Time to Freeze: Development of OFF ‐ and OFFON ‐State Freezing of Gait in Parkinson's Disease

Freezing of gait (FOG) can be a debilitating feature in People with Parkinson's disease (PwPD) with limited treatment options. Different FOG subtypes have been defined with varying nomenclature over the years1, 2 with a push to define FOG based on witnessed episodes.2, 3 OFF-FOG or levodopa-responsive FOG refers to episodes that primarily occur in the OFF-levodopa state.1, 2 OFFON-FOG or levodopa unresponsive FOG indicates episodes occurring in both the ON- and OFF-levodopa states.1, 2 People with OFFON-FOG have more severe disease, and lower quality of life than those with OFF-FOG.1 Both groups show equivalent improvement in motor UPDRS and objectively measured spatiotemporal gait parameters with levodopa.4 Rarely, levodopa also induces FOG in those that do not freeze in the OFF-levodopa state, termed ON-state or ON-FOG.1, 2 In early disease an estimated 7% of PwPD have FOG,5 however, the development and progression of OFF-FOG and OFFON-FOG subtypes over the disease course has not been reported. PwPD enrolled in a longitudinal multimodally monitored study between 2014 and 2025 were included (University of Arkansas for Medical Sciences Institutional Review Board protocol # 203234). The levodopa response of FOG in participants with witnessed FOG was noted either retrospectively at initial visits or prospectively at semiannual visits. The approximate date of levodopa-responsive FOG onset was defined as participants’ OFF-FOG onset date. The approximate date when participants developed FOG which improved but did not resolve, or did not significantly improve with levodopa, and attempts to adjust levodopa dosing had failed, was defined as their OFFON-FOG onset. No pure ON-FOG participants enrolled. Those remaining non-freezers did not report FOG, nor was it witnessed during semiannual 3-h research visits. The median age at motor onset was 59.6 (IQR: 53.5–67.4; N = 136, 60 female). Even after motor onset, most PwPD live OFF-FOG free for a long time; 98 PwPD developed FOG with median time from motor onset of 9.1 years (Kaplan–Meier CI95%: 7.5–10.7) (Fig. 1A). Fifty-four of those with OFF-FOG progressed to OFFON-FOG with median time from OFF-FOG onset of 5.7 years (Kaplan–Meier 95% CI: 3.9–7.3) (Fig. 1B). In the 38 PwPD who remained non-freezers, when last assessed motor disease duration was 7.4 (IQR: 5.5–12.5) years with median monitoring of 3.5 years. For the 44 PwPD who had not progressed from OFF-FOG to OFFON-FOG, disease duration was 13.1 (IQR: 9.2–16.1), monitored for 6.3 years. Three people developed OFFON-FOG at FOG onset. Limitations of these findings are partial reliance on self-report of FOG levodopa response, exact onset in those with FOG pre-enrollment, and certainty of remaining non-freezers status. Without validated objective home monitoring technology this remains a limitation of all such studies. With ~28% of PwPD remaining FOG-free after 7 years of motor disease, and ~5 years between OFF- to OFFON-FOG conversion, the development of targeted neuroprotective strategies should be achievable. Multi-center progression monitoring studies utilizing defined criteria are needed to develop FOG conversion prediction models. Without accurate risk-stratification of participants with an estimated time to developing the FOG phenotype of interest, disease modifying trials will not be successful. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3). Manuscript: A. Writing of the first draft, B. Review and Critique. T.V.: 1A, 1B, 1C, 2A, 2B, 3A, 3B. L.P.: 1B, 3C. R.D.L.: 1C, 2A, 2B, 3B. All authors approved the final version of the manuscript. The authors appreciate the dedication of the participants to repeated longitudinal assessments over time, without which this work would not have been possible. Ethical Compliance Statement: This study was approved by University of Arkansas for Medical Sciences Institutional Review Board protocol # 203234. Informed consent was obtained from participants before performance of study assessments. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Financial Disclosures and Conflict of Interest: This work was supported in part by the UAMS Clinician Scientist Program, NIH NIGMS (grant number GM110702) and the Parkinson's Foundation (grant number PF-JFA-1935). For parts of this work, TV received salary support from the University of Arkansas for Medical Sciences (UAMS), salary from the UAMS clinician scientist program (UAMS CSP), salary from a grant from the Parkinson's Foundation (PF-JFA-1935) and a pilot NIGMS award (GM110702). LP, received salary support from the UAMS CSP, PF and NIGMS pilot awards (to TV). RDL received salary support from NIH/NCATS (UL1 TR003107, UM1 TR004909) and the PF grant. None of the authors have any financial disclosures or conflicts of interest related to the research covered in this manuscript. Financial Disclosures (Preceding 12 Months): TV received salary support from employment at the University of Arkansas for Medical Sciences and NIH/NCATS award (PI: Laura James; UM1 TR004909). Speaking fees from the International Consortium of Freezing of Gait Annual Meeting. LP received salary support from employment at the University of Arkansas for Medical Sciences. RL received salary support from employment at the University of Arkansas for Medical Sciences and NIH/NCATS award (PI: Laura James; UL1 TR003107 and UM1 TR004909). The data that support the findings of this study are available from the corresponding author upon reasonable request.