Atypical neuropathological sCJD‐MM phenotype with abundant white matter Kuru‐type plaques sparing the cerebellar cortex

We describe an atypical neuropatholgical phenotype of sporadic Creutzfeldt‐Jakob disease (sCJD) in a 64‐year‐old man presenting with a 5‐month history of rapidly progressive dementia, comprising behavioral disturbances, memory complaints, disorientation and language alterations. MRI showed diffuse atrophy and hyperintensities in parietal, occipital, temporal and frontal cortices and left caudate nucleus on T2‐weighted and fluid‐attenuated inversion recovery images. No typical EEG alterations were observed. Repeated 14‐3‐3 assay was positive after a first negative test. Neuropathology showed classical CJD changes with small cortical foci of large confluent vacuoles and relatively well‐preserved cerebellar cortex. The most striking feature was the presence of abundant Kuru‐type plaques in both cerebral cortex and subcortical white matter. Sparse Kuru‐type plaques were also seen in cerebellum, although only in white matter. Immunohistochemistry showed, in addition to unicentric plaques, diffuse synaptic and patchy perivacuolar, as well as plaque‐like and periaxonal pathological prion protein deposits (PrP^res). Western blot studies demonstrated the co‐occurrence of PrP^res types 1 and 2 in frontal cortex and a relatively weak type 2 signal in cerebellum. PRNP genotyping revealed methionine homozygosity at codon 129 and excluded mutations. This case shows a previously undescribed combination of histopathological features which preclude its classification according to the current phenotypic and molecular sCJD classification. The observation demonstrates that Kuru‐type amyloid plaques mainly involving the cerebral white matter may also occur in sCJD cases with short clinical course and the co‐existence of PrP^res types 1 and 2. This case further highlights the complexity of the correlations between histopathological phenotype and PrP^res isotype in prion diseases.     

Multiple system atrophy (MSA) with massive macrophage infiltration in the ponto‐cerebellar afferent system

Multiple system atrophy (MSA) is characterized pathologically by a systemic degeneration of the olivopontocerebellar (OPC), striatonigral (SN) and autonomic systems. Massive glial cytoplasmic inclusions (GCIs) are specific for this disease. Massive lipid‐laden macrophage infiltration in the degenerating tracts has not been described up to now. We here report a case of MSA with this rare event in the ponto‐cerebellar (cerebellopetal) fibers. The patient, 54‐year‐old housewife, developed ataxia. At the age of 55 years, she was diagnosed as having MSA by cerebellar ataxia, extrapyramidal signs, autonomic failure and Horner syndrome. She died from asphyxia at the age of 57. The autopsy revealed OPC and SN system atrophy, degeneration and numerous GCIs, compatible with MSA. Numerous lipid‐laden macrophages were seen in the pontine nuclei and its transverse fibers including the white matter of the cerebellum, which has not been reported up to now. There was no macrophage infiltration in the other areas. Transient ischemia, infarction and wallerian degeneration do not account for this rare event. The ponto‐cerebellar (cerebellopetal) tract pathology, as observed by postmortem neuropathological study, may occur in the context of MSA.     

Protease‐resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion

Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt‐Jakob disease (sCJD, case 1), two cases of dura mater graft‐associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann‐Sträussler‐Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease‐resistant PrP (PrP^res) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size‐exclusion gel chromatography assay. PPS infusions were started 3–10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque‐type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP^res in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP^res was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain.     

The neuropathology, pathophysiology and genetics of multiple system atrophy

Multiple system atrophy (MSA) is an unrelenting, sporadic, adult-onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. MSA is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies, due to the presence of abnormal α-synuclein positive cytoplasmic inclusions in oligodendrocytes, termed glial cytoplasmic inclusions. These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α-synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA.     

Perirhinal accumulation of neuronal alpha‐synuclein in a multiple system atrophy patient with dementia

We report the case of a 79‐year‐old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited. NCIs were frequent in the deep layer, whereas NFTs were more frequent in superficial cortical layers. Other hippocampal subregions including subiculum, dentate fascia and cornu ammonis were minimally involved. NCIs in the perirhinal cortex showed intense argyrophilia with the Campbell‐Switzer silver impregnation method, but not argyrophilic with the Gallyas method. Most neuronal alpha‐synuclein aggregates in dendrosomatic fraction formed globular/tadpole‐like, and ultrastructurally comprised granular‐coated fine fibrils 12–24 nm in diameter. To the best of our knowledge, alpha‐synuclein‐related neuronal pathology localized in the perirhinal region without hippocampal involvement has not been previously reported in MSA, and may provide clues to elucidate how neuronal pathology evolves in the hippocampal/parahippocampal regions in MSA, particularly in cases with dementia.     

Multiple system atrophy: α‐synuclein and neuronal degeneration

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy–Drager syndrome (SDS). The histopathological hallmark is the formation of α‐synuclein‐positive glial cytoplasmic inclusions (GCIs) in oligodendroglia. α‐synuclein aggregation is also found in glial nuclear inclusions, neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurites. We evaluated the pathological features of 102 MSA cases, and presented the pathological spectrum of MSA and initial features of α‐synuclein accumulation. We found that 39% of the 102 cases showed equivalent SND and OPCA pathologies, 33% showed OPCA‐ and 22% showed SND‐predominant pathology, whereas 6% showed extremely mild changes. Our pathological analysis indicated that OPCA‐type was relatively more frequent and SND‐type was less frequent in Japanese MSA cases, compared to the relatively high frequency of SND‐type in Western countries, suggesting that different phenotypic patterns of MSA may exist between races. In the early stage, in addition to GCIs, NNIs and diffuse homogenous α‐synuclein staining in neuronal nuclei and cytoplasm were observed in lesions in the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic spinal cord, lower motor neurons and cortical pyramidal neurons. A subgroup of MSA cases with severe temporal atrophy showed numerous NCIs, particularly in the limbic system. These findings suggest that primary non‐fibrillar and fibrillar α‐synuclein aggregation also occur in neurons. The oligo‐myelin‐axon‐neuron complex mechanism, along with the direct involvement of neurons themselves, may synergistically accelerate the degenerative process of MSA.     

Tau‐positive glial cytoplasmic granules in multiple system atrophy

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by the filamentous aggregation of α‐synuclein. We report a case of MSA showing unusual neuropathological findings and review six autopsied cases of MSA. The patient progressively developed parkinsonism and ataxia for the 9 years prior to her death at the age of 72 years. Neuropathological examinations revealed neuronal loss restricted to the olivopontocerebellar and striatonigral region, which was more severe in the putamen. Staining with anti‐α‐synuclein antibody demonstrated widespread occurrence of glial cytoplasmic inclusions, which mainly accumulated in oligodendroglial cells and corresponded closely to the degree of disease progression. In addition, tau‐positive granules were detected within the glial cytoplasm in the neurodegenerative region, which was especially prominent in the putamen and internal capsule. Tau accumulation was also clearly recognized by staining with specific antibodies against three‐repeat or four‐repeat tau. The glia that demonstrated deposition of tau‐positive granules were distinguished from α‐synuclein‐positive oligodendroglia by double immunohistochemical staining. These characteristic glial accumulations of tau were also present in all six cases of MSA. These results indicate that tau‐positive granules in glia are common findings in MSA and that tau aggregation might be another pathway to neurodegeneration in MSA.     

Prion protein oligomers in Creutzfeldt‐Jakob disease detected by gel‐filtration centrifuge columns

Prion diseases are diagnosed by the detection of accumulation of abnormal prion protein (PrP) using immunohistochemistry or the detection of protease‐resistant abnormal PrP (PrP^res). Although the abnormal PrP is neurotoxic by forming aggregates, recent studies suggest that the most infectious units are smaller than the amyloid fibrils. In the present study, we developed a simplified method by applying size‐exclusion gel‐filtration chromatography to examine PrP oligomers without proteinase K digestion in Creutzfeldt‐Jakob disease (CJD) samples, and evaluated the correlation between disease severity and the polymerization degree of PrP. Brain homogenates of human CJD and non‐CJD cases were applied to the gel‐filtration spin columns, and fractionated PrP molecules in each fraction were detected by western blot. We observed that PrP oligomers could be detected by the simple gel‐filtration method and distinctly separated from monomeric cellular PrP (PrP^c). PrP oligomers were increased according to the disease severity, accompanied by the depletion of PrP^c. The separated PrP oligomers were already protease‐resistant in the case with short disease duration. In the cases with quite severe pathology the oligomeric PrP reached a plateau, which may indicate that PrP molecules could mostly develop into amyloid fibrils in the advanced stages. The increase of PrP oligomers correlated with the degree of histopathological changes such as spongiosis and gliosis. The decrease of monomeric PrP^c was unexpectedly obvious in the diseased cases. Dynamic changes of both oligomerization of the human PrP and depletion of normal PrP^c require further elucidation to develop a greater understanding of the pathogenesis of human prion diseases.     

Somatic sprouts of the Purkinje cells in a patient with multiple system atrophy

We describe the post mortem case of a 71‐year‐old Japanese woman diagnosed as having multiple system atrophy (MSA), showing somatic sprouting formation of Purkinje cells. The patient had suffered from frequent falling episodes and clumsiness of the left hand since the age of 67 years. Orthostatic hypotension and parkinsonism subsequently emerged. Typical neuropathological features of MSA, including degeneration of the striatum, pontine base and cerebellum with abundance of phosphorylated α‐synuclein‐positive neuronal and glial cytoplasmic and nuclear inclusions in the brain, were observed. In addition to gliosis of the cerebellar white matter and notable loss of Purkinje cells, several Purkinje cells showed somatic sprouting. Somatic sprouting of Purkinje cells has been demonstrated in several specific conditions, such as developing brains and several neurodegenerative disorders, including Menkes kinky hair disease, familial spinocerebellar ataxia, acute encephalopathy linked to familial hemiplegic migraine, and Huntington’s disease; however, no MSA cases have been reported with sprouting from the soma of Purkinje cells. Axonal damage caused by oligodendroglial dysfunction could be crucial in the development of Purkinje cell loss in MSA. Moreover, no apparent α‐synuclein accumulation has been described in the Purkinje cells of MSA. We propose that MSA is another degenerative disorder associated with somatic sprouts of Purkinje cells.     

Cellular pathology in multiple system atrophy

Multiple system atrophy (MSA) is a sporadic, adult‐onset neurodegenerative disease, which is characterized by striatonigral degeneration, olivopontocerebellar atrophy, and preganglionic autonomic lesions in any combination. The histological hallmark is the presence of argyrophilic fibrillary inclusions in the oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs). Fibrillary inclusions are also found in the neuronal somata, axons, and nucleus. Neuronal cytoplasmic inclusions are frequently found in the pontine and inferior olivary nuclei. Since the discovery of α‐synuclein as a major component of glial and neuronal inclusions in MSA, two neurodegenerative processes have been considered in this disease: one is due to the widespread occurrence of GCIs associated with oligodendroglia–myelin degeneration (oligodendrogliopathy) in the central nervous system, and the other is due to the filamentous aggregation of α‐synuclein in the neurons in several brain regions. These two degenerative processes might synergistically cause neuronal depletion in MSA.     

Neuropathological features of multiple system atrophy with cognitive impairment

Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA‐related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's‐related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA‐specific α‐synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted. © 2014 International Parkinson and Movement Disorder Society     

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.     

An autopsy case of preclinical multiple system atrophy (MSA‐C)

Multiple system atrophy (MSA) is divided into two clinical subtypes: MSA with predominant parkinsonian features (MSA‐P) and MSA with predominant cerebellar dysfunction (MSA‐C). We report a 71‐year‐old Japanese man without clinical signs of MSA, in whom post mortem examination revealed only slight gliosis in the pontine base and widespread occurrence of glial cytoplasmic inclusions in the central nervous system, with the greatest abundance in the pontine base and cerebellar white matter. Neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) were almost restricted to the pontine and inferior olivary nuclei. It was noteworthy that most NCIs were located in the perinuclear area, and the majority of NNIs were observed adjacent to the inner surface of the nuclear membrane. To our knowledge, only four autopsy cases of preclinical MSA have been reported previously, in which neuronal loss was almost entirely restricted to the substantia nigra and/or putamen. Therefore, the present autopsy case of preclinical MSA‐C is considered to be the first of its kind to have been reported. The histopathological features observed in preclinical MSA may represent the early pattern of MSA pathology.     

Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited progressive neurological disorder characterized by neuronal degeneration and reactive gliosis in the cerebellum, brainstem, spinocerebellar tracts, and dorsal columns. Multiple system atrophy is a sporadic progressive neurological disorder with degeneration and gliosis in the basal ganglia, cerebellum, brainstem, and spinal autonomic nuclei, and with argyrophilic glial cytoplasmic inclusions. We describe 4 members of a family with the SCAl mutation and a dominantly inherited progressive ataxia in which autopsy examination of 1 member showed neuropathological changes typical of multiple system atrophy, including glial cytoplasmic inclusions. In this patient, magnetic resonance imaging revealed marked brainstem and cerebellar volume loss and mild supratentorial generalized volume loss. Positron emission tomography with [¹⁸F]fluorodeoxyglucose revealed widespread hypometabolism in a pattern found in sporadic multiple system atrophy and not in dominantly inherited olivopontocerebellar atrophy. Positron emission tomography with [^llC]flumazenil revealed normal benzodiazepine receptor distribution volumes, similar to those seen in sporadic multiple system atrophy. Two other family members still living had similar changes in the imaging studies. The findings in this family suggest that the SCAl gene mutation can result in a disorder similar to multiple system atrophy, both clinically and neuropathologically.     

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.     

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 (PrP^Sc) and type 2 PrP^Sc. Based on the relationship between the neuroimaging and pathological findings, we speculated that cerebral cortical lesions with large confluent vacuoles and type 2 PrP^Sc would show higher brightness and continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrP^Sc. 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.     

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.     

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.     

Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt-Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes

B. A. Faucheux, E. Morain, V. Diouron, J.‐P. Brandel, D. Salomon, V. Sazdovitch, N. Privat, J.‐L. Laplanche, J.‐J. Hauw and S. Haïk (2011) Neuropathology and Applied Neurobiology 37, 500–512 Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrP^Sc) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrP^Sc deposits common to the various molecular subtypes Aims: Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease‐related prion protein (PrP^Sc) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrP^Sc deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt–Jakob disease (sCJD; n = 100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrP^Sc molecular types. Methods: The numerical density of neurones was estimated with a computer‐assisted image analysis system and the accumulation of PrP^Sc deposits was scored. Results: The scores of PrP^Sc immunoreactive deposits of the punctate type (synaptic type) were correlated with neurone counts – the higher the score the higher the neuronal loss – in all sCJD subtypes. Large 5‐ to 50‐µm‐wide deposits (focal type) were found in sCJD‐MV2 and sCJD‐VV2 subtypes, and occasionally in a few cases of the other studied groups. By contrast, the highest scores for 5‐ to 50‐µm‐wide deposits observed in sCJD‐MV2 subtype were not associated with higher neuronal loss. In addition, these scores were inversely correlated with neuronal counts in the sCJD‐VV2 subtype. Conclusions: These results support a putative pathogenic role for small PrP^Sc deposits common to the various sCJD subtypes. Furthermore, the observation of a lower loss of neurones associated with PrP^Sc type‐2 large deposits is consistent with a possible ‘protective’ role of aggregated deposits in both sCJD‐MV2 and sCJD‐VV2 subtypes.     

A novel grading scale for striatonigral degeneration (multiple system atrophy)

Summary. Striatonigral degeneration (SND) is commonly thought to represent the neuropathological substrate of L-Dopa unresponsive parkinsonism in patients with multiple system atrophy (MSA). Other neuropathological hallmarks of MSA include olivopontocerebellar atrophy (OPCA) and preganglionic sympathetic spinal cord lesions. Clinicopathological evaluation of MSA patients recruited into ongoing natural history studies or neuroprotective intervention trials will require standardized grading of MSA pathology. Based on 25 autopsy cases of MSA, we propose a novel SND grading scale which allows semiquantitative assessment of lesion severity based on neuronal loss, astrogliosis and presence of α-synuclein positive glial cytoplasmic inclusions (GCIs) in substantia nigra, putamen, caudate nucleus, and globus pallidus. SND grade I is defined as degeneration of the substantia nigra pars compacta (SNC) with relative preservation of the striatum except for minimal gliosis and GCIs in the posterior putamen ("minimal change MSA"). SND grade II is characterized by neuronal loss, astrogliosis and presence of GCIs in SNC and posterior/dorsolateral putamen. Caudate nucleus and external globus pallidus may exhibit slight gliosis. Striatal pathology is severe and extends to anterior ventromedial subregions in SND grade III. There is neuronal loss in caudate nucleus and globus pallidus. GCIs are more abundant in grade II than grade III SNC and putamen. Preliminary clinicopathologic correlation studies suggest milder parkinsonian disability and better initial L-Dopa responsiveness in SND grade I and II cases compared to grade III cases. Prospective clinicopathologic studies are required to validate the proposed SND grading scale and may result in further subdivisions, particularly of SND grade III. Received April 11, 2001; accepted July 11, 2001