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.     

MM1‐type sporadic Creutzfeldt‐Jakob disease with unusually prolonged disease duration presenting with panencephalopathic‐type pathology

We report an autopsy case of MM1‐type sporadic Creutzfeldt‐Jakob disease (sCJD) with an unusually prolonged disease duration of 58 months. The initial symptom was progressive mental disorder followed by advanced cognitive impairment. Clinical progression was generally slow; myoclonus appeared at 17 months and periodic sharp‐wave complexes on electroencephalogram at 21 months. A state of akinetic mutism occurred 29 months after the onset of symptoms. MRI showed gradually progressive cerebral atrophy. Neuropathologic examination showed widespread severe brain involvement. In the cerebral neocortex, widespread severe tissue rarefaction, hypertrophic astrocytosis and neuron loss (so‐called status spongiosus) were observed. The cerebral white matter showed diffuse myelin pallor with intense hypertrophic astrocytosis, numerous foamy macrophages and emperipolesis, indicating panencephalopathic‐type sCJD pathology. The brainstem was relatively preserved from sCJD pathology, with the exception of the pontine nucleus and pyramidal tract. This may explain the prolonged disease duration without respiratory insufficiency until the terminal stage. Immunohistochemistry for prion protein (PrP) showed widespread synaptic‐type PrP deposits in the cerebral neocortex, hippocampus and thalamus. The striatum and cerebellar cortex showed faint synaptic‐type PrP deposition with some areas of small plaque‐like PrP deposition. Sparse PrP deposition was also observed in the brainstem. Analysis of the PrP gene showed no mutation but methionine homozygosity at polymorphic codon 129. Western blot analysis of protease‐resistant PrP indicated type 1 PrP. To our knowledge, this is the longest reported disease duration of MM1‐type sCJD.     

Coexistence of Creutzfeldt‐Jakob disease,Lewy body disease,and Alzheimer's disease pathology: An autopsy case showing typical clinical features of Creutzfeldt‐Jakob disease

We report here an autopsy case of sporadic Creutzfeldt‐Jakob disease (CJD) without hereditary burden and with a clinical course typical of sporadic CJD. A 77‐year old man developed memory disturbance, followed by gait disturbance and myoclonus. He died of bronchopneumonia 5 months after the disease onset. Post‐mortem examination revealed neuronal loss, astrocytosis, and patchy spongiosis in the cerebral cortex and lenticular nuclei. Synaptic‐type deposits of prion protein were present in the cerebral cortex. Additionally, Lewy bodies were observed in the cerebral cortex and substantia nigra. Furthermore, senile plaques compatible with definite Alzheimer's disease according to Consortium to Establish a Registry for Alzheimer's disease criteria and neurofibrillary changes of the limbic system consistent with Braak stage IV were found. Based on a review of the published literature, this autopsy case is very rare, and we suppose that the incidence of CJD accompanied by Lewy body disease and Alzheimer's disease is very low.     

Report on the first Chinese family with Gerstmann‐Sträussler‐Scheinker disease manifesting the codon 102 mutation in the prion protein gene

The authors found a female patient aged 33‐years with dementia and cerebellar ataxia rapidly progressing for a year. EEG tracings were abnormal but without features of typical CJD. The patient died 13 months after the onset of illness. Biopsy of her cerebral cortex showed moderate spongiform changes, neuronal loss and gliosis. Numerous deposits of eosinophilic substance amorphous or in the shape of Kuru plaques were disclosed in the cerebral cortex. All deposits stained strongly with monoclonal 3F4 antibody to human prion protein. Genetic studies disclosed the Pro to Leu point mutation at codon 102 with a 102 Leu‐129 Met in the PrP gene. Codon 129 was heterozygous for Met/Val, and codon 219 was homozygous for Glu/Glu. It was established; moreover, that the patient’s grandfather had a similar disease and died at age 48 and the patient’s brother died after a 10‐year long neurological disease diagnosed as hereditary cerebellar ataxia. On the basis of clinical, neuropathological and genetic findings, the authors diagnosed the Gerstmann‐Sträussler‐Scheinker disease, a familial prion disease with an autosomal dominant character. This is the first report on this disease in China.     

Clinicopathological characteristics of Creutzfeldt-Jakob disease with a PrP V180I mutation and M129V polymorphism on different alleles]

We report an 80-year-old Japanese man with histologically-diagnosed Creutzfeldt-Jakob disease (CJD). The patient was admitted to our neurological unit because of sudden onset motor aphasia-like symptoms and right hemiparesis. His medical and family histories were unremarkable, and he had taken no medications. Urine, blood counts and blood chemistry were all within normal limits. Cerebrospinal fluid was normal except for elevation of neuron specific enolase (29.9 ng/ml). High-signal intensity was demonstrated in the cortex of the left temporal lobe on T2-weighted MRI images, and the lesion swelled during the initial stage of the disease. There was no enhancement with Gd-DTPA. Serial MRI showed that the high-signal lesion had spread into the bilateral cerebral cortex. The patient developed myoclonus followed by akinetic mutism within 6 months of onset. Consecutive EEGs revealed no periodic synchronous discharge (PSD). He died of pneumonia 21 months after of admission. Autopsy revealed spongiform changes in the cerebral cortex with Kuru plaques, confirming the diagnosis of CJD. The Cerebellar cortex was well preserved. The high-signal lesions corresponded to the spongiform changes in the cerebral cortex. Immunohistochemical analysis showed weak synaptic prion staining. Prion protein (PrP) gene analysis of genomic DNA isolated from the autopsied brain by polymerase chain reaction, the restriction fragment length polymorphisms, and direct sequencing revealed a point mutation (Val-->Ile) at codon 180 and a polymorphism (Met/Val) at codon 129 on different alleles. A few CJD patients with point mutations in codon 180 of the PrP gene have been reported. Combination of the codon 180 point mutation and codon 129 polymorphism may yield an atypical clinicopathological form of CJD that includes late onset, negative PSD, and atypical MRI findings, with preservation of the cerebellar cortex.     

Creutzfeldt-Jakob disease and cerebral amyloid angiopathy

An 83-year-old female with no personal or familial neurological history developed progressive gait and speech disturbance and left motor deficit. She suffered intractable seizures and died 3 months after the onset of neurological signs. Neuropathology showed severe spongiosis and gliosis in the cortex and basal ganglia, and diffuse cerebral amyloid angiopathy. Immunostaining for prion protein (PrP) showed intense PrP positivity in areas of confluent spongiosis and some granular staining in astrocytes. The cortical vessel walls stained positively for /A4 amyloid but not for PrP amyloid. Both types of amyloid were only observed in pericapillary parenchyma, in areas with severe spongiosis. There were only a few tangles and neuritic plaques in the temporal cortex; amyloid plaques were not present either by silver stains or immunostains. There was neither arteriopathic leukoencephalopathy nor cerebral hemorrhage. Immunoblot analysis of brain extracts revealed an abnormal proteinase K-resistant isoform of PrP. Association of Creutzfeldt-Jakob disease and Cerebral amyloid angiopathy in the absence of Alzheimer changes is unusual. The association of PrP and /A4 amyloid deposits could have been fortuitous in an 83-year-old patient. An etiopathogenic relationship between /A4 amyloid deposition and PrP accumulation may also be considered.Supported by a Concerted Action of the European community This case was the subject of a preliminary presentation at the eighty-seventh meeting of the British Neuropathological Society [17]     

Cerebral amyloid in human prion disease

The clinical and neuropathological features of 21 patients with prion disease were reviewed with special reference to the morphology and immunoreactivity of cerebral amyloid. Six cases had a mutation at codon 102 of the prion protein (PrP) gene and in these the characteristic pathology was the formation of multicentric amyloid plaques which were stained with PrP antibody, whereas spongiform changes were absent in one and minimal in two. In one case, with a 216 base-pair insertion in the PrP gene, there was no spongiform encephalopathy (SE) but cerebellar amyloid was a prominent feature of the pathology. One case with a PrP gene mutation at codon 200 had severe SE but no amyloid. Two iatrogenic and 11 sporadic cases had SE and some form of amyloid was identified in all but three. Amyloid angiopathy and senile neuritic plaques, which stained with antibody to β-protein, were present in familial as well as in sporadic cases, including some who were rather young to be regarded as having Alzheimer's disease. Cerebellar amyloid and degeneration of granule and Purkinje cells were particularly common findings in sporadic as well as in genetically determined cases. This study serves to emphasize the association between prion disease and amyloid deposition in the brain. PrP is a component of some amyloid plaques in a high proportion of cases with inherited prion disease but may also be found in cases of sporadic SE without known mutations or base-pair insertions in the PrP gene.     

Prion disease with 144 base pair insertion in a Japanese family line

We describe an insert mutation in the prion protein (PrP) gene in a Japanese family line that encodes six octapeptide repeats. This is the second report to date of an inherited prion disease with a 144-base pair insertion, although the order of the repeat sequences differ from that reported for the disease in an English family line. The clinical features, like those in the English patients, were characterized by a slowly progressive generalized dementia with some neurological signs and cortical focal symptoms. Postmortem examination disclosed diffuse atrophy of cerebral gray matter and the cerebellar cortex; histologically, there were marked patchy and regional neuronal loss with astrocytosis in the frontal cortex, amygdala and hippocampus and PrP-immunoreactive plaques in the molecular layer of the cerebellum. These plaques were different from typical kuru plaques. The prion disease in the present Japanese family line is compared with that in the English family line.     

An inherited prion disease with a PrP P105L mutation: clinicopathologic and PrP heterogeneity.

OBJECTIVE: To clarify a clinical and neuropathologic phenotype of an inherited prion disease associated with a missense mutation at codon 105 in the prion protein (PrP) gene that was originally described as a variant of Gerstmann-Str?ussler-Scheinker disease demonstrating spastic paraparesis. METHODS: Two siblings from a Japanese family are described. PrP gene analyses, neuropathologic studies with immunohistochemistry, and Western blot analysis of the PrP were performed. RESULTS: Both patients showed a missense (proline-->leucine) mutation at codon 105 and a methionine/valine polymorphism at codon 129 of the PrP gene. Clinically, Patient 1 presented with progressive spastic paraparesis, ataxia, and dementia. Patient 2, the sister of Patient 1, showed prominent action myoclonus and dementia. Neuropathologically, multiple PrP-positive amyloid plaques and diffuse PrP deposition in the deep cortical layers were found in the cerebral cortex with primarily frontal dominant atrophy in both patients. Tau-positive pathologic structures including neurofibrillary tangles, neuropil threads, and dystrophic neurites around the plaques were abundant in the brain of Patient 2. In contrast, the tau pathology was scarce in Patient 1. Western blot analysis of the brain showed different patterns of detergent-insoluble PrP fragments between the patients. CONCLUSIONS: Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic differences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.     

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.     

Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease

We have compared the immunomorphological spectrum of the deposition of the disease-associated prion protein (PrP(Sc)) in the cerebral and cerebellar cortex of 32 Creutzfeldt-Jakob disease (CJD) patients with the PrP gene (PRNP) E200K mutation to 45 sporadic CJD and 14 other genetic prion disease cases. PrP deposits correlate with the genotype at the methionine/valine (MV) polymorphic codon 129. While the diffuse/synaptic and patchy/perivacuolar PrP deposits and PrP plaques have a similar distribution and correlation with the genotype at codon 129 as in sporadic CJD, an additional peculiar PrP immunostaining pattern occurs in the cerebellum in 81% E200K mutation brains including 93% of M129M, 71% of M129V, but not in the single V129V case. It is localized to the molecular layer and consists of coarse granular PrP deposits arranged in a stripe-like manner predominantly perpendicular to the surface, closely resembling the parasagittal arborization of climbing fibers. Our results suggest that (1) the type of PrP deposits in the cerebellum may suggest genetic disease and the need for genetic testing; and (2) the peculiar stripes of PrP deposits might reflect selective vulnerability of cerebellar structures.     

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 PrP^Sc and type 2 PrP^Sc. 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.     

Extensive cortical spongiform changes with cerebellar small amyloid plaques: The clinicopathological case of MV2K+C subtype in Creutzfeldt‐Jakob disease

We report a clinical case report of the MV2K+C subtype of sporadic Creutzfeldt‐Jakob disease (sCJD). The patient was a 72‐year‐old woman who exhibited progressive dementia over the course of 22 months. Diffusion‐weighted MRI during this period showed abnormal hyperintensity in the cerebral cortex in the early stage. The clinical course was similar to that of previously reported patients with the MV2K or MV2K+C subtype of sCJD. However, histopathological examination revealed unique features: severe extensive spongiform changes with perivacuolar deposits in the cerebrum and basal ganglia, plaque‐like PrP deposits in the cerebrum, and only mild changes in the cerebellum with small amyloid plaques (～20 μm in diameter), smaller than those in the MV2K subtype or variant CJD (40–50 μm in diameter). Molecular analysis showed a methionine/valine heterozygosity at codon 129 and no pathogenic mutation in the PrP gene (PRNP). Western blot analysis of the protease‐resistant PrP (PrP^Sc) in the right temporal pole revealed the type 2 pattern, which is characterized by a single unglycosylated band, in contrast to the doublet described for the typical MV2 subtype of sCJD. The other intermediate band might exist in the cerebellum with kuru plaques. Therefore, small amyloid plaques in the cerebellum can be crucial for MV2K+C subtype.     

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.     

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.     

Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Sträussler-Scheinker syndrome P102L mutation complicated with dementia

Hyperphosphorylated tau (p-tau) deposition has been documented in a limited population of patients with Gerstmann-Str?ussler-Scheinker syndrome (GSS) with particular point mutations of the prion protein (PrP) gene. Although its pathogenesis is only poorly understood, p-tau in GSS is known to be identical to that in Alzheimer's disease (AD). We conducted immunohistochemical and quantitative image studies on the brain from a 44-year-old man with a 7-year history of dementia, diagnosed as having GSS with a point mutation of the PrP gene at codon 102 (GSS102), the commonest mutation in GSS. Severe spongiform degeneration and numerous PrP plaques were disclosed in the cerebral cortices and hippocampus, consistent with the diagnosis. However, rarely described in GSS102, prominent p-tau deposits as pretangles, neurofibrillary tangles and degenerating neurites were demonstrated adjacent to or around PrP plaques. beta-Amyloid protein (Abeta) plaques were generally sparse and appeared invariably to be of a diffuse type. Double-labeling immunohistochemistry yielded co-localization of p-tau with PrP but not with Abeta. Most PrP plaques did not contain Abeta. These results excluded a diagnosis of concomitant AD. Quantitative analysis on a fractional area density of immunoreactive pixels demonstrated that burdens of PrP and p-tau but not Abeta were significantly correlated. These results suggest that p-tau deposition in this GSS102 is secondarily induced by PrP but not by Abeta (secondary tauopathy). Our study also suggests that p-tau deposition might be a more common phenomenon in long-standing GSS.     

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 PrP^Sc. 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.     

Fatal familial insomnia with an unusual prion protein deposition pattern: an autopsy report with an experimental transmission study

We recently performed a post-mortem examination on a Japanese patient who had a prion protein gene mutation responsible for fatal familial insomnia (FFI). The patient initially developed cerebellar ataxia, but finally demonstrated insomnia, hyperkinetic delirium, autonomic signs and myoclonus in the late stage of the illness. Histological examination revealed marked neuronal loss in the thalamus and inferior olivary nucleus; however, prion protein (PrP) deposition was not proved in these lesions by immunohistochemistry. Instead, PrP deposition and spongiform change were both conspicuous within the cerebral cortex, whereas particular PrP deposition was also observed within the cerebellar cortex. The abnormal protease-resistant PrP (PrP(res)) molecules in the cerebral cortex of this case revealed PrP(res) type 2 pattern and were compatible with those of FFI cases, but the transmission study demonstrated that a pathogen in this case was different from that in a case with classical FFI. By inoculation with homogenate made from the cerebral cortex, the disease was transmitted to mice, and neuropathological features that were distinguishable from those previously reported were noted. These findings indicate the possibility that a discrete pathogen was involved in the disease in this case. We suggest that not only the genotype of the PrP gene and some other as yet unknown genetic factors, but also the variation in pathogen strains might be responsible for the varying clinical and pathological features of this disease.     

MM2-thalamic-type sporadic Creutzfeldt-Jakob disease with widespread neocortical pathology

We report an autopsy case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) with widespread cerebral neocortical pathology. Initial symptoms were progressive insomnia and mental disturbance. Magnetic resonance imaging revealed no high-signal intensity lesions on diffusion-weighted images and later showed gradually progressive cerebral atrophy. Periodic synchronous discharges and myoclonus were not observed. Upon neuropathologic examination, widespread cerebral neocortical involvement with fine vacuole-type spongiform change was observed. Severe degeneration with almost complete neuronal loss, tissue rarefaction, numerous fat-laden macrophages and hypertrophic astrocytosis of the medial thalamic nucleus was evident. The inferior olivary nucleus showed severe involvement with neuronal loss and hypertrophic astrocytosis. In the cerebellar cortex, moderate depletion of Purkinje neurons was evident, with no spongiform change in the molecular layer and no neuronal loss in the granule cell layer. Immunohistochemistry for prion protein (PrP) revealed widespread synaptic-type deposits with some primitive plaque-type deposits in the cerebral neocortex, basal ganglia and cerebellar cortex. PrP deposition was also observed in the brainstem, particularly the tegmentum, substantia nigra and pontine nucleus, and spinal cord, particularly the posterior horn. In the medial thalamus and inferior olivary nucleus, PrP deposition was sparse. Analysis of the PrP gene showed no mutation but did show methionine homozygosity at polymorphic codon 129. Western blot analysis of protease-resistant PrP indicated the presence of type 2 PrP. We believe that this patient suffered from MM2-thalamic-type sCJD (sporadic fatal insomnia) with widespread cerebral neocortical pathology due to prolonged disease duration. The present case showed different patterns of spongiform degeneration and PrP deposition in the cerebral neocortex than those in previously reported MM2-thalamic-type sCJD cases.     

A second case of Gerstmann-Sträussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient

A rare case of Gerstmann-Str?ussler-Scheinker disease in a 36-year-old Dutch man is reported. The clinical phenotype was characterized by slowly progressive cognitive decline, later followed by ataxia and parkinsonism. Neuropathologic findings consisted of numerous amyloid plaques in the cerebellum, which showed positive staining for the abnormal prion protein (PrP(Sc)). In addition, there were tau accumulations around numerous amyloid deposits in the cerebral cortex, striatum, hippocampal formation, and midbrain. There was no spongiform degeneration. Western blot analysis showed the co-occurrence of 2 distinct abnormal prion protein species comprising an unglycosylated, protease-resistant fragment of approximately 8 kd, which was found to be truncated at both N- and C-terminal ends by epitope mapping, and a detergent-insoluble but protease-sensitive form of full-length PrP(Sc). Sequence analysis disclosed a mutation at codon 131 of the prion protein gene (PRNP), resulting in a valine-for-glycine substitution (G131V). The patient was heterozygous at the polymorphic codon 129 and carried the mutation on the methionine allele. To our knowledge, this is the second family worldwide in which this mutation has been identified. Gerstmann-Str?ussler-Scheinker disease should be considered in patients with a clinical diagnosis of familial frontotemporal dementia.