Shinsui Tatsumi

Direct Comparison of Histology of Microbleeds with Postmortem MR Images

Background: Although the clinical significance of so-called microbleeds (MBs) in gradient-echo MR images (GRE-MRI) has been extensively researched, the histopathological evaluation is notably insufficient. Methods: Postmortem GRE-MRI was obtained of water-immersed formalin-fixed tissue blocks from a 97-year-old hypertensive woman with 9 antemortem MBs. Histologic slides were compared with those of MRI. Results: Microscopic examination revealed clusters of hemosiderin-laden macrophages in 8 MBs and arteriolar pseudocalcification in 1 MB in the left pallidum. Hypertensive microangiopathies were found in 5 lesions. The sizes of the lesions with hemosiderin deposits were roughly comparable with the MBs of GRE-MRI. Conclusions: All of the MBs but for 1 exception were proved to be hemosiderin deposits and frequently associated with hypertensive microangiopathy.

An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement

A Japanese male patient presented with gait disturbance at the age of 69 years. His principal symptom was cerebellar ataxia for several years. He was initially diagnosed as having olivopontocerebellar atrophy because dysarthria and ataxia gradually developed, and head CT scan showed apparent atrophy of the cerebellum and brainstem and dilatation of the fourth ventricle. Later, he showed vertical gaze palsy, dysphagia, retrocollis, parkinsonism, axial dominant rigidity and grasp reflex, and therefore, the diagnosis was modified to progressive supranuclear palsy (PSP). Progressive atrophy of the frontotemporal lobe, cerebellum and brainstem, and dilatation of the lateral, third and fourth ventricles were evident on MRI. Gastrostomy and tracheotomy were performed 9 and 10 years after onset, respectively, and the patient died after 11 years disease duration. At autopsy the brain weighed 1000 g and showed atrophy of the frontotemporal lobe, cerebellum and brainstem. Neurofibrillary tangles, mainly globose‐type revealed by Gallyas‐Braak silver staining, were extensively observed in the cerebral cortex and subcortical grey matter. Numerous glial fibrillary tangles, including tuft‐shaped astrocytes and coiled bodies, and extensive argyrophilic threads were also recognized, particularly in the frontal lobe, basal ganglia, cerebellar white matter, brainstem and spinal cord. The Purkinje cell layer showed severe neuron loss with Bergmanns gliosis, and the dentate nucleus showed severe neuron loss with grumose degeneration. Tau‐positive/Gallyas‐positive inclusions in the Purkinje cells and the glial cells of the Purkinje cell layer were observed. Pathological findings of the present patient were consistent with the diagnosis of PSP, but the olivopontocerebellar involvement, particularly in the cerebellum, was generally more severe, and the quantity of tau‐positive/Gallyas‐positive structures were more abundant than in typical PSP cases. The existence of a distinct, rare PSP subtype with severe olivopontocerebellar involvement, “PSP‐C“, which tends to be clinically misdiagnosed as spinocerebellar degeneration in the early disease stage, is noteworthy. The present case corresponded to this rare subtype of PSP.

Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis

Objective Progressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype of amyotrophic lateral sclerosis (ALS) in which upper motor neuron (UMN) signs are undetectable. To elucidate the clinicopathological features of patients with clinically diagnosed PMA, we studied consecutive autopsied cases. Design Retrospective, observational. Setting Autopsied patients. Participants We compared clinicopathological profiles of clinically diagnosed PMA and ALS using 107 consecutive autopsied patients. For clinical analysis, 14 and 103 patients were included in clinical PMA and ALS groups, respectively. For neuropathological evaluation, 13 patients with clinical PMA and 29 patients with clinical ALS were included. Primary outcome measures Clinical features, UMN and LMN degeneration, axonal density in the corticospinal tract (CST) and immunohistochemical profiles. Results Clinically, no significant difference between the prognosis of clinical PMA and ALS groups was shown. Neuropathologically, 84.6% of patients with clinical PMA displayed UMN and LMN degeneration. In the remaining 15.4% of patients with clinical PMA, neuropathological parameters that we defined as UMN degeneration were all negative or in the normal range. In contrast, all patients with clinical ALS displayed a combination of UMN and LMN system degeneration. CST axon densities were diverse in the clinical PMA group, ranging from low values to the normal range, but consistently lower in the clinical ALS group. Immunohistochemically, 85% of patients with clinical PMA displayed 43-kDa TAR DNA-binding protein (TDP-43) pathology, while 15% displayed fused-in-sarcoma (FUS)-positive basophilic inclusion bodies. All of the patients with clinical ALS displayed TDP-43 pathology. Conclusions PMA has three neuropathological background patterns. A combination of UMN and LMN degeneration with TDP-43 pathology, consistent with ALS, is the major pathological profile. The remaining patterns have LMN degeneration with TDP-43 pathology without UMN degeneration, or a combination of UMN and LMN degeneration with FUS-positive basophilic inclusion body disease.

Type of Gradient Recalled-Echo Sequence Results in Size and Number Change of Cerebral Microbleeds

Microbleeds (MBs) are thought to be clusters of hemosiderin-containing macrophages and are more commonly observed in hypertensive microangiopathy (lacunar infarct or intracerebral hemorrhage), cerebral amyloid angiopathy, or cerebral autosomal dominant arteriopathy with subcortical infarcts and

An autopsied case of an apparent pontine branch atheromatous disease.

normotensive without medication. Nine months later, he died of pneumonia. The main findings of general pathology were pneumonia and mild diabetic nephropathy. Neuropathological findings included an old cavitary infarction of the right pontine base ( fig. 1 B), multiple lacunar infarcts in the bilateral basal ganglia, and slight senile changes. At the brain base, severe atherosclerosis was observed. We separated the basilar artery from the brain, and evaluated it posteriorly. One right-sided branch at the level of the pontine infarct lost transparency at its most proximal segment ( fig. 1 B). Serial 4m thick cross sections of the basilar artery including that branch were made for about 5 mm of length. Organized thrombosis with recanalization was observed at the origin of that branch, where numerous macrophages were infiltrated within the fibrous atheroma ( fig. 1 C). Throughout the serial sections, the parental basilar artery was markedly atherosclerotic without thrombus formation ( fig. 1 C). There were additional 6 branches from the basilar artery in the sections. One left-sided branch at the same Dear Sir, Based on 3 autopsied cases with pontine infarcts [1, 2] , the ‘branch atheromatous disease’ was proposed by Caplan [3] in 1989 as a new distinct category of cerebral infarction caused by a localized atheromatous lesion at the mouth of the branch from the major artery’s branch. Although there has been no histopathological report since then, some types of infarction are believed to fit into that category in clinical practice. Here we present the case with MR images compatible with ‘branch atheromatous disease’, but the histopathological findings were those of a large artery atherothrombotic infarct. A 79-year-old man with risk factors of diabetes mellitus, hyperlipidemia and smoking was admitted to our hospital because of complete left-sided hemiplegia in October 2006. Brain MRI revealed an acute right-sided pontine infarct reaching its ventral surface (in the territory of the paramedian, and short and long circumferential arteries), along with multiple old lacunes in the bilateral basal ganglia. The basilar artery appeared normal on MRI/ MRA ( fig. 1 A). The patient remained Received: November 17, 2009 Accepted: December 14, 2009 Published online: March 4, 2010

Argyrophilic grains are reliable disease-specific features of corticobasal degeneration.

Argyrophilic grains are discrete punctate structures that bind to silver stains; they can be observed within the neuropil of the limbic system, particularly in the elderly. It has been reported that argyrophilic grains are more frequent in patients with corticobasal degeneration (CBD) compared with the elderly population in general. To determine the frequency and significance of argyrophilic grains in CBD, we examined the temporal lobes from 35 patients with autopsy-proven CBD (mean age, 69.1 years) and 28 patients with argyrophilic grain disease (mean age, 95.7 years). Grain distributions and densities were evaluated semiquantitatively using Gallyas-Braak stains and immunohistochemistry with AT8 and RD4 antibodies. Argyrophilic grains were observed in all CBD cases (100%) despite a lower average age at death in this population. We also observed the following features that were specific to argyrophilic grains in CBD: 1) grains were likely to be widespread throughout the temporal lobe, 2) grains were consistently found with abundant argyrophilic threads, and 3) the ultrastructure of grains contained paired helical filaments with a periodicity of 120 to 130 nm. In conclusion, we confirm that argyrophilic grains in CBD are specifically related to the 4-repeat tau pathology of CBD and are not simply a result of aging.

Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis

IMPORTANCE TAR DNA-binding protein of 43 kDa (TDP-43) plays a major role in the pathogenesis of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Although a pathological continuity between FTLD and ALS has been suggested, the neuropathological changes of the lower motor neuron (LMN) systems have not been assessed in TDP-43-associated FTLD (FTLD-TDP), to our knowledge. OBJECTIVE To investigate a pathological continuity between FTLD-TDP and ALS by comparing their respective neuropathological changes in the motor neuron system. DESIGN AND SETTING A retrospective clinical medical record review and a semiquantitative neuropathological evaluation of the cranial motor nerve nuclei and spinal cord were conducted at autopsy. We included 43 patients with sporadic FTLD-TDP, type A, B, or C, from 269 consecutively autopsied patients with TDP-43 proteinopathy. Patients were categorized as having FTLD without ALS, FTLD-ALS (onset of FTLD symptoms/signs preceded those of ALS), or ALS-FTLD (onset of ALS symptoms/signs preceded those of FTLD). MAIN OUTCOMES AND MEASURES Neuronal TDP-43 pathological changes and neuronal loss. RESULTS Forty-three patients were included in the clinical analysis, and 29 from whom spinal cords were obtained were included in the neuropathological analysis. Survival time was significantly shorter in the FTLD-ALS and ALS-FTLD groups than in the FTLD without ALS group (P < .001). At neuropathological examination, 89% of patients in the FTLD without ALS group showed aggregations of TDP-43 in the spinal motor neurons. The LMN loss was most severe in ALS-FTLD, followed by FTLD-ALS and FTLD without ALS. All the patients with type A or C FTLD-TDP were included in the FTLD without ALS group, and all those with type B pathological changes were in the FTLD-ALS or the ALS-FTLD group. Lower motor neuron loss and TDP-43-positive skeinlike inclusions were observed in all pathological subtypes. CONCLUSIONS AND RELEVANCE The LMN systems of FTLD-TDP frequently exhibit neuropathological changes corresponding to ALS. Thus, a pathological continuity between FTLD-TDP and ALS is supported at the level of the LMN system.

Relation between clinical findings and progression of cerebral cortical pathology in MM1-type sporadic Creutzfeldt–Jakob disease: Proposed staging of cerebral cortical pathology

In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.

Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of 99mTc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt–Jakob disease

We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT.

A case of sporadic adult Alexander disease presenting with acute onset, remission and relapse

Adult Alexander disease is a rare leucodystrophy with severe atrophy of the lower brainstem and upper cervical cord.1 The pathological character is the presence of Rosenthal fibres that contain aggregates of intermediate protein, GFAP, associated with mutations in GFAP gene.2 Because pathogenesis is degenerative, the most typical clinical course is slowly progressive; the intermittent course has not been sufficiently described so far.2 We show a case of genetically confirmed adult Alexanders disease with acute exaggeration and remission, and relapse. A 33-year-old woman had been well until she suddenly fell down and lost consciousness in 2002. She had left-sided paresis and dysarthria, and was admitted to a hospital. Her medical history was unremarkable except for mild diabetes mellitus. There was no family history of neurological diseases or consanguineous marriage. Her father died of heart disease (in his 40s), her mother died of diabetes mellitus and angina pectoris (in her 50s), and her two daughters were healthy. Brain MRI showed atrophy of the upper cervical cord and T2-hyperintensity in the bilateral periventricular areas and the medulla. The patient was treated for acute ischaemic stroke with medical therapy and rehabilitation (figure 1A). She gradually improved, with the ability to walk with an aid 6 months after the onset and was discharged home 1 year after the onset with left-sided weakness and slight dysarthria. There was no exacerbation or improvement of …