An Emerging Framework for Parkinson Disease Therapeutics

Ratliff, MD,Jeffrey;

An Emerging Framework for Parkinson Disease Therapeutics

December 20, 2021

Jeffrey Ratliff, MD

Publication

Article

NeurologyLiveDecember 2021

Volume 4

Issue 7

The diagnosis of Parkinson disease may seem straightforward at first, requiring neurologists to rely on their eyes and hands, but the treatment process can present challenges for both physicians and patients.

Jeffrey Ratliff, MD

FOR CENTURIES, the diagnosis of Parkinson disease (PD) has relied on clinicians’ ability to recognize the clinical manifestations of the disease, both motoric and nonmotoric.^1,2 The diagnosis may seem straightforward at first, requiring neurologists to rely on their eyes and hands to detect the cardinal motor features of bradykinesia, resting tremor, and rigidity. In 1912, the neuropathological finding of what would come to be called Lewy bodies in the neurons of brains of patients with PD helped shape the clinicopathologic model of the disease.³ Decades later, key research identified the presence of α-synuclein in Lewy bodies and its potential pathogenic role in PD.^4,5 This model that Lewy bodies, comprised primarily of α-synuclein, are the pathogenic hallmark of PD has been instrumental in driving understanding of PD and its underlying mechanisms. The discovery of α- synuclein in extracerebral tissues such as the gut or the peripheral nervous system has increased excitement about possible biomarkers and their potential utility in making the diagnosis of PD earlier on.^6,7 With potentially earlier diagnosis comes increased hope for early interventions with yet-to-be-developed disease-modifying drugs and compounds.⁸

Despite increased knowledge about the role of α-synuclein and Lewy bodies in PD, the challenges in making more progress toward disease-modifying therapies has become a sticking point for many in the scientific and clinical Parkinson communities. Although not a new idea, the call to question the prevailing clinicopathologic model of PD has been increasing in its intensity.^9,10 Emerging now is the idea that the quest for disease-modifying therapies should not rely solely on defining PD by aggregates of α-synuclein but instead consider that the underlying mechanisms for what clinicians define as PD may be myriad. Thus, the future of therapeutic offerings in PD may be similarly varied and tailored to patients’ individual Parkinson syndromes, which are defined molecularly rather than clinically.¹¹

In this issue, we feature emerging information about the role of acetylcholine in gait and gait dysfunction by Alex Dalrymple, MD. One need not treat many patients with PD before encountering the disability and frustration that can come with the difficulties inherent to gait instability and dysfunction. This frustration is compounded by the often underwhelming or downright ineffectual impact of levodopa and other dopaminergic therapies for this disabling issue. Dalrymple’s article builds upon a larger body of research that has demonstrated that degeneration in cholinergic nuclei and dysfunction of cholinergic systems may underlie many of the disabling clinical features of PD that fail to respond to standing dopaminergic therapies.^12-16

The work to build a more complete and effective armamentarium of therapies for PD will be complex. With increased understanding of the nondopaminergic neurophysiologic mechanisms that result in the constellation of clinical manifestations in PD, there is hope that we can develop more therapies that target the non–dopamine-responsive symptoms that have frustrated patients, families, and clinicians alike. In addition, with evolution in the conceptual framework of the underlying molecular mechanisms in PD, perhaps there will follow more ready development of disease-modifying therapeutics for individuals with PD. These therapeutics may rely less on our eyes and hands in defining someone’s clinical syndrome and more on an individualized molecular profile that guides selection of therapeutic options. Ultimately, with an open mind as well as expanding innovation in clinical trial design, there is a reason for optimism in the Parkinson community.