Author ORCID Identifier

https://orcid.org/0000-0001-7513-1804

Semester

Spring

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Committee Chair

Sergiy Yakovenko

Committee Member

Valeriya Gritsenko

Committee Member

Jean McCrory

Committee Member

Ann Murray

Committee Member

Richa Tripathi

Abstract

Movement is a fundamental human activity, enabling us to engage with our surroundings. Consequently, a well-operating neuromuscular system is essential for maintaining quality of life. Motion is not only integral for the basic function of daily living, but also plays a significant role in enhancing our physical, mental, and emotional health. The importance of this system becomes abundantly clear when it is compromised, such as with neurodegenerative disease.

Alzheimer’s disease (AD), followed by Parkinson’s disease (PD) are the two most common neurodegenerative diseases that profoundly affect millions of individuals worldwide (Lamptey et al., 2022). Characterized by distinct but sometimes overlapping symptomatology, both conditions lead to significant impairments in daily functioning, autonomy, and quality of life. Presently, there is no cure for these diseases, but rather symptomatic treatment with medication, therapies, and/or surgery. Among the various challenges posed by these diseases, the decline in sensorimotor control, particularly affecting balance and gait, stands out as a critical issue contributing to increased healthcare costs and decreased quality of life (Gras et al., 2015; Hsu et al., 2014).

PD and AD impose a significant economic burden on healthcare systems, patients, and their families. The costs associated with these diseases encompass direct medical expenses such as hospitalizations and medications, and indirect expenses such as lost wages and the need for long-term care. Given the global demographic shift towards an older population, the prevalence of PD and AD is expected to increase, amplifying these costs significantly. In the United States, approximately 630,000 people were diagnosed with PD in 2010, with an expected increase to over 1.2 million by 2040. Further, the national economic burden exceeded $14.4 billion in 2010, including medical expenses, and indirect costs such as reduced employment and caregiver support (Kowal et al., 2013). Although dated economic data due to a lack of new surveys, with expenses rising in all areas, we can hypothesize the burden is now even greater. The economic burden of AD is even greater; in 2020, United States healthcare costs were estimated to be $305 billion, with an additional 18.6 billion unpaid caregiver hours valued at $244 nearly billion (Alzheimer’s Association, 2020).

Beyond the economic impact, the social implications of PD and AD extend widely. Patients experience a progressive loss of independence, culminating in increased caregiver burden and significant lifestyle alterations. Central to these challenges is the decline in sensorimotor control, particularly affecting balance and gait. This not only deteriorates quality of life, but also raises the risk of falls and subsequent health complications. Addressing the early stages of gait dysfunction and sensorimotor decline in PD and AD through research into their pathophysiological mechanisms is vital for devising interventions to improve mobility, minimize fall risk, and improve patient outcomes.

The deterioration of sensorimotor control in PD and AD must be considered in tandem with gait dysfunction, even in early neurodegenerative disease. Research into the underlying mechanisms of sensorimotor control and gait disturbances is crucial for developing targeted interventions that can help improve mobility, reduce fall risk, and enhance overall patient well-being.

The assessment and quantification of limb dysfunction in neurodegenerative diseases such as PD and AD are of paramount importance, given the impact of these conditions on motor and cognitive functions, particularly in the aging population. In PD, motor symptoms, including tremors, rigidity, and bradykinesia, are predominantly asymmetric and progressively impair limb function. Traditional clinical scales like the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr are extensively utilized to evaluate motor decline. However, these assessments are somewhat subjective and may not capture subtle motor deficits or the fluctuating nature of symptoms effectively.

In AD, while cognitive decline is the most prominent feature, motor impairments such as apraxia, gait disturbances, and coordination problems also significantly affect the quality of life. Conventional measures like the Mini-mental status examination (MMSE) focus primarily on cognitive deficits, with less emphasis on motor dysfunction. Thus, there is an urgent need for more comprehensive evaluation tools that encompass both motor and cognitive aspects of AD.

Recent technological advances have led to developing more sensitive and objective measurement tools. Wearable sensors and motion capture systems enable continuous, high-resolution monitoring of limb movements in naturalistic environments, providing data that is not only more detailed but also more representative of daily living conditions than data from time-constrained clinical tests. These technologies can detect minute changes in motor performance and symmetry, which are crucial for early diagnosis and fine-tuning treatment plans, especially in PD.

This dissertation will investigate limb speed perception accuracy during split-belt ambulation in individuals with early Parkinson’s disease. Additionally, the effects of Lecanemab, a new monoclonal therapy for the treatment of AD, will be explored in the context of its efficacy in improving motor-related functional outcomes. A multi-part experiment was performed to address these goals. It is organized into 2 research chapters with an additional introductory chapter and a chapter addressing future directions. Chapter 1 describes the anatomical and physiological principles of the human motor system and introduces the reader to the neurodegenerative diseases of interest: PD and AD. Chapter 2 describes a case series study where we investigated functional gait changes pre- and post-Lecanemab infusions over 9-months in an individual with early AD. Our patient demonstrated disrupted visuomotor processing and execution functions during the treadmill obstacle avoidance task. Monoclonal therapy potentially reversed this early functional metric and helped maintain it throughout the treatment period. At the 6-month mark, the participant showed no difference from her neurotypical cohort, with results enduring at 9-months. Psychometric testing indicated stable limb speed perception accuracy over the 9-month period, suggesting no disruption in the representation of limb dynamics. Chapter 3 describes a study of limb speed perception accuracy among people with PD. Advanced age and neurological disorders like PD are often associated with sensorimotor problems of limb control. Limb coordination is linked to the perception of limb movement; given the disruption of the dopaminergic system in PD, exercise may have beneficial effects. Discrimination of limb speed was tested with a 2-alternative forced-choice method during split-belt treadmill walking. Participants chose which limb was moving faster for a representative selection of bilateral speed differences. Findings suggest PD is associated with diminished limb speed accuracy. However, regular exercise may serve as a beneficial intervention to enhance or preserve sensorimotor function. These results advocate for physical activity promotion among those with or susceptible to PD. Further research is warranted to develop targeted therapies to improve sensory perception in PD populations. Finally, further questions and future directions for this work are discussed in Chapter 4.

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