5.0 Treatment of Alzheimer's Disease

Treatment of Alzheimer's Disease
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Courtesy of: www.cnn.com

Alzheimer's disease (AD) is often characterized as both a progressive and irreversible brain disease which has been linked to the eventual loss of all cognitive function [1]. Although AD has been widely studied throughout; at present, there are no methods in which to fully cure AD due to not knowing the underlying cause of the condition. Instead, current methods in treatment aim to alleviate some symptoms of Alzheimer’s disease relying on a variety of pharmaceutical and psychosocial treatments that can be administered to the patient. The 2 main groups of drugs in use are acetylcholinesterase inhibitors and NMDA receptor antagonist, which help to regulate the amount of acetylcholine and glutamine present- allowing for better cognitive functioning [2-3]. As well, it has been shown that psychosocial treatments prescribed in conjunction with pharmaceutical treatments have had great results for patients with AD [4]. Many on-going experiments have also shown great potential in offering a cure, such as Deep Brain Stimulation and Methylene Blue. As with the introduction and development of Magnetic Resonance Image-guided Focused Ultrasound Surgery technology, this has also opened up many new opportunities for the development and incorporation of other treatment methods, such as targeted drug and stem cell delivery to the specific regions of the brain affected by AD.

Current Treatment Methods

Current treatment methods for Alzheimer’s disease are split into 3 major categories of treatment of Pharmaceuticals, Psychosocial, and Caregiving. The main focus of the current treatment methods will be focused on the pharmaceuticals, as there is a lot published on their efficacy in AD patients. In contrast, psychosocial treatments are often done in conjunction with pharmaceutical treatments and there is not much information on its standalone efficacy available. For caregiving, much of this burden is placed upon the shoulders of those that interact with the AD patient, and can't not evaluated as a result. For the pharmaceuticals that are used today, it is important to note that although these treatment methods do not affect the underlying causes of Alzheimer’s disease, and that they aim to alleviate much of the cognitive hindrance.

Cholinesterase Inhibitors

Figure 1: Cholinesterase Inhibitors
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Displayed above are the chemical structures of the 4 most
widely used Cholinesterase Inhibitors used today
Courtesy of: www.ekohou.net

Acetylcholine plays an important role in the body, for both the peripheral (PNS) and the central nervous system (CNS)[5]. In the CNS, acetylcholine and neurons form the cholinergic system which is crucial for anti-excitatory actions. However, as a symptom of AD, the cholinergic system is affected due to the death of cholinergic neurons, resulting in memory deficits[6]. The most common treatment to compensate for this, is through the use of cholinesterase inhibitors, which reduce the breakdown of acetylcholine- resulting in a higher concentration of acetylcholine in the system[2]. The three main cholinesterase inhibitors that are prescribed today are Rivastigmine, Galantamine, and Donepezil. Where Rivastigmine and Galantamine are commonly prescribed to treat for mild to moderate AD, and Donepezil is approved for all stages including advanced AD [7]. Similar to most medications, this treatment has its side effects, which include the many side effects resulting from the high amount of acetylcholine present, such as nausea, vomiting, muscle cramps, and etc [8]. As well, it has been shown that cholinesterase inhibitors does not prevent the onset of AD from the mild cognitive impairment stage – so it would only be effective before the development of advanced AD [9].

NMDA Receptor Antagonists

Figure 2: NMDA Receptor Antagonists
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Displayed above is the chemical structure of Memantine
Courtesy of: www.theodora.com

Glutamate is also an important and prominent neurotransmitter involved in learning and memory [10]. Another common symptom that is present in AD, is the overstimulation of glutamate receptors in the brain leading to excitotoxicity [11]. This is often caused by an excessive amount of glutamate in the brain, which can later lead to neuronal cell death as a result [11]. To reduce stimulation, NMDA receptor antagonists such as Memantine can be used, which compete with glutamate by blocking NMDA receptors and inhibiting glutamate binding- preventing overstimulation as a result [12]. It has been shown to be moderately effective in treating patients with MCI and advanced AD, but similar to the cholinesterase inhibitors, there are also many side effects to regular body function as neurotransmitter levels are greatly altered [13].

Recents studies by Tan et al have shown that cholinesterase inhibitors and NMDA receptors antagonists do have significant impacts on cognition. When 20 mg Memantine was applied, it was found that the patients had an average of -1.29 points in difference on the Clinician’s Global Impression of Change scale, and similarly, when 32mg Galantamine was applied daily, it resulted in an average of -3.20 points in difference[14] . And that overall, they were able demonstrate that cholinesterase inhibitors and Memantine were able to slow the decline in cognition for AD patients [14].

Deep Brain Stimulation (DBS)

The Brain Campaign: DBS

Recently, improvements in technology have allowed for the integration of new technology in developing new methods of treatments for AD. One area that has shown to have promising results is through Deep Brain Stimulation (DBS). DBS has been shown to have the capability for treating for many types of neuropsychiatric disorders , and recent studies have shown that DBS to the medial temporal lobe (MTL) have had great results in treating for MTL-related disorders; such as Alzheimer’s disease [15].

How DBS works

Figure 3: Deep Brain Stimulation Implant
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Displayed above is where the electrodes and stimulator
are located on the patient
Courtesy of:www.minclinic.ru

Deep brain stimulation works by inserting the electrode through the surface of the brain and into the specific area of the brain that requires stimulation [16]. This can be done through the use of a stereotactic frame that is secured to the patients head so that the insertion is precise, and while the patient is awake- through local anesthetics. The specific regions of the brain can determine during the operation through listening to neuronal firing, firing patterns and through X-ray [16]. Next, battery implantation must be implemented, where the stimulator is specifically programed for each unique patient[16].

Deep Brain Stimulation on the Fornix

Figure 4: DBS on the Fornix
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Location of DBS electrode on a sagittal MRI scan [17]

A study was conducted by Laxton et al. that aimed to examine the effects of ongoing DBS treatment on 6 patients that had mild AD [17]. The patients had an electrode inserted bilaterally in the fornix with DBS stimulation affecting the surrounding regions. Here, they examined that the map of the brain areas whose functions were to be affected by the stimulation through standardized low-resolution electromagnetic tomography (sLORETA) [17]. As well, PET scans were used to see whether DBS had an effect in adjusting and correcting the changes in cerebral glucose metabolism caused AD. And finally, they measured the effects DBS had on cognitive function over the span of a year [17].

Figure 5: PET scan post-DBS
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The summed PET scan image of the 5 patients (patients 2-6) was created,
and compared to the summed PET scan of 6 age-matched healthy controls.
PCg= posterior cingulate gyrus, MTG= middle temporal gyrus,
ITG= inferior temporal gyrus; FG= fusiform gyrus [17]

It was found from the sLORETA that the fornix/hypothalamus stimulations had indeed produced specific activations of the brain[17]. Additionally, both the sLORETA and PET studies showed the DBS to be affecting regions of the brain closely related to the brain default network – which is known to be impaired in AD patients, and also hypothesized to play an important role in modulating memory functions [17]. From Figure 5, after 1 month, it is evident that DBS created widespread changes in metabolism in various cortical areas. Laxton et al. found that not only are areas affected by AD such as temporal, and parietal cortical areas were showing an increase in metabolism, but other regions such as the primary sensory and motor regions were showing an increase too [17]. These temporal regions include the left, middle, and inferior temporal gyri, while the parietal cortical regions include the fusiform gyri, superior parietal lobes and other regions.

Figure 6:Glucose metabolism post-DBS
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Where the metabolic values shown are scaled to mg/100 tissue/min,
with blue representing decreased glucose metabolism and
red representing increased glucose metabolism. [17]

In their paper, Laxton et al. also examined the regions that showed glucose metabolism after 1 year of constant DBS to see whether the changes after 1 month were sustained or if they were changed due to the progressive onset of AD (Figure 6) [17]. To this, it was found that the changes after 1 month were not only sustained, but that there was greater metabolism in 1 year when compared to after 1 month. The areas that had the biggest increases in metabolism was found to be those that were most affected by AD, which had large accumulation of amyloid deposits, and the lowest amounts of glucose utilization [17].

Similar studies in DBS

A different study done by Hardenacke et al looked at the effects of DBS on the Nucleus Basalis of Meynert (NBM) in the basal forebrain area (BFA) of AD patients [18]. The NBM plays an important role in the brain, in that close to 90% of NBM neurons are basal forebrain cholinergic neurons (BFCN) that release acetylcholine [19]. Thus, degeneration in the BFA would include loss of cells at the NBM, which may account for some of the drop in acetylcholine levels in AD patients [18]. To treat for this, Hardenacke et al proposed that stimulation of the NBM with DBS would stimulate the release of nerve growth factors which are important for cholinergic neuron survival. It was found that when a patient with advanced dementia was treated with DBS of NBM, the patient showed sustained improvements in both cognitive and memory functions [18].

Future direction

DBS to various regions of the brain related to AD has shown to have great results in terms of the recovery of cognitive and memory functions. However, currently, this new idea of having neuronal surgeries with electrodes implanted in the brain has deterred many AD patients from taking this approach, even though DBS surgeries have proven to be quite safe, and the benefits of DBS drastically outweigh the risks [20]. In the future, as the idea of DBS becomes more familiar and accepted to the general public, its use as a treatment method for AD will definitely increase.

Methylene Blue (MB)

Figure 7: Methylene Blue
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Displayed above is the chemical structure of Methylene Blue
Courtesy of: commons.wikimedia.org

Metyhlthioninium chloride (better known as Methylene Blue) is a tricyclic phenothiazine drug, and was the first completely synthetic drug used in medicine [21]. It has been around since 1891, when it was first developed for the treatment of malaria; since then, it has found new uses in applications against AD. Methylene Blue (MB) is good in that it has been shown to have to be able to pass through the blood brain barrier (BBB) and has shown capabilities in inhibiting Aβ42 oligomerization in in vitro biochemical studies [22]. This is important, because according to the amyloid hypothesis of AD, Aβ aggregation leading to amyloid plaques is one of the causes of AD [23]. Even though the initial success of Methylene Blue (MB) treatment reported in a phase II study conducted by Wischik et al. showing the ability of MB to slow down the development of AD by 81% seems suspicious, there is still merit in MB research with AD [24]. In recent findings, trials conducted in various animal models give great evidence of MB’s ability in preventing amyloid plaques– a cause of AD.

Methylene Blue on Aβ and Tau

Figure 8: Aβ levels after treatment with MB
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(A,B) MB significantly reduced the Aβ levels, measured by enzyme-linked
immunosorbent assay. (C-D) Microphotographs showing CA1 pyramidal neurons,
and stained by 6E10 antibody[25]

Figure 9: Tau levels after treatment with MB
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(A) Western blot of proteins taken from mice, HT7- Human tau specific antibody
AT270-antibody recognizing phosphorylated tau (B) MB had no significant effect on tau
accumulation nor phosphorylation, measured by enzyme-linked immunosorbent assay.
(C-D) Microphotographs showing CA1 pyramidal neurons, and stained by 6E10 antibody
showing no change in Tau localization[25]

Medina et al were able to examine the effects of MB on AD pathology through the use of a mouse model (3xTg-AD) that was capable of developing age-dependant accumulation of both Aβ and tau [25]. This study was invaluable in demonstrating the effect of MB in vivo, in live mammals. It was found that after 8 and 16 week treatments to the 6 month old 3xTg-AD mice with MD, the 3xTg-AD mice showed similar performance in the Morris Water Maze as the NonTg (normal mice) groups [25]. Overall, the data indicated that MB treatments were able to rescue the spatial memory in the 3xTg-AD mice. Medina’s group then examined the measured the quantitative levels of Aβ through sandwich ELISA, and found that soluble Aβ40 and Aβ42 levels were significantly reduced in the MB treated mice in comparison to the untreated 3xTg-AD mice (Figure 8)[25]. Nonetheless, it was surprising that although Aβ levels changed, MB seemed to have no effect on tau phosphorylation (Figure 9) [25]. This correlated to results from other studies, where abnormal tau was not affected by MB treatment in transgenic zebrafish [26]. Recently, the effect of MB on tau has been confirmed by Spires-Jones et al, where they found that MB had little effect on existing tau tangle pathology, but was able to reduce the soluble tau that was present by 35% [27]. This ability of MB in reducing soluble tau could have alternative benefits as soluble tau has shown to be more toxic than tangles, and reducing the amount of soluble tau would eventually reduce the amount of tangles over a period of time [27].

Other interactions concerning Alzheimer's Disease

In AD, Aβ has also been shown to bind to the mitochondrial enzyme Amyloid binding alcohol dehydrogenase (ABAD), in causing mitochondrial dysfunction [28]. Through MB application, it was noticed by Abdel-kader et al that in the LTP mouse model, there was a decrease in ABAD levels in conjunction with the Aβ levels [28]. This in turn allows the protection of the mitochondria from oxidative stress and drastically improves neuron viability.

Future implications

From these several studies of MB on AD mouse models, it is predicted that MB will have a greater effect on patients in the early stages of AD, as it will be able to greatly reduce the Aβ present, but in the later stages of AD, where there are also more tau tangles present, it will be less effective. In addition, more human trials are needed to see the full effects of MB, as most of the past studies have been done on mouse models.

Magnetic Resonance Image-guided Focused Ultrasound Surgery

Yoav Medan: Ultrasound Surgery- Healing Without Cuts
How MRIgFUS is being used for various brain-related treatments

In modern healthcare today, ultrasounds are often used for various types of screening – especially in terms of looking at the development of the baby in pregnancies. While in the past, magnetic resonance imaging has only been used as a diagnostic tool for Alzheimer's disease . Recently, it has been shown that focused ultrasounds that utilized frequencies suitable for transcranial sonifications on the head, allowed for opening of the blood brain barrier (BBB) through the use of intravenously injected micro bubbles that resonated as a result of stimulation [29]. This is extremely important as the BBB is one of the main barriers preventing certain drug delivery and posses as a large problem for drugs designed for the brain. Likewise, this method offers a non-invasive and safe way in altering the permeability of the BBB [29].

Delivering intravenous antibodies to the brain

Figure 10: Brain section after MRIgFUS
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(A) No biotinylated BAM-10 due to lack
of stimulatioin (A') Adbundant biotinylated BAM-10
as a result of MRIgFUS [30]

Figure 11: MRIgFUS delivery of BAM-10 reduced Aβ plaques
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There is a discernible difference between the left and right sides
caused by the MRIgFUS, even though BAM-10 was present in both sides.
(A) Significant drop in number of Aβ plaques between left and right
(B) Significant drop on the size of Aβ plaques between left and right
(C) Significant drop in surface area of Aβ plaques between left and right [30]

Since then, magnetic resonance image-guided focused ultrasound (MRIgFUS) has proven its usefulness in allowing for the delivery of anti-Aβ antibodies directed against the harmful Aβ peptides in the brain of AD patients. Jordão et al were able to demonstrate this mechanism in TgCRND8 mice which were double mutants that would develop the amyloid pathology at 3 months, and would also have the cognitive deficiency associated with it [30]. These mice were injected intravenously with both MRI and FUS contrast agents and BAM 10 – an anti-Aβ antibody. It was found that after the MRIgFUS was administered, that there was indeed co-localization of the BAM-10 with the Aβ plaques on the right side of the mice brains, as this was the side that was targeted by the MRIgFUS, whereas there was no delivery of the BAM-10 from the peripheral circulation to the left hemisphere of the brain (Figure 10) [30]. Jordão et al also noticed that the BAM-10 + MRIgFUS was quite effective in reducing the plaque load in the TgCRND8 mice, and that even though a low dosage of 40μg of the anti- Aβ-antibody was used, a significant reduction was achieved within 4 days after the treatment (Figure 11)[30].

Positive effects of MRIgFUS by itself

Figure 12: Aβ internalization in Iba1- and GFAP-cells
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There is a discernible difference between the amount of Aβ that is internalized
between the cells treated with MRIgFUS and those untreated. (A) Iba1 microglia cells.
(B) GFAP astrocytes [31]

More recently, Jordão et al also showed the positive benefits of MRIgFUS on the brain regions effected by AD by itself, without the use of intravenous antbodies. It was found that that 4 days after MRIgFUS treatment by itself, there was a significant reduction in both plaque size, and the total Aβ surface area when compared to the untreated [31]. This was thought to be correlated to the increased amount of IgG and IgM caused by the MRIgFUS in stimulating the BBB and allowing for entry of endogenous antibodies [31]. As such, there was also a higher co-localization of both endogenous IgG and IgM to the plaques on the MRIgFUS-treated cortex [31]. Jordão’s group also found that after MRIgFUS, there was an increase in expression levels of Iba1 in microglia and GFAP in astrocytes in the stimulated areas which would be useful in the internalization of Aβ plaques [31]. From further examination, they found that the volume and surface area of the glial cells were greatly increased but the cell counts remained unchanged, suggesting that although MRIgFUS enhanced stimulation and intake of Aβ plaques, it did not affect cell proliferation or recruitment to the treated site [31]. Overall, the effects of MRIgFUS itself are quite significant in terms of treating specific areas of the brain for Aβ plaques.

Integration for other treatments and future implications

MRIgFUS has also been shown to have the ability to be utilized for other purposes as well. It was recently shown by Burgess et al as a new non-invasive approach for delivering stem cells from the blood and into the brain [32]. They were able to deliver stem cells that expressed green fluorescent protein (GFP) to the striatum and hippocampus in rats, and were subsequently able to determine the successful entry into the targeted regions through immunohistochemistry analysis [32].

Overall, this opens up many new areas of research, as new stem cells can be easily transplanted to specific regions of the brain, and showing the versatility of MRIgFUS as an alternative to invasive intracranial surgery. The benefits of MRIgFUS treatment to AD patients are vast and incredible, as is demonstrated in recent research. Clearly, human trials will be still need to be conducted before it is put into clinical practice, but the future looks to be bright –as we are ever closer to finding a cure for AD.

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Alzheimer's Disease and LTP Impairment

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