Neuropathology 2018 doi:10.1111/neup.

12503

Case Report

Autopsied case of non-plaque-type dura mater graft-

associated Creutzfeldt-Jakob disease presenting with
extensive amyloid-β deposition
Yasushi Iwasaki,1 Kazuhiro Imamura,2 Katsushige Iwai,3 Yasushi Kobayashi,4 Akio Akagi,1
Maya Mimuro,1 Hiroaki Miyahara,1 Tetsuyuki Kitamoto5 and Mari Yoshida1
1
Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute,
2
Department of Neurology, Nakatsugawa Municipal General Hospital, Nakatsugawa, 3Department of Neurology,
Toyohashi Municipal Hospital, Toyohashi, 4Department of Neurology, Okazaki City Hospital, Okazaki and 5Department
of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan

We present an autopsied case of non-plaque-type dura transactivation response DNA-binding protein 43 kDa
mater graft-associated Creutzfeldt-Jakob disease (dCJD) were not detected on immunostaining. Although this
with extensive amyloid-β (Aβ) deposition in the brain. A report describes only one case, various speculations were
39-year-old Japanese woman presented with memory dis- made based on detailed clinical and pathological observa-
turbance and abnormal behavior. The patient had a his- tions in conjunction with previous reports of dCJD. In
tory of craniotomy with dura matter-graft transplant for a particular, this report provides significant insight into the
head injury which occurred when she was 19 years old. characteristics and progression of dCJD pathology and its
Magnetic resonance imaging (MRI) showed hyper- relationship with Aβ pathology.
intensities in the cerebral cortex and striatum on diffusion-
weighted images, particularly on the dura mater-grafted Key words: amyloid-β, Creutzfeldt-Jakob disease, dura
right side. Her clinical symptoms, including rapidly pro- mater graft, non-plaque-type, prion protein.
gressing cognitive impairment, myoclonus, and periodic
sharp wave complexes on electroencephalogram, could INTRODUCTION
not be distinguished from typical sporadic CJD cases. The Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenera-
patient died 11 months after symptom onset, and patho- tive disease and can be classified as sporadic (idiopathic),
logical investigations showed extensive spongiform degen- genetic (hereditary), or acquired (infectious).1 Although
eration with prion protein (PrP) deposition without Kuru
the cause of sporadic CJD is still unknown, acquired forms
plaques; these observations were essentially the same as
are caused by the transmission of abnormal prion protein
those of typical sporadic CJD cases. Furthermore, Aβ
(PrP), not only from humans to humans, but also from cat-
immunohistochemistry showed extensive diffuse staining
tle to humans.1–3 Accidental transmission of CJD between
in the cerebral neocortex, plaque-type deposition, positive
humans appears to occur after cadaveric dura mater
staining in the pia mater, and cerebral amyloid
grafts, corneal transplantations, receipt of human growth
angiopathy. Although the MRI findings suggested that the
pathological involvement originated from the dura mater- hormone or pituitary gonadotropin, contaminated electro-
grafted right side, the PrP and Aβ depositions showed no encephalogram (EEG) electrodes, and contaminated sur-
apparent regionalization and laterality. Tau-pathology gical instruments or apparatus.1–3 Since the first report of
including neurofibrillary tangles was hardly identified. The association between dura mater grafts and CJD was publi-
proteins phosphorylated α-synuclein and phosphorylated shed in 1987, many cases of dura mater graft-associated
CJD (dCJD) have been reported.1–3 The most probable
vehicle of transmission was a single product used in sur-
Correspondence: Yasushi Iwasaki, MD, PhD, Department of Neuro- gery called Lyodura® (B. Braun Melsungen AG,
pathology, Institute for Medical Science of Aging, Aichi Medical Uni-
versity, 1-1 Yazakokarimata, 480-1195 Nagakute, Japan.
Melsungen, Germany) produced before May 1987.3 In
Email: [email protected] 1997, a CJD surveillance group in Japan reported 43 cases
Received 14 May 2018; Revised 12 June 2018; Accepted 24
of dCJD,4 and 154 cases of dCJD were reported before
June 2018. June 2017 by the CJD Surveillance Committee in Japan,
© 2018 Japanese Society of Neuropathology
2 Y Iwasaki et al.

comprising over 60% of the total reported global dCJD onset. Tracheotomy and mechanical ventilation were not
cases.5 The widespread use of Lyodura in neurosurgical performed. Autopsy and PrP gene analyses were per-
procedures in Japan is the most probable source of the formed with the informed consent of the patient’s family.
unusually high number of dCJD cases in this country.2,5,6
Recently, the possibility of human-to-human transmis- METHODS
sion of cerebral β-amyloidosis has been also suggested in
autopsy studies of patients with iatrogenic CJD associated Neuropathological examination
with human growth hormone injections or dura mater The brain was fixed in 20% neutral buffered formalin for
grafts.7,8 We report the clinicopathological findings of an 4 weeks. After brain cutting and trimming, tissue blocks
autopsied case of non-plaque-type dCJD with extensive were immersed in 95% formic acid for 1 h to inactivate
amyloid-β (Aβ) deposition in the brain. prion infectivity. Eight-micrometer sections sliced using a
microtome were mounted, deparaffinized, dehydrated, and
CLINICAL SUMMARY stained. For routine neuropathological examinations, sec-
tions were subjected to hematoxylin and eosin and Klüver-
A Japanese woman developed memory disturbances and Barrera stainings, as well as Gallyas-Braak silver staining.
abnormal behaviors at the age of 39 years. For instance, Immunohistochemical analyses of selected sections were
she forgot the orders of customers at her workplace, she performed using a mouse monoclonal antibody against PrP
repeatedly said the same thing and panicked, she could (clone 3F4; diluted 1:100; Dako, Glostrup, Denmark). The
not exit from a public bus, and she could not wear her 3F4 antibody is specific to human PrP amino acids 109–112.
work clothes due to executive function disorders. Her cog- The immunostaining protocol for PrP detection used a
nitive dysfunction rapidly progressed, and she was admit- hydrolytic autoclaving procedure and the EnVision ampli-
ted to the department of neurology 1 month after the fied visualization method as previously described.9,10 Immu-
onset of symptoms. She had a history of head trauma nohistochemistry with a mouse monoclonal antibody
resulting from a motorcycle accident in 1990 at the age of against amyloid-β (Aβ) (clone 4G8; diluted 1:2000; Signet,
19 years. To treat this injury, craniotomy with a dura Dedham, MA, USA), a mouse monoclonal antibody
matter-graft transplant was performed; although the oper- against hyperphosphorylated tau (clone AT-8; diluted
ation record could not be found, Lyodura® was most likely 1:2000; Innogenetics, Ghent, Belgium), a mouse monoclo-
used in the surgery. Neurological examination revealed nal antibody against phosphorylated α-synuclein (clone
poor facial expression, few eye blinks, no apparent dysar- pSyn#64; diluted 1:3000; Wako Pure Chemical Industries,
thria, slow and simple verbal responses to questions, rigid- Osaka, Japan), and a rabbit polyclonal antibody against
ity in the left extremities, and no Babinski reflex. Mild phosphorylated transactivation response DNA-binding pro-
myoclonus was recognized in the face and upper extremi- tein 43 kDa (TDP-43) (Cat. No. pTDP-43 pS409/410;
ties. The Revised Hasegawa’s dementia scale (commonly diluted 5000; CosmoBio, Tokyo, Japan) was also per-
used in Japan to assess dementia; graded on a scale of formed. In these immunostainings, primary antibody bind-
0–30, where < 21 suggests dementia) and Mini-Mental ing was detected using the labeled streptavidin-biotin
State Examination scores were 13 and 16, respectively. method. Peroxidase-conjugated streptavidin was visualized
Computed tomography (CT) showed the scar of the crani- with 3,30 -diaminobenzidine as the final chromogen. Immu-
otomy in the right temporoparietal region (Fig. 1A). Mag- nostained sections were lightly counterstained with Mayer’s
netic resonance imaging (MRI) showed hyperintensities in hematoxylin.
the cerebral cortex and striatum on T2-weighted images
(Fig. 1B) and diffusion-weighted images (DWI) (Fig. 1C),
Genetic and Western blot analyses
particularly on the dura mater-grafted right side. Two
months after symptom onset, myoclonus became severe in The cryopreserved right frontal cerebral cortex, which was
degree, and EEG showed typical periodic sharp wave snap frozen and stored at −80 C prior to use, was homoge-
complexes (PSWCs) without apparent laterality. Three nized, and Western blot analysis of protease-resistant PrP
months after symptom onset, the patient reached an (PrPSc) was performed using 3F4 antibodies as previously
akinetic mutism state, and feeding via a nasogastric tube described.9,10 PrPSc typing was performed according to the
was initiated. Thereafter, the patient’s general condition sporadic CJD classification system proposed by Parchi
remained stable, and myoclonus gradually disappeared et al.11
7 months after symptom onset. MRI showed progression Genomic DNA was extracted from the cryopreserved
of brain atrophy with ventricular dilation (Fig. 1D). The brain tissue and used to amplify the open reading frame of
patient’s general condition suddenly worsened due to aspi- the PrP gene using polymerase chain reaction. We searched
ration pneumonia, and she died 11 months after symptom for mutations and investigated the polymorphisms at codons
© 2018 Japanese Society of Neuropathology
Dura mater graft-associated CJD 3

Fig. 1 Neuroradiological findings of

the present case. (A) Head CT
images obtained 1 month after symp-
tom onset show the large craniotomy
scar in the skull approximately 12 cm
× 12 cm in the right temporoparietal
region. (B) MRI T2-weighted images
obtained 1 months after symptom
onset show no apparent cerebral
atrophy. Neither white matter degen-
eration nor brain contusion scarring
is apparent. Slight hyperintensities
can be recognized in the cerebral
cortex and striatum on the dura
mater-grafted right side. (C) MRI
DWIs obtained 1 months after symp-
tom onset show extensive hyper-
intensities in the cerebral cortex and
striatum, particularly on the right
side. (D) MRI DWIs show obtained
11 months after symptom onset (one
week before death) show diffuse
cerebral atrophy with lateral ventric-
ular dilatation without apparent
laterality. The hyperintensities are
decreased in dimension but remain
in some parts of the cortex of the
convexity. R, right side.

129 and 219 using restriction fragment length polymorphism with enlargement of the lateral ventricles (Fig. 2B). The
analysis, as previously described.9,10 The patient’s DNA was cerebellum also showed severe atrophy, whereas the
also used for apolipoprotein E (ApoE) genotyping. brainstem did not.

Microscopic findings
PATHOLOGICAL FINDINGS
Extensive severe gliosis with hypertrophic astrocytosis and
Macroscopic findings tissue rarefaction of the neuropil were observed in the
The yellowish transplanted dura mater was recognized cerebral neocortex (Fig. 4A-C). Florid-type plaques or
after craniotomy at the autopsy, but it was strongly stuck Kuru-type plaques were not observed. Neuronal loss was
to the skull and hard to remove. The brain weight was extensively observed but to varying degrees in each
reduced to 930 g before fixation due to severe cerebral region. Many inflated neurons were observed, particularly
atrophy (Fig. 2A). Coronal sections of the cerebrum in deeper layers of relatively preserved neocortical
showed diffuse atrophy of the cortex and white matter regions. The precentral gyrus, including Betz cells, was
© 2018 Japanese Society of Neuropathology
4 Y Iwasaki et al.

Fig. 2 Macroscopic appearance of

the brain after formalin fixation.
(A) Convexity of the cerebrum
shows severe general cerebral atro-
phy with widened sulci. (B) A coro-
nal section of the cerebrum shows
thinning of the cerebral cortex and
enlargement of the lateral ventricles.
The striatum, medial thalamus, and
white matter also show atrophy, but
the hippocampal formation is pre-
served. Apparent laterality of the
cerebral atrophy is not recognized.
Scale bars: 10 mm. L, left side.

relatively preserved from neuronal loss. These pathologi- cell layer showed severe neuron loss (Fig. 3I). The
cal findings showed no apparent laterality between the Purkinje cell layer showed mild neuron loss with mild
right and left cerebral hemispheres. Although the fine vac- Bergmann gliosis. The cerebellar white matter also
uoles were indistinct in the cerebral neocortex, typical showed mild myelin pallor, but the cerebellar dentate
spongiform changes with fine vacuolization were observed nucleus was relatively preserved.
in the hippocampus and subiculum (Fig. 4D). Although Regarding the anti-PrP immunostaining, diffuse synaptic-
the cerebral white matter showed diffuse myelin pallor type PrP deposition was extensively observed in the gray
and gliosis, the pathology varied across different brain matter, particularly in the cerebral cortex (Fig. 3B, 5A), stri-
regions (Fig. 3A). Some circumscribed spongy foci were atum, medial thalamus, pontine nucleus, inferior olivary
observed under the crown of the cerebral gyri (Fig. 4E). nucleus, cerebellar cortex (Fig. 5B), and dentate nucleus.
The U-fibers, corpus callosum, internal capsule, and para- PrP deposition showed no apparent laterality between both
hippocampal gyrus were relatively preserved from myelin cerebral hemispheres. Anti-Aβ immunostaining also showed
pallor. Regarding the subcortical gray matter, the striatum extensive diffuse staining in the cerebral cortex (Fig. 3C,
showed similar involvement as the cerebral neocortex 5C-I); the diffuse Aβ staining tended to be strong and
(Fig. 4F). There was no apparent neuron loss within the mainly observed in the superficial layer of the cerebral cor-
globus pallidus, but mild spongiform changes and gliosis tex. Plaque-type Aβ deposition (senile plaques; SPs) and
were observed. The medial thalamus showed severe neu- positive staining of the pia mater were also extensively
ron loss with gliosis, whereas the lateral thalamus was rela- observed. Severe cerebral amyloid angiopathy was also
tively preserved. These pathological findings of the extensively observed (Fig. 5J). Aβ deposition showed no
subcortical gray matter also showed no apparent laterality. apparent laterality. The dura mater showed no apparent Aβ
In the brainstem, the pontine nucleus showed mild neuron deposits, whereas the arachnoid granule did (Fig. 5K). The
loss with gliosis (Fig. 3H). The substantia nigra and the distribution and density of the SPs were judged as Braak
inferior olivary nucleus were preserved. Pyramidal tract SPs stage C and Consortium to Establish a Registry for
degeneration was not observed. In the cerebellum, the Alzheimer’s disease (CERAD) SPs stage B.12,13 The Thal
molecular layer showed severe atrophy, and the granule phase of Aβ deposition was judged as 5.14

Fig. 3 Macroscopic images of the coronally sectioned right cerebral hemisphere after staining. (A) Extensive mild myelin pallor of the
white matter is observed, but the degree varies among regions. A circumscribed spongy focus under the crown of the gyrus is observed
with relatively preserved adjacent U-fibers (arrow) (Klüver-Barrera stain). (B) PrP immunohistochemistry with 3F4 shows diffuse
staining in the cerebral cortex. (C) Aβ immunohistochemistry with 4G8 shows extensive staining in the cerebral neocortex. It is noted
that there are scattered regions that are not stained. Scale bars: 10 mm.
© 2018 Japanese Society of Neuropathology
Dura mater graft-associated CJD 5

Fig. 4 Representative microscopic images of the brain sections stained with hematoxylin-eosin. (A-C) Severe neuronal loss and gliosis
with hypertrophic astrocytosis can be extensively observed in the cerebral neocortex. Due to the progression of tissue rarefaction of the
neuropil, fine vacuoles of typical spongiform change are no longer distinct. Betz cells are relatively preserved in number. Laterality of
the severeity of the involvement could not be determined (A1/A2, left/right superior parietal lobules; B1/B2, left/right precentral gyrus;
C1/C2, left/right striate areas). (D) The subiculum shows mild spongiform change with fine vacuoles with clear boundaries. Gliosis and
neuronal loss are not apparent. (E) The circumscribed spongy focus of the subcortical white matter shows tissue rarefaction with hyper-
trophic astrocytosis and appearance of foamy macrophages (frontal lobe). (F, G) The striatum and medial thalamus show spongiform
change, neuronal loss and gliosis with hypertrophic astrocytosis (F, putamen; G, medial thalamic nucleus). (H) The pontine nucleus
shows mild neuronal loss with gliosis. (I) In the cerebellar cortex, the molecular layer shows severe atrophy and the granule cell layer
shows severe neuronal loss. The Purkinje cell layer shows mild neuronal loss and exhibits mild Bergmann gliosis. Scale bars: 200 μm.

Neurofibrillary tangles (NFTs) were hardly identified unglycosylated band being approximately 21 kDa (data
(Braak NFTs stage I),12 using Gallyas-Braak silver not shown).
staining and AT-8 immunostaining (Fig. 5L). No
argyrophilic grains were observed. Lewy bodies and DISCUSSION
α-synuclein pathology were not observed on anti-
Two distinct subtypes of dCJD are recognized according
phosphorylated α-synuclein immunostaining. No apparent
to the clinical and neuropathological features of cases;
positive findings were observed for anti-phosphorylated
non-plaque- and plaque-type dCJD.1,16–18 The non-plaque
TDP-43 immunostaining.
type is a dominant form of dCJD and shows synaptic-type
PrP deposition, whereas plaque-type dCJD comprises
RESULTS OF GENETIC ANALYSIS around one-third of total dCJD cases and shows wide-
No mutation in the PrP gene open reading frame was spread PrP plaques (Kuru plaques).1,16–18 Clinically, non-
identified. Methionine homozygosity at codon 129 and glu- plaque-type dCJD cases show a rapidly progressive clinical
tamic acid homozygosity at codon 219, which are the most course, myoclonus, and PSWC on EEG, similar to typical
common polymorphic genotypes of the PrP gene in the classic-type sporadic CJD, whereas plaque-type dCJD
Japanese population,15 were identified. ApoE gene analy- cases show a slowly progressive clinical course with the
sis revealed epsilon 3 (e3) homozygosity. absence or late occurrence of myoclonus and PSWCs on
EEG.1,16–18 In terms of the incubation period, there is no
significant difference between the two subtypes.18 Because
RESULTS OF WESTERN BLOT ANALYSIS the patient in the present case presented with a rapidly
Western blot analysis of PrPSc indicated the presence of a progressive clinical course and did not show Kuru plaques,
type 1 PrPSc, with the relative molecular mass of the her CJD was considered to belong to the non-plaque-type.
© 2018 Japanese Society of Neuropathology
6 Y Iwasaki et al.

Fig. 5 Representative microscopic images of the brain sections immunostained for PrP by 3F4 (A, B), Aβ by 4G8 (C-K), and
hyperphosphorylated tau by AT-8 (L). (A, B) Diffuse synaptic type PrP deposits are extensively observed (A, neocortex of the superior
frontal gyrus; B, cerebellar cortex). (C) Extensive diffuse Aβ immunostaining in the cerebral cortex is observed. Plaque-type deposits
and positive staining of vessels in the pia mater and parenchyma are also observed. The diffuse staining pattern tends to be stronger and
mainly observed in the superficial layer (right superior parietal lobe). (D) Aβ seemingly aggregates around a blood vessel. Many diffuse
plaques are also observed. (E) Typical neuritic plaques can also be recognized. (F-H) Extensive Aβ deposits are observed (F, amygdala;
G, ambient gyrus; H, locus ceruleus). (I) The cerebellar cortex also shows diffuse Aβ immunostaining. Amyloid deposits in the vascular
wall of the pia mater are also observed. (J) Severe cerebral amyloid angiopathy is also extensively observed (occipital lobe). (K) The
dura mater, not transplanted, shows no apparent Aβ deposits (arrow), whereas the arachnoid granules show positive staining (arrow-
head). (L) Hyperphosphorylated tau deposition is very mild in the transentorhinal cortex. Scale bars: 1 mm (K), 500 μm (C, J), 200 μm
(A, B, D, F-I, L), 100 μm (E).

Several reports have speculated that Aβ pathology statistically significant correlation between the incubation
might result from seeding of Aβ aggregation by dura period and both subpial Aβ deposition and cerebral amy-
mater grafts.6,19,20 Frontzek et al. investigated amyloid loid angiopathy.6 Preusser et al. also reported an
angiopathy and brain parenchymal Aβ plaques in dCJD Alzheimer-type pathology in a 28-year-old patient with
and speculated that Aβ pathology may occur after long dCJD after dura grafting at the age of 5 years.20 Although
intervals (> 20 years) post dura mater-graft transplant.19 the incidence of dCJD appears to have peaked in the late
Hamaguchi et al. reported a significant association of 1990s and has been declining since,5,21 there remains a
cadaveric dura mater grafting with subpial Aβ deposition possibility that cases of dCJD with long incubation periods
and meningeal amyloid angiopathy in an investigation of will manifest in the future, especially in Japan. Therefore,
Japanese dCJD cases (the present case was not included the future onset of dCJD cases may present as a higher
in their study series);6 their observations indicated that Aβ occurrence of Aβ pathology.
deposition in the brain was observed in 13 of 16 patients The pathological findings using anti-Aβ immunostaining
with dCJD (81.2%). They also indicated that there was a in the present case suggested direct Aβ infection of the
© 2018 Japanese Society of Neuropathology
Dura mater graft-associated CJD 7

surface of the cerebral cortex. How the infective agent observed post mortem, it is necessary to investigate the
migrates from the site of initial infection into the brain sequential changes of the neurological and MRI findings
remains a matter of speculation. Initial manifestations to speculate on the progression of the neuropathologic
and/or EEG findings have been reported to be correlated lesions.
with the graft site in some cases of dCJD.1,9 In addition, In conclusion, this report provides significant insight
initial symptoms of dCJD have been associated with MRI into the characteristics and progression of dCJD pathology
abnormalities of dura mater-graft sites;22 the present case and its relationship with Aβ pathology. Given the limited
also showed similar characteristics. The symptoms at onset number of autopsied cases of dCJD, however, future work
in patients with dCJD who receive dura mater transplants and evaluation of additional cases are necessary in order
below the cerebellar tent tend to show cerebellar or to clarify the interpretations of the present case study and
brainstem involvement, whereas the patients who receive the pathogenesis of dCJD.
the transplant above the cerebellar tent tend to show cere-
bral cortical involvement.9,23 Sakai et al. statistically inves-
tigated the clinical courses in Japanese dCJD cases
ACKNOWLEDGMENTS
according to the grafting sites (supratentorial and This work was supported by the Research Committee of
infratentorial groups) and concluded that PrP shows direct Prion Disease and Slow Virus Infection, Research on Pol-
propagation into the brain from contaminated dura mater icy Planning and Evaluation for Rare and Intractable Dis-
grafts in the non-plaque-type dCJD cases.23 When we con- eases, Health and Labour Sciences Research Grants from
sider these findings together, Aβ transmission may be the Ministry of Health, Labour and Welfare of Japan, and
driven by a similar mechanism. JSPS KAKENHI Grant Number 15K08369. This research
Although the present case showed extensive Aβ deposi- is partially supported by the Strategic Research Program
tion, tau pathology including NFTs was hardly observed. for Brain Sciences from Japan Agency for Medical
Because the ABC scores for the neuropathologic changes Research and Development, AMED.
in AD of the present case were A3 (the Thal phase of Aβ
deposition was 5), B1 (Braak NFTs stage was 1), and C2
(CERAD SPs stage was B),24 the combination score was
DISCLOSURE
judged as “low.”24 Therefore, the pathologic findings of The authors declare that there are no conflicts of interest.
the present case did not lead to a diagnosis of AD and the
cognitive impairment seen in the present case could not be
definitively attributed to AD pathology. Although the
REFERENCES
APOE e4 allele is associated with increased risk of AD 1. Head MW, Ironside JW, Ghetti B, Piccardo MJP,
including SPs, the present case had e3 allele Will RG. Prion disease. In: Love S, Budka H,
homozygosity. Ironside JW, Perry A, (eds). Greenfield’s Neuropathol-
Our neuropathologic observations of the present case ogy, Vol 2, 9th edn. London: CRC Press, 2015;
were essentially the same as those of prior reports of spo- 1016–1086.
radic CJD with panencephalopathic pathology reported by 2. Brown P, Preece M, Brandel JP et al. Iatrogenic
our laboratory,10,25 except for the extensive Aβ deposition. Creutzfeldt-Jakob disease at the millennium. Neurol-
Although regionalization or laterality of both neuropatho- ogy 2000; 55: 1075–1081.
logical involvements and PrP depositions were not appar- 3. Brown P, Brandel JP, Preece M, Sato T. Iatrogenic
ent in the present case, the clinical features and MRI Creutzfeldt-Jakob disease: The waning of an era. Neu-
findings suggested that these changes originated from the rology 2006; 67: 389–393.
region around the implanted cadaveric dura mater graft. 4. Centers for Disease Control and Prevention (CDC).
Aβ deposition with plaques and cerebral amyloid Creutzfeldt-Jakob disease associated with cadaveric
angiopathy were also extensively and symmetrically dura mater grafts—Japan, January 1979-May 1996.
observed not only in the cerebrum, but also in the cerebel- MMWR Morb Mortal Wkly Rep 1997; 46: 1066–1069.
lum and the brainstem. Although there was no apparent 5. Ae R, Hamaguchi T, Nakamura Y et al. Update: Dura
evidence of particular accentuation of neuropathologic mater graft-associated Creutzfeldt-Jakob disease -
findings or PrP and Aβ accumulation near the dura mater- Japan, 1975-2017. MMWR Morb Mortal Wkly Rep
graft sites, we speculate that such neuropathologic involve- 2018; 67: 274–278.
ment must have begun at the right cerebral cortical region 6. Hamaguchi T, Sakai K, Noguchi-Shinohara M et al.
contact to the graft and must have progressed extensively Insight into the frequent occurrence of dura mater
due to the long disease duration by the time of the graft-associated Creutzfeldt-Jakob disease in Japan. J
autopsy. Because the pathological findings can only be Neurol Neurosurg Psychiatry 2013; 84: 1171–1175.
© 2018 Japanese Society of Neuropathology
8 Y Iwasaki et al.

7. Hamaguchi T, Taniguchi Y, Sakai K et al. Significant disease in Japan: Clinicopathological and molecular
association of cadaveric dura mater grafting with sub- characterization of the two distinct subtypes. Neuropa-
pial Aβ deposition and meningealamyloid angiopathy. thology 2009; 29: 609–618.
Acta Neuropathol 2016; 132: 313–315. 17. Kobayashi A, Matsuura Y, Mohri S, Kitamoto T. Dis-
8. Kovacs GG, Lutz MI, Ricken G et al. Dura mater is a tinct origins of dura mater graft-associated
potential source of Aβ seeds. Acta Neuropathol 2016; Creutzfeldt-Jakob disease: Past and futureproblems.
131: 911–923. Acta Neuropathol Commun 2014; 2: 32.
9. Iwasaki Y, Mimuro M, Yoshida M, Hashizume Y, 18. Noguchi-Shinohara M, Hamaguchi T, Kitamoto T
Kitamoto T, Sobue G. Clinicopathologic characteris- et al. Clinical features and diagnosis of dura mater
tics of five autopsied cases of dura mater-associated graft associated Creutzfeldt Jakob disease. Neurology
Creutzfeldt-Jakob disease. Neuropathology 2008; 28: 2007; 69: 360–367.
51–61. 19. Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H.
10. Iwasaki Y, Yoshida M, Hashizume Y, Kitamoto T, Amyloid-β pathology and cerebral amyloid angiopathy
Sobue G. Clinicopathologic characteristics of sporadic are frequent in iatrogenic Creutzfeldt-Jakob disease
Japanese Creutzfeldt-Jakob disease classified after dural grafting. Swiss Med Wkly 2016; 146: w14287.
according to prion protein gene polymorphism and 20. Preusser M, Ströbel T, Gelpi E et al. Alzheimer-type
prion protein type. Acta Neuropathol 2006; 112: neuropathology in a 28 year old patient with iatro-
561–571. genic Creutzfeldt-Jakob diseaseafter dural grafting. J
11. Parchi P, Giese A, Capellari S et al. Classification of Neurol Neurosurg Psychiatry 2006; 77: 413–416.
sporadic Creutzfeldt-Jakob disease based on molecu- 21. Nozaki I, Hamaguchi T, Sanjo N et al. Prospective
lar and phenotypicanalysis of 300 subjects. Ann Neurol 10-year surveillance of human prion diseases in Japan.
1999; 46: 224–233. Brain 2010; 133: 3043–3157.
12. Braak H, Braak E. Neuropathological stageing of 22. Sato T, Masuda M, Utsumi Y et al. Dura mater related
Alzheimer-related changes. Acta Neuropathol 1991; Creutzfeldt-Jakob disease in Japan: Relationship
82: 239–259. between sites of grafts and initial clinical features. In:
13. Mirra SS, Heyman A, McKeel D et al. participating Kitamoto T, (ed). Prions: Food and Drug Safety.
CERAD neuropathologists; The consortium to estab- Tokyo: Springer-Verlag, 2005; 31–40.
lish a registry for Alzheimer’s disease (CERAD). Part 23. Sakai K, Hamaguchi T, Noguchi-Shinohara M et al.
II. Standardization of the neuropathologic assessment Graft-related disease progression in dura mater graft-
of Alzheimer’s disease. Neurology 1991; 41: 479–486. associated Creutzfeldt-Jakob disease: A cross-
14. Thal DR, Rüb U, Orantes M, Braak H. Phases of a sectional study. BMJ Open 2013; 3: e003400.
beta-deposition in the human brain and its relevance 24. Montine TJ, Phelps CH, Beach TG et al., National Insti-
for the development of AD. Neurology 2002; 58: tute on Aging, Alzheimer's Association; National Insti-
1791–1800. tute on Aging-Alzheimer’s Association guidelines for
15. Doh-ura K, Kitamoto T, Sakaki Y, Tateishi J. CJD the neuropathologic assessment of Alzheimer’s disease:
discrepancy. Nature 1991; 353: 801–802. A practical approach. Acta Neuropathol 2012; 123: 1–11.
16. Yamada M, Noguchi-Shinohara M, Hamaguchi T 25. Iwasaki Y. Creutzfeldt-Jakob disease. Neuropathology
et al. Dura mater graft-associated Creutzfeldt-Jakob 2017; 37: 174–188.

© 2018 Japanese Society of Neuropathology