Two articles published on January 22, 2024, in The Lancet Neurology journal are proposing complementary but different research frameworks for biological definitions of Lewy body disease, a label reflecting the underlying biological changes behind dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). Two groups of preeminent PD researchers have each proposed a biological framework against which research theories can now be rigorously tested. These frameworks will help advance the understanding of PD and its similarities with and differences from dementia with Lewy bodies (DLB).
Lewy Bodies: The Tie that Binds Parkinson’s Disease and Dementia with Lewy Bodies
Lewy bodies are deposits of a misfolded natural protein called alpha-synuclein (a-syn); this abnormal a-syn can be seen by microscope in brain cells called neurons and is characteristic of Lewy body disease. Over time, Lewy body disease causes clinical changes including impairment in cognition and movement, as well as disrupting sleep, behavior and automatically regulated bodily functions like maintaining blood pressure and temperature.
DLB is the second most common form of neurodegenerative dementia after Alzheimer’s disease. In DLB people experience disabling cognitive impairment early; some changes in movement may accompany or follow the cognitive impairment. In contrast, people with PD typically experience changes in movement and variable degrees of cognitive and non-motor symptoms; PD is also associated with the presence of Lewy bodies in the brain. Many people with PD will go on to develop PD dementia (PDD). Both PD dementia and DLB are contained within the umbrella term Lewy body dementia.
The distinctions between PD, PDD and DLB are based on the clinical differences in the timing of movement and cognitive-behavioral symptoms. It is unclear why some people with Lewy body disease develop DLB while others develop PD; at present, there is a lack of consensus in the research community about whether DLB and PD have identical disease processes or not. These proposed research frameworks will enable researchers to examine this question and other important questions more thoroughly to advance the field.
Leveraging Biomarkers for Lewy Body Disease
Recently, methods have been developed to detect abnormal a-syn during life such as from spinal fluid or skin tissue biopsy. Previously, Lewy body disease could only be detected after death by looking at brain tissue. Using a test called the “a-syn seeding amplification assay” (a-syn SAA), a small sample of spinal fluid can now be tested for the presence of abnormal a-syn. In another method, a skin sample is tested for a form of a-syn. These spinal fluid and skin tissue biomarkers have gained scientific attention for their ability to detect evidence of a-syn in Lewy body disease. Based on spinal fluid tests or skin biopsies from people in several longitudinal studies across the globe, these biomarkers have been validated in those studies’ participants to detect a-syn in Lewy body disease during life.
Recent studies by Swedish researchers suggest that the presence of a-syn in spinal fluid in healthy adults can identify people at risk for future Lewy body diseases like PD and DLB. By detecting the presence of misfolded a-syn at much earlier timepoints, researchers may now have a wider window of opportunity to study potential treatments that could slow or even stop the progression of Lewy body disease, perhaps early in its course or even before clinical symptoms emerge.
Two Biological Frameworks Available for Research Use – Complementary but Different
A “biological definition” of a disease uses medical tests called biomarkers which detect measurable biological changes in a disease over time. Biological definitions and frameworks have also been applied in Alzheimer’s disease (AD), and their use in research has advanced researchers’ ability to detect biomarkers of AD pathology in people long before features of cognitive impairment or dementia manifest. Opportunities for early identification of a disease, like in AD, open up possibilities for early treatments that may alter the course of disease.
One group of PD researchers, led by Drs. Tanya Simuni and Ken Marek, have proposed a biological framework called the “Neuronal alpha-Synuclein Disease Integrated Staging System” (NSD-ISS). The “neuronal” in the NSD-ISS refers to the finding of Lewy bodies mainly in neurons, as is typical of PD and DLB, but in contrast to multiple system atrophy where the misfolded a-syn proteins are found primarily in a different type of brain cell called glial cells. The NSD-ISS framework proposes a research staging system comprised of a biological definition and a schema of disease symptom progression. This staging system is anchored on detecting a-syn in spinal fluid by the SAA test and also by neuroimaging tests (i.e., dopamine transporter scan, or DaT scan) that detect neurodegeneration in areas of the brain that make dopamine). The NSD-ISS framework enables researchers to study PD and DLB as a single disease entity under a common biological staging system.
Of note, the NSD-ISS does not represent all cases in the clinical spectrum of PD and DLB. For example, some individuals with inherited (genetic) forms of PD do not have Lewy bodies on autopsy or a-syn detected on SAA tests; these cases would not meet the NSD-ISS biological definition. Likewise, some people with DLB may test positive for a-syn but may not develop evidence of neurodegeneration on DaT imaging.
Another group of PD researchers, led by Drs. Günter Höglinger and Anthony Lang, have developed a different biological classification system for PD under the name “SynNeurGe Research Diagnostic Criteria.” SynNeurGe is pronounced “synergy” and reflects combinations of three biomarkers used: synuclein, neuronal degeneration (loss of brain cells), and genetics. This research definition is inclusive of the genetic cases of PD without underlying Lewy body pathology. The SynNeurGe framework focuses on evidence of a-syn in spinal fluid or skin tissue, genetic causes, and neurodegeneration that can be detected on a variety of brain or other imaging tests.
The SynNeurGe classification system also aims to unify research on several clinically diagnosed conditions (e.g., PD, DLB, REM sleep behavior disorder, pure autonomic failure) that share the same underlying biology of a-syn deposition and neurodegeneration.
Both new research tools are the first of their kind and were developed by experts in PD. The frameworks will require extensive testing and refinement before either can be considered sufficiently validated. The researchers who proposed both NSD-ISS and SynNeurGe frameworks stated very clearly these tools are for research purposes and NOT for routine clinical use. They are meant to facilitate research including clinical trials. It would be inappropriate to use these tools to make clinical diagnoses.
More work is needed to understand how the progression of Lewy body disease differs between DLB and PD. Additional research, especially in DLB, is essential and may strengthen the case for one or both of these frameworks, or it may suggest that further iterations of the frameworks are needed. At present, the clinical diagnoses of PD and DLB remain applicable to people affected by the disease and allow clinicians to make the diagnosis and plan treatments accordingly. Additional research and validation studies particularly in DLB will be essential to establish an understanding of shared biologies and whether a single framework fits both DLB and PD.
What LBDA is Doing on Your Behalf
The LBDA is working actively to increase both scientific discourse and the sharing of scientific advances and lessons learned across the DLB and PD fields. The LBDA also is advocating for the rapid expansion of research studies using a-syn and other biomarkers and applying the new biological frameworks of NSD-ISS and SynNeurGe.
New research discoveries such as detecting a-syn and other markers during life shine a bright light of hope for people with DLB, PD and their families. Accelerating research in PD and DLB can bring increased opportunities to join clinical trials of drugs that may slow or stop the progression of Lewy body disease as well as improve clinical symptoms.
We have seen how the discovery of biomarkers has changed the pace of Alzheimer’s disease research over the years, and in recent times, FDA-approved drug treatments for Alzheimer’s that target specific proteins associated with the disease.
Now it’s time to change the pace of LBD research. Together, with your partnership and support, we can!