How you’ll grow up, and how you’ll grow old

By Nathan Ahlgrim

Nathan Ahlgrim is a third year Ph.D. candidate in the Neuroscience Program at Emory. In his research, he studies how different brain regions interact to make certain memories stronger than others. In his own life, he strengthens his own brain power by hiking through the north Georgia mountains and reading highly technical science...fiction.

An ounce of prevention can only be worth a pound of cure if you know what to prevent in the first place. The solution to modifying disease onset can be fairly straightforward if the prevention techniques are rooted in lifestyle, such as maintaining a healthy diet and weight to prevent hypertension and type-II diabetes. However, disorders of the brain are more complicated – both to treat and to predict. The emerging science of preclinical detection of brain disorders was on display at Emory University during the April 28th symposium entitled, “The Use of Preclinical Biomarkers for Brain Diseases: A Neuroethical Dilemma.” Perspectives from ethicists, researchers conducting preclinical research, and participants or family members of those involved in clinical research were brought together over the course of the symposium. The diversity of panelists provided a holistic view of where preclinical research stands, and what must be considered as the field progresses.

Throughout the day, panelists discussed different ethical challenges of preclinical detection in the lens of three diseases: preclinical research and communicating risk in the context of Autism Spectrum Disorder (ASD), interventions and treatment of preclinical patients in the context of schizophrenia, and the delivery of a preclinical diagnosis and stigma in the context of Alzheimer’s disease. The symposium was bookended, appropriately, by discussions of two diseases that typically emerge at the beginning and end of life: ASD and Alzheimer’s disease. Drs. Cheryl Klaiman and Allan Levey discussed the clinical research of ASD and Alzheimer’s, respectively. Drs. Paul Root Wolpe and Dena Davis framed the clinical research by highlighting the ethical challenges that must be addressed with preclinical research of those diseases. 

Attempting to detect markers of ASD in infants and Alzheimer’s disease in middle aged adults raises distinct ethical challenges; even so, common hurdles arise in both diseases, highlighting the universality of the questions that all preclinical research must address. The shortcomings of current scientific practice were vividly portrayed during the symposium by people who are both involved in the research and touched by these diseases. As is true for many ethical dilemmas, day-long discussions of these ethical concerns did not produce resolutions. The discussion did spawn a consensus, however: transparency in conveying the implications of preclinical research and the options for the patient going forward is critical to ensuring all patients and families are treated with the dignity they deserve. 

Image courtesy of The Blue Diamond Gallery.

Both ASD and Alzheimer’s disease are proliferating in their prevalence and visibility. ASD, a developmental disorder that disproportionately affects boys over girls, is principally characterized by deficits in social communication and repetitive behaviors. It is now estimated that 1 in every 68 children will be on the autism spectrum [1]. Alzheimer’s disease, the most common cause of dementia, is an age-related progressive neurodegenerative disease that is characterized by a progressive loss of memory and other cognitive functions. Furthermore, over 5.5 million people are currently living with Alzheimer’s disease in the United States, and that number is expected to double in the next 20 years. Given the prevalence of both disorders, most of us know someone diagnosed with ASD or Alzheimer’s even if we have not been personally affected by these disorders. 

However, visibility can backfire by putting a spotlight on the frightening implications of an Alzheimer’s disease or ASD diagnosis. One parent of an autistic patient shared how he was forced to deal with the consequences of such fear after consulting a doctor about his son’s social development. Although the pediatrician believed that the child was autistic, the pediatrician refrained from sharing this diagnosis because he could not bring himself to deliver what he deemed a ‘death sentence.’ Only later, after the family received the diagnosis by seeking a second opinion, did the pediatrician disclose the original diagnosis. 

This doctor’s (poor) choice of words and delayed diagnosis were discussed, largely unfavorably, during the symposium. Even so, we can all empathize with the fear of a diagnosis that we do not fully understand. Being given a diagnosis of either Alzheimer’s disease or ASD before clinical symptoms manifest raises the specter of a loss of autonomy. As Alzheimer’s disease develops, a patient can lose his or her autonomy as cognitive functions fail. In addition to the personal loss of control, patients with Alzheimer’s disease are often unfairly stigmatized by their community. Loved ones can fear of becoming a caregiver and prematurely withdraw from relationships. Misinformation about early-stage Alzheimer’s can also jeopardize a patient’s employment long before he or she becomes cognitively impaired. Autonomy can similarly concern parents of a child with ASD. After the diagnosis, parents may feel cornered into lifelong care for their child, who may lack access to community resources and never be able to live independently. Not only that, but the mountains of evidence disproving the role of parenting in ASD development are not always sufficient to protect parents from being blamed for their child’s disorder, either by themselves or their community. 

Of course, the goal of preclinical research is to strike before the disease progresses – before it is too late to intervene. Clinical trials for both ASD and Alzheimer’s suggest that effective treatments rely on early detection, asking researchers to push the current boundaries for preclinical detection and diagnosis. Treatment outcomes in ASD drastically improve the earlier that intervention starts, which is why Dr. Cheryl Klaiman and the Marcus Autism Center are continuing research of behavioral markers that identify differences in the social behavior of infants as early as 6 months of age [2]. 

Artisitc representation of the neurodegeneration and memory

loss that occur in Alzheimer's disease.  Image courtesy

of Flickr user, Kalvicio de las Nieves.

Sadly, all drugs to treat Alzheimer’s disease that were promising in animal models have failed to show any benefit for human patients. FDA-approved drugs taken by patients with Alzheimer’s only act to treat the symptoms, not the disease. And even those few approved treatments do not provide symptom relief for all patients. The repeated failures of Alzheimer’s clinical trials may be a product of intervening too late. Dr. Allan Levey described how the brain pathologies of Alzheimer’s disease – plaques of amyloid-beta and tangles of tau – are developing for decades before any cognitive impairments appear [3]. 

However, pushing preclinical diagnosis earlier and earlier raises several concerns. In favor of early diagnosis is the notion that even when scientists do not have good news, the patient’s (or parents’) autonomy must be respected (see the Belmont Report). Therefore, the ethical course of action would appear to be to inform the patient when a positive diagnosis is present, whether the disease is in a clinical or preclinical stage. Only then can the patient (or family member) make an informed decision about his or her health. 

Dr. Paul Root Wolpe presented a counter-argument against informing a patient in all circumstances: given that the preclinical state is, by definition, before clinical symptoms exist, any preclinical diagnosis is probabilistic. What is the threshold before informing and intervening, 80%? 50%? Is it more ethically responsible to subject a family to intensive and expensive treatment for ASD when it is not present, or to let the disorder go untreated? The Belmont Report’s mandate on beneficence and non-maleficence does not offer a clear answer. When striving to act with beneficence and non-maleficence, preclinical research relies on relative risk. That is problematic, given that Dr. Wolpe believes that humans are not built to understand relative risk. 

The risk for Type I error (a false positive) in the case of preclinical ASD may be negligible. Behavioral therapy designed to help those with ASD has been shown to benefit all children, typically developing or not. Therefore, the only possible harm would be asking extensive time and effort of the family that was not strictly necessary. Still, with the universality of the benefit, one wonders why scientists should bother with early detection for ASD. Integrating such therapy into all classrooms would both provide treatment for the children who needed it and reduce the stigma of being “abnormal” or “other,” since all children would participate in the same experience. 

Image courtesy of Flickr user, Melissa.

Alzheimer’s disease is different. Science has yet to provide an effective treatment for the disease, and thus a preclinical diagnosis cannot initiate a treatment plan. As mentioned previously, the discovery of effective treatments will likely depend on the ability to detect the disease and intervene early in its progression. This order of events unfortunately means the first cohorts of research participants will not reap the benefits of the science they contribute to. The panelists and audience at the symposium were, unsurprisingly, more split on whether they would rather receive a preclinical Alzheimer’s disease diagnosis for themselves than a preclinical ASD diagnosis for their child. Luckily, patients with preclinical Alzheimer’s disease retain full cognitive function, and thus maintain their capacity for autonomy. However, this does not hold true as patients progress from preclinical to clinical Alzheimer’s disease. Changes in personality coincide with [4] or even precede [5] a clinical diagnosis of Alzheimer’s disease, often causing the clinical Alzheimer’s disease patient to have different wishes and beliefs than the preclinical Alzheimer’s disease patient. With this in mind, many audience members voiced the opinion that they would prefer to die before the cognitive symptoms of Alzheimer’s began.

However, Dr. Dena Davis brought more nuance to this idea, saying that our prospective sympathy as healthy individuals – our ability to accurately predict how we will feel once in a disease state – is profoundly flawed. A proponent of the right to die, Dr. Davis painted a troubling portrait of a patient given a diagnosis of preclinical Alzheimer’s disease. Say that person chooses to end his life once he becomes severely cognitively impaired. By the time the impairment has taken hold, he may no longer remember the initial wish, or may completely change mind. Whose wishes are to be honored: those of the clinical patient or those of the preclinical patient? This conundrum was also heartbreakingly described in Lisa Genova’s novel, Still Alice. 

This quandary is why discussions between ethicists, scientists, and patients are necessary. The ability to detect a disease before clinical symptoms appear is a laudable scientific achievement, but knowledge must be put in context of the consumer of those technologies. Without context, scientific discoveries fail to do good, and can often do harm. 

Effective medicine requires support and trust from the community. Two doses of the Measles-Mumps-Rubella (MMR) vaccine are 97% effective against measles, and yet there were 61 cases in the U.S. in the first four months of this year. These cases occurred a full 17 years after endemic measles was effectively eliminated in the U.S. [6], and are primarily a result of poor vaccination rates. A combination of fear of unsafe vaccines, mistrust in doctors, and a lack of belief in the need of vaccinations drove parents away from the established research of the effectiveness and necessity of vaccines. In parallel, fear of stigma and an unwillingness to face the diagnosis of a brain disorder could similarly push patients away from treatments if scientists are not diligent in their education and branding of the research. 

Nathan created this image to be used as the logo for the

April 28th neuroethics symposium. 

The investment of patients enrolled in preclinical research may produce a larger effect size in clinical trials than would ever be practical outside of a research environment due to the self-selectivity of the participants. Only invested parents would enroll their children in studies that demand time and continuing effort. Similarly, only highly self-motivated study participants would stick to a treatment schedule of infusions and lumbar punctures before Alzheimer’s symptoms ever appeared. One symposium speaker was first drawn to participate in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study because of a family member who suffered from Alzheimer’s disease. Personal ties to the research are stronger motivators to patients than any academic rationale scientists can create. If preclinical research for either disease does produce an effective treatment, both scientists and community health partners will need to put forth the additional effort to instill the treatment with broad appeal and accessibility. 

The burden of garnering community support may fall on scientists more than many scientists might like to admit. Our representative participant in the preclinical Alzheimer’s study was quick to say that personal interactions keep him motivated to continue the study. A large part of the reason why he voluntarily receives infusions of a trial drug by Dr. Allan Levey’s team, and is considering doing a lumbar puncture, is because of the people on the team. The need for scientists to consider the ethics of their research is obvious. However, as our representative study participant underscored, scientists’ interpersonal relationships with their patients must also be consciously developed. That is the only way that the resulting research will do any good in the community. 

Scientists are still developing treatments for Alzheimer’s disease and ASD. No magic bullet is likely to ever appear. However, a diagnosis does not need to be a death sentence. Preclinical detection enables intervention before clinical pathology appears, allowing for an ounce of prevention to be applied before a pound of cure is needed. This is not to diminish the years of demanding, often heartbreaking labor that is asked of caregivers of people with Alzheimer’s disease or ASD. What should drive the scientific research and treatment plans? When asking what is good for the patient and his or her family, we as scientists must always remember who we are serving, and what our end goals are. As one parent at our meeting remarked, “we may not have the cure, but we have the care.”

References



1. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. 2016, Centers for Disease Control and Prevention.



2. Jones, W. and A. Klin, Attention to eyes is present but in decline in 2-6-month-old infants later diagnosed with autism. Nature, 2013. 504(7480): p. 427-431.



3. Serrano-Pozo, A., et al., Neuropathological Alterations in Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine:, 2011. 1(1): p. a006189.



4. Mega, M.S., et al., The spectrum of behavioral changes in Alzheimer's disease. Neurology, 1996. 46(1): p. 130-135.



5. Balsis, S., B.D. Carpenter, and M. Storandt, Personality Change Precedes Clinical Diagnosis of Dementia of the Alzheimer Type. The Journals of Gerontology: Series B, 2005. 60(2): p. P98-P101.



6. Katz, S.L. and A.R. Hinman, Summary and conclusions: measles elimination meeting, 16-17 March 2000. J Infect Dis, 2004. 189 Suppl 1: p. S43-7.



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Ahlgrim, N. (2017). How you’ll grow up, and how you’ll grow old. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2017/05/how-youll-grow-up-and-how-youll-grow-old.html