Psy 625 Week 5










Early Diagnosis and Treatment of Alzheimer’s and other related Dementia’s


PSY625: Biological Bases of Behavior

Irene Nielsen

May 21, 2018



Early Diagnosis and Treatment of Alzheimer’s and other related Dementia’s

Specific Aims


Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder, currently projected to affect 5.7 million in 2018. An early and accurate diagnosis could save the lives of $7.9 trillion in costs associated with medical and other types of care necessary for those who are living with Alzheimer’s disease. Alzheimer’s disease (AD) is the leading form of dementia worldwide and is becoming a global epidemic.

The proposed research seeks to examine one of the most expensive diseases in the country. AD-related expenses average five times higher than the average per-person payments for seniors without these conditions. As the disease advances, patients will require a wide range of services as most patients survive an average of 4 to 8 years after being diagnosed. This condition has been identified as the imbalance between production and clearance of amyloid β (Aβ) and tau proteins.

The plan is to eliminate Alzheimer’s disease can be accomplished by identifying the cause of the disease. This can be made possible through further research to identify the cause of the plaque which damages cells in the brain affecting memory. Progress made in this area in addition to identifying ways to reduce the risk of developing dementia by completing research efforts specific to this area of neurology is necessary.

This can be accomplished by understanding brain health and early detection of the onset of the disease. AD research has shown some positive results in mice but has yet to be introduced to humans on a grand scale, (Morgan, 2006). Treatments have not been identified to slow the progression and unfortunately there is no cure. As a result, further funding is required to pay for the research needed to identify how to make an impact. Many organizations, such as AIM and the Alzheimer’s Association are working to prevent AD by 2025, however, additional and much-needed funding is required to accomplish that goal.





Based on the Alzheimers Association, the medical costs of AD are projected to increase to 14 million by 2050 and reach as high as $277 billion in 2018. Alzheimer’s disease is the sixth leading cause of deaths in the US, killing more than Breast Cancer and Prostate Cancer combine. Alzheimer’s disease-related deaths have shown an increase of 123% from 2000 to 2015. People currently living with the disease number 5.7 million and that number is projected to increase by nearly 14 million by 2050, (


Because of the inability to identify what causes AD, the plan to eliminate the disease by 2025 may be unrealistic, however, making strides on early detection is not as far-reaching. With the addition of funding for existing and new trials, as well as research development, for those who are of higher risk of being diagnosed with the disease, advanced screening of high-risk populations is necessary in order to detect the amyloid signatures. This testing will include people who may have the APP hereditary gene identified as presenline 1 and presenilin 2 (Goldman JS, Hahn SE, Bird T., N.D.)

Based on studies conducted by N. J. Ashton (2017), this can be accomplished using a Positron Emission Tomography (PET) scans and Cerebral Spinal Fluid (CSF) analyses which can be done before substantial neural damage has occurred. AD biomarkers with the ability to spot and track the disease progression in the earliest of phases will aid in this critical research and provide the ability to create a much-needed therapy to address this disease. According to N. J. Ashton (2017), these biomarkers, vivo amyloid-beta (Aβ) deposition (e.g. 11C-PiB) combined with a PET scan or CSF examination are becoming widely utilized as an essential criterion for AD prevention trials.

Immunotherapy has made strides in being able to

In order to make the progress needed to impact the early diagnosis of AD, funding is required to provide the support needed to conduct early studies on those who show a high probability of being affected by the disease as early as 10 years prior to symptoms being noticed. Lesions are detectable which can identify those who are at risk for developing AD as early as 10 years prior to the development of symptoms through the increase of lesions which develop before measurable cognitive impairments are detectable, (Pesini et al., 2012).

In order to accomplish the goal of identifying biomarkers which would increase the ability to determine if a person is of higher risk for developing the disease, it is important to identify the right subject for the study to aids in providing more accuracy of the data collected (Pesini et al., 2012). Providing more accurate information based on biomarkers and risk factors, will help with the selection of AD partners to participate in clinical trials.

These trials would assist with the evaluation and creation of new therapies specifically for amyloid-targeting drugs and vaccines (Pesini et al., 2012). The article by Pesini et al., (2012) provides clarification of the ability to identify the lesions which can appear over the course of many years prior to the development of the disease.

Histopathological hallmarks referred to as hyperphosphorylated tau protein, create signs referred to as neurofibrillary tangles. These biomarkers provide accurate information regarding the likelihood of the individual being diagnosed with AD in the future.

Introduction of histopathological hallmarks of AD is senile plaques and neurofibrillary tangles, (Cedarbaum, Crans, and Grundman, 2010). It has been determined that the development of these lesions may develop over the course of many years before cognitive impairment which can be measured may be detected. The clinical course of Alzheimer’s disease (AD) can be seen as the progress from normal cognition, to Mild Cognitive Impairment (MCI) and to dementia. Clinical processes that utilize both clinical and biomarker information can aid in the early identification of AD patients and potentially those who are at risk of developing the disease, (Cedarbaum, Crans, & Grundman, 2010).

At this time, anti-amyloid immunotherapy is in a position to be the first to test the amyloid hypothesis for the treatment of AD. In contrast to the early predictions regarding the memory decline related to inflammation, the vaccine used which protected amyloid depositing mice from developing memory deficits showed positive results and that further studies were able to confirm that passive immunization could reverse deficits. These findings were encouraging and supported the trial of an Aβ vaccination in Alzheimer patients. While the trial was cut short due to meningoencephalitis symptoms in 6% of patients, a subclass of patients, who had developed brain-reactive antibodies showed slower rates of cognitive decline, (Morgan, 2006). Proposed changes for future studies would include steroidal therapy to avoid this in the future, as this was administered and those patients recovered. (Morgan, 2006)




The proposed research will aid in the understanding and early detection of those at risk for developing AD. Having the ability to fund studies which can provide early detection methods will allow clinicians the ability to diagnose and treat the disease early in the developmental stages before the decline of cognitive abilities begins. It will also allow the potential of finding a cure.

This particular study would be presented as a double-blind study to avoid influencing the data analysis and results by preventing the clinicians and participants from knowing who was provided a placebo vs the real medication. This would require the use of a controlled sample group who would receive ongoing care at a small facility in the beginning and expand during each phase of the program. Each group would be provided the drug designed to stop or slow the growth of the amyloid-plaque, which is taken orally and numerically assigned, based on the test group allocations. Each dose would be administered and would then be tracked numerically for cases of emergency or data collection later. The main goal of this approach is to solve questions related to the brain and the complexity of what causes the debilitating condition such as Alzheimer’s when it cannot be resolved solely by looking at the molecular structure and biology of genes/DNA.

It has been determined that an estimated 1 percent or less of all Alzheimer’s patients is the result of three specific genes which have been found to be hereditary, (Bekris, Bird, Tsuang, 2010). This is created by a genetic mutation caused by abnormalities of the chemical make-up in the genes. These are mutations involving the amyloid precursor protein (APP) and both the presenilin 1 and presenilin 2 proteins.

According to Goldman, Hahn, and Bird, N.D., those inheriting an Alzheimer’s mutation to the APP or presenilin 1 gene provide a high probability of developing the disease. Those inheriting an Alzheimer’s mutation to the presenilin 2 gene have a 95 percent chance of developing the disease (Goldman JS, Hahn SE, Bird T., N.D.). Because individuals with these mutations can show signs as early as 30 years of age, early diagnosis is critical to the treatment of Alzheimer’s disease especially as a result of these genetically altered genes. Early identification of those most likely to suffer from the decline in cognitive functions related to AD is needed to further progress in its treatment and an eventual cure. If this theory is proven, further studies will be expanded by longitudinal study of the same participants over the course of the next 3-5 years.

The traditional case studies often show disregard to the connection of in-clinical heterogeneity in AD, causing preclinical neuropathology to go unnoticed. For this reason, it is critical that biologically relevant markers are identified and that vivo surrogates of AD pathology would be considered extremely important to the progress which could be made, Ashton, N. J. (2017). In order to continue the progress made to date, more funding is needed in the specific areas which identify early signs. This will allow more time to observe the progression of the disease on participants during trials to determine if current approaches are slowing the progression of the disease.

Progress made would have a monumental impact on other neurophysiological disorders related to AD as well by opening doors to other conditions which show a cognitive decline in the sample study. The participants who may not develop either AD may exhibit other cognitive disorders within the sample group which can be researched as well in the developmental stages of these conditions. Other conditions which show similarities are vitamin deficiencies to the side effects of drugs. The proposed research will work with the Alzheimer’s and dementia research team of Alz Company to determine the long-term research needed at the Neurological Alz Center at Alz Dem University.

The successful development of AD treatment drugs requires more development. What is needed is a more methodical approach to drug development which can aid in reducing the high rate of negative trials. The lessons learned from trials with negative outcomes can provide better drug development, preclinical models of AD, dose-response, including a more accurate diagnosis using biomarkers, (Cummings, 2018). In order to confirm or refute the neurological effects of AD, the biomarkers would focus on the ability of participants to control attention to difficult issues, memory and theoretical reasoning.

In conclusion, being able to identify biomarkers early, which are consistent with the amyloid-precursor, senile plaques and neurofibrillary tangles, aid in early identification of those at risk for developing AD.


Proposed Study


Participants in the study would include those between the ages of 30 and 65, considered high risk for developing the disease. These individuals should include those who have a family history of the disease, have been tested to show signs of genetic abnormalities of the chemical make-up in the genes involving the amyloid precursor protein (APP) and both the presenilin 1 and presenilin 2 proteins, or those who shows cognitive decline in memory or other symptoms of Alzheimer’s disease. Participants will be recruited from existing patients at Alz Hospitals at a controlled location and expanding the number of participants as the study progresses. This will include those on a national level as the phase’s progress bases on results from each phase. In order to move forward, there must be at least be progress in at least 51% of the participants in the study.

The patients will be split into two groups based on whether they are participating due to heredity based on the gene or due to lifestyle. The study for both groups will be handled as a double blind so that the outcome of the result will be unknown to the participants and those administering the program administrators. Both of these groups will receive the anti-Aβ antibodies after a baseline has been determined following the initial testing. Each group will be monitored monthly to track results and to identify any changes over a 3 month period.

Results by participants which are consistent with previous studies conducted by N. J. Ashton (2017), PET scans after 30 days showing a reduction in pointers with amyloid binding following therapy who have participated in the trial and with the anti-Aβ antibodies revealed, will be moved to the next phase of the research at the end of the first 90 day evaluation period. This testing/process will continue for those showing signs of improvements and until we are able to move participants to phase 3 and immunotherapy. While this is likely to be the first test of the amyloid hypothesis of Alzheimer’s disease, there have been some successes using immunotherapies specifically related to tau pathology, however, these trials have not been introduced to humans but restricted to mouse models, Ashton (2017).

As with the study conducted by Schenk et al., (1999), the application of a beta amyloid, prevented beta-amyloid plaque formation in platelet-derived growth factor promoter (PDAPP) transgenic mice was monitored. After the application of the beta amyloid, the study confirmed that animals treated with this active immunotherapy also revealed a reduction in neuritic dystrophy. The components are critical in the diagnosis of dementia and Alzheimer’s. This is promising and worthy of further funding for research with a short turnaround of two days as opposed to related analyses which typically require up to 13 days, Schenk, et al. 1999. The next step in the process would be to introduce the trials to humans once FDA approval has been granted, and monitored using a closely controlled sample group.


Once the sample group has been identified, each participant will receive a visit at their home to cover preliminary protocols. Each individual will have the study procedures described to them and will be provided informed consent if they wish to enroll. In addition, the availability of necessary internet access will be confirmed.

Once enrolled, patients will be provided with a personal ID# to access The Alz/Dem Research Program and will be assigned to a research assistant who will provide guidance as needed throughout the initial setup process. The procedure will follow the standard Alz/Dem Research processes including an initial assessment on a range of cognitive functions followed by 8 20-minute assessment sessions over approximately 4 weeks. The rate of training sessions recommended is 2 sessions per week but is ultimately chosen by the patient.

These sessions are reassessed within the Alz/Dem Research project of the performance based on 7 cognitive functions within their identified group.

Participants’ will complete a personal lifestyle self-assessment and weighed against a Quality of Life-Alzheimer’s disease (QoL-AD) scale described by Logson et al. (2002). All participants will be required to complete an assessment of quality of life appropriate for cognitively impaired individuals or individuals genetically at risk. Cognitive improvements in these participants will be compared with a group of patients previously receiving a diagnosis of mild cognitive impairment (MCI) and who are currently involved in the Alz/Dems Research program, utilizing identical sets of performance improvement instruments to provide maximum comparability across all groups Logson et al. (2002).

The trials are administered in a controlled environment on a weekly basis, by first confirming the health of the participants in advance and then providing medication and/or placebo to the participants and completing observations to measure changes in the brain. These participants will not be informed if they are taking the drug or a placebo which looks exactly like the drug and will be delivered in the same manner. The difference is the placebo will not contain the drugs contents. Based on the results off the short study, a longitudinal study could be pursued if warranted based on results.

The length of time anticipated to complete the study is 12 months. During the progression of the study varying cognitive testing conducted and PET imaging will be collected to track the progress of each participant and changes will be documented for each subject. A third party research company, Alz Research will be responsible for gathering, reviewing, interpreting and disseminating information from the data collected for the study.

Hypotheses & Analysis:

In Alzheimer’s research, the primary goal is to develop a treatment of the disease, (Morgan, D., 2006). The amyloid cascade hypothesis mainly focuses on efforts to decrease amyloid. One methodology showing success in mouse models and the potential for success in human trials as well is anti-Aβ immunotherapy, which Schenk first confirmed to reduce active immunization in 1999.

The research for this study is based on previous studies which have identified the correlation between heredity and amyloid proteins in patients diagnosed with AD. The study is expected to show the correlation between heredity and AD in the sample control group vs those without prior APP and both the presenilin 1 and presenilin 2 proteins. As mentioned by Blurton-Jones, (2014), “If amyloid accumulation is the driving cause of Alzheimer’s disease, then therapies that either decrease amyloid-beta production or increase its degradation could be beneficial, especially if they are started early enough,” (para. 4).

Current research studies are needed to identify innovative therapies, to determine the possibility of altering the course of AD. The likelihood of identifying potential treatments, able to reduce the risk, to postpone or prevent the clinical onset of AD are possible but it is necessary to determine the methodology able to diagnose AD in the early stages. Finding a safe and effective treatment for AD through psychometric tests, biomarkers and AD trials, as well as utilizing participants for these studies are necessary, (Cedarbaum, Crans & Grundman, 2010).

In this study, we hypothesize that immunotherapy targeting both Aβ and tau concurrently has the greatest potential to be effective in the positive impact on the general improvement in characteristics of AD. Understanding and identifying the commonality in the tau and Aβ toxic compound or specific molecular structure and using the results to control immune response by imitating the success in humans.

While there may not be marked improvements in the decrease of amyloid proteins within the first 6 weeks of the study, as some of these participants are not yet showing signs of impairment, PET scans should show a decrease in the plaque or tangles in those who are showing general cognitive impairments or MCI. This would confirm that improvements on this measure are a key factor to indicate the potential of future success of the program for those at risk and significant benefits to those currently showing signs of AD.

Assessment of improvement will be made for only the participants who completed the trials during the first 6 weeks. Performance of patients who do not complete the trials will be measures as the potential to lose participants is a factor as well and will impact the overall results if 25% or more do not complete least 6 weeks but more likely the first 90 days of the study. All participants will be asked to complete an exit survey to obtain feedback for further consideration and studies.

Participating in clinical trials has the potential to help both the participants and other individuals who have Alzheimer’s or who are at risk of developing the disease. The introduction of new drugs requires the completion of a three phase clinical trial process, prior to being approved by the U.S. Food and Drug Administration (FDA); during these trials, the drug must perform well enough in each phase to progress to the next step and a collection of the data must be completed and evaluated to support the safety of the new treatment. While there are risks associated with the trial such as allergic reactions or other medical issues, this a necessary step before the clinical trials in humans begins. Phase I of human testing generally involves a review of the risks and side effects and a sample of less than100 healthy volunteers. Phase II generally involve a sample of a few hundred volunteers diagnosed with Alzheimer’s. Safety of the participants is considered and a dosage is determined which is best suited for the study.

Phase III trials involve hundreds to thousands of volunteers, and are likely conducted in multiple locations throughout the world. Evidence of safety and effectiveness is provided to the FDA who determines if the drug will be approved. After the drug has been approved the FDA will require post-marketing study. This is considered phase IV and during this time researchers monitor the health of those taking the medication to determine its long-term safety and effectiveness.

Budget Justification


Funding is requested for a part-time research assistant to be responsible for all aspects of subject recruitment, training and data collection. Additional funding of 10% is requested for the principal investigator who will oversee the study and conduct data analysis and publication of results.

Travel funding is requested for attendance at an annual conference for the investigator to obtain additional research data analysis and to present preliminary results of the Alz/Dems Research study. Additional expenses are requested for mileage reimbursements to the research assistant for necessary home visits of participants.

Subject payment of $50 each subject (40 total) is requested to reimburse subjects for the time spent participating in the study.

Funding is requested for a HP Laptop computer (15” with retina display, 2.8 GHz processor, 1 TB hard drive) that will be used for data collection and analysis. Additional funding will be used to purchase the Quality of Life Scale, office supplies and miscellaneous medical supplies.

See Appendix A: Budget for detailed budget figures.





Cedarbaum, J. M., Crans, G., & Grundman, M. (2010). Seeing with new eyes: finding a path to early intervention trials in Alzheimer’s disease. The Journal of Nutrition, Health & Aging, 14(4), 306-309.

Chenco, C. (2012). Prevention and care of Alzheimer’s disease – A practical guide to reducing your risk, slowing the progression and living with dementia by L. Steckbeck.  Australasian Journal on Ageing31(3), 203. doi:10.1111/j.1741-6612.2012.00630.x

Cummings, J. (2018). Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes. CTS: Clinical & Translational Science, 11(2), 147-152. doi:10.1111/cts.12491

Lobello, K., Ryan, J. M., Enchi, L., Rippon, G., & Black, R. (2012). Targeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer’s Disease. International Journal of Alzheimer’s Disease, 1-14. doi:10.1155/2012/628070

Morgan, D. (2006). Immunotherapy for Alzheimer’s disease. Journal of Alzheimer’s Disease, 9(3), 425-432.

Morgan, D. (2011). Immunotherapy for Alzheimer’s Disease. Journal of Internal Medicine269(1), 54–63.

Pesini, P., Pérez-Grijalba, V., Monleón, I., Boada, M., Tárraga, L., Martínez-Lage, P., & … Sarasa, M. (2012). Reliable Measurements of the β-Amyloid Pool in Blood Could Help in the Early Diagnosis of AD. International Journal of Alzheimer’s Disease, 2012604141. doi:10.1155/2012/604141

Rygiel, K. (2016). Novel strategies for Alzheimer’s disease treatment: An overview of anti-amyloid beta monoclonal antibodies. Indian Journal of Pharmacology48(6), 629-636. doi:10.4103/0253-7613.194867

Schneider, L. S. (2010). The potential and limits for clinical trials for early Alzheimer’s disease and some recommendations. The Journal of Nutrition, Health & Aging, 14(4), 295-298

Schneider, L. S., Mangialasche, F., Andreasen, N., Feldman, H., Giacobini, E., Jones, R., … Kivipelto, M. (2014). Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. Journal of Internal Medicine275(3), 251–283.

Schroeder, S. K., Joly-Amado, A., Gordon, M. N., & Morgan, D. (2016). Tau-Directed Immunotherapy: A Promising Strategy for Treating Alzheimer’s Disease and Other Tauopathies. Journal of Neuroimmune Pharmacology : The Official Journal of the Society on Neuroimmune Pharmacology11(1), 9–25.

Malmstrom, T., Voss, V., Cruz-Oliver, D., Cummings-Vaughn, L., Tumosa, N., Grossberg, G., & Morley, J. (2015). The Rapid Cognitive Screen (RCS): A point-of-care screening for dementia and mild cognitive impairment. Journal of Nutrition, Health & Aging19(7), 741-744. doi:10.1007/s12603-015-0564-2

Nicholas, J. A., & Hall, W. J. (2011). Screening and preventive services for older adults. The Mount Sinai Journal of Medicine, New York78(4), 498-508. doi:10.1002/msj.20275

Rizk-Jackson, A., Insel, P., Petersen, R., Aisen, P., Jack, C., & Weiner, M. (2013). Early indications of future cognitive decline: stable versus declining controls. Plos One, 8(9), e74062. doi:10.1371/journal.pone.0074062

Serrano-Pozo, A., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2016). Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease. The American Journal of Pathology, 186(2), 375–384.

Linking Disclaimer: The Alzheimer’s Association is not responsible for information or advice provided by others, including information on websites that link to Association sites and on third party sites to which the Association links. Please direct any questions to .

Appendix A: Budget





Alz/Dems Research Project




Instructor S. Carlson, PhD





A. PERSONNEL: PI/PD, Co-PIs, Faculty, Graduate Assistants, etc. Funds
List each separately with name and title. Requested By
1. Instructor S. Carlson, PhD ($75,000/year) – 10% effort for 12 months $7,500
2. Research Assistant (RA) – 50% effort for 12 months $20,000
C. TRAVEL 1. DOMESTIC – PI attendance at national meeting $1,500
  2. OTHER – Travel for RA to participants home $1,225
1. STIPENDS $ 100    
2. TRAVEL   1900    
3. SUBSISTENCE        
4. OTHER        
1. MATERIALS AND SUPPLIES- Computer for patient training, data collection and analysis $2800
2. OTHER Quality of Life scale $1200
3 OTHER Office supplies $1000
4. OTHER Misc. Medical $200
G. TOTAL INDIRECT COSTS (F&A) (Rate = 37.5%) $19,300.00







Annotated Bibliography



Chenco, C. (2012). Prevention and care of Alzheimer’s disease – A practical guide to reducing your risk, slowing the progression and living with dementia by L. Steckbeck. Australasian Journal on Ageing31(3), 203. doi:10.1111/j.1741-6612.2012.00630.x

This book covers the support given by those who care for people suffering from various types of dementia-related conditions. Steckbeck takes us through time as a caregiver based on personal experience. The book covers three parts of her journey. The first was what she experienced caring for her husband from pre-diagnosis and her personal experiences as the disease progressed until his death. In the second part of her book, Steckbeck shares what she has learned about the disease since her husband’s passing related to research into the prevention of the disease and how caretakers should take time to take care of themselves. The final part discusses what the caregiver experiences once they realize they can no longer provide in-home care for the person with Alzheimer’s. Steckbeck makes the point that some of the newer therapies such as reminiscence therapy (remembering and discussing past events) are more useful than other interventions because it provides a positive experience for people with dementia.


The information in this study is relevant as it supports the need for funding for research to find a prevention or cure to reduce the medical costs associated with caring for a person with Alzheimer’s. Shared personal experiences are powerful for those wishing to learn from the experiences of others.


Lobello, K., Ryan, J. M., Enchi, L., Rippon, G., & Black, R. (2012). Targeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer’s Disease. International Journal Of Alzheimer’s Disease, 1-14. doi:10.1155/2012/628070

In the article by Lobello, Ryan, Enchi, Rippon & Black the promise of improvements in immunotherapy discuss adverse reactions. The present findings indicate that oral administration of K6Aβ1 reduces Aβ plaque burden and Aβ levels in Tg2576 mice. A change in the application by using amyloid-β (Aβ) derivatives is a safer approach. To assess the feasibility of oral immunization that promotes mucosal immunity, mice were treated prophylactically three times over 6 weeks.


This article supports the possibility that providing an oral vaccine is safer by reducing the potential for hemorrhage. This could allow for testing in humans as the risks decrease. These results further our findings and demonstrate its efficacy when given orally, and may provide added benefits for human use.

Logsdon, R. G., Gibbons, L. E., McCurry, S. M., & Teri, L. (2002). Assessing quality of life in older adults with cognitive impairment. Psychosomatic Medicine64(3), 510-519.


Morgan, D. (2011). Immunotherapy for Alzheimer’s Disease. Journal of Internal Medicine269(1), 54–63.

This article researches the ability of immunotherapy to reduce memory deficits in mice. The study has been able to identify methods which detect Alzheimer’s dements from other disorders without the need for an autopsy using PET scan. The benefit is that there now appear to be individuals who are cognitively normal, but carry positive PET amyloid ligand signals and now there are cerebrospinal fluid analyses that appear to specify Alzheimer cases. This appears in some individuals that do not yet have dementia. This study also has the capability of accurately defining those individuals with dramatically increased risk of dementia.


This article provides research data which shows the progress made with early detection prior to the onset of notable symptoms. This will provide the evidence I need to support the grant proposal for further studies of early detection by up to 10 years before symptoms and raises the possibility of attempting to prevent the development of Alzheimer’s.


Rygiel, K. (2016). Novel strategies for Alzheimer’s disease treatment: An overview of anti-amyloid beta monoclonal antibodies. Indian Journal Of Pharmacology48(6), 629-636. doi:10.4103/0253-7613.194867

This article by Rygiel states that the growing knowledge of genetic and molecular pathogenesis related to Alzheimer’s Disease. The study states that there are pathophysiological changes in the brain which occur years prior to the decline in cognitive functions. In this review by Rygiel therapeutic concepts focused on anti‑amyloid beta monoclonal antibodies and solanezumab and has already shown some beneficial cognitive effects in mild AD patients. It further states that prevention trials on crenezumab will examine when exactly the AD treatment should be started to obtain the most benefit (e.g., in pre-symptomatic AD individuals, who harbor AD‑related genetic mutations or patients with prodromal AD stages). Furthermore, a spectrum of plaque‑associated targets for AD therapies has broadened, and it appears that multimodal therapies targeting amyloid beta accumulation, tau protein malformation, or their combination can modify the AD course.


This article further supports the need for additional research to identify the possible benefit of therapies which include amyloid and tau proteins in various forms and combinations.


Schneider, L. S., Mangialasche, F., Andreasen, N., Feldman, H., Giacobini, E., Jones, R., … Kivipelto, M. (2014). Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. Journal of Internal Medicine275(3), 251–283.

This article questions the sustainability of methods used to for large clinical programs in Alzheimer’s disease. Many trials are including earlier-stage diagnoses or at-risk due to longer follow-up periods extending beyond 18 months with a longer wait on trials which may include a majority of participants who do not develop clinical Alzheimer’s disease during the follow-up period. Schneider states consideration has been given for late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines.


This article is relevant as it involves the challenges of clinical trials over the past 30 years and the need for more focus on the samples of participants and analyses.



Schroeder, S. K., Joly-Amado, A., Gordon, M. N., & Morgan, D. (2016). Tau-Directed Immunotherapy: A Promising Strategy for Treating Alzheimer’s Disease and Other Tauopathies. Journal of Neuroimmune Pharmacology : The Official Journal of the Society on Neuroimmune Pharmacology11(1), 9–25.

This article studied safer methods of immunotherapy which were less toxic than some existing amyloid type studies. The general absence of extracellular tau deposits may avoid the opsonization and phagocytosis mechanisms activated by antibodies against amyloid, and make anti-tau approaches a safer method of immunotherapy for Alzheimer’s disease. While these potential treatment strategies continue to be explored, an emerging approach that has shown promise in mouse models of tau deposition is immunotherapy. Vaccination is the most common form of immunotherapy, which typically involves administration of antigen, often with adjuvant, to actively increase the body’s production of antibodies. Additionally, immunotherapy can be accomplished by injecting antibodies or antisera against the unwanted substance, thereby eliminating the need for the recipient’s body to produce its own antibodies (passive immunization) (Lee et al., 2001, Wisniewski and Boutajangout, 2010).


This article supports the need for further studies related safer methods and options in support of further studies with immunotherapy.


Malmstrom, T., Voss, V., Cruz-Oliver, D., Cummings-Vaughn, L., Tumosa, N., Grossberg, G., & Morley, J. (2015). The Rapid Cognitive Screen (RCS): A point-of-care screening for dementia and mild cognitive impairment. Journal Of Nutrition, Health & Aging19(7), 741-744. doi:10.1007/s12603-015-0564-2

This article was intended to assess the need for a brief screening tool for cognitive impairment. The Rapid Cognitive Screen (RCS) exhibited construct validity to screen for dementia and Mild Cognitive Impairment (MCI) in both studies. The first study showed that the 3-item RCS and the 2-item CDT showed sensitivity for the detection of dementia and study 2 showed detection of dementia in the Saint Louis University Mental Status (SLUMS) exam. The study was conducted to identify sensitivity and specifics for MCI and dementia, evaluate the RSC predictability and to compare RXS to clock drawings for tests (Clock Drawing Test –CDT).


The validity of this article is to show the ability for early detection of AD by using varying methods to gather and evaluate data.


Nicholas, J. A., & Hall, W. J. (2011). Screening and preventive services for older adults. The Mount Sinai Journal of Medicine, New York78(4), 498-508. doi:10.1002/msj.20275

The article by Nicholas and Hall, point out the importance of preventive services for the aged population. Efforts are being made by federal, professional, and academic avenues working together to address the preventive care needed for older Americans. The article addresses the strain placed on the population due to rising medical costs, requiring a focus on preventive care services for older adults. With the passage of the Patient Protection and Affordable Care Act, access to preventive services has been enhanced by reducing out-of-pocket costs for older adults and increasing reimbursement to healthcare providers. In addition, attempts to modify national screening recommendations based on age and expected risk/benefit for older adults is being addressed.


This article is relevant because it also supports the impact AD has on the aging population and how early detection is key to preventing the disease and controlling costs of care.



Rizk-Jackson, A., Insel, P., Petersen, R., Aisen, P., Jack, C., & Weiner, M. (2013). Early indications of future cognitive decline: stable versus declining controls. Plos One, 8(9), e74062. doi:10.1371/journal.pone.0074062

This study identified the model of normal subjects showing cognitive decline which happens at a later date. Public data from the Alzheimer’s Disease Neuroimaging was used to find differences in model assessments (ADAScog, AVLT, FAQ) between healthy individuals who ultimately experience a decline in cognition within 48 months. Analysis models created using model features obtained from MRI and FDG-PET data were successful in predicting MCI within 48 months or if the subject remained stable. The findings from this study support the idea that information from this study can predict changes between normal people who will later develop cognitive impairments and those who will remain cognitively stable for up to four years.


This article is necessary as it supports that idea that proactive studies can provide early detection of models who appear to be normal but could later develop a decline in cognition.


Serrano-Pozo, A., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2016). Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease. The American Journal of Pathology, 186(2), 375–384.

This article by Serrano-Pozo focused on Amyloid (senile) plaques, one of two pathologic markers of Alzheimer disease (AD), which are associated with dystrophic neurites and glial responses. Although the evidence of plaque remained stable through the clinical phase of AD, the determination could not be made that plaque toxicity continued to worsen over the course of the disease. Serrano-Pozo conducted unbiased plaque-centered quantification of 40 AD subjects with a symptom durations ranging from 4 to 20 years, and nine subjects not showing signs of dementia with dense-core plaques.

With the use of quantitative postmortem measures, we previously showed that amyloid both plaque burden and plaque size remain relatively constant throughout the clinical course of AD.

This article is relevant as it supports the theory that plaque-related local toxicity accrues with increasing duration of the disease, which was identified in a large series of autopsied subjects who had a symptomatic AD for various durations. Overall, we found an accumulation of markers of local damage around plaques as the disease advanced.


PSY625: Biological Bases of Behavior Ashford University
















Effects of Caffeine on Autism Spectrum Disorder


PSY625: Biological Bases of Behavior

Instructor: Dr. Irene Nielsen

May 22, 2018


Title of Grant Proposal



Specific Aims

Autism Spectrum disorder (ASD) is a neurological disorder that effects people of all ages. Generally, this disorder will show different symptoms based on the age range of the person (Gottfried, Bambini-Junior, Francis, Riesgo, & Savino, 2015). Therefore, a close attention is paid to the age range of the groups being tested when doing a study. ASD has many different symptoms. The most common are related to language developmental impairments, social interaction inabilities, learning disabilities, anxieties, and unawareness of others’ emotions.

Caffeine plays a large role in the central nervous system. Caffeine is a drug that acts as an antagonist for the adenosine receptors (Diukova, Ware, Smith, Evans, Murphy, Rogers, & Wise, 2012). This causes interference within the vascular and neural regions. A direct impact on the frontal cortex via the use of caffeine can create an increase if focus. The frontal cortex is responsible for the higher-thinking processes, and the executive thinking processes. The use of caffeine has a sole purpose of creating an increased amount of concentration and motivation (Cappeletti, Daria, Sani, & Aromatario, 2015).

The specific aim of this study is to research the effects caffeine may have on children suffering with ASD. Caffeine in the amount of 50mg given to children is low enough to hopefully be non-addictive. Anything more than 200mg can create an addiction, seizures, dehydration, and create fatigue while affecting the heart.

Past research has determined the effects caffeine plays within the brain. It’s ability to enhance concentration and act as a stimulant can have a huge impact on a child with ASD. This impact can be strong enough to allow a better ability to treat this disorder. By comparing the role caffeine plays on children with ASD to children of normalcy the same age with the use of fMRI screenings and various surveys, the theory caffeine will help children with ASD may be determined. Thus, can offer a better option to treat.





There really are no concrete research-based affiliations between caffeine and Autism Spectrum Disorder (ASD). Caffeine may help with concentration, but caffeine also has many other side effects. Just as any drug, there are side effects. Caffeine is a stimulant that will attach to the receptors of adenosine. Adenosine is a neuromodulator that can be found throughout the body. This is specifically found within the central nervous system.

Adenosine plays an important role in the alteration of many symptoms related to ASD. These may include epilepsy and sleep disorders, which are commonly found in patients with ASD. The adenosine modulator must be increased to achieve the reverse effect of seizures and sleep disorders (Masino, Svedova, Kawamura, Dimario, & Eigsti, 2011). Coupling adenosine with caffeine to alter the effects of ASD is the basis of this study.

Adenosine will build up within the central nervous system throughout the day which makes a person feel tired at the end of the day. A person with ASD may have a low level of adenosine making them sleep deprived. Patients with a high level of adenosine may feel exhausted all the time and sleep more frequently. When adenosine is paired with a methylxanthine, the metabolism and cell signaling are affected. When adenosine was paired with the G-proteins (A1, A2A, A2B, and A3 receptors), the cell signaling became more enhanced (Masino, Svedova, Kawamura, Dimario, & Eigsti, 2011). To help increase focus, the trimethylxanthine (pure alkaloid) caffeine is used to target the sub-types of adenosine. These subtypes targeted are A1R and A2R (Masino, Svedova, Kawamura, Dimario, & Eigsti, 2011). There is a limit to the amount of this pure alkaloid to prevent harmful side effects.

Caffeine is found in many of the beverages and foods that are taken in daily. Regulating the amount of caffeine can have a reverse effect of harmful side effects for a person with ASD. Although a person with ASD may be unable to focus, they are also susceptible to seizures. An increased amount of caffeine can trigger epileptic seizures (Chroœciñska-Krawczyk, Jargieo-Baszak, Waek, Tylus, & Czuczwar, 2011). Research found the normal amount of methylxanthine (caffeine) per person to be on average 200mg per day (Chroœciñska-Krawczyk, Jargieo-Baszak, Waek, Tylus, & Czuczwar, 2011). When rodents were given double that amount (400mg) the rodents became subjected to epileptic seizures (Chroœciñska-Krawczyk, Jargieo-Baszak, Waek, Tylus, & Czuczwar, 2011).

To put in theory, ASD patients suffer from a multitude of symptoms, and some of the prescriptions provided for the treatment are drugs with some harmful side effects. The levels of adenosine in a patient with ASD should be increased to allow for reverse effects of behavior defects, epileptic seizures, and sleep disorders. Caffeine paired with adenosine helps to improve cell signaling which can help improve focus and may alter sleep disorders. If caffeine is given within a safe range of ≤ 200mg daily, then there will be a decline in seizure risks, and a reverse for the better affect in behavior defects while increasing metabolism and sensory concerns.



Autism Spectrum Disorder is becoming more common. This is still a new disorder because it is many disorders combined into one disorder. The method of treatment is based on therapy combined with antipsychotic medications. These medications can have some detrimental side effects and can alter the moods of these patients. Some have been found to be like zombies or in their own world and not themselves. This proposed study will elicit the use of caffeine to patients with ASD in a safe dose range. The comparisons between the patients taking the medications with treatment, and the patients being give caffeine and treatment should give basic insight to the issue regarding the use of antipsychotic medications.

This project will enhance the knowledge of the disorder further to help scientist develop a better strategy to helping a person with ASD to cope with their world in a healthy manner. Teachers will gain from this study because they will be better equipped with handling their students that suffer with ASD. Doctors will not have to keep changing the medications for the patients that are having unwanted side effects.

Teachers and parents will be able to work easier with their children who suffer with this disorder because they will not be dealing with the side effects of the antipsychotic medications and will be more able to provide a healthy therapy for their patients. If the proposed aims of this study are achieved, the entire outlook of autism spectrum disorder can be looked at from a different angle. The basic treatment can be based on the use of caffeine with a combination of a specific diet and therapy.

What does caffeine do to a child’s brain between the ages of 8 and 13? What does caffeine do to a child’s brain that has autism spectrum disorder? These are the questions that need to be answered from this study. To hypothesize, if caffeine is given to a child with ASD, the prefrontal cortex will be affected to enhance the higher executive thinking processes. To conduct this study the variable needed are based on children between the ages of 8 and 13 with ASD taking and not taking medicine. The control group are the children that do not have any diagnosis or symptoms of ASD and are not on any medication.

Patients with ASD have trouble being social. Their language is interrupted, their level of anxiety is increased. Based on a neurological stand point, the entire brain is affected by ASD. The specific area that is affected by this disorder and interferes with the social ability is known as the superior temporal sulcus, also known as the social river (Deweerdt, 2016). This river is what is responsible for the social phenomena. The ability to carry on a conversation or even decode body language are within this region. Based on fMRI research, there is still much more to be studied regarding the responsibilities of the superior temporal sulcus, and the effects it has in patients with ASD (Deweerdt, 2016).


Proposed Study


Being that Autism Spectrum Disorder is found common in children at young ages, the study will consist of children between the age ranges of 8 to 13 years. There will consist an equal amount of each sex. There will be 15 girls and 15 boys in this study to equal a total of 30 participants. The participants will be divided up into three groups. The first group will consist of 5 girls and five boys with diagnosed ASD that are taking medication. In the second group, there will also be 5 girls and 5 boys with diagnosed ASD without taking medication. Lastly, the control group will contain 5 girls and 5 boys as well, but these participants will have no history of ASD symptoms, no diagnosis, and no history of epilepsy or seizures.

As a precaution, this study includes children that are taking medication. These children will need approval from their doctors as well as their parents to participate. Each participant will undergo an fMRI test. This test is radioactive; therefore, this too needs approval. Any one getting or giving this exam will need safety gear to protect them from radiation exposure. Any pregnancies shall be reported, any metal within the body shall also be reported prior to examination. Any allergies shall be reported in case of medical attention. Allergies to any dyes (such as iodine), latex, and caffeine if such exists.



After all required consents have been provided, the participants will be divided up into their groups. These participants will take a short survey to show the extent of their symptoms before any caffeine is given. The participants will be evaluated by a professional in ASD (psychologist) that will provide a thorough description of each participants mental state prior to administration of caffeine.

The amount of caffeine given to a child is important. A child that starts taking caffeine at an early age can become addicted to caffeine very quickly. The addiction comes from caffeine being a drug. As like any drug, a person has a high risk of having side effects. This drug affects the central nervous system in many ways. The main use of caffeine is the stimulant effect it has on the central nervous system.

If caffeine is given in an excess of over 200mg per day, there is a high risk of a child not only becoming addicted to the drug, but sudden seizures can occur. ASD patients have a variety of symptoms, and one of those symptoms is seizures. Caffeine given in a small dose can help decrease the episodes of seizures. The amount of caffeine in an 8oz cup of coffee is averaged at 100mg. This study will administer half that amount. Using half a cup of black coffee, the amount of caffeine given per participant will be 50mg. This will be done consecutively for 14 days. After the 14 days, the participants will be monitored for 7 days of any withdrawal symptoms that may have been caused from the caffeine. This will show how addicting the given dosage may be for a child between the ages of 8 and 13.

While the participants are using the drug caffeine, they will be evaluated by the same professional in ASD to distinguish any differences no matter how slight. The participants will also be examined through an fMRI test. Caffeine has been noted to show a bold signal in the prefrontal cortex region of the brain (Diukova, Ware, Smith, Evans, Murphy, Rogers & Wise, 2012). The prefrontal cortex region of the brain is responsible for any higher-level thinking skills. The problem with patients with ASD, their thinking skills and attention can be affected, or disrupted, because of the symptoms caused by the disorder.


Hypotheses & Analysis:

If a small dose of caffeine is given to a child between the ages of 8 and 13 with ASD, the child will have enhanced higher thinking skills and a decreased chance of seizures. To prove this hypothesis, the data needs to be collected and administered correctly. Based on the survey, the evaluation, and the fMRI, the data will be collected and examined thoroughly. The data will be compared based on the before and the after effects of caffeine. The data will also be compared based on gender, and the different groups that either take medication or not and the control group that does not have ASD getting caffeine.

The effects of caffeine and the effects of the diagnosed antipsychotic drug utilized for the treatment of ASD will be compared. This will show which drug is a healthier choice to use if a drug is absolutely needed for the treatment of ASD. If the dosage of caffeine used in this study is low enough to have no effect on addiction, but can improve higher thinking abilities, then the drug can be used temporarily to get a child started on their therapeutic treatment without drugs in the future.

Budget Justification

This research study requires some expenses. The total expense needed is $60,000.00. This study requires fees for needed personnel such as: Instructor T.J. Bailey which shall receive $8,000.00 which is 10% of the effort of the annual amount earned of $80,000.00. A research assistant is needed for the help with the research who shall receive 50% for six months totaling $12,500.00. A psychologist is needed for evaluation of all participants and will receive 10% of salary ($80,000) which totals to $8,000.

The participants shall receive $100.00 for participation fee for each participant. There are 30 participants in all. This totals out to $3,000 total for all participants stipend money. The stipends for the participants are to act as an incentive as well as a contract binder. Being the participants are below age, the money will go to the parents of the participants because the allowance to do the study is coming from the parents.

An fMRI test is required for this study to measure the difference in brain activity before and after caffeine is administered. This machine costs a total of $20,000.00. This machine is known as the Toshiba Visart 1.5T MRI System. This is a state of the art system that can show all parts of the brain that can be affected by any substance.

There is a request for a small travel fee for the PI to facilitate the PI to arrive at meetings when needed. There is also a request for help with some much-needed supplies. These supplies are needed for the research and data collection for this study. The supplies include a new Apple computer system with three 1TB hard drives to help keep track of participants data. Printers with fax and copy capable are also needed. The supplies total to $5,000.00 with all office supplies and data collecting supplies included. Lastly, there is a total of $2,000.00 needed for indirect costs that may arise. Below are the figures needed for this study.


See Appendix A: Budget for detailed budget figures.




Cappelletti, S., Daria, P., Sani, G., & Aromatario, M. (2015). Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug? Current Neuropharmacology13(1), 71–88.

Cornacchio, D., Crum, K. I., Coxe, S., Pincus, D. B., & Comer, J. S. (2016). Irritability and Anxiety Severity Among Youth with Anxiety. Journal of the American Academy of Child and Adolescent Psychiatry55(1), 54–61.

Diukova, A., Ware, J., Smith, J. E., Evans, C. J., Murphy, K., Rogers, P. J., & Wise, R. G. (2012). Separating neural and vascular effects of caffeine using simultaneous EEG–FMRI: Differential effects of caffeine on cognitive and sensorimotor brain responses. Neuroimage62(1), 239–249.

Dombrowski, S. C. (2013). Autism spectrum disorder. Salem Press Encyclopedia of Health,

Gottfried, C., Bambini-Junior, V., Francis, F., Riesgo, R., & Savino, W. (2015). The Impact of Neuroimmune Alterations in Autism Spectrum Disorder. Frontiers in Psychiatry6, 121.

Magdalena Chroœciñska-Krawczyk, Magorzata Jargieo-Baszak, Magdalena Waek, Boydar Tylus, & Stanisaw J. Czuczwar. (2011). Caffeine and the Anticonvulsant Potency of Antiepileptic Drugs: Experimental and Clinical Data. Institute of Pharmacology Polish Academy of Sciences. Retrieved from:

Sarah Deweerdt. (2016). Brain’s Social ‘River’ Carries Clues about Autism. Retrieved from:

Sherkow, S. P., & Harrison, A. M. M. (2013). Autism spectrum disorder: perspectives from psychoanalysis and neuroscience. Retrieved from

Susan A. Masino, Julia Svedova, Masahito Kawamura, Jr., Francis D. DiMario, Jr., & Inge-Marie Eigsti. (2011). Adenosine and Autism – Recent Research and a New Perspective. Trinity College Trinity College Digital Repository. Retrieved from:

Van der Heijden, K. B., Stoffelsen, R. J., Popma, A., & Swaab, H. (2018). Sleep, chronotype, and sleep hygiene in children with attention-deficit/hyperactivity disorder, autism spectrum disorder, and controls. European Child & Adolescent Psychiatry27(1), 99–111.

Verly, M., Verhoeven, J., Zink, I., Mantini, D., Peeters, R., Deprez, S., … Sunaert, S. (2014). Altered functional connectivity of the language network in ASD: Role of classical language areas and cerebellum. Neuroimage: Clinical4, 374–382.



Appendix A: Budget





Spectrum Awareness


Instructor, PhD

A. PERSONNEL: PI/PD, Co-PIs, Faculty, Graduate Assistants, etc. Funds
List each separately with name and title. Requested By
1. Instructor T.J. Bailey, PhD ($80,000/year) – 10% effort for 12 months $8,000
2. Research Assistant (RA) – 50% effort for 6 months $12,500
3. Psychologist $ 8,000
Toshiba Visart 1.5T MRI System $20,000
C. TRAVEL 1. DOMESTIC – PI attendance at national meeting $1,500
1. STIPENDS $ 100    
2. TRAVEL        
3. SUBSISTENCE        
4. OTHER        
1. MATERIALS AND SUPPLIES- Computer for patient training, data collection and analysis $4,000
2. OTHER Office supplies $1,000
3. OTHER  
G. TOTAL INDIRECT COSTS (F&A) (Rate = 37.5%) $2,000






PSY 625: Biological Bases of Behavior Ashford University

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