Links to research with relevance to Alzheimers
http://www.fasebj.org/cgi/content/ab...j.05-4890fjev1


another transmissible protein amyloidosis? what does this implicate with Alzheimer's and TSE, if anything?.........TSS


CJD1/9 0185



http://www.bseinquiry.gov.uk/files/y...1/05004001.pdf






http://www.bseinquiry.gov.uk/files/y...1/04001001.pdf



Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)



http://www.bseinquiry.gov.uk/files/y...7/08014001.pdf





snip...


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


snip...


http://www.bseinquiry.gov.uk/files/y...3/12003001.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/y...7/06005001.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/y...7/09001001.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



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


#### 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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19. Burkhardt CR, Tilley CM, Kleinschmidt-DeMasters BK, de la Monte S,
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20. Dickson DW, Davies P, Mayeux R, et al. Diffuse Lewy body disease:
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24. Brown P, Gibbs CJ Jr, Gajdusek DC, Cathala F, LaBauge R. Chemical
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25. Brumbach RA. Routine use of phenolipid formalin in fixation of autopsy
brain tissue reduce risk of inadvertent transmission of Creutzfeldt-Jakob
disease. N Engl J Med. 1988;319;654.

26. Rosenberg RN, White CL, Brown P, et al. Precautions in handling tissues,
fluids and other contaminated materials from patients with documented or
suspected Creutzfeldt-Jakob disease. Ann Neurol. 1986;12:75-77.

27. Lloyd B, Brinn N, Burger PC. Silver-staining of senile plaques and
neurofibrillary change in paraffin-embedded tissues, J Histotech. 1985;8:
155-156.

28. Brady RO. Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury
JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The
Metabolic Basis of Inherited Disease. 5th ed. New York, NY: McGraw-Hill
International Book Co; 1983:831-841.

29. Cogan DG, Chu FC, Reingold D, Barranger J. Ocular motor signs in some
metabolic diseases. Arch Ophthalmol. 1981:99:1802-1808.

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& Sons Inc; 1984;491-572.

31. Pentchev PC. Comly ME, Kruth HS, et al. A defect in cholesterol
esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci
USA. 1985;82;8247-8251.

32. Vanier MT, Wenger DA, Comly ME, Rousson R. Brady RO, Pentchev PG.
Niemann-Pick disease group C: clinical variability and diagnosis based on
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33. Hulette CM, Earl NL, Anthony DC, Crain BJ. Adult onset Niemann-Pick
disease type C: a case presenting with dementia and absent organomegaly.
Clin Neuropathol. In press.

31. Pentchev PC, Comly ME, Kruth HS, et al. A defect in cholesterol
esterfication in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci
USA. 1985;82;8247-8251

32. Vanier MT, Wenger Da, Comly ME, Rousson R, Brady Ro, Pentchev PG.
Niemann-Pick disease group C: clinical variability and diagnosis based on
defective cholesterol esterification. Clin Genet. 1988;33;331-348

33. Hulette CM, Earl NL, Anthony DC, Crain Bj. Adult onset Niemann-Pick
disease type C; a case presenting with dementia and absen organomegaly.
Cliln Neuropathol. In Press.

34. Groves R, Moller J. The value of the cerebral cortical biopsy. Acta
Neurol Scand. 1966;42;477-482

35. Kaufman HH. Catalano LW. DiaGnostic brain biopsy: a series of 50
cases and a review. NeUROSURGERY. 1979:4:129-136.

36. Blemond A. Indications, legal and moral aspects of cerebral biopsies,
In: Proceedings of Fifth International Congress of Neuropathology, Zurich,
1965, Princeton, NJ: Excerpta Medica; 1966:372-375.

37. Guthkelch AN. Brain biopsy in infancy and childhood. Dev Med Child
Neurol, 1968;10;107-109.

38. Blackwood W, Cumings JN. The combined histological and chemical aspects
of cerebral biopsies. In: Proceeedings of Fifth International Congress of
Neuropathology, Zurich, 1965. Princeton, NJ: Excerpta Medica; 1966:364-371.

39. Green MA, Stevenson LD, Fonseca JE, Wortis SB. Cerebral biopsy in
patients with presenile dementia. Dis Nerv Syst. 1952;13:303-307.

40. Sim M, Turner E, Smith WT. Cerebral biopsy in the investigation of
presenile dementia, I: clinical aspects, Br J Psychiatry. 1966;112:119-125.

41. Turner E, Sim M. Cerebral biopsy in the investigation of presenile
dementia, II: pathological aspects, Br J Phychiatry. 1966;112:127-133.

42. Bowen DM, Benton JS, Spillane JA. Smith CCT, Allen SJ. Choline
acetyltransferase activity and histopathology of frontal neocortex from
biopsies of demented patients. J Neurol Sci. 1982;57:191-202.

43. Neary D, Snowden JS, Bowen DM, et al. Cerebral biopsy in the
investigation of presenile dementia due to cerebral atrophy. J Neurol
Neurosury Psychiatry. 1986;49:157-162.

44. Neary D, Snowden JS, Mann DMA, et al. Alzheimer's disease: a corelative
study. J Neurol Neurosurg Psychiatry. 1986;49:229-237.

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


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

snip...

full text;

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




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



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




TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES


http://www.bseinquiry.gov.uk/files/y...1/05004001.pdf






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

Subject: Alzheimer-type neuropathology in a 28-year old patient with iatrogenic CJD after dural grafting
Date: March 9, 2007 at 9:15 am PST

HUMAN-04

Alzheimer-type neuropathology in a 28-year old patient with iatrogenic

Creutzfeldt-Jakob disease after dural grafting

M Preusser1, T Stroebel1, E Gelpi1, 2, M Eiler3, G Broessner4, E Schmutzhard4, H Budka1, 2

1 Institute of Neurology, Medical University Vienna, Austria; 2 Austrian Reference Centre for Human Prion Diseases

(OERPE), General Hospital Vienna, Austria; 3 Department of Neurology, LKH Rankweil, Austria; 4 Department of

Neurology, Medical University Innsbruck, Austria

We report the autopsy case of a 28-year old male patient who had received a cadaverous dura

mater graft after a traumatic open skull fracture with tearing of dura at the age of 5 years. A

clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months

prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according

to WHO criteria. Immunohistochemistry showed widespread cortical depositions of diseaseassociated

prion protein (PrPsc) in a synaptic pattern and western blot analysis identified PrPsc of

type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and

cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid

was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for

diagnosis of definite Alzheimer´s disease (AD) were met in the absence of neurofibrillar tangles

or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any

other neurological disease, and genetic analysis showed no disease-specific mutations of the

prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents 1. the

iCJD case with the longest incubation time after dural grafting reported so far, 2. the youngest

documented patient with concomitant CJD and Alzheimer-type neuropathology to date, 3. the

first description of Alzheimer type-changes in iCJD, and 4. the second case of iCJD in Austria.

Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly

related to the childhood trauma.


249 of 411 pages...tss


http://www.tse-forum.de/tse_forum/de...FINAL_nov2.pdf


TSS

Subject: Every 72 seconds someone in America develops Alzheimer's
Date: March 20, 2007 at 5:35 pm PST
Alzheimer's Disease Prevalence Rates Rise to More than Five Million in the United States
Someone develops Alzheimer's every 72 seconds, according to new Alzheimer's Association report

The Alzheimer's Association today reports that in 2007 there are now more than 5 million people in the United States living with Alzheimer's disease. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early onset Alzheimer's disease and other dementias. This is a 10 percent increase from the previous prevalence nationwide estimate of 4.5 million.

The greatest risk factor for Alzheimer's is increasing age, and with 78 million baby boomers beginning to turn 60 last year, it is estimated that someone in America develops Alzheimer's every 72 seconds; by mid-century someone will develop Alzheimer's every 33 seconds.

These new estimates, as well as other data concerning the disease and its effects, are issued today as hundreds of advocates from across the country gather in the nation's capitol for the Alzheimer's Association's annual Public Policy Forum. The report titled, 2007 Alzheimer's Disease Facts and Figures, is being released at a hearing today chaired by Senator Barbara Mikulski. Senators Barbara Mikulski and Christopher Bond and Representatives Edward Markey and Christopher Smith have introduced bipartisan legislation to address problems identified in the Association's report. The Association's report details the escalation of Alzheimer's disease which now is the seventh leading cause of death in the country and the fifth leading cause of death for those over age 65. It also offers numerous statistics that convey the burden that Alzheimer's imposes on individuals, families, state and federal governments, businesses, and the nation's health care system. For example:

Without a cure or effective treatments to delay the onset or progression of the Alzheimer's, the prevalence could soar to 7.7 million people with the disease by 2030, which is more than the population of 140 of the 236 United Nations countries.
By mid-century, the number of people with Alzheimer's is expected to grow to as many as 16 million, more than the current total population of New York City, Los Angeles, Chicago and Houston combined.
As the prevalence impact of Alzheimer's grows, so does the cost to the nation. The direct and indirect costs of Alzheimer's and other dementias amount to more than $148 billion annually, which is more than the annual sales of any retailer in the world excluding Wal-Mart.
"Alzheimer's Disease Facts and Figures clearly shows the tremendous impact this disease is having on the nation; and with the projected growth of the disease, the collective impact on individuals, families, Medicare, Medicaid, and businesses will be even greater," says Harry Johns, President and CEO of the Alzheimer's Association. "However there is hope. There are currently nine drugs in Phase III clinical trials for Alzheimer's several of which show great promise to slow or stop the progression of the disease. This, combined with advancements in diagnostic tools, has the potential to change the landscape of Alzheimer's."

According to the latest statistics from the Centers for Disease Control and Prevention, from 2000-2004 death rates have declined for most major diseases -- heart disease (-8 percent), breast cancer (-2.6 percent), prostate cancer (-6.3 percent) and stroke (-10.4 percent), while Alzheimer's disease deaths continue to trend upward, increasing 33 percent during that period.

"We must make the fight against Alzheimer's a national priority before it's too late. The absence of effective disease modifying drugs, coupled with an aging population, makes Alzheimer's the health care crisis of the 21st century," Johns said.

Medicare currently spends nearly three times as much for people with Alzheimer's and other dementias than for the average Medicare beneficiary. Medicare costs are projected to double from $91 billion in 2005 to more than $189 billion by 2015, more than the current gross national product of 86 percent of the world's countries. In 2005, state and federal Medicaid spending for nursing home and home care for people with Alzheimer's and other dementias was estimated at $21 billion; that number is projected to increase to $27 billion by 2015.

The new report also highlights the impact that Alzheimer's has on states with more than 6 in 10 (62%) having double digit growth in prevalence by the end of the decade. In addition, Alaska (+47%), Colorado (+47%), Utah (+45%), Wyoming (+43%), Nevada (+38%), Idaho (+37%), Oregon (+33%), and Washington (+33%) will experience increases ranging from one-third to one-half. The states with the largest numbers of deaths due to Alzheimer's disease in 2003 were (1) California, (2) Florida, (3) Texas, (4) Pennsylvania, and (5) Ohio.

The Alzheimer's Association is the first and largest voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer's. For more than 25 years, the Association has provided reliable information and care consultation; created services for families; increased funding for dementia research; and influenced public policy changes.

Contact: Call our media line at 312.335.4078


Download Report: 2007 Alzheimer's Disease Facts and Figures (28 pages)

Quote Sheet (2 pages)

http://www.alz.org/national/document...quotesheet.pdf

Fact sheet (2 pages)


http://www.alz.org/national/document...Ffactsheet.pdf



http://www.alz.org/news_and_events_rates_rise.asp



Every 72 seconds

someone in America

develops Alzheimer's.


http://www.alz.org/national/document...AndFigures.pdf



More Evidence Mad Cow Same
As CJD And Alzheimer's
1-24-3


IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

http://www.bseinquiry.gov.uk/files/y...1/05004001.pdf

full text ;
http://www.rense.com/general34/cjmd.htm



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



Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)

http://www.bseinquiry.gov.uk/files/y...7/08014001.pdf

snip...

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

snip...

http://www.bseinquiry.gov.uk/files/y...3/12003001.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/y...7/06005001.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/y...7/09001001.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

snip...

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



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


Alzheimer's and Transmissible Spongiform Encephalopathies


snip...


Subject: Alzheimer-type neuropathology in a 28-year old patient with iatrogenic CJD after dural grafting
Date: March 9, 2007 at 9:15 am PST

HUMAN-04

Alzheimer-type neuropathology in a 28-year old patient with iatrogenic

Creutzfeldt-Jakob disease after dural grafting

M Preusser1, T Stroebel1, E Gelpi1, 2, M Eiler3, G Broessner4, E Schmutzhard4, H Budka1, 2

1 Institute of Neurology, Medical University Vienna, Austria; 2 Austrian Reference Centre for Human Prion Diseases

(OERPE), General Hospital Vienna, Austria; 3 Department of Neurology, LKH Rankweil, Austria; 4 Department of

Neurology, Medical University Innsbruck, Austria

We report the autopsy case of a 28-year old male patient who had received a cadaverous dura

mater graft after a traumatic open skull fracture with tearing of dura at the age of 5 years. A

clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months

prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according

to WHO criteria. Immunohistochemistry showed widespread cortical depositions of diseaseassociated

prion protein (PrPsc) in a synaptic pattern and western blot analysis identified PrPsc of

type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and

cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid

was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for

diagnosis of definite Alzheimer´s disease (AD) were met in the absence of neurofibrillar tangles

or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any

other neurological disease, and genetic analysis showed no disease-specific mutations of the

prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents 1. the

iCJD case with the longest incubation time after dural grafting reported so far, 2. the youngest

documented patient with concomitant CJD and Alzheimer-type neuropathology to date, 3. the

first description of Alzheimer type-changes in iCJD, and 4. the second case of iCJD in Austria.

Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly

related to the childhood trauma.


249 of 411 pages...tss


http://www.tse-forum.de/tse_forum/de...FINAL_nov2.pdf


full text ;


http://neurotalk.psychcentral.com/sh...ad.php?p=78281


FELINE ALZHEIMER'S OR MAD CAT DISEASE I.E. FSE ???

http://lists.ifas.ufl.edu/cgi-bin/wa...-mg&T=0&P=8385


From: terry <[log in to unmask]>
Subject: Re: FELINE ALZHEIMER'S OR MAD CAT DISEASE I.E. FSE ???
In-Reply-To: <[log in to unmask]>
Content-Type: text/plain; charset="Windows-1252"


I have 2 questions for you, terry singeltary. Do you agree with colm kelleher where he states there may be a relationship between vCJD and alzeheimer's in that alzheimers may be misdiagnosed. And is it true that BSE cannot be destroyed by heat or chemical so that any instrument that touches it must be thrown out.
Sent wirelessly via BlackBerry from T-Mobile.



http://lists.ifas.ufl.edu/cgi-bin/wa...-mg&T=0&P=8525


Sender: Sustainable Agriculture Network Discussion Group
<[log in to unmask]>
From: "Terry S. Singeltary Sr." <[log in to unmask]>
Subject: Re: FELINE ALZHEIMER'S OR MAD CAT DISEASE I.E. FSE ???
Comments: To: [log in to unmask]
Content-type: text/plain; charset=Windows-1252


i have written about this many times and spoke with colm on several
occasions when he was writing his book.....


> Do you agree with colm kelleher where he states there may be a
relationship

> between vCJD and alzeheimer's in that alzheimers may be misdiagnosed


NOT JUST vCJD but all human TSE, especially sporadic CJD, there are studies
showing
''CJD'' as being misdiagnosed as Alzheimer's (see below).

AND personally i think there is a potential that Alzheimers may be low
level TSE.

may be something else too, i mean, just what is Alzheimer's???


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



snip...end


http://lists.ifas.ufl.edu/cgi-bin/wa...-mg&T=0&P=8673


TSS

Here is some information relevant to transmissible spongiform encephalopathies - "A Case for the Role of Copper Deficiency in 'Mad-Cow' Disease and Human Creutzfeldt-Jakob Disease"

http://www.copper.org/innovations/2001/12/mad-cow.html

I think that another possible cause for Alzheimer's that needs further investigation is Lyme disease:

"In 1995 Dr. Mattman obtained positive cultures for Bb from 43 of 47 persons with chronic illness. Only 1 of 23 control patients had a positive Bb culture. Dr. Mattman has subsequently recovered Bb spirochetes form 8 out of 8 cases of Parkinson’s Disease, 41 cases of multiple sclerosis, 21 cases of amyotrophic lateral sclerosis and all tested cases of Alzheimer’s Disease."

http://www.digitalnaturopath.com/cond/C351537.html

This group found no association between Lyme and Alzheimer's:

http://www3.niaid.nih.gov/research/t...antibiotic.htm

This group did find an association between Lyme and Alzheimer's:

http://www.canlyme.com/alzjournal6.html

http://infoventures.com/emf/topics/bu42ni05.html

Damaging the blood brain barrier would allow pathogens such as bacteria, viruses and prions easier access to the brain.

"The brain is protected by tight junctions between adjacent cells of capillary walls, the so-called blood-brain barrier, which, like a border patrol, lets nutrients pass through from the blood to the brain, but keeps toxic substances out. Since 1988, researchers in the laboratory of a Swedish neurosurgeon, Leif Salford, have been running variations on this simple experiment: they expose young laboratory rats to either a cell phone or other source of microwave radiation, and later they sacrifice the animals and look for albumin in their brain tissue. Albumin is a protein that is a normal component of blood but that does not normally cross the blood-brain barrier. The presence of albumin in brain tissue is always a sign that blood vessels have been damaged and that the brain has lost some of its protection.

Here is what these researchers have found, consistently for 18 years: Microwave radiation, at doses equal to a cell phone’s emissions, causes albumin to be found in brain tissue. A one-time exposure to an ordinary cell phone for just two minutes causes albumin to leak into the brain. In one set of experiments, reducing the exposure level by a factor of 1,000 actually increased the damage to the blood-brain barrier, showing that this is not a dose-response effect and that reducing the power will not make wireless technology safer."

http://www.mindfully.org/Technology/...ment1jan06.htm

Press Release 07-048
Alzheimer's, Parkinson's, Type 2 Diabetes Similar at Molecular Level

Protein analysis may offer new therapeutic route

April 30, 2007


Alzheimer's disease, Parkinson's disease, type 2 diabetes, the human version
of mad cow disease, and other degenerative diseases are more closely related
at the molecular level than scientists realized, a team reports this week in
an advanced online publication of the journal Nature.

While still preliminary, the research, could help scientists develop tools
for diagnosing such diseases, and potentially for treating them through
"structure-based drug design," said David Eisenberg, a UCLA chemist and
molecular biologist who is part of the research team.

The researchers studied the harmful rope-like structures known as amyloid
fibrils--linked protein molecules that form in the brain. The fibrils
contain a stack of water-tight "molecular zippers."

"With each disease, a different protein transforms into amyloid fibrils, but
all of these diseases are similar at the molecular level," Eisenberg said.

If the molecular zipper is universal in amyloid fibrils, as Eisenberg
believes, is it possible to pry open the zipper or prevent its formation?

Eisenberg's research team used X-ray analysis and a sophisticated computer
algorithm to study proteins known to be associated with human diseases. When
the computer said a protein will form an amyloid fibril, it almost always
did. And one team member is experimenting with various compounds to break up
the fibrils.

"Structural analysis of micro-crystals of proteins is an example of how
basic research can have a profound impact on our understanding of health,
biotechnology and other practical issues," said Parag Chitnis, program
director in National Science Foundation's (NSF) Division of Molecular and
Cellular Biosciences.

NSF, the Howard Hughes Medical Institute and the National Institutes of
Health supported the research.

See the UCLA news release at http://www.newsroom.ucla.edu/.

-NSF-



Media Contacts
Cheryl Dybas, NSF (703) 292-7734 cdybas@nsf.gov
Stuart Wolpert, UCLA (310) 206-0511 swolpert@support.ucla.edu






http://www.nsf.gov/news/news_summ.js...=NSF&from=news



TSS


----- Original Message -----
From: "Terry S. Singeltary Sr." <flounder9@VERIZON.NET>
To: <BSE-L@aegee.org>
Sent: Wednesday, April 25, 2007 8:48 PM
Subject: TRANSMISSION OF B-amyloidosis TO PRIMATES strengthens the parallels
between Alzheimer's disease and CJD - IN CONFIDENCE



Subject: TRANSMISSION OF B-amyloidosis TO PRIMATES strengthens the parallels
between Alzheimer's disease and CJD - IN CONFIDENCE
Date: April 25, 2007 at 6:25 pm PST

IN CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

H F BAKER, R M RIDLEY, L W DUCHEN, T J CROW, C J BRUTON


As part of a larger series of experiments designed to assess the
transmissibility of various neurodegenerative disease including the
spongiform encephalopathies (eg Creutzfeldt-Jakob disease and BSE we
injected several marmosets (Callithrix Jacchus) intracerebrally with brain
homogenate from :

1) a 56 year old patient with severe Alzheimer's disease - B - amyloid
plaques and conogophilic angiopathy (CAA) and neurofibrillary tangles; and

2) a 62 year old patient with Gerstmann-Straussler disease, a spongiform
encephalopathy with PrP Plaques and, in this case, B-amyloid plaques and
CAA.

These monkeys were killed more than 6 years after inoculation and their
brains were found to contain moderate numbers of B-amyloid plaques and CAA
but NO neurofibrillary tangles NO PrP. The brains of more than 12 monkeys
killed at an older age did not contain these changes. B-amyloid was not
found in the brains of monkeys injected with brain material which did not
contain B-amyloid. These results suggest that B-amyloidosis is a
transmissible process resembling the transmissibility of PrP amyloidosis in
transmissible dementia and strengthens the parallels between Alzheimer's
disease and Creutzfeldt-Jakob disease.

It should be stressed, however, that we are not claiming to have transmitted
Alzheimer's disease because

1) the animals were behaving normally when killed and

2) no neurofibrillary tangles were seen.

We have argued previously that transmission of spongiform encephalopathy,
particularly from the genetic cases (GSS and some CJD), does not imply that
the donor cases themselves acquired the disease by infection. We would apply
the same arguments in this case, particularly in view of the genetic basis
of some cases of Alzheimer's disease and the extensive epidemiological data
which does not link Alzheimer's disease to infection.


DISCLOSURE


This work is currently under preparation for publication BUT IN VIEW OF
PUBLIC CONCERN OVER THE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (eg BSE)
AND THE HIGH INCIDENCE OF ALZHEIMER'S DISEASE IN THE GENERAL POPULATION, IT
IS IMPORTANT THAT THESE FINDINGS ARE NOT DISCUSSED OPENLY BEFORE FULL
PUBLICATION.

Furthermore, BEFORE DISCLOSURE, IT IS IMPORTANT THAT INTERESTED PARTIES BE
PROPERLY APPRAISED OF THE DATA AND THERE IMPLICATIONS.

Previous attempts to transmit Alzheimer's disease to rodents and large
primates have been unsuccessful. It is our belief that post-mortem tissue
from these animals still exists and we are anxious that research workers (in
the USA) SHOULD NOT RE-EXAMINE this material until our data are published.


SAFETY

At this point we would like to stress again the lack of evidence relating
Alzheimer's disease to exposure to brain tissue through neurosurgery or
occupation. NEVERTHELESS it is appropriate that proper bodies should
consider whether the results of our experiments have any implications for
human health.


FURTHER EXPERIMENTS

The interpretation we have made that B-amyloidosis as a self-peretuating
process has important implications for understanding the process of
neurodegeneration, which are best studied at the level of protein chemistry.
However, we can see arguments for some transmission experiments including:

1) serial passage of B-amyloidosis in order to strengthen the evidence of
transmissibility;

2) transmission from other cases of Alzheimer's disease in order to
establish the generality of this effect;

3) transmission to primates which are allowed to run their full course, ie
to see whether the full syndrome of Alzheimer's disease develops including
neurofibrillary tangle formation, astrocytosis, neuronal loss and
concomitant cognitive decline. (We are already expert in the
neuropsychological assessment of marmosets). It should be remembered that,
at the present time, only the amyloidosis have been found to be
transmissible such that Alzheimer's disease PER SE has not been transmitted;

4) comparison of transmission from cases which contain only CAA and those
which contain only B-amyloid plaques. These two forms of amyloid differ very
slightly and it is not known whether this difference is preserved on
transmission;

5) establishment of the time course of the development of B-amyloidosis. The
present experiment suggests that the time course is somewhere between 1-5
years;

6) transmission using larger quantities of purified preparations of
B-amyloid. This may reduce the transmission time considerably;

7) transmission using animals of different initial ages to investigate the
relationship between transmission time and chronological age, eg
transmission into mature animals may decrease transmission time through an
interaction between the pathological process and senescence;

8) manipulation of transmission time by treatments which may speed up plaque
formation, eg by increasing the production of amyloid precursor protein, or
which may slow down plaque formation and protect from disease progression.

The proposal is to inoculate about 25 marmosets in the first instance and to
replace them in a 'rolling' experiment as they die or are killed according
to the experimental design. The marmosets will be kept in the MRC Marmoset
Colony in Cambridge. Additional facilities and personnel are not required
over and above that awarded to Dr. Ridley in an MRC Programma Grant.

A preliminary report of our findings will be presented by Professor L W
Duchan at the January 1993 meeting of the British Neuropathological Society.



http://www.bseinquiry.gov.uk/


TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

http://www.bseinquiry.gov.uk/files/y...1/05004001.pdf




Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)

http://www.bseinquiry.gov.uk/files/y...7/08014001.pdf


snip...


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


snip...


http://www.bseinquiry.gov.uk/files/y...3/12003001.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/y...7/06005001.pdf


TSS

Great information. Thanks.

Also, did you read my post linking to "A Connection between Simian Virus 40 and Alzheimer's?" on my thread "Helpful Information about Alzheimer's" ?

Published online before print June 15, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0609621104

Neuroscience

Cellular prion protein regulates -secretase cleavage of the Alzheimer's amyloid precursor protein

( lipid raft | proteolysis | scrapie | glycosaminoglycan )

Edward T. Parkin *, Nicole T. Watt *, Ishrut Hussain , Elizabeth A. Eckman ¶, Christopher B. Eckman ¶, Jean C. Manson ||, Herbert N. Baybutt ||, Anthony J. Turner *, and Nigel M. Hooper ***
*Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom; Neurodegeneration Research, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom; ¶Mayo Clinic, Jacksonville, FL 32224; and ||Roslin Institute, Neuropathogenesis Unit, Edinburgh EH9 3JF, United Kingdom



Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved May 10, 2007 (received for review October 30, 2006)

Proteolytic processing of the amyloid precursor protein (APP) by -secretase, -site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid (A) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrPC), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, remains enigmatic. Because both APP and PrPC are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrPC in the proteolytic processing of APP. Cellular overexpression of PrPC inhibited the -secretase cleavage of APP and reduced A formation. Conversely, depletion of PrPC in mouse N2a cells by siRNA led to an increase in A peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, A levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the -secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrPC on the -secretase cleavage of APP required the localization of PrPC to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrPC via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A is regulated by PrPC and may have implications for both Alzheimer's and prion diseases.




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

Author contributions: E.T.P., J.C.M., and N.M.H. designed research; E.T.P., N.T.W., I.H., E.A.E., C.B.E., and H.N.B. performed research; E.T.P., N.T.W., E.A.E., C.B.E., and N.M.H. analyzed data; I.H., E.A.E., and C.B.E. contributed new reagents/analytic tools; and E.T.P., J.C.M., A.J.T., and N.M.H. wrote the paper.

The authors declare no conflict of interest.

Present address: Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, United Kingdom.

**To whom correspondence should be addressed.

Nigel M. Hooper, E-mail: n.m.hooper@leeds.ac.uk

www.pnas.org/cgi/doi/10.1073/pnas.0609621104


http://www.pnas.org/cgi/content/abst...9621104v1?etoc


Human and Animal Food Poisoning with Mad Cow a Slow Death

http://www.slowfoodforum.org/showthread.php?p=4042


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


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


More Evidence Mad Cow Same
As CJD And Alzheimer's
1-24-3

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

TSS

Subject: Alzheimer’s prevention role discovered for prions
Date: June 29, 2007 at 6:38 pm PST

Alzheimer’s prevention role discovered for prions

30 June 2007

A role for prion proteins, the much debated agents of mad cow disease and
vCJD, has been identified. It appears that the normal prions produced by the
body help to prevent the plaques that build up in the brain to cause
Alzheimer’s disease. The possible function for the mysterious proteins was
discovered by a team of scientists led by Medical Research Council funded
scientist Professor Nigel Hooper of the University of Leeds.

Alzheimer’s and diseases like variant Creutzfeldt-Jakob Disease follow
similar patterns of disease progression and in some forms of prion disease
share genetic features. These parallels prompted Professor Hooper’s team to
look for a link between the different conditions. They found an apparent
role for normal prion proteins in preventing Alzheimer’s disease.

‘‘Our experiments have shown that the normal prion proteins found in brain
cells reduce the formation of beta-amyloid, a protein that binds with others
to build plaques in the brain that are found in Alzheimer’s disease,’’
explains Professor Hooper.
He continues: ‘‘In vCJD, the normal version of prion protein, PrPc, found
naturally in the brain is corrupted by infectious prions to cause disease.
The normal function of PrPc has been unclear.’’
Using cells grown in the lab, the team looked at the effect of high and low
levels of normal prion protein on the successful formation of beta amyloid,
the source of Alzheimer’s plaques. They found that beta amyloid did not form
in cells with higher than usual levels of PrPc. In comparison, when the
level of PrPc was low or absent, beta amyloid formation was found to go back
up again.

Mice genetically engineered to lack PrPc were also studied. Again, this
revealed that in its absence, the harmful beta-amyloid proteins were able to
form.

It appears that PrPc, the normal prion protein, exerts its beneficial effect
by stopping an enzyme called beta-secretase from cutting up amyloid protein
into the smaller beta-amyloid fragments needed to build plaques.

Further evidence for the protective role of normal prion proteins is
provided by mutated versions that are linked to genetic forms of prion
disease because beta-amyloid fragments are able to form when the normal
prion protein is corrupted by genetic mutation.

Professor Hooper concludes:

‘‘Until now, the normal function of prion proteins has remained unclear, but
our findings clearly identify a role for normal prion proteins in regulating
the production of beta-amyloid and in doing so preventing formation of
Alzheimer’s plaques. Whether this function is lost as a result of the normal
ageing process, or if some people are more susceptible to it than others we
don’t know yet.’’
‘‘The next step for our research will be to look in more detail at how the
prion protein controls beta amyloid, knowledge that could be used to design
anti-Alzheimer’s drugs. Theoretically, if we can find a way of mimicking the
prion’s function we should be able to halt the progress of Alzheimer’s.
However, there’s still a lot of work to be done in looking at levels of
prions in the human system and how these may alter as we age.”
Original research paper: ‘Cellular prion protein regulates ß- secretase
cleavage of the Alzheimer’s amyloid precursor protein’ is published in the
Proceedings of the National Academy of Sciences USA.

Press contact
Phone: 020 7637 6011
press.office@headoffice.mrc.ac.uk

http://www.mrc.ac.uk/consumption/gro.../mrc003835.pdf



Published online before print June 15, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0609621104

Neuroscience

Cellular prion protein regulates -secretase cleavage of the Alzheimer's
amyloid precursor protein



www.pnas.org/cgi/doi/10.1073/pnas.0609621104


http://www.pnas.org/cgi/content/abst...9621104v1?etoc


Subject: Inactivation of amyloid-enhancing factor (AEF): study on
experimental murine AA amyloidosis
Date: June 24, 2007 at 1:11 pm PST

Masatoshi Omoto · Tadaaki Yokota · Dan Cui
Yoshinobu Hoshii · Hiroo Kawano · Toshikazu Gondo
Tokuhiro Ishihara · Takashi Kanda

Inactivation of amyloid-enhancing factor (AEF): study on experimental
murine AA amyloidosis

Abstract It is known that amyloid-enhancing factor (AEF)
shortens the preamyloid phase in experimentally induced
AA amyloidosis in mice. Because it is reported that AEF
serves as both a nidus and a template for amyloid formation,
AA amyloidosis may have transmissibility by a prionlike
mechanism. It has been shown that amyloid fi brils also
have AEF activity, and amyloid fi brils with AEF activity
were named fi bril-amyloid enhancing factor (F-AEF). In
this study, we investigated methods to inactivate the AEF
activity. AEF was extracted from the thyroid gland obtained
at autopsy of a patient with AA amyloidosis. Before
injection into mice, AEF was treated with several methods
for inactivation. Of all the tested treatments, 1 N NaOH,
0.1 N NaOH, and autoclaving consistently demonstrated
complete inactivation of AEF. Heat treatment led to incomplete
inactivation, but 0.01 N NaOH, 0.001 N NaOH,
pepsin, trypsin, pronase, and proteinase K treatment had
no effect on AEF activity. By analysis with transmission
electron microscopy, the AEF preparation contains amyloid
fi brils, and a change of ultrastructure was shown after
1 N NaOH, 0.1 N NaOH, and autoclaving treatment. Furthermore,
immunoblotting of AEF with antihuman AA
antibody revealed that the protein band was scarcely found
after autoclaving, 1 N NaOH, and 0.1 N NaOH treatment.
Our results suggest that, similar to Creutzfeldt–Jakob
M. Omoto (*) · T. Kanda
Department of Neurology and Clinical Neuroscience, Yamaguchi
University School of Medicine, 1-1-1 Minamikogushi, Ube City,
Yamaguchi 755-8505, Japan
Tel. +81-836-22-2719; Fax +81-836-22-2364
e-mail: omoto-path@umin.ac.jp
T. Yokota
Department of Pathology, Kokura Memorial Hospital, Yamaguchi,
Japan
D. Cui · Y. Hoshii · H. Kawano · T. Ishihara
Department of Radiopathological and Science, Yamaguchi
University School of Medicine, Fukuoka, Japan
T. Gondo
Department of Surgical Pathology, Yamaguchi University Hospital,
Yamaguchi, Japan
disease (CJD), amyloidosis may require chemical or autoclaving
decontamination.
Key words Amyloid-enhancing factor · Amyloidosis ·
Creutzfeldt–Jakob disease · Prion · Transmission electron


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Discussion

Secondary amyloidosis occurs in individuals with longstanding
infl ammatory diseases. Since the incidence of
chronic infl ammatory diseases such as tuberculosis and leprosy
has decreased in recent years, rheumatoid arthritis
(RA) is now the most common disease involving secondary
AA amyloidosis, especially in elderly patients with a long
history of RA. Autopsy studies indicate that the incidence
of secondary amyloidosis in RA patients may be between
20% and 25%.21 Generally, treating the underlying disease
is the conventional approach in AA amyloidosis, because
no specifi c treatment exists. It is not yet certain whether
preventing amyloid proteins from aggregating will be therapeutically
beneficial.
An essential factor for the development of AA amyloidosis
is a continual high plasma concentration of SAA.
However, it is still unclear why only a subset of such individuals
develops AA amyloidosis. Therefore, in addition to
high concentrations of an amyloidogenic protein, other
factors are thought to be necessary in the pathogenesis of
AA amyloidosis. AEF is thought to be one of the essential
factors for the development of amyloidosis, although the
mechanism responsible for the formation of amyloid fi brils
is still unclear. Many studies have identifi ed that AEF activity
is a large macromolecular complex, and all tissue extracts
studied to date appear to contain glycoprotein with
an approximate size of 10–15 kD.4,22–24
Most strains of mice are susceptible to developing AA
amyloid deposition following chronic administration of
infl ammatory stimuli such as casein or azocasein.25 The
prolonged preamyloid phase in experimentally induced AA
amyloidosis can be dramatically shortened by intravenous
or intraperitoneal administration of AEF with the infl am-
matory stimuli.2–4 All mice that were exposed to AEF and
injected with silver nitrate developed amyloidosis by day
7.16 Amyloid fi brils extracted from different types of amyloidosis
from a wide variety of species display biologically
similar AEF activity to that in experimental animals. In fact,
Niewold et al.26 showed that intravenous and intraperitoneal
injection of hamster AA amyloid fi brils, bovine AA
amyloid fi brils, and human light chain-derived (A?) amyloid
fi brils markedly accelerated hamster amyloidosis.
The AEF activity found in the amyloid fi bril preparation
was named F-AEF.6 Furthermore, intravenous injection
of amyloid-like fi brils made from synthetic peptides of
transthyretin27 or denatured silk28 accelerates murine AA
amyloidosis. By double immunogold labeling and microautoradiographic
methods, Johan et al. reported that intravenously
administered, radiolabeled, heterologous,
amyloid-like, synthetic fi brils reached the lung and spleen,
accelerated amyloidosis, and were associated with topographical
deposition of murine protein AA fi brils in the recipient
mouse.29
Drastic structural changes of amyloid protein from the
normal and soluble forms to the unique ß-sheet fi brils may
be the most important event in amyloidosis. Recently, it was
reported that AEF serves as both a nidus and a template
for amyloid formation,8 and AA amyloidosis may show
transmissibility as a prion-like mechanism.9 Johan et al. also
suggested that amyloid-like synthetic fi brils had a nidus activity,
29 and amyloid-enhancing activity may occur through
the mechanism of amyloid-like fi brils serving as seed for
fi bril formation. Moreover, by using the method of negative
staining with TEM, electron micrographs of amyloid fi brils
were observed under some conditions. O’Nuallain et al.
revealed that electron micrographs of islet amyloid polypeptide
showed aggregates initially and then grew into fi bril
formations after incubation.30 In contrast, Santhoshkumar
et al. revealed that, using TEM, amyloid ß-peptide showed
signifi cantly decreased fi bril formation and some amorphous
aggregates after incubation with aA-crystallin in
their in vitro study.31 They suggested that aA-crystallin had
the ability to inhibit amyloid fi bril formation. Similarly, in
our study, electron micrographs of F-AEF revealed some
amorphous aggregates after autoclaving, 1 N NaOH, and
0.1 N NaOH treatment and short and transformed fi brils
after heat treatment. Furthermore, immunoblotting of AEF
with antihuman AA antibody revealed that a protein band
was scarcely found after autoclaving, 1 N NaOH, and 0.1 N
NaOH treatments and that weak protein bands were found
after heat treatment. We suggested that these results indicated
the activity of F-AEF disappeared after autoclaving,
1 N NaOH, and 0.1 N NaOH treatments and that the activity
of F-AEF was decreased after heat treatment.
Prion diseases are associated with the accumulation of a
conformational isomer (PrPSc) of host-derived prion protein
(PrPC), and PrPSc forms amyloid fi brils. The exogenous abnormal
form of the prion protein is generally regarded as a
seed that promotes the association of cellular proteins.
Prions are very resistant to inactivation, and accidental
transmission has occurred through the use of inadequate
decontamination procedures.

In our experiments with mice, the activity of F-AEF was
markedly decreased after autoclaving treatment under conditions
of 132°C for 1 h and 1 N NaOH and 0.1 N NaOH
treatment for 1 h. For CJD materials, the Committee on
Health Care Issues of the American Neurological Association
recommended treatment with 1 N NaOH as a standard
sterilization procedure.18 Heat treatment led to substantial
but incomplete inactivation in this study. The Committee
on Health Care Issues of the American Neurological Association
reported that boiling was an ineffective procedure
for CJD tissues and contaminated materials.18 Tateishi et al.
showed that heat treatment with SDS was effective.17
The acceleration of amyloid deposition may be a primary
event in disease, CJD, bovine spongiform encephalopathy
(BSE), familial amyloid polyneuropathy, and AA and
human senile systemic amyloidosis.32 Walker et al. reported
Aß amyloid extracted from an Alzheimer disease brain may
have potential of prion protein.33

The property described for F-AEF is similar to that
of prion reported in CJD. Chemical or autoclaving decontamination
for CJD is necessary for most items associated
with surgery or autopsy.34 We suggest that amyloidosis may
need chemical or autoclaving decontamination similar to
CJD.

Acknowledgments We thank Mr. Jitsuo Kashitani for excellent technical
assistance. This work was supported by a grant from the Intractable
Disease Division, the Ministry of Health and Welfare, a Research
Committee for Epochal Diagnosis and Treatment of amyloidosis in
Japan, and a Research Committee for amyloidosis.


http://www.springerlink.com/content/...8/fulltext.pdf




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Unexpectedly high incidence of visceral AA-amyloidosis in slaughtered cattle
in Japan

Authors: Kana Tojo a; Takahiko Tokuda a; Yoshinobu Hoshii b; Xiaoying Fu
c; Keiichi Higuchi c; Takane Matsui d; Fuyuki Kametani e; Dr Shu-Ichi
Ikeda a Affiliations: a Third Department of Medicine, Shinshu University School
of Medicine. Matsumoto. Japan
b First Department of Pathology, Yamaguchi University School of Medicine.
Ube. Japan
c Department of Aging Biology, Institute on Aging and Adaptation, Shinshu
University, Graduate School of Medicine. Matsumoto. Japan
d Department of Pathobiological Science, School of Veterinary Medicine,
Obihiro University of Agriculture and Veterinary Medicine. Obihiro. Japan
e Department of Molecular Biology, Tokyo Institute of Psychiatry. Tokyo.
Japan

DOI: 10.1080/13506120500107097
Publication Frequency: 4 issues per year
Published in: Amyloid, Volume 12, Issue 2 June 2005 , pages 103 - 108
Subjects: Biochemistry; Medicine;
Number of References: 30
Formats available: HTML (English) : PDF (English)
Previously published as: Amyloid: International Journal of Experimental &
Clinical Investigation (1350-6129) until 2004
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Abstract

Experimental mouse AA amyloidosis can be transmissible by dietary ingestion
of amyloid fibrils and it is well known that AA amyloidosis occasionally
develops in aged cattle. Bovine liver and intestine have conventionally been
used in Oriental foods, and the incidence of visceral AA amyloidosis in
slaughtered cattle was evaluated. Renal tissues from 302 aged cattle older
than 4 years were obtained from a local abattoir. Amyloid deposition was
microscopically examined and amyloid protein was immunochemically
determined. Renal amyloid deposition was seen in 15 out of 302 cattle with
no previous history of diseas, an incidence of 5.0%. Amyloid protein in
these cattle was AA and they had pathological findings in their visceral
organs on gross examination. The incidence of visceral AA amyloidosis in
slaughtered cattle in this study was disturbingly high compared with those
(0.4-2.7%) previously reported from Japan and other foreign countries. AA
amyloidosis is a life-threatening complication in patients with chronic
inflammatory diseases and these patients at risk should avoid ingesting food
that may possibly contain AA amyloid fibrils. More detailed information on
cattle amyloidosis is required to guarantee the safety of our food.

Keywords: Cattle amyloidosis; transmissible amyloidosis; reactive
amyloidosis; AA amyloidosis; chronic inflammation
view references (30)


http://www.informaworld.com/smpp/con...all~order=page



Subject: Amyloidogenic potential of foie gras
Date: June 22, 2007 at 2:23 pm PST

http://lists.ifas.ufl.edu/cgi-bin/wa...anet-mg&P=9621


Creutzfeldt-Jakob Disease Mortality in Japan, 1979-2004: Analysis of
National Death Certificate Data



Yuriko Doi1), Tetsuji Yokoyama2), Miyoshi Sakai2) and Yosikazu Nakamura3)

1) Department of Epidemiology, National Institute of Public Health.
2) Department of Technology Assessment and Biostatistics, National Institute
of Public Health.
3) Department of Public Health, Jichi Medical University.

(Received: September 13, 2006)
(Accepted: March 18, 2007)


Abstract
BACKGROUND: Trend of the mortality rate of Creutzfeldt-Jakob disease (CJD)
in Japan is still unclear. This study aimed to estimate annual crude
mortality rates due to CJD and examine the CJD mortality trend in Japan
during the period of 1979-2004.
METHODS: National death certificate data on CJD were used (CJD coded as
046.1 for ICD-9 and A81.0 for ICD-10). Trends in age-standardized mortality
rates for CJD were examined by using time series analyses including the
joinpoint regression analysis.
RESULTS: A total of 1,966 deaths (862 males and 1,104 females) were
identified with CJD coded as the underlying-cause-of-death. The annual
number of deaths and crude mortality rates peaked in 2004 at 163 (66 for
males and 97 for females) deaths and 1.28 (1.06 for males and 1.48 for
females) deaths per million population per year, respectively. The
age-specific mortality rates rapidly increased with age between 50 and 74
years, especially among females, and sharply declined at 80+ years.
Throughout the observed period, there were no significant change points, and
the annual percentage changes (95% confidence intervals) were +3.09 (2.18 -
4.02) % for males and +3.90 (2.98-4.83) % and females. The total number of
CJD deaths under 50 years of age was 131, and there was found no increase in
the annual number of deaths for the past few years in this age group.
CONCLUSION: CJD mortality in trend data based on death certificates has
significantly increased in Japan during the period of 1979-2004.
J Epidemiol 2007; 17: 133-139.

Key words: Creutzfeldt-Jakob Syndrome; Regression Analysis; Mortality;
Death Certificate; Japan



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AS demonstrated in this study, we found a significant linear increase in
trends for age standardized mortality rates from the disease, with +3-4% of
annual percentage change, between 1979 and 2004. In interpreting the
results, we should consider some factors that might contribute to a false
increase in mortality, such as the change of ICD codes and the enhancement
of case findings (e.g., physicians9 recognition of the disease, diagnostic
tests, and quality of health care). No revolutionary new diagnostic test for
CJD became available throughout the observational period. On the other hand,
there were a few critical points of time to consider: in 1991, patients with
CJD transmitted by cadaveric dura transplants were identified in Japan9, in
1995, the ICD code for CJD was changed from 9th to 10th version in Japan;
and in 1996, a new case of vCJD causally linked to BSE was reported from the
United Kingdom.6 Without an abrupt rise of age-standardized mortality rates
from CJD after these years for both sexes, however, it is unlikely that
these events artificially affected the increase in CJD mortality.

Rather, it may be the true fact that in Japan our results reflect to a large
extent a genuine increase in CJD. The number of iCJD cases may still
increase even after the total ban on the practice of causal grafts.5,8
Regarding sporadic CJD (sCJD), a recent report from the European Unions
collective study on CJD suggests that the mortality rates from sCJD
increased with time between 1993 and 2002.20 It is quite probable that this
temporal increase of sCJD may also exist in Japan. The increase may have
been accompanied to some extent by the improvement of physicians diagnostic
skills for CJD since 1997 when a manual for clinical practice on CJD was
introduced in our country.20,21


http://www.jstage.jst.go.jp/article/...7_133/_article

http://www.jstage.jst.go.jp/article/jea/17/4/133/_pdf


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