Likewise, neuroimaging has highlighted pathophysiological changes that occur in Parkinson’s disease. Parkinson’s is caused by the gradual deterioration of dopaminergic neurons in the substantia nigra, a structure responsible for the generation of movement.23 The motor symptoms of Parkinson’s, however, begin only after about 50% of these neurons have been lost.1 As in Alzheimer’s, the long prodromal phase in Parkinson’s provides opportunities for neuroimaging to facilitate early diagnosis, including at the pre-motor stage.24
One disadvantage of these neuroimaging tools is that they are expensive: a single PET scan costs up to $4000 USD and is, in many cases, not covered by health insurers. Instead, a more cost-efficient and more widely available approach may be to detect markers of disease through a simple blood test.
Recent studies of Alzheimer’s disease have shown that the same amyloid proteins that accumulate in the brain can also be found in the blood of high-risk patients.25-26 These discoveries may one day make it possible to screen patients for Alzheimer’s disease in a primary care setting. In Parkinson’s disease, preliminary research suggests that blood tests could be used to distinguish the disease from other neurological problems that share some of the same clinical features.27 In recent years, peripheral tissue biopsies (e.g., of skin, salivary glands or gastrointestinal tract) to detect pathological aggregates of alpha-synuclein have also shown promise as diagnostic biomarkers.28 Although these tests are not ready for clinical use, they represent a first step toward cost-effective technologies that could be used to detect these neurodegenerative diseases prior to the onset of disabling symptoms.
Once detected, the early stages of Alzheimer’s and Parkinson’s disease offer a valuable opportunity for clinical intervention. Pre-patients may be able to reduce their risk of Alzheimer’s disease progression through lifestyle adjustments, such as by exercising or seeking out social or cognitive stimulation.29 Other evidence points to the importance of controlling cardiovascular risk factors in midlife—vascular problems, for example, may accelerate the buildup of amyloid plaques in the brain.30 In all, nearly one-third of Alzheimer’s cases may be preventable based on modifiable risk factors.31-32
Pharmacological treatments for Alzheimer’s disease that act early in the disease process have also become more promising. In particular, one landmark study (the “A4 Study”) is currently testing whether disease-modifying therapies can prevent cognitive decline due to Alzheimer’s in high-risk older adults who have no symptoms of disease.33 The success of these new therapeutic agents in clinical trials would make it even more important and timely to diagnose Alzheimer’s earlier and more accurately. In Parkinson's disease, evidence is sufficiently strong to recommend physical activity and, arguably, moderate doses of caffeine, for primary prevention.34 Pharmacological interventions targeting numerous pathophysiological pathways are under active investigation. Besides the role of biomarkers in identifying patients earlier in their disease course, "biomarker-driven phenotyping" in Parkinson's disease (which is heterogeneous regarding the underlying molecular pathogenesis) could be used to enrich clinical trials with biologically more homogenous subtypes which are more likely to respond optimally to therapies that affect the biological processes within each subtype (for example, where mitochondrial dysfunction or inflammation is central).35
Because effective disease-modifying treatments for Alzheimer’s and Parkinson’s are not yet available, advancements in the earlier detection of disease raise a key question: how many patients would want to know whether they had a high risk of developing a neurodegenerative disorder 10, 15, or even 20 years prior to the onset of noticeable symptoms? Would you want to know, even if there was no treatment to stop the disease? The answers that most people give to these questions may surprise you. A large, global survey of more than 10,000 people conducted by a healthcare company in 2014 found that nearly 75% of people would want to know if they were prone to developing a neurological disease, even if there was no cure.36 The survey also found that an overwhelming majority of respondents (83%) thought that early detection and diagnosis was important and over half would be prepared to pay for testing themselves, even if not covered by health insurance.
Because Alzheimer’s and Parkinson’s disease are characterized by devastating neurodegenerative changes, informing someone who has yet to receive a diagnosis of either disease that he or she may experience life-changing problems in the near or distant future is a sensitive topic. Although our understanding of the risk factors linked with neurodegenerative diseases has advanced, it is important to note that not all patients experiencing these disease “markers” will in fact go on to develop disease in the future. The inherent uncertainty of preclinical diagnosis poses numerous ethical concerns, which will be discussed in Part 4 of this four-part series. Briefly, however, a few benefits and risks of early detection and management should be mentioned. On the one hand, early detection provides pre-patients with the valuable gift of time—time to make decisions about their personal and medical life while they still retain decisional capacity.37 Patients with a high likelihood of developing Alzheimer’s, for example, have time to create a living will, travel, and experience life in a manner that may not be possible after full symptom onset. On the other hand, receiving news that one is at high-risk of developing a neurodegenerative disease can cause significant psychological distress. An ongoing conversation among healthcare providers, geneticists, and patient advocacy groups is therefore needed to ensure that early diagnostic markers are used in the most appropriate and sensitive manner.
Earlier recognition, coupled with thoughtful and compassionate intervention, may improve the overall quality of life for patients in the preclinical or prodromal stages of disease and increase the number of years that patients live without disability. With the ability to detect markers of disease earlier and earlier prior to clinical onset, researchers have also begun examining treatments that may either stop or slow the progression or development of disease altogether. If such initiatives are successful, the world may one day see a dramatic decrease in the number of patients suffering from Alzheimer’s and Parkinson’s disease. While these advancements may still be years in the future, the ambition to prolong a healthy and fulfilling life for future patients is a worthy cause.
We would like to thank Professor John Hardy for discussing what is currently known as well as ongoing issues in preclinical and prodromal neurology which provided the foundation for this article.