superficial cortical layers, while tau-positive NFT were densest in the deeper layers. In the frontal and temporal cortices that were most severely affected, the COX-2-positive neurons were damaged and decreased in number. The COX-2 expression in these cells might contribute to Aβ accumulation or represent a cytoprotective reaction against the Aβ-related inflammatory process.

We report a family of Japanese origin that has five individuals from two generations affected by an illness characterized by dementia, a stooped posture and an antiflexion gait with an onset in the fourth or fifth decade of life. Two siblings had a clinical phenotype characterized by dementia and Parkinsonism with stooped posture, rigidity and bradykinesia. Neuropathological alterations in both patients included numerous 'cotton wool' plaques (CWPs), senile plaques, severe amyloid angiopathy, neurofibrillary tangles, neuronal rarefaction and gliosis. CWPs were present throughout the cerebral cortex as well as in the caudate nucleus, putamen, claustrum, thalamus, substantia innominata and colliculi. These plaques contained a small quantity of argyrophilic and tau-immunopositive neurites as well as glial fibrillary acidic protein-immunopositive elements. They were mildly fluorescent with thioflavin S and immunopositive using monoclonal antibodies recognizing amyloid beta (A beta) ending at residue 42. The main constituents of CWPs were neuropil elements and extracellular amyloid fibrils. These neuropil elements were small dendrites including spines, axon terminals containing synaptic vesicles and astrocytic processes. Dendrites occasionally contained bundles of paired helical filaments. Dendrites and axons often had an irregular outline and appeared as degenerating osmiophilic processes containing electron-dense mitochondria. Genetic analysis of the proband's affected sibling revealed a novel nucleotide substitution (G to A) in exon 8 of the Presenilin 1 ( PSEN1) gene. This nucleotide change results in a glycine to aspartic acid substitution at residue 217 of the PSEN1 protein. This study provides further evidence of clinical and pathological heterogeneity in dementing illnesses associated with PSEN1 mutations.

Recently, the functions of several putative neurotransmitters such as catecholmines, acetylcholine (ACh) and neuropeptides have been elucidated in the cerebrovasculature. The interaction of such neurotransmitters and their receptors, however, has not been sufficiently clarified. The purpose of this study is to explore the relation of recently demonstrated neurokinin-1 (NK-1) receptor-containing cerebrovascular nerve fibers with the cerebrovascular vasodilatory nerves by means of the sequential-staining immunohistochemical method. Numerous sites of NK-1 receptor immunoreactivities were noted along the nerve fibers with vasoactive intestinal polypeptide (VIP) immunoreactivity in the pial arteries in all regions of the brain. They consisted of fine, delicate varicose fibers and thick bundles without varicosities. After sequential staining with VIP, NK-1 receptor immunoreactive material was demonstrated in the VIP-positive nerve fibers. The majority of fibers were positive for VIP alone (75%). The number of fibers positive for both NK-1 receptor and VIP was about one-third the number of fibers for VIP alone (22%). Fibers positive for NK-1 receptor alone comprised a small population (3%). This study demonstrated that NK-1 receptors are localized in axonal membrane of VIP-containing parasympathetic nerves. This suggests that the sensory nerves modulate the functions of parasympathetic nerves in peripheral nervous system, such as those on cerebral vessels.

Calbindin-D28k, one of the calcium-binding proteins, belongs to the EF hand family and is commonly found in neurons. It serves as a representative neuronal marker for neuroanatomical investigations. The authors' knowledge of its precise function, however, is yet very limited. In this study, we examined the existence of nerve fibers with calbindin-D28k immunoreactivity in the cerebral blood vessels and ganglia that innervate the cerebral blood vessels in the rat. Numerous nerve fibers with calbindin-D28k immunoreactivity were observed on the walls of the major extracerebral arteries forming the circle of Willis and its branches. Calbindin-D28k immunoreactivity was seen in many neurons of the trigeminal, dorsal root and jugular ganglia. A small number of neurons showed calbindin-D28k immunoreactivity in the otic and superior cervical ganglia. Calbindin-D28k immunoreactivity was not detected in the sphenopalatine or internal carotid ganglia. Pericellular basket-like formations of nerve terminals with calbindin-D28k immunoreactivity were observed in the sphenopalatine, otic, internal carotid and superior cervical ganglia. The present study demonstrated calbindin-D28k immunoreactivity in the cerebrovascular nerve fibers as well as in their origins--the cranial ganglia. These findings are significant in understanding the calcium-mediated mechanism of the neural control of the cerebral blood vessels.

We report a case with portal systemic encephalopathy who presented with dressing and constructional apraxia and subtle weakness of the left hand. We initially suspected a cerebrovascular attack in the right cerebral hemisphere, but brain T1-weighted magnetic resonance (MR) imaging revealed high intensity in the basal ganglia and hyperammonemia was detected. We performed abdominal MR angiography, which visualized an intrahepatic portal systemic shunt. Cerebral blood flow, measured by xenon-enhanced computed tomography, was decreased in the bilateral, but more dominantly right-sided, parietal watershed regions. We speculate that these boundary territories might be susceptible to damage by toxic metabolites of hepatic encephalopathy.

The pathologic features of silent hyperintense white matter lesions in T2-weighted images on MRI were studied in patients with no neurologic signs or symptoms. The small patchy hyperintense white matter lesions represented myelin pallor associated with vessels showing hypertension and arteriosclerotic changes. 'Caps' also showed myelin pallor with dilated perivascular spaces. There were no lacunar infarcts in these lesions. Some of 'caps' was shown to be elongated normal lateral ventricle. 'Rims' of early stage revealed subependymal gliosis that was a part of normal aging processes.

Background . Paraplegia remains a serious complication of thoracoabdominal aortic operations. However, despite growing in vitro evidence, it has been difficult to demonstrate glutamate neurotoxicity in vivo because of the reuptake activity that occurs. We hypothesized that glutamate can be toxic to the spinal cord under metabolic stress. Methods . Infrarenal aortic isolation was performed in New Zealand white rabbits. Group A animals (n = 7) then received a segmental infusion of glutamate (50 mmol/L) for 5 minutes. Group B animals (n = 7) received saline as a negative control. Group C animals (n = 6) were pretreated with a segmental infusion of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline (4 mg/kg), a competitive α-amino-3-hydroxy-5-methylisoazole-4-propionic acid/kainate antagonist, followed by the segmental infusion of glutamate (30 mmol/L) for 4 minutes. Group D animals (n = 6) received the vehicle agents only, followed by the same glutamate infusion (30 mmol/L) as in group C as a control for group C. Neurologic status was assessed at 12, 24, and 48 hours after operation and scored using the Tarlov system. Results . Group A animals exhibited paraplegia or paraparesis with marked neuronal necrosis. Group B animals recovered fully. Group C animals had better neurologic function than group D animals ( p = 0.0039). Conclusions . Exogenous glutamate can have detrimental effects on spinal cord neurons during a brief period of ischemia. This model may be useful for the purpose of assaying a glutamate receptor antagonist in vivo. (Ann Thorac Surg 1997;63:1057–62)

We investigated rapid changes in pial arterial diameter and in cerebral blood flow (CBF) caused by transient ipsilateral common carotid artery occlusion (CCA-O) in anesthetized rats in order to elucidate how the cerebral circulation reacts to acute stem artery occlusion. In separate groups of rats, pial arterial diameter was recorded through a closed cranial window and CBF was recorded by laser-Doppler flowmetry. CCA-O was performed for 5 minutes under normotension and normocapnia (control) and under graded hypotension, hypercapnia and hypocapnia. In the control condition, pial arterial diameter increased rapidly, triggered by CCA-O. It took 12 +/- 3 s to reach the maximum of 204 +/- 42% of the value before CCA-O, and 60 +/- 24 s to become stable at 131 +/- 11%. CBF decreased rapidly to 66 +/- 11%, then increased reactively to 135 +/- 9%, and again decreased to 91 +/- 3%. The reactive increase in CBF caused by CCA-O decreased in parallel with the degree of hypotension, and also became barely detectable under hypercapnia. Our data suggest that active vascular dilation in the territory of the occluded artery is important for inducing collateral circulation.

A 27-year-old-woman with paramyotonia congenita was reported. She began to suffer from myotonia since infancy. Myotonia was aggravated by cold, but with intense cooling myotonia did not change to flaccid paralysis. Four generations of her family showed the same symptoms that suggested autosomal dominant inheritance. Neurological examinations revealed no impairments of mental function, cranial nerves and sensory system. Muscular atrophy or hypertrophy was not observed. Percussion myotonia of the tongue and thenar muscles could be elicited at room temperature. Myotonia was aggravated by cold. An oral intake of potassium chloride (7 grammes) did not provoke any muscle weakness or flaccid paralysis. Routine laboratory data and findings of head CT scan, cerebrospinal fluid and electroencephalogram were normal. The nosological distinction between paramyotonia congenita and hyperkalemic periodic paralysis has been debated since 1956. Paralysis induced by cold is thought to be a feature of paramyotonia congenita, thus raising a possible relationships to hyperkalemic periodic paralysis. In our case cold paralysis never occurred spontaneously and could not be provoked by immersion in ice water or by potassium loading. This finding confirms the existence of paramyotonia congenita without cold paralysis and may provide a nosological distinction between paramyotonia congenita and hyperkalemic periodic paralysis.

A 36-year-old man who suffers from gait disturbance is reported. He noticed deformity of his feet at the age of 15. When he was 32 years old, he complained of heaviness in his lower extremities. Since then his legs have been always stiff. He had no previous illness or familial neuromuscular diseases. Neurological examination revealed no impairment of mental function or cranial nerves. Marked weakness and wasting of the feet were noted. The legs showed an inverted champagne bottle shape and pes cavus deformity was evident. Deep tendon reflexes were normal in the arms but abnormally brisk in the legs. Bilateral Babinski sign and ankle clonus were elicited. The patient tended to walk on his toes and the legs scissored. The motor nerve velocities were less than normal. Sural nerve biopsy showed reduced myelinated fiber density and increased endoneurial connective tissue. Electron microscopy showed axonal swellings filled with neurofilaments. Distal wasting and weakness involving the legs more than the arms resembled that of Charcot-Marie-Tooth disease. According to the classification by Dyck, this disorder could be referred to as hereditary motor and sensory neuropathy type V. Spastic paraplegia with amyotrophy is rare, but should be identified as a distinct disorder. Recognition of this disorder would imply the clinical and genetic heterogeneity of Charcot-Marie-Tooth disease.

The vesicles of adventitial autonomic nerve terminals were examined quantitatively under an electron microscope in controlled ultraviolet ray (UV)-irradiated cerebral vessels. Five cats whose basilar arteries were irradiated with UV (UV group) and 5 cats whose basilar arteries were irradiated with visible rays (control group) were compared. Endothelial vacuolation was observed only in the UV group. There was no statistically significant difference in the diameters of the dense-cored vesicles, related to noradrenaline, and clear vesicles, related to acetylcholine, between the two groups. It is concluded that controlled UV irradiation which generates endothelial damage does not affect the vascular adventitia ultrastructurally.

A quantitative morphological analysis of the perivascular nerve terminals of cerebral arteries during moderate hypoglycemia was performed. 5-Hydroxydopamine (5-OHDA) was applied to discriminate dense-cored vesicles, related to noradrenaline, and clear vesicles, related to acetylcholine, under the electron microscope. Five hypoglycemic and 5 normoglycemic cats, all receiving 5-OHDA, were compared. In both the middle cerebral artery and vertebral artery, the dense-cored vesicles were significantly smaller and clear vesicles were significantly larger in hypoglycemia than in normoglycemia. These morphological changes in the vesicles may indicate hyperactivity of the sympathetic system and hypoactivity of the parasympathetic system of the cerebral vessels during hypoglycemia.

To determine the function of cerebrovascular parasympathetic nerves, the calibre of rat pial arteries was continuously measured when the nerves (the postganglionic fibres originating from the sphenopalatine ganglion) were electrically stimulated in vivo. The pial arteries (72.3 +/- 2.8 microns) dilated immediately after electrical stimulation (5 V, 10 Hz, 0.5 ms, 1 min duration). Their diameter increased 4.7 +/- 0.1% (p less than 0.01), 6.3 +/- 1.7%, 5.1 +/- 0.3% (p less than 0.05), 6.3 +/- 1.4%, at 15, 30, 45 and 60 s after initiation of stimulation, respectively. No significant change was observed in systemic arterial blood pressure or the expiratory carbon dioxide content during stimulation. This is the first direct demonstration of in vivo cerebrovascular neurogenic vasodilatation in the rat.

Pure red cell aplasia (PRCA) is well known to be concomitant with myasthenia gravis (MG), but it is difficult to predict the development of PRCA in patients with MG. Of 135 patients with MG, four (2.9%) had PRCA. All patients developed PRCA after thymectomy during a period when MG was in remission. The frequencies of thymoma, bulbar involvement and high anti-acetylcholine receptor (AChR) antibody levels were significantly higher in four patients with PRCA. Japanese MG patients with these characteristics at presentation were at significant risk for the development of PRCA after thymectomy.

An unbiased functional screening with brain cDNA library from an Alzheimer's disease (AD) brain identified a novel 24-residue peptide Humanin (HN), which suppresses AD-related neurotoxicity. As the 1567-base cDNA containing the open reading frame (ORF) of HN is 99% identical to mitochondrial 16S ribosomal RNA as well as registered human mRNA, it was elusive whether HN is produced in vivo. Here, we raised anti-HN antibody and found that long cDNAs containing the ORF of HN (HN-ORF) produced the HN peptide in mammalian cells, dependent on the presence of full-length HN-ORF. Immunoblot analysis detected a 3-kDa protein with HN immunoreactivity in the testis and the colon in 3-week-old mice and in the testis in 12-week-old mice. HN immunoreactivity was also detected in an AD brain, but little in normal brains. This study suggests that HN peptide could be produced in vivo, and would provide a novel insight into the pathophysiology of AD.

Historical Review of Developments in the Field of Cerebral Blood Flow and Metabolism.- Mechanisms of Mechanochemical Transduction in Vascular Cells.- Ultra Long Range Forces Between Macroscopic Bodies.- Role of the Endothelial Surface Coat in Microvessel Blood Flow.- Blood-Brain Barrier: Role of Brain Endothelial Surface Charge and Glycocalyx.- The Role of the Endothelial Surface Coat in Microvascular Permeability.- Mechanism of Inhibitory Effect of Hypoxia/Reoxygenation on Gap Junctional Intercellular Communication of Vascular Endothelial Cells in Culture.- Proteoloytic Opening of the Blood-Brain Barrier During Neuroinflammation.- Endothelial Dysfunction After Brain Ischemia and Reperfusion.- Local Blood-Brain Barrier Damage, Cerebral Edema, and Cell Injury During Reperfusion After 2 Hours of Focal Cerebral Ischemia.- Temporal Profile of Ischemic Edema: Comparison of Ultrastructure, Gravimetry, and Evans Blue Permeability.- Perivascular Cells of Small Cerebral Vessels (FGP, Mato cells) and Their Permeability Under Pathological Conditions.- Effects of Ischemia on Expression of Cyclooxygenase and Endothelial Nitric Oxide Synthase in the Cerebral Circulation.- Role of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 in the Mechanisms of Ischemic Brain Injury.- Dual Pathways of Free Radical Injury in Vascular Endothelial Cells: Loss of Nuclear DNA Integrity and Membrane Asymmetry During Enhanced Cysteine Protease Activity.- Vascular Endothelial Growth Factor: Protection Against Ischemic Brain Damage with MCA Occlusion in Rats.- Effect of Induction of Inducible Nitric Oxide Synthase on the Blood-Brain Barrier in the Rat.- Adenovirus-Mediated Gene Transfer to Cerebral Blood Vessels and Ischemic Brain: Perivascular Approach and Ischemic Threshold.- Recombinant Nitric Oxide Synthase Gene Transfer: Potential Roles in Gene Therapy of Cerebrovascular Disease.- Microvascular Integrin-Matrix Responses to Focal Cerebral Ischemia Are Rapid and Reflect Neuron Injury.- Glial Cell Line-Derived Neurotrophic Factor: Protection Against Ischemic Brain Injury in Association with Reduced Apoptotic Signals but No rCBF Improvement.- Postischemic Hyperperfusion Does Not Necessarily Indicate Good Recovery of Brain Tissue. From the Viewpoint of PKA-Mediated Intracellular Signal Transduction.- Hemorrhage-Induced Brain Ischemia: Modulatory Role of Endogenous Opioids and Antiopioids in the Cerebrovascular Bed.- Pathophysiological Consequences of White Matter Compared to Gray Matter Ischemia.- Apoptosis in Cerebral Vasospasm After Subarachnoid Hemorrhage.- Multitracer PET Studies in MCAO of Cats as a Model for Acute Ischemic Stroke.- Activation CBF Varied by Perturbation of PaCO2 and PaO2 Level: PET Study.- Comparison of Multitracer PET and Functional MRI in a Pig MCAO Model for Acute Ischemic Stroke.- Cerebral Blood Flow, Hemoglobin Oxygenation, and Water Diffusion Changes During Stroke: Fingerprinting with Near-Infrared Spectroscopy and MRI.- Evolution of Capillary Perfusion Deficits in Ischemic Rat Brains.- In Vivo Investigation of the Cortical Microcirculation Under Ischemia/Reperfusion in Rats Using Dynamic Laser Confocal Fluorescence Microscopy.- Blood Flow Values in the Ischemic Brain Tissue as Influenced by Factor m with Loss of Tissue Vivacity.- Role of Nitric Oxide in Variations of the Response of Cerebral Blood Flow to Hypotension and Focal Ischemia.- Heterogeneous Autoregulatory Capacity in the Rat Cerebral Cortex as Observed by a Novel Two-Dimensional Flow Mapping Technique.- Changes in Cerebrovascular Reactivity After Stimulation and Depletion of Sensory Fibers in Rats.- Impact of Focal Ischemia/Reperfusion on the Microcirculation in Cerebral Cortex in Rats.- Erythrocyte Flow in the Cerebral Capillary Network During Ischemia and Hypoxemia: Observations with Intravital Microscopy.- Brain Microvasculature: Evidence for Interactive Endothelium-Dependent Responses Induced by Endothelin-1 and Nitric Oxide.- Acute and Delayed Effects of Transient Global Cerebral Ischemia on Rat Brain Capillary Endothelial Cells In Vivo.- Heme Oxygenase-Carbon Monoxide System as a Regulator of Microvascular Function.- Evidence for CSD or CSD-Like Phenomena in Human Brain in Relation to Migraine and Stroke.- Responses to Cortical Spreading Depression During Normoxia and Ischemia: Multiparametric Monitoring Study in Animals and the Human Brain.- Profiles of Transient Cortical Depolarization and Calcium Ion Influx in Periinfarct Regions of Focal Cerebral Ischemia in Cats.- Temporal and Spatial Evolution of Cortical Blood Flow in the Penumbra of Venous Infarcts.- Quantitative Topography of the Hemodynamic-Oxidative Metabolic Interrelation by Multispot Measurement Approach in Rat Ischemia Models.- Role of Altered Blood Properties in the Propagation of Ischemic Blood Flow: Contribution of Aging and Oxidative Stress.- Direct Repeated Measurements of POD in the Brain During Ischemia and Reperfusion.- TNFa, Endothelium, and Microcirculation in Stroke Initiation, Progression, and Tolerance.- Coagulation Triggered by Erythrocyte Membrane and Its Possible Significance in Thrombus Formation.- Effect of Intraischemic Hypothermia on Intercellular Adhesion Molecule-1 and Migration of Neutrophils.- Selective Thrombin Inhibitor (Argatroban): Amelioration of Platelet Adhesion to Human Brain Microvascular Endothelial Cells In Vitro: Observation with Video-Enhanced Contrast Microscopy.- MRI to Demonstrate that Tissue Plasminogen Activator Increases Stroke Volume If Cerebral Arteries Are Not Successfully Recanalized.- Microvascular Pathology in Familial Multiinfarct Dementia or CADASIL: Implications for Cerebral Blood Flow.- Neural Activation and Glucose Metabolism in Hemodynamic Ischemia.- Effects of Hyperthermia and Hypothermia on Ischemic Vascular Damages.

Nitric oxide (NO) has been found to have a crucial role in the development of ischemic brain damage and of endotoxin shock. This study observed vascular changes and elucidated mechanisms of development of the brain damage during induction of inducible nitric oxide (iNOS). Five male Sprague-Dawley rats weighing 250–300 g were used. They were anesthetized with a-chloralose and urethane and ventilated with room air. The brain cortical blood flow (CoBF) in the parietal cortex supplied by the right middle cerebral artery (MCA) was recorded by a laser Doppler flowmeter. CoBF and systemic blood pressure were continuously recorded before and after an intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) (4 mg/kg body weight). Three hours after injection of LPS, horseradish peroxidase was injected intravenously. One hour later the animals were deeply anesthetized and per-fused with 5% glutaraldehyde. The whole brain was dissected and frozen sections of the deep frontal cortex were incubated with HRP using the method of Graham and Karnovsky, postfixed in osmic acid, then processed and observed with an electron microscope. A simultaneous electron microscopic NADPH-diaphorase histochemistry assay was performed on these sections. The blood pressure was significantly decreased about 30 min after LPS administration and a sustained increase (about 30%) in CoBF was observed. The HRP deposits were observed as dark clusters at the outer edge of the endothelial cells. NADPH-diaphorase-positive deposits were observed in the nuclear membranes, endoplasmic reticulum, and mitochondria in smooth muscle and the endothelium. Induction of iNOS may affect the function of the endothelium and smooth muscle as a crucial mediator during derangement of the blood-brain barrier.

The effects of bilateral locus ceruleus (LC) lesions on the pericapillary nerve terminals were investigated in the feline brain parenchyma using electron microscopy. LC lesions were induced stereotaxically and the animals were sacrificed after intravenous administration of 5-hydroxydopamine (5-OHDA). The diameter and number of dense-cored vesicles (DCVs) and clear vesicles (CVs) in the pericapillary nerve terminals were measured. The number of DCVs in the nerve terminal was significantly decreased by bilateral LC lesions. The diameters of the DCVs and CVs decreased significantly as compared with those in the non-operated control group. These data suggest that the LC is closely related to the pericapillary nerve terminals in the brain parenchyma and that not only nerve terminals with DCVs but also those with CVs are affected by LC lesions.

A 27-year-old woman with Miyoshi’s distal muscular dystrophy devised a unique form of standing up from a squatting position; She held her ankles with her hands to support the weight transfer, fixed the heels, extended the knees to elevate the hips, raised the upper half of the body, and finally stood up. This strategy illustrates the characteristic and specific distribution of the wasted muscle in this disease.

The distribution of immunoreactivity to the receptor for substance P was examined in the cerebral blood vessels of the rat. Substance P immunoreactivity has been demonstrated in the nerve fibers of the cerebral blood vessels. Recently, the production of substance P receptor specific antibody has enabled the detection of localization of the substance P receptor in the central nervous system. In this study, we examined the existence of nerve fibers with substance P receptor immunoreactivity in the cerebral blood vessels and the cranial ganglia innervating the cerebral blood vessels. Sprague-Dawley rats were perfused with fixative and the pial arteries and the cranial ganglia known to innervate the cerebral blood vessels, i.e., trigeminal, sphenopalatine, internal carotid, otic and superior cervical ganglia, were dissected. All specimens were incubated with anti-substance P receptor IgG, then stained by the avidin-biotin-peroxidase complex method. Numerous nerve fibers with varicosities forming plexuses, with substance P receptor immunoreactivity were observed on the walls of the major extracerebral arteries forming the circle of Willis and its branches. Substance P receptor immunoreactivity was also detected in the endothelium of the cerebral arteries. Substance P receptor immunoreactivity was positive in many neurons of the sphenopalatine ganglion, otic ganglion, trigeminal ganglion, superior cervical ganglion and internal carotid ganglion. The present study demonstrated the existence of nerve fibers with substance P receptor immunoreactivity in the cerebral blood vessels and the cranial ganglia that innervate the cerebral blood vessels. These findings are important in understanding the responsiveness of the cerebral blood vessels to substance P.

The authors report a case of localized hypertrophic mononeuropathy involving the femoral nerve in a 20-year-old woman referred because of progressive weakness and atrophy of the left thigh. MRI showed an enlarged femoral nerve and biopsies of fascicles displayed a concentric pattern of cells resembling an onion bulb. These cells were positive for epithelial membrane antigen immunostaining and had an incomplete basal lamina.

Recently, nitric oxide (NO) has been found to act a crucial role in the development of the endotoxin shock. This study aims to observe vascular changes and to elucidate mechanisms of development of the brain damage in the endotoxin shock.

Neuronal NADPH-diaphorase has been proved to be nitric oxide synthase itself. In this study, we investigated distribution and origins of NADPH-diaphorase-containing nerve fibers in the cerebral vessels in the rat. Adult male Sprague-Dawley rats were divided into 4 groups. Nasociliary nerves were transected bilaterally in group 1. In group 2, intracranial branches of the sphenopalatine ganglion were transected bilaterally. In group 3, both of these structures were transected. The remaining animals were served as control (group 4). Two weeks after the above procedures, they were perfused with paraformaldehyde and glutaraldehyde. The pial arteries and superior cervical, trigeminal, internal carotid, otic and sphenopalatine ganglia were dissected. All specimens were processed for NADPH-diaphorase histochemistry. Numerous NADPH-diaphorase-containing nerve fibers with varicosities forming plexuses were observed in the circle of Willis and its branches. Relatively thick nerve bundles were noted in the anterior half of the circle of Willis. They are most abundant in the internal ethmoidal artery. Approximately 5% of such fibers in anterior half of the circle of Willis disappeared in group 1, 90% in group 2, and no fibers were seen to remain in group 3. NADPH-diaphorase reaction was positive in the neurons of sphenopalatine, otic trigeminal and internal carotid ganglia. Among these ganglia, the reaction was prominent in sphenopalatine, otic and internal carotid ganglia. In summary: (1) NADPH-diaphorase-containing nerve fibers distribute to the circle of Willis and its branches. The density is higher in the anterior half of the circle of Willis than its posterior half; (2) NADPH-diaphorase activity is observed in the parasympathetic and sensory cranial ganglia which are known to innervate the cerebral vessels; and (3) the main source of cerebrovascular NADPH-diaphorase-containing nerve fibers is the sphenopalatine ganglion.

Recently, neuronal nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase has been elucidated to be the nitric oxide synthase (NOS) per se. In order to examine the existence and distribution of cerebrovascular nerve fibers containing these substances, NADPH-diaphorase histochemistry was applied to the cerebral blood vessels and the cranial ganglia known to innervate the cerebral vessels in the rat. Numerous nerve fibers with varicosities forming plexuses were observed in the circle of Willis and its branches. In addition, thick nerve bundles were seen to run along the wall of the internal ethmoidal artery. NADPH-diaphorase reaction was prominent in neurons of the sphenopalatine, otic and internal carotid ganglia. This study demonstrated, for the first time, the NADPH-diaphorase-containing nerve fibers in the cerebral vessels and ganglion cells in the parasympathetic and sensory ganglia known to innervate the cerebral vessels.

We investigated the clinical and pathologic characteristics of stroke in 234 patients with systemic lupus erythematosus. Thirteen patients (5.6%) developed cerebrovascular disease. Cerebral infarction was noted in eight, cerebral hemorrhage in two, and subarachnoid hemorrhage in three. In seven (54%) of these 13 patients, stroke occurred less than or equal to 5 years after systemic lupus erythematosus was diagnosed. Among the predisposing risk factors for stroke, hypertension was the most important. Lupus anticoagulant was detected in three (38%) and anticardiolipin antibody in three (43% of seven investigated) of the patients with infarction. Evaluation of the clinical manifestations and autoantibodies indicated that renal involvement and high titers of anti-deoxyribonucleic acid antibody were more frequent in the stroke group than in the non-stroke group. Autopsy studies on six of the patients with stroke revealed small infarcts and hemorrhages in all, but in no case was true angiitis observed. Libman-Sacks endocarditis was found in two of the three patients with infarction. In conclusion, the important contributory factor to the development of stroke in patients with systemic lupus erythematosus is considered to be hypertension mediated by immunologic abnormalities. Antiphospholipid antibodies and Libman-Sacks endocarditis are closely associated with occlusive cerebrovascular disease.

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare multisystem disorder. Although its pathogenesis remains elusive, there is evidence that vasculopathy may have an important role.1-3 We report an autopsied case of POEMS syndrome in which necrotizing vasculitis was identified as a salient pathologic feature. A 63-year-old man was admitted to the hospital because of difficulty in walking and a tingling sensation in his legs. On physical examination, edema of the bilateral legs was prominent. Neurologic examination revealed muscle weakness and atrophy of the legs, more marked in the proximal muscles, and deep-tendon reflexes were diminished. Blood cell counts showed mild leukocytosis and thrombocytosis. Tests for autoantibodies such as rheumatoid factor, cryoglobulin, anti-ribonucleoprotein (RNP) antibody, anti-double stranded DNA antibody, anti-SS-A/Ro antibody, and antineutrophil cytoplasmic autoantibody (ANCA) were negative. Serum level of vascular endothelial growth factor (VEGF) was elevated (>2000 pg/mL). Hyperprolactinemia (339.7 ng/mL) was noted. The level of testosterone was decreased (0.4 ng/dL). Estradiol level was elevated (79 ng/mL). There was impaired glucose tolerance. M-protein (IgGλ) was detected in the serum. Motor and sensory conduction velocity of the peripheral nerves was reduced. …

周期性四肢麻痺を主訴とするSjogren症候群の1例を経験したので報告する.症例は48才,女性.四肢麻痺状態で入院. CPK正常,低K血症より周期性四肢麻痺が考えられ,高CI性代謝性アシドーシス,アルカリ尿より,遠位尿細管性アシドーシスが明らかとなつた.電解質補正により筋力は正常に復したが,その後の精査でSjogren症候群(sicca complex)が確診された.周期性四肢麻痺を前景にしたSjogren症候群は従来その存在が注目されていないが,文献的考察によりSjogren症候群における周期性四肢麻痺の出現率は2.6%,また,周期性四肢麻痺を呈するSjogren症候群の92%はsicca complexであると算定された.

A fatal case of an apparently congenital form of hemophagocytic reticulosis is reported. The onset was manifested by hyperbilirubinemia and hepatosplenomegaly which were present at birth and persisted throughout life. Fever, anemia and pancytopenia developed at 1 month of age and became progressively worse. A splenectomy was performed at the age of 3 months, but the child died one day later with disseminated intravascular coagulation and pulmonary hemorrhage. The literature is reviewed with regard to the relationship of this case to (familial) hemophagocytic reticulosis and malignant histiocytosis (histiocytic medullary reticulosis). It is suggested that congenital hemophagocytic reticulosis, as described here, (familial) hemophagocytic reticulosis in infants, and malignant histiocytosis in adults all represent the same basic disorder with different ages of onset and clinicopathologic manifestations.

Autoregulation and chemical vasomotor control of cerebral blood flow (CBF) were measured in 14 patients with cerebral ischemia and infarction classified according to severity and anatomical location before and after intracarotid injection of the beta-adrenergic blocking agent, propranolol hydrochloride (PPL). Intracarotid injection of 1.45 µg per kilogram body weight per minute of PPL (average total dose 2 mg) was followed by a reduction in CBF and oxygen consumption and an increase of cerebrovascular resistance. Mean arterial blood pressure, intracranial venous pressure, and cerebrospinal fluid pressure were unchanged. Cerebral autoregulation was tested by raising and lowering cerebral perfusion pressure (CPP) by the use of a tilt-table. Chemical vasomotor control of CBF was tested by inhalation of 7% CO 2 + air and voluntary hyperventilation. Following the injection of PPL, cerebrovascular resistance was significantly increased when autoregulation was tested by raising CPP. The autoregulation index decreased significantly during the head-down position and tended to increase during the head-up position, but the latter trend did not reach the level of statistical significance. The chemical regulation index was not altered by propranolol during changes of Pa co co2 . These results support the view that beta-adrenergic innervation influences cerebral metabolism as well as exerting a tonic cerebral vasodilator tonus. Hence, intracarotid injection of PPL blocks the beta-adrenergic dilator tonus and CBF and oxidative metabolism decrease. Likewise, the ability of cerebral vessels to constrict is improved when CPP is increased since cerebral vasoconstrictor tonus is enhanced. When CPP is lowered, cerebral autoregulation is unchanged or worsens. Chemical regulation of CBF to changes in Pa co co2 , is unchanged by beta blockade.

✓ A supratentorial cyst in the leptomeninges of an 8-month-old infant was studied with the electron microscope. The lining of the cyst consisted of a single layer of pegshaped epithelial cells rich in organelles and glycogen. Their free border had numerous microvilli but no cilia, and their basal portions rested on a basement membrane. Tight junctions and interdigitations were frequent between contiguous cells. The blood vessels were fenestrated. Since these features characterize developing choroidal epithelial cells, we felt the diagnosis of choroidal epithelial cyst was justified. Cysts lined by choroidal epithelium may continue to secrete cerebrospinal fluid after surgical extirpation when this is incomplete. Accumulation of the fluid in the partially excised cyst bed may therefore account for recurrence of symptoms.

脳血管壁に分布する自律神経と上頚神経節との関連を明らかにする目的で同神経節摘出後の中大脳動脈 (MCA) 及び椎骨動脈 (VA) 壁神経終末の電顕像を定量的に検討した.【方法】ネコ5匹を用い一側上頚神経節摘出3週後に5-hydroxydoparnineを静注し15分後にglutaraldehydeにて灌流固定し, 両側MCA起始部及びVA (PICA分岐部) より切片を作成し, これら4本の血管壁に含まれる神経終末内のadrenergic及びnon-adrenergic vesicleの最大径を画像解析装置 (Luzex 500) にて測定した.対照群 (sham operation) 4匹についても同様に標本を作成した.【結果】MCA : 摘出側adrenergic vesicle (98.44±0.69nm, n=500) (M±SEM) は対側 (80.00±0.62nm, n=500) 及び対照 (82.25±0.78nm, n=400) に比し有意に大であり (p

Cerebral autoregulation was tested in 32 patients with various anatomical locations and stages of ischemic cerebrovascular disease. Cerebral perfusion pressure (CPP) was raised or lowered in a standard manner by the use of head-up tilting (induced hypotension) and head-down tilting (induced hypertension). Any impairment of cerebral autoregulation was analyzed quantitatively by the ratio of the change in cerebral blood flow (CBF) over the change in CPP. There was significant correlation between the degree of dysautoregulation whether CPP was increased or decreased. An inverse correlation was shown between the degree of dysautoregulation and the duration after the ischemic episode during both induced hypotension and hypertension. Patients with brainstem lesions including those with transient ischemic attacks (TIAs) showed a greater impairment of autoregulation which persisted longer than those with hemispheric lesions. Patients with severe cerebral hemispheric infarction showed greater impairment of autoregulation than those with minor hemispheric lesions. Dysautoregulation also was greater in patients with subcortical lesions compared to those with cortical lesions. Hypertensive patients showed significantly greater decreases in CBF and effective MABP during induced hypotension than normotensive patients although autoregulation index was the same. Thus, symptoms are more frequent in hypertensives because of greater changes in CPP. Paradoxical responses in CBF to changes in CPP occurred in six patients. These were noted in moderately severe lesions in relatively young patients with hypertension and deeply located cerebral or brainstem lesions in the subacute stage. The mechanisms which control cerebral autoregulation were discussed and the nervous structures situated in the deep cerebral regions and brainstem, possibly the central structures of the autonomic nervous system, were proposed to control autoregulation of CBF.