Year: 2025
Type: article
Abstract: A 56-year-old man presents with parkinsonism.Brain imaging reveals calcium deposits in the basal ganglia.His clinician, concluding that the calcifications triggered his symptoms, prescribes calcium chelation therapy.This faux clinical vignette illustrates a fallacy in inductive reasoning.While the observations (brain calcifications, parkinsonism) are accurate, the omission of additional evidence leads to a flawed causal inference: calcifications !parkinsonism.Most clinicians would recognize these calcifications as markers of an underlying calcium metabolism disorder, hypoparathyroidism, expanding the logical framework to hypoparathyroidism !hypocalcemia ![calcifications] !parkinsonism, and prescribe calcium and calcitriol supplementation (or PTH replacement) to increase calcium, not to lower it. Could Pathological Accumulation be Compared to Calcifications?Fictitious clinician: Treating a disorder characterized by excessive calcification with more calcium?Wouldn't that worsen the disorder?The dominant "proteinopathy" model of α-synuclein (αSyn) in Parkinson's disease (PD) follows a similarly flawed logic:As a result, research efforts have focused on eliminating the "accumulation" of pathological αSyn, 1 with animal models extensively used to evaluate how αSyn is "toxic." 2 Increasing monomeric αSyn has not been in the research radar, not even as what might be expected from anti-aggregation interventions in the pipeline.Today's clinician-scientists, akin to the fictitious clinician in our vignette, advocate for "pathology chelation," an agent to bind and remove the pathology.If it fails, they assume that chelation wasn't aggressive enough or did not target all "toxic αSyn species" 3 -and a better chelator is pursued.(In case it is unclear: the reports of negative clinical trials of interventions directly or indirectly lowering αSyn, such as nilotinib, venglustat, minzasolmin, or cinpanemab, have been explained as artifacts of inadequate dosing, insufficient target engagement, or treatment initiated too late.We keep on searching for better anti-αSyn molecules, improved trials, earlier patients, without questioning the relevance of lowering αSyn).
DOI: 10.1002/mdc3.70400
Authors: Alberto J. Espay, Andrew J. Lees
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,400
OpenAlex ID: W4415221093