Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

BACKGROUND: The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. METHOD: Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aß production in COS cells transfected with wild-type or mutant PSEN1. RESULTS: The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aß42 in PSEN1 G266S-transfected cells significantly increased. CONCLUSION: Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Age-Related Pathology in Corticobasal Degeneration.

Elderly human brains are vulnerable to multiple proteinopathies, although each protein has a different transmission pathway. Tau-immunoreactive astrocytes are well-known in elderly brains. In contrast, astrocytic plaques, a hallmark in corticobasal degeneration (CBD), rarely occur in aging and neurodegenerative disease other than CBD. To elucidate the clinicopathological correlation of aging-related pathology in CBD, we examined 21 pathologically proven CBD cases in our institute (12 males and 9 females, with a mean age of death 70.6 years). All CBD cases showed grains and neurofibrillary tangles (NFTs). Fifteen cases (71.4%) showed beta-amyloid deposition such as senile plaques or cerebral amyloid angiopathy. Three cases (14.3%) had Lewy body pathology. One case was classified as amygdala-predominant Lewy body disease, although no cases met the pathological criteria for Alzheimer's disease. Five cases (23.8%) displayed Limbic-predominant and age-related TDP-43 encephalopathy (LATE). NFTs, grains, and TDP-43-positive neuronal inclusions were widely distributed throughout the limbic system of CBD patients, but their densities were low. CBD might a have similar cell vulnerability and transmission pathway to that of multiple proteinopathy in aging brains.

Efficacy of Endoscopic Resection for Rectal Neuroendocrine Tumors Smaller than 15 mm.

BACKGROUND: Local resection, including endoscopic resection, is recommended for rectal neuroendocrine tumors (NETs) < 15 mm in patients without risk factors for metastasis, though the short- and long-term outcomes are unclear. AIMS: This study investigates the efficacy of endoscopic resection for rectal NETs < 15 mm. METHODS: The short- and long-term outcomes of patients with rectal NETs < 15 mm who underwent endoscopic resection and the outcomes of each endoscopic technique were analyzed. The tumors were stratified as < 10 mm (small-size group, SSG) and 10-14 mm (intermediate-size group, IMG). RESULTS: Overall, 139 lesions (SSG, n = 118; IMG, n = 21) were analyzed. All tumors were classified as G1 (n = 135) or G2 (n = 4) according to the 2019 World Health Organization grading criteria. The complete resection rate was not different between the groups (P = 0.151). Endoscopic submucosal dissection (ESD) and endoscopic submucosal resection with a ligation device (ESMR-L) achieved complete resection rates > 90% in the SSG. The ESMR-L procedure time (P < 0.001) and hospitalized period (P < 0.001) were significantly shorter than those of ESD. ESD achieved a complete resection rate of 80.0% in the IMG. The tumor size did not affect the overall survival or rate of lymph node/distant metastases. CONCLUSIONS: Endoscopic resection is a feasible and effective treatment for patients with rectal NETs < 15 mm without the risk factors of metastasis. ESMR-L and ESD are optimal techniques for resecting tumors smaller than 10 mm and 10-14 mm, respectively.

Chameleons and mimics: Progressive supranuclear palsy and corticobasal degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that show parkinsonism as their main symptom. Both PSP and CBD are sporadic tauopathies associated with hyperphosphorylated four-repeat tau aggregation in neurons and glial cells. The characteristic pathologies of PSP are midbrain atrophy and the appearance of tufted astrocytes and globose-type neurofibrillary tangles. PSP shows severe degeneration in the globus pallidus, substantia nigra, subthalamic nucleus, and cerebellar dentate nuclei. Conversely, the characteristic pathologies of CBD are cortical atrophy and the appearance of astrocytic plaques and argyrophilic threads. CBD is associated with severe degeneration in the cerebral white matter, substantia nigra, and globus pallidus. Clinical symptoms depend on the topographical distribution and severity of degeneration rather than on the type of aggregated protein or inclusions. PSP and CBD present clinically differential diagnostic difficulties because of their overlapping pathological distributions.

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.

Autopsied case with MERRF/MELAS overlap syndrome accompanied by stroke-like episodes localized to the precentral gyrus.

We present an autopsied case with A8344G-mutated myoclonus epilepsy with ragged red fibers (MERRF)/mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) overlap syndrome accompanied by stroke-like episodes localized to the precentral gyrus. A 16-year-old Japanese woman suddenly experienced repetitive consciousness disturbances with increased serum lactate and creatine kinase levels. Magnetic resonance imaging showed abnormal intensity of bilateral precentral gyrus. She was clinically diagnosed as having a mitochondrial disorder and the A8344G mutation was detected in mitochondrial DNA. At 17 years of age, she died from congestive heart failure secondary to a third episode of lactic acidosis. Neuropatho-logically, multifocal laminar necrosis, which is responsible for stroke-like episodes in MELAS, was seen in the frontal cortex including the precentral gyrus, but there was no neuronal loss and gliosis in the basal ganglia, cerebellum, and brainstem, which were compatible with MERRF. Hypertrophy of the vascular smooth muscle and choroidal epithelium were seen, and were strongly visualized by an anti-mitochondrial antibody. Skeletal muscles showed uneven muscular diameters, increased central nuclei, and ragged red fibers (RRFs). Decreased cytochrome c oxidase (COX) activity and strongly succinate dehydrogenase (SDH)-reactive blood vessels were also noted. Stroke-like episodes in MERRF/MELAS overlap syndrome are thought to be rare in the frontal cortex including the precentral gyrus. Only two cases of MERRF/MELAS overlap syndrome with A8344G mutation, including this case, have shown stroke-like episodes in the frontal lobes. Other than the A8344G mutation and frontal lobe involvement, they had a high degree of similarity in terms of presence of RRFs, gastrointestinal dysfunction, and lack of typical MERRF neuropathology. In conclusion, this is an important case describing the clinical spectrum associated with A8344G-mutated MERRF/MELAS overlap syndrome.

Autopsied case of sporadic Creutzfeldt-Jakob disease classified as MM1+2C-type.

We encountered an autopsy case of sporadic Creutzfeldt-Jakob disease (CJD) pathologically classified as MM1+2C-type, where Western blot analysis of prion protein (PrP) mainly showed type-1 scrapie PrP (PrPSc ) but also, partially, mixed type-2 PrPSc . A Japanese woman complained of visual disorder at the age of 86 years and then showed disorientation and memory disturbances. Magnetic resonance imaging (MRI) showed cerebral cortical hyperintensity on diffusion-weighted images. The patient died 2 months after the onset of symptoms; her condition did not reach the akinetic mutism state and periodic sharp-wave complexes on electroencephalography and myoclonus were not recognized. The brain weighed 1100 g and neuropathological examination showed extensive fine vacuole-type spongiform changes in the cerebral cortex. In some cortical regions, large confluent vacuole-type spongiform changes were also present. Gliosis and hypertrophic astrocytosis were generally mild, and tissue rarefaction of the neuropil and neuronal loss were not apparent. PrP immunostaining showed diffuse synaptic-type PrP deposition in the cerebral gray matter, but some regions with large confluent vacuoles showed perivacuolar-type deposition. We speculated, based on the clinicopathological findings and previous reports, that most MM1-type sporadic CJD cases may be associated with type-2 PrPSc , at least partially, within certain regions of the cerebrum.

Autopsy case of MV2K-type sporadic Creutzfeldt-Jakob disease with spongiform changes of the cerebral cortex.

Comprehensive analysis is required for the accurate diagnosis of MV2-type sporadic Creutzfeldt-Jakob disease (sCJD) because it shows a wide clinicopathological spectrum. Here, we describe the clinical findings and neuropathologic observations of an autopsy-confirmed MV2K-type sCJD case with extensive spongiform changes of the cerebral cortex. In the early disease stages, the patient exhibited gait disturbance with ataxia and gradually showed cognitive dysfunction. Diffusion-weighted magnetic resonance images revealed hyperintense regions in the cerebral cortex, basal ganglia, and particularly in the thalamus. Prion protein (PrP) gene analysis revealed no mutations, and polymorphic codon 129 exhibited methionine and valine heterozygosity. During the course of the disease, a startle reaction was observed, whereas myoclonus was not observed. Electroencephalography showed no periodic sharp wave complexes. The patient died at age 61 years with 13 months total disease duration and did not reach the akinetic mutism state. Pathologic investigation revealed extensive fine vacuole-type spongiform change in the cerebral cortex, and the appearance of vacuolation tended to be more pronounced in the deeper layers. Numerous kuru plaques were observed in the cerebellum. PrP immunostaining revealed extensive diffuse synaptic-type PrP deposition in the cerebral cortex, and the finding was prominent in the deeper layer with perineuronal-type PrP deposition. In the limbic system, basal ganglia, and thalamus, mixed small plaque-type PrP with synaptic-type PrP deposition was observed. In the cerebellar cortex, diffuse synaptic-type PrP depositions were observed with numerous strongly immunopositive plaques. Western blot analysis of examined brain samples revealed mixed type 2 PrPSc (scrapie type) and intermediate-type PrPSc .

Amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Hohara focus of the Kii Peninsula: A multiple proteinopathy?

The high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) has been previously known in the Kii Peninsula of Japan and in Guam. Recently, the accumulation of various proteins, such as tau, trans-activation response DNA binding protein 43 kDa (TDP-43), and alpha-synuclein (αSyn), was reported in the brains of patients with ALS/PDC in Guam. To confirm whether similar findings are present in Kii ALS/PDC, we neuropathologically examined the brains and spinal cords of 18 patients with ALS/PDC (clinical diagnoses: eight ALS and 10 PDC) in Hohara Village, which is the eastern focus of Kii ALS. The average age at death was 71.6 years, and 16 patients (88.9%) had a family history of ALS/PDC. Autopsy specimens were immunohistochemically examined with antibodies against four major proteins. Neurofibrillary tangles, including ghost tangles, and tau-positive astrocytes were distributed widely in all of the brains examined, and TDP-43-positive neuronal cytoplasmic inclusions were observed mainly in the limbic system. Synuclein pathology was present in 14 patients (77.8%). These patients were classified into three pathological subtypes according to the most prominent proteinopathy: the tauopathy-dominant type, the TDP-43 proteinopathy-dominant type, and the synucleinopathy-dominant type. Five patients with severe tau deposition showed clinical features of atypical parkinsonism and dementia with or without motor neuron disease. Eight patients were predominated by phosphorylated TDP-43 inclusions and clinically showed ALS, and five patients were predominated by synuclein pathology and clinically showed signs of PDC. Based on the common characteristic tau pathology, three subtypes seemed to be pathologically continuous on a spectrum of a single disease. Thus, we conclude that ALS/PDC in the Hohara focus of the Kii Peninsula is a single disease characterized neuropathologically by a multiple proteinopathy, even though the clinical manifestations of the three subtypes differed from each other. It remains unclear whether the coexistence of the three proteinopathies was incidental or pathogenetically related.

Autopsy case of V180I genetic Creutzfeldt-Jakob disease presenting with early disease pathology.

The patient was a Japanese woman who experienced a decrease in activity and gait disturbance as the initial symptoms at the age of 86, followed by disorientation and memory dysfunction. Magnetic resonance imaging showed extensive cortical regions with hyperintensity in diffusion-weighted images, and these regions showed swelling in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. The medial occipital cortex and striatum showed no apparent hyperintensity on diffusion-weighted imaging (DWI). Mild myoclonus was detected, and the patient died 10 months after the onset of symptoms; she did not enter the akinetic mutism state. The patient's brain weighed 1050 g, and neuropathological examination showed extensive characteristic various-sized and non-confluent (VaSNoC) vacuoles in the cerebral cortex. These vacuoles were observable macroscopically by loupe on images of hematoxylin and eosin-stained tissue. Gliosis, hypertrophic astrocytosis, and neuron loss were generally mild in character. Prion protein (PrP) immunostaining showed very mild diffuse-synaptic-type PrP deposition in the cerebral gray matter. These clinicopathological findings led us to several conclusions relative to the early disease pathology of V180I genetic Creutzfeldt-Jakob disease: (i) spongiform change was not found in the medial occipital cortex, which corresponds to the results of DWI; (ii) VaSNoC-type spongiform changes, extensively recognized in the cerebral cortex, corresponded to the DWI findings showing continued hyperintensity with higher brightness, and T2-weighted and FLAIR images findings showing a swelling; and (iii) spongiform changes first appear in the deeper layer and subsequently in the superficial layer in the cerebral cortex.

Autopsied case of non-plaque-type dura mater graft-associated Creutzfeldt-Jakob disease presenting with extensive amyloid-ß deposition.

We present an autopsied case of non-plaque-type dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with extensive amyloid-ß (Aß) deposition in the brain. A 39-year-old Japanese woman presented with memory disturbance and abnormal behavior. The patient had a history of craniotomy with dura matter-graft transplant for a head injury which occurred when she was 19 years old. Magnetic resonance imaging (MRI) showed hyperintensities in the cerebral cortex and striatum on diffusion-weighted images, particularly on the dura mater-grafted right side. Her clinical symptoms, including rapidly progressing cognitive impairment, myoclonus, and periodic sharp wave complexes on electroencephalogram, could not be distinguished from typical sporadic CJD cases. The patient died 11 months after symptom onset, and pathological investigations showed extensive spongiform degeneration with prion protein (PrP) deposition without Kuru plaques; these observations were essentially the same as those of typical sporadic CJD cases. Furthermore, Aß immunohistochemistry showed extensive diffuse staining in the cerebral neocortex, plaque-type deposition, positive staining in the pia mater, and cerebral amyloid angiopathy. Although the MRI findings suggested that the pathological involvement originated from the dura mater-grafted right side, the PrP and Aß depositions showed no apparent regionalization and laterality. Tau-pathology including neurofibrillary tangles was hardly identified. The proteins phosphorylated α-synuclein and phosphorylated transactivation response DNA-binding protein 43 kDa were not detected on immunostaining. Although this report describes only one case, various speculations were made based on detailed clinical and pathological observations in conjunction with previous reports of dCJD. In particular, this report provides significant insight into the characteristics and progression of dCJD pathology and its relationship with Aß pathology.

Paraneoplastic autoimmune encephalitis associated with pleomorphic lung carcinoma: An autopsy case report.

A 64-year-old man was admitted with acute onset disturbed consciousness. Cerebrospinal fluid analysis revealed pleocytosis and elevated protein, with negative cultures and PCR. Serum antibodies for autoimmune encephalitis were also negative. Brain magnetic resonance imaging (MRI) was unremarkable, but whole-body CT scan showed a tumor in the left lower lung lobe. Bronchial brush cytology demonstrated clusters of malignant cells, and 18 F-fluorodeoxyglucose positron emission tomography showed multiple lesions and increased uptake in the lung tumor. Clinically the patient had a stage IV lung carcinoma, graded as T3N3M1b (OSS). Steroid therapy had limited efficacy, but chemotherapy dramatically improved his neurological symptoms. Therefore, he was diagnosed with paraneoplastic autoimmune encephalitis based on the diagnostic criteria for paraneoplastic neurological syndromes. He died due to disease progression 14 months later. Subsequent postmortem examination revealed white ill-defined nodules in the left lung, with similar nodules in other organs. The brain weighed 1500 g before fixation, and a nodule was observed in the right precentral gyrus. Microscopically, the lung tumor was a pleomorphic carcinoma with an adenocarcinoma component. Multiple areas of micro-softening (≤500 µm) were identified in the cerebral cortex, gray-white matter junction and basal ganglia, and were distributed diffusely in both the limbic and non-limbic systems. Mild lymphocytic infiltrates were observed involving few intraparenchymal vessels. Few tumor metastases were observed in the right precentral gyrus. The multiple micro-softenings may reflect a chronic neuropathologic change of paraneoplastic autoimmune encephalitis. They were too small to be detected by brain MRI. However, these lesions may have the potential to cause the neurological symptoms in the acute phase because they were observed in many anatomical regions. We should pay attention to subtle findings such as micro-softenings when estimating the neuropathology of autoimmune encephalitis. Further investigations are needed to understand the characteristic neuropathology of this condition.

Autopsied centenarian case of Alzheimer's disease combined with hippocampal sclerosis, TDP-43, and α-synuclein pathologies.

A Japanese woman showed slowly progressive memory disturbance starting at the age of 84 years, and disorientation gradually appeared. Head computed tomography revealed severe hippocampal atrophy, whereas the atrophy of the frontal lobe was considerably mild for her age. Behavioral and psychological symptoms of dementia were relatively inconspicuous during the disease course. Apolipoprotein E gene analysis showed ε3/ε4 heterozygosity. She died at the age of 100 years and she was clinically diagnosed as having Alzheimer's disease (AD). Autopsy revealed numerous neurofibrillary tangles, particularly in the hippocampal region, and extensively distributed senile plaques in the brain. Although the findings were compatible with the pathological criteria for AD, combined pathologies of hippocampal sclerosis, trans-activation response DNA-binding protein 43 kDa, and α-synuclein were also revealed. We believe that the clinicopathological findings of the present case are of significance for the diagnosis of elderly dementia and pathogenesis of AD.

Pathological diagnosis of combined Alzheimer's disease and argyrophilic grain dementia in a very elderly man who presented with advanced behavioural and psychological symptoms.

This case report describes a Japanese man who presented with slowly progressive memory disturbances that began at the age of 79 years. The man also displayed conspicuous behaviour and psychological symptoms in the early stage of dementia. Computed tomography revealed atrophy of the amygdala and severe hippocampal deterioration, particularly in the anterior portion. Lateral ventricular dilatation, mainly affecting the anterior and inferior horns, was also observed. Interestingly, cerebral neocortical atrophy in the frontal and temporal lobes was considerably mild for the patient's age. Apolipoprotein E gene analysis showed epsilon 3 homozygosity. The patient died at the age of 96 years, and his clinical diagnosis was Alzheimer's disease with severe behavioural and psychological symptoms of dementia. In addition to indicating considerable hippocampal atrophy, an autopsy revealed numerous neurofibrillary tangles and argyrophilic grains in the brain, as well as extensive senile plaques. Cerebral amyloid angiopathy was also recognized. The pathological findings were suggestive of both Alzheimer's disease and argyrophilic grain dementia; other neurodegenerative disorders were not apparent. The clinicopathologic findings of the present case suggest significant consideration should be made when determining the clinical diagnosis and pathogenesis of senile dementia.

An autopsied case of corticobasal degeneration presenting with frontotemporal dementia followed by myoclonus.

A Japanese woman developed frontotemporal dementia (FTD)-like symptoms of abnormal behavior, such as stereotyped behavior and disinhibition. The patient developed these symptoms at the age of 59 years, although aphasia symptoms were not apparent at early disease stages. Progressive parkinsonism was dominant on the left side, and conspicuous myoclonus was recognized in the late disease stage. MRI indicated severe, right side-dominant frontotemporal lobe atrophy with white matter degeneration. Brainstem and cerebellar atrophy were also observed. The patient underwent gastrostomy 7 years after the onset of her symptoms and died at the age of 70 years. Neuropathological examination showed diffuse neuron loss with gliosis and tissue rarefaction in the frontotemporal lobe, particularly in the right anterior portion of the frontal lobe. Spongiform changes and ballooned neurons were also observed in the frontotemporal cortex, particularly in the superficial layer and deeper layers, respectively. Gallyas-Braak silver staining and anti-phosphorylated tau immunostaining indicated numerous argyrophilic and tau-positive structures, including pretangles, astrocytic plaques, coiled bodies and neuropil threads. We speculate that the myoclonus observed in the present case was at least partly caused by or related to the spongiform change and ballooned neurons in the cerebral cortex. The clinical phenotypes of corticobasal degeneration (CBD) vary considerably, and the clinical presentation of the present patient was compatible with frontal behavioral-spatial syndrome in the early disease stage. However, in the later disease stages, her symptoms were reflective of corticobasal syndrome. Because it is not rare for the clinical phenotype to change along with disease progression in cases of CBD, we should consider CBD in cases presenting with FTD at symptom onset.

An autopsied case of MM1 + MM2-cortical with thalamic-type sporadic Creutzfeldt-Jakob disease presenting with hyperintensities on diffusion-weighted MRI before clinical onset.

A 78-year-old Japanese man presented with rapidly progressive dementia and gait disturbances. Eight months before the onset of clinical symptoms, diffusion-weighted magnetic resonance imaging (DWI) demonstrated hyperintensities in the right temporal, right parietal and left medial occipital cortices. Two weeks after symptom onset, DWI showed extensive hyperintensity in the bilateral cerebral cortex, with regions of higher brightness that existed prior to symptom onset still present. Four weeks after clinical onset, periodic sharp wave complexes were identified on an electroencephalogram. Myoclonus was observed 8 weeks after clinical onset. The patient reached an akinetic mutism state and died 5 months after onset. Neuropathological examination showed widespread cerebral neocortical involvement of fine vacuole-type spongiform changes with large confluent vacuole-type spongiform changes. Spongiform degeneration with neuron loss and hypertrophic astrocytosis was also observed in the striatum and medial thalamus. The inferior olivary nucleus showed severe neuron loss with hypertrophic astrocytosis. Prion protein (PrP) immunostaining showed widespread synaptic-type PrP deposition with perivacuolar-type PrP deposition in the cerebral neocortex. Mild to moderate PrP deposition was also observed extensively in the basal ganglia, thalamus, cerebellum and brainstem, but it was not apparent in the inferior olivary nucleus. PrP gene analysis showed no mutations, and polymorphic codon 129 showed methionine homozygosity. Western blot analysis of protease-resistant PrP showed both type 1 scrapie type PrP (PrPSc ) and type 2 PrPSc . Based on the relationship between the neuroimaging and pathological findings, we speculated that cerebral cortical lesions with large confluent vacuoles and type 2 PrPSc would show higher brightness and continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrPSc . We believe the present patient had a combined form of MM1 + MM2-cortical with thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD), which suggests a broader spectrum of sCJD clinicopathological findings.

An autopsied case of MV2K + C-type sporadic Creutzfeldt-Jakob disease presenting with widespread cerebral cortical involvement and Kuru plaques.

MV2-type sporadic Creutzfeldt-Jakob disease (sCJD), which was previously called "Kuru-plaque variant", was gradually revealed to have a wide spectrum and has been classified into three pathological subtypes: MV2K, MV2C and MV2K + C. We herein describe the detailed clinical findings and neuropathologic observations from an autopsied MV2K + C-type Japanese sCJD case with widespread cerebral cortical pathology and Kuru plaques. In the early stages of the disease, the patient exhibited gait disturbance with ataxia and dysarthria as well as gradual appearance of cognitive dysfunction. Diffusion-weighted images (DWI) on MRI revealed extensive cerebral cortical hyperintensity. Pathologic investigation revealed extensive spongiform change in the cerebral cortex, particularly in the deeper layers. Vacuole size varied, and some were confluent. Prion protein (PrP) immunostaining revealed extensive PrP deposition in the cerebral cortex, basal ganglia, thalamus, cerebellum, brainstem and spinal cord. In the cerebral cortex, synaptic-type, Kuru plaque-like, and coarse plaque-type PrP depositions were mainly observed, along with some perivacuolar-type PrP depositions. Kuru plaques and coarse plaque-type PrP depositions also were observed in the cerebellar cortex. PrP gene analysis revealed no mutations, and polymorphic codon 129 exhibited Met/Val heterozygosity. Western blot analysis revealed a mixture of intermediate-type PrPSc and type 2 PrPSc . Based on previous reports regarding MV2-type sCJD and the clinicopathologic findings of the present case, we speculated that it may be possible to clinically distinguish each MV2 subtype. Clinical presentation of the MV2K + C subtype includes predominant cerebral cortical involvement signs with ataxia and DWI hyperintensity of the cerebral cortex on MRI.

An autopsy case of Creutzfeldt-Jakob disease with a prion protein gene codon 180 mutation presenting with pathological laughing and an exaggerated startle reaction.

A 78-year-old Japanese woman presented with slow progressive disorientation and memory disturbances. Pathological laughing was observed at an early disease stage and continued for several months. Around the same time, the patient began to exhibit an exaggerated startle reaction and mild myoclonus. The pathological laughing and startle reaction disappeared before the patient reached an akinetic mutism state approximately 16 months after symptom onset. MRI showed extensive hyperintensity of the cerebral cortex and striatum on diffusion-weighted images, and swelling in the cerebral cortex on T2-weighted and fluid attenuated inversion recovery images. A prion protein (PrP) gene analysis revealed a V180I mutation with methionine homozygosity at codon 129. Neuropathological examination showed extensive spongiform changes with characteristic various-sized and non-confluent (VaSNoC) vacuoles in the cerebral neocortex and striatum. Gliosis and hypertrophic astrocytosis were generally mild in character. Neurons were relatively preserved in number. We believe that pathological laughing and an exaggerated startle reaction are possible pathognomonic findings of V180I genetic Creutzfeldt-Jakob disease. Based on the pathological findings of the present case, the presence of the VaSNoC-type spongiform changes with relative preservation of the neurons in the cerebral cortex and a lack of apparent brainstem involvement are associated at least in part with the pathological laughing and startle reaction.

MM1-type sporadic Creutzfeldt-Jakob disease with 1-month total disease duration and early pathologic indicators.

A 62-year-old man presented with abnormal behavior and cognitive impairment. Diffusion-weighted images (DWI) obtained on MRI showed extensive hyperintense regions in the cerebral cortex and striatum. Myoclonus was recognized, and the patient died 1 month after the onset; his condition did not reach the akinetic mutism state. The brain weighed 1300 g and showed no apparent atrophy. Extensive spongiform changes were observed in the cerebral neocortex, striatum, thalamus and cerebellar cortex, but gliosis was mild or absent. Neuropil rarefaction and neuron loss were not apparent. Mild proliferation of anti- GFAP-positive astrocytes was observed in the cerebral cortex, but unaffected regions were noted. Regions without spongiform changes and GFAP-positive astrocytes included the hippocampal formation and subiculum. PrP immunostaining showed extensive diffuse synaptic-type PrP deposition in the gray matter, including the hippocampal region, but it was also mild. PrP gene analysis revealed no mutation with methionine homozygosity at polymorphic codon 129. Western blot analysis of proteinase K-resistant PrP indicated type 1 PrPSc . The clinicopathological findings of the present case confirm several hypotheses: (i) the earliest pathologic evidence observed by HE staining in CJD are spongiform changes; (ii) DWI hyperintense regions indicate these spongiform changes; and (iii) regions without spongiform changes, gliosis and proliferation of GFAP-positive astrocytes, but with PrP deposition, exist in the early disease stage.

An autopsy case of a centenarian with the pathology of senile dementia of the neurofibrillary tangle type.

A Japanese woman showed slowly progressive memory disturbance since the age of 85 years. Later, disorientation gradually appeared. Head computed tomography revealed severe hippocampal atrophy, particularly in the posterior portion, and lateral ventricular dilatation, particularly in the inferior horn at the age of 99 years. The amygdala was relatively preserved from atrophy, and atrophy of the frontal lobe was relatively mild for her age. Apolipoprotein E gene analysis showed the ε3 homozygous phenotype. The woman died at the age of 101 years, and her clinical diagnosis was mild Alzheimer's disease. No apparent behavioural and psychological symptoms of dementia were observed during the disease course. Autopsy revealed severe hippocampal atrophy with numerous neurofibrillary tangles and ghost tangles, particularly in the hippocampal region, but senile plaques were rarely observed in the brain. The pathological findings were compatible with senile dementia of the neurofibrillary tangle type, whereas other neurodegenerative disorders were not recognized. The clinicopathologic findings of the present case are considered significant for the clinical diagnosis and pathogenesis of senile dementia of the neurofibrillary tangle type.