Acta Neuropathol (1994) 88:106-111

9 Springer-Verlag 1994

E Gray 9 E Chrrtien 9 E Cesaro 9 J. Chatelain
R B e a u d r y 9 J.L. Laplanche 9 J. Mikol 9 J. Bell
E Gambetti 9 J.D. Degos

Creutzfeldt-Jakob disease and cerebral amyloid angiopathy

Received: 23 December 1993 / Revised, accepted: 11 February 1994

Abstract A n 83-year-old female with no personal or

familial neurological history developed progressive gait
and speech disturbance and left m o t o r 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. T h e cortical vessel walls
stained positively for ~/A4 amyloid but not for PrP
amyloid. B o t h types of amyloid were only observed in
pericapillary parenchyma, in areas with severe spongio-

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]
E Gray (P:~I)
DEpartement de Pathologie (Neuropathologie),
H6pital Henri Mondor, F-94010 Crrteil cedex, France
E Gray 9E Chrrtien
Laboratoire d'Anatomie Pathologique (Neuropathologie),
H6pital Raymond Poincarr, Garches,
Facult6 de Mrdecine Paris-Ouest, France
E Gray 9P. Cesaro 9J.D. Degos
D6partement de Neurosciences Mrdicales,
Facult6 de Mrdecine de Crrteil, Universit6 Paris-Val de Marne,
France
J. Chatelain 9P. Beaudry 9J.L. Laplanche
Service de Biochimie et de Neurobiologie, Hrpital Saint Louis,
Paris, France
J. Mikol
Service Central d'Anatomie et de Cytologie Pathologiques,
Hrpital Lariboisibre, Facult6 de M6decine Paris VII, France
J. Bell
Neuropathology Laboratory, Western General Hospital,
The University of Edinburgh, UK
P. Gambetti
Division of Neuropathology, Institute of Pathology,
Case Western Reserve University, Cleveland, Ohio, USA

sis. T h e r e were only a few tangles and neuritic plaques
in the temporal cortex; amyloid plaques were not present either by silver stains or immunostains. T h e r e was
neither arteriopathic leukoencephalopathy nor cerebral
hemorrhage. I m m u n o b l o t 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. T h e association of PrP and [3/
A4 amyloid deposits could have been fortuitous in an
83-year-old patient. A n etiopathogenic relationship
between [3/A4 amyloid deposition and PrP accumulation may also be considered.
Key words Creutzfeldt-Jakob disease
Cerebral amyloid angiopathy 9 Prion protein
~/A4 amyloid

Introduction
Prion diseases are characterized by the accumulation of
an abnormal protease-resistant isoform of a cell protein, the prion protein (PrP). H u m a n prion diseases
include
three
familial
conditions:
GerstmannStr~ussler-Scheinker disease (GSS), familial Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia
(FFI) [31]; a sporadic form: sporadic CJD, and two
transmitted forms: Kuru [37] and iatrogenic conditions.
PrP accumulation is usually demonstrated by immunoblotting [31, 37]. A t neuropathological examination,
PrP accumulation may be obvious, forming extraceUular amyloid deposits such as "Kuru plaques" or "multicentric plaques" in GSS [43]. This particular type of
amyloid may be specifically recognized by immunocytochemistry which may also demonstrate small deposits
not evident with classical amyloid staining [19, 26].
Cerebral amyloid angiopathy ( C A A ) is characterized by the deposition of amyloid within the walls of
small to medium-sized arteries, in the cerebral cortex
and leptomeninges [41]. In most cases, C A A is due to a

107
deposition of the A l z h e i m e r [~/A4 amyloid [41]; it is frequently associated with cortical changes characteristic
of Alzheimer-type d e m e n t i a ( A D ) , i. e. senile plaques
and neurofibrillary tangles ( N F F ) , but is not necessarily
related to these lesions [15, 43]. Severe C A A m a y also
be responsible for spontaneous non-traumatic petechial
and/or larger lobar cortical and subcortical h e m o r r h ages [23], or be associated with l e u k o e n c e p h a l o p a t h y
[15] or cerebral granulomatous angiitis [16].
Association of PrP amyloid and [3/A4 amyloid
deposition in the same brain has occasionally b e e n
described in elderly patients with GSS [6, 21, 32] or
C J D [38]. We report a new case with the association of
PrP amyloid and [3/A4 amyloid in an 83-year-old patient
with C J D and C A A in the absence of neuropathological
evidence of Alzheimer's disease, cerebral h e m o r r h a g e s
or leukoencephalopathy, raising the possibility of a relationship b e t w e e n the mechanisms of deposition of these
two types of amyloid.

Case repod
A n 83-year-old female with no family history of neurological disorder or relevant past medical history, was
admitted to H e n r i M o n d o r hospital with a 3-week history of progressive weakness of her left arm, gait ataxia
with frequent falls, slurred speech, sleep and m e m o r y
disturbance. O n admission, she was alert and conscious
with m o d e r a t e intellectual slowing, mild disorientation
in time and place and intermittent dysarthria. Neurological examination showed a left m o t o r deficit predominantly involving the u p p e r limb; deep tendon reflexes
were brisk but symmetrical; plantar responses were
equivocal. A grasp reflex was present in the left hand
and intermittent myoclonus in the proximal muscles of
the left arm. T h e r e was no obvious sensory deficit, no
signs of cerebellar involvement; cranial nerves were
normal. CSF was u n r e m a r k a b l e . C T scan, with and
without contrast infusion, was normal. E E G revealed a
slow wave epileptic focus in the right frontal lobe but no
pseudo-periodic activity.
During hospitalization, her condition worsened rapidly, she b e c a m e confused and drowsy, unable to walk,
with severe dysarthria. Myoclonic jerks b e c a m e p e r m a nent bilaterally, she d e v e l o p e d generalized intractable
epileptic seizures and died f r o m aspiration bronchop n e u m o n i a , sepsis, and acute renal failure, 3 months
after the onset of neurological signs.

Blocks from many regions of the cerebral hemispheres, brain
stem and cerebellum were embedded in paraffin and in celloidin.
Sections were stained with hematoxylin and eosin, Loyez stain for
myelin, Bodian silver impregnation combined with Luxol fast
blue, periodic acid-Schiff, Congo red, and Masson Trichrome.
Immunocytochemistry was performed on selected paraffin sections by an avidin biotin peroxidase technique, utilizing formic
acid pretreatment of tissue to enhance amyloid immunoreactivity,
using polyclonal antibodies raised against [5/A4 amyloid protein
(Dako) and Tan protein (courtesy of Andr6 Delacourte). PrP was
looked for using a polyclonal antibody (1A8, Dr. Hope, Edinburgh Neuropathogenesis Unit) after pretreatment by formic acid
and guanidine thiocyanate as previously described [19]. All sections were counterstained with hematoxylin.
Double immunostaining was carried out after pretreatment
with formic acid and microwave oven exposure [18] using the
monoclonal antibody to PrP 3F4 [23] and a polyclonal anti-[3/A4
amyloid (Dako). The monoclonal antibody was shown as a brown
color by a peroxidase-antiperoxidase method with 3,3'-diaminobenzidine (DAB) as chromogen. For the polyclonal antibody the
product was colored blue using an avidin-biotin system, and
naphtol-AS-MX-phosphate/Fast blue BB as chromogen.
Immunoblot analysis was performed on frozen cortical brain
tissue homogenized in a 0.32 M sucrose buffer. After incubation
with proteinase K at a concentration of 85 Ixg/ml, at 37 ~ for 3 h
and precipitation by methanol, the pellet was exposed to 1% sarcosyl, then in a second step to guanidine thiocyanate 3 M. The
final pellet was dissolved in 10 ~tl of Laemmli sample buffer before
electrophoresis in 12% SDS-polyacrylamide gel according to
Laemmli [28] and a 2-h protein transfer to immobilon membrane
(Millipore). The membrane was then incubated overnight at 4 ~
with a rabbit polyclonal antibody raised against the hamster PrP
27-30 (RO73, kindly provided by D. Serban and S.B. Prnsiner
[39]). Immunostaining was obtained using an alkaline
phosphatase-conjugated donkey anti-rabbit IgG (Immunoresearch laboratories) shown by nitroblue tetrazolium and 5-bromo4-chloro-3-indolylphosphate (Amresco). A known neuropathologically verified and PrP-positive CJD brain sample was prepared
in the same manner and analyzed on the same gel.
For molecular genetic study, genomic DNA was purified from
frozen cortical brain. The prion protein gene (PrNP)-coding
region was screened for sequence variations using polymerase
chain reaction (PCR) and denaturing gradient gel electrophoresis
(DGGE). Oligonucleotide primers and conditions were as previouly described in detail [36].

Results
Neuropathological study

Gross examination
Gross examination of the brain did not reveal any macroscopic abnormality. In particular, the brain was not
atrophic (1280 g) and did not show any vascular
changes. Large intracranial and cervical arteries were
unremarkable.

Methods

Microscopic examination

Postmortem was performed 18 h after death and was restricted to
the brain. Samples from the left frontal lobe were immediatly frozen for molecular biology. Gross examination of the brain was performed after 1 month fixation in 10 % buffered formalin, on coronal sections of the cerebral hemispheres and sections of the brain
stem and cerebellum perpendicular to their axes.

Microscopy showed changes characteristic of C J D
including severe spongiosis and hypertrophic astrocytic
gliosis of the gray m a t t e r (Fig.la). T h e s e changes
involved the cerebral cortex predominantly, most marked in the occipital, frontal and parietal areas bilater-

108

Fig. l a - g Microscopical changes in the cerebral neocortex, a
Spongiosis and gliosis characteristic of CJD, there is also neuronal
loss. H&E. b Cerebral amyloid angiopathy associated with gliosis
and spongiosis in the neocortex H&E. c Immunocytochemistry
for 13/A4 amyloid strongly stains the arterioles and capillaries in
the neocortex, d, e Immunostaining of the PrP is strongly positive
in areas of confluent spongiosis (d) and reveals parenchymal

deposits forming "plaques" which were not demonstrated by routine techniques (e). f, g Double immunostaining for ~/A4 amyloid
(blue) and PrP (brown). Arterioles (f) and capillaries (g) only
express ~/A4 amyloid while PrP is only present in the parenchyma, mostly in areas with spongiosis, a - g x 100 (CJD
Creutzfeldt-Jakob disease, PrP prion protein)

109
ally. Ammon's horn was spared and the remaining temporal cortex only mildly affected. Spongiosis and gliosis
involved all the cortical layers except the molecular
layer and were associated with significant neuronal loss.
Similar, although milder changes were also found in the
striatum, thalamus and substantia nigra. The cerebellum was less affected; there was mild spongiosis of the
molecular layer and occasional loss of Purkinje cells
with proliferation of Bergmann glia and axonal "torpedoes".
In addition, there was diffuse amyloid angiopathy
involving the cortical and leptomeningeal arterioles the
walls of which were thickened with an acellular,
hyaline, eosinophilic material (Fig.lb). This material
was positively stained with Congo red and showed characteristic birefringence in polarized light. No inflammatory reaction was observed in and around leptomeningeal and cortical vessels. Amyloid infiltration also
involved intracortical capillaries, leaking into the adjacent parenchyma "dyshoric angiopathy". The vessels of
the hemispheric white matter, brain stem and cerebellum were unremarkable. Only a few NFT and exceptional neuritic plaques were found in the temporal cortex. There were no amyloid plaques. There were neither
senile plaques nor NFF in the neocortex. There was no
cerebral hemorrhage either small petechial bleeding or
large lobar hematoma. The white matter was unremarkable; in particular there was no obvious myelin pallor.

the neocortex and only exceptional changes in
Ammon's horns.
PrP immunostaining showed intense PrP positivity in
areas of confluent spongiosis (Fig.ld) and some granular staining in astrocytes. It revealed a few parenchymal
deposits forming "plaques" which were not demonstrated by routine techniques (Fig.le).The blood vessels
were not stained.
Double immunostaining confirmed that the blood
vessels only expressed ~/A4 amyloid, while parenchymal areas with severe spongiosis only showed PrP
immunoreactivity (Fig. If, g). Both proteins were
expressed in pericapillary parenchyma, in areas with
severe spongiosis; however, even in these places it was
obvious that one was vascular while the other was
parenchymal.

Immunocytochemistry

D N A analysis using PCR and D G G E revealed a
methionine-methionine homozygotism at codon 129 of
the PrNP gene.

Immunocytochemistry showed that the amyloid deposits in arterioles and capillaries were strongly stained
with the ~/A4 antibody. The latter did not reveal any
amyloid senile plaques (Fig.lc). Immunostaining for
Tau protein showed neither senile plaques nor NFT in
Fig. 2 Western immunoblot of
proteinase K-treated brain
extracts from a neuropathologically confirmed CJD case
(lane 1) and our patient (lane
2) revealed with a rabbit polyclonal antibody against
scrapie-infected hamster PrP
27-30 (RO 73)

Immunoblot analysis
Immunoblot analysis revealed the presence of the
abnormal proteinase K-resistant isoform of PrP, the
biochemical hallmark of the spongiform encephalopathies. The pattern of bands (from 27 to 30 kDa) was
identical to that obtained from a PrP-positive sporadic
CJD brain (Fig. 2).
D N A analysis

Discussion

In an 83-year-old woman with progressive ataxia,
dementia and myoclonic jerks, leading to death within 3
months, immunoblotting and neuropathology confirmed the diagnosis of CJD. Homozigotism at codon
129 of the PrNP gene is also often associated with sporadic CJD [34]. Immunostaining for PrP was positive in
areas with marked spongiform changes. In addition
there was marked CAA, diffuse to the entire hemispheric cortex, expressing ~/A4 amyloid and not PrP,
without significant changes of AD.
Association of changes characteristic of spongiform
encephalopathies, either CJD or GSS, and senile
degenerative cortical lesions including senile plaques,
NFT and/or CAA, has been reported in various instances.
The possibility of senile and neuritic plaques in addition to Kuru plaques and multicentric plaques in GSS
was mentioned in the initial descriptions of the disease,
but NFT were classically absent [4, 42]. However, NFT
were found in young patients with a family history and
neuropathological changes characteristic of GSS [27,
33] and particularly in the "Indiana kindred" [2, 13, 40].

110
Immunostaining of the amyloid was p e r f o r m e d in the that one single disease may produce variable neuropaIndiana kindred [12] and in the family of Nochlin [33]; thological changes [9]. It is noteworthy that cerebrovasit was strongly immunoreactive with the PrP antibody cular amyloidosis was observed in 11 of 20 sheep with
and negative for the ~/A4 amyloid antibody, suggesting scrapie [14] and evidence for the experimental transthat these cases represented just a neuropathological mission of cerebral ~-amyloidosis to primates has been
variant of GSS. On the other hand the presence of PrP recently reported [3].
Deposition of ~/A4 amyloid may only represent an
and [3/A4 amyloid was recently demonstrated in elderly
patients with GSS [7, 10, 21, 32]. C A A was described in age-related p h e n o m e n o n superimposed on PrP accutwo cases with clinical and neuropathological features mulation. This is particularly likely for patients with
consistent with GSS [1, 7]. Both patients were 62 years C A A who all were over 63 years of age and in whom the
old and presented with NFT. Immunostaining of the two types of amyloid deposits involved different strucamyloid was p e r f o r m e d later in one case [1]; it showed tures and never really colocalized. However, the two
that the vessel wall expressed [5/A4 amyloid only, while conditions may interact in some way. A disturbance in
cortical plaques expressed either PrP or [5/A4 amyloid. the metabolism of [3PP or [5/A4 due to the accumulation
It is not known whether these were different plaques or of PrP might have increased the age-related deposition
whether some could be stained by both antibodies [43]. of ~/A4 in the blood vessel walls in the 83-year-old
Two other possible cases were also described by Worster woman. It is noteworthy that C A A was only found in
areas with changes of CJD and that the severity of both
Drought et al. [44] in siblings.
The coexistence of clinical and neuropathological types of change more or less paralleled in the different
features characteristic of sporadic CJD and Alzheimer's neocortical areas. On the other hand, C A A may have
disease has b e e n reported in a few cases [5, 11, 29, 35]. accelerated the course of CJD. The duration of the neuIn two cases, amyloid plaques in the cerebral cortex rological disease was indeed very short (less than 6
expressed [5/A4 amyloid and not PrP; however, abund- months) in eight of nine cases with C A A and CJD
ant PrP was identified by Western blot analysis of brain (L.W. Duchen, personal communication). The short
extracts [5, 35] and one case was transmitted to prima- duration of the disease may also account for the
tes [5]. It is possible that the lack of PrP reaction in absence of any complication of C A A such as hemorrhthose cases only reflected the weaker sensitivity of the ages, leukoencephalopathy, infarcts or angiitis.
m e t h o d compared to our more recent technique which
Acknowledgments We are very grateful to Dr. J. Hope for the
is able to stain parenchymal PrP in the absence of obvi- 1A8 antibody, Dr. R.J. Kascsak for providing the 3F4 antibody, to
ous amyloid deposit [19].
D. Serban and S.B. Prusiner for their generous gift of the RO73
Association of C A A and CJD has been reported in a antibody and also to D. Borchelt and D. Westaway for their advice
few cases ([11] case 1; [20, 25, 30]; and [43] cases 18, 20, about the immunodetection of PrP. We wish to thank Prof. Jean
Marie Briicher and Dr. Henry Baron for their useful comments on
21) of which only two [11, 25] are well documented; the this case, Dr. Catherine Keohanc for kindly reviewing the
others are just mentioned in tables within wider studies. English, Ms. Diane Kofskey for her technical expertise in carrying
All these cases were over 63 years old. Most of them out double immunostaining, Ms. Linda McArdle for PrP immuhad cortical changes of A D . In only one case ([43] case nostaining, Line Bazeille, Gis61e Corcket, Martine Francesco,
Halloche, Vdronique Levy and Genevi6ve Mesnil for his18), as with our case, was C A A not associated with Annick
tological preparations, Marie Claude Lescs and Lucile Mernier for
changes of A D . Immunostaining was p e r f o r m e d in four photography and Leila Breton for secretarial help.
cases only [25, 43]. C A A always expressed fi/A4 amyloid and not PrE The latter was expressed in cerebellar
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