Prodromal Neurologic Disease: Early Markers and Earlier Opportunities for Treatment*

Date/Time: Monday, September 11, 2023 - 8:45 AM – 10:45 AM
Track: Plenary
Room: Salons E-F (5th Floor)
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Chair: Rebecca Gottesman, MD, PhD, FANA

Co-Chair: Allison Willis, MD, FANA

The growth of our understanding of the development and progression of neurodegenerative disease, through clinical translational neurology research, has only been matched by the actual growth of the population at risk of being diagnosed with these disorders. Due to recent breakthroughs in understanding, the potential for treatments that prevent neurodegeneration before it presents as symptoms such as memory loss, shaking, shuffling, and hallucinations, is greater than ever before. But many questions remain- what do we still need to know to develop effective neuropreventative treatments? Who would receive such treatments and why? This plenary session focuses on current knowledge gaps, as well as the research, clinical, policy, and ethical considerations of success (and failure) to identify and intervene in Alzheimer's Dementia (AD), Parkinson's Disease (PD), and Huntington disease (HD) while they are their pre-symptomatic/ prodromal state. The panel will include leading clinical-translational neuroscientists focused on pre-symptomatic/prodromal AD, PD, and HD, and a neurodegenerative disease bioethicist.

Learning Objectives: 

  • To be able to describe the current state of clinical translational research focused on the prodromal stages of Alzheimer Dementia, Parkinson Disease and Huntington Disease.
  • To understand the current barriers to development or delivery of neuroprotective treatments to the population of persons with premanifest Alzheimer Dementia, Parkinson Disease and Huntington Disease.
  • To describe the bioethical principles that may present barriers to achieving the goal of equitable neuropreventive treatment of Alzheimer Dementia, Parkinson Disease and Huntington Disease, and understand the associated challenges in medical-decision-making academic neurologists may face relating to these principles. 

Raymond D. Adams Lectureship Award:
Preclinical Alzheimer Disease

Speaker / Award Recipient: Marilyn Albert, PhD, FANA

The hallmarks of Alzheimer’s disease (AD) pathology, amyloid plaques and tau tangles, begin to accumulate in the brain as early as middle age, when individuals are cognitively normal. Recent studies of cognitively unimpaired individuals who have been followed longitudinally over time indicate that AD biomarkers of these pathological features have accelerated rates of change prior to the onset of clinical symptoms of mild cognitive impairment (MCI), and are associated with time to onset of MCI. These, and related findings, suggest that this preclinical phase of AD offers a window of opportunity for early intervention. Additional research is needed to identify novel biomarkers that may improve prediction and reveal new treatment targets. It is also important to quantify the additional pathologies that are commonly seen in older individuals with cognitive impairment (e.g., vascular disease, TDP-43) in order to develop optimal treatment strategies.

Prodromal Parkinson Disease

Speaker: Ron Postuma, MD, MSc

The presentation will outline the major features of the early stages of PD, discussing predictive power, specificity and lead time.  The potential for prodromal PD as a means to test neuroprotective therapy will be outlined.  

From Gene Mutation to Disease Prevention: Progress and Challenges in the Huntington Disease Continuum

Speaker: Jane S. Paulsen, PhD, FANA

As an autosomal dominant disorder, HD natural history studies have followed gene mutation carriers throughout the HD continuum. As early as 2001, large-scale multi-national prodromal HD research showed abnormalities decades before clinical expression. While over twenty years of research have now reported extensive biofluid, brain imaging and clinical outcome measures showing very early differences from healthy controls, no qualified biomarkers exist. Despite limitations, endeavors to prevent onset or delay progression of HD continue to propagate. Efforts to identify gaps in our knowledge base to better identify and intervene upon HD in its prodromal state are exigent. Two clear priorities for the HD field are to answer the questions, “when can treatments begin?” and “how can we determine whether a treatment is working?”. Though applications have been limited, numerous strong susceptibility/risk and prognostic HD biomarkers have been identified. Assertions to address the first question have been offered though reproducibility is lacking. Monitoring biomarkers to date are largely restricted to smaller epochs of the HD continuum and most candidates are lacking sufficient longitudinal data. Diagnostic biomarkers to identify individuals with a subtype have been used in a few clinical trials. Efforts to map the current research landscape suggest that some elements essential to fill knowledge gaps and advance progress in prodromal HD are missing. Questions remain about how the scientific community might draw attention to the research, clinical, policy, and ethical considerations impacting prodromal HD intervention. Given rapid advances in technology impacting genetics, wearables, brain imaging and emerging multimodal biomarkers, the opportunities are vast for HD as well as other autosomal dominant neurodegenerative disorders. Progress shared across distinct genetic neurodegenerative diseases has often been synergistic for scientific advancements in the greater translational neuroscientific research fields. More recent ventures to build collaborative research partnerships using autosomal dominant diseases can be expected to further capitalize and expand our shared purpose to facilitate earlier opportunities for identification and intervention.

What are the broader implications of diagnosing preclinical disease?

Speaker: Emily Largent, JD, PhD, RN

"Preclinical" Alzheimer’s disease (AD) presently remains a research construct. Yet, US Food and Drug Administration approval of disease-modifying therapies for symptomatic individuals and advancement toward more accessible AD biomarker testing suggest preclinical diagnoses may be introduced into clinical care sooner rather than later.  This will change the lived experience of AD for millions of patients and their families, as well as surface ethical, legal, and policy challenges for society.  The presentation will address individual and broader implications. 

Early Changes in α-Synuclein Membrane-Binding in the Central and Enteric Nervous System in Parkinson’s Disease

Emerging Scholar Speaker: Virginia Gao, MD, PhD

The physiologic, synaptic functions of Synuclein (αSyn) are mediated by its membrane-binding region, and loss of membrane-binding leads to αSyn aggregation. αSyn aggregates are the main components of Lewy bodies found in both the brain and in the enteric nervous system of Parkinson’s disease (PD) patients. Pathological changes and accompanying neurodegeneration precede diagnosis by years, with changes in gastrointestinal motility among the earliest prodromal symptoms of PD, pointing to the gut as a potential starting point for pathology. We hypothesize that changes in αSyn membrane-binding occur first in the gut and are a marker of early pathology. We measured αSyn membrane-binding in the enteric and central nervous system using both a novel, humanized mouse model and PD human tissue. First, we characterized motor and gastrointestinal function in αSynBAC mice, which express human αSyn under all its regulatory elements, thus enabling human-like spatiotemporal expression of αSyn. αSynBAC mice demonstrate typical motor impairments, as well as impairments of gastrointestinal motility. We then examined expression of αSyn in the brain and gut in these mice, as well as in post-mortem human brain, and colon tissue collected during routine screening colonoscopy in subjects with PD and healthy controls. We show reduced membrane-binding of αSyn in brain and gut in our mouse model as well as in PD cortex. In preliminary results from human PD gut tissue, compared to healthy controls, we see a trend towards decreased membrane-binding of αSyn in the colon as well as changes in post-translational modifications that are known to affect membrane-binding. Changes in αSyn membrane-binding can be detected in a mouse model of PD and in tissue from humans with PD. This study represents the first biochemical assessment of αSyn in the gut, and suggests that decreased αSyn membrane-binding can serve as an early biomarker of disease.

Plasma-Derived Alpha-Synuclein Strains Distinguish Parkinson’s Disease from Dementia with Lewy Bodies

Emerging Scholar Speaker: George Kannarkat, MD, PhD

There is significant phenotypic heterogeneity in neurodegenerative diseases associated with alpha-synuclein (aSyn) misfolding and aggregation, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Multiple Systems Atrophy (MSA). Multiple, recent studies have demonstrated that disease-specific aSyn “strains”, conformations with distinct biochemical properties, can be isolated from brain tissue. Strain-specific properties may influence clinical and pathologic trajectory in synucleinopathies.To determine whether antibodies recognizing two, distinct in vitro-generated aSyn strains have biological relevance, we evaluated their ability to distinguish aSyn strains in vivo using immunohistochemistry, immunoblotting, and ELISA. These strain-selective antibodies recognize different subsets of aSyn pathology in human brain tissue but do not readily detect aSyn in cerebrospinal fluid by ELISA. Remarkably, plasma levels of aSyn species recognized by strain-selective antibodies using ELISA reliably differentiated individuals with DLB from PD in two independent cohorts (AUC up to 0.83, n = 25-115 / group). Furthermore, elevated plasma levels of aSyn recognized by one of these antibodies predicted a slower rate of cognitive decline in individuals with PD. However, levels of plasma aSyn species did not reflect brain levels within two years of autopsy and the biochemical properties of plasma aSyn species isolated by immunoprecipitation differed from those in brain. Finally, aSyn species isolated by strain-selective antibodies from plasma but not brain were able to induce fibrillization of aSyn in vitro.In summary, this study has multiple important findings: 1) aSyn strains are enriched in plasma but not CSF suggesting an origin outside the central nervous system (CNS), 2) plasma aSyn strains could serve as novel biomarkers to differentiate PD and DLB for which no reliable biomarkers exist, and 3) plasma aSyn strains differ from brain counterparts in size and ability to induce aSyn fibrillization. As aSyn pathology is increasingly identified outside the CNS, understanding how and where these strains develop may inform PD and DLB pathogenesis. Determining whether plasma aSyn contributes to the spread of aSyn pathology within the CNS may also lead to novel targets for drug development.