Macroscopic diagnostic clue for parkinsonism.

The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The pathological diagnostic procedure begins by assessing the macroscopic findings to evaluate the degenerative lesions in brains with the naked eye. Usually, degenerative lesions show variable atrophy and brownish discoloration in accordance with disease-specific profiles. These macroscopic appearances support neuropathologists in identifying the relevant regions for microscopic examination. The neuropathological diagnosis of parkinsonism is based on regional distribution and fundamental proteinopathies in neurons and glia cells. LBD and MSA are synucleinopathies, and PSP and CBD are tauopathies. Among them, glial-predominant proteinopathy (MSA, PSP, and CBD) may play a significant role in volume reduction. Therefore, macroscopic inspection provides the appropriate direction for assessment. The disease duration, the severity of lesions, and mixed pathologies make the validation of macroscopic observations more complicated. In this review, we outline the macroscopic diagnostic clues in LBD, MSA, PSP, and CBD that could help with pathological refinement.

Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

Identification of intracerebral hemorrhage in the early-phase of MM1+2C-type sporadic Creutzfeldt-Jakob disease: A case report.

We report a case of early-phase sporadic Creutzfeldt-Jakob disease (sCJD) complicated by intracerebral hemorrhage (ICH), classified as MM1 + 2C-type based on autopsy. A 61-year-old Japanese man presented to our hospital with speaking difficulties including repeated usage of the same words. He was hospitalized on the seventh day after symptom onset, and diffusion-weighted images on magnetic resonance imaging showed hyperintense regions in the frontal cortex and caudate nucleus. On the 11th day after symptom onset, head computed tomography revealed ICH in the right occipital and parietal lobes. Routine laboratory evaluations and angiography revealed no cause of ICH. Myoclonus of the extremities and drowsiness were observed on the 15th day after symptom onset. He reached the state of akinetic mutism approximately two months after symptom onset. The cerebrospinal fluid test revealed positive real-time quaking-induced conversion and 14-3-3 protein. Electroencephalography revealed periodic sharp wave complexes. A clinical diagnosis of probable Creutzfeldt-Jakob disease was made according to the diagnostic criteria. After a relapse of pneumonia, he passed away on the 103rd day after symptom onset. Postmortem examination revealed ICH in the right posterior cingulate gyrus. No pathological change that might have caused ICH was obtained. Although the effect of sCJD on the onset of ICH is undeniable, the cause of ICH was unknown. Prion protein immunohistochemistry revealed the following results: (1) weak synaptic-type deposits in the tissue rarefacted by ICH; (2) synaptic-type deposits in the cerebral cortex, which showed fine vacuoles; and (3) perivacuolar-type deposits in the inferior temporal gyrus and lingual gyrus, which showed frequent large confluent vacuoles. Although it could be considered MM1-type sCJD clinically, this case was neuropathologically diagnosed as having MM1 + 2C-type sCJD. It was shown that ICH may occur in early-phase sCJD. To improve sCJD prognosis, treatment of complications and careful follow up are important. Furthermore, pathological diagnosis is indispensable for sCJD type diagnosis.

Globular glial tauopathy Type I presenting with behavioral variant frontotemporal dementia.

Globular glial tauopathy (GGT) is a recently proposed tauopathy characterized by the globular accumulation of four-repeat (4R) tau in the oligodendroglia (globular oligodendroglial inclusion (GOI)) and astrocytes (globular astrocytic inclusion (GAI)), in addition to deposition in neurons. Although it is proposed that GGT should be classified into three different neuropathological subtypes, previous reports have indicated that subclassification might be difficult in some cases. We report an autopy case of a 79-year-old man with behavioral variant frontotemporal dementia (bvFTD). He developed behavioral changes at 67 years of age and had auditory hallucinations and persecutory delusions at admission to a psychiatric hospital at 69 years of age. Neuropathologically, marked atrophy of the frontotemporal lobes and severe degeneration of the white matter and frontopontine tract were observed. The present case corresponded to GGT Type I, as numerous GOIs were observed, predominantly in the frontotemporal region. However, concurrent degeneration of the motor cortex and corticospinal tract suggest characteristics of Type II. Although the relationship between psychotic symptoms and GGT remains unclear, the present case demonstrates heterogeneity of GGT subtypes.

Characteristic asymmetric limbic and anterior temporal atrophy in demented patients with pathologically confirmed argyrophilic grain disease.

PURPOSE: The purpose of this study is to clarify the characteristic structural magnetic resonance imaging (MRI) findings in demented patients with pathologically confirmed argyrophilic grain disease (AGD). METHODS: Nine pathologically confirmed AGD patients with cerebral three-dimensional T1-weighted MRI were evaluated in this study. In addition to visual rating scales of atrophic and asymmetric changes in the limbic and temporal lobes, voxel-based morphometry (VBM) was performed to assess group difference between pathologically confirmed AGD and Alzheimer's disease (AD) patients. RESULTS: On visual analyses of AGD patients, the medial temporal, anterior temporal, and posterior temporal atrophy scores were 3.3 ± 0.7, 1.7 ± 0.5, and 1.0 ± 0.7, respectively. Asymmetric scores of the hippocampus and parahippocampal gyrus, amygdala and ambient gyrus, anterior temporal, and posterior temporal lobes were rated as 1.1 ± 0.7, 1.6 ± 0.5, 1.3 ± 0.8, and 0.4 ± 0.7, respectively. In spite of no statistical differences in atrophic scores, AGD patients showed the higher score and proportion of anterior temporal asymmetric score than AD (p = 0.03 and 0.02). Compared with controls, VBM analysis revealed left dominant asymmetric atrophy predominantly in the limbic and anterior temporal lobe in AGD patients. By contrast, there was no significant gray matter reduction between AGD and AD patients. CONCLUSIONS: Asymmetric atrophy relatively localized to the anterior temporal and limbic lobes including the amygdala and ambient gyrus is a characteristic MRI finding of AGD. For the precise antemortem diagnosis, especially to differentiation from AD, it is important to pay attention to this asymmetric change.

Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism.

We herein report an autopsy case of a 69-year-old man with pseudopseudohypoparathyroidism. The patient suffered from mental retardation and spastic tetraparesis and had all the features of Albright's hereditary osteodystrophy with a normal response to parathyroid hormone in the Ellsworth-Howard test. Computed tomography demonstrated symmetrical massive brain calcification involving the bilateral basal ganglia, thalami, dentate nuclei and cerebral gray/white matter junctions, which was consistent with Fahr's syndrome. Magnetic resonance imaging revealed extensive white matter changes sparing the corpus callosum. Severe ossification of the posterior longitudinal ligament of the cervical spine was also demonstrated. A neuropathological examination revealed massive intracranial calcification within the walls of the blood vessels and capillaries with numerous calcium deposits. The calcium deposits aligned along the capillaries, and deposits in the vessel wall at the initial stage were confined to the border between the tunica media and adventitia. The vascular calcification in the basal ganglia continuously spread over the surrounding white matter into the cortex. The area of vascular calcification in the white matter was very well correlated with the area of the attenuated myelin staining. Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. We should recognize the continuous area of vascular calcification and its correlation with extensive white matter changes as possible causes of neuropsychiatric symptoms in pseudopseudohypoparathyroidism with Fahr's syndrome.

Fatal Intraperitoneal Bleeding after Intravenous Administration of Tissue Plasminogen Activator.

We report a case of acute ischemic stroke, which developed fatal intraperitoneal bleeding after intravenous administration of alteplase. An 86-year-old woman developed acute infarction of the right middle cerebral artery during admission for chronic heart failure. Two days before the stroke, liver biopsy was performed; the result was benign. Although rivaroxaban was prescribed for atrial fibrillation, the rivaroxaban had been discontinued for liver biopsy until the time when she developed the stroke. A condition of recent biopsy required careful determination of eligibility of intravenous alteplase; however, we considered that the benefit of intravenous alteplase outweighed the hemorrhagic adverse effects. Alteplase (0.6 mg/kg) was started 2 hours after the stroke onset, however, no clinical improvement was obtained. One hour after the completion of alteplase, she suddenly developed a shock state. Emergent computed tomography disclosed massive intraperitoneal hemorrhage. She died 8 hours after the completion of alteplase. In the present case, mechanical thrombectomy without intravenous alteplase can be an alternative therapeutic option.

Multiple system atrophy variant with severe hippocampal pathology.

The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. We assessed 146 consecutively autopsied MSA patients. Semi-quantitative analysis of anti-alpha-synuclein immunohistochemistry revealed that 12 of 146 patients (8.2%) had severe NCIs in two or more of the following areas: the hippocampal granule cells, cornu ammonis areas, parahippocampal gyrus, and amygdala. In contrast, the remaining 134 patients did not show severe NCIs in any of these regions. Patients with severe hippocampal involvement showed a higher representation of women (nine women/three men; Fisher's exact test, p = 0.0324), longer disease duration (13.1 ± 5.9 years; Mann-Whitney U-test, p = 0.000157), higher prevalence of cognitive impairment (four patients; Fisher's exact test, p = 0.0222), and lower brain weight (1070.3 ± 168.6 g; Mann-Whitney U-test, p = 0.00911) than other patients. The hippocampal granule cells and cornu ammonis area 1/subiculum almost always showed severe NCIs. The NCIs appeared to be ring-shaped or neurofibrillary tangle-like, fibrous configurations. Three of 12 patients also had dense, round-shaped NCIs that were morphologically similar to pick bodies. The patients with Pick body-like inclusions showed more severe atrophy of the medial temporal lobes and broader spreading of NCIs than those without. Immunohistochemistry for hyperphosphorylated tau and phosphorylated TDP-43 revealed minimal aggregations in the hippocampus of the hippocampal MSA patients. Our observations suggest a pathological variant of MSA that is characterized by severe involvement of hippocampal neurons. This phenotype may reinforce the importance of neuronal alpha-synucleinopathy in the pathogenesis of MSA.

Correlating diffusion-weighted MRI intensity with type 2 pathology in mixed MM-type sporadic Creutzfeldt-Jakob disease.

The existence of affected subjects with both abnormal prion protein (PrPSc) types has been reported, and their clinical features were somewhat similar to the dominant PrPSc type but varied in sporadic Creutzfeldt-Jakob disease (sCJD). Presently, the antemortem identification of both PrPSc types in sCJD is not possible. In this study, we attempted to clinically predict the concurrence of MM-type sCJD with another PrPSc type in the same individual. We retrospectively identified seven MM-type sCJD cases with both fine vacuole-type spongiform (FV) and large confluent vacuole-type spongiform change (LCV) among 49 sCJD cases. We reviewed clinical features, pathological findings, and radiological abnormalities in these seven cases. We also conducted a regional systemic study with five brains to associate the spongiform-change pattern with hyperintensity on magnetic resonance diffusion-weighted imaging (DWI) using the signal intensity index (SII). In the case series study, the one patient with dominant LCV showed longer disease duration, later onset of typical symptoms, no periodic sharp wave complexes in electroencephalography, and negative 14-3-3 protein findings compared to the six FV-dominant patients. LCV-dominant lesions tended to show higher intensity on DWI than did the FV-dominant lesions in respective patients. In the regional systemic study, LCV-dominant regions showed significantly higher SII on DWI than did the FV-dominant regions. In conclusion, mixed MM-type sCJD generally showed the clinical features of the phenotype that was dominant in pathological distribution. The SII may be clinically useful for investigating the concurrence of PrPSc type 2 in cases with the typical clinical course of MM1-type sCJD.

Cerebral infarction due to cardiac myxoma developed with the loss of consciousness immediately after defecation-a case report.

A 74-year-old man lost consciousness immediately after defecation. The loss of consciousness lasted for several minutes, and he experienced difficulty in walking when he regained consciousness. He was transferred to our hospital via an ambulance. Upon neurological examination, nystagmus and ataxia in the left arm and leg were noted. An MRI of the brain revealed multiple acute infarcts mainly in the bilateral cerebellum. Intravenous thrombolytic therapy with alteplase was initiated 3 h and 20 min after the onset of symptoms, and an improvement in neurological symptoms was observed. Echocardiography displayed a mobile mass in the left atrium, suggesting myxoma. After 14 days from the onset of symptoms, the tumor was surgically resected, and a pathological diagnosis of myxoma was established. Because of the unique event surrounding the onset in this case, we considered that there was a potential detachment of myxoma and/or thrombi fragments triggered by an increase in intrathoracic pressure induced by the action of defecation. This present case suggests that clinicians should consider cardiac myxoma in patients with cerebral infarction if the stroke is preceded by a Valsalva maneuver-like action and accompanied by the loss of consciousness.

Carotid Artery Stenting Successfully Prevents Progressive Stroke Due to Mobile Plaque.

We report a case of progressive ischemic stroke due to a mobile plaque, in which carotid artery stenting successfully prevented further infarctions. A 78-year-old man developed acute multiple infarcts in the right hemisphere, and a duplex ultrasound showed a mobile plaque involving the bifurcation of the left common carotid artery. Maximal medical therapy failed to prevent further infarcts, and the number of infarcts increased with his neurological deterioration. Our present case suggests that the deployment of a closed-cell stent is effective to prevent the progression of the ischemic stroke due to the mobile plaque.