Cognitive Effects of Progressive Supranuclear Palsy
Introduction
Observing the decline associated with a terminal diagnosis represents one of the most difficult tasks facing the family and friends of a patient. Progressive supranuclear palsy (PSP), a difficult disease to pronounce and even more difficult disease to fully understand, presents such a case. The first recorded the first instance of PSP in 1964 as an anomaly associated with a diagnosis of Parkinson’s disease presenting added symptoms. The disease often behaves similar to Parkinson's during the onset of symptoms, which commonly results disease that is elusive and diagnosis troublesome (Boxer et al., 2017). The DSM V lists current criteria for diagnosis through modification of the cognitive assessment criteria of Parkinson’s. PSP is only listed under associated temporal frontal cognitive disorders with presentation in 2-10 in every 100,000 of population (American Psychiatric Association, 2013).
Early in 1996 researchers established the National Institute of Neurological Disorders and Stroke (NINDS) identification, and validation criteria for PSP were established as physicians via MRI witnessed the repeated presence of neurofibrillary tangle defects in multiple patients (Boxer, et al., 2017). The diagnosis of tangles within the basal ganglia and brainstem became the first area associated with the original diagnosis of PSP. The physiological commonality in symptoms of the disease begins with the onset of rogue tau protein binding. The mutation-based on chromosome 17, which initiates via RARA control protein binding, effects behavioral attributes of tau proteins (Young, Mok, & Gestwicki, 2018). Tau protein directly aids in the creation of microtubules within axons. The microtubules in the axon provide the necessary communication across the axon to send messages.
The current hypothesis of this research suggests that the construction of a symptom-specific diagnostic assessment may allow for prolonged lifespan and possibly slowing the cognitive decline of the patient via early detection. The question posed begs the question, are there specific cognitive decline symptoms for PSP not associated with Parkinson's related symptoms? The current assessments used by physicians to assess the neurological/ cognitive decline of PSP patients utilize a modified version of Parkinson’s symptom identification (Dickson, Kouri, Murray, and Josephs, 2011). Inadequate identification of symptoms and misdiagnoses accelerates cognitive decline, and the patient loses precious time in treatment. The early identification will allow physicians a chance to begin possible CBT therapy while constructing an effective pharmaceutical treatment. Every disorder or disease has an origin at the microscopic level and requires proper research to grasp its overall complexity Analyzing the available literature may shed light on the physiology that predicts PSP in patients.
Literature Review
The origins of progressive supranuclear palsy begin with a detectable chromosome mutation that precedes the onset of PSP. The MAPT gene mutation (an associated mutation to chromosome 17) prevents stabilized tubule construction and proper assembly (Young, Mok, & Gestwicki, 2018). The physiological disease markers begin by an increase in caspase-3 resulting in increased tau protein production; subsequently, microtubule malformations within axons throughout the subject's anatomy form consequently initiating both mixed polarity and malformed axons (Boxer et al., 2017; Dickson, Kouri, Murray, and Josephs, 2011). Malformations in the microtubules affect polarity in the axon or disrupt communication entirely (Boxer, et al., 2017). The lack of connectivity affects everything from cognitive behaviors to motor control and all axons of nerves within the body become affected by the disease (Young, Mok, & Gestwicki, 2018). The truth behind the disease, in fact, was much more ominous and devastating.
The disorder begins with unique and easily overlooked symptoms so subtle that they present as common symptoms associated with aging. The varying symptoms of PSP range from the ambiguous to extreme in nature. The early presentation is simple depression, which quickly escalates to difficulty with simple social interactions, sleep disorders, lack of vertical eye movement, and unsteady/delayed gait (Bradykinesia) (Boxer et al., 2017; Walsh et al., 2016). The final stages of the disorder include a lack of mobility, difficulty swallowing, weight loss, and complete loss of problem-solving capability (Boxer et al., 2017; Walsh et al., 2016). Sleep researcher suggests in late stages of the disorder the patient may enter a dream-like state where the mind is not fully awake often patients believe they are dreaming yet very much awake (Walsh et al., 2017). Experiments following the path of malformations in gray matter within the brain have also been very fruitful.
Zhao, et al., (2015) experiments use a combination of random selected group of mice that are predetermined to have tau gene mutation to produce tau excess tau proteins. There are human brain tissue samples to verify the effects of excessive tau proteins on the human brain (producing neurofibrillary tangles) that compare to those of the mice following necropsy. Both sides of the experiment also have control groups isolating both unaffected mice and human brain tissue samples (Zhao et al., 2015). The modification comes in the form of control vs permuted mice have producing excessive tau proteins. The reason for the control group is to match unaffected human brains without the mice control group (non-mutation selection the mice may not show reaction to the appoptosin but would still produce tau proteins above normal, which could skew test results).
The experiment hypothesis suggests that increases or decreases in appoptosin levels of mice affected with tau mutation (increased tau production) show increases in fibrillary tangles (Martin and Bridgmon, 2012; Zhao et al., 2015). Researchers selected mice from matching litters to gain the most random selection among the mice created for the experiment. Researchers then compared mice samples to human postmortem brain samples. The verification set of the neurofibrillary tangles (NFT) via human brain samples were used to compare to the infected mice (Control, n=22; PSP, n=26)(Zhao et al., 2015). The increase in tau proteins cause the malformations of microtubules (Pan, et al, 2017).
Several white matter tissue experiments performed in mice have shown just how damaging malformed microtubules affect axon polarity function. The malformations present in the brain of infected individuals as discolorations in the white matter signaling attempted repair of damaged areas (Koga, et al., 2018). Researchers then compared samples to human PSP patients that indicated the same level of tau proteins and examined for neurofibrillary tangles (Zhao, Tseng, Heyser, Rockenstein, Mante, Adame, and Xu, 2015). The human and mice upon examination of gene studies found T-allele malformations in mutated mice. When the human subjects with the experiment analyzed PSP samples for similar T-allele alterations found, 77% of the infected group showed one or more T-allele alterations (Zhao et al., 2015). The mutations also corresponded with increases in tau proteins and appoptosin (see Fig 1 and Fig 2). The control and the mutated group appoptosin measurement either displayed either excessive tau proteins or tau at normal levels.
Zhao, Y., Tseng, I. C., Heyser, C. J., Rockenstein, E., Mante, M., Adame, A., … Xu, H. (2015). Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron, 87(5), 963–975. doi:10.1016/j.neuron.2015.08.020
Fig 1- Occurrence of T-allele (Control, n=22; PSP, n=26)(p. 16).
T-allele levels in the control group measure 33% or less, showing a difference of 0.44 versus 0.18.
Zhao, Y., Tseng, I. C., Heyser, C. J., Rockenstein, E., Mante, M., Adame, A., … Xu, H. (2015). Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron, 87(5), 963–975. doi:10.1016/j.neuron.2015.08.020
Fig 2 -Appoptosin, Tau proteins, Caspase, and PHF-1 vs control group
(Control, n=22; PSP, n=26)(p. 16).
The control group had no mutation and were of generally good health. When researchers took measurements of the control group for either tau proteins or NFTs none existed. The results showed that those with increases in appoptosin, tau proteins, and caspase are all subject to increased neurotoxicity and the likelihood of developing PSP exponentially. The conclusion of the testing indicated appoptosin levels do in fact cleave tau proteins to regulate their production. Zhao et al., (2015) explains the use of therapies to control the appoptosin in individuals with PSP early in life may counteract the long-term effects of excessive tau proteins thereby halting PSP. Zhao et al. (2015) indicates more trials and testing are needed, but Caspase-3 Inhibitor (CAS 210344-95-9) show promise which will be addressed later in this work.
The greatest threats to the validity with such testing could come in the form of the predesignated mice with the T-allele modification/tau mutation. The ambiguous temporal precedence indicates validity issues may arise if it is difficult to know which issue happened first (Skidmore, 2008; Zhao et al., 2015). The experiment, though well-designed, one could argue that the mice with mutations at no time received examination for the level of mutation nor how the mutation had affected the mice before the experiment. The lack of verification of each mouse before the experiment causes a lack of information regarding tau and appoptosin (Skidmore, 2008). Elevated levels in the mice before the experiment could skew results and measurements.Currently, within the realm of PSP, researchers more concerned with a finding a cure often tend not to focus on identifying and easing the cognitive difficulties associated with PSP instead choosing to treat physical symptoms (Ghosh, et al., 2012; Rittman, Coyle-Gilchrist, & Rowe, 2016).
Testing of subjects with PSP to isolate a specific set of symptoms led to the identification of a Tau protein increase leading to malformations of microtubules within the formation of axons (Young, Mok, & Gestwicki, 2018). MRI and Pet scans of the brain isolated identifiable decline in the midbrain and superior peduncles (Boxer, et al., 2017). The degenerative identification via MRI represents either morning glory (MGDA) or hummingbird sign (see fig. 1 and fig. 2 of the structures of the brain to those items (Jalal, and Menon, 2017). The current research chooses to focus on a combination of specific symptomology and the use of physical information. The experiment proposed does not resemble any known previous experiments as the selection of specific PSP symptoms has not appeared in any publication. Though many physical signs exist in identifying PSP, little research exists regarding a unified set of cognitive diagnostic tests in the identification of PSP.
Jalal MA, Menon MK. 'Humming bird sign', 'Mickey Mouse sign', and 'morning glory sign' in progressive supranuclear palsy. Menoufia Med J [serial online] 2017 [cited 2019 Sep 28];30:325-6. Available from: http://www.mmj.eg.net/text.asp?2017/30/1/325/211489
Currently, many of the early onset symptoms are either misdiagnosed or left unaddressed. Phokaewvarangkul and Bhidayasiri (2019) for example suggest ocular conditions associated with aging at times are overlooked but may also provide an early indication of possible underlying neurological disorders. The physician left attempting to manage symptoms rather than provide early response treatments preventing the advance of the disease (Young, Mok, & Gestwicki, 2018). The consequence of miss or underdiagnoses allows the disease to progress until symptoms become pronounced by which point the patients' decline becomes obvious, and treatments lean toward palliative care. PSP having the general diagnosis also includes seven subgroups Richardson syndrome PSP, PSP-Parkinsonism, PSP-Corticobasal syndrome, PSP-Speech and language, PSP- Frontal presentation, PSP-w/Cerebella ataxia, and mixed pathology (Boxer et al., 2017) The early onset symptoms most common to all PSP diagnosis include Bradykinesia and cognitive impairment (Boxer, et al., 2017; Koga, et al., 2018; Young, Mok, & Gestwicki, 2018). The identification of the earliest symptoms provides an outlet for physicians to concentrate efforts toward full identification as the primary issue. Treatment of the disease through difficult is not impossible if recognized early (Young, Mok, & Gestwicki, 2018).
Jalal MA, Menon MK. 'Humming bird sign', 'Mickey Mouse sign', and 'morning glory sign' in progressive supranuclear palsy. Menoufia Med J [serial online] 2017 [cited 2019 Sep 28];30:325-6. Available from: http://www.mmj.eg.net/text.asp?2017/30/1/325/211489
Researchers have identified several treatment approaches associated with PSP and as result have conducted several trials with varying success (Young, Mok, & Gestwicki, 2018). Davunetide, BMS-986168 immunotherapy, and medications targeting microglia-specific receptor (CX3CR1) currently have entered the final testing phases and, results seem promising (Young, Mok, and Gestwicki, 2018). The three medications listed have shown the best results in regards to the reestablishment of cognitive abilities. All three medications are in the trial stage but have shown promising results. Davunetide, the most interesting of the group, addresses the manufacturing and stabilization of microtubule structures (Young, Mok, & Gestwicki, 2018). Treating the microtubule condition suggests the medication limits cognitive loss and increases polarity control within the axons (Young, Mok, & Gestwicki, 2018). Results suggest that the path to finding a cure for PSP may come in the form of tau protein control. C3I is a caspase inhibitor that regulates caspase production, which is responsible for maintaining the regulation of tau proteins. Preventing excessive and mutated tau proteins shows promise in preventing the formation of malfunctioning microtubules within nerve axons. Prevention of malformed microtubules greatly reduces the progression of symptoms extending the patient's lifespan Currently, there are no perfected treatments for PSP, but the future looks much brighter with advances in medical technology.
(Boxer et al., 2017)
PSP’s rarity makes a simple diagnosis difficult, and at times many physicians overlook the warning signs. The variety of symptoms though limited, also mimic several other diseases, most commonly Parkinson’s (Boxer, et al., 2017). The identification of connecting symptoms to Parkinson’s often leads to misdiagnosis and chasing ghosts as symptoms increase. Cognitive symptom identification may provide the best approach in identifying PSP (Rittman, Coyle-Gilchrist, and Rowe, 2016). The creations of a specialized assessment from several patients harboring PSP may provide a road map to both treatment and increase to the quality of life for the patient. Medications combined with CBT seem to provide the best course of treatment for the future (Rittman, Coyle-Gilchrist, and Rowe, 2016). PSP can provide a difficult puzzle, but just as with any puzzle understanding the complete picture aids in a path toward completion…or, in this case, finding an acceptable course of treatment.
The issue for physicians begins in the early onset presentation of symptoms, which mask themselves as Parkinson’s disease hiding the ominous debilitating nature of the underlying cause. Though both Parkinson’s and PSP fall under the tauopathy realm, PSP’s symptom acceleration and resulting mortality take ten years or less (Boxer et al., 2017). The mortality rate of the disease is currently one hundred percent, but many treatment medications are currently in a testing (Boxer et al., 2017). Research to find an answer via the scientific method begins by first identifying the issue or areas that require further research. Progressive Supranuclear Palsy (PSP) remains one of the most difficult neuro-degenerative diseases to diagnose (Boxer et al., 2017; Dickson, Kouri, Murray, and Josephs, 2011).
Methods
Martin and Bridgmon (2012) suggest the best experiment design given the type of testing required would be pretest/post-test. The research method for the experiment seeks to identify symptoms specifically associated with PSP alone. Testing will require a pretest/posttest method to identify specific symptoms. Establishing a control group and essential criteria used in a blind study will attempt to identify those with PSP out of a randomly selected group of subjects. The test will first use current assessment criteria. The second test will use the isolated specific symptoms for testing and results presented during debriefing. The research will not select PSP subjects. A local neurological center will refer patients willing to participate in the research upon request.
Design
Once researchers establish assessment criteria questions, each participant in the experiment group will be interviewed with the new criteria and graded by symptoms. During debriefing the results will be presented to the researcher to verify whether the hypothesis was valid. The research process of using a blind study will add validity to the study as a whole. Researchers will not know which patients in the test group physicians have previously diagnosed with PSP; therefore, researchers may only rely on assessment criteria created for the experiment as a means of proper diagnosis. The assessment will combine both medical information (MRI &PET )scan plus questions extracted from related symptoms of the PSP only selection interviewed at the pretest portion of the experiment.
Quantitative VS Qualitative
The research project will consist of a triangulation method, including a quantitative survey, qualitative interviews, qualitative grounded theory/coding and interpretive phenomenological analysis (Frost, 2011).
Interview/Narrative
Interviews of patients will provide information on both symptoms and the impact of those symptoms on the patient’s life. The patients may also provide information regarding symptoms unidentified with current assessment criteria (Frost, 2011).
Grounded Theory
Charmaz (2006)Sergi Fàbregues, and Paré (2007) indicate interviews and coding provide information bases on identifying commonalities with a specific problem. Following the transcription of all interviews, researchers will perform four levels of coding to isolate symptom commonality and anomalies. The hypothesis, if found correct, a group of PSP specific symptoms, may begin to take shape. Researchers will then develop a series of questions and test the control and unknown (blind group). Upon successful completion a series of symptoms should isolate those only diagnosed with PSP. The use of IPA will indicate the patient’s interpretation of their symptoms and register the impact of those symptoms (Frost, 2011). During the interview process, the researcher will ask the patient to list symptoms in level of difficulty. The patients will also indicate any symptoms that affect their lives unlisted by physicians or outside of the criteria.
Participants
The experiment consists of first a PSP group of 25 patients. These patients will provide survey and interview information regarding symptoms. The small groups' answers/interviews/coding will provide a pool of symptoms from which to construct questions for the experiment group. The test of the second group (experiment group) will be a mix of a healthy control group and PSP diagnosed patients (N=40). The experiment will present a blind study as the research will not know which individuals’ physician previously diagnosed with PSP.
Procedures
The specific research design analysis parameters chosen for the assignment cover the areas of survey collection, ethnology/grounded theory, pre-test/posttest/control group, and interpretive phenomenological analysis (Rugg & Petre, 2007). The use of semi-experimental designs in the case of PSP symptom research provides a useful tool for collecting patient information (Barnes, 2019). Though ethical consideration and of both HIPAA laws and patient privacy may come into play, ways of protecting privacy do exist (American Psychological Association, 2017). The use of a letter/number system (3A, for example) can protect the privacy of the patient effectively (American Psychological Association, 2017). Bulmer (2009) explains that often during university studies, instructors put forth little effort in teaching useful surveying processes and methods.
Pinter, Toninelli, and De Pedraza (2015) describe a survey as a means to collect a sample set of information as a representation of a larger group of individuals. The term sample, in this case, is used to indicate a set of information providing a statistical representation of the group as a whole (Pinter, Toninelli, & De Pedraza, 2015). The information can then generate a percentage of the representation of the group, which reflects the thoughts or behaviors of a larger group. Surveys provide important information toward PSP research for two purposes. The collection of symptom information the most important but also a visual example of those with accelerated symptoms and loss of motor/neurological control. The surveys used during the research will focus on both the number and earliest onset of symptoms via multiple surveys (Bulmer, 2009; Rugg & Petre, 2007). The first survey will organize general symptoms; the second will close in on specific early onset symptoms, and the third will consider specific about the focus symptoms. Dwindling to a specific number of symptoms and focus information will become the foundation of the assessment creation.
The five survey questions are as follows:
Are you currently diagnosed with PSP? If so, what are your current symptoms?
How are the symptoms being managed?
Were you diagnosed with another neurodegenerative disorder before a PSP diagnosis?
Place each PSP in order of difficulty (one being the least difficult ten being the most difficult?
Do you currently have a support structure? If so, describe the support
Would you consider the use of a PSP support group?
The collection of surveys combined with ethnographies provides not only sampling information but also direct experiences of those either supporting patients or suffering from PSP. Stinnett (2012) suggest the use of ethnography had difficulties maintaining an observational status and often succumbed to its history of colonialization and narcissism, which riddle its past use. Ethnography is the use of direct stories and experiences from those living with or experiencing a particular situation or living in a specific region (Stinnett, 2012). The use of ethnography in the case of the current research serves the explicit purpose of telling the story of the disease. Stinnett (2012) explains ethnography can provide a direct connection to an event that a researcher may not grasp with ordinary observation.
The case of using ethnography in PSP research may isolate the most subtle underlying symptoms by speaking directly from the patients and caretakers themselves. All individuals interviewed will fill out a letter of informed consent, and upon signing the letter, receive an assignment of a letter-number code to preserve privacy (American Psychological Association, 2017). The researcher will collect the name and age of the individual only for purposes of further questioning (American Psychological Association, 2017). All personal information will be assigned a digital folder, and all information will be held securely for five years. At the end of the five years, all individuals interviewed will receive a notification, and all information will be destroyed (American Psychological Association, 2017). The study will conduct thirty interviews (15 male and 15 female). The individuals, selected at random, have no other selection criteria except the indication that the patient has a diagnosis of PSP. The individuals will answer the same following questions during the ethnographic interviews to isolate symptoms.
Ethnographic Interview Questions:
What is your current age and occupation?
Where do you classify your residence (urban or rural)?
What is the current stage of your PSP diagnosis?
Using today's date, how long ago was the presentation of your first PSP symptom?
What was your first symptom related to PSP?
Prior to the first noticeable symptom, were there any other noticeable physical issues?
Can you indicate your symptoms from least severe to most severe?
What is the most difficult part of living with PSP?
Have you ever been diagnosed with macular degeneration, Fuch’s Disease, or any form of corneal dystrophy?
Data Analysis
The data analysis portion of the experiment comes in the form of selecting specific symptoms not associated with other neurodegenerative disorders. IPA will provide insight during interviews along with ethnography and grounded theory (Frost, 2011). Coding provides the main analysis process by which to select symptoms meeting PSP only criteria. There are intentions during the coding to possibly identify currently unknown symptoms that patients overlook as simply aging or age-related memory issues. The use of exploratory data analysis when performing research provides validity while removing research bias from the data collected. Goeman and Solari (2011) explain that exploratory research and analysis is the interplay between exploratory data analysis and confirmatory data analysis. The foundation of the current study hinges on first the exploration ad identification of symptom-based criteria. The information analyzed then renders a confirmed set of data via the combination of ethnographic and survey information. Given the current hypothesis that a possible specific set of PSP symptoms exist independently, the need for openminded research approaches is of the utmost importance. Goeman and Solari (2011) suggest that performing ethnographic and survey testing supplies information correctly identifying specific symptomology of non-biased data provided by patients. The data analysis then provides a non-discriminatory out as the information is not a matter of speculation but instead directly from the patients suffering from PSP. The symptomology of PSP, along with the difficulties in past diagnosis have not provided a complete understanding of the symptom timeline. The difficulty with PSP and the data collection approach is quite simply time. The time taken for proper diagnosis lacks important treatment response time (Boxer et al., 2017). The use of triangulation to isolate specific symptoms of PSP and allowing more time for treatment performs an invaluable service to physicians and patients. The use of exploratory data verifying symptom detection combined with the accumulation of ethnographic data bridges the gap in symptom identification.
Future stages of the experiment would have physicians administer treatment medications along with CBT created for the symptoms indicated. The researcher could reassess cognitive abilities following at one, three, six, and twelve-month duration following administering the medication. The research would not only isolate the symptoms but also create an assessment and follow along with cognitive results before and after treatment. The testing to isolate symptoms could also indicate CBT intervention effects alone, and in the future, medication, later a combined CBT and medication treatment which could meet the criteria of the Solomon Four Group test structure (Rugg & Petre, 2007). Boxer et al., (2017) indicate the use of CBT techniques during the early onset of PSP has shown promise by keeping the patient engaged cognitively. The act of keeping the patient engaged may lead to an invaluable time to organize and test responses to pharmaceutical treatments.
Ethical Considerations
Do No Harm (3.04)The most important aspect of the research comes in the form of working with a group of subjects with cognitive impairment. Researchers must take time to assure caregivers and patients that care is taken to avoid harming the patient's psychological state (American Psychological Association, 2017). Confidentiality (4.01) The researcher will assure patients and caregivers that all information will remain confidential. The researcher will assign each patient a letter-number combination of assuring confidentiality (American Psychological Association, 2017). Informed Consent (8.02)The researcher will create a letter of informed consent and explain the experiment thoroughly. The researcher will instruct patients that they may quit the project at any time without reprisal (American Psychological Association, 2017). Voice and Images (8.03) The researcher will explain that all images, photographs, MRI, PET scans, and voice recordings will remain confidential. The information will only by of use in creating the new assessment criteria. All recorded information, photographs, MRI, and PET scans will either be returned to the patient or destroyed. Upon the need for publication all participants will be contacted, and another letter of consent will be created to authorize use of the information in submission for publication (American Psychological Association, 2017).
Conclusion
Progressive Supranuclear Palsy remains a debilitating disease with a particularly difficult
Diagnosis. The origin of the identification of PSP came in the form of assessment and
treatment of Parkinson’s disease. Physicians are often perplexed by PSP as it presents
Parkinson’s like symptoms, but as symptoms progress physicians realize they are
beyond the scope of a standard diagnosis. The loss of time is the most detrimental part
of a PSP as the lack of proper diagnosis combined with the lack of correct treatment allows
the disease to progress with little or no intervention. The time for a new assessment criterion
based specifically on PSP symptoms has come. The days of a modified assessment originating
from dated information only puts patients at risk. The combined use of identification
criteria and holistic approach may provide the best chance to manage the cognitive decline
Associated with PSP. The future of PSP research comes in the form of medication and gene
therapies designed to target tau proteins, which are the origin of PSP’s microtubule dysfunction. Working together with collaborative efforts between neurologists, psychologists, and family practice doctors may be the best chance for organizing a treatment and one day finding a cure.
References
American Psychological Association. (2017). Ethical principles of psychologists and code of conduct: Including 2010 and 2016 amendments Retrieved from http://www.apa.org/ethics/code/index.aspx
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.
Barnes, B. (2019). Quasi-experimental designs in applied behavioral health research. In Laher S., Fynn A., & Kramer S. (Eds.), Transforming Research Methods in the Social Sciences: Case Studies from South Africa (pp. 84-96). Johannesburg: Wits University Press. Retrieved from http://www.jstor.org.proxy-library.ashford.edu/stable/10.18772/22019032750.11
Boxer, A. L., Yu, J. T., Golbe, L. I., Litvan, I., Lang, A. E., & Höglinger, G. U. (2017). Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. The Lancet. Neurology, 16(7), 552–563. doi:10.1016/S1474-4422(17)30157-6
Bulmer, M. (2009). Survey Research and Sociology. Sociologisk Forskning, 46(1), 90-95. Retrieved from http://www.jstor.org.proxy-library.ashford.edu/stable/20853644
Charmaz, Kathy C. (2006) Sergi Fàbregues, & Marie-Hélène Paré. (2007). Constructing Grounded Theory: A Practical Guide Through Qualitative Analysis. Papers, (0), 284. https://doi-org.proxy-library.ashford.edu/10.5565/rev/papers/v86n0.825
Dickson, D. W., Kouri, N., Murray, M. E., & Josephs, K. A. (2011). Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). Journal of molecular neuroscience: MN, 45(3), 384–389. doi:10.1007/s12031-011-9589-0
Frost, N. (2011). Qualitative research methods in psychology. New York, NY: McGraw-Hill.
Ghosh, B. C., Calder, A. J., Peers, P. V., Lawrence, A. D., Acosta-Cabronero, J., Pereira, J. M., … Rowe, J. B. (2012). Social cognitive deficits and their neural correlates in progressive supranuclear palsy. Brain: a journal of neurology, 135(Pt 7), 2089–2102. doi:10.1093/brain/aws128
Goeman, J., & Solari, A. (2011). Multiple Testing for Exploratory Research. Statistical Science, 26(4), 584-597. Retrieved from http://www.jstor.org.proxy-library.ashford.edu/stable/23208743
Jalal, MA, Menon, MK. (2017) 'Hummingbird sign,' 'Mickey Mouse sign,' and 'morning glory sign' in progressive supranuclear palsy. Menoufia Med J [serial online] [cited 2019 Sep 28];30:325-6. Available from: http://www.mmj.eg.net/text.asp?2017/30/1/325/211489
Koga, S., Kouri, N., Walton, R. L., Ebbert, M., Josephs, K. A., Litvan, I., … Dickson, D. W. (2018). Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype. Acta neuropathologica, 136(3), 389–404. doi:10.1007/s00401-018-1878-z
Martin, W. E., & Bridgmon, K. D. (2012). Research methods for the social sciences, Volume 42: Quantitative and statistical research methods: From hypothesis to results. Somerset, NJ: John Wiley & Sons.
Pan, P., Liu, Y., Zhang, Y., Zhao, H., Ye, X., & Xu, Y. (2017). Brain gray matter abnormalities in progressive supranuclear palsy revisited. Oncotarget, 8(46), 80941–80955. doi:10.18632/oncotarget.20895
Pinter, R., Toninelli, D., & De Pedraza, P. (2015). Mobile Research Methods: Possibilities and Issues of a New Promising Way of Conducting Research. In Pinter R., Toninelli D., & De Pedraza P. (Eds.), Mobile Research Methods: Opportunities and challenges of mobile research methodologies (pp. 1-10). London: Ubiquity Press. Retrieved from http://www.jstor.org.proxy-library.ashford.edu/stable/j.ctv3t5r9n.6
Phokaewvarangkul, O., & Bhidayasiri, R. (2019). How to spot ocular abnormalities in progressive supranuclear palsy? A practical review. Translational neurodegeneration, 8, 20. doi:10.1186/s40035-019-0160-1
Rittman, T., Coyle-Gilchrist, I. T., & Rowe, J. B. (2016). Managing cognition in progressive supranuclear palsy. Neurodegenerative disease management, 6(6), 499–508. doi:10.2217/nmt-2016-0027
Rugg, G., & Petre, M. (2007). A gentle guide to research methods. [electronic resource]. Open University Press. Retrieved from http://search.ebscohost.com.proxy library.ashford.edu/login.aspx?direct=true&db=cat02191a&AN=aul.10197031&site=eds-live&scope=site
Skidmore, S. (2008). Experimental design and some threats to experimental validity: A primer Paper presented at the Annual Meeting of the Southwest Educational Research Association (New Orleans, LA, February 6, 2008). Retrieved from the ERIC database in the Ashford University Library.
Stinnett, J. (2012). Resituating Expertise: An Activity Theory Perspective on Representation in Critical Ethnography. College English, 75(2), 129-149. Retrieved from http://www.jstor.org.proxy-library.ashford.edu/stable/24238136
Walsh, C. M., Ruoff, L., Varbel, J., Walker, K., Grinberg, L. T., Boxer, A. L., … Neylan, T. C. (2016). Rest-activity rhythm disruption in progressive supranuclear palsy. Sleep medicine, 22, 50–56. doi:10.1016/j.sleep.2016.05.002
Walsh, C. M., Ruoff, L., Walker, K., Emery, A., Varbel, J., Karageorgiou, E., … Neylan, T. C. (2017). Sleepless Night and Day, the Plight of Progressive Supranuclear Palsy. Sleep, 40(11), zsx154. doi:10.1093/sleep/zsx154
Young, Z. T., Mok, S. A., & Gestwicki, J. E. (2018). Therapeutic Strategies for Restoring Tau Homeostasis. Cold Spring Harbor perspectives in medicine, 8(1), a024612. doi:10.1101/cshperspect.a024612
Zhao, Y., Tseng, I. C., Heyser, C. J., Rockenstein, E., Mante, M., Adame, A., … Xu, H. (2015). Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron, 87(5), 963–975. doi:10.1016/j.neuron.2015.08.020