Should old acquaintance be forgot: A call for recognition and inclusion of advanced Parkinson’s disease patients & care partners in evolving research models

1. Introduction

In 2024, the International Parkinson and Movement Disorder Society released a statement with a panoply of considerations regarding the biological definition, staging and classification of Parkinson’s Disease (PD) [1]. Two new proposed staging systems for PD include biological assays that may identify not only early-stage, treatment-naïve patients but even pre-symptomatic individuals who may be ideally positioned for investigating neuroprotective strategies [2,3]. One proposed biomarker-guided system combines “advanced PD, motor fluctuations, cognitive deficits/dementia” [2] in the same biologic stage, illustrating a constellation of symptoms covering a heterogeneous population of people with PD (PWP). The other staging system incorporates evidence of α-synuclein, neurodegeneration, and pathogenic gene variants, collapsing the spectrum of clinical symptoms and signs—both motor and non-motor—into a binary variable, present or absent, without distinguishing prodromal or clinical disease stages [3]. As staging frameworks work towards delineating functional impairment across disease [4], the research community must outline PD stages distinctly and be particularly mindful of advanced Parkinson’s disease (APD) groups. Prior to the new biomarker-based systems, individuals who met the original or modified Hoehn and Yahr (HY) system’s stage 4 or 5 criteria were operationally defined as having late-stage or advanced disease [5]. Herein, APD refers to those individuals meeting HY 4 or 5. The HY system is clinically grounded with relative ease in communicating disease stage to patients and families, but its limitations include its motor-centric focus, which is particularly inadequate in APD as non-motor symptoms mount and impact daily function, care needs, and prognosis [6].

Historically, recruitment and retention of individuals with APD in observational and interventional studies have been limited and even more so among minority populations [5,7]. The longstanding absence of individuals with APD from research translates into a myriad of gaps in the literature: reliable epidemiologic data, clinical management strategies and guidelines, therapeutic trial inclusion, models of care to mitigate loss to follow-up, and development and provision of appropriate community resources to serve the needs of individuals with APD and their families.

As biomarker-driven staging systems emerge that shift research focus towards early disease, it is imperative that we simultaneously investigate the APD population. Biases may hinder this ideal. These include ascertainment bias influenced by prior expectations and fatalism—viewing individuals with APD as “too far gone.” Such subconscious biases negatively impact management and limit research inclusion. Substantiating the existence of such biases: greater than 60 % of a late-stage PD population were not taking medications that offer symptomatic support in PD, including levodopa in any formulation [6], and evidence that advanced nursing home residents (38 % HY 4, 49 % HY 5) were inadequately dosed with levodopa even though dyskinesias were infrequent [8]. Countering such biases: recent consultation with a PD-specialized nurse has been associated with better self-rated health among individuals with APD [9]. While cognitive or neuropsychiatric concerns may explain some of the reported undertreatment, such explanations are unsubstantiated and unlikely to explain the entirety of the problem. Our colleagues in neurocritical care have increasingly recognized the extent to which fatalism and other biases drove counseling and treatment decisions in comatose survivors of severe brain injury, resulting in self-fulfilling prophecies of poor outcomes and a prolonged absence of research into such vulnerable populations [10]. While less dramatic than terminal extubation, our lack of attention and inquiry around APD may represent an unintentional withdrawal of care.

As improved symptomatic treatments and greater life expectancy translate to more individuals with PD living longer and spending more time in APD stages, the prolonged disease burden and its detrimental individual and economic toll will rise. The profiles and needs of not only APD patients but also their closely interwoven care partners require greater recognition, study, and allocation of resources, as do the biases that limit our understanding and inclusion of these groups in research.

2. Challenging but promising prospects of reaching APD patients

Determining an accurate percentage of individuals with PD living in each HY stage is challenged by a host of issues, as HY stage may be absent from national registries or those with APD may be lost to follow-up care and data collection due to advancing disease rendering them homebound. Limited APD representation can be appreciated even in large scale studies, although this may be improving in the past decade. In the landmark 2009 Parkinson and Non motor Symptoms (PRIAMO) study evaluating PD nonmotor symptoms and QoL across 55 Italian centers, individuals staged as HY 4–5 constituted only 4.6 % of 1072 participants surveyed [11]. An international study involving ten countries and twelve centers across three continents assessed non-motor symptoms in PD with greater APD representation: 10.5 % HY 4, 1.7 % HY 5 [12]. Separately, a 2024 US-based study estimated that about 20 % of patients fulfill late stage PD criteria (HY 4–5) [6].

More recent studies have focused exclusively on recruiting and studying the APD population. The Care of Late Stage Parkinsonism (CLaSP) project across six European countries included a large cohort of APD patients (71 % HY 4, 21 % HY 5) and aimed to identify variables associated with health related QoL in APD with an emphasis on health care provision [13]. In a nonrandomized controlled trial of quarterly telehealth-enhanced interdisciplinary home visits, baseline staging prevalence was 63.1 % HY 4 and 15.4 % HY 5. Those receiving home visits experienced stabilization of PD-specific QoL over one year compared to longitudinal decline in usual care, with a significant difference in favor of the study intervention [7]. Among the 258 APD patients across 18 countries who completed the global long-term registry on efficacy and safety of levodopa-carbidopa intestinal gel (LCIG) [GLORIA] registry—where mean OFF HY was 4.0 (standard deviation 0.9)—the average time ON with bothersome dyskinesia decreased by 25 % at 24 months. Moreover, several non-motor symptoms and QoL improved in the LCIG-treated group [14]. These studies demonstrate not only the potential to recruit and retain this population but to effect meaningful clinical change.

3. Shifting value from homogeneity to capturing the Parkinson’s disease spectrum

In the current research landscape, individuals with APD are often reported as a single group combining HY 4 and 5. The lack of clarity in clinical trial criteria for these patients not only complicates but deters research participation. While inclusion criteria can appear generous by including at least HY 4 or leaving HY parameters ambiguous, this population is often barred by descriptive exclusionary criteria that target characteristic features of APD, including unstable treatment response to levodopa and motor complications including dyskinesias [15], use of assistive devices, and eligibility or receipt of device-aided treatments [16] (Table 1). Clinical trials must include more specific and transparent inclusion and exclusion criteria to improve APD representation in research. Distinct HY stages should be delineated in study results, acknowledging the potential for sample size limitations and lack of statistical power for analyzing each stage individually.

Table 1.

Selected active/recruiting PD clinical trials March 2025.

ClinicalTrials.gov Identifier	Intervention	Key Inclusion Criteria	Key Exclusion Criteria
NCT04553185	Observational: genetic variations, motor, cognitive, sleep symptoms	HY not specified	Inability to travel for assessments
NCT02360683	Observational: Subthalamic nucleus stimulation, QoL	HY not specified	Levodopa response <30 %
NCT05094219	Observational: PD economic burden, falls	HY not specified	Wheelchair or bed-bound
NCT06329739	Observational: genetic mutation, behavioral, cognitive outcomes	HY not specified	Prior DBS
NCT05960331	Behavioral: autonomy, motor learning	HY not specified	Severe tremor in upper extremities, prior DBS
NCT06002581	Device: repetitive transcranial magnetic stimulation, motor function	HY 1–4	Prior neurosurgical intervention for PD
NCT05992701	Device: directional DBS, efficacy, safety	HY ≥ 2.5	Prior lesioning surgical treatment, “unwilling or unable to cooperate with post-operative follow-up”
NCT06028529	Device: exoskeleton to improve mobility, feasibility, safety	Modified HY 2–5	Symptomatic orthostatic hypotension with exertion
NCT06840678	Device: home-based transcranial static magnetic stimulation of supplementary motor area, corticostriatal activity, feasibility, safety	HY not specified	Levodopa-induced dyskinesias
NCT04453033	Device: phototherapy, motor, non-motor function	HY not specified	Significant OFF or bothersome dyskinesia
NCT05881460	Device: vibrotactile coordinated reset stimulation, motor function	HY 2–4 ON	Any brain surgery or neurostimulators
NCT05901818	Drug: transplantation of autologous induced neural stem cell-derived dopamine precursor cells, clinical outcomes, safety	HY ≤ 4 ON	Severe dyskinesia, prior brain surgery
NCT06596876	Drug: HRG2010, efficacy, safety	HY 1–4 ON	Prior or planned functional neurosurgical treatment for PD, non-responsive to levodopa
NCT06068465	Drug: pimavanserin, PD psychosis, efficacy, safety	HY not specified	Prior ablative stereotactic surgery for PD
NCT06195124	Drug: RGL-193, APD, safety, tolerability	Modified HY ≥ 3	Prior PD-related brain surgery
NCT06319118	Drug: dihydroergotine mesylate extended release, saliva weight	HY not specified	Severe orthostatic hypotension
NCT04491383	Drug: tocotrienols, motor, non-motor outcomes	HY ≥ 2 ON	Prior surgical intervention for PD
NCT06263010	Drug: allopregnanolone, feasibility, safety, tolerability, efficacy	HY 1–4	Prior DBS for PD
NCT06487975	Dietary supplement: bacillus subtilis, gut, blood biomarkers	HY not specified	Clinically significant motor fluctuations, history of postural instability or falls

Abbreviation: DBS deep brain stimulation.

The trend of combining HY 4 and 5 limits our understanding of disease scope, especially for APD. Many studies have drawn data from the formidable Parkinson’s Progression Markers Initiative (PPMI), with its broad analytical use in studies, accessibility to PWP beyond academic centers, and large sample size. Research from PPMI tends to focus on early-stage PD patients (i.e. two years from diagnosis) [17] which strengthens our knowledge of this population; however, the issue of APD underrepresentation endures. Greater investment and funding could be directed towards retaining APD participants by expanding PPMI’s reach: leveraging its established infrastructure and collaborations and developing additional retention efforts for participants lost to follow-up. Attrition from registries and outpatient practices, common in APD and disproportionately the case among minority groups [7], could be ameliorated by culturally congruent contacts and advertisements, as well as community-based outreach and partnerships to improve retention [18].

We offer two recommendations for consideration. First, when designing studies aside from neuroprotective trials—where methodologically, restricting to those at the earliest clinical or even preclinical stages makes logical and statistical sense—we would encourage careful consideration of any exclusion criteria that unnecessarily restrict participation of those with APD, as the results will also suffer in generalizability. A corollary: as advanced therapies such as Deep Brain Stimulation become more widespread and individuals live longer with interventional therapies, we must reconsider the standard practice of excluding such individuals from trials. Second, the APD population has symptoms and needs that vary from those in earlier stages and thus warrant investigations specifically studying or intervening on APD symptoms (e.g., freezing of gait, dysphagia, unintentional weight loss, cognitive impairment). We acknowledge that design, recruitment, retention, and analysis of studies that incorporate individuals with APD can be fraught with challenges. However, science rarely progresses and the health and quality of life of the population rarely improve if we avoid the most complex challenges.

4. Technology as potential tool, not panacea

Technology has shown potential to augment APD inclusion in research from telemedicine enhancement [7] to the use of online platforms. In a Fox Insight cross-sectional study comparing a Facebook advertising campaign vs. standard recruitment (distribution of information via foundation websites, community events, and printed fliers), more APD patients enrolled with the Facebook campaign (190 vs. 35, p < 0.0001). Initiatives using focused criteria to target patient subgroups, such as APD, recruited significantly more individuals who had never participated in PD research [19].

Although technology can support APD inclusion, remote evaluation may still limit and reinforce preference for early-stage PD. The scope of bringing technology such as wearable sensors into the home to evaluate motor fluctuations may still not reach PWP greater than HY 3. The Parkinson@Home study objectively monitored habitual activity in and around the home during a defined ON and OFF period for HY 1–3 participants. Receipt of any advanced treatment as an exclusionary criterion [20], such as deep brain stimulation or intestinal levodopa, likely precluded APD and even some HY 3 participation.

We must also have a better gauge of APD receptivity towards technology and remote evaluation. An online survey evaluating factors that most impact QoL and preferred use of self-monitoring technology involved 492 PWP who showed strong support for the use of devices to monitor their disease. Although 87 % expressed interest in recording data to monitor well-being, only 49 % were actively doing so [21]. The disease stages of those who expressed this interest were not delineated and the discrepancy between interest and adherence among participants was not explored. Doing so could shed light on barriers in research engagement that will inform future studies.

5. Challenges & opportunities for APD care partner and dyadic research

Beyond the challenges of inclusion for individuals with APD, their care partners are also underrepresented to the detriment of both groups. One descriptive study investigated the lived experiences of female care partners of husbands staged HY 2–4 [22] but specifically excluded HY 5. In the PREDICT study that focused on care partner burden in APD, HY 5 in the OFF state was also an exclusionary criterion [23]. Such exclusions represent missed opportunities to hear from those with both the most advanced disease and the most experience living with, navigating, and overcoming barriers presented by PD. Even though strides have been made to characterize APD patients and their care partners, the need for greater understanding of both groups and their effects on each other remains.

6. Reconsidering PD care partners as healthy controls

The practice of involving care partners as healthy controls to compare with PWP—sometimes by virtue of just not having PD—requires reconsideration. First, care partners who cohabitate with their PWP—whether spousal or adult child caregivers, for example—face shared environmental exposures such as air pollution or pesticides. Such exposures increase the risk of incident PD [24,25] and thus may compromise the validity of cohabitating individuals as healthy controls. Second, PD care partners face significantly higher medical comorbidities compared to age-matched controls, including higher rates of hypertension, backache, and irritable bowel syndrome (p < 0.05), even before their PWP’s diagnosis [26]. The causal mechanisms behind these findings demand investigation, however, the impact of care partner strain, physical exertion, and sleep deprivation are likely contributors [27].

APD care partners are a precarious and high-risk population, with their wellbeing often contingent on that of their PWP. The former group faces complex and high caregiving demands that can increase care partner burden and adverse health outcomes. In a registry-based cohort study evaluating the effect of marriage to a PWP on mortality, spouses of PWP had a higher risk of all-cause mortality compared to controls even five years after the first hospitalization of their PWP [28]. Care partner burden may insidiously evolve even if the PWP transitions away from the home and their care partner into a skilled nursing facility. Burden may be related to changes in financial obligations, logistical strain involving commuting to the facility where the PWP resides, and altered relational dynamics between the PWP and care team which impacts the well-being of all involved. In light of mounting evidence that PD care partners face their own formidable health challenges [25], [–29] their comorbidities and health status must be comprehensively assessed. Assuming PD care partners are appropriate healthy controls may bias analyses towards the null, yielding false negative results that could prematurely and erroneously end pathways to therapeutic interventions.

Ample research demonstrates care partner outcomes using terms such as burden, strain or worry [29]. Insufficient weight, however, is allotted to physical health outcomes. The Zarit Burden Inventory, the most commonly used care partner burden measure in PD [30], considers care partner physical health in general terms highlighted by item 19 of the burden interview: “I feel that my health has suffered because of my involvement with my spouse.” [31] When subjective measures are employed to define care partner burden, mechanistic explanations may be obscured.

We must aim to characterize care partner outcomes with finer specificity, especially in APD. Validated instruments such as the Self-Administered Comorbidity Questionnaire (SCQ) could serve as a model to account for negative health consequences. While chart abstraction-based comorbidity measures such as the Charlson Index are the gold standard, researchers typically have access to PWP records without those of the care partner. However, the SCQ correlates with record-based indices and is particularly useful as a self-reported measure in the absence of medical records. A national online survey assessing self-reported comorbidities of Lewy Body Dementia care partners using the SCQ showed disproportionately greater prevalence of comorbidities including depression with age-matched groups [32]. Details regarding comorbidities and even medication use in PD care partners could inform the trajectory of care partner health in early, intermediate, and advanced stages and illuminate opportunities to intervene.

We cannot afford to overlook the trajectory of care partner health, as their well-being not only affects their involvement in research but chiefly in so many aspects of their loved one’s care. PWP—and their treating healthcare providers—rely on care partners to support medication adherence, establish healthy routines, transport PWP to healthcare visits and exercise classes, and to advocate and raise concerns during healthcare encounters. Although challenging to accommodate during routine clinical care, recent US Centers for Medicare & Medicaid Services approval of billing codes and modifiers for provision of complex longitudinal care, care partner training, assessments of social determinants of health, and care coordination for individuals with serious chronic illnesses could facilitate such attention to care partners and resulting dialogue between providers [33].

7. Recommendations for APD care partner engagement in research

Research design and study teams have evolved to be more inclusive of PWP and their care partners over the past several decades; however, these efforts must expand further with underrepresented populations in mind inclusive of APD. As a case example, the National Parkinson’s Project, which aims to prevent, diagnose, and cure PD, outlined an annual research meeting open to the public with federal and non-federal members, including PWP advocates and minority community representatives [34]. Inclusion of APD care partners and information related to the respective stages of their PWP would be invaluable to contextualize gathered insights.

We should also emphasize learning about the lived experiences of PD research participation from individuals with APD and their care partners. In Lewy Body Dementia—an umbrella term inclusive of individuals with PD dementia—recognized challenges related to participant recruitment and retention in clinical trials include transportation, finances, and lodging [35]. Similarly, in unpublished research, APD care partners have voiced concerns such as long distances or steep ramps between parking facilities and clinical trial locations, as well as the intangible but often insurmountable physical strain and fatigue for both groups during full-day or multi-day study visits. While studies will necessarily be limited by funding and facilities, we propose the recommendations in Table 2 for consideration when designing research to expand inclusion of APD individuals and caregivers.

Table 2.

Recommendations to bolster APD patient and caregiver inclusion.

Research areas for improvement	Recommendations
Study Design	Offer completion of remote assessments/questionnaires in diverse formats (e.g., physical paper, tablets, remote devices) before or after on-site visits to minimize study visit length and PWP fatigue Utilize focus groups to receive feedback on and refine study design where able [36] Integrate home visits to reach APD individuals where possible [13] Delineate questionnaire responses specifically from PWP and/or caregivers; allow caregiver to assist PWP with completion as necessary Permit s/p DBS inclusion as long as settings and clinical status are unchanged in preceding 30 days to treatment phase (e.g., consider DBS akin to standard pharmacologic treatment in clinical trials) Develop a robust regulatory framework to include APD individuals in assisted living or skilled nursing facilities to participate in remote research Offer and arrange wheelchair-accessible transportation to study site directly, or prompt reimbursement of such, with appropriate support of family and/or trained professional caregivers to facilitate research participation Consider remote or in-home training sessions for APD caregivers on device or application management and study drug administration rather than prolonging in-clinic study visits, which may prevent participation due to PWP fatigue, off-time, travel distance and duration, or dependence on assistive transportation
Study Recruitment	Offer APD education and study recruitment information to diverse local support and patient advocacy groups, adult day programs, care facilities, community centers, federally-qualified health centers, community neurology or multispecialty practices, geriatric, palliative, and primary care settings [37] Record and share testimonials from prior research participants about their experiences and gains with potential participants (with documentation of consent for image/video sharing)
Study Visit	Exercise transparency in anticipated total study duration and individual study visit duration in advance to allow for PWP and caregiver planning (e.g., transportation needs, work leave, mobilizing additional support structures) Organize paid valet parking and timely transport assistance from site entry to research visit room; train research staff to safely and expediently transport as needed to honor everyone’s schedule Provide research and waiting rooms that allow for: maneuverability of stretchers, walking devices, places for caregivers to rest comfortably, designated spaces to walk, and close proximity to family/single stall bathrooms for both PWP and caregivers Offer ample levodopa-friendly (low-protein) snacks, hydration, simple lunch if appropriate, entertainment or activities during waiting periods (TV, magazines, resistance bands and physical therapy exercise handouts) at study sites for PWP and caregivers Maintain an emergency supply and protocol for administration of common medications (e.g., carbidopa-levodopa 25–100, acetaminophen or non-steroidal anti-inflammatory medications) and pill cutters in case home medications are forgotten for daylong visits Stock adult protective garments, wipes, portable urinals, and scrubs in case of bowel or bladder emergencies
Study Retention	Ensure team contact information is readily available and share at the start of every study Implement regular study follow-up [37] via preferred communication method (e.g.:, e-mail, telephone, video) of PWP/caregiver Provide regular health-literacy friendly updates on study progress and findings (e.g., print or e-newsletters) Minimize the administrative steps and delays involved in compensating PWP and caregiver for research participation and travel
Support Groups	Identify local and regional support groups, determine inclusivity of PWP, caregivers, or both, meeting frequency and modality (e.g., in-person only, virtual only, hybrid), and recognize such groups as sources of emotional and resource support, community, lived experience, and referrals to both care and research participation for PWP and caregivers. Establish long-term relationships with local and regional support groups, which may involve presence as a speaker or expert for multiple sessions before requesting group approval to present research opportunities

8. Conclusion

The striking underrepresentation of APD patients and their care partners in research limits our understanding of heterogeneity across the PD continuum. Conventions and biases we hold contribute to the challenges of greater inclusion of both groups in studies. We need to acknowledge the adverse health outcomes of PD care partners, especially with advancing disease, as care partner strain is not only detrimental to the individuals themselves but also their PWP. We must foster systems and opportunities to support and engage both groups in research. These endeavors will not only allow us to learn about their needs and priorities but also improve their retention and longitudinal engagement in research, yielding more effective interventions. We anticipate that the development and iterative revisions of new staging systems may enrich the characterization of PWP across the disease spectrum. As we design more inclusive research, we will not only uncover important discoveries for APD individuals and care partners, but findings may also generalize to the broader PD population. Our field recognizes that investigating the earliest mechanistic changes of synucleinopathies informs our future understanding of symptoms, and ultimately, potential therapeutics. We submit that thoughtful and inclusive investigation of the symptoms and management of individuals with APD and their care partners can reciprocally inform our approach to those earlier in the condition, too.

Abbreviations

APD

Advanced Parkinson’s Disease

CLaSP

Care of Late Stage Parkinsonism

DBS

Deep brain stimulation

GLORIA

Global long-term registry on efficacy and safety of levodopa-carbidopa intestinal gel

HY

Hoehn and Yahr

LCIG

Levodopa-carbidopa intestinal gel

PD

Parkinson’s Disease

PPMI

Parkinson’s Progression Markers Initiative

PRIAMO

PaRkInson And non Motor symptOms

PWP

People with Parkinson’s Disease

QoL

Quality of Life

SCQ

Self-Administered Comorbidity Questionnaire