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Comparison of survival times of mice inoculated with brain tissue from various neurological diseases.

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R. D. D. is supported by a New Investigator Research Award,
NS20742, from the National Institute of Neurological and Communicative Disorders and Stroke.
The authors thank Ms Joanne Rush for enthusiastic technical assistance and Ms Grace Stauffer for manuscript preparation. We also
thank Dr J. Richard Baringer for helpful suggestions.
References
1. Baringer JR: Herpes simplex infection of the nervous system. In
Vinkin PJ, Bruyn GW (eds): Handbook of Clinical Neurology.
Amsterdam, North Holland, 1978, vol 32, pp 145-159
2. Bone DR, Courtney RJ: A temperature-sensitive mutant of
herpes simplex virus type 1 defective in the synthesis of the
major capsid polypeptides. J Gen Virol 24:17-27, 1974
3. Cappel R, Kiastersky J: Herpetic meningitis (type 1) in a case of
acute leukemia. Arch Neurol 28:415-416, 1973
4. Center for Disease Control Task Force on Kaposi’s Sarcoma and
Opportunistic Infections: Epidemiological aspects of the current
outbreak of Kaposi’s sarcoma and opportunistic infections. N
Engl J Med 306:2,48-252, 1982
5. Fauci AS, Macher AM, Longo DL, et al: Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic,
and therapeutic considerations. Ann Intern Med 10092-106,
1984
6. Harford CG, Wellinghoff W, Weinstein RA: Isolation of herpes
simplex virus from the cerebrospinal fluid in viral meningitis.
Neurology (Minneap) 25: 198-200, 1975
7. Heller M, Dix RD, Baringer JR, et al: Herpetic proctitis and
meningitis: recovery of two strains of herpes simplex virus type
1 from cerebrospinal fluid. J Infect Dis 146:584-588, 1982
8. Jaffe HW, Bregrnan DJ, Selik RM: Acquired immune deficiency syndrome in the United States: the first 1000 cases. J
Infect Dis 148:339-345, 1983
9. Linneman CC Jr, First MR, Alvira MM, et ah Herpesvirus
hominis type 2 meningoencephalitis following renal transplantation. Am J Med 61:703-708, 1976
10. Mathur U, Enlow RW, Spigland I, et al: Generalized lymphadenopathy: a prodrome of Kaposi’s sarcoma in male homosexuals?
Program and Abstracts of the 22nd Interscience Conference o n
Antimicrobial Agents and Chemotherapy (abstract no. 853).
Washington, DC, American Society for Microbiology, 1982
11. Nahmias AJ, Whitley RJ, Visintine AN, et al: Herpes simplex
virus encephalitis: laboratory evaluations and their diagnostic
significance. J Infect Dis 145:829-836, 1982
12. Oommen KJ, Johnson PC, Ray CG: Herpes simplex type 2
virus encephalitis presenting as psychosis. Am J Med 73:445448, 1982
13. Pereira L, Dondero DV, Gallo D, et al: Serological analysis of
herpes simplex virus types 1 and 2 with monoclonal antibodies.
Infect Immunol 35:363-367, 1982
14. Persistent generalized lymphadenopathy among homosexual
males. Morbid Mortal Weekly Rep 31:249-251, 1982
15. Steel JG, Dix RD, Baringer JR: Isolation of herpes simplex
virus type 1 in recurrent (Mollaret) meningitis. Ann Neurol
11:17-21, 1982
16. Sutton AL, Smithwick EM, Seligman SJ, Kim DS: Fatal disseminated herpesvirus hominis type 2 infection in an adult with
associated thymic dysplasia. Am J Med 56:545-553, 1974
CornParison of Survival
Tim& of Mice Inoculated
with Brain Tissue from
Various Neurological
Diseases
Leighton W. Greenham, PhD,
and David B. Peacock, MB, ChB
~
~
Mice inoculated intracerebrally before the age of 5 days
with homogenates of autopsied brain tissue from patients with Creutzfeldt-Jakob (C-J), Alzheimer’s, or
Picks diseases showed highly significant decreases in
life span when compared with sham-inoculated control
mice. With C-J disease there was strong indication of
horizontal transmission of the agent to uninoculated
mice caged with the inoculated mice. While the results
with C-J disease were not unexpected in view of the
known infectious etiology of the disease, the results obtained with Alzheimer’s and Pick’s diseases suggest that
previously undetermined infectious or toxic agents may
be associated with these two diseases, which currently
have unresolved etiologies. Mice inoculated with autopsied brain tissue from patients with multiple sclerosis or
subacute sclerosing panencephalitis had life spans similar to those of the control mice.
Greenham LW, Peacock DB: Comparison of survival
times of mice inoculated with brain tissue from various
neurological diseases. Ann Neurol 17206-209, 1985
In a previous report we described astrocytic proliferation and status spongiosus between 18 and 24 months
in 3 of 30 mice inoculated with homogenate of brain
tissue removed at postmortem examination from a patient (PR) with fulminating Creutzfeldt-Jakob (C-J)
disease [2}. One of the 3 mice exhibited hind limb
paralysis. The transmission of C-J agent to laboratory
rodents was subsequently confirmed and extended by
others C3, 5 , 8, 91.
The remaining 2 7 mice inoculated with homogenate
from the same patient were kept under extended observation and, although n o signs of paralysis or other
neurological deficits were observed, their dates of death
were recorded. The plotted survival times of these
mice did not differ significantly from those of shaminoculated control mice but, because the C-J agent is
From the Department of Microbiology, University of Bristol, Bristol
BS8 lTD, England.
Received Feb 29, 1984, and in revised form Jun 21. Accepted for
publication Jun 23, 1984.
Address reprint requests to Dr Greenham.
206
Inocuhtion Data and Statistical Evaluation of the Derived Survival Plots
Source of
Inoculum
Neurological
Disease
Mouse Pass
No.
PR
C-J
Squirrel monkey
C-J
JL
MA
Uninoculated mice
caged with PR pass 2
C-J
1
2
1
2
1
1
NA
sw
SSPE
SSPE
MS
Alzheimer
Pick
NA
C-J
NA
AP
DC
AW
RLR
S ham-inoculated
control
NA = not applicable; C-J
=
1
1
1
1
1
NA
Experimental Mice
MaledFernales
Mean Age (days)
Statistical Comparison
with Control Mice (p)
1819
2412 1
617
5
2
2
4
2.5
1
1.5
< 0.25 > 0.1
< 0.001
> 0.75
< 0.001
< 0.25 > 0.1
< 0.01 > 0.005
< 0.001
1.5
2
1
2.5
1
1
< 0.75 > 0.5
< 0.75 > 0.5
< 0.5 > 0.25
< 0.001
< 0.001
613
615
511
16124
717
916
7/18
814
10/12
1118
NA
Creutzfeldt-Jakob disease; SSPE = subacute sclerosing panencephalitis; MS = multiple sclerosis.
considered to be scrapielike and because the virulence
of scrapie agent for mice may be increased by serial
passage in this rodent 111, we attempted to determine
if the virulence of the agent might be increased by
further passage. The brain tissue from the first-pass
mouse exhibiting hind limb paralysis was therefore inoculated into more mice.
Here we present the survival data from first-pass and
second-pass transmissions of the C-J agent from patient PR in mice and compare them with survival data
recorded from mice inoculated with brain tissue removed at postmortem examination from patients with
other neurological diseases of known or putative infectious etiology, namely, subacute sclerosing panencephalitis (SSPE), multiple sclerosis, Alzheimer’s disease. and Pick‘s disease.
Materials and Methods
Cortical brain tissue specimens were removed at postmortem
examination from patients with C-J disease (patients PR, JL,
and MA), SSPE (patients SW and AP), multiple sclerosis
(patient DC), Alzheimer’s disease (patient AW), and Picks
disease (patient RLR). Before inoculation into mice, all diseases were confirmed by histopathological examination. Cortical tissue removed at previous biopsy from patient PR had
been inoculated into a squirrel monkey, and a specimen of
cortex from this animal was also inoculated into mice.
All brain tissue specimens were prepared as 10% homogenates in medium 199 (Gibco Europe, Paisley, Scotland) at
pH 7.0 and inoculated intracerebrally in 0.05 ml amounts
into 0.5- to 5-day-old Bristol outbred Swiss mice (Table).
Less than 1% of deaths occurred within 24 hours in mice
aged 5 days or less when inoculated. Inoculated mice were
tail-tattooed for identification and segregated into male and
female groups when weaned at 3 weeks. Mice inoculated
with one homogenate were caged separately from those inoculated with another homogenate, and all mice were kept
under continual daily observation until death. Mice killed for
neuropathological examination because of the onset of
neurological or other disease were excluded from the accumulated survival data.
Litters of control mice, sham-inoculated with normal 4day-old mouse brain homogenate, were caged separately
from mice inoculated with diseased brain homogenate.
In second-pass experiments with C-J agent, unrnoculated
mice were caged with inoculated mice to detect horizontal
transmission of the agent.
Results
C-J Disease
Although there was no statistically significant difference between the survival of PR-inoculated first-pass
mice and the control mice (Fig l A , Table), there was
a highly significant difference between second-pass
mice, and also the uninoculated mice caged with them,
and control mice (Fig lA, Table). Mice inoculated at
first and second pass with squirrel monkey cortex reproduced the results obtained with PR cortex (Fig IB,
Table). No neuropathologicd lesions were detected in
killed mice from these groups.
Of the C-J specimens from the 2 remaining patients,
the survival of mice inoculated with JL cortex was
not significantly different from that of control mice,
whereas the survival of mice inoculated with MA cortex was significantly different (Fig lB, Table). One
mouse inoculated with JL cortex exhibited C-J-like
lesions in the central nervous system.
Brief Communication: Greenham and Peacock: CJD Transmission in Mice
207
3
WEEKS
post inoculation
WEEKS
post in o c u I a t ion
Fig 1 . Survival plots of mi1.e inoculated with autopsied Creutzfeldtt;lakob brain tissue at first and second passes. (A)First-pass
mice (open circles) were inoculated with cortical tissue from patient PR. Second-pass mice (solid circles) were inoculated with
cortical tissue from 2 first-pass mice that exhibited bind limb
paralysis at 71 and 9.2 weeks. Uninoculated mice (triangles)
were caged with second-pass mice to test for horizontal transmission. (B) Cortical tissuefmm a squiwel monkey inoculated with
autopsied cortical tissue from patient PR, and killed at 60 weekc
when exhibiting paralysis, was the starting materialfor similar
first (open circles) and second (solid circles) passes in mice. Second-pass mice were inoculated with cortical tissue from a firstpass mouse that deyeloped tail biting at 67 weeks. First passes of
cortical tissue from patients J L (open triangles) and M A (solid
triangles) gave additional comparative plots. In both A and B
sham-inoculated mice (squares) constituted controls.
SSPE and Multiple Sclerosis
There was no significant difference between the survival of mice inoculated with SSPE or multiple sclerosis cortices and that of control mice (Fig 2A, Table).
Alzheimer's and Pick's Diseases
The survival of mice inoculated with AW and RLR
cortices differed significantly from that of control mice
(Fig 2B, Table). No neuropathological lesions were
detected in killed mice from these groups.
208 Annals of Neurology Vol 1 7 No 2
February 1985
Fig 2. Survival plots of mice inoculated with autopsied brain tissue from other neurological diseases at first pass only. (A)Mice
were inoculated with cortical tissue from patients SW (open circles) and AP (solid circles) with subacute sclerosing panencephalitis, and from patient DC (triangles) with multiple scler0si.r.
(B) Mice were inoculated with cortical tissuefrom patient AW
(open circles) with Alzbeimeri^ disease and patient RLR (solid
circles) with Pick's disease. In both A and B sham-inoculated
mice (squares) constituted controls.
Discussion
Despite the absence of overt neuropathological disease
in life, or of histopathological lesions in killed mice,
the survival of mice inoculated with PR-derived and
squirrel monkey-derived C-J agent was significantly
reduced at second-pass inoculation (Fig 1). The apparent increase in virulence of the transmissible C-J agent
from patient PR at its second pass mimics the increase
in virulence of scrapie agent during passage in mice
{l]. Mice inoculated with C-J agent from patient MA
showed reduced survival times at the first pass (Fig
1B); this may be due to quantitative or qualitative
(strain) variations of the agent as are known to occur
with scrapie agent { 11. Further transmission experiments are needed to decide among such alternatives.
When uninoculated mice were caged with second-
pass C-J-inoculated mice, there was a similar reduction in the survival of both groups (Fig lA), and this is
considered indicative of horizontal transmission. It is
likely that biting and scratching constitute major transmission routes, whether the aggressor is initially infected or noninfected. If the aggressor is noninfected,
the oral route of infection is most probable f9J.
The negative results obtained with SSPE and multiple sclerosis tissues (Fig 2A) were not unexpected in
view of the need for fresh, unstored tissue for best
transmission of SSPE-measles virus fb] and in view of
all previous failures to isolate an infectious agent in
multiple sclerosis 171. The normal survival times of
these inoculated mice emphasize the meaningfulness
of the reduced survival times of C-J-inoculated mice.
The reduced survival times of mice inoculated with
tissue from subjects with Alzheimer's and Pick's diseases (Fig 2B) offer no real evidence to support current speculation about slow virus etiologies of senile
dementia 14, lOJ. While a transmissible agent appears
to be associated with familial Alzheimer's disease {4J,
our records indicate that patient AW had the nonfamilial form. Our results do not answer the question of
whether Alzheimer's and Pick's diseases are transmissible since they may be alternatively explained by
other chronic agents, of either an infectious or a toxic
nature, which might be present in the inoculated brain
tissues but which need not have had an etiological role
in these human diseases. There is a clear need for
more extensive investigation of the diseases.
Overall, our results suggest that survival data from
inoculated mice constitute a valid method of investigation of C-J disease and other neurological diseases with
a more tenuous infectious etiology.
We thank Drs Gudrun Agnarsdottir, Betty Brownell, D. H. Johnson, M. A. Nurbhai, and I. Zlotnik for providing the various specimens of human and primate cortex. We especially acknowledge the
cooperation afforded by Dr Betty Brownell, who confirmed the
diagnosis of C-J disease, multiple sclerosis, and Alzheimer's and
Pick's diseases in the various patients and who examined a number
of experimental mice for disease transmission. We gratefully acknowledge the funding of the British Medical Research Council.
References
1. Adams DH, Bell TM: Slow Viruses. Reading, MA, AddisonWesley, 1976, pp 144-146
2. Brownell B, Campbell MJ, Greenham LW, Peacock DB: Experimental transmission of Creuttfeldt-Jakob disease. Lancet
2:186-187, 1975
3. Chino F: Experimental transmission of Creutzfeldt-Jakob disease to guinea pigs. Acta Pathol Jpn 31:763-972, 1981
4. Gibbs CJ, Gajdusek DC: Subacute spongiform encephalopathies: the transmissible virus dementias. In Katzman R,
Terry RD, Bick KL (eds): Senile Dementia and Related Disorders. Aging, Vol7. New York, Raven, 1978, pp 559-575
5. Gibbs CJ, Gajdusek DC, Amyx H: Strain variation in the viruses of Creutzfeldt-Jakob disease and Kuru. In Prusiner SB,
Hadlow WJ (eds): Slow Transmissible Diseases 'of the Nervous
System. New York, Academic, 1979, Vol 2, pp 87-1 10
6. Greenham LW, Peacock DB, Hill TJ, et al: The isolation of
SSPE measles virus in newborn mice. Arch Ges Virusforsch
441109-120, 1974
7. Kurtzke JF: Multiple sclerosis: an overview. In Rose FC (ed):
Clinical Neuroepidemiology. Progress in Neuroepidemiology
series. Tunbridge Wells, Pitman, 1980, pp 170-195
8. Manueledis EE, Gorgacz EJ, Manueledis L Transmission of
Creutzfeldt-Jakob disease with scrapie-like syndromes to mice.
Nature (Lond) 2711778-779, 1978
9. Tateishi J, Koga M, Mori R: Experimental transmission of
Creurzfeldt-Jakob disease. Acta Pathol Jpn 31943-75 1, 1981
10. Wisniewski HM, Kozlowski PB: Evidence for blood-brain barrier changes in senile dementia of the Alzheimer type (SDAT).
Ann N Y Acad Sci 396:119-129, 1982
Brief Communication: Greenham and Peacock: CJD Transmission in Mice
209
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