Evidence for

Human
Transmission of
Amyloid-
Pathology and
Cerebral Amyloid
Angiopathy
 Why this paper?
1. CJD sounded interesting!
(probably not the greatest
selection method)
2. It is a good example of the need to
thoroughly read through articles as
they may be misinterpreted

What is the correct method of

selecting an article for a journal
club?
 This article received lots of media
attention, the authors held multiple
press conferences and addressed several
news agencies, and was discussed in
journal clubs throughout the world, in
universities such as Harvard and
Stanford. It got everyone to ask the
question:
Can Alzhemiers disease be
transmitted through certain
medical and surgical
procedures?
 Is this a valid question?
Does the study provide enough
data to force us to consider this
question in the first place?

This is what you should ask

yourself throughout this
presentation, and this is
what we will answer at the
end!
Lets start breaking down this
study by talking about

Prions!
Prions are only composed of protein and do
not have their own genetic material.
They are formed of long chains of
misshapen proteins that can grow in the
brain and then replicate, forming more
prions.
This leads to progressive brain damage and
is fatal.
erson-Person Transmission of Prions
Medical and surgical procedures: prion-
contaminated surgical instruments or by blood
transfusion
RARE
Treatment of children of short stature with
injections of GH extracted from glands removed
from cadavers
 Among the diseases involving human-
human prion transmission is Iatrogenic
CJD

There are 450 cases of iCJD WORLDWIDE as of 2012, the

transmission methods include those mentioned in the
 Receiving GH extracted from cadaver-
sourced pituitary glands for treatment of
short stature
This treatment began in 1958 and was banned in
1985, it was used worldwide

Incidence rates of CJD, were assessed in a cohort of 1,848

patients treated with hGH in the United Kingdom from
1959 through 1985
and followed to the end of 2000.

By 2000, 38 developed iCJD with a peak incubation period

of 20 years.
By 2012, recipients who developed iCJD in France 119 out of 1880
(6.3%), in the UK it was 65 out of 1800 (3.6%) and in the USA it was
29 out of 7700 (0.4%)
It was noticed that all those who developed the disease
had one common preparation of the hormone:

the WILHELMI extraction method

It was therefore suspected that the size-exclusion

chromatography used in non-wilhelmi preparations may
have reduced prion contamination

The estimated lifetime cumulative risk of CJD in Wilhelmi-

treated patients was 4.5%.
 This has led several countries to develop
cohorts in order to follow these patients and
understand the burden of prion disease in their
lives over time
The National Prion
Monitoring Cohort Study -
UK
Since 2008, most UK patients with prion disease have
been recruited into this study
Funded by The University College London
Hospitals
By mid-2015, there were around 800 participants, a
remarkable achievement for a rare disease!
 Now, enough background
information, lets begin
discussing the core of the
study!
What does CJD and
Prions have to do with
Alzheimers and
Cerebral Amyloid
Angiopathy?!
 Both Alzheimers and CAA involve Amyloid-
deposition and aggregation in the grey matter
and the vascular structure of the CNS

Both A deposits and prion protein deposits occur

by a polymerization process in which certain
misfolded oligomers "seeds" can induce other A
molecules to also take the misfolded oligomeric
form, leading to a similar chain reaction
 This raises the question Are similar
prion-like mechanisms involved in other
degenerative brain diseases? Such as
Alzheimers and CAA?

Can they have similar modes of

transmission?
Recently, Jaunmuktane and colleagues
(2015) performed an autopsy study
providing evidence of a possible prion-like
transmission of the amyloid- protein in
prion disease patients
 8 patients aged 36-51 were the focus of
this study

All of whom died at a young age due to

iCJD

They underwent autopsy with extensive

brain tissue sampling at the University
College
IP: 27.9-38.9 years London
from firstHospital
treatment to onset
18.8-30.8 years from their last treatment to onset
 Selection Method:

All patients with possible CJD who had

received cadaver-derived GH were referred
to the NPC and
since 2008 were recruited into the National
Prion Monitoring Cohort study. The patients
were selected out of a group of 24 patients
with iCJD related to c-hGH treatment over
this period, all of whom necessarily have
long incubation periods

Ethical approval for these studies was

 1 2 3 4 5 6 7 8
Abnormal prion X X X X X X X X
protein labeling
and
microplaques
Adeposition in X X X X
CNS
parenchyma
Focal A X X
pathology
A entrapment X
in PrP plaques
Entirely negative X
for A
Cortical and X X X
leptomeningeal
CAA
They found abnormal levels of A protein in 7 of
them.

In four, there was moderate-severe grey matter

and vascular A pathology, and the deposition at
each site was typical of that seen in Alzheimer's
disease and CAA respectively.

In the other three, the deposition was mainly

focal. And only one patient was entirely negative
Why were these for A

findings
significant?
 Such pathology is extremely rare in these
age groups, and has not been documented
in patients with no specific genetic
predisposition

This marked deposition of

parenchymal and vascular AB in these
relatively young patients with iCJD in
contrast with other prion diseases

Is consistent with iatrogenic

transmission of AB pathology in
addition to iCJD!
 1. Genetic
Predisposition?
First, the authors excluded any genetic
predisposition that these patients might have for
several neurodegenerative diseases
None of these patients presented causal mutations, but
three of them presented possible risk factor alleles for
frontotemporal dementia (patient 4) and frontotemporal
dementia (patients 6 and 8).

Although A deposits are not common in frontotemporal

dementia, these patients were the ones presenting
widespread cortical and leptomeningeal cerebral A
angiopathy.
Considering the large controversy
relating genetic risk factors other
than ApoE and actual AD
development, such minor mutations
seem negligible in the presented
scenario.
 2. Comparison
Next, they looked at the frequency of A deposits in
brain tissue from people who had died of other forms
of prion disease, in an attempt to connect the
iatrogenic transmission specifically to A burden.

The authors examined a series of 116 patients with

other prion diseases who had undergone autopsy,
recruited from The National Prion Monitoring
Cohort

They found no evidence of amyloid beta pathology in

the brains of patients of a similar age, with the
exception of two cases aged 57 and 58 positive for
APOE e4 alleles. This was done using 4 different
quantification methods
The authors interpreted this as an evidence
of human transmission.

However, the authors can't exclude the

possibility of a stimulation of endogenous A
production by the prion protein, since other
studies with larger cohorts found
considerable amyloidopathy in the brain of
sporadic CJD patients.

This argues against the idea of the A burden

being specific for iCJD.
 3. The authors considered
whether prion disease itself
might predispose to, or
accelerate, Ab pathology
for example by cross-seeding of protein aggregation
(amyloid deposits that might trigger deposition of
other amyloid proteins) or overload of clearance
mechanisms for misfolded proteins although such
How did they evaluate this?
observations are unprecedented
 prion protein as the
cause:

The study team

checked whether the
prion protein deposits
that are typically
associated with CJD
were in the same
place in the brain as
the amyloid beta
deposits.

This was clearly not

Method for detecting Ab:
the case, suggesting Anti-human Ab monoclonal antibody 82E1
that cross-seeding recognizes an epitope specific to the amino
terminus of Ab while 6E10 recognizes an epitope
hadnt occurred, spanning residues 38 of Ab and cross-reacts with
consistent with these full-length APP or APP fragments that contain the
epitope
pathologies
 However, the lack of co-localization is not
enough to completely exclude cross-seeding.

Testing whether or not prion pathology might

induce A aggregation in healthy animals
might be of interest
 4. Analysis of Pituitary
Do normal AD patientsGlands
have A deposits in their pituitary
glands?
They examined the pituitary glands of patients in search for the
presence of A deposits:
55 Pituitary glands were examined
6 from patients without A pathology
49 from patients with cerebral A pathology 7 of these
were found to have A

This confirmed frequent A in pituitaries of patients with Alzheimer's

disease-like pathology, and further supported the possibility of
contamination of c-GH batches with A as well as prion proteins and
that AB seeds have been iatrogenically transmitted to these patients
with iCJD
A biochemical analysis of residual batches
of c-GH for A as well as their use in animal
models of propagation could shed light into
 5. Supporting Evidence
Although an observational study such as this cannot prove that the
A deposits in the patients brains were caused by A seeds,
their hypothesis is supported by the fact that iatrogenic transmission
of A has been demonstrated more than once in mice by both
intracerebral and peripheral routes,
such studies established that aggregated A can
behave like prions.
Strikingly, when A seeds were introduced into the abdomens of
mice, rather than directly into the brain, A deposition was more
prominent in cerebral blood vessels than in A plaques. This finding
mirrors the vascular A accumulation observed by this study and
reinforces the supposition that the A seeds in the affected people
travelled to the brain from elsewhere in the body.
This experimental study and our findings suggest
that there are mechanisms to allow the transport
of A seeds as well as prions (and possibly other
proteopathic seeds such as tau) from the periphery
 6. Tau, the other
component involved in
AD
Although A is a hallmark of Alzheimer's disease, no
tau pathology was found in the brain of such
patients.

The authors suggested that, had the patients not

died of prion disease, the tau accumulation might
have developed over time.
It is indeed known that tau pathology
develops after the A deposits in AD, but
with the presented findings is still
uncertain if they would or not develop tau
pathology and AD
Outcomes and Further Research

A. The findings should prompt consideration

of whether other known iatrogenic routes of
prion transmission, including surgical
instruments and blood products, may also
be relevant to Ab and other proteopathic
seeds seen in neurodegenerative diseases.

Ab seeds are known, like prions, to adhere to

metal surfaces and to resist formaldehyde
inactivation and conventional hospital
sterilisation
Outcomes and Further Research
B. Continued surveillance of surviving c-hGH
recipients

will be essential to determine whether they are

at unusually high risk of developing Alzheimers
disease or CAA

The severe CAA seen in the patients with iCJD in

the study is unquestionably concerning and
individuals with such pathology would be at
increasing risk of cerebral haemorrhages had they
lived longer.

At-risk individuals, including patients who had

received dura mater grafts could be screened by
MRI for CAA-related pathologies and by PET for Ab
Outcomes and Further Research

C. The original c-hGH extracts, if available,

should be assessed for the presence of A
seeds using biochemical and animal-
transmission experiments

in order to strengthen the case for the prion-

like seeding of A in humans and better
assess its implications
 Conclusion
This transmission of A pathology occurred in the
uncommon context of long-term c-hGH therapy.

So far, there is no indication that Alzheimers disease can

be transmitted between people under ordinary
circumstances.

Furthermore, the replacement of c-hGH by genetically

engineered growth hormone has eliminated the risk that
growth-hormone treatment will inadvertently transmit
brain disorders between humans.

However, it is conceivable that the human transmission of

A seeds can occur under other conditions, which must
now be carefully defined
 Conclusion
Jaunmuktane and colleagues findings should
stimulate new research in this direction, and,
more generally, will inspire further investigation
into the mechanisms that govern the formation,
transmissibility and toxicity of misfolded protein
seeds in neurodegenerative diseases.
 Collectively, the literature still doesn't support prion-
. like transmission as a relevant form of developing AD

Since other larger studies found controversial results,

the next step to test Jaunmuktane et al. (2015)
hypothesis would be to obtain data from larger cohorts
. of CJD patients

Once confirmed, we can imagine two scenarios: a

scientific fun-fact with little epidemiological
significance for the general population

or a revolution in AD prevention, patient management

. and treatment development

.Let's wait for the next chapter

THANK YOU