Abstract: The Mini-Mental State Examination (MMSE) has been criticized as being an insufficient screening test for patients with vascular cognitive impairment because of its insensitivity to visuospatial and executive functional deficits. The Montreal Cognitive Assessment (MoCA) was designed to be more sensitive to such deficits, and thus may be a superior screening instrument for vascular cognitive impairment. Twelve patients with extensive leukoaraiosis detected on magnetic resonance imaging (average age, 76.0 ± 8.7 years) underwent neurologic and cognitive testing, including MMSE and the Japanese version of the MoCA (MoCA-J). Accepted cutoff scores of <27 for the MMSE and <26 for the MoCA-J were taken to indicate cognitive impairment. Z-scores were calculated to evaluate the discriminating ability of individual MMSE and MoCA-J subtest scores. Although there was a strong correlation between the total MMSE and total MoCA-J scores (r = 0.90; P < .0001), MMSE scores were skewed toward the higher end of the range (range, 18-30; median, 28), whereas MoCA-J scores were normally distributed (range, 9-28; median, 21). Of the 7 patients with an unimpaired MMSE score, 6 (86%) had an impaired MoCA-J score. Z-scores were >5 for 4 MMSE subtests (orientation, registration, naming, and language) but for only 1 MoCA-J subtest (naming). The MoCA-J better discriminated cognitive status in subjects with extensive leukoaraiosis. Our findings suggest that the MoCA-J is more sensitive than the MMSE in screening for cognitive impairment in patients with subcortical vascular cognitive impairment.
Abstract: X-linked inhibitor of apoptosis protein (XIAP) blocks the apoptosis by binding to and inhibiting caspases-3, 7, and 9. XIAP is negatively regulated by the mitochondrial serine protease, HtrA2/Omi. The aim of this study was to investigate the role of XIAP and the relationship between XIAP and HtrA2/Omi in patients with Parkinson's disease or dementia with Lewy bodies. We conducted immunohistochemical studies on XIAP in formalin-fixed, paraffin-embedded sections from eight normal participants, 10 patients with Parkinson's disease, five patients with dementia with Lewy bodies, and seven patients with Alzheimer's disease, and then double-labeling immunohistochemistry for XIAP and HtrA2/Omi in sections from the Parkinson's disease and dementia with Lewy bodies cases. Brainstem-type and cortical Lewy bodies were intensely immunostained for XIAP, and XIAP immunoreactivity was localized to the halos of brainstem-type Lewy bodies and to the entire bodies of cortical Lewy bodies. Double immunofluorescence analyses showed that XIAP and HtrA2/Omi immunoreactivities were colocalized to both types of Lewy bodies. Our results suggest that XIAP may be partially associated with the pathogenesis of Parkinson's disease and dementia with Lewy bodies.
Abstract: With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. Vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease and is frequently responsible for the cognitive decline of the elderly. It is characterized by cerebrovascular white matter changes; thus, in order to investigate the underlying mechanisms involved in white matter changes, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. The purpose of this paper is to provide a comprehensive summary of the achievements made with the model that shows good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion. Detailed characterization of this model may help to decipher the substrates associated with impaired memory and move toward a more integrated therapy of vascular cognitive impairment.
Abstract: This paper describes the synthesis and biological evaluation of novel phenyldiazenyl benzothiazole (PDB) derivatives as probes for imaging neurofibrillary tangles (NFTs) in patients with Alzheimer's disease (AD). We successfully synthesized three PDB derivatives using a diazo coupling reaction. In binding experiments in vitro, the compounds displayed higher affinity for tau aggregates than for A[small beta] aggregates. In fluorescent staining experiments using AD brain sections, 9 visualized NFTs clearly. No-carrier-added radioiodinated PDB derivatives were successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivatives. [125I]9 labeled NFTs in sections of brain tissue from a patient with AD, but not a control. In biodistribution experiments using normal mice, the PDB derivatives displayed an uptake into the brain, sufficient for imaging NFTs, ranging from 0.94 to 3.2% ID g-1, but a relatively slow washout. Although further modifications are necessary to improve the pharmacokinetics in the brain, PDB with high affinity for tau aggregates may be useful as a backbone structure to develop agents for imaging NFTs in AD brains.
Abstract: BACKGROUND AND PURPOSE: The Cilostazol Stroke Prevention Study II has shown a similar efficacy in stroke prevention but markedly fewer hemorrhagic events with the phosphodiesterase inhibitor cilostazol versus aspirin. The purpose of this study is therefore to investigate how cilostazol affects cerebral hemodynamics and whether it prevents hemorrhagic transformation induced by recombinant tissue plasminogen activator (rtPA) in a mouse model of focal ischemia/reperfusion. Particular emphasis will be placed on the plasma-microvessel interface. METHODS: After receiving food containing 0.3% cilostazol or standard food for 7days, adult C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion with or without rtPA (10mg/kg) intravenously administered prior to reperfusion. Cerebral blood flow was monitored at several time points by laser speckle imaging in the 24 hour period post reperfusion, before neurobehavioral and histological assessment. The long-term effect of cilostazol on cerebral ischemia was analyzed in the non-rtPA cohort. RESULTS: In the non-rtPA cohort, pretreatment by cilostazol significantly decreased the endothelial expression of adhesion molecules (P-selectin and intercellular adhesion molecule-1) and prevented platelet aggregation and leukocyte plugging in the microvessels after cerebral ischemia/reperfusion in the acute phase. Cilostazol significantly reduced mortality rate and improved motor function at 7days post-ischemia/reperfusion. In the rtPA cohort, cilostazol significantly suppressed edema formation and hemorrhagic transformation with reduced density of microglial cells positive for matrix metalloproteinase-9 in the cerebral cortex and the striatum. In both cohorts, cilostazol significantly suppressed focal no-reflow, mitigated cerebral infarct, and improved neurological outcome. CONCLUSIONS: Cilostazol may possess protective properties against cerebral ischemic injury by preventing no-reflow and hemorrhagic transformation, via maintenance of microvascular integrity.
Abstract: The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased β-amyloid (Aβ) oligomers as well as Aβ deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.
Abstract: Cu/Zn superoxide dismutase (SOD1) is a major component of Lewy body-like hyaline inclusion (LBHI) found in the postmortem tissue of SOD1-linked familial amyotrophic lateral sclerosis (FALS) patients. In our recent studies, 14-3-3 proteins have been found in the ubiquitinated inclusions inside the anterior horn cells of spinal cords with sporadic amyotrophic lateral sclerosis (ALS). To further investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical analysis of 14-3-3 proteins and compared their distributions with those of SOD1 in FALS patients and SOD1-overexpressing mice.
Abstract: Approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases are linked to mutations in the antioxidant enzyme, Cu/Zn superoxide dismutase (SOD1). Controversy exists as to whether SOD1-related FALS and sporadic ALS (SALS) share common mechanistic pathways, since very few SOD1-related FALS cases exhibit cytoplasmic inclusions composed of 43-kDa TAR DNA-binding protein (TDP-43), a pathologic hallmark of SALS and SOD1-unrelated FALS.(1,2,e1,e2) We describe prominent TDP-43 pathology in the spinal cord of a patient with SOD1-related ALS with SOD1 I112T mutation, a relatively uncommon variant form leading to rapid disease progression.(3).
Abstract: Recently, we have reported that a vasoactive peptide adrenomedullin promotes angio/arteriogenesis and prevents cognitive decline after chronic cerebral hypoperfusion in mice. Adrenomedullin upregulated brain levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, although the regulation mechanism needs to be determined. In this study, we showed that VEGF neutralization partially suppressed adrenomedullin-induced neovascularization and cognitive restoration in vivo. In-vitro, adrenomedullin promoted capillary tube formation of the cultured endothelium, whereas VEGF neutralization abolished these effects. Adrenomedullin was found to upregulate VEGF and basic fibroblast growth factor through the adrenomedullin receptor and the phosphatidylinositol 3-kinase pathway. These results suggest that adrenomedullin has potential as therapy for dementia through enhancement of functional vascular growth.
Abstract: It has long been debated whether watershed infarcts are caused by hemodynamic or embolic mechanisms. In the present study, we investigated microembolic roles in the pathogenesis of watershed infarcts by examining MRI in a macaque monkey model of multiple microinfarcts. 50μm microbeads were injected into each internal carotid artery twice with a month interval. Monkeys (n=4) injected with 2250-2800 microbeads per unilateral side showed both cortical and internal watershed infarcts in the acute phase and atrophic changes with microbleeds in the chronic phase. These results suggest embolic pathogenesis can contribute to the genesis of both cortical and internal watershed infarcts in primates.
Abstract: We investigated a family manifesting amyotrophic lateral sclerosis (ALS) with a heterozygous E478G mutation in the optineurin (OPTN) gene. Clinically, slow deterioration of motor function, mood and personality changes, temporal lobe atrophy on neuroimaging, and bizarre finger deformity were noted. Neuropathologically, TAR DNA-binding protein 43 (TDP-43)-positive neuronal intracytoplasmic inclusions were observed in the spinal and medullary motor neurons. In these cells, the immunoreactivity of nuclear TDP-43 was reduced. Consecutive sections revealed that the inclusions were also reactive with anti-ubiquitin and anti-p62 antibodies, but noticeably negative for OPTN. In addition, TDP-43/p62-positive glial cytoplasmic inclusions (GCIs) were scattered throughout the spinal cord and the medullary motor nuclei. Furthermore, Golgi fragmentation was identified in 70% of the anterior horn cells (AHCs). The presence of AHCs with preserved nuclear TDP-43 and a fragmented Golgi apparatus, which are unrecognizable in sporadic ALS, indicates that patients with the E4787G OPTN mutation would manifest Golgi fragmentation before loss of nuclear TDP-43. In the neocortex, GCIs were sparsely scattered among the primary motor and temporal cortices, but no neuronal TDP-43-positive inclusions were detected. In the amygdala and the ambient gyrus, argyrophilic grains and ballooned neurons were seen. The thorough neuropathologic investigations performed in this work demonstrated that OPTN-positive inclusion bodies, if any, were not prominent. We postulate that optineurinopathy is closely linked with TDP-proteinopathy and speculate that this heterozygous E478G mutation would cause ALS by acting through a dominant-negative mechanism.
Abstract: Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia.
Abstract: Cognitive impairment resulting from cerebrovascular insufficiency has been termed vascular cognitive impairment, and is generally accepted to be distinct from Alzheimer's disease resulting from a neurodegenerative process. However, it is clear that this simple dichotomy may need revision in light of the apparent occurrence of several shared features between Alzheimer's disease and vascular cognitive impairment. Nevertheless, it still remains largely unknown whether the burden of vascular- and Alzheimer-type neuropathology are independent or interdependent. Therefore, we investigated whether chronic cerebral hypoperfusion influences cognitive ability or amyloid β deposition in amyloid precursor protein (APP) overexpressing transgenic mice.
Abstract: Rats subjected to bilateral common carotid artery (CCA) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia. However, this model possesses an inherent limitation in that cerebral blood flow (CBF) drops too sharply and substantially after ligation of CCAs. To circumvent such hypoxic-ischemic conditions, we tested implantation of the ameroid constrictor device on bilateral CCAs of male Wistar-Kyoto rats and more precisely replicated chronic cerebral hypoperfusion by gradual narrowing of the CCAs (2-vessel gradual occlusion; 2VGO). The acute cerebral blood flow reduction and resultant inflammatory responses observed in the 2VO rats were eliminated in the 2VGO rats. Thus, chronic cerebral hypoperfusion was segregated, and induced selective white matter changes with relatively preserved neurovascular coupling and substantially less metabolic and histological derangements in the gray matter including the hippocampus. This led to significant spatial working memory impairment of a magnitude similar to the 2VO rats at 28 days postoperation. The 2VGO model may more closely mimic cognitive impairment subsequent to selective white matter damage.
Abstract: The integrity of the white matter is critical in regulating efficient neuronal communication and maintaining cognitive function. Damage to brain white matter putatively contributes to age-related cognitive decline. There is a growing interest in animal models from which the mechanistic basis of white matter pathology in aging can be elucidated but to date there has been a lack of systematic behavior and pathology in the same mice. Anatomically widespread, diffuse white matter damage was induced, in 3 different cohorts of C57Bl/6J mice, by chronic hypoperfusion produced by bilateral carotid stenosis. A comprehensive assessment of spatial memory (spatial reference learning and memory; cohort 1) and serial spatial learning and memory (cohort 2) using the water maze, and spatial working memory (cohort 3) using the 8-arm radial arm maze, was conducted. In parallel, a systematic assessment of white matter components (myelin, axon, glia) was conducted using immunohistochemical markers (myelin-associated glycoprotein [MAG], degraded myelin basic protein [dMBP], anti-amyloid precursor protein [APP], anti-ionized calcium-binding adapter molecule [Iba-1]). Ischemic neuronal perikarya damage, assessed using histology (hematoxylin and eosin; H&E), was absent in all shams but was present in some hypoperfused mice (2/11 in cohort 1, 4/14 in cohort 2, and 17/24 in cohort 3). All animals with neuronal perikaryal damage were excluded from further study. Diffuse white matter damage occurred, throughout the brain, in all hypoperfused mice in each cohort and was essentially absent in sham-operated controls. There was a selective impairment in spatial working memory, with all other measures of spatial memory remaining intact, in hypoperfused mice with selective white matter damage. The results demonstrate that diffuse white matter pathology, in the absence of gray matter damage, induces a selective impairment of spatial working memory. This highlights the importance of assessing parallel pathology and behavior in the same mice.
Abstract: Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer's disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer's disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm(2) in mild, 0.584/cm(2) in moderate, and 4.370/cm(2) in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs.
Abstract: The aim of this study was to characterize myelin loss as one of the features of white matter abnormalities across three common dementing disorders. We evaluated post-mortem brain tissue from frontal and temporal lobes from 20 vascular dementia (VaD), 19 Alzheimer's disease (AD) and 31 dementia with Lewy bodies (DLB) cases and 12 comparable age controls. Images of sections stained with conventional luxol fast blue were analysed to estimate myelin attenuation by optical density. Serial adjacent sections were then immunostained for degraded myelin basic protein (dMBP) and the mean percentage area containing dMBP (%dMBP) was determined as an indicator of myelin degeneration. We further assessed the relationship between dMBP and glutathione S-transferase (a marker of mature oligodendrocytes) immunoreactivities. Pathological diagnosis significantly affected the frontal but not temporal lobe myelin attenuation: myelin density was most reduced in VaD compared to AD and DLB, which still significantly exhibited lower myelin density compared to ageing controls. Consistent with this, the degree of myelin loss was correlated with greater %dMBP, with the highest %dMBP in VaD compared to the other groups. The %dMBP was inversely correlated with the mean size of oligodendrocytes in VaD, whereas it was positively correlated with their density in AD. A two-tier regression model analysis confirmed that the type of disorder (VaD or AD) determines the relationship between %dMBP and the size or density of oligodendrocytes across the cases. Our findings, attested by the use of three markers, suggest that myelin loss may evolve in parallel with shrunken oligodendrocytes in VaD but their increased density in AD, highlighting partially different mechanisms are associated with myelin degeneration, which could originate from hypoxic-ischaemic damage to oligodendrocytes in VaD whereas secondary to axonal degeneration in AD.
Abstract: To investigate the efficacy of bone marrow mononuclear cell (BMMNC) treatment against ischemic white matter (WM) damage in a hypoperfused brain.
Abstract: The effect of telmisartan, an angiotensin II Type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma-modulating activity, was investigated against spatial working memory disturbances in mice subjected to chronic cerebral hypoperfusion.
Abstract: We are reporting a 36 year-old woman, gravid 3, para 1, aborta 2, who was 18 weeks pregnant and developed a sudden onset of motor aphasia and hemiparesis on the right side. On the initial visit to our hospital, the NIH stroke scale was 6, and the brain MRI revealed high intensity areas in the left insular cortex and the periventricular white matter with occlusion of the left middle cerebral artery (MCA) branches. We diagnosed her as having cerebral embolism, and treated with intravenous recombinant tissue plasminogen activator (rt-PA) with subsequent recanalization of the occuluded left MCA branches. Her motor aphasia and hemiparesis disappeared within a few hours of initiating the therapy. She received aspirin for four months and then heparin until delivery to prevent recurrence. She delivered a healthy term infant without any apparent complications. An 18-week pregnancy itself is not considered a risk factor of stroke, and we ruled out the possibilities of dysfibrinogenemia, homocysteinemia, hereditary or acquired deficiencies of protein C, protein S, and antithrombin III deficiencies, and antiphospholipid antibody syndrome. However, her plasma factor VIII level was significantly elevated to more than 200% (reference for 18-week pregnant woman: 151 +/- 44%), which may have led to her acquired activated protein C resistance or hypercoagulability. As safety of thrombolytic therapy with rt-PA during pregnancy has not been established, this therapy could be carefully used upon due consideration of risks and benefits for both mother and fetus.
Abstract: We have previously described effects of chronic cerebral hypoperfusion in mice with bilateral common carotid artery stenosis (BCAS) using microcoils for 30 days. These mice specifically exhibit working memory deficits attributable to frontal-subcortical circuit damage without apparent gray matter changes, indicating similarities with subcortical ischemic vascular dementia. However, as subcortical ischemic vascular dementia progresses over time, the longer-term effects that characterize the mouse model are not known.
Abstract: Cortical microinfarcts are reported in Alzheimer's disease, but not in subcortical vascular dementia; the disease specificity of cortical microinfarcts therefore remains unclear. The distribution of cortical microinfarcts in Alzheimer's disease (n = 8) and subcortical vascular dementia (n = 6) was analyzed. Cortical microinfarcts were frequently detected in Alzheimer's disease, whereas they were rarely observed in subcortical vascular dementia. In Alzheimer's disease, cortical microinfarcts were present predominantly in the occipital lobe, the area of predilection for amyloid angiopathy, and also in the vascular borderzone. Cortical microinfarcts were invariably located very close to amyloid beta-deposited vessels with intercellular adhesion molecule-1 expression. These results indicate that cortical microinfarcts are caused by the pathomechanism related to Alzheimer's disease, most likely to amyloid angiopathy.
Abstract: Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid beta deposition in amyloid protein precursor transgenic (APP-Tg) mouse. At 5, 8, and 11 months of age, C57Bl/6J male mice overexpressing a mutant form of the human APP bearing the both Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd) and their litterrmates were subjected to either sham operation or bilateral carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm (short-period group). One month after the sham operation or BCAS, these animals were examined by immunohistochemistry for glial fibrillary acidic protein, amyloid beta(1-40) (Abeta(1-40)), amyloid beta(1-42) (Abeta(1-42)), as well as Western blotting and filter assay for Abeta. Another batch of the littermates of APPSwInd mice were subjected to either sham operation or BCAS at 3 months and were examined in the same manner after survival for 9 months (long-period group). In the BCAS-treated group, the white matter was rarefied and astroglia was proliferated. Amyloid beta(1-40) immunoreactivity was found in a few axons in the white matter after BCAS, whereas Abeta(1-42) was accumulated in the scattered cortical neurons and the axons at ages of 6 months and thereafter in the short- and long-period groups. In the neuropil, both Abeta(1-40) and Abeta(1-42) were deposited in the sham-operated and BCAS-treated mice at ages of 9 and 12 months. There were no differences between the short-period group at ages of 12 months and the long-period group. Filter assay showed an increase of Abeta fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased Abeta fibrils and induced Abeta deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease.
Abstract: The biological agent tocilizumab, is a humanized, anti-human interleukin-6 receptor antibody. A 72-year-old woman developed cognitive impairment during the Phase III clinical trial of tocilizumab for the treatment of rheumatoid arthritis. MRI demonstrated hyperintense dissemination throughout the white matter on T2WI. An initial diagnosis of possible progressive multifocal leukoencephalopathy was made, but the PCR for JC virus DNA was negative in the CSF. The leukoencephalopathy might have been caused by a mechanism related to tocilizumab itself. It is strongly recommended to perform MRI if a patient develops any cognitive impairment during tocilizumab therapy.
Abstract: Cytoskeletal polymers are component of cellular infrastructure that are required for fundamental biological processes ranging from cell division to brain functions. Unlike the knowledge available for tubulin and actin, our understanding of unconventional cytoskeletal structures composed of GTP-binding proteins belonging to the septin family is limited, despite their ubiquity and implications in human diseases. Recent studies have revealed that septin plays unique modulatory roles as an accessory component of microtubules and the actin cytoskeleton. Morphological analyses of the mammalian brain and neural cells have revealed that septins preferentially cluster beneath the extra-synaptic membrane domains in dendritic shafts and spine necks, presynaptic terminals of major neurons, and astroglial processes. Live imaging analysis revealed that septin polymers are remarkably stable in these clusters, which may serve as local cytoskeleton and/or scaffold for the organization of specialized cortical domains in neurons and glia. This hypothesis has been supported by the hypo-dopaminergic phenotype of mice that lack the Sept4 subunit and the hyper-dopaminergic phenotype of those with excess Sept4. In these cases, the septin scaffold in the dopamine neurons is considered as a determinant of the quantity of a subset of presynaptic molecules, including tSNAREs (membrane-fusion machinery) and the dopamine transporters. This finding in mouse models is in agreement with the recent findings that qualitative and/or quantitative dysregulation of septins is involved in neurodegenerative disorders such as Parkinson disease and psychological disorders such as schizophrenia and bipolar disorder. Studies on tubulin/actin indicate that a better understanding of the septin family of proteins will improve our insight into neuropathological phenomena in neurodegenerative and psychological disorders, which may help develop diagnostic markers and therapeutic strategies for such diseases.
Abstract: White matter (WM) hyperintensities on MRI or leukoaraiosis is characteristic of stroke syndromes. Increased MRI signals in the anterior temporal pole are suggested to be diagnostic for cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with 90% sensitivity and 100% specificity. The structural correlates of these specific WM hyperintensities seen on T2-weighted and FLAIR sequences in the temporal pole of CADASIL are unclear. We assessed pathological changes in postmortem tissue from the temporal pole to reveal the cause of CADASIL-specific WM hyperintensities.
Abstract: White matter lesions are frequently observed in the elderly, and have been postulated to be responsible for dementia and parkinsonism. At first, we revealed that cholinergic pathways are damaged in the external capsule due to white matter lesions in Binswanger's disease. In addition, a flumazenil (FMZ)-PET study, a marker of benzodiazepine/GABAA receptors, revealed that FMZ-binding was decreased in the prefrontal cortex and the insular cortex in demented patients with extensive white matter lesions. In contrast, FMZ-binding was decreased in the premotor cortex and the striatum in the patients with extensive white matter lesions and parkinsonism, as compared to those with white matter lesions but without parkinsonism. These results indicate that subcortical nerve fiber damages may impair neural networks and hence, the neural function in the corresponding gray matter.
Abstract: Septins are the major constituents of the annulus, a submembranous ring that separates the middle and principal pieces of spermatozoa. We previously reported its essential role in spermiogenesis and reproduction in mice. In the current study we investigated septin abnormality in infertile men.
Abstract: We recently designed a mouse model of chronic cerebral hypoperfusion, in which the cerebral white matter is damaged without significant gray matter lesions. The behavioral characteristics of these mice were studied using a test battery for neurological and cognitive functions.
Abstract: The purpose of this study is to identify the underlying differences between patients with white matter lesions (WMLs) who manifested gait disturbance suggestive of vascular parkinsonism (VaP) and those who did not, using the PET scan. Fourteen patients with extensive WMLs, as determined by MRI, were divided into two groups - 7 with gait disturbance and 7 without it. Neuronal integrity was evaluated with a PET scan using [(11)C]flumazenil (FMZ) by calculating the distribution volume of FMZ (FMZ-V(d)) in various regions of interest by non-linear curve fitting. Additionally, tracer kinetic analysis was applied for voxel-by-voxel quantification of FMZ-V(d) and data analysis was performed using statistical parametric mapping. The striatal FMZ-V(d) values were inversely correlated with the motor UPDRS scores (r = 0.70, p < 0.005), and their reductions were associated with the presence of gait disturbance. Therefore, differences in neuronal integrity in the striatum may determine whether patients with WMLs develop VaP or not.
Abstract: Morphological abnormalities of the cortical microvessels have been reported in Alzheimer's disease (AD), but not in Binswanger's disease (BD), a form of vascular dementia. Therefore, we compared the capillary beds in AD and BD brains, using a modified Gallyas silver impregnation method and immunohistochemistry for beta amyloid. Eight autopsied brains with AD and seven with BD were compared with six control brains. The cortical microvessels in AD were frequently narrowed, and torn off, especially in close proximity to the senile plaques. The capillary densities in AD were significantly decreased as compared with the control brains. In contrast, there were no significant changes in the capillary densities and their morphologies in BD brains. Immunohistochemistry for beta amyloid revealed numerous deposits in the vascular wall and perivascular neuropil exclusively in AD brains. Cortical microvascular changes in AD and their absence in BD may indicate a role of beta amyloid for the microvessel pathology in AD.
Abstract: In Parkinson disease (PD), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PD model, insoluble deposits of Ser129-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser129 phosphorylation. Taken together, these data show that Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.
Abstract: Gluten sensitivity is associated with multiple neurological abnormalities including gluten ataxia, motor neuron disease-like neuropathy, small fiber type neuropathy, cognitive impairment, and even parkinsonism. We investigated whether or not gluten sensitivity is involved in Japanese patients with idiopathic cerebellar ataxia with extracerebellar presentation.
Abstract: alpha-Synuclein is a major constituent of Lewy bodies, the neuropathological hallmark of Parkinson's disease (PD). Three types of alpha-synuclein mutations, A53T, A30P, and E46K, have been reported in familial PD. Wild-type alpha-synuclein accumulates at high concentrations in Lewy bodies, and this process is accelerated with mutated A53T alpha-synuclein. The accumulation of alpha-synuclein is thought to be toxic, and causes neuronal death when alpha-synuclein aggregates into protofibrils and fibrils. Lewy bodies contain not only alpha-synuclein, but also other proteins including 14-3-3 proteins and synphilin-1. 14-3-3 Proteins exist mainly as dimers and are related to intracellular signal transduction pathways. Synphilin-1 is known to interact with alpha-synuclein, promoting the formation of cytoplasmic inclusions like Lewy bodies in vitro. To investigate the colocalization of alpha-synuclein, synphilin-1, and 14-3-3 proteins, we performed immunohistochemical studies on alpha-synuclein, 14-3-3 proteins, and synphilin-1 in the brain and spinal cord of A53T transgenic mice. In homozygous mouse brains, alpha-synuclein immunoreactivity was observed in the neuronal somata and processes in the medial part of the brainstem, deep cerebellar nuclei, and spinal cord. The distribution of 14-3-3 proteins and synphilin-1 immunoreactivity was similar to that of alpha-synuclein in the homozygous mice. Double immunofluorescent staining showed that alpha-synuclein and synphilin-1 or 14-3-3 proteins were colocalized in the pons and spinal cord. These results indicate that the accumulation of mutant alpha-synuclein occurs in association with 14-3-3 proteins and synphilin-1, and may cause the sequestration of important proteins including 14-3-3 proteins and synphilin-1. The sequestration and subsequent decrease in 14-3-3 proteins and synphilin-1 levels may account for neuronal cell death.
Abstract: Cerebrovascular white matter (WM) lesions contribute to cognitive impairment and motor dysfunction in the elderly. A disruption of the blood-brain barrier (BBB) is believed to be a critical early event leading to these WM lesions. Previous studies have suggested the involvement of matrix metalloproteinase-2 (MMP-2) in BBB disruptions and the upregulation of MMP-2 after chronic cerebral hypoperfusion in a rat model. In the present study, we asked whether MMP-2 is involved in the BBB disruption and the subsequent WM lesions after chronic cerebral hypoperfusion.
Abstract: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary small artery disease which is phenotypically similar to Binswanger's disease (BD), a nonhereditary form of small artery disease. Recent studies have indicated that lesions in the temporopolar, medial frontopolar areas and external capsule are frequently seen in Caucasian patients with CADASIL. However, it remains unclear whether magnetic resonance (MR) imaging findings are helpful in diagnosing small artery disease outside countries with Caucasian populations, since CADASIL is rare despite the high prevalence of small artery disease in Japan. We examined 58 patients with small artery disease, all of whom were devoid of major vessel occlusion or severe stenosis. These patients included 7 patients from 3 families with CADASIL, 27 nondemented patients with extensive leukoaraiosis (LA) and 24 patients with BD. On T(2)-weighted MR images, hyperintensities in the temporopolar areas were observed in all 7 patients with CADASIL, whereas these lesions were observed in only 1 subject from each of the nondemented LA and BD groups. Hyperintensities in the medial frontopolar areas were seen in 4 of the 7 patients with CADASIL (57%) and in 14 of the 24 patients with BD (58%), and were more frequent than in the nondemented LA group (4 of the 27 patients; 15%). In contrast, hyperintensities in the external capsule were frequently observed in all groups. Therefore, temporopolar lesions can also serve as diagnostic markers for CADASIL in non-Caucasian patients.
Abstract: Septins are polymerizing GTP binding proteins required for cortical organization during cytokinesis and other cellular processes. A mammalian septin gene Sept4 is expressed mainly in postmitotic neural cells and postmeiotic male germ cells. In mouse and human spermatozoa, SEPT4 and other septins are found in the annulus, a cortical ring which separates the middle and principal pieces. Sept4-/- male mice are sterile due to defective morphology and motility of the sperm flagellum. In Sept4 null spermatozoa, the annulus is replaced by a fragile segment lacking cortical material, beneath which kinesin-mediated intraflagellar transport stalls. The sterility is rescued by injection of sperm into oocytes, demonstrating that each Sept4 null spermatozoon carries an intact haploid genome. The annulus/septin ring is also disorganized in spermatozoa from a subset of human patients with asthenospermia syndrome. Thus, cortical organization based on circular assembly of the septin cytoskeleton is essential for the structural and mechanical integrity of mammalian spermatozoa.
Abstract: Septins are evolutionarily conserved GTP-binding proteins that can heteropolymerize into filaments. Recent studies have revealed that septins are involved in not only diverse normal cellular processes but also the pathogenesis of various diseases, including cancer. SEPT6 is ubiquitously expressed in tissues and one of the fusion partner genes of MLL in the 11q23 translocations implicated in acute leukemia. However, the roles of this septin in vivo remain elusive. We have developed Sept6-deficient mice that exhibited neither gross abnormalities, changes in cytokinesis, nor spontaneous malignancy. Sept6 deficiency did not cause any quantitative changes in any of the septins evaluated in this study, nor did it cause any additional changes in the Sept4-deficient mice. Even the depletion of Sept11, a close homolog of Sept6, did not affect the Sept6-null cells in vitro, thus implying a high degree of redundancy in the septin system. Furthermore, a loss of Sept6 did not alter the phenotype of myeloproliferative disease induced by MLL-SEPT6, thus suggesting that Sept6 does not function as a tumor suppressor. To our knowledge, this is the first report demonstrating that a disruption of the translocation partner gene of MLL in 11q23 translocation does not contribute to leukemogenesis by the MLL fusion gene.
Abstract: We sought to determine the changes in the cholinergic pathways, which project from the nucleus basalis of Meynert (nBM) and travel in the subinsular region, in vascular dementia of the Binswanger type (VDBT) and Alzheimer's disease (AD). The subinsular regions were examined in 6 autopsied brains with VDBT, 5 brains with AD and 4 control brains without any neurologic diseases. The cholinergic pathway was labeled either by histochemistry for acetylcholine esterase (AChE), a degradatory enzyme of ACh, or by immunohistochemistry for choline acetyltransferase, its synthetic enzyme. The numerical density of nBM neurons did not differ significantly between these groups (163 +/- 49 in the VDBT, 105 +/- 82 in the AD and 198 +/- 76 in the control groups), but with a tendency towards a decrease in the AD group. The subinsular cholinergic fibers were impaired, with relative preservation of the nBM neurons in VDBT, whereas both the subinsular cholinergic fibers and the nBM neurons were degraded in AD. These results indicate that the cholinergic pathway is damaged not only in AD, but also in VDBT, and may further provide a pharmacological basis for treatment with AChE inhibitors in VDBT.
Abstract: Cerebrovascular white matter (WM) lesions are closely associated with cognitive impairment and gait disorders in the elderly. We have successfully established a mouse model of chronic cerebral hypoperfusion that may provide new strategies for the molecular analysis of cerebrovascular WM lesions.
Abstract: Previous neuroimaging studies have indicated that corpus callosum atrophy in Alzheimer's disease (AD) and large vessel occlusive disease (LVOD) is caused by interhemispheric disconnection, namely Wallerian degeneration of interhemispheric commissural nerve fibers originating from pyramidal neurons in the cerebral cortex. However, this hypothesis has not been tested from a neuropathological viewpoint. In the present study, 22 brains with AD (presenile onset, 9; senile onset, 13), 6 brains with Binswanger's disease (BD), a form of vascular dementia and 3 brains with LVOD were compared with 6 non-neurological control brains. White matter lesions in the deep white matter and corpus callosum were quantified as a fiber density score by image analysis of myelin-stained sections. Axonal damage and astrogliosis were assessed by immunohistochemistry for amyloid precursor protein and glial fibrillary acidic protein, respectively.The corpus callosum thickness at the anterior part of the body was decreased in AD and LVOD,but not in BD significantly, as compared with the controls. The corpus callosum thickness correlated roughly with brain weight in AD (R=0.50),and with the severity of deep white matter lesions in BD (R=0.81). Atrophy of the brain and corpus callosum was more marked in presenile onset AD than in senile onset AD. With immunohistochemistry, the corpus callosum showed axonal damage and gliosis with a decreased fiber density score in BD and LVOD, but not in AD. Thus, corpus callosum atrophy was correlated with brain atrophy in AD, which is relevant to the mechanism of interhemispheric disconnection,whereas corpus callosum lesions in BD were secondary to deep white matter lesions. Corpus callosum atrophy in LVOD may indicate interhemispheric disconnection, but focal ischemic injuries may also be involved.
Abstract: [11C]flumazenil (FMZ), a ligand that selectively binds to the central benzodiazepine receptor in the neuronal membrane, is useful for evaluating neuronal viability in a positron emission tomography (PET) scan. Using this ligand, we investigated whether there was a correlation between neuronal integrity in various brain structures and dementia in patients with leukoaraiosis.
Abstract: 11C-Flumazenil ((11)C-FMZ) is useful to estimate central benzodiazepine receptors by PET. The binding potential (BP) can be calculated with dynamic PET and continual blood sampling. Because conventional metabolite analysis of plasma samples is complicated and time consuming, a simple method is required to obtain an input function. In this article, a whole blood solvent extraction method was evaluated using data of 13 subjects.
Abstract: alpha-Synuclein-positive cytoplasmic inclusions are a pathological hallmark of several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Here we report that Sept4, a member of the septin protein family, is consistently found in these inclusions, whereas five other septins (Sept2, Sept5, Sept6, Sept7, and Sept8) are not found in these inclusions. Sept4 and alpha-synuclein can also be co-immunoprecipitated from normal human brain lysates. When co-expressed in cultured cells, FLAG-tagged Sept4 and Myc-tagged alpha-synuclein formed detergent-insoluble complex, and upon treatment with a proteasome inhibitor, they formed Lewy body-like cytoplasmic inclusions. The tagged Sept4 and alpha-synuclein synergistically accelerated cell death induced by the proteasome inhibitor, and this effect was further enhanced by expression of another Lewy body-associated protein, synphilin-1, tagged with the V5 epitope. Moreover, co-expression of the three proteins (tagged Sept4, alpha-synuclein, and synphilin-1) was sufficient to induce cell death. These data raise the possibility that Sept4 is involved in the formation of cytoplasmic inclusions as well as induction of cell death in alpha-synuclein-associated neurodegenerative disorders.
Abstract: Cerebrovascular white matter (WM) lesions, which are frequently observed in vascular cognitive impairment and vascular dementia, can be produced in rats by clipping the common carotid arteries bilaterally. Since TNF-alpha is known to cause the degeneration of myelin, we examined whether these lesions can be ameliorated by ibudilast, a cyclic AMP phosphodiesterase (PDE) inhibitor that suppresses tumor necrosis factor (TNF)-alpha production. After the ligation of both common carotid arteries in 29 rats, 21 rats received a daily oral administration of 10, 30 or 60 mg/kg ibudilast and 8 rats received vehicle for 14 days. The pathological changes in the white matter were quantified in terms of white matter lesions and the emergence of activated microglia immunoreactive for major histocompatibility complex (MHC) antigen. In the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. A low dose (10 mg/kg) of ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg ibudilast ameliorated these lesions (p<0.001). Without an alterations in laboratory blood data, 60 mg/kg ibudilast exhibited percent reduction of the white matter lesions ranging between 50% and 70%, which was more effective than 30 mg/kg ibudilast (p<0.05). The TNF-alpha immunoreactive glia decreased in number in the 60 mg/kg ibudilast-treated group as compared to the vehicle-treated group (p<0.001). These results indicate a dose-dependent protective effect of ibudilast against cerebrovascular white matter lesions and suggest a potential use for ibudilast in the treatment of vascular dementia.
Abstract: Prostaglandins and leukotrienes (eicosanoids), metabolites of the arachidonic acid pathway, are subjected to altered synthesis or relocation after an ischemic insult. Although cyclooxygenase (COX) expression has been reported in human cerebral ischemia, no information is available on the expression of 5-lipoxygenase (5-LO) and its topographical correlation to COX induction. The objective of this study was to elucidate the comparative distribution of eicosanoids in ischemic tissues. COX and 5- LO, key enzymes for the synthesis of prostaglandins and leukotrienes, respectively, were examined in autopsied brains. COX1 was expressed intensely in the microglia but weakly in the neurons in control brains. These COX1-immunoreactive microglia showed a more activated form following ischemic damage and hypoxemia. In contrast, COX2 was absent in the control brains, and was induced robustly in the neuronal cell bodies and dendrites during the acute stages of focal ischemic damage, and then subsided at the subacute stages. These COX2-immunoreactive neurons accumulated in the peri-infarct regions, but were absent from the distant regions. In focal ischemic damage and Binswanger's disease, COX2 was up-regulated in the microglia. Neuronal immunostaining for 5-LO was up-regulated occasionally during hypoxemia and focal ischemic damage. Glial cells immunoreactive for 5-LO appeared in the foci of the ischemic damage, with small blood vessels being infiltrated by 5-LO-immunoreactive mononuclear leukocytes. These findings indicate that the isozymes of COX are differentially regulated depending on the cellular source and the types of ischemic damage, and that vascular 5-LO may accelerate the migration of leukocytes and augment the blood-brain barrier permeability. The possibility of increased substrate availability for the other should be noticed in specific inhibition of either COX or 5-LO since these two enzymes are accumulated in parallel in ischemic tissues.
Abstract: The authors describe a patient with dopa-responsive dystonia who developed neuroleptic malignant syndrome with prolonged catatonia following treatment with neuroleptic agents. Use of these agents probably expanded the patient's neuronal dysfunction beyond the nigrostriatal system to involve multiple dopaminergic systems. Electroconvulsive treatment alleviated the prolonged catatonia.
Abstract: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant muscle disease with a worldwide distribution. Recent findings reveal the genetic basis of this disease to be mutations in the polyA binding-protein 2 (PABP2) gene that involve short expansions of the GCG trinucleotide repeat encoding a polyalanine tract. The underlying mechanism causing the triplet-expansion mutation in PABP2 remains to be elucidated, although the DNA slippage model is thought to be a plausible explanation of that.
Abstract: Cerebral white matter (WM) lesions are observed frequently in human ischemic cerebrovascular disease and have been thought to contribute to cognitive impairment. This type of lesion can be experimentally induced in rat brains under chronic cerebral hypoperfusion by the permanent occlusion of both common carotid arteries. However, it remains uncertain whether chronic ischemia can damage both the gray and white matter, and whether it can induce demyelination with or without axonal damage. Therefore, we examined axonal damage using immunohistochemistry for the amyloid beta/A4 precursor protein (APP), chromogranin A (CgA) and demyelination using immunohistochemistry for the encephalitogenic peptide (EP) in this model. Severe WM lesions such as vacuolation and the loss of nerve fibers appeared in the optic nerve and optic tract after 3 days of ligation, and less intense changes were observed in the corpus callosum, internal capsule, and fiber bundles of the caudoputamen after 7 days with Klüver-Barrera and Bielschowsky staining. These WM lesions persisted even after 30 days. The APP, CgA, and EP-immunopositive fibers increased in number from 1 to 30 days after the ligation in the following WM regions: the optic nerve, optic tract, corpus callosum, internal capsule, and fiber bundles of the caudoputamen. In contrast, only a few APP, CgA, or EP-immunopositive fibers were detected in the gray matter regions, including the cerebral cortex and hippocampus. These results indicate that the WM is more susceptible to chronic cerebral hypoperfusion than the gray matter, with an involvement of both axonal and myelin components. Furthermore, immunohistochemistry for APP, CgA, and EP is far superior to routine histological staining in sensitivity and may become a useful tool to investigate WM lesions caused by various pathoetiologies.
Abstract: Using a signal sequence trap method and database search, we identified a series of human cDNAs encoding two structurally related type I membrane proteins of approximately 25 kDa with multiple glycosylation motifs. These genes, termed endomucin-1/-2, are expressed in several human tissues including heart, kidney, and lung. Exogenously expressed human endomucin-1/-2 proteins were modified into 80-120 kDa glycoproteins, which were susceptible to O-sialoglycoprotein endopeptidase digestion. Transient overexpression of endomucin-1/-2 reduced the number of adhesion plaques and reduced cell attachment to the substrate. This phenotype was suppressed by laminin or the protein kinase inhibitor staurosporine. Our findings suggest that human endomucin-1/-2 negatively regulate cell adhesion to the extracellular matrix.
Abstract: Reversible vasospasm in the bilateral middle cerebral artery in a patient with postpartum cerebral angiopathy was evaluated with serial transcranial color-coded sonography (TCCS). The authors propose TCCS as the method of choice for assessing the time course of vascular changes in postpartum cerebral angiopathy because it allows for precise placement of the sample volume and adjustment of the incident angle.
Abstract: We report a case of HTLV-I associated myelopathy (HAM) with polyneuropathy. A 59-year old man suffering from progressive paraparesis associated with subclinical polyneuropathy was admitted to our hospital. HTLV-I antibodies in the serum and CSF were positive, and a diagnosis of HAM was made. His laboratory investigation revealed elevated serum IgG and IgM anti GM-1 antibodies. The nerve conduction study showed a mild reduction in motor and sensory conduction velocity in all extremities. A sural nerve biopsy revealed active demyelination and globule-like changes, which are specific for HAM neuropathy. Anti-GM1 antibodies are frequently present in autoimmune motor neuropathy. They are thought to inflict a damage on both the myelin and axons of the peripheral nerves. Ours is believed to be the first case of HAM associated with anti-GM1 antibodies, although polyneuropathy is often associated with HAM. While it is not clear whether the lesion observed in HAM neuropathy results from the direct cytopathic effect of the virus or from the immune response, some immune-mediated reactions are thought to play an important role. This case suggests that a case of HAM with polyneuropathy should be examined for the presence of the anti-ganglioside antibodies. More investigations are needed to fully understand the mechanism of the HAM neuropathy.
Abstract: Two rare cases of Wernicke's encephalopathy (WE) in non-alcoholic patients on hemodialysis (HD) are reported. They presented with the clinical triad of WE (ophthalmoplegia, ataxia and disturbance of consciousness) and intravenous administration of thiamine led to complete elimination of these manifestations. Reduced plasma thiamine levels prior to the administration confirmed the diagnosis of WE. Interestingly, a reduction in plasma thiamine levels by about half was seen in one of the patients on HD, suggesting that thiamine, a water-soluble vitamin, can be depleted with HD. In the literature, nine HD-dependent patients have been reported to develop WE, seven of whom were diagnosed postmortem. Their premortem diagnoses included uremic encephalopathy, dysequilibrium syndrome and dialysis dementia, which can often complicate HD and present symptoms similar to those of WE. We therefore emphasize that WE, even though a rare complication, should be suspected in all patients on HD who present with at least one of the clinical triad of WE.
Abstract: We examined the usefulness of color duplex ultrasonography in patients suspected of having temporal arteritis. Five patients, who were all aged 70 or older, developed a new onset of localized headache with temporal artery abnormalities, and had an elevated erythrocyte sedimentation rate of > 100 mm/hour. The final diagnoses were temporal arteritis in three patients, polymyalgia rheumatica in one, and probable healed temporal arteritis in one. Color duplex ultrasonography showed stenoses, which were confirmed histologically as well, in the superficial temporal artery of all patients. The characteristic findings of active temporal arteritis were, however, demonstrated in only three biopsy specimens, and in the remaining two the stenoses were thought to be related to previous arteritis. The hypoechoic halo, which has been reported to be a characteristic finding of color duplex ultrasonography in active temporal arteritis, was detected in only one patient with active temporal arteritis and another one with probable healed temporal arteritis. No stenoses were demonstrated in the superficial temporal arteries of 30 control subjects (20 with at least one risk factor of atherosclerosis and 10 without it). Color duplex ultrasonography can therefore be considered a powerful method for detecting stenoses in the superficial temporal artery. Its ability to identify their etiology is, however, unsatisfactory, so that temporal artery biopsy remains undoubtedly the most reliable test for etiological evaluation. We thus recommend color duplex ultrasonography as a supplementary method for the diagnosis of temporal arteritis, because it can provide useful information concerning the appropriate site of temporal artery biopsy.
Abstract: A 35-year-old woman was admitted to our hospital with complaints of a two-year history of recurrent, daily episodes of transient ischemic attacks; the symptoms consisted of scotoma of her left eye, vertical diplopia, and paresthesia of her right arm. The presence of lupus anticoagulants and anticardiolipin antibodies led to the diagnosis of antiphospholipid syndrome (APS). After thrombotest values had decreased to 30% (international normalized ratio: 1.5) with warfarin, her symptoms did not recur. This suggests that anticoagulant therapy is effective for the prevention of recurrence of ischemic events complicated by primary APS, even when they occur repeatedly.
Abstract: A 76-year-old woman was admitted to our hospital with complaints of a three-day history of severe postural headache without any apparent cause. Neurological examination revealed nuchal rigidity, and right auditory nerve paresis. Lumbar puncture yielded a low opening pressure of 50mmH2O and an elevated total protein up to 77mg/dl. Cranial magnetic resonance imaging (MRI) using gadolinium revealed diffuse dural enhancement, and effacement of the prepontine cistern. Spontaneous intracranial hypotension was strongly suspected, and to ascertain the presence of a cerebrospinal fluid (CSF) leak, radionuclide cisternography (RNC) was performed, which demonstrated a spinal CSF leak along the nerve root at the level of the lower lumbar spine. Interestingly, computed tomography-myelography (CTM) did not detect these abnormalities. An epidural blood patch with 15 ml of autologous blood at the L3-L4 interspace brought a dramatic symptomatic relief. Follow-up MRI, RNC, and CSF analysis demonstrated that the abnormal findings had disappeared. It is speculated that RNC is more sensitive for detecting small dural tears and CTM for anatomical anomalies including meningeal diverticula and perineural (Tarlov) cysts. We wish to stress, however, that RNC and CTM are complementary and sometimes interchangeable diagnostic modalities, and should be actively employed for detecting CSF leakage in SIH and for appropriate treatment.
Abstract: A 25-year-old man developed nausea, vomiting, severe headache, and confusion. He had a past history of hyperuricemia and mild renal dysfunction. On admission he had somatic growth retardation, hypertrichosis, and bilateral auditory impairment. A cranial CT scan showed a small area of low density in the left temporal lobe and cerebellar atrophy. Five days later, he developed right homonymous hemianopia, sensory aphasia, and sensory inattention, and a new, large area of low density in the left occipital lobe on a cranial CT scan. On laboratory examination, lactate, pyruvate, and the lactate-to-pyruvate ratio were elevated in both the serum and cerebrospinal fluid. The biopsied muscle showed ragged red fibers and strongly SDH-reactive blood vessels. Gene analysis revealed the presence of the A 3243 G point mutation of the mitochondrial tRNA(Leu) gene in his blood leucocytes and muscle. Serum concentrations of BUN and creatinine were elevated to 46 mg/dl and 2.2 mg/dl, respectively. Creatinine clearance was 14.1 ml/min. An abdominal CT scan disclosed atrophy of his left kidney with subcapsular calcification and the findings of his abdominal ultrasonography were compatible with chronic renal failure. His mother, who suffered from renal failure and became dialysis dependent in her late forties also bore the A 3243 G mutation of the mitochondrial tRNA(Leu) gene in her circulating leucocytes. Though the association between MELAS and renal dysfunction still remains obscure, we speculate that renal failure can be a manifestation of MELAS.
