An atypical case of sporadic Creutzfeldt–Jakob disease with Parkinson's disease

We report here an autopsy case of a 64‐year‐old female with slowly progressive dementia and parkinsonism in a 4‐year‐long clinical course. Post‐mortem examination revealed a severely atrophic brain with spongiform degeneration, neuronal loss and gliosis in the gray matter. Many prion protein plaque deposits were present in the occipital lobe, amygdala and cerebellum. Additionally, Lewy bodies were observed in the brainstem. Prion protein gene analysis of the patient revealed polymorphism at the codon‐129 valine heterozygote. This genotype is known to sometimes accompany a missense mutation of the gene in uncommon hereditary prion diseases, but no mutation was found in the open reading frame. Thus, it might be suggested that this case showed simultaneously the features of both sporadic Creutzfeldt‐Jakob disease (CJD) with codon‐129 valine and Parkinson's disease. However, the predisposing factors for contracting both diseases simultaneously remain to be determined, because the incidence of Parkinson's disease accompanied by CJD is very low.     

A sporadic case of Creutzfeldt–Jakob disease with beta‐amyloid deposits and alpha‐synuclein inclusions

Neurodegenerative disorders are characterized by the correlation of clinical symptoms and neuropathological changes in the brain. However, overlaps between distinct entities are becoming more and more evident. We report the coexistence of Alzheimer pathology and alpha‐synuclein inclusions in a sporadic, methionine/valine type 1, Creutzfeldt–Jakob disease (CJD) case. There were neurofibrillary changes in the neocortex and beta amyloid cerebral angiopathy was marked. Several Lewy bodies were present in the substantia nigra, locus ceruleus and the dorsal motor nucleus of the vagus, and alpha‐synuclein cytoplasmic inclusions were also found in cortical neurons. These findings raise the debated relationship between Parkinson’s disease with dementia, dementia with Lewy bodies and a Lewy body variant of Alzheimer disease. Among the factors that may have contributed to this considerable morphological overlap are the patient’s age (79 years at autopsy) and the over 2‐year duration of the disease. As the average disease duration in sporadic methionine/valine type 1 CJD is less than 6 months, it seems legitimate to speculate that the initial symptoms resulted from Alzheimer and alpha‐synuclein related pathologies. This observation shows that CJD can be present in elderly patients who are suspected of having other neurodegenerative diseases, which could underline the importance of neuropathology‐based surveillance systems.     

Coexistence of mixed phenotype Creutzfeldt‐Jakob disease,Lewy body disease and argyrophilic grain disease plus histological features of possible Alzheimer's disease: A multi‐protein disorder in an autopsy case

We report hereby an autopsy case of sporadic mixed phenotype CJD without hereditary burden and a long‐term clinical course. An 80‐year old man was diagnosed with mild cognitive impairment 27 months before death, caused by bronchopneumonia and severe respiratory impairment. During this time, the patient developed gradual mental deterioration, some sleeping problems and myoclonus. Other clinical manifestations were progressive gait problems, language deterioration, presence of primitive reflexes and irritability. In keeping with those symptoms, a rapidly evolving dementia was clinically suspected. Cerebrospinal fluid test for 14‐3‐3 protein was negative. However, an abnormal EEG and MRI at end‐stage of disease were finally consistent with CJD. Post‐mortem examination revealed a massive cortical neuronal loss with associated reactive astrocytosis, also evident in the white matter. Diffuse spongiform changes involving some basal ganglia, especially medial thalamus, some troncoencephalic nuclei, mainly inferior olivary nucleus and the molecular layer of the cerebellum were seen. Immunorreactive deposits for anti‐prion protein antibody were present at different areas of the CNS. Additionally, Lewy bodies were observed at the brainstem and amygdala. Furthermore, argirophilic grains together with oligodendroglial coiled bodies and pre‐tangle inclusions in the neurons from the limbic system containing hyperphosphorylated 4R tau were noted. To the best of our knowledge, this is the first case of CJD combined with Lewy body disease and argirophilic grain disease. Furthermore, we believe this case is an extremely rare combination of MM2‐cortical‐type and MM2‐thalamic‐type sporadic CJD (sCJD), which explains the broad spectrum of MM2‐type sCJD findings and symptoms. Moreover, histological features of possible Alzheimer's disease were also reported.     

Movement disturbances in the differential diagnosis of Creutzfeldt‐Jakob disease

Movement disturbances are common in dementia disorders and are a central feature of the clinical classification criteria of Creutzfeldt‐Jakob disease (CJD). Polymorphism at codon 129 of the prion protein gene is known to determine the clinical picture of CJD. The frequency and characteristics of movement disturbances in other dementing disorders, such as Alzheimer's disease (AD), is barely known and leads to misdiagnoses. We investigated the occurrence and characteristics of movement disturbances in 143 patients neuropathologically confirmed with CJD (n = 100), AD (n = 29), dementia with Lewy bodies (DLB) (n = 7), or other diagnoses (n = 7). All patients had been referred with the differential diagnosis of prion disease. Ataxia and dysmetria were significantly more frequent in CJD than in AD or DLB patients, whereas hypokinesia was up to five times more frequent in AD or DLB (P < 0.05). Using an ordered logistic regression to identify constellations of movement disturbances, the diagnosis of CJD was likely in patients presenting ataxia but not hypokinesia. The reverse situation was statistically associated with AD. Ataxia and cogwheel rigidity were associated with valine‐homozygosity and akinesia with methionine‐homozygosity in the CJD patients. Our results indicate that the careful assessment of movement disturbances may be helpful in the differential diagnosis of Creutzfeldt‐Jakob disease. © 2008 Movement Disorder Society     

Creutzfeldt‐Jakob disease

This review will explore the clinical and pathological findings of the various forms of Creutzfeldt‐Jakob disease (CJD). Clinical findings of CJD are characterized by rapidly progressive cognitive dysfunction, diffusion‐weighted magnetic resonance imaging (DWI) hyperintensity, myoclonus, periodic sharp‐wave complexes on electroencephalogram and akinetic mutism state. Neuropathologic findings of CJD are characterized by spongiform changes in gray matter, gliosis—particularly hypertrophic astrocytosis—neuropil rarefaction, neuron loss and prion protein (PrP) deposition. The earliest pathological symptom observed by HE staining in the cerebral cortex is spongiform change. This spongiform change begins several months before clinical onset, and is followed by gliosis. Subsequently, neuropil rarefaction appears, followed by neuron loss. Regions showing fine vacuole‐type spongiform change reflect synaptic‐type PrP deposition and type 1 PrP^Sc deposition, whereas regions showing large confluent vacuole‐type spongiform changes reflect perivacuolar‐type PrP deposition and type 2 PrP^Sc deposition. Hyperintensities of the cerebral gray matter observed in DWI indicate the pathology of the spongiform change in CJD. The cerebral cortical lesions with large confluent vacuoles and type 2 PrP^Sc show higher brightness and more continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrP^Sc. CJD cases showing diffuse myelin pallor of cerebral white matter have been described as panencephalopathic‐type, and this white matter pathology is mainly due to secondary degeneration caused by cerebral cortical involvement, particularly in regard to neuron loss. In conclusion, clinical and neuroimaging findings and neuropathologic observations are well matched in both typical and atypical cases in CJD. The clinical diagnosis of CJD is relatively easy for typical CJD cases such as the MM1‐type. However, even in atypical cases it seems that clinical findings can be used for an accurate diagnosis.     

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 (PrP^Sc) but also, partially, mixed type‐2 PrP^Sc. 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 PrP^Sc, at least partially, within certain regions of the cerebrum.     

Creutzfeldt‐Jakob disease with an M232R substitution: report of a patient showing slowly progressive disease with abundant plaque‐like PrP deposits in the cerebellum

Patients with genetic Creutzfeldt‐Jakob disease in which arginine is substituted for methionine at codon 232 (M232R) of the prion protein gene (CJD232) have been described in Japan, and a recent study has revealed the presence of two clinical phenotypes: a rapidly progressive type (rapid‐type) and a slowly progressive type (slow‐type). Although the former is known to show pathologic features similar to those of classical CJD, the neuropathology of the latter still remains unclear. We report the autopsy findings of slow‐type CJD232 of 37 months' duration in a 73‐year‐old man who had methionine homozygosity at codon 129 of the prion protein gene (129MM). His initial symptoms included agraphia and memory disturbance, followed by relatively slowly progressive dementia. Myoclonus and akinetic mutism became evident 5 and 23 months after disease onset, respectively. The electroencephalogram revealed periodic sharp wave complexes at 7 months before death. The neuropathologic features were partly reminiscent of those of MM2‐cortical‐type sporadic CJD, showing spongiform change of the large confluent vacuole type, neuronal loss with gliosis, and coarse, perivacuolar prion protein deposits, which were later shown to consist of protease‐resistant type 2 prion protein, in the cerebral cortex and striatum. It was of considerable interest that not only was the medial thalamus severely involved, but also that the cerebellar cortex showed loss of Purkinje cells and abundant plaque‐like prion protein deposits. These findings are not a feature of MM2‐cortical‐type sporadic CJD. Whether or not the M232R substitution, in combination with the genetic polymorphism and the molecular type of pathological prion protein, really participates in the development of CJD232 and its different phenotypes awaits further studies.     

Spatial pattern of prion protein deposits in patients with sporadic Creutzfeldt–Jakob disease

The spatial pattern of the prion protein (PrP) deposits was studied in the cerebral cortex and cerebellum in 10 patients with sporadic Creutzfeldt–Jakob disease (CJD). In all patients the PrP deposits were aggregated into clusters and, in 90% of cortical areas and in 50% of cerebellar sections, the clusters exhibited a regular periodicity parallel to the tissue boundary; a spatial pattern also exhibited by β‐amyloid (Aß) deposits in Alzheimer's disease (AD). In the cerebral cortex, the incidence of regular clustering of the PrP deposits was similar in the upper and lower cortical laminae. The sizes of the PrP clusters in the upper and lower cortex were uncorrelated. No significant differences in mean cluster size of the PrP deposits were observed between brain regions. The size, location and distribution of the PrP deposit clusters suggest that PrP deposition occurs in relation to specific anatomical pathways and supports the hypothesis that prion pathology spreads through the brain via such pathways. In addition, the data suggest that there are similarities in the pathogenesis of extracellular protein deposits in prion disease and in AD.     

Autopsy case of sporadic Creutzfeldt–Jakob disease presenting with signs suggestive of brainstem and spinal cord involvement

We describe an autopsy case of MM1‐type sporadic Creutzfeldt–Jakob disease (CJD), the duration of which was 93 days. The patient was a 59‐year‐old Japanese man with no family history of prion disease or known iatrogenic exposure to CJD. His first symptom was dysesthesia in the left arm, suggestive of cervical cord involvement, and he showed rapidly progressive neurologic signs, such as dysarthria, dysphagia, lethargy, sleep apnea and respiratory failure, suggestive of brainstem involvement. Progressive mental deterioration combined with episodes of myoclonic seizure and periodic synchronous discharges on the electroencephalogram were observed in the later disease stage. Autopsy showed typical spongiform change to be widespread in the cerebral and cerebellar cortices, thalamus and basal ganglia. Synaptic‐type PrP deposition was marked in the cerebral cortex, thalamus and basal ganglia. In the cerebellum, although the granular, molecular and Purkinje cell layers were well preserved from neuronal loss and gliosis, PrP deposition was marked in the molecular and granular cell layers. Spongiform degeneration and neuronal loss were not seen in the brainstem and spinal cord, but relatively marked PrP deposition was observed in the quadrigeminal body, substantia nigra, pontine nucleus, inferior olivary nucleus and posterior horn. Immunohistochemical staining for HLA‐DR showed proliferation of activated microglia in the cerebral and cerebellar cortices, pontine nucleus, inferior olivary nucleus and posterior horn. The mechanisms underlying the neurologic symptoms and signs were unclear, but we speculate that, in addition to widespread involvement of the cerebral cortex, PrP deposition and microglial activation in the brainstem and spinal cord were responsible.     

Coexistence of CJD and Alzheimer's disease: An autopsy case showing typical clinical features of CJD

The present report concerns an autopsy case of CJD showing typical clinical features of CJD. The patient was a Japanese woman without hereditary burden or dementing disorder anamnesis who was 70‐years‐old at the time of death. She developed gait disturbance at age 68, followed by memory impairment, visual disturbance, and myoclonus. A neurological examination approximately 2 months after the disease onset revealed akinetic mutism, in addition to periodic synchronous discharges on electroencephalogram. Serial neuroradiological examinations disclosed progressive atrophy of the brain. She died of bronchopneumonia 25 months after the disease onset. The brain weighed 560 g (cerebrum 490 g, brainstem with cerebellum 70 g). Macroscopically, neuropathological examination showed prominent atrophy of the cerebrum, caudate nucleus, and cerebellum, in addition to necrosis of the cerebral white matter, compatible with panencephalopathic CJD. Histologically, there was neuronal loss with or without spongiform change in the cerebral cortex, parahippocampal gyrus, amygdala, striatum, pallidum, thalamus, pontine nucleus, and cerebellar granule cells, in addition to diffuse synaptic‐type prion staining in the cerebrum and cerebellum. Furthermore, senile plaques, compatible with definite Consortium to establish a registry for Alzheimer's disease rank Alzheimer's disease, and neurofibrillary changes of the limbic system, consistent with stage IV of Braak's classification, were found. Based on these clinicopathological findings and a review of the published literature, it is concluded that there were two forms of coexistence of CJD and Alzheimer's disease in the same patient.     

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 PrP^Sc (scrapie type) and intermediate‐type PrP^Sc.     

Autopsied case of non‐plaque‐type dura mater graft‐associated Creutzfeldt‐Jakob disease presenting with extensive amyloid‐β deposition

We present an autopsied case of non‐plaque‐type dura mater graft‐associated Creutzfeldt‐Jakob disease (dCJD) with extensive amyloid‐β (Aβ) 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, Aβ 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 Aβ 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 Aβ pathology.     

Clinicopathologic characteristics of five autopsied cases of dura mater‐associated Creutzfeldt‐Jakob disease

We present five cases of dura mater‐associated Creutzfeldt‐Jakob disease (dura‐CJD) that were analyzed clinicopathologically and review previous reports. The average age at dura mater transplantation was 54.4 ± 7.3 years, and the average age at CJD onset was 66.0 ± 8.2 years, with an average latency period of 11.6 ± 1.1 years. The average age at death was 67.6 ± 8.7 years, with an average CJD disease duration of 16.8 ± 10.4 months. Symptoms of CJD onset in four patients who received dura mater transplantation below the cerebellar tent reflected cerebellar or brainstem dysfunction, whereas symptoms of one patient who received transplantation above the cerebellar tent reflected cerebral cortical involvement. All patients showed rapidly progressive cognitive impairment, and both periodic sharp‐wave complexes on electroencephalogram and myoclonus were observed in the early disease stage. Neuropathologic evaluation showed one case of subacute spongiform encephalopathy and four cases of panencephalopathic‐type CJD. Widespread cerebral neocortical, subcortical gray matter and cerebellar cortical involvement were observed to varying degrees, and severity tended to be associated with CJD disease duration. There were no instances of kuru plaques or florid plaques. Prion protein (PrP) immunostaining showed widespread synaptic‐type PrP deposition. No differences between our dura‐CJD cases and typical cases of sporadic CJD were found with respect to clinicopathologic findings, except history of dura mater transplantation. Although a specific association between the dura mater graft site and neuropathologic observations was not evaluated in the present study, the initial symptoms appear to be closely related to the graft site, indicating a direct transmission of CJD from the graft site to the adjacent brain.     

Creutzfeldt–Jakob disease

Creutzfeldt–Jakob disease (CJD) is a progressive, degenerative, and fatal disease of the central nervous system. It is caused by abnormal accumulation of prion proteins and is characterized mainly by progressive dementia, myoclonus, and cerebellar, pyramidal, and extrapyramidal findings. Psychiatric symptoms may also accompany CJD and are often the first signs of the disease. The incidence of CJD is approximately 1 in 1 000 000. In certain cases, a diagnosis can be made by demonstrating the accumulation of pathological prion proteins. However, in many cultures brain biopsies or post‐mortem evaluations are not welcomed by either the patients or their relatives. In these cases, the importance of additional diagnostic tools increases. Herein, we report on a CJD patient who first consulted a psychiatrist with early psychiatric symptoms. The patient developed neurological symptoms later and was subsequently diagnosed as sporadic CJD based on clinical and laboratory findings rather than brain biopsy. Repeated electroencephalograms (EEG) played a pivotal role in our evaluation of the patient. This case is an interesting presentation of CJD both because of the timing of the symptoms and because of the typical EEG findings that led to the diagnosis.     

Immunohistochemical studies of the PrPCJD deposition in Creutzfeldt‐Jakob disease

The PrP^CJD deposition in eight brains of sporadic Creutzfeldt‐Jakob disease (CJD) was examined immunohistochemically using both hydrolytic autoclaving and formic acid pretreatment in order to understand the pathogenesis of CJD. Synaptic‐type PrP immunoreactivity was revealed in the gray matter in all cases and had a tendency to be weaker in devastated areas in cases with a longer duration of illness. However, in one particular case with numerous prion plaques, the degeneration was relatively mild while PrP^CJD immunoreactivity was intense despite the longest duration of illness among the examined cases. Deep layer accentuation of PrP^CJD immunoreactivity was observed in the cerebral cortices in most cases. This staining pattern, however, disappeared in a burnt‐out lesion exhibiting status spongiosus. The granular layer was damaged mostly in the cerebellum of the advanced cases. PrP^CJD and synaptophysin immunoreactivities decreased as the tissue degeneration progressed. Interestingly, the Purkinje cells had no positivity for PrP^CJD in all cases, although the neurons in relatively preserved cerebellum showed apparent positivity for synaptophysin. In the Ammon’s horn and subiculum the neurons were well preserved despite the marked immunoreactivity for PrP^CJD in all cases, although some cases demonstrated severe spongiform change. Approximately half of the cases showed intracytoplasmic inclusion body‐like immunoreactivity for PrP^CJD in neurons of the dentate nucleus. These findings suggest that PrP^CJD deposition may be an event that precedes neuronal degeneration evolving from deeper layers of the cerebral cortex. Although the Ammon’s horn and subiculum showed striking PrP^CJD deposition and spongiform change, neuronal loss did not take place, suggesting that deposited PrP^CJD itself seems not to be directly harmful to the neurons. Some investigators have assumed that microglia activated by PrP^CJD plays an important role in neuronal degeneration. Considering this, we speculate that microglia in the Ammon’s horn and subiculum may have a unique characteristic of not responding to PrP^CJD.     

Neuropathological and biochemical criteria to identify acquired Creutzfeldt‐Jakob disease among presumed sporadic cases

As an experimental model of acquired Creutzfeldt‐Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock‐in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP^Sc). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP^Sc in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft‐associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion‐contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP^Sc, represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.     

A case of sporadic Creutzfeldt‐Jakob disease with both plaque and synaptic‐type deposition of prion protein

We report a Japanese case of sporadic Creutzfeldt‐Jakob disease (CJD) with particular clinical course and neuropathological findings. A 74‐year‐old female exhibited parkinsonism and later, dementia, myoclonus as well as visual hallucinations, lacking periodic synchronous discharges in the electroencephalogram. The duration of her illness was 2 years, longer than typical CJD cases which average 8 months’ duration. Gray matter was severely affected, the Ammon’s horn and subicular cortex were well preserved and many kuru plaques were observed in the cerebellum using routine histological stainings. Immunohistochemistry for prion protein (PrP) using both formic acid and hydrolytic autoclaving pretreatment revealed numerous prion plaques throughout the brain together with intense synaptic‐type deposition of PrP^CJD (abnormal isoform of PrP) in all gray matter examined, particularly in the Ammon’s horn and subicular cortex. The definite combination of these two types of stain has never been reported previously in Japan other than in Gerstmann‐Sträussler– Scheinker syndrome. Relative resistance of the Ammon’s horn and subicular cortex to the PrP^CJD deposition is also discussed.     

An autopsied case of V180I Creutzfeldt‐Jakob disease presenting with panencephalopathic‐type pathology and a characteristic prion protein type

A 73‐year‐old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2‐weighted images in the initial stage, and a later high‐signal intensity region was observed in the cerebral cortex in diffusion‐weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp‐wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patient's clinical symptoms and disease course were atypical for Creutzfeldt–Jakob disease (CJD), and a stable state with nasal tube‐feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic‐type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long‐term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic‐type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque‐like PrP deposition. Western blot analysis of protease‐resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings.     

The risk of iatrogenic Creutzfeldt‐Jakob disease through medical and surgical procedures

There have been more than 400 patients who contracted Creutzfeldt‐Jakob disease (CJD) via a medical procedure, that is, through the use of neurosurgical instruments, intracerebral electroencephalographic electrodes (EEG), human pituitary hormone, dura mater grafts, corneal transplant, and blood transfusion. The number of new patients with iatrogenic CJD has decreased; however, cases of variant CJD that was transmitted via blood transfusion have been reported since 2004. Clearly, iatrogenic transmission of CJD remains a serious problem. Recently, we investigated medical procedures (any surgery, neurosurgery, ophthalmic surgery, and blood transfusion) performed on patients registered by the CJD Surveillance Committee in Japan during a recent 9‐year period. In a case‐control study comprising 753 sporadic CJD (sCJD) patients and 210 control subjects, we found no evidence that prion disease was transmitted via the investigated medical procedures before onset of sCJD. In a review of previously reported case‐control studies, blood transfusion was never shown to be a significant risk factor for CJD; our study yielded the same result. Some case‐control studies reported that surgery was a significant risk factor for sCJD. However, when surgical procedures were categorized by type of surgery, the results were conflicting, which suggests that there is little possibility of prion transmission via surgical procedures. In our study, 4.5% of sCJD patients underwent surgery after onset of sCJD, including neurosurgeries in 0.8% and ophthalmic surgeries in 1.9%. The fact that some patients underwent surgery, including neurosurgery, even after the onset of sCJD indicates that we cannot exclude the possibility of prion transmission via medical procedures. We must remain vigilant against prion diseases to reduce the risk of iatrogenesis.     

An autopsied case of Creutzfeldt‐Jakob disease with mutation in the prion protein gene codon 232 and type 1+2 prion protein

A 68‐year‐old Japanese man gradually showed abnormal behavior and gait disturbance with bradykinesia. Slowly progressive dementia, including memory disturbance and disorientation, was also observed. Cerebral cortical hyperintensity on diffusion‐weighted MRI was observed 6 months after onset. The patient progressed to an akinetic mutism state with mild myoclonus, and atypical periodic sharp‐wave complexes were observed by electroencephalogram 13 months after onset. He was clinically suspected of having atypical CJD and died after 19 months total disease duration. The brain weighed 1160 g and showed mild atrophy of the cerebrum and cerebellum with ventricular dilatation. Spongiform changes with varying vacuole size and gliosis was extensive in the cerebral cortex and basal ganglia. Neuron loss in the cerebral cortex, basal ganglia and thalamus was relatively mild. The cerebellum showed mild spongiform changes of the molecular layer and mild neuron loss in the Purkinje cell layer. PrP immunostaining showed mainly coarse‐type combined with diffuse synaptic‐type PrP deposition in the cerebral gray matter. Some perivacuolar‐type PrP deposition was also present. Numerous plaque‐type PrP depositions were observed in the molecular layer of the cerebellum. Analysis of the PrP gene revealed a methionine‐to‐arginine (Met‐to‐Arg) substitution at codon 232 (M232R) with Met homozygosity at codon 129. Western blot analysis of protease‐resistant PrP indicated type 2 dominant PrP combined with type 1. Genetic CJD with M232R substitution in the PrP gene has only been reported in Japan. Although two clinical phenotypes (rapid‐type and slow‐type) were suggested in the M232R CJD cases (despite the presence of the same PrP genotype), the pathological and molecular backgrounds have not been well understood because there have only been a few autopsied case reports. This is the first case report of M232R CJD presenting with 1 + 2 PrP.