Disease modification and biomarker development in Parkinson disease

Abstract

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.

GBA‐Related Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

“…This evidence does not merely carry a clinical implication, but it is relevant in the attempt of developing disease-modifying strategies. 33 A fundamental research question now is whether GBA phenotypes related to distinct mutation types have a different rate of disease progression and survival in a prospective cohort. If so, stratification by mutation type will be mandatory when designing a clinical trial focusing on GBA-PD.…”

“…Our data expand the spectrum of nonmotor features associated to GBA and suggest that different types of mutations might underlie distinct phenotypic profiles. This evidence does not merely carry a clinical implication, but it is relevant in the attempt of developing disease‐modifying strategies 33 . A fundamental research question now is whether GBA phenotypes related to distinct mutation types have a different rate of disease progression and survival in a prospective cohort.…”

Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction

“…The olfactory bulb and lower brainstem have been considered as the induction site for the onset of histopathological features comprising of both Lew bodies and Lewy neurites [73,77]. Along with the peripheral nervous system, such histological aberrations also begin to appear in gut nerve plexa and the olfactory bulb, thereby indicating participation of olfactory bulb cell layers in the progression of neurodegenerative pathology of PD [78].…”

Phenotype-Agnostic Molecular Subtyping of Neurodegenerative Disorders: The Cincinnati Cohort Biomarker Program (CCBP)

“…We have long assumed that the neuropathological findings of aggregated α-synuclein (α-syn) into Lewy bodies and Lewy neurites define and cause Parkinson’s disease (PD) and that aggregations of amyloid (Aβ) into plaques and tau into neurofibrillary tangles define and cause Alzheimer’s disease (AD), and that the distribution of these proteins explains their clinical heterogeneity ( Espay et al, 2020 ). These pathological findings are, however, ubiquitous and do not correlate with agnostic post-mortem analysis: α-syn, Aβ, and tau aggregation are frequent “co-pathologies” in AD and PD ( Irwin et al, 2017 ; Boyle et al, 2018 ; Karanth et al, 2020 ) and can be found even in super-survivors without dementia or parkinsonism ( Head et al, 2009 ; Wallace et al, 2019 ).…”