Hidehiko Konno

Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease.

Objective: To evaluate the usefulness of diffusion-weighted MRI (DWI) for the early diagnosis of Creutzfeldt–Jakob disease (CJD). Methods: Thirty-six consecutive patients (age 56 to 82 years) were enrolled, and 26 were examined by DWI. Nine were definite based on the World Health Organization criteria, and 27 were probable. The percentages of DWI abnormalities, periodic sharp wave complexes (PSWCs) on the EEG, detection of CSF 14-3-3 protein, and increase of CSF neuron-specific enolase (>25 ng/mL) on the first examination were compared. For DWI, 32 patients (age 31 to 84 years) who showed progressive dementia or impaired consciousness served as disease controls. Results: The percentage of DWI abnormalities was 92.3%, of PSWCs 50.0%, of 14-3-3 protein detection 84.0%, and of NSE increase 73.3%. Two of the 32 control subjects were falsely positive on DWI. The sensitivity of DWI was 92.3% (95% CI 74.8 to 99.5%) and specificity 93.8% (95% CI 79.2 to 99.2%). In 17 patients who did not show PSWCs on the first EEG, abnormal DWI findings were still clearly detected. Four patients who were negative for 14-3-3 protein also showed DWI abnormalities. DWI abnormalities were detected as early as at 3 weeks of symptom duration in four patients in whom PSWCs were not yet evident. Conclusions: DWI can detect characteristic lesions in the majority of patients with CJD regardless of the presence of PSWCs. DWI was the most sensitive test for the early clinical diagnosis of CJD; consideration should be given to its inclusion in the clinical diagnostic criteria of CJD.

Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica

Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial. Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient. We have distinguished six different lesion types. The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2). Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6). In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis. Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes. Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion.

IDENTIFICATION OF THE NORMAL MICROGLIAL POPULATION IN HUMAN AND RODENT NERVOUS TISSUE USING LECTIN–HISTOCHEMISTRY

Identification of the normal microglial population in human and rodent nervous tissue using lectin–histochemistry

Shy-Drager syndrome and amyotrophic lateral sclerosis ☆: Cytoarchitectonic and morphometric studies of sacral autonomic neurons

In order to elucidate the morphological correlates of bladder-rectal dysfunctions in Shy-Drager syndrome, the sacral spinal cord was cytoarchitectonically studied and 3 groups of sacral motor neurons, the posterolateral motor neuron column (PL), inferior intermediolateral nucleus (IML) and cell group X of Onuf (Onuf), were morphometrically quantitated at the S3 level (5 cases), after which the results were compared with those from amyotrophic lateral sclerosis (5 cases) and an age-matched control group (4 cases). The sacral autonomic preganglionic nucleus of IML was localized chiefly in the S3-4 segments and was maximally developed in the caudal one-third of S3. The cell group X of Onuf was localized between the middle of S2 and the rostral one-third of S3 as a longitudinal slender column in the ventral horn. Between these two nuclei at the rostral S3 level, a connecting cellular bridge of neurons of intermediolateral cell type was identified. Morphometry disclosed a marked deprivation of IML, Onuf and somatic motor neurons in Shy-Drager syndrome and a severe loss of somatic motor neurons and a modest deprivation of IML neurons in ALS. These results imply that these two disorders distinguished by different clinical manifestations share a common loss of somatic motor and parasympathetic motor neurons at least in the sacral cord. There are, however, certain gradients in the severity of involvement in these heterogeneous cell groups.

Retrograde axoplasmic transport of Adriamycin An experimental form of motor neuron disease

Adriamycin (ADM) is a DNA-directed RNA inhibitor. In attempts to produce an experimental form of motor neuron disease, we injected the agent into rat sciatic nerve. Retrograde axoplasmic flow conveyed ADM into soma of the spinal motor neurons, as confirmed by fluorescence microscopy. Motor neuron degeneration, which included nuclear heterochromatinization and diffuse chromatolysis, was observed after 6 to 8 days. After 2 weeks, many neurons that gave rise to sciatic nerve efferents underwent dissolution. Retrograde axoplasmic flow and DNA-injurious substances could affect survival of motor neurons.

Intraneuronal laminin-like molecule in the central nervous system: demonstration of its unique differential distribution

Laminin, an extracellular matrix glycoprotein rich in basement membrane, is a multifunctional molecule of approximately 1000 kDa and is known to possess a potent neurotrophic activity. Laminin-like immunoreactivity (LLI) was for the first time demonstrated in mouse and rat CNS neurons by a sensitive immunohistochemical technique. Transblotting of SDS-PAGE of the supernatant of the mouse and rat brain homogenate identified distinct 180 kDa and weak 380 kDa bands immunoreactive to anti-laminin and these molecules differed from authentic laminin subunits. The intraneuronal distribution of LLI disclosed two distinct patterns; LLI-1 (diffuse perikaryal stain) and LLI-2 (coarse granular stain). By immunoelectron microscopy, LLI was localized to the ERs in LLI-1 neurons, whereas it appeared to be confined to lysosomes in LLI-2 neurons. LLI-1 neurons were found predominantly in hippocampal pyramidal, granule and neocortical layers 1-3, 6 neurons, in most of the striatal and thalamic neurons, and Purkinje cells. The majority of neurons in neocortical layers 4-5, medial septal and Meynert neurons, somatic motor neurons, and neurons of the deep cerebellar nuclei were classified as LLI-2 cells. No LLI was found in hypothalamic mammillary, habenular and vagal dorsal motor neurons (LLI-3). These observations may indicate intraneuronal production of laminin-related molecules in central neurons. We speculate that the laminin-related molecules (neurolaminin) play important roles in trophic or servo mechanisms in the CNS.

Forebrain ischemia induced by temporary bilateral common carotid occlusion in normotensive rats

Ischemic brain lesions were induced in adult Wistar and Fischer rats by temporary occlusion of the bilateral common carotid artery. The severity of ischemic lesions depended on the duration of carotid occlusion. While 2 h occlusion resulted in 15 deaths among 40 rats and the development of ischemic lesions in 16 of 25 asymptomatic survivors, none died after 0.5 h occlusion and yet 13 of 30 apparently asymptomatic rats had ischemic lesions when examined on day 7. Histological examination combined with immunohistochemistry of autologous albumin for assessing the integrity of the blood-brain barrier (BBB) revealed two distinct lesions: (1) ischemic neural damage with extensive tissue permeation of serum albumin, (2) death of individual neurons sparing other neural elements in the absence of the BBB breakdown. Ischemic neural damage with BBB breakdown was common in animals dying within 48 h after reflow. The lesions without BBB breakdown, on the other hand, were found solely in asymptomatic animals in which groups of severely degenerated neurons were preferentially located in the CA 1 region of the hippocampus, the caudoputamen and deeper layers of the neocortex. The sequential measurements of regional cerebral blood flow (rCBF) in the bilateral hippocampus by the hydrogen clearance method disclosed a steady decrease in rCBF after the occlusion, 51% of the pre-occlusion state at 10 min, 35% at 25 min and 32% at 40 min. The simplicity of procedure could make this model suitable for the study of the pathogenesis of ischemic neuronal damage in a critically low perfusion state.

Wallerian degeneration induces Ia-antigen expression in the rat brain

Strong expression of class II major histocompatibility (MHC II, Ia) antigens was observed in areas of Wallerian degeneration following either a cryoinjury to the cerebral and cerebellar cortex or unilateral eye enucleation in adult Wistar and Lewis rats. The Wallerian degeneration was disclosed by the Fink-Heimer method but not by routine histological examination. The Ia antigens were localized exclusively to the cells labeled with OX-42 antibody and mistletoe-1 lectin (ML-1) and possessing the morphological identity of microglia. Development of Ia-expressing microglia at the sites of Wallerian degeneration was accompanied by neither tissue permeation of serum components as assessed by immunohistochemistry for autologous albumin nor tissue migration of hematogenous inflammatory cells.

FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion

Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases.

Clinical features of Creutzfeldt-Jakob disease with V180I mutation

The authors describe the clinical features of Creutzfeldt-Jakob disease (CJD) with the causative point mutation at codon 180. The symptoms never started with visual or cerebellar involvement. The patients showed slower progression of the disease compared with sporadic CJD. They never showed periodic sharp and wave complexes in EEG. MRI demonstrated remarkable high-intensity areas with swelling in the cerebral cortex except for the medial occipital and cerebellar cortices. These characteristic MRI findings are an important clue for an accurate premortem diagnosis.