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From: TSS ()
Subject: Transmissibility of mouse AApoAII amyloid fibrils: inactivation by physical and chemical methods
Date: March 22, 2006 at 6:31 am PST

The FASEB Journal Express Article doi:10.1096/fj.fj.05-4890fje
Published online March 20, 2006


Transmissibility of mouse AApoAII amyloid fibrils: inactivation by physical and chemical methods

Huanyu Zhang, Jinko Sawash!ta, Xiaoying Fu, Tatsumi Korenaga, Jingmin Yan, Masayuki Mori, and Keiichi Higuchi

E-mail contact: khiguchi@sch.md.shinshu-u.ac.jp


AApoAII amyloid fibrils have exhibited prion-like transmissibility in mouse senile amyloidosis. We have demonstrated that AApoAII is extremely active and can induce amyloidosis following doses less than 1 pg. We tested physical and chemical methods to disrupt AApoAII fibrils in vitro as determined by thioflavin T binding and electron microscopy (EM) as well as inactivating the transmissibility of AApoAII fibrils in vivo. Complete disruption of AApoAII fibrils was achieved by treatment with formic acid, 6 M guanidine hydrochloride, and autoclaving in an alkaline solution. Injection of these disrupted AApoAII fibrils did not induce amyloidosis in mice. Disaggregation with 6 M urea, autoclaving, and alkaline solution was incomplete, and injection of these AApoAII fibrils induced mild amyloidosis. Treatment with formalin, delipidation, freeze-thaw, and RNase did not have any major effect. A distinct correlation was obtained between the amounts of amyloid fibrils and the transmissibility of amyloid fibrils, thereby indicating the essential role of fibril conformation for transmission of amyloidosis. We also studied the inactivation of AApoAII fibrils by several organic compounds in vitro and in vivo.

AApoAII amyloidosis provides a valuable system for studying factors that may prevent transmission of amyloid disease as well as potential novel therapies.


http://www.fasebj.org/cgi/content/abstract/fj.05-4890fjev1

another transmissible protein amyloidosis? what does this implicate with Alzheimer's? thought alzheimer's was not suppose to be transmissible either? low level TSE maybe?

Medical Sciences
Transmissibility of systemic amyloidosis by a prion-like mechanism
Katarzyna Lundmark*, Gunilla T. Westermark, Sofia Nyström, Charles L. Murphy, Alan Solomon, and Per Westermark§,¶

Divisions of * Molecular and Immunological Pathology and Cell Biology, Linköping University, 581 83 Linköping, Sweden; § Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; and Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996

Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved March 15, 2002 (received for review April 26, 2001)

The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this "amyloid enhancing factor" (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.


--------------------------------------------------------------------------------


http://www.pnas.org/cgi/reprint/99/10/6979


CJD1/9 0185


Ref: 1M51A

IN STRICT CONFIDENCE


Dr McGovern From: Dr A Wight

Date: 5 January 1993

Copies: Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray


TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES


1. CMO will wish to be aware that a meeting was held at DH yesterday,
4 January, to discuss the above findings. It was chaired by Professor
Murray (Chairman of the MRC Co-ordinating Committee on Research in
the Spongiform Encephalopathies in Man), and attended by relevant
experts in the fields of Neurology, Neuropathology, molecular biology,
amyloid biochemistry, and the spongiform encephalopathies, and by
representatives of the MRC and AFRC.

2. Briefly, the meeting agreed that:

i) Dr Ridley et als findings of experimental induction of p amyloid
in primates were valid, interesting and a significant advance in the
understanding of neurodegeneradve disorders;

ii) there were no immediate implications for the public health, and no
further safeguards were thought to be necessary at present; and

iii) additional research was desirable, both epidemiological and at the
molecular level. Possible avenues are being followed up by DH
and the MRC, but the details will require further discussion.

93/01.05/4.1


http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

BSE101/1 0136


IN CONFIDENCE

5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992


TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES


1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have
recognised the public sensitivity of these findings and intend to report
them in their
proper context. This hopefully will avoid misunderstanding and possible
distortion by
the media to portray the results as having more greater significance than
the findings
so far justify.


2. Using a highly unusual route of transmission (intra-cerebral injection)
the
researchers have demonstrated the transmission of a pathological process
from two
cases one of severe Alzheimer's disease the other of Gerstmann-Straussler
disease to
marmosets. However they have not demonstrated the transmission of either
clinical
condition as the "animals were behaving normally when killed'. As the report
emphasises the unanswered question is whether the disease condition would
have
revealed itself if the marmosets had lived longer. They are planning funher
research
to sec if the conditions, as opposed to the partial pathological process, is
transmissible.


What are the implications for public health?


3. . The route of transmission is very specific and in the natural state of
things
highly unusual. However it could be argued that the results reveal a
potential risk,
in that brain tissue from these two patients has been shown to transmit a
pathological
process. Should therefore brain tissue from such cases be regarded as
potentially
infective? Pathologists, morticians, neuro surgeons and those assisting at
neuro
surgical procedures and others coming into contact with "raw" human brain
tissue
could in theory be at risk. However, on a priori grounds given the highly
specific
route of transmission in these experiments that risk must be negligible if
the usual
precautions for handling brain tissue are observed.


92/11.4/1-1


BSE101/1 0137


4. The other dimension to consider is the public reaction. To some extent
the GSS
case demonstrates little more than the transmission of BSE to a pig by
intra-cerebral
injection. If other prion diseases can be transmitted in this way it is
little surprise that
some pathological findings observed m GSS were also transmissible to a
marmoset.
But the transmission of features of Alzheimer's pathology is a different
matter, given
the much greater frequency of this disease and raises the unanswered
question whether
some cases are the result of a transmissible prion. The only tenable public
line will
be that "more research is required" before that hypothesis could be
evaluated. The
possibility on a transmissible prion remains open. In the meantime MRC needs
carefully to consider the range and sequence of studies needed to follow
through from
the preliminary observations in these two cases. Not a particularly
comfortable
message, but until we know more about the causation of Alzheimer's disease
the total
reassurance is not practical.

JS METTERS
Room 509
Richmond House
Pager No: 081-884 3344
Callsign: DOH 832

121/YdeS

92/11.4/1.2


http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf


TSS

Proof Mad Cow Is The Same
As Alzheimer's And CJD ???

How Many Of Them Are Really Mad Cow/vCJD/TSEs ???

How Can Government Claims Of Just 'One In A Million' Be Accurate
When CJD Is Not A Reportable Disease? And When The Elderly Do
Not Get Routinely Autopsied??


By Terry Singletary, Sr
12-27-03


Note - This extensive, powerful assemblage of science was first posted on
1-24-3. The
following data is even more important today. -ed

snip...


Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)


http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf


snip...


The pathogenesis of these diseases was compared to Alzheimer's disease at a
molecular level...


snip...


http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf


And NONE of this is relevant to BSE?

There is also the matter whether the spectrum of ''prion disease'' is wider
than that recognized at present.


http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf


Human BSE

snip...

These are not relevant to any possible human hazard from BSE nor to the much
more common dementia, Alzheimers.

snip...


http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf


=====================================================

From: TSS
Subject: CJD or Alzheimer's, THE PA STUDY...full text
Date: May 7, 2001 at 10:24 am PST

Diagnosis of dementia: Clinicopathologic correlations

Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD

Article abstract--Based on 54 demented patients consecutively autopsied at
the University of Pittsburgh, we studied the accuracy of clinicians in
predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had
Alzheimer's disease, while 15 (27.7%) had other CNS diseases (four
multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and
subcortical gliosis; three Parkinson's disease; one progressive supranuclear
palsy; one Huntington's disease; and one unclassified). Two neurologists
independently reviewed the clinical records of each patient without
knowledge of the patient's identity or clinical or pathologic diagnoses;
each clinician reached a clinical diagnosis based on criteria derived from
those of the NINCDS/ADRDA. In 34 (63 %) cases both clinicians were correct,
in nine (17%) one was correct, and in 11 (20%) neither was correct. These
results show that in patients with a clinical diagnosis of dementia, the
etiology cannot be accurately predicted during life.

NEUROLOGY 1989;39:76-79

Several recent papers and reports have addressed the problem of improving
the clinician's ability to diagnose dementia. Notable among those reports
are the diagnostic criteria for dementia of the American Psychiatric
Association, known as DSM III,1 as well as the clinical and neuropathologic
criteria for the diagnosis of Alzheimer's disease (AD).2,3 Other researchers
have published guidelines for the differentiation of various types of
dementia4 and for antemortem predictions about the neuropathologic findings
of demented patients.5

Most studies on the accuracy of clinical diagnosis in patients with
dementia, especially AD, have used clinicopathologic correlation,6-15 and
have found a percentage of accuracy ranging from 43% to 87%. Two recent
reports, however,16,17 have claimed an accuracy of 100%. These two reports
are based on relatively small series and have consisted of very highly
selected patient samples. In our own recent experience, several cases of
dementia have yielded unexpected neuropathologic findings,18 and we
hypothesized that, in larger series, there would be a significant number of
discrepancies between clinical diagnoses and autopsy findings. The present
paper reviews the neuropathologic diagnosis of 54 demented patients who were
autopsied consecutively at the University of Pittsburgh over a 7-year
period, and reports the ability of clinicians to predict autopsy findings.

Material and methods. We independently reviewed the pathologic data and
clinical records of 54 consecutive patients who had had an autopsy at the
University of Pittsburgh (Presbyterian University Hospital [PUH] and the
Pittsburgh (University Drive) Veterans Administration Medical Center
[VAMC]), between 1980 and 1987.

The 54 cases included all those where dementia was diagnosed clinically but
for which an obvious etiology, such as neoplasm, trauma, major vascular
lesions, or clinically evident infection had not been found. The brains,
evaluated by the Division of Neuropathology of the University of Pittsburgh,
were obtained from patients cared for in different settings at their time of
death.

On the basis of the amount of information available in each case, we divided
the patients into three groups. Group 1 included 12 subjects who had been
followed for a minimum of 1 year by the Alzheimer Disease Research Center
(ADRC) of the University of Pittsburgh. ADRC evaluations include several
visits and neurologic and neuropsychological testing as well as repeated
laboratory tests, EEG, and CT.19,20

Group 2 included 28 patients who had been seen in the Neurology Service of
PUH, of the VAMC, or in geriatric or psychiatric facilities of the
University of Pittsburgh or at Western Psychiatric Institute and Clinic. All
patients were personally evaluated by a neurologist and received a work-up
to elucidate the etiology of their dementia.

Group 3 included 14 patients seen in other institutions; in most cases, they
had also been seen by a neurologist and had had laboratory studies that
included CT of the head. In three of the 14 cases, however, the information
could be gathered only from the clinical summary found in the autopsy
records.

Many of these subjects were referred for autopsy to the ADRC because of a
public education campaign that encourages families to seek an autopsy for
their relatives with dementia.

Pathologic data. All brains were removed by a neuropathologist as the first
procedure of the autopsy at postmortem intervals of between 4 and 12 hours.
The unfixed brain was weighed and the brainstem and cerebellum were
separated by intercollicular section. The cerebral hemispheres were
sectioned at 1-cm intervals and placed on a glass surface cooled by ice to
prevent adhesion of the tissue to the cutting surface. The brainstem and
cerebellum were sectioned in the transverse plane at 6-mm intervals. Brain
sections were fixed in 10% buffered formalin. Selected tissue blocks for
light microscopy were obtained from sections corresponding as exactly as
possible to a set of predetermined areas used for processing brains for the
ADRC protocol; additional details of the neuropathologic protocol have been
previously published.18,21 Following standard tissue processing and paraffin
embedding, 8-um-thick sections stained with hematoxylin and eosin and with
the Bielschowsky ammoniacal silver nitrate impregnation were evaluted.
Additional stains were used when indicated by the survey stains, including
the Bielschowsky silver technique as previously reported.21

Clinical data. The medical history, as well as the results of examinations
and laboratory tests, were obtained from the medical records libraries of
the institutions where the patient had been followed and had died. We
supplemented these data, when appropriate, with a personal or telephone
interview with the relatives.

One neurologist (O.L.L.) recorded the information to be evaluated on two
forms. The first form included sex, age, handedness, age at onset, age at
death, course and duration of the disease, education, family history, EEG,
CT, NMR, medical history, and physical examinationas well as examination of
blood and CSF for factors that could affect memory and other cognitive
functions. The form also listed the results of neuropsychological
assessment, and the characteristics and course of psychiatric and neurologic
symptoms. The form provided details on the presence, nature, and course of
cognitive deficits and neurologic signs. The second form was a 26-item
checklist derived from the NINCDS-ADRDA Work Group Criteria for probable
Alzheimer's disease.2 The forms did not include the patient's identity, the
institution where they had been evaluated, the clinical diagnosis, or the
pathologic findings.

Each form was reviewed independently by two other neurologists (F.B. and
J.M.), who were asked to provide a clinical diagnosis. In cases of probable
or possible AD, the two neurologists followed the diagnostic criteria of the
NINCDS/ ADRDA work group.2

The results were tabulated on a summary sheet filled out after the two
neurologists had provided their diagnosis on each case. The sheet included
the diagnosis reached by the two neurologists and the diagnosis resulting
from the autopsy.

Table 1. Pathologic diagnosis in 54 patients with dementia

N %

Alzheimer's disease alone 34 62.9

Alzheimer's disease and 2 3.7 Parkinsons's disease

Alzheimer's disease with 2 3.7 multi-infarct dementia

Alzheimer's disease with amyotrophic lateral sclerosis 39 72.2

Total Alzheimers disease 39 72.2

Multi-infarct dementia 4 7.4

Multi-infarct dementa 1 1.8 with Parkinson's disease

Parkinson's disease 2 3.7

Progressive subcortical gliosis 2 3.7

Creutzfeldt-Jakob disease 3 5.5

Progressive supranuclear palsy 1 1.8

Huntington's disease 1 1.8

Unclassified 1 1.8

Total other disease 15 27.7

Total all cases 54

Table 2. Clinical diagnosis

Clinical diagnosis Clinician #1 --- #2

Probable AD 29 21

Probable AD and MID 3 0

Probable AD and thyroid disease 1 2

Probable AD and PD 3 1

Probable AD and ALS 1 0

Probable AD and 0 1 olivopontocerebellar degeneration

Total probable AD 37 25 (68.5%) (46.2%)

Possible AD 3 2

Possible AD and MID 2 2

Possible AD and alcoholism 0 1

Possible AD and depression 1 0

Possible and thyroid disease 0 3

Possible AD and traumatic 1 2 encephalopathy

Possible AD and PD 3 6

Total Possible AD 10 16 (18.5%) (29.6%)

Atypical AD 0 1

Atuypical AD and MID 0 1

MID 2 4

MID and PD 3 0

Dementia syndrome of depression 0 1

HD 1 1

Wernicke-Korsakoff syndrome 1 0

Dementia of unknown etiology 0 5

Total 54 54

Results. The subjects included 26 women and 28 men who ranged in age from 30
to 91 years (mean, 72.2; SD, 10.7).

Autopsy findings. Table 1 shows that 39 (72.2%) of the 54 cases fulfilled
histologic criteria for AD, with or without other histopathologic findings.
The remaining 15 cases (27.7%) showed changes corresponding to other
neurodegenerative disorders, cerebrovascular disease, or Creutzfeldt-Jakob
disease (CJD). Seven cases met the histopathologic criteria for
multi-infarct de-mentia (MID). Five cases (9.2%) showed changes associated
with Parkinson's disease (PD).

Twenty-two of the 39 AD patients (56%) were age 65 or greater at the time of
the onset of the disease. Seven of the 15 patients in the group with other
diseases (47%) were age 65 or older at the time of disease onset.

Clinical diagnosis. There was a general adherence to the criteria specified
by McKhann et al.2 However, the two clinicians in this study considered the
diagnosis of probable AD when the probability of AD was strong even if a
patient had another disease potentially associated with dementia that might
or might not have made some contribution to the patient's clinical state
(table 2).

Accuracy of the clinical diagnosis (table 3). Group 1 (N = 12). There were
six men and six women. Ten cases (83.3%) met the histologic criteria for AD.
In nine cases (75.0%), the diagnosis of both clinicians agreed with the
pathologic findings; in the other case (8.3%), one clinical diagnosis agreed
with the histologic findings. The remaining two cases (16.6%) had
histopathologic diagnoses of CJD and progressive supranuclear palsy (PSP),
respectively. Both cases were incorrectly diagnosed by both clinicians.

Group 2 (N = 28). There were 11 women and 17 men. Eighteen cases (64.2%) had
the histopathologic features for AD with or without additional findings.
Sixteen of these cases (57.1%) were correctly diagnosed by both clinicians,
one case by one of them, and both incorrectly diagnosed one case. The
remaining ten cases (35.7%) included two with CJD; two with subcortical
gliosis (SG); two with PD, one of which was associated with MID; one case of
Huntington's disease (HD); two cases with MID; and one unclassifed. Only
one, the HD case (3.5%), was correctly diagnosed by both observers, and four
cases (14.2%), two MID and two PD, one associated with MID, were correctly
diagnosed by one clinician.

Group 3 (N = 14). In this group there were nine women and five men. Eleven
cases (78.5%) met the histopathologic criteria for AD with or without
additional findings. Eight of these cases (57.1%) were correctly diagnosed
by both clinicians, two cases by one of them, while both were incorrect in
one case. Of the remaining three cases (21.4%), only one was correctly
diagnosed (7.1%) by one clinician. Both missed the two other cases of MID.

There was no statistically significant difference in diagnostic agreement
across patient groups in which the amount of clinical information was
different (X2 = 1.19; p > 0.05).

Table 3. Accuracy of the clinical diagnosis by two clinicians

Both One Neither Correct Correct Correct

Group 1 (N = 12) 9 1 2(16.6%)

Group 2 (N = 28) 17 5 6(21.4%)

Group 3 (N = 14) 8 3 3(21.4%)

Table 4. Previously reported studies of clinicopathologic correlation in
demented patients*

Agreement %

Number of cases AD

Retrospective studies

Todorov et al, 1975(7) 776 43

Perl et al, 1984(9) 26 81

Wade et al, 1987(12) 65 85

Alafuzoff et al, 1987(13) 55 63

Kokmen at al, 1987(14) 32 72

Joachim et al, 1987(15) 150 87

Prospective studies

Sulkava et al, 1983(8) 27 82

Molsa et al, 1985(10) 58 71

Neary et al, 1986(11) 24 75

Martin et al, 1987(16) 11 100

Morris et al, 1987(17) 25 100

* Certain differences in methodology need clarification. Some
authors7,8,10,11,12,13,16,17 tabulated patients with AD alone, and
others9,14,15 included patients with AD plus other diseases, eg, Parkinson's
disease and MID. We have combined AD alone and AD plus MID and other
neurodegenerative diseases.

Discussion. Our results indicate that in a population of patients with
dementias of varied etiology, the diagnosis could be correctly inferred by
at least one of two clinicians in approximately 80% of cases. For one
observer, the sensitivity of clinical diagnosis for AD was 85% and the
specificity was 13%, and for the other, it was 95% and 33% respectively.

In the cases with a discrepancy between the clinical diagnosis and the
neuropathologic findings, the great majority of patients had atypical
clinical courses and findings. The three cases with autopsy findings of CJD
had a much longer course than is usually seen with that condition and failed
to show the usual EEG abnormalities. The patient with autopsy findings of
PSP did not show the disorder in the extraocular movements usually
associated with that condition. An atypical course was also present for two
AD cases and two MID cases that did not have any feature suggestive of
vascular disease. In one MID case, the CT did not show any focal lesions,
while in the other it was not available. With regard to the two patients
with SG, the pathologic diagnosis is so unusual and so infrequently recorded
that clear clinical correlates are not evident.18 The third category of
possible error is the patient listed as unclassified, for whom no specific
neuropathologic diagnosis could be reached.22

The small number of neuropathologic diagnoses of Parkinson's disease
reflects that, for the purpose of this series, the diagnosis of PD was made
only when there were both a clear-cut clinical history and the
neuropathologic findings characteristic of the disease, such as Lewy bodies,
neuronal loss, globose neurofibrillary tangles, astrocytosis, and
extraneuronal melanin pigment in substantia nigra and locus ceruleus.

Are these results derived from a sample of 54 patients representative of
disease patterns in the community? Generally, the diagnosis of patients
reported from major medical centers tend to be biased since the more
complicated cases are referred there. In this study, however, this bias may
be less important. Due to the major public education campaign about dementia
and AD sponsored by the ADRC, there is a widespread awareness in Pittsburgh
and in the surrounding regions of Western Pennsylvania of the value of an
autopsy for a definitive diagnosis. Therefore, the great majority of cases
were referred to us because the family wanted to know the precise etiology
of a case of dementia.

The significant improvement in the clinical diagnosis of AD is a recent
phenomenon. Due to the publicity and the advances in communication of
scientific investigations, most physicians are more likely to consider AD as
the main cause of dementia. The current risk of overdiagnosing AD reminds
one of what occurred during the 1960s with the diagnosis of "atherosclerotic
dementia."6 The high sensitivity and low specificity for AD shown in our
study may reflect that possibility.

Because of the varying criteria for "other dementias" in many publications,
we chose to analyze the accuracy of clinical diagnosis in terms of the
diagnosis of AD alone or AD plus other neuropathologic findings. Several
retrospective studies have attempted to point out reliable clinical and
pathologic features for diagnosing the dementias, especially AD. The study
of Tomlinson et al6 is not included in table 4 because there was no attempt
to validate the clinical diagnosis with pathologic findings. The reports
surveyed vary considerably in size and methodology. Sample size, for
example, ranges from 26 subjects9 to 776 subjects.7 Some studies base the
diagnosis on limited clinical information,7'9'14'15 others use widely
accepted diagnostic criteria such as those specified in DSM III,13 and one
group uses a standardized clinical assessment of patients enrolled in a
longitudinal study.12 The reported accuracy of the clinical diagnosis of AD
ranges from 43%7 to 87%.15

Recent prospective studies that adhere to strict clinical criteria,10'11'17
those in DSM III8 or those proposed by McKhann et al,16 indicate improved
accuracy of clinical diagnosis of the most common causes of dementia,
especially AD. In sample sizes ranging from 11 subjects16 to 58 subjects,l0
the accuracy of clinical diagnosis is reported as ranging from 71%10 to
100%16'17' Only two series, both based on small samples, report a 100%
accuracy. We consider it unlikely that such accuracy could be confirmed in
large series because of some inevitable imprecision in clinical diagnoses
and the variability of clinical pictures. Furthermore, although researchers
generally agree on the application of uniform criteria in clinical diagnosis
of dementia, opinions still differ about specific diagnostic criteria, as
well as about the pathologic characterization of dementia. Except for those
small series, the results summarized in table 4(7-15) is are remarkably
consistent with ours.

In table 3, although there was no statistical difference (p > 0.05) in
diagnostic agreement across patient groups, there is a trend toward a lower
percentage of diagnostic errors for the patients who had been followed most
intensely (16% in group 1 compared with 21% in groups 2 and 3). The
difference is not great, and it is, in fact, surprising to find out that in
the patients about whom relatively little was known (group 3) the percentage
of diagnostic error was the same as among patients seen by neurologists and
for whom much more data were available (group 2). These paradoxical findings
probably indicate that both clinicians learned to extract essential
diagnostic criteria2 in spite of the variations in the amount of information
available for consideration. It may well be that clinical, radiographic, and
laboratory assessment of patients with dementia is burdened with information
that is excessive and unessential for purely diagnostic purposes.

Acknowledgments

We thank Dr. A. Julio Martinez and Dr. Gutti Rao from the Division of
Neuropathology for autopsy data. Mrs. Margaret Forbes, Ms. Annette Grechen,
and Mrs. Paula Gent helped in the preparation of the manuscript.

References

1. American Psychiatric Association. Diagnostic and statistical manual of
mental disorders. Organic Dementia Disorders, 3rd ed. Washington DC, APA,
1983:101-161.

2. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E.
Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work
group under the auspices of Department of Health and Human Services Task
Force on Alzheimer's Dis-ease. Neurology 1984;34:939-944.

3. Khachaturian Z. Diagnosis of Alzheimer's disease. Arch Neurol
1985;42:1097-1105.

4. Cummings J, Benson F. Dementia: a clinical approach, 1st ed. Boston:
Butterworths, 1983.

5. Rosen WG, Terry R, Fuld P, Katzman R, Peck A. Pathological verification
of ischemic score in differentiation of dementias. Ann Neurol
1980;7:486-488.

6. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented
old people. J Neurol Sci 1970;11.205-242.

7. Todorov A, Go R, Constantinidis J, Elston R. Specificity of the clinical
diagnosis of dementia. J Neurol Sci 1975;26:81-98.

8. Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical
diagnosis in primary degenerative dementia: correlation with
neuropathological findings. J Neurol Neurosurg Psychiatry 1983;46:9-13.

9. Perl D, Pendlebury W, Bird E. Detailed neuropathologic evalua-tion of
banked brain specimens submitted with clinical diagnosis of Alzheimer's
disease. In: Wirtman R, Corkin S, Growdon J, eds. Alzheimer's disease:
advances in basic research and therapies. Proceedings of the Fourth Meeting
of International Study Group on the Treatment of Memory Disorders Associated
with Aging. Zurich, January 1984. Cambridge, MA: CBSM, 1984:463. Molsa PK,
Paljarvi L, Rinne JO, Rinne UK, Sako E. Validity of clinical diagnosis in
dementia: a prospective clinicopathological study. J Neurol Neurosurg
Psychiatry 1985;48:1085-1090.

11. Neary D, Snowden JS, Bowen D, et al. Neuropsychological syn-dromes in
presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry
1986;49:163-174.

12. Wade J, Mirsen T, Hachinski V, Fismm~ M, Lau C, Merskey H. The clinical
diagnosis of Alzheimer disease. Arch Neurol 1987;44:24-29.

13. Alafuzoff I, Igbal K, Friden H, Adolfsson R, Winblad B.
Histopathological criteria for progressive dementia disorders:
clinicalpathological correlation and classification by multivariate data
analysis. Acta Neuropathol (Berl) 1987,74:209-225.

14. Kokmen E, Offord K, Okazaki H. A clinical and autopsy study of dementia
in Olmsted County, Minnesota, 1980-1981. Neurology 1987;37:426-430.

15. Joachim CL, Morris JH, Selkoe D. Clinically diagnosed Alzheimer's
disease: autopsy neuropathological results in 150 cases. Ann Neurol
1988;24:50-56.

16. Martin EM, Wilson RS, Penn RD, Fox JH, Clasen RA, Savoy SM. Cortical
biopsy results in Alzheimer's disease: correlation with cognitive deficits.
Neurology 1987;37:1201-1204.

17. Morris JC, Berg L, Fulling K, Torack RM, McKeel DW. Validation of
clinical diagnostic criteria in senile dementia of the Alzheimer type. Ann
Neurol 1987;22:122.

18. Moossy J, Martinaz J, Hanin I, Rao G, Yonas H, Boiler F. Thalamic and
subcortical gliosis with dementia. Arch Neurol 1987;44:510-513.

19. Huff J, Becker J, Belle S, Nebes R, Holland A, Boller F. Cognitive
deficits and clinical diagnosis of Alzheimer's disease. Neurology
1987;37:1119-1124.

20. Huff J, Boiler F, Lucchelli F, Querriera R, Beyer J, Belle S. The
neurological examination in patients with probable Alzheimer's disease. Arch
Neurol 1987;44:929-932.

21. Moossy J, Zubenko G, Martinez AJ, Rao G. Bilateral symmetry of
morphologic lesions in Alzheimer's disease. Arch Neurol 1988;45:251-254.

22. Heilig CW, Knopman DS, Mastri AR, Frey W II. Dementia without Alzheimer
pathology. Neurology 1985;35:762-765.

From the Departments of Neurology (Drs. Boller, Lopez, and Moossy),
Psychiatry (Dr. Boller), Pittsburgh (University Drive) Veterans
Administration Medical Center (Dr. Boller), Department of Pathology
(Division of Neuropathology) (Dr. Moossy), and the Pittsburgh Alzheimer
Disease Research Center (Drs. Boller, Lopez, and Moossy), University of
Pittsburgh Medical School, Pittsburgh, PA.

Supported in part by NIH Grants nos. AG05133 and AG03705, NIMH Grant no.
MH30915, by funds from the Veterans Admin., and by the Pathology Education
and Research Foundation (PERF) of the Department of Pathology, University of
Pittsburgh.

Presented in part at the fortieth annual meeting of the American Academy of
Neurology, Cincinnati. OH, April 1988.

Received April 7, 1988. Accepted for publication in final form July 20,
1988.

Address correspondence and reprint requests to Dr. Boller, Department of
Neurology, 322 Scaife Hall, University of Pittsburgh Medical School,
Pittsburgh, PA 15261.

January 1989 NEUROLOGY 39 79

TSS

http://www.vegsource.com/talk/lyman/messages/9249.html

From: TSS (216-119-130-151.ipset10.wt.net)
Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia
Date: May 8, 2001 at 6:27 pm PST

Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date:
Tue, 8 May 2001 21:09:43 -0700 From: "Terry S. Singeltary Sr." Reply-To:
Bovine Spongiform Encephalopathy To: BSE-L@uni-karlsruhe.de


#### Bovine Spongiform Encephalopathy ####

Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

Christine M. Hulette, MD; Nancy L. Earl, Md; Barbara J. Crain, MD, Phd

· To identify those patients most likely to benefit from a cerebral biopsy
to diagnose dementia, we reviewed a series of 14 unselected biopsies
performed during a 9-year period (1980 through 1989) at Duke University
Medical Center, Durham, NC. Pathognomonic features allowed a definitive
diagnosis in seven specimens. Nondiagnostic abnormalities but not diagnostic
neuropathologic changes were seen in five additional specimens, and two
specimens were normal. Creutzfeldt-Jakob disease was the most frequent
diagnosis. One patient each was diagnosed as having Alzheimer's disease,
diffuse Lewy body disease, adult-onset Niemann-Pick disease, and anaplastic
astrocytoma. We conclude that a substantial proportion of patients
presenting clinically with atypical dementia are likely to receive a
definitive diagnosis from a cerebral biopsy. However, in those with
coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs,
cerebral biopsies are less likely to be diagnostic. (Arch Neurol.
1992;49:28-31)

"Dementia" is a syndrome characterized by global deterioration of cognitive
abilities and is the general term used to describe the symptom complex of
intellectual deterioration in the adult. It is associated with multiple
causes, although Alzheimer's disease (AD) alone accountsfor approximately
60% of cases.1-3

Interest in the accuracy of the diagnosis of dementia is a relatively recent
phenomenon, reflecting both an increase in physicians' awareness of multiple
specific causes of dementia and a marked increase in both the incidence and
prevalence of dementia associated with the increase in the elderly
population.4' The clinical evaluation remains the key to the differential
diagnosis, and in most cases dementia can be diagnosed accurately by
clinical criteria. However, the definitive diagnoses of AD.1'5'7 Pick's
disease,8'10 Creutzfeldt-Jakob disease (CJD),11-16 Binswanger's
disease,17'18' and diffuse Lewy body disease19-22 still require histologic
examination of the cortex to identify characteristic structural changes.

Brain tissue is almost invariably obtained at autopsy, and the vast majority
of pathologic diagnoses are thus made post mortem. Alternatively, an
antemortem histologic diagnosis can be provided to the patient and his or
her family if a cerebral biopsy is performed while the patient is still
alive. Because brain biopsies for dementia are not routinely performed, we
sought to define the spectrum of pathologic changes seen in a retrospective
unselected series of adult patients undergoing cerebral biopsy for the
diagnosis of atypical dementing illnesses and to determine the patient
selection criteria most likely to result in a definitive diagnosis.

MATERIALS AND METHODS

Cerebral biopsies performed solely for the diagnosis of dementia in adult
patients were identified by a manual search of the patient files of the
Division of Neuropathology, Duke University Medical Center Durham, NC, and
by a computerized search of discharge diagnoses of patients undergoing brain
biopsies. Fourteen cases were identified from the period 1980 to 1989.
Patients undergoing biopsies for suspected tumor, inflammation, or
demyelinating disease were excluded. A clinical history of dementia was an
absolute requirement for inclusion in the study. Diagnosis was based on
Dignostic and Statistical Manual of Mental Disorders, Third Edition, and on
National Institute of Neurological and Communicative Disorders and
Stroke/Alzheimer's Disease and Related Disorders Association (ADRDA)
criteria for probable AD.23

The published recommendations for handling tissue from patients with
suspected CJD were followed in every case.24-26 Briefly, tissue was
transported in double containers clearly marked "Infectious Disease
Precations." Double gloves, aprons, and goggles were used at all times.
Tissue was fixed in saturated phenol in 3.7% phosphate-buffered formaldehyde
for 48 hours25 and subsequently hand processed for paraffin embedding. At
least 1 cm(to 3 power) of tissue was available for examination from each
patient, except for patient 7, who underwent bilateral temporal lobe needle
biopsies. Patient 14 underwent biopsy of both frontal and temporal lobes.

One paraffin block was prepared for each biopsy specimen, and sections were
routinely stained with hematoxylin-eosin, luxol fast blue, Congo red, alcian
blue, periodic acidSchiff, and modified King's silver stain27 in every ease,
except for case 7, in which the diagnosis was made by frozen section.
Portions of both gray and white matter were primarily fixed in
glutaraldehyde and embedded in epoxy resin (Epon). Tissue was examined by
electron microscopy if abnormalities, such as neuronal storage or other
inclusions, were seen in routine paraffin sections.

Khachaturian's5 National Institute of Neurological and Communicative
Disorderers and Stroke/ADRDA criteria for quantitation of senile plaques and
the diagnosis of AD were used in all cases after 1985. At the time of our,
study, these criteria were also applied retrospectively to cases accessioned
before 1985. No attempt was made to grade the severityof other abnormalities
(eg, gliosis and spongiform change), and the original pathologic diagnoses
were not revised.

RESULTS

The clinical presentations, biopsy findings, and follow-up data, including
postoperative complications, are summarized in Table 1 for all 14 patients.
Their biopsy findings are summarized in Table 2.

The ages of this unselected group of 14 patients who underwent cerebral
biopsies for dementia ranged from 32 to 78 years (mean, 51.6 years). There
were seven men and seven women. Duration of symptoms ranged from 1 month to
6 years (mean, 2.3 years). No differences were noted between the group with
diagnostic biopsies (cases 1 through 7) and the group with nondiagnostic
biopsies (cases 8 through 14) with regard to age at the time of biopsy or
duration of symptoms. However, five of seven patients in the nondiagnostic
group had hemiparesis, chorea, athetosis, or lower motor neuron signs. None
of these findings was present in the patients with diagnostic biopsies.
Visual disturbances, abnormal eye movements, and ataxia were present in four
of seven cases with diagnostic biopsies but were absent in the group with
nondiagnostic biopsies.

In this series of 14 patients, two experienced postoperative complications,
one of which was severe. Patient 2 developed an intraparenchymal parietal
cortex hemorrhage and was mute after biopsy. Patient 9 developed a subdural
hygroma that was treated uneventfully.

Eight patients died 1 month to 9 years after biopsy. An autopsy was
performed in five of these eight patients. One of these patients (patient 4)
had a firm diagnosis of presenile AD on biopsy, which was confirmed at
autopsy. Patient 3 had a biopsy diagnosis of CJD, which was also confirmed
at autopsy. Two patients with only white-matter gliosis diagnosed at biopsy
had autopsy diagnoses of amyotrophic lateral sclerosis with dementia
(patient 8) and CJD (patient 9). One patient in whom a biopsy specimen
appeared to be normal had Huntington disease identified at autopsy (patient
14). At the time of this writing, four patients are still alive, two are in
clinically stable condition 1 to 2 years after biopsy, and two are severely
demented 2 to 3 years after biopsy. Two patients (one with a definite and
one with a possible diagnosis of CJD) have been unavailable for follow-up.

COMMENT Our study of patients presenting with atypical dementia reaffirms
the diagnostic utility of cerebral biopsy. In selected cases, cerebral
biopsy results in a high yield of definitive diagnostic information. A wide
variety of disorders may be encountered, including CJD, AD, diffuse Lewy
body disease, and storage disorders, such as Niemann-Pick disease.28-30 The
diagnosis of Niemann-Pick disease type C was confirmed by assay of
cholesterol esterification in cultured fibroblasts31'32' with markedly
abnormal results in one patient, who was described in detail elsewhere.33

One example of an unsuspected anaplastic astrocytoma (case 7) was also
encountered. This case was unusual in light of currently used sensitive
imaging techniques. This patient may have been suffering from gliomatosis
cerebri.

Table 1.--Summary of Clinical Presentation and Course*

Case/Age,y/Sex

Duration of Symptoms, y

Clincial Findings

Biopsy

Follow-up ==========

1/60/F

0.1

Dementia, left-sided homonymous hemianopia, myoclonus, EEG showing bilateral
synchronous discharges

CJD

Unavailable ==========

2/57/M

0.4

Dementia, aphasia, myoclonus; visual disturbance; facial asymmetry, abnormal
EEG

CJD

Postoperative intraparenchymal hemorrhage, mute dead at 58 y, no autopsy
==========

3/59/M

2

Dementia, apraxia, visual disturbance, bradykinesia, EEG showing periodic
sharp waves

CJD

Dead at 61 y, autopsy showed CJD =========

4/32/M

1

Dementia, myclonus, ataxia, family history of early-onset dementia

AD

Dead at 40 y, autopsy showed AD =========

5/78/M

6

Dementia, paranoia, agitation, rigidity

Diffuse Lewy body disease

Dead at 78 y, no autopsy =========

6/37/F

6

Dementia, dysarthria, abnormal eye movements, ataxia

Neuronal storage disorder, adultonset N-P type II

Stable at 39 y =========

7/58/F

0.3

Dementia, amnesia, depression, partial complex seizures

Anaplastic astrocytoma

Dead at 58 y, no autopsy ==========

8/37/M

2

Dementia, dysarthria, upper-extremity atrophy and fasciculations

Gliosis

Dead at 38 y, auotpsy showed amyotrophic lateral sclerosis with white-matter
gliosis =========

9/45/F

2

Dementia, aphasia, right-sided hemiparesis, rigidity, athetosis

Gliosis

Postoperative subdural hygroma, dead at 50 y, autopsy showed focal CJD
=========

10/56/F

2

Dementia, myoclonus, cerebellar dysaarthria, EEG showing biphasic periodic
sharp waves

Consistent with CJD

Unavailable ==========

11/60/F

2

Dementia, dysarthria, right-sided hemiparesis, hypertension, magnetic
resonance image showing small vessel disease

Plaques, gliosis

stable at 61 y =========

12/52/F

2

Dementia, aphasia, right-sided hemiparesis

Gliosis

Bedridden, severely demented at 54 y =========

13/40/M

0.5

Dementia, mild bifacial weakness, concrete thinking, altered speech

Normal

Stable at 41 y =========

14/52/M

6

Dementia, choreoathetosis, family history of senile dementia, computed
tomographic scan showing normal caudate

Normal

Dead at 61y, autopsy showed Huntington's disease, grade II/IV ========== *
EEG indicates electroencephalogram; CJD, Creutzfeldt-Jakob disease; AD,
Alzheimer's disease; and N-P, Niemann-Pick disease.

Table 2.--Pathologic Findings at Biopsy *

Case Site of Biopsy Type of Biopsy Tissue Examined Spongiform Change
Neuritic Plaques per X 10 Field Tangles White Matter Gliosis Other

1 R temporal Open 1 cm3 + 0 0 0 0 =====

2 L temporal Open 1 cm3 + 0 0 0 0 =====

3 R temporal Open 1 cm3 + 0 0 0 0 =====

4 R frontal Open 1 cm3 0 >100 + + Amyloid angiopathy =====

5 R temporal Open 1 cm3 0 9 0 0 Lewy bodies =====

6 R temporal Open 1 cm3 0 0 0 0 Neuronal storage =====

7 R temporal/L temporal Needle/needle 1 X 0.3 X 0.3 cm / 1 X 0.3 X 0.1 cm
0/0 0/0 0/0 +/0 0/anaplastic astrocytoma =====

8 R frontal Open 1 cm3 o o o + 0 =====

9 L parietal Open 1 cm3 0 0 ± + 0 =====

10 R temporal Open 1 cm3 ± 0 0 0 0 =====

11 L temporal Open 1 cm3 0 23 0 + 0 =====

12 L temporal Open 1 cm3 0 0 0 + 0 =====

13 r frontal Open 1 cm3 0 0 0 0 0 =====

14 L temporal/L frontal Open/open 1 cm3/ 1 cm3 0/0 0/0 0/0 0/0 0/0 ===== *
Plus sign indicates present; zero, absent; and plus/minus sign, questionably
present

Positron emission tomography showed multiple areas of increased uptake, even
though the magnetic resonance image was nondiagnostic and showed only subtle
increased signal intensity on review. Bilateral temporal lobe needle
biopsies yielded abnormal findings. Biopsy of the right side showed only
reactive gliosis, which may have been adjacent to tumor. Biopsy of the left
side, performed 3 days later, was diagnostic for anaplastic astrocytoma.
Unfortunately, permission for an autopsy was refused, and complete
evaluation of the underlying pathologic process thus must remain
speculative.

The high incidence of definite and probable CJD in our series indicates that
it is imperative that appropriate precautions are taken to prevent the
transmission 0f disease to health care workers when biopsy tissue from
patients with dementia is handled.24-26

At our institution, cerebral biopsy for the diagnosis of dementia is
reserved for patients with an unusual clinical course or symptoms that
cannot be diagnosed with sufficient certainty by other means. In most
instances, cerebral biopsy is unnecessary and is clearly not a procedure to
be proposed for routine diagnostic evaluation. In all cases, extensive
clinical, metabolic, neuropsychological and radiologic evaluations must be
performed before cerebral biopsy is considered. In addition, preoperative
consultations among neurologists, neurosurgeons, neuroradiologists, and
neuropathologists are necessary to ascertain the optimal biopsy site given
the clinical data to ensure that maximal infornmtion is derived from the
biopsy tissue.

An optimal biopsy specimen is one that is taken from an affected area,
handled to eliminate artifact, and large enough to include both gray and
white matter.34 Open biopsy is generally preferred because it is performed
under direct visualization and does not distort the architecture of the
cerebral cortex. This method also provides sufficient tissue (approximately
1 cm3) to perform the required histologic procedures.

Some physicians question the utility of diagnostic cerebral biopsies in
dementia, stating that the procedure is unlikely to help the patient. While
it is frequently true that the diagnoses made are untreatable with currently
available therapeutic modalities, this is by no means universally true.
Kaufman and Catalano35 noted that cerebral biopsy has revealed specific
treatable illnesses, such as meningoencephalitis and multiple sclerosis. Our
patient with anaplastic astrocytoma (patient 7) underwent radiation therapy,
although she quickly died of her disease. Furthermore, when a definitive
diagnosis can be made, even of incurable illnesses, such as CJD and AD, it
is often possible to give an informed prognosis to the family and to help
them plan for the future.

The formulation of indications, for diagnostic cerebral biopsy raises
difficult and complex issues. In 1986, Blemond36 addressed the clinical
indications and the legal and moral aspects of cerebral biopsy, and his
recommendations remain valid today: (1)The patient has a chronic progressixe
cerehral disorder with documented dementia. (2) All other possible
diagnostic methods have already been tried and have failed to provide
sufficient diagnostic certainty. (3) The general condition of the patient
permits cerebral biopsy. (4) Several specialists are in agreement regarding
the indication. (5) Informed consent is obtained from relatives. (6) Modern
diagnostic tools, such as immunocytochemistry and electron microscopy, are
used to the fullest capacity in the examination of the material obtained.

As with any intracranial surgical procedure involving the cerebral cortex,
the risks of cerebral biopsy include anesthetic complications, hemorrhage,
infections, and seizures. Guthkelch37 stated that the mortality associated
with brain biopsy is not greater than that associated with general
anesthesia. Cerebral biopsy, however can result in substantial morbidity. In
our series, two of 14 patients suffered operative complications,
intraparenchymal hemorrhage in one patient (patient 2) resulted in aphasia,
while another patient (patient 10) developed a subdural hygroma, which was
successfully treated, and recovered her baseline status.

The current diagnostic accuracy of cerebral biopsy in the evaluation of
dementia is unknown. Most of the larger general series 34'38-41 were
reported before computed tomography was available and included many
pediatric cases presenting with genetic neurodegenerative disorders that are
now more readily diagnosed by other means. For adults with dementia, less
information is available. Katzman et al4 recently reviewed the literature
concerning the diagnostic accuracy of cerebral biopsy for dementia and
concluded that 75% of these procedures result in diagnostic material.
Patient selection is very important, and the literature is heavily weighted
toward patients with a clinical diagnosis of AD.35'42-44 Our study thus
provides documentation of the diagnostic accuracy of cerebral biopsies in
unselected patients with atypical dementia.

Autopsy follow-up is imperative in any dementia program,2 as a definitive
diagnosis will not be made in a substantial proportion of patients. In our
series, three patients died without a diagnosis, and autopsy was performed
in all three. The diagnostic features were not present in the cortical area
in which the biopsy was performed. In case 8, examination of the spinal cord
revealed amyotrophic lateral sclerosis. Diffuse gliosis of the white matter
was noted, which was the pathologic basis of the patient's dementia. In case
9. the spongiform change of CJD was focal, according to the pathologist's
report; unfortunately, the tissue was not available for our review. In case
14, the diagnosis of Huntington's disease grade II/IV was made after close
examination of the caudate nucleus. As one might predict, fewer autopsies
were performed in the group with diagnostic biopsies; only two of five
deaths in this category were followed by postmortem examinations. The
diagnosis of AD was confirmed in case 4. In ease 3, the biopsy diagnosis of
CJD was confirmed.

In summary, a series of 14 unselected cerebral biopsies performed for the
diagnosis of atypical dementia was reviewed to define the spectrum of
pathologic changes seen and to estimate the likelihood of obtaining
diagnostic tissue. Histologic diagnoses of CJD, AD, diffuse Lewy body
disease, Niemann-Pick disease type C, or anaplastic astrocytoma were made in
seven patients. The high incidence of CJD in this population (four of 14
cases) emphasizes the need to use appropriate precautions when tissue from
patients with unusual dementing illnesses is handled. Consultation among
neurologist, neurosurgeons, neuroradiologists, and neuropathologists is
essential to select appropriate patients and to choose the proper biopsy
site. Demented patients with coexisting hemiparesis, chorea, athetosis, or
lower motor neuron signs are unlikely to benefit from cortical biopsy.

This investigation was supported by Clinical Investigator Award PHS AG-00446
from the National Institute on Aging (Dr. Hulette) and by grant PHS
SP50AG05128-03 from the Joseph and Kathleen Bryan Alzheimer's Disease
Research Center (Drs Earl and Crain). Dr Hulette is a College of American
Pathologists Foundation Scholar, Northfield, Ill.

The Authors thank Ms Bonnie Lynch and Ian Sutherland, PhD, for thier
assistance.

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Cerebral Biopsies in Dementia-- Hulette et al 31

Accepted for publication July 11, 1991. From the Department of Pathology,
Division of Neuropathology (Drs Hulette and Crain), the Department of
Medicine, Division of Neurology (Dr Earl), and the Department of
Neurobiology (Dr. Crain), Duke University Medical Center, Durham, NC.

Arch Neurol--Vol 49, January 1992

TSS/5/7/01

http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html


http://www.vegsource.com/talk/lyman/messages/9254.html


==============================
OTHER URLS OF INTEREST

1996). Stanley Prusinger, the scientist who coined the term prion,
speculates Alzheimer's may in fact turn out to be a prion disease (Prusiner,
1984). In ...

http://www.cyber-dyne.com/~tom/Alzheimer_cjd.html#similar

http://216.239.39.100/search?q=cache:ujKcH823WucC:www.bse.org.uk/files/ws/s1
94.pdf+
PRION++ALZHEIMER%27S+BSE+INQUIRY&hl=en&start=4

http://www.bseinquiry.gov.uk/files/ws/s194.pdf

http://www.cjd.ed.ac.uk/path.htm

MULTIMODAL EVOKED POTENTIALS IN MOUSE MODELS OF NEURODEGENERATION

Transmissible spongiform encephalopathies and Alzheimer's disease are
neurodegenerative disorders in which neuropathologic changes are associated
with accumulation of prion protein and deposition of amyloid ß-protein,
respectively. Recently, transgenic mice that overexpress a mutant human
ß-amyloid precursor protein and mice devoid of prion protein were generated.
However, few electrophysiologic studies in intact freely moving...

snip...

full text;

http://www.scripps.edu/research/sr2000/np11.html

Causes of Alzheimer's and "Mad-Cow" Diseases

Alzheimer's and "mad-cow" diseases are unique in that their infectious
agents are not viruses or germs, but rather proteins. The brains of patients
who suffered from Alzheimer's or cows that died of "mad-cow" disease show
deposits of abnormal tissue called amyloid plaques. The primary component of
these plaques is a protein called prion protein or PrP. Chemical and
biochemical analysis showed that there was no difference in composition or
primary structure between the normal, cellular form of PrP (PrPC, shown at
right) and the disease form of PrP (PrPSc). Further analysis showed that
PrPC can change into PrPSc when two of the a helices (shown in green) change
into ß sheets. This ß sheet can then induce a similar change in another
molecule of PrPC and hydrogen bond to it. The PrPSc 's then polymerize and
come out of solution, forming the plaques found in Alzheimer's patients and
mad cows. How the plaques cause the symptoms of the diseases is still not
clear, but the prion protein holds the unique distinction of causing a
disease solely through a small alteration in secondary structure.

full text;

http://genchem.chem.wisc.edu/netorial/modules/biomolecules/protein2/prot210.
htm

importantly, recent findings indicating that the cellular accumulation of
incorrectly folded proteins is the molecular basis of many diseases,
including Alzheimer's Disease, Prion Diseases and Huntington Disease,
underscore the importance of understanding the mechanisms of folding in
vivo. Alzheimer's and prion disease appear to be caused by the generation of
a "pathological" conformation in the newly translated protein that would
otherwise fold to a normal conformation that does not produce the disease.
In some model systems, molecular chaperones appear to play a role in this
conformational change. Thus, developing approaches to study protein folding
under physiological conditions is essential to understand how folding
defects can lead to disease.

full text;

http://www.stanford.edu/group/frydman/interests.htm

Implications for Alzheimer's disease

Harris also has recently expanded his research to include Alzheimer's
disease, which shares several features with prion diseases despite being
non-infectious. Leonard Berg, M.D., professor of neurology and former
director of the Alzheimer's Disease Research Center at the medical school,
and other colleagues say Harris readily applies his extensive knowledge of
cell biology to this area as well.

http://record.wustl.edu/archive/1998/02-12-98/3678.html

RESEARCH LETTERS

Early-Onset Familial Alzheimer Disease With Coexisting [beta] -Amyloid and
Prion Pathology

To the Editor: Familial Alzheimer disease (AD) with early onset has been
linked to 3 different genes with an autosomal dominant mode of inheritance:
[beta] -amyloid, protein precursor, and the presenilins 1 and 2,
representing not more than 50% of all cases of early-onset AD cases.1 Thus,
the genetic defect remains unexplained in at least half of the families with
histories of early onset of AD. We have recently described such a Swiss
family whose members presented with a standard clinical and neuropathologic
profile of AD.2 In particular, severe neurofibrillary tangle degeneration
was present in the hippocampus and in several cortical areas, together with
a large amount of [beta] -amyloid deposits and senile plaques (SPs).
However, known mutations have not been found, either in the [beta] -amyloid
precursor protein or in the presenilin 1 and 2 genes.2 We now report that
the brains of 5 deceased members of this family, from 2 generations, present
a coexisting [beta] -amyloid and prion protein (PrP) pathology.


Methods

Five available cases with clinical AD were diagnosed using the Diagnostic
and Statistical Manual of Mental Disorders, Revised Third Edition, criteria.
The age at onset of disease ranged from 43 to 64 years (mean, 55.8 years)
and age at death ranged from 55 to 81 years (mean, 67.4 years). In addition,
4 of the 5 cases had epileptic features. Serial frozen sections (50 µm
thick) through the temporal and frontal cortex of the 5 formalin-treated
brains were pretreated with formic acid. They were then processed using
monoclonal antibodies against amyloid- [beta] 40 peptide (1:100; [Sigma] )
and against PrP106-126 (1:200; produced by one of us).3 The latter antibody
specifically marks the pathological isoform of the PrP and does not
cross-react with [beta] -amyloid deposits. In addition, double
immunostaining using successive anti- [beta] -amyloid and anti-PrP106-126
antibodies was performed.


Results

In all 5 cases, the cerebral cortex revealed spongiform changes, mainly in
superficial layers, and some degree of gliosis. Neurofibrillary tangle and
neuritic plaques revealed by Gallyas were numerous in all cortical regions
including the primary visual area. In addition, frequent
[beta] -amyloid-positive SPs were observed, together with SP stained by the
monoclonal antibody against PrP106-126. Successive sections alternately
stained with the 2 antibodies showed that both [beta] -amyloid and
PrP106-126 positive SP are deposited in all layers of the frontal and
temporal cortex. A population of SP, marked on 2 serial sections with both
antibodies, was positive for both [beta] -amyloid and PrP106-126.
Double-stained sections with [beta] -amyloid and PrP106-126 antibodies
further demonstrate that 3 populations of plaques exist: only
[beta] -amyloid, only PrP106-126 positive, or positive for both antibodies
(Figure 1) and a majority of SPs (>50%) are immunopositive for both
[beta] -amyloid and PrP106-126 antibodies. Comparatively, the relative
proportion of SPs marked for each antibody alone is smaller. In particular,
SPs marked for PrP106-126 represent approximately 5% to 10% of the whole
population.


Comment

Coexistence of Creutzfeldt-Jakob disease (CJD) and AD in some patients has
been described but appears mainly related to age in patients proven to have
CJD.4 However, since the individuals in the Swiss family died over a long
interval and were all similarly affected, it is unlikely that CJD is purely
coincidental. On the other hand, familial Gerstmann-Straüssler-Scheinker
disease can present a variant with concomitant neurofibrillary tangle and
prion-positive plaques, but not [beta] -amyloid-positive plaques. Within
this variant, 2 mutations in the gene for the PrP have been identified in 2
different families, and the clinical profile with cerebellar ataxia and
extrapyramidal signs5 differs from our findings.2 Base pair deletion in the
prion gene segregating as an uncommon polymorphism has been described in a
family with a history of late-onset AD, but there is no neuropathological
confirmation and the genetic association is uncertain.6

Thus, the data presented herein support the existence of a possible new
subtype of familial early-onset AD with a concomitant [beta] -amyloid and
prion brain pathology, together with a massive neurofibrillary tangle
degeneration. Although all known mutations have been excluded in the coding
regions of the AD genes, numerous candidate chromosome sites, either in the
AD genes outside the coding regions or in other genes including PrP, must be
considered.


G. Leuba, PhD, PD K. Saini, PhD University Psychogeriatrics Hospital
Lausanne-Prilly, Switzerland

A. Savioz, PhD Y. Charnay, PhD University of Geneva School of Medicine
Geneva, Switzerland


1. Cruts M, Van Broekhoven C. Molecular genetics of Alzheimer's diease. Ann
Med. 1998;6:560-565.

2. Savioz A, Leuba G, Forsell C, et al. No detected mutations in the genes
for the amyloid precursor protein and presenilins 1 and 2 in a Swiss
early-onset Alzheimer's disease family with a dominant mode of inheritance.
Dement Geriatr Cogn Disord. 1999;10:431-436. MEDLINE

3. Boris N, Mestre-Frances N, Charnay Y, Tagliavini F. Spontaneous
spongiform encephalopathy in a young adult rhesus monkey. Lancet.
1996;348:55. MEDLINE

4. Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka
H. Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob
disease. Acta Neuropathol (Berl). 1998;96:116-122. MEDLINE

5. Ghetti B, Tagliavini F, Giaccone G, et al. Familial
Gerstmann-Straüssler-Scheinker disease with neurofibrillary tangles. Mol
Neurobiol. 1994;8:41-48. MEDLINE

6. Perry RT, Go RCP, Harrell LE, Acton RT. SSCP analysis and sequencing of
the human prion protein gene (PRNP) detects two different 24 bp deletions in
an atypical Alzheimer's disease family. Am J Med Genet. 1995;60:12-18.
MEDLINE


Funding/Support: This study was supported by grants 3100-045960.95 and
3100-043573.95 from the Swiss National Science Foundation.

http://jama.ama-assn.org/issues/v283n13/ffull/jlt0405-5.html

Slide show

... Many neurodegenerative disorders -- such as prion diseases, Parkinson's
disease, Huntington's disease, Alzheimer's disease, frontotemporal
dementia -- are ...

www.nature.com/nrm/journal/v1/n3/slideshow/nrm1200_217a_F1.html

Occasional PrP plaques are seen in cases of Alzheimer's Disease

snip...

full text;

http://www.bseinquiry.gov.uk/files/ws/s310.pdf

2 3 Once isolated, the agent must be capable of reproducing the disease in
experimental animals. 4 The agent must be recovered from the experimental
disease produced. 3. In the case of transmissible spongiform
encephalopathies (TSEs), these postulates are not fulfilled in the following
ways: 4. Unfulfillments of Postulate 1. 4.1 Transgenic mice with a codon 102
mutation involving a leucine substitution spontaneously develop spongiform
encephalopathy with no detectable mutant prion protein (PrPsc). (Ref. Hsiao
K.K. et al. Spontaneous neurodegeneration in transgenic mice with mutant
prion protein. Science (1990) 250: 1587-1590.) (J/S/250/1587) 4.2 Spongiform
encephalopathy in zitter rats does not involved PrP. (ref. Gomi H. et al.
Prion protein (PrP) is not involved in the pathogenesis of spongiform
encephalopathy in zitter rats. Neurosci. Lett (1994) 166: 171-174.)
(J/NSC/166/171) 4.3 Many viruses and retroviruses can produced spongiform
encephalopathies without PrPsc involvement. (Ref. Wiley C.A. Gardner M. The
pathogenesis of murine retroviral infection of the central nervous system.
Brain Path (1993) 3: 123-128.) (J/BRP/3/123) 4.4 Experiments involving the
transmission of the 'BSE agent' in mice produced symptoms of TSE, but in 55%
no PrPsc could be detected. (Ref. Lasmesaz. C. et al. Transmission of the
BSE agent to mice in the absence of detectable abnormal prion protein.
Science (1997) 275: 402- 405.) (J/S/275/402) 5. Unfulfillment of Postulate 2
5.1 Occasional PrP plaques are seen in cases of Alzheimer's Disease, where
they coexist with the more usual beta amyloid plaques. (Ref. Baker H. F.
Ridley R.M. Duchen L.W. Crow T.J. Bruton C.J. Induction of beta

full text;

http://www.bse.org.uk/files/ws/s310.pdf

Wednesday, 23 August, 2000, 23:54 GMT 00:54 UK Alzheimer's and CJD 'similar'
[Brain] Rogue proteins are thought to cause degenerative brain disorders
Scientists have discovered striking similarities between Alzheimer's disease
and the human form of mad cow disease, vCJD.

They believe the breakthrough could lead to drugs to treat both conditions.

Both are marked by a gradual and ultimately fatal deterioration of the brain
and both are associated with rogue proteins.

Now Professor Chi Ming Yang, of Nankai University in Tianjin, China, has
discovered that these proteins have very similar structures.

This could mean that the molecular mechanism underlying Alzheimer's disease
and vCJD is the same.

Professor Yang used a computer model to map the prion protein associated
with vCJD and the amyloid precursor protein associated with early stage
Alzheimer's.

He found that the two proteins had a similar pattern of component parts
known as amino acids.

Each are made up of a reductive amino acid followed by three non-reductive
amino acids.

Reductive amino acids are more prone to damage by free radicals - charged
oxygen particles that can disrupt the DNA of the body's cells.

Normally, the body can clear itself of free radicals. But with age, this
system may fail.

When enough free radicals accumulate to damage a protein molecule it can
malfunction.

Scientists believe this mechanism may lead to Alzheimer's, the most common
cause of dementia, affecting an estimated 12 million people worldwide.

The disease is characterised by include messy "tangles" of nerve fibres and
"plaques" rich in the amyloid proteins.

CJD is the human version of bovine spongiform encephalitis (BSE or mad cow
disease).

It occurs naturally in about one in a million people but a new version,
vCJD, has been linked with eating BSE-infected meat.

BSE and vCJD are believed to be caused by prion proteins that do not fold
normally.

http://news.bbc.co.uk/hi/english/health/newsid_892000/892819.stm

Stanley Prusiner, M.D.

Stanley Prusiner, M.D., a neurobiologist at the University of California at
San Francisco, was awarded the 1997 Nobel Prize in Medicine for his
groundbreaking discovery and definition of a new class of disease-causing
agents called prions (pronounced pree-ons). The Nobel Prize, is the most
prestigious award given for research in medicine.

Dr. Prusiner's award is the culmination of 25 years of sometimes
controversial research on the prion, a natural human protein that, under
certain conditions, can interact with other prion proteins, ultimately
forming harmful deposits in the brain. The American Health Assistance
Foundation (AHAF) has awarded more than $1.2 million in research grants
through its Alzheimer's Disease Research program to Dr. Prusiner to develop
his prion theory as a model for Alzheimer's disease. According to AHAF
President Eugene Michaels, "Dr. Prusiner has proven that the most promising
discoveries are often the result of innovative scientific inquiry. We are
honored to have played a part in Dr. Prusiner's groundbreaking research."

Prions have been implicated in dementia-causing diseases such as mad cow
disease and scrapie in animals, and Creutzfeldt-Jakob Disease (CJD) and
Gerstmann-Straussler-Scheinker syndrome (GSS) in humans. Unlike infectious
agents such as bacteria, viruses and parasites, whose ability to grow and
reproduce is governed by genetic material made up of RNA and DNA, prions
appear to be made up entirely of proteins with no accompanying DNA or RNA.
Prions are present in normal cells, and the gene that codes for the
production of the prion protein is part of a normal human chromosome.

Since 1985, the American Health Assistance Foundation has supported studies
of the structures and properties of prions, and investigations that led to
the purification and identification of the prion protein in the brains of
scrapie-infected sheep. AHAF also awarded a grant to Dr. Prusiner to study
CJD and GSS, using molecular biology methods to introduce genes from mutated
prion proteins into mice to create an animal model for these diseases. His
current AHAF grant is focused on the development of a new system to
determine when in the life of a mouse the prion protein leads to disease. He
is also studying a method to prevent prion disease by blocking prions from
converting normal proteins into more prions.

There are similarities between the loss of brain function in prion diseases
and in Alzheimer's disease, and an understanding of how prion diseases begin
and develop will add to our understanding of what happens to the brain in
Alzheimer's disease. Dr. Prusiner's research may one day lead to a treatment
and a cure for Alzheimer's.

http://www.ahaf.org/alzdis/about/prusiner.htm

Date: Posted 8/24/2000

"Strikingly Similar" Protein May Be In Alzheimer's And Mad Cow Disease
Washington D.C., August 23 -- A "striking similarity" between proteins
involved in the early stages of Alzheimer's disease and mad cow disease was
described here today at the 220th national meeting of the American Chemical
Society, the world's largest scientific society. The theory, if verified by
other researchers, could help focus efforts to develop preventive drugs,
according to the study's lead researcher, Chi Ming Yang, Ph.D., a professor
of chemistry at Nankai University in Tianjin, China.

Prion diseases -- which include, among others, neurodegenerative diseases
such as mad cow disease and its human counterpart, Creutzfeldt-Jakob
disease -- are caused by a malfunctioning prion protein. In Alzheimer's
disease, another neurodegenerative disease, the amyloid precursor protein
has been implicated.

Using computer modeling, Yang discovered a similar pattern of amino acids in
the prion protein and the amyloid precursor protein: a reductive amino acid
followed by three non-reductive amino acids.

"This suggests a common molecular mechanism underlying the initiation stages
of sporadic Alzheimer's disease and both sporadic and genetic prion
diseases," says Yang.

Reductive amino acids are more prone to damage by oxygen-containing free
radicals (molecules with a highly reactive unpaired electron) than other
amino acids, explained Yang. Normally, the body can clear itself of free
radicals. But with age, this system may fail. When enough free radicals
accumulate to damage a protein molecule, it can malfunction, he says.

Proteins typically fold into specific three-dimensional structures that
determine their functions. A malfunctioning protein may remain partially
unfolded, which can place different amino acids in close proximity, Yang
explained. In the case of Alzheimer's and prion diseases, the reductive
amino acids in close proximity can lead to the formation of protein plaques,
according to Yang.

Although Alzheimer's and prion diseases seem to start in similar ways, they
progress differently. This may explain why Alzheimer's disease advances at a
much slower pace than Creutzfeldt-Jakob disease, says Yang.

The paper on this research, PHYS 460, will be presented at 7 p.m.,
Wednesday, Aug. 23, in the Washington Convention Center, Exhibit Hall D.

Chi Ming Yang, Ph.D., is a chemistry professor at Nankai University,
Tianjin, China.

A nonprofit organization with a membership of 161,000 chemists and chemical
engineers, the American Chemical Society publishes scientific journals and
databases, convenes major research conferences, and provides educational,
science policy and career programs in chemistry. Its main offices are in
Washington, D.C., and Columbus, Ohio.

http://www.sciencedaily.com/releases/2000/08/000824081151.htm

http://www.sciencedaily.com/releases/2000/08/000824081151.htm


====================

Some references that may be interesting on the topic...

References. Aguzzi, A. and Weismann, C. Prion Research: the Next Frontiers.
Nature, Vol.389 pp.796-79 ,1997. Alper , T.; Cramp, W.; Haig , D. and
Clarke, M. Does the agent of scrapie replicate without nucleic acid?,
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Valdivieso, F.; and Vazquez, J. Presenilin-1 genotype[2/2] is associated
with late onset Alzheimer's disease in Spanish patients. Alzheimer's Res.
Vol.3, pp.141-143.1997 Avila , J. and Colaco, A.L. The role of sulphated
glycosaminoglycans in Alzheimer's disease.: a hypothesis. Alzheimer's Res.,
Vol.3,pp.77-81.1997 Avila, J. Modification of proteins related with the
onset of Alzheimer's disease: Tau phosphorilation, glycosylation and
oxydation in Alzheimer's disease. Current Drugs , Vol.2,pp.141-143.1997
Baldwin , M.; James , T.; Cohen, F.; and Pruisiner , S. The
three-dimensional structure of prion protein : implications for Prion
disease. Biochemical Society Transactions , Vol.26, pp.481-486.1998 Baldwin,
M.; Pan ,K.; Nguyen , J.; Huang, Z. Groth, D.; Serban, A. et al.
Spectroscopic Characterization of conformational differences between PrPc
and PrPsc-An Alpha-helix to Beta-sheet transition. Philosophical
Transactions of the Royal Society of London, series B-Biological
Sciences,Vol.343, number 1306, pp-435-441.1992 Ball, M. Features of
Creutzfeldt-Jakobs disease in brains of patients with familial dementia of
Alzheimer's type. Canadian Journal of Neurological Sc.Vol.7 , pp.51-57.1980
Banissi-Sabourdi, C.; Planques, B.; David, J.P.; Jeannin, C.; Potel , M;
Bizien, M.; Di Menza, C.; Brugère -Picoux, J.; Brugère, H.; Chatelain , J.
Electroanalytical characterization of Alzheimer's disease and ovine
spongiform encephalopathy by repeated cyclic voltametry at a capillary
graphite paste electrode .Bioelectrochemistry and Bioenergetics. Vol. 28,
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accidental person to person transmission of Creutzfeldt-Jakobs disease by
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I.; Mattman ,C.; Tschopp, J.; and Martinou ,J.C. Dissection of functional
domains in bcl-2 alpha by site directed mutagenesis . Biochemical Cellular
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Fischer ,M.; Sailer, A.; Koyba et al. normal host prion protein necessary
for scrapie-induced neurotoxicity.Nature.Vol.379, pp.339-343.1996 Braham, J
. Ceutzfeldt-Jakob Disease: treatment by Amantidine. Brit. Med . J. Vol. 4,
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temoin biochimique urinaire de l'infection du mouton par la tremblante.
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Brugère-Picoux ,J .;Chatelain, J.; Tournaire, M.C et Buvet, R.
Electrochemical analysis of urine in Alzheimer's patients and ruminants with
spongiform encephalopaties ( scrapie and BSE) .III Int. Symp. on
Transmissible subacute spogiform encephalopaties: Prion diseases, Paris, Val
de Grace, 18-20 March.1996 Bruce, M.; Will, r.; Ironside, J.; McConnell, I.;
Dummond , D,; and Suttie, A. Transmission to mice indicates that "new
variant" CJD is caused by BSE agent. Nature. Vol.389, pp.498-501.1997
Byeler, H.; Aguzzi, A.; Sailer, A.; Greiner, r.; Autenreid, P.; Aguet, M..
and Weissman, C. Mice devoid of PrP are resistant to scrapie. Cell.vol.73,
pp.1339-1347.1993 Carpenter, C.; Fishl, M.; Hammer, S.M; et al .
Anti-retroviral therapy for HIV infection in 1996: Recommendations of an
international panel. JAMA. Vol. 276,pp.146-154.1996 Cathala, F.; Brown, P.;
Rahison, S et al. Maladie de Creutzfeldt-Jakob en France. Revue Neurologique
(Paris).Vol.7,pp56-62.1982 Caughey, W.; Raymond, L .; Horiuchi, M.; and
Caughey, B. Inhibition of protease-resistant prion protein formation by
porphyrins and
phtalocyanines.PNAS.Vol.95.Iss.21,pp.12117-12122.Oct.17th,1998. Cohen, F.;
Pan, K.; Huang, Z; Baldwin, M.; Fletterick, R. and Pruisiner, S. Structural
clues to prion replication.Science.Vol.264, pp.530-531. 1994 Collinge, J.;
and Hawke, S. B lymphocytes in prion neuroinvasion: central or peripheral
players?. Nature Medicine .Vol.4,pp.1369-1370.1998. Collinge, J. and Palmer,
M. Prion Diseases. Oxford University Press.1997 Collinge, J.; Whittington
,M.; Siddle, K. et al. Prion protein is necessary of synaptic formation.
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Studies in ageing in the brain IV. Familial Alzheimer's disease : elation to
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Wolfe, F.; Lukashnov, V. Danner, S et al .Clearance of HIV-1 following
treatment with two, three, four or five anti-HIV drugs. Program and
abstracts of the 5th conference on retroviruses and opportunistic
infections.Feb.1-5th. Chicago, Ill.1998.Abs.384 Garrett, L. The Coming
Plague. Penguin USA. 1995 Gibbs, T.; Baldwin, M.; Lloyd, D. et al. Predicted
alpha-helical regions of the prion protein when synthesized as peptides from
amyloid. PNAS.Vol.89,pp.10940-10944.1992 Goudsmith, J.; Morrow, C.; Asher,
D. et al. Evidence for and against the transmissibility of Alzheimer's
disease.Neurology.Vol.30pp.945-950.1980 Herishanu, Y. Antiviral drugs in
Creutzfeldt-Jakob disease. J. of Am. Soc. of
Geriatrics.Vol.21,pp.229-273.1973 Ikeda, K.; Kawada, N.; Wang ,Y. et al
.Expression of cellular prion protein in activated hepatic stellate cells.
Am. J. of Path.Vol.6,N.6, pp.1695-1700.1999 Jellinger, K.; and Seitelberger,
F. Spongy degeneration in the central nervous system in infancy. Curr. Top.
in Path.Vol.53, pp.90-160.1970 Kimberlin, R. and Walker , C. Anti-viral
compound effective against experimental scrapie. The Lancet.Vol.2,
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pedunculopontine neurons in vitro: comparison with cholinergic septal cells
and response to nerve growth factor, ciliary neurothrophic factor and
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inhibits Alzheimer's disease-like tau protein phosphoryllation in neurons
.FEBS Lett.Vol.411,pp.183-188.1997 Perez, M.; Wandosell, F.; Colaco, C. and
Avila, J. Sulphated glycosaminoglycans prevent neurotoxicity of human prion
protein fragment . Pruisiner,S.Prions.PNAS.1998 Sadler, I.; Smith, D.;
Sherman, M. et al .sulphated compounds attenuate Beta-amyloid toxicity by
inhibiting its association with cells .Neuroreport.Vol.7,pp.49-53.1995
Sadler, I.; Hawtin, S.; Tailor, V. et al . Glucosaminoglycans and sulphated
polyanions attenuate neurotoxic effects of beta-amyloid. Biochem. Soc.
Trans. Vol.23,p.1065.1995 Sukhalayan,C.; Khalequz, Z.; Hoon, R.; Conforto,
A.; and Rajiv, R. Sequence-Selective DNA binding drugs Mitramyacin A and
Chromomyacin A3 are potent inhibitors of neuronal apoptosis induced by
oxidative stress and DNA damage in cortical
neurons.Ann.Neurol.Vol.49,pp.345-354.2001

Diagnosis and Reporting of Creutzfeldt-Jakob Disease T. S. Singeltary, Sr;
D. E. Kraemer; R. V. Gibbons, R. C. Holman, E. D. Belay, L. B. Schonberger

http://jama.ama-assn.org/issues/v285n6/ffull/jlt0214-2.html


IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf


Subject: Re: Hello Dr. Manuelidis Date: Fri, 22 Dec 2000 17:47:09 -0500
From: laura manuelidis Reply-To: laura.manuelidis@yale.edu Organization:
Yale Medical School To: "Terry S. Singeltary Sr."

References: <39B5561A.87B84A28@wt.net> <39B64574.A4835745@yale.edu>
<39B680D8.3872535B@wt.net> <39B66EF1.4CE25685@yale.edu>
<39BBB812.425109F@wt.net> <39BE84CB.D7C0C16B@yale.edu>
<3A3BA197.7F60D376@wt.net>


Dear Terry,

One of our papers (in Alzheimer's Disease Related Disord. 3:100-109, 1989)
in text cites 6 of 46 (13%) of clinical AD as CJD. There may be a later
paper from another lab showing the same higher than expected incidence but I
can't put my hands on it right now. We also have a lot of papers from 1985
on stating that there are likely many silent (non-clinical) CJD infections,
i.e. much greater than the "tip of the iceberg" of long standing end-stage
cases with clinical symptoms. Hope this helps.

best wishes for the new year laura manuelidis

"Terry S. Singeltary Sr." wrote: Hello again Dr. Manuelidis, could you
please help me locate the 2 studies that were done on CJD where it showed
that up to 13% of the people diagnosed as having Alzheimer's actually had
CJD. trying to find reference... thank you, > Terry S. Singeltary Sr.


4.5 MILLION DEMENTED ALZHEIMER'S PATIENTS, HOW MANY ARE CJD/TSEs ???

HOW CAN ONE-IN-A-MILLION BE ACCURATE WHEN CJD IS NOT REPORTABLE,

AND WHEN THE ELDERLY DO NOT GET AUTOPSIED??????

TSS


Proof Mad Cow Is The Same As Alzheimer's And CJD
As Alzheimer's And CJD How Many Of Them Are Really Mad Cow/vCJD/TSEs ??? ...
I have posted some data below on CJD and Alzheimer's that you may find
interest ...
www.rense.com/general46/proofa.html - 124k -

http://www.rense.com/general46/proofa.html

More Evidence Mad Cow Same As CJD And Alzheimer's
I have posted some data below on CJD and Alzheimer's that you may find
interest
... Diagnosis and Reporting of Creutzfeldt-Jakob Disease TS Singeltary, Sr;
...
www.rense.com/general34/cjmd.htm - 123k -


http://www.rense.com/general34/cjmd.htm


TSS




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