Professional Documents
Culture Documents
Aadya Sharma
Independent Research
05/10/2017
Advisor: Me Kim
Aadya Sharma
May 2017
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Advisor: Me Kim
The general area of research for this project is why curcumin has not been implemented
as a cognition-improving drug in humans, how the BBB impedes drug delivery to the brain, and
how Focused Ultrasound Therapy (FUS) can disrupt this barrier to allow otherwise barricaded
molecules to pass into the brain. A number of authentic studies about the applications of FUS, the
resulting disruption of the BBB, and the ability of curcumin to improve cognition will be
analyzed, cross-referenced, and evaluated to determine whether FUS can effectively improve the
preventative for the progression of the disease. A short film will then be produced by the
researcher to showcase and propagate the findings to scientists and those who are affected
Introduction:
After the age of 85, half of the population will suffer from Alzheimers Disease (AD).
This trend, however, can be changed. Derivatives of the anti-inflammatory drug curcmin have
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been shown to reverse some of the symptoms of Alzheimers in mice models of the disease
(Prior Marguerite, et al. 2013)[14]. In fact, Alzheimers has lower prevalence and incidence in
regions where turmeric, the source of curcumin, is used as a staple herb (Prasad Sahdeo and
Bharat B. Aggarwal 1970; Prince, Martin, et al. 2015, 10)[17],[15]. The drug, however, has not been
implemented successfully in humans primarily because of it inability to traverse the Blood Brain
Barrier (BBB) that encases and protects blood vessels in the brain. To combat this issue, Focused
Ultrasound Therapy (FUS) can be used to facilitate the delivery of curcumin to the brain. Due to
its ability to temporarily disrupt the Blood Brain Barrier, the application of FUS is crucial for
Alzheimers. The purpose of this essay is to explain the role of inflammation in Alzheimers,
played by the BBB, and justify the use of FUS. Additionally, it will provide suggestions for other
techniques that can be coupled with FUS to further improve the bioavailability of curcumin.
Review of Literature:
impairment, dementia, and paralysis. It was first scientifically discovered in 1906 by Doctor
Alois Alzheimer when he observed unusual markings in the brain of his senile patient, Auguste
Deter (Alzheimers Association)[3]. Over the course of a century, scientists have researched this
mysterious disease and have proposed several theories as to what its cause might be. The most
recent one attempts to explicate the relationship between beta-amyloid plaques and the
plaques, called protein aggregates cluster throughout the brain and lead to neuronal death. This
initiates a cascade effect that leads to cognitive impairment, significant memory loss, dementia
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and immobility (Stevens 2016)[19]. Additionally, neurofibrillary tangles, such as tau protein
tangles, within neurons impair nutrient flow, thereby contributing to neuronal death (Stevens
2016)[19]. The beta amyloid hypothesis has led several pharmaceutical companies, including
Biogen and Eli Lilly, to formulate and experiment drugs targeting beta amyloid in the brain, but
the unfortunate lack of success of these drug trials, a 99.6% failure rate, has led scientists to
reexamine the beta amyloid hypothesis and target other possible contributors to the disease, such
Inflammation is the natural response of living tissues to injuries, in which parts of the
body become reddened, swollen, hot and painful. In essence, it is the bodys attempt at self-
protection by removing harmful stimuli. Inflammation has been suspected to be both a symptom
biochemical, and molecular studies, it has been shown that there are many inflammatory
mediators in the Alzheimers brain (Akiyama, Haruhiko, et al)[1], such as microglia. Microglia
are cells in the Central Nervous System (CNS) that function as macrophages, consuming foreign
substances in the CNS. Their activation appears to be the most prominent inflammatory
component in chronic inflammatory diseases (Streit, Wolfgang J., et al. 2004)[20]. Alzheimers is
believed to be one such inflammatory disease in which beta amyloid plaques in the brain are the
center of microglia activation and clustering (Streit, Wolfgang J., et al. 2004)[20]. The chronic
impairment. In fact, a Harvard University research groups study stated that the elimination of
amyloid plaques might not be the optimal method to treat Alzheimers, and instead, treating
inflammation may be crucial in preventing or reducing the progression of the disease (Weintraub
2016)[23]. Another study led by Johns Hopkins University Professor Michela Gallagher found that
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reducing neural hyperactivity in patients with amnestic Mild Cognitive Impairment (aMCI) using
the epilepsy drug levetiracetam improved the patient's cognitive function (Gallagher 2011)[6].
discouraging patients from receiving any treatment. Curcumin appears to be the potent and
Studies, reviews and historical usage of turmeric attest to its remarkable abilities as an
anti-inflammatory drug, the reason being that the herb contains chemicals called curcuminoids,
the active ingredients in turmeric. The most important of these curcuminoids is curcumin itself.
Curcumin is a drug with high levels of antioxidant and anti-inflammatory properties, including
blocking inflammatory molecules and boosting levels of BDNF (Brain Derived Neurotrophic
Factor Proteins) in the brain. These proteins are the caretakers of neurons, they protect them from
harmful chemicals, promote their growth, connection, and the formation of memories (Prior,
Marguerite, et al. 2013)[16]. According to Ghalandar Laki, Negar, et al. (2014), curcumin also has
antitumoral, and antiangiogenesis effects, which simply means that it has tumor inhibiting and
cancer fighting properties. Rightfully, this suggests that it can be a potential preventative for
other diseases, such as cancer, cardiovascular diseases, and macular degeneration (Ghalandar
Laki, Negar, et al. 2014)[7]. An example of its anti-inflammatory effects were shown by a study
conducted by Lim Giselle P., et al. 2001, in which certain doses of curcumin lowered oxidized
proteins and the inflammatory cytokine, interleukin-1, in the brain of APPSw transgenic, or
genetically modified mice (Lim Giselle P., et al. 2001)[13]. In addition to its physical healing
effects, curcumin has been purported to improve cognition. To test this, scientists from Salk
University created the curcumin derived drug, J147, which they orally administered to mice
models of Alzheimers (Prior, Marguerite, et. al 2013)[16]. They found that, when administered in
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food at a stage when pathology is advanced in 20-month-old transgenic AD mice, rescued the
severe loss of cognitive function, reduced soluble levels of A and increased neurotrophic factors
essential for memory, (Prior Marguerite, et al. 2013)[16]. Specifically, after administrations,
genetically modified mice used to model Alzheimers Disease were able to complete a memory
task almost as well as the healthy mice (Prior Marguerite, et al. 2013)[16]. The scientists attribute
the brain boosting effects to the promotion of the formation of brain-derived neurotrophic factor
by J147, a protein that protects neurons from harmful chemicals, promotes neuronal growth,
J147s creation was sparked by the need to enhance curcumins neurotrophic effects and
to improve its bioavailability. Purified curcumin has a low bioavailability in part due to its low
water solubility, its rapid metabolism in the body, and the protective layer of cells in the brain
that form whats called the blood brain barrier. Comprised of tight junctions between the
endothelial cells lining blood vessels in the brain, the Blood Brain Barrier can be imagined as the
Great Wall of China of the Brain. Its high efficiency causes it to [prevent] 99% of molecules,
from passing through. (Downs ME, Buch A, et al. 2015)[5]. Purified curcumin, although being
only is 368 Daltons (g/mol), has other molecular properties which cause it to be blocked by the
BBB. Although the BBB protects and surrounds blood vessels, its dysfunction is suggested to be
a symptom of AD. As stated in Banks et al. (2015), A accumulation in the CNS can be both a
cause and consequence of BBB dysfunction in AD, (Banks et al. 2015)[4]. However, the limited
amount of clear cut evidence substantiating the role of BBB disruption in the pathological
progression of AD suggests that other critical functions of the BBB, such as altered transport
and communication within the neurovascular unit, may become impaired in Alzheimers
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Giselle P., et al. (2001) concluded that large amounts of curcumin are expelled by system. It cited
a study that determined that 60-70% of orally administered curcumin was expelled in the feces of
rats, (cited in Lim Giselle P., et al. 2001)[13]. Curcumins bioavailability is further decreased by its
rapid metabolism in the body, its low absorption, and subsequently, its low blood serum
Ultrasound Therapy can be implemented to combat this issue and permeate the BBB.
FUS is a technique that uses ultrasound waves to carry energy and disrupt tissue. Using
frequencies between 200-600 kiloHertz, this completely non-invasive technology has great
potential for tumor ablation as well as hemostasis, thrombolysis and targeted drug/gene
delivery, (Kim, Young-sun et al. 2008)[11]. FUS with Microbubbles (MB) has been shown in
many cases to effectively permeate the BBB and facilitate the delivery of several drugs.
Microbubbles are cells containing a gas that injected into the bloodstream . In a pilot study of
BBB opening for cancer-drug delivery to brain tumors by MRI guided FUS, spots that were
treated with FUS and microbubbles were shown by MRI to have clear BBB disruption (Lipsman
2016)[12]. Furthermore, it has been established that FUS and MB can temporarily disrupt the BBB
in targeted regions, allowing therapeutic agents as large as 100 nm in size to the CNS, (Timbie,
Kelsie F., et al. 2015)[21], indicating that the treatment can be implemented to facilitate the
In addition to being a facilitator, FUS can directly target beta-amyloid in the brain. In
studies conducted by Jordo, Jessica F., et. al. (2013) and Leinenga, G., & Gotz, J. (2015), the
application of FUS & MB and Scanning Ultrasound (SUS) & MB, respectively, was found to
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(Jordo, Jessica F., et. al. 2013; Leinenga, G., & Gotz, J. 2015)[10],[12]. Regarding Scanning
throughout the entire brain. Microglia and astrocytes in FUS-treated regions were also activated
and internalized beta-amyloid, although the actual number of cells did not increase, (Jordo,
Jessica F., et. al. 2013; Leinenga, G., & Gotz, J. 2015)[10],[12]. Thus, FUS/SUS & MB itself can
reduce the levels of harmful protein aggregates hypothesized to be initiators of the disease.
Queensland University Alzheimers specialist Juergen Gotz reported that there was no indication
study (J. Gotz, Personal Communication, March 23, 2017). In regards to the study, the subjects
An attest to the safety of FUS are the studies conducted by Downs ME, Buch A, et al.
(2015) and Lipsman (2016). In the former, FUS was coupled with microbubbles to disrupt the
BBB in specific regions of the brains of macaques over a 4-20 month period. A pulse length of
10 milliseconds and a total sonication duration of 2 minutes per location resulted in BBB
opening, and BBB closure was observed within a week. A number of tests and MRI scans were
performed and were used determine any effects on cognitive function or any hemorrhage or
edema. Overall, FUS and MB procedure, within given parameters, were shown to be a safe
method to temporarily open the BBB with no long term effects (Downs ME, Buch A, et al. 2015)
[5]
. In the clinical trial by Lipsman (2016), the method utilized to deliver chemo-drugs to brain
tumors by MRIgFUS in humans was with Definity MB ultrasound contrast, a total sonication
time of 50 seconds, with iterations of 2.6 milliseconds on and 30.4 milliseconds off, (Lipsman
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From the letter A to Z, there are a few other techniques that can be used in alongside FUS
nanotechnology. By encasing curcumin in lipid cells similar to microbubbles, the drug can
effectively traverse the BBB due to the properties of the nanoparticles that enhance the cellular
permeability processes of curcumin, (Ghalandar Laki, Negar, et al. 2014)[7]. Nanoparticles such
silvers, and solid lipids have [also] been shown to deliver therapeutic concentrations of
curcumin, and prove to be extremely useful because they elongate the circulation of curcumin
and provide stronger resistance to metabolic processes, (Ghalandar Laki, Negar, et al. 2014)[7].
Implementing FUS alongside curcumin storing nanoparticles will be much more efficient in
transporting curcumin to the brain than simply implementing FUS with orally administered
curcumin. Nanoparticles will allow for a lower FUS sonication time, thus reducing the temporary
Piperine, another plant based product, can also improve the bioavailability of curcumin. A
chemical found in black pepper, piperine has been shown to improve the bioavailability of
piperine 20 mg produced much higher concentrations [of curcumin] from 0.25 to 1 h post drug,
compared to human trials in which 2 grams of curcumin alone were administered and the serum
concentration was nearly undetectable (G. Shoba , et al.)[18]. Thus the pepper based alkaloid can
Since an actual experiment was not feasible nor reasonable, the researcher decided to
conduct a quantitative meta-analysis of five authentic studies. Of these five studies, three
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analyzed the effects of Ultrasounds on the brains of healthy and/or cognitively impaired animals,
and the remaining two pertained to the effects of curcumin or its derivative on the brain. Charts
were used to record the information in order to compare the findings from each study. The
studies analyzed and respective charts created are Downs ME, Buch A, et al. (2015), Appendix
A; Leinenga, G., & Gotz, J. (2015), Appendix B; Jordo, Jessica F., et. al. (2013), Appendix C;
Prior, Marguerite, et al. (2013), Appendix D; Lim Giselle P., et al. (2001), Appendix E.
Two other studies by Lipsman, Nir. (2016) and Hynynen, K., et. al. (2005) were also
reviewed, but seeing as the former has not been published, and only the abstract of the latter is
Nine researchers and Alzheimers professionals were contacted with requests for
interviews, but only two responded and only one with agreement for an interview. A Queensland
University Scientist, Professor Juergen Gotz, one of the primary authors of the study analyzed in
Appendix B, was contacted and interviewed over a Skype call on March 23 of this year. A list of
questions asked and paraphrased responses from the interview are found on Appendix H. Other
than clarifying a few misunderstandings about the subject, the interview did not provide the
Ultrasound frequencies and pulse repetition frequencies amongst different animal studies. Pulse
Repetition Frequency is the number of pulses of a single frequency that are emitted in one
second. It is dependent on the velocity of sound and on the depth of tissue being interrogated,
(V., Peter J. N.d.)[22]. At a glance, Figure 1 would suggest that smaller animals would require a
higher frequency (or conversely, larger animals would need lower frequencies to penetrate the
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skull), however, at a careful observation, the little correlation between animal size and frequency
in Figure 1 suggests that the frequency appears to be more of the choice of the experimenters
than requirements for skull penetration, although the FUS/SUS frequencies must be above 200
kHz to be considered Ultrasounds. The same initial hypothesis can be made in regards to Pulse
Repetition Frequency (PRF), but with the little correlation with increasing animal size and
decreasing frequency and the unavailable PRF for the human trials conducted by Lipsman, Nir.
(2016), there seems to be an ambiguous relationship between animal size and PRF as well.
Perhaps the high frequency and PRF used by Leinenga, G., & Gotz, J. (2015) in column 1 of
Only the study by Jordo, Jessica F., et. al. (2013) and Lipsman, Nir. (2016) used
Definity as their Microbubble contrast agent, and all of the Ultrasound studies used
microbubbles (Jordo, Jessica F., et. al. 2013; Lipsman, Nir. 2016)[10],[14]. Microbubbles vibrate at
the same frequency of the transducer and can aid in safer BBB disruption.
Although Downs ME, Buch A, et al. (2015) observed BBB closure within a week of
treatment, Professor Gotz stated in his interview that BBB closure should occur within 8-10
hours (Downs ME, Buch A, et al. 2015; J. Gotz, Personal Communication, March 23, 2017)[5].
The one week closing time was probably due to a later measuring date. The BBB closing times
were not available for the other studies, except in the unanalyzed study by Hynynen, K., et. al.
(2005), in which complete BBB closure was observed after 5 hours, with closure beginning
minutes after sonication (Hynynen, K., et. al. 2005)[9]. Therefore, it may be concluded that BBB
reparation begins after sonication and reaches completion within a few hours, and complete
closure time may depend on the method of Ultrasound treatment conducted and the times of
measurement.
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was only studied in Jordo, Jessica F., et. al. (2013) and Leinenga, G., & Gotz, J. (2015). Figure
internalization by the aforementioned cells after FUS treatment in each study. The beta-amyloid
internalization by microglia in Leinenga, G., & Gotz, J. (2015), which used SUS, increased by
200% after treatment, compared to only 159% in Jordo, Jessica F., et. al. (2013) (Jordo, Jessica
F., et. al. 2013; Leinenga, G., & Gotz, J. 2015)[12],[10]. Astrocyte beta-amyloid internalization was
only measured in the latter and increased by 270% (Jordo, Jessica F., et. al. 2013)[12]. However,
the studies did not specify whether the plaques internalized were soluble or insoluble. Soluble
beta-amyloid is harmful compared to insoluble versions of the same protein. Major treatment-
induced inflammation was not observed in either study. Thus, it can be concluded that FUS and
SUS could inhibit the pathological progression of the cellular aspects of Alzheimers by causing
microglia and astrocytes to internalize beta-amyloid to prevent further accumulation and further
cell death.
The curcumin and derivatives (J147s) studies were conducted by Lim Giselle P., et al.
(2001) and Prior, Marguerite, et al. (2013), respectively. The memory recall of the mice in Prior,
Marguerite, et al. (2013) improved with the administration of J147, as shown in the first column
of Figure 4, Appendix G, in which transgenic mice given J147 were able to locate a target in a
maze 50 seconds before the control mice (Prior, Marguerite, et al. 2013)[16]. Figure 4 also shows
the increase in freezing times for transgenic mice given J147 in the fear conditioning test,
indicating improved performance of the hippocampus and amygdala which are required for
memory formation, memory retrieval, and recall of association to cues (Prior, Marguerite, et al.
2013)[16]. This improvement was hypothesized by the scientists to be a result of increased Brain
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Derived Neurotrophic Factor protein levels by J147 (Prior, Marguerite, et al. 2013)[16]. The SUS
study conducted by Leinenga, G., & Gotz, J. (2015) saw a minor improvement in mice memory
when the same type of memory recall was tested as in the fear conditioning test (Leinenga, G., &
Gotz, J. 2015; Appendix B)[10]. Mice were taught to avoid a shock zone in a rotating arena, and
the average number of shocks received by mice who had received SUS treatment (and had had
subsequent beta-amyloid reduction) was lower than the sham-treated mice (Leinenga, G., &
Gotz, J. 2015; Appendix B)[10]. Because microglia activation and almost complete beta-amyloid
internalization and minor memory improvement was observed in Leinenga, G., & Gotz, J.
(2015), it indicates that memory could also have been improved by J147 induced beta-amyloid
reduction in the study conducted by Prior, Marguerite, et al. (2013), although there is no mention
of microglia activation in the study (Leinenga, G., & Gotz, J. 2015; Prior, Marguerite, et al.
2013)[10],[16].
Levels of beta-amyloid were reduced in Lim Giselle P., et al. (2001), Figure 5, Appendix
G, by curcumin, and levels of inflammatory and oxidized protein levels were reduced by 61%
(Lim Giselle P., et al. 2001)[13]. In comparison, in Prior, Marguerite, et al. (2013), a 58% decrease
in levels of soluble beta-amyloid and 75% decrease in insoluble beta amyloid in the
hippocampus of untreated transgenic mice compared to transgenic mice given J147 was
observed, as shown in Figure 3, Appendix F (Prior, Marguerite, et al. 2013)[16]. The percentage of
reduction of beta amyloid was not indicated in the first study, neither was the effect on cognition.
Professor Gotz noted that there is no difference between the BBB of mice and that of
humans (J. Gotz, Personal Communication, March 23, 2017). Although it appears that curcumin
might not be able to pass through the BBB of humans, the above note and the positive effects of
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unaided curcumin administration in mice in the study by Lim Giselle P., et al. (2001) indicate
that curcumin does not seem to be as hindered by the BBB as the researcher previously thought.
However, more evidence is necessary to completely refute the researchers original hypothesis.
FUS/SUS should not be entirely disregarded, for it has been shown to have positive
effects on the brain, with the activation of microglia and subsequent internalization of beta-
administered with FUS/SUS could also have cognition-improving effects. There might be a
the SUS and J147 study, but other factors, such as increase in levels of BDNF and other
neurotrophic effects of curcumin in the latter study could have come into play with cognition
improvement (Prior, Marguerite, et al. 2013)[16]. Overall, FUS/SUS alongside pure or modified
early stage.
Every three seconds, a new case of dementia arises from the depths of the Earth, and its
prevalence is on the rise, with its effects on society set to increase exponentially with the ageing
of people worldwide suffering from dementia is expected to rise from 30 million today, to over
100 million in 2050 (Alzheimers Association)[3]. Alzheimers is the one of the most detrimental
forms of dementia, in which beta-amyloid aggregates and tau protein tangles formed in the brain
are believed to initiate a cascade effect which ultimately leads to paralysis and death. The people
who are affected by Alzheimers branch far off from merely patients; they are intertwined by
neuron-like connections, from caregivers to loved ones, coworkers, friends, and even the
country, which has to pay the expenses for the plights of the disease. The unease arises from the
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knowledge that these victims die alone in their world, with few memories of their loved ones and
essential in reducing the pathological progression of the disease. The most potent, natural, anti-
inflammatory agent is curcumin, but its anti-inflammatory properties are futile against the
blockade created by the Blood Brain Barrier. Through the use of FUS, along with microbubbles,
nanoparticles, and even piperine, the bioavailability of curcumin as a cognition improving drug
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References
[1]
Akiyama, Haruhiko , Steven Barger, et al. "Inflammation and Alzheimer's
Biological Studies." Salk Institute for Biological Studies. N.p., 30 Dec. 2011. Web.
[3]
"Alzheimer's & Dementia Causes, Risk Factors | Research Center| Alzheimer's Association."
[6]
Gallagher, Michela. Improving Memory and Brain Function on the Path to Alzheimer's
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[10]
Jordo, Jessica F., et. al. "Amyloid- Plaque Reduction, Endogenous Antibody Delivery and
doi:10.1126/scitranslmed.aaa25127.
[13]
Lim Giselle P., et al. The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid
83708377. Web.
[14]
Lipsman, Nir. "Lipsman - Pilot study of BBB opening for chemo-drug delivery to brain
aged Alzheimer's disease mice." Alzheimer's Research & Therapy. N.p., 14 May 2013.
Web.
[17]
Sahdeo Prasad and Bharat B. Aggarwal. "Turmeric, the Golden Spice." Herbal Medicine:
Biomolecular and Clinical Aspects. 2nd edition. U.S. National Library of Medicine, 01
human volunteers." Planta medica. U.S. National Library of Medicine, n.d. Web.
[19]
Stevens, Michael. Alzheimers and the Brain Online video. Youtube. Youtube, July 22,
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2016. Web
[20]
Streit, Wolfgang J., et al. "Microglia and neuroinflammation: a pathological perspective."
- Basic physics of ultrasound and the Doppler phenomenon | ICU Sonography. N.p., n.d.
[23]
Weintraub, Karen. "Harvard Researchers Unveil New Alzheimer's Theory." USA Today.
Appendix A
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Downs ME, Buch A, et al. (2015) Long-Term Safety of Repeated Blood-Brain Barrier Opening
via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive
Task. PLOS ONE 10(6): e0130860. doi: 10.1371/journal.pone.0130860
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Appendix B
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-2 cohorts of -After int. APA -Too many things -What was the
male APP23 mice test, mice were were tested in cost of SUS?
(median age, grouped based this study (all not -Equipment?
12.8 months) on performance included) -Procedure?
tested -Received weekly therefore -What does it
-Received SUS or SUS or sham for something is mean if the
sham for 6 weeks 7 weeks bound to be healthy sham
-Beta amyloid -APA retest- SUS positive mice spent
pathology treated mice -Microglia longer with the
measured in were found to number familiar object
brain receive lower avg remained the than the SUS
-2nd cohort of shocks (learned same treated
gender-balanced to avoid zones) -in SUS mice transgenic mice?
APP23 tested than non-SUS models, they -Was it a fluke, or
with healthy mice models, but were activated could the
mice more than sham and contained 2x memory of the
-65 weeks treated healthy more beta- SUS transgenic
median age mice amyloid in mice have
-Memory tested -Novel Object lysosomal improved?
using test conducted to compartments -Why werent
active place test time spent than sham mice other memory
avoidance (APA) with new object models tests
-mice learn to vs. familiar -In cortical areas administered-
avoid shock zone - SUS spent 20 of SUS-treated they could have
in rotating arena, sec with novel mice, Ab tested for
then are tested. and 11 sec was almost different aspects
-Lipid-shelled familiar. completely of memory (as in
microbubbles -Sham spent 18 consumed by Prior Marguerite
with an sec with novel microglial and et al.)?
octafluoropropan and 23 sec with trapped in -Is there any
e core were also familiar lysosomes: seen difference in the
used and mixed -Healthy mice in 75% of the permeability of
in a in a 0.9% with sham spent SUS-treated the BBB of mice
solution of NaCl 19 sec with novel mice; 0% sham and the BBB of
-Concentration of and 15 sec with -Ab-degrading humans?
MB was 1 107 familiar. enzyme IDE -Can the same
to 5 107 -Silver stain (insulin- SUS frequency be
microbubbles/ml showed that SUS degrading translated to
with had 30 beta- enzyme) humans?
size of 1 to 10 amyloid plaques slightly increased - Sonograms
mm and a mean per section vs. by SUS, but no operate at the
diameter of 4 60 plaques in significant same range of
mm. sham mice inflammation frequency as
-Mice models observed SUS, if the
anesthetized with - SUS: 1MHz, -SUS equipment: equipment were
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- No difference of
NF-kB in SUS and
sham transgenic
mice
-SUS showed no
DAMAGING
inflammation
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Leinenga, G., & Gotz, J. (2015). Scanning ultrasound removes amyloid- and restores memory in
an Alzheimer's disease mouse model. Science Translational Medicine, 7(278).
doi:10.1126/scitranslmed.aaa25127.
Appendix C
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Jordo, Jessica F., et. al. "Amyloid- Plaque Reduction, Endogenous Antibody Delivery and
Glial Activation by Brain-targeted, Transcranial Focused Ultrasound." Experimental Neurology.
U.S. National Library of Medicine, 2013.
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Appendix D
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-Male & Female Water Maze: Improper APP Would J147 work
Transgenic AD- 100sec cleavage is in humans?
APPswe/Pi^E9 escape time caused by beta How would a
mice; 20 months AD + J147- ~50 secretase, whose
J147+don. Work
old sec level was
-Test group fed Scopolamine + reduced by J147, in transgenic
high fat diet and Healthy mice- thus increasing mice?
10mg/kg/day J147+don. And levels of whole What is the cost
J147 for 3 J147 halved the APP. efficiency of
months. time APP may have a synthesizing
Cognition tests: Elevated Plus role in synaptic J147?
-Water maze Maze: structure and
of donepezil?
used: trained AD- ~15 sec time function as well.
mice to find a in open arms In the Are there any
platform within AD + J147- ~1 scopolamine side effects of
180sec, some sec trials, the J147 + either drug?
could not do (implies a better donepezil combo. Can
within time limit, anxiety improved times J147+donepezil
then J147 response) the most for all permeate the
administered Fear Conditioning tests.
BBB?
mice took the Day 1: BDNF & NGF
test -Elevated AD- ~10 sec time stimulate growth Answers:
plus maze used: frozen and maintenance J147 is $89 for
maze with 2 AD + J147: ~20 of neurons, 2mg (solid) and
open & 2 closed sec survival of is 350 Daltons
arms used to Scopolamine + mature neurons, Donepezil:
measure mices Healthy mice- and play a role in
100%
response to J147 + donepezil synaptic
anxiety. Mice had the longest plasticity, bioavailable,
were habituated time frozen after cognition, and category c
to the room control group memory pregnancy risk,
25hrs b/f & Fear Cond. Day formation. Levels 379.5g/mol, $70
habituated to the 3: of these increase for 10mg, $110
maze 2min b/f AD- ~2 sec time in response to for 100mg
the test. frozen neuronal injury.
-Fear AD + J147- ~3.5 -Fear
conditioning: Day sec conditioning:
1- mice explored Scopolamine + measures ability
a chamber for 2 Healthy mice- of hippocampus
min and J147 alone, & amygdala to
conditioned to donepezil alone form and receive
fear tone with a and J147 + don. new memories:
30sec tone Increased
followed by 2sec freezing time,
foot shock. but combo did
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Prior, Marguerite, et al. "The neurotrophic compound J147 reverses cognitive impairment in
aged Alzheimer's disease mice." Alzheimer's Research & Therapy. N.p., 14 May 2013.
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Appendix E
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Lim Giselle P., et al. The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid
Pathology in an Alzheimer Transgenic Mouse The Journal of Neuroscience 21(2001): 8370
8377.
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Figure 1
Frequency and PRF Comparisons
Appendix F
Figure 2
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Figure 3
From Prior Marguerite, et al. 2013
Appendix G
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Figure 4
From Prior Marguerite, et al. 2013
Figure 5
From Lim Giselle P., et al. (2001)
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Appendix H
1. Is there any difference in the permeability of the BBB of mice and the BBB of
humans?
a. No, but sheep do have a different BBB than humans.
2. What was the cost of the scanning ultrasound used in your study?
a. About $80,000.
3. What is the average cost of FUS?
a. About $150k-200k including equipment.
4. Can the same SUS frequency be translated to humans?
a. A 1Mz frequency was used in the study. Humans have a thicker
skull, therefore a lower frequency would be required to penetrate it.
5. Sonograms operate at the same range of frequency as SUS, if the equipment
were to be modified, would it be possible to use sonograms in the place of SUS?
If yes, what are possible modifications?
If no, please elaborate
a. Sonogram frequencies are higher than those of FUS/SUS. If the
steering mechanism was modified and a lower frequency was used, it could be
used as an alternative for FUS/SUS, but again, he is not an ultrasound expert,
but an Alzheimers expert.
6. How long did the BBB remain open?
a. About 8-10 hours.
7. At what stage in the disease would SUS be most effective?
a. Vague answer: Most likely in the early stages.
8. Would it be used as a preventative or a treatment?
a. Most likely as a treatment.
9. Could SUS be used repeatedly in humans without extensive brain damage?
a. Yes, it is safe when conducted in the right parameters.
May 2017