Visuomotor Control of Stepping over Obstacles Improves in Early Alzheimer’s Disease after Lecanemab Treatment: A Single Subject Case Series

Visuomotor Control of Stepping over Obstacles Improves in Early Alzheimer’s Disease after Lecanemab Treatment: A Single Subject Case Series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Visuomotor Control of Stepping over Obstacles Improves in Early Alzheimer’s Disease after Lecanemab Treatment: A Single Subject Case Series Cheryl L Brandmeir, Emily Herrick, Serhii Bahdasariants, Sergiy Yakovenko This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4021983/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Alzheimer’s disease (AD), an incurable, progressive neurological disease, is the most common cause of dementia among older adults. While traditionally recognized for cognitive impairments, the emergence of gait disturbances presents a pivotal aspect of disease advancement, necessitating consideration of associated sensorimotor dysfunction. AD affects cortical visuomotor transformations, evidenced by diminished cortical thickness and altered reaction times in reaching tasks. Furthermore, eye-tracking studies have identified cognitive interference during visuomotor tasks, manifesting as increased saccadic movements and prolonged fixations, likely attributable to heightened cognitive demands. Although these findings support AD’s effects on the visuomotor transformation in locomotion, its diagnostic and assessment potential remains unexplored. Moreover, the recent use of monoclonal antibody therapies targeting β-amyloid show cognitive improvements, yet their efficacy in improving motor-related functional outcomes remains largely unexplored. Case Presentation: In this case study, we present a 75-year-old female diagnosed with early AD treated with Lecanemab. We explore gait changes pre- and post-Lecanemab infusions over 9-months. Before treatment, the patient scored 23/30 on the Mini Mental State Examination (MMSE) and 25/30 on the Functional Gait Assessment (FGA). Visuomotor processing was assessed using treadmill locomotion with and without obstacles of different sizes. Response time was measured as the period between the obstacle presentation and the initiation of stepping over that obstacle at preferred walking speed maintained across sessions. Additionally, we assessed for potential disruption of embedded limb representation in planning pathways through psychometric testing of limb speed perception. Measurements were repeated every 3-months for 9-months. At 9-months, the patient scored a 29/30 on the MMSE and a 30/30 on the FGA. During advanced gait assessment, she cleared obstacles, with an overall RT of 1.50 ± .39s. Limb speed perception accuracy remained stable. Conclusion: Our patient demonstrated disrupted visuomotor processing and execution functions during the treadmill obstacle avoidance task. Treatment 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. Neurology Alzheimer’s disease Lecanemab Visuomotor Gait disturbance Obstacle negotiation Functional outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Targeting β-amyloid presents an appealing focus for prospective therapeutic interventions ( 1 – 4 ). β-amyloid accumulation in the brain, occurring up to two decades before the manifestation of clinical symptoms is a pathological hallmark of AD, with subsequent emergence of tau protein coinciding with symptom onset, such as decreased memory, repeating oneself, and getting lost ( 5 ). Higher-order neurological processes that link sensorimotor functions are involved in the ability to plan movements and respond to environmental changes ( 6 ). Early gait dysfunction, particularly in the domain of obstacle avoidance, highlights the need to investigate the role of visuomotor behavior and processing in ambulation. β-amyloid accumulation interferes with neural processing through colocalized evidence of apoptosis ( 7 ), and interventions that address this mechanism are likely to maintain cognitive and motor cortical functions. Despite controversy surrounding the amyloid hypothesis, developing drugs to slow or delay the progression of AD has historically been the focus of research efforts ( 2 ). The amyloid hypothesis posits that β-amyloid, the primary component of extracellular plaques discovered in the brains of individuals with AD, triggers the disease’s progression ( 5 ). This includes inflammation, the formation of neurofibrillary tangles, and the eventual neuronal cell death and cognitive decline observed in individuals with AD ( 8 , 9 ). Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily affecting older adults, resulting in cognitive decline, memory impairment and gait dysfunction ( 1 , 10 – 12 ). Although AD is largely considered a cognitive disorder, the sensorimotor functions are also affected ( 13 , 14 ). Among the various motor manifestations of AD, gait disturbances are prevalent and can significantly impact an individual’s mobility and overall quality of life ( 15 ). Locomotion is one of the most vital behaviors that is tightly correlated with the quality of life and longevity; mobility deficits present in early AD may be closely related to the expected cortical disruption of visuomotor processing ( 16 , 17 ). Disruptions in cortical processing, such as those seen in AD, can lead to deficits in locomotion and movement control. These deficits may manifest as gait disturbances, balance problems, or difficulties navigating in complex environments. Both the ventral and dorsal processing streams, spanning multiple cortical areas such as the prefrontal parietal cortex (PPC), premotor areas (premotor cortex - PM, supplementary motor area - SMA), and inferotemporal cortex (IT), have been implicated in visuomotor deficits. These areas are involved in processing the "where" and "what" aspects of visual inputs, as illustrated in Fig. 1 . The classical model of visuomotor processing, originating from the discovery of corresponding cortical dorsal and ventral streams by Ungerleider et al. in 1983, initially proposed a clear dissociation between these streams. However, subsequent research has revealed that the distinction between the two streams may not be as rigid as initially thought, as demonstrated by asymmetric disruptions observed in patients with lesions causing spatial/optic ataxia or visual agnosia ( 18 ). For example, damage to the "where" stream not only leads to motor and cognitive impairments but also disrupts spatial attention and gaze ( 19 ). During more complex activities, such as navigating a cluttered environment or stepping over obstacles, the “what” pathway, or ventral stream, is primarily involved in object recognition and identification, providing information about the size, shape, and identity of the object. Additional regions in the “what” pathway contribute to determining how to interact with the recognized obstacle. The “where” pathway, or dorsal stream, as previously noted, is primarily involved in spatial processing and guiding action; this helps determine the location and spatial relationship of the object relative to the body ( 20 ). Obstacle negotiation requires both the “what” and “where” pathways to work together, processing visual information during locomotion, allowing the individual to perceive the obstacle, determine their spatial location, and plan and execute appropriate motor responses to successfully navigate over or around them. Disruptions in either pathway may lead to movement planning and execution deficits, impacting one’s ability to successfully navigate through the environment. Cortical activity in balance and walking tasks may be decreased due to cortical atrophy affecting the motor cortical regions and corpus collosum, with the prefrontal cortex and basal ganglia most strongly affected ( 21 ). In the case of neurological disease, locomotor control is impaired. Not only are the “what” and “where” pathways disrupted ( 22 ), but the ability to perceive limb speed may also be impaired ( 23 ). Accurate perception of limb speed allows individuals to adjust step length and cadence accordingly, ensuring stable locomotion ( 24 , 25 ). Visual cues, such as the speed of limb movement relative to the environment provide crucial input, and when combined with proprioceptive feedback from the muscles and joints, allows for additional fine-tuning of limb speed perception ( 26 ). Furthermore, the thickness of cortical regions involved in the “what” and “where” visual processing streams may play a crucial role in the planning and execution of obstacle negotiation tasks ( 22 , 27 ). Cortical thickness is closely linked to the functional integrity of these regions ( 28 ), affecting their abilities to process visual information and guide motor responses ( 29 ). Specifically, alterations in cortical thickness in areas of the "where" pathway, such as the posterior parietal cortex, may impact spatial processing and the ability to perceive the location and orientation of obstacles in the environment ( 29 ). Similarly, changes in cortical thickness in regions associated with the "what" pathway, such as the inferotemporal cortex, may influence object recognition and identification, affecting the ability to recognize obstacles and assess their properties ( 29 ). Neurodegeneration is frequently measured through measurements of cortical thickness using structural magnetic resonance imaging (MRI) ( 17 , 30 ). Among individuals with late mild cognitive impairment, only three clusters showed significant atrophy compared with cognitively normal or early mild cognitive impairment- the left supramarginal gyrus, left middle, and inferior occipital gyrus. These areas are all located in the “where” pathway, associated with spatial processing and may impact obstacle negotiation ( 22 ). Recently, larger study of individuals with AD showed decreased cortical thickness; volumes of various regions within the frontal lobes were compared to areas in the mesial temporal lobes, which are conventional biomarkers of memory deficits in AD ( 17 ). It was observed that the decrease in cortical thickness across frontal, parietal, and temporal regions provided a better explanation for performance variation than an individual structural measurement. Moreover, the reduced volume of brain regions has been shown to correlate with symptoms when these regions interact with one another ( 17 ). For instance, while the frontal lobe is traditionally associated with learning ( 31 ), learning performance was found to be enhanced through the interaction of the entorhinal cortex ( 32 ), known for its role in memory, navigation, and spatial perception. Other studies suggest that degeneration in the posteromedial parietal cortex, a structure responsible for the transformation of visual cues into motor action, may be a key indicator of AD risk ( 16 , 33 ). Furthermore, it is suggested that motor tasks may serve as significant predictors of the transition from mild cognitive impairment to AD ( 16 , 33 ). Functional MRI shows AD disrupts multiple pathways, including the thalamo-cortical, dorsal attention, visual, and sensorimotor pathways ( 34 – 36 ). Disruptions in cognitive and motor functions are prevalent among individuals with Alzheimer's disease (AD), particularly affecting visuomotor transformation—an essential process guiding purposeful actions, including locomotion ( 37 ). Vision plays a pivotal role in facilitating coordinated movements, particularly in intricate environments, by providing critical information on factors such as heading direction, object size, shape, and distance ( 38 ). Previously, head orientation has been demonstrated to affect the choice of limb movements ( 39 ) and to predict turning behavior during walking on both straight and curved paths ( 40 ). For example, if an individual intends to turn their head to the right when walking, they are more likely to initiate limb movements that correspond to that direction such as stepping forward with their right leg, Further, to complete a turn to the right, their left leg will need to move faster than their right. This coordination between head orientation and limb movement is thought to be driven by the integration of sensory information from the visual, vestibular, and proprioceptive systems ( 39 , 40 ). Visual input, including environmental information and obstacles, is processed to formulate and enact timely motor plans, such as stepping over obstacles. Typically, individuals plan two steps ahead, allowing themselves time to modify their gait pattern as needed ( 38 , 41 ). Accurate stepping and locomotor strategies necessitate real-time adjustments for obstacle avoidance, constituting specialized tasks for these pathways that are susceptible to disruption ( 42 ). Such disruption is likely to impede precise stepping and obstacle avoidance functions, essential for ensuring safe ambulation. During the seemingly simple task of stepping over an obstacle such as curb negotiation or stepping into the shower, requires the involvement of a top-down hierarchy to process visual information ( 38 ) and the integration of external environmental constraints and demands, alongside the neuromechanical dynamics defined by bottom-up organization (Fig. 1 ) ( 43 ). To avoid tripping or falling, the period of planning gait modification must be adequate; a shorter available period may result in a higher risk for falling, particularly among persons with mild cognitive impairment ( 44 ). The reaction time to obstacle presentation in self-paced locomotion can be used as a measure of sensory processing and planning. Here we report measures of obstacle negotiation response times and limb perception over time in a longitudinal case study focusing on a 75-year-old female diagnosed with AD and explore gait changes pre- and post-Lecanemab infusions over 9-months (Fig. 2 ). Methods Patient : A 75-year-old Caucasian female with a 4-year history of progressive memory loss and repetition during conversations, more notable over the prior 3 months, presented to the memory care clinic with her daughter. No fall history was noted, and the patient denied a fear of falling. The patient, unaware of her deficits, partook in a comprehensive evaluation including medical history, cognitive tests, neurological examinations, brain imaging, and lumbar puncture. Past medical history is significant for hypothyroidism, hypertension, hyperlipidemia, atrial fibrillation, and depression. Current medications include Eliquis, Metoprolol, Synthroid, Hydrochlorothiazide, Irbesartan, and Rosuvastatin. Neurological examination revealed 5/5 strength throughout bilateral upper and lower extremities and 23/30 on the Mini-Mental Status Examination (MMSE). On the Functional Gait Assessment (FGA), she scored 25/30, with difficulties noted with horizontal and vertical head turns during ambulation, walking with eyes closed, and ambulating backwards. MRI was abnormal, showing moderate bilateral parietal cortical atrophy and left greater than right perisylvian volume loss in temporal opercular region. Further, bilateral hippocampal volume loss and moderate left entorhinal cortical atrophy were evident. A lumbar puncture confirmed the presence of abnormal proteins in the cerebrospinal fluid, including Abeta42 at 1036 pg/mL, total tau 420 pg/mL, P-tau 43.3 pg/mL, and a p-tau/ABeta42 ratio of 0.042 (normal value ≤ 0.023). APoE genotype is heterozygous, E3/E4. Based on the Unites States National Institute of Aging and the Alzheimer’s Association guidelines for diagnosis ( 45 ), this patient was diagnosed with AD. At diagnosis, Zoloft (25mg) and memantine (5mg) were prescribed, and she was scheduled to begin Lecanemab infusions every 2 weeks. Session design : In this longitudinal study, we tracked sensorimotor performance in AD prior to initiation of and throughout anti-amyloid treatment. Motor performance was assessed overground with the functional gait assessment (FGA), a clinical test documenting postural stability and motor function during ambulation (i.e., stepping over obstacles, turning, stair negotiation, backward walking), as well as walking tasks on the split-belt treadmill (Bertec, Columbus, OH)—standard gait analysis, limb speed perception accuracy and stepping over obstacles. All gait pre-testing was performed after initiation of Zoloft and memantine, but prior to Lecanemab infusions. At 3-months, Eliquis was discontinued, and a baby aspirin was initiated due to Lecanemab prescribing recommendations. There were no reported amyloid related imaging abnormalities throughout treatment. All procedures were approved by the institutional review board of West Virginia University (IRB #2210669796). Control group : To compare the performance to a neurotypical cohort, we recruited 3 age-matched females (75.7 ± 1.2y) to perform the same obstacle negotiation task (table 1). We tested the performance of the patient with AD relative to the neurotypical group using a two-way ANOVA to analyze the effect of obstacle type and group [neurotypical vs AD session (pre-treatment)] on available RT. The performance of the patient with AD over time was assessed using a two-way ANOVA to analyze the effect of obstacle type and AD session (pre-treatment vs. post-3 months vs. post-6 months vs. post- 9-months) on available RT. At 9-months, we tested the performance of the AD patient relative to the neurotypical group using a one-tailed t-test across all obstacle types. Analysis reveals a significant difference between the patient and her cohort pre-treatment; however, significant improvement toward matching her neurotypical cohort by 3 months, with no significant differences noted by 6 months, and enduring results at 9 months (table 1). Analysis of limb speed perception was performed with speed-matched neurotypical controls and a test of equivalence was performed to establish there was no difference between the groups, as well as no difference between the participant with AD pre- and post-treatment, indicating perception stability Step analysis was also performed on the stepping limb to categorize the stepping strategy: long step, short step, regular step, or kick step. Notably, the participant the AD was the only one to demonstrate a kick step as a strategy, and the neurotypical cohort had a greater proportion of short and long stepping strategies. Psychometric Task : Throughout the session, the participant utilized a body weight support system (BWSS, Pneumex, Sandpoint, ID) with an overhead gantry without unloading for safety. While secured in the BWSS she walked on the tied-belt treadmill with different speeds and selected her preferred speed (PS). She maintained PS (0.9m/s) for 2 minutes, acclimating to treadmill walking. Next, lower visual field blocking glasses were donned and worn while she walked at her PS for 2 minutes, acclimating to treadmill walking under this condition. The split-belt paradigm was introduced during the interim 5-minute rest period. She was instructed to determine which leg was moving faster (left or right) without visual input (looking down). To minimize visual and auditory cues, she received automated cues to assess the speed difference (3s) as well as report limb speed perception (4s). No performance feedback was provided during the walking trial. Belt speed variations were randomized based on her PS, including 0%, ± 2%, ± 5%, ± 20%, and ± 30% variations of her PS. All responses and belt speed data from the instrumented treadmill were recorded and used to identify the just noticeable difference in limb speed and her perception accuracy. Before the experimental procedure, the participant performed 10 practice trials for familiarization with the split-belt treadmill paradigm. Following this, she had another 5-minute rest period before another 2-minute treadmill walking session at her PS in a symmetrical condition under typical conditions. Obstacle Avoidance Task : Following another brief rest and explanation, the participant was asked to perform an obstacle negotiation task. Small obstacles were placed on the treadmill every 10 seconds during this task. Obstacles, standardized as 2 cm, 5 cm, and 10 cm blocks, were placed on the treadmill in a pseudo-randomized order between the height and belt sides. Seven repetitions were performed under each condition. While walking at 0.5m/s, the participant was asked to clear the obstacle without upper extremity support. We measured the response time, determined by the period between block placement and toe off events for each obstacle type and side. Finally, the participant was asked to walk for 2 minutes at 1.0 m/s following a 5-minute rest period. Statistics and Data Analysis : Custom-written MATLAB (The MathWorks, Inc., Natick, MA, United States) code was used to control the treadmill to impose desired speed differences and randomizations during all treadmill tasks, including the perception and obstacle negotiation tasks. Gait trials were also visually inspected using Adobe software for frame analysis to accurately determine the time of block placement, toe-off, and categorize stepping strategy. ANOVA and one-tailed t-test were used for the comparative analysis with the significance threshold set to 0.05. Assessment of Perception in Psychometric Task : For each trial, participant response (i.e., left or right) was compared to the correct answer, and the percentage correct for each interlimb speed difference category was determined. The threshold for detecting the interlimb speed difference was determined by finding the last speed difference category to have a probability less than or equal to 50%. For all the speed difference categories prior to the threshold, the probability was adjusted to 50% to represent that the participant had a 50% probability of answering correctly based on chance. Plots of the probability of detecting which leg is moving faster versus the interlimb speed difference were made for pre- and post-medication sessions and speed-matched neurotypical controls. The area under the curve (AUC) for each session was determined using trapezoidal numerical integration to quantify both sensory and cognitive deficits. The sensory deficits would be expected in the larger thresholds in speed difference detection (Fig. 4 , “a”); cognitive deficits would be expected in the depression of probability of detection even at large values of speed differences (Fig. 4 , “b”). The AUC was normalized to the maximum area possible (100% probability x 30% speed difference). To account for the fact that one of the individual control sessions and the post-9-month session were recorded with 0%, 5%, 12.5%, 20%, and 30% speed differences while the rest of the sessions were recorded with 0%, 2%, 5%, 20%, and 30% speed differences, linear interpolation was used to fill in any missing speed difference categories for a given session. Results Baseline and interval testing was obtained every 3 months throughout the initial 9 months of this participant’s treatment (table 1). Prior to Lecanemab infusion, MMSE score was 23/30, with difficulties with word recall, backward counting, and orientation. Overground walking assessment with the FGA had decreased performance in the areas of horizontal head turns, walking with eyes closed, and walking backwards, receiving an overall score of 25/30. Available RT at baseline 2.61 ± 0.41s overall. The individual responses to obstacle type and stepping limb are reported in Table 1. Stepping strategy revealed a kick step strategy as the most utilized strategy (38%), as compared to the incidence of short step and long step strategies, particularly with the 10cm obstacles. Initial pre-infusion gait testing showed that while this patient could clear each obstacle successfully, her strategy for obstacle clearance ranged widely between obstacle height and side. The initial probability of detecting which leg was moving faster versus the interlimb speed difference was 76% using the AUC method. Table 1. Subject population and summary of test results participant with AD and neurotypical cohort. Stepping strategies: LS: long step, SS: short step, RS: regular step; KS: kick step Following 3-months of Lecanemab infusions, all metrics were re-evaluated. MMSE score improved to 27/30, with difficulties on world recall only. Overground walking assessment with the FGA revealed improvement to 28/30, noting ongoing difficulties with horizontal head turns (deviation out of bounds) and gait with eyes closed. Post 3-months, available RT decreased significantly in all areas, with overall available RT decreasing to 1.67 ± 0.32s (see Table 1 for details). Stepping strategy continues to show a kick strategy as the most utilized strategy (40%), particularly with the 10cm obstacles. Limb speed detection abilities were maintained at this time (78%). Following 6-months of Lecanemab infusions, MMSE score was maintained at 27/30, with difficulties on world recall only. Overground walking assessment with the FGA revealed improvement to 30/30. Post 6-months, decreased available RT persists in all areas, with overall available RT 1.48 ± 0.39s (see Table 1 for details). Stepping strategy shifted: the long step strategy is now the most predominant strategy (36%), although the kick step strategy continues to be utilized frequently (24%). Limb speed detection abilities were slightly improved (80%) at this time. At 9-months post Lecanemab infusions, MMSE score improved to 29/30, with a single point lost on word recall, and FGA remained at 30/30. Post 9-months, decreased available RT endures, with overall available RT 1.50 ± 0.39s (see Table 1 for details). Stepping strategy shifted again with a balance between the long step strategy (33%) and the kick step strategy (33%). Results from the available RT during obstacle negotiation under all conditions from the pre-test (2, 5, and 10 cm blocks) indicate that treatment with Lecanemab may have influenced improved advanced gait skills with available RT decreasing in all conditions. Left and right-sided obstacle available RT significantly decreased overall from pre-treatment to 3-months and maintained improvements through the 9-month testing period (p<.001). All individual obstacle heights showed significant and enduring results (p<.001). Compared to her age and sex-matched neurotypical peers prior to treatment, available RT for this patient was significantly longer in all categories (p<.001). However, no significant difference was evident in any obstacle category at 9-months of treatment between this patient and her neurotypical peers as evaluated by a series of direct post-hoc comparisons (overall left 1.52 ± 0.39s vs 1.44 ± 0.35s, p = .19; overall right 1.48 ±0.34s vs 1.48 ± 0.34s, p = .42; 2cm left 1.64 ± 0.41s vs 1.41 ± 0.30s, p = .06; 2cm right 1.51 ± 0.45s vs 1.49 ± 0.37s, p = .15; 5cm left 1.39 ± 0.50s vs 1.45 ± 0.39s, p = .36; 5cm right 1.49 ± .46s vs 1.42 ± 0.39s, .35; 10cm left 1.54 ± .25s vs 1.48 ± 0.36s, p = .32, and 10cm right 1.45 ± .32s vs 1.51 ± 0.27s, p = .32). Limb speed detection abilities were stable over 9-months (fig. 4) with no difference noted with equivalence testing using a 95% confidence interval for AUC. No difference was also noted between the patient with AD and neurotypical cohort. Further, compared with speed-matched neurotypical controls (n= 5, 54.6 ± 5.41y), she remains within approximately 1 S.D. (79% ± 5%). Discussion This described case of a 75-year-old patient with newly diagnosed AD and early intervention with Lecanemab may be interesting for the practice of physicians due to the current dearth of research on the role of monoclonal therapy on gait. Psychometric testing indicated that the disruption and subsequent recovery were not influenced by limb representation within control pathways. This reinforces the notion that Alzheimer's disease affects the 'where' dorsal stream pathway responsible for planning and coordinating frame transformations. These findings are noteworthy as, typically, in the absence of monoclonal therapy, we observe a decline in both cognition and overall function within a similar timeframe (46). Gait disturbances in AD manifest as alterations in walking speed, stride length, and balance, often leading to an increased risk of falls and injuries (47,48). Managing these gait abnormalities can be challenging, often necessitating specialized interventions to enhance mobility and reduce the risk of falls. Older adults with poor motor function, particularly those with impaired balance and gait abnormalities, are at an increased risk of cognitive impairment, with gait disturbances being predictive of incident AD (13,49,50). Before receiving the Lecanemab infusion, the patient exhibited a behavior of waiting for the obstacle to approach her, resembling a 'rusty water mill' scenario where she could see the obstacle. However, an apparent error in visual-motor transformation resulted in a delayed step-over. Because gait speed was constant, increased RT was acquired on the treadmill by moving toward the backmost area and decreasing step length to allow increased stability and afford trip avoidance. Post-infusion, the decreased available RT may be attributed to improved visuomotor processing rather than a product of learning due to the length of time between trials (3 months). Further, obstacle negotiation and successful walking rely on intact cognitive processes and accurate sensorimotor capabilities (51,52). As previously shown, reaction time increases with choice and decreases with learning (53). Here, learning chance was minimized through a computer-generated algorithm for random obstacle height and side of placement. Further, placing random obstacles is analogous to the patient being presented with an unanticipated obstacle. Unanticipated obstacles require higher levels of attention, visuospatial, and information processing, all skills associated with executive function, thus increasing the cognitive demand associated with motor planning (54). These unanticipated obstacles require quicker recruitment of cognitive resources, and inadequate sensorimotor planning may lead to increased available RT via a modified obstacle negotiation strategy. Stepping strategies for obstacle negotiation have been previously identified and defined as stride lengthening (crossing the obstacle via a lengthening cross step) or stride shortening during which the preceding step is shortened and the obstacle is crossed in the next step (55). In the case series, we also identified two additional strategies—a kick step during which the knee was flexed, and the obstacle was allowed to pass underfoot, as well as a regular step during which the participant did not alter their preceding or crossing step to negotiate the obstacle. This observation was much like receiving full credit for obstacle negotiation on overground obstacle negotiation in the FGA. The kick step was only observed in the participant with AD and appeared to be an atypical obstacle negotiation strategy. This strategy, persisting throughout all phases of treatment, was frequently observed during the highest obstacle negotiations and may afford increased stability in dynamic situations, thus allowing improved trailing limb foot placement (24). Conclusion Studying gait modifications in AD is an essential aspect of comprehensive research efforts to understand the progression of disease, improve early diagnosis, develop effective treatments, and enhance the overall care and management of individuals living with AD. Detecting early gait aberrations may provide valuable insights into the progression of the disease and its impact on a person’s functional abilities. 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Visual Control of Locomotion: Strategies for Changing Direction and for Going Over Obstacles. Boisgontier MP, Nougier V. Ageing of internal models: from a continuous to an intermittent proprioceptive control of movement. AGE. 2013 Aug;35(4):1339–55. Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci. 2000 Sep 26;97(20):11050–5. Luders E, Narr KL, Bilder RM, Thompson PM, Szeszko PR, Hamilton L, et al. Positive correlations between corpus callosum thickness and intelligence. NeuroImage. 2007 Oct;37(4):1457–64. Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RSJ, et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci. 2000 Apr 11;97(8):4398–403. for the Alzheimer’s Disease Neuroimaging Initiative, Chandra A, Dervenoulas G, Politis M. Magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment. J Neurol. 2019 Jun;266(6):1293–302. Kolb B. Brenda Milner: Pioneer of the Study of the Human Frontal Lobes. Front Hum Neurosci. 2022 Jan 3;15:786167. Canto CB, Wouterlood FG, Witter MP. What Does the Anatomical Organization of the Entorhinal Cortex Tell Us? Neural Plast. 2008;2008:1–18. Ilardi CR, Iavarone A, La Marra M, Iachini T, Chieffi S. Hand movements in Mild Cognitive Impairment: clinical implications and insights for future research. J Integr Neurosci. 2022 Mar 23;21(2):067. Zhou B, Liu Y, Zhang Z, An N, Yao H, Wang P, et al. Impaired Functional Connectivity of the Thalamus in Alzheimer’ s Disease and Mild Cognitive Impairment: A Resting-State fMRI Study. Curr Alzheimer Res. 2013 Aug 1;10(7):754–66. Li R, Wu X, Fleisher AS, Reiman EM, Chen K, Yao L. Attention‐related networks in Alzheimer’s disease: A resting functional MRI study. Hum Brain Mapp. 2012 May;33(5):1076–88. Zheng W, Liu X, Song H, Li K, Wang Z. Altered Functional Connectivity of Cognitive-Related Cerebellar Subregions in Alzheimer’s Disease. Front Aging Neurosci. 2017 May 16;9:143. Georgopoulos AP, Grillner S. Visuomotor Coordination in Reaching and Locomotion. Science. 1989 Sep 15;245(4923):1209. Drew T, Andujar JE, Lajoie K, Yakovenko S. Cortical mechanisms involved in visuomotor coordination during precision walking. Brain Res Rev. 2008 Jan;57(1):199–211. Dancause N, Schieber MH. The impact of head direction on lateralized choices of target and hand. Exp Brain Res. 2010 Apr;201(4):821–35. Hicheur H, Vieilledent S, Berthoz A. Head motion in humans alternating between straight and curved walking path: Combination of stabilizing and anticipatory orienting mechanisms. Neurosci Lett. 2005 Jul;383(1–2):87–92. Patla A, Vickers J. How far ahead do we look when required to step on specific locations in the travel path during locomotion? Exp Brain Res. 2003 Jan 1;148(1):133–8. Maidan I, Shustak S, Sharon T, Bernad-Elazari H, Geffen N, Giladi N, et al. Prefrontal cortex activation during obstacle negotiation: What’s the effect size and timing? Brain Cogn. 2018 Apr;122:45–51. Sobinov A, Yakovenko S. Model of a bilateral Brown-type central pattern generator for symmetric and asymmetric locomotion. Pieruccini-Faria F, Sarquis-Adamson Y, Montero-Odasso M. Mild Cognitive Impairment Affects Obstacle Negotiation in Older Adults: Results from “Gait and Brain Study.” Gerontology. 2018 Oct 12;65(2):164–73. Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, et al. Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group. Lancet Neurol. 2021 Jun;20(6):484–96. Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023 Jan 5;388(1):9–21. Pieruccini-Faria F, Black SE, Masellis M, Smith EE, Almeida QJ, Li KZH, et al. Gait variability across neurodegenerative and cognitive disorders: Results from the Canadian Consortium of Neurodegeneration in Aging (CCNA) and the Gait and Brain Study. Alzheimers Dement. 2021 Aug 1;17(8):1317–28. Wake Med Health and Hospitals. Raleigh, North Carolina, US, Bader K, Lah JJ, Emory University, Department of Neurology, Atlanta, Georgia, US, Levey AI, Emory University, Department of Neurology, Atlanta, Georgia, US, et al. A Retrospective Study of Progressive Gait Impairment in Alzheimer’s Disease. OBM Geriatr. 2022 Dec 27;6(3):1–1. Kueper JK, Speechley M, Lingum NR, Montero-Odasso M. Motor function and incident dementia: a systematic review and meta-analysis. Age Ageing. 2017 Sep;46(5):729–38. Ahn S, Chung JW, Crouter SE, Lee J, Lee CE, Anderson JG. Gait and/or balance disturbances associated with Alzheimer’s dementia among older adults with amnestic mild cognitive impairment: A longitudinal observational study. J Adv Nurs. 2023 Jun 29;jan.15768. Caetano MJD, Lord SR, Allen NE, Song J, Paul SS, Canning CG, et al. Executive Functioning, Muscle Power and Reactive Balance Are Major Contributors to Gait Adaptability in People With Parkinson’s Disease. Front Aging Neurosci. 2019 Jun 28;11:154. Galna B, Peters A, Murphy AT, Morris ME. Obstacle crossing deficits in older adults: A systematic review. Gait Posture. 2009 Oct;30(3):270–5. Nissen MJ, Bullemer P. Attentional requirements of learning: Evidence from performance measures. Cognit Psychol. 1987 Jan;19(1):1–32. Trés ES, Brucki SMD. Visuospatial processing: A review from basic to current concepts. Dement Neuropsychol. 2014 Jun;8(2):175–81. Weerdesteyn V, Nienhuis B, Duysens J. Advancing age progressively affects obstacle avoidance skills in the elderly. Hum Mov Sci. 2005 Oct;24(5–6):865–80. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4021983","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":276826839,"identity":"ffd461ac-14c9-4f99-b142-8595e1be29e7","order_by":0,"name":"Cheryl L Brandmeir","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIie3QwUrDMADG8dTBdin0+omKrxAJ1Mn6MC2F7hI7oSA7iBQG3dFrYL6El95l0FO9B7fLEDz1UNhlp2FqBUVSxZuH/CEhkPxICCEm038MzXRF/I81iIPPTdpN6BdyKP5I1Fr+QpzFrNjalMTn86fHZzkdTthqvqmtbBmkg1kODcG6CBeKJMdlHI54iYt8XTK8E7u41hEKznqKBIJw9+gyA3Ul7xMrj4IU3NWTybYlTqXIHpSJ8WtLTqsOwnstQXNLCkrhu4p46hZbSyAjZt1TJEDFRrwAheQMwd5jmR0lQ92PifCFVFMvhsPPVvzmljpivKnrEid3g+WD1JCmA5t8f4CvRr/jeJO1+2HTZDKZTOQNu8tYB/JsFqQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-7513-1804","institution":"West Virginia University","correspondingAuthor":true,"prefix":"","firstName":"Cheryl","middleName":"L","lastName":"Brandmeir","suffix":""},{"id":276826840,"identity":"22341523-6228-4af6-8347-c63dcec62c8c","order_by":1,"name":"Emily Herrick","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Emily","middleName":"","lastName":"Herrick","suffix":""},{"id":276826841,"identity":"f7acf429-a360-4638-83fe-e44dfddbec48","order_by":2,"name":"Serhii Bahdasariants","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Serhii","middleName":"","lastName":"Bahdasariants","suffix":""},{"id":276826842,"identity":"d852bbff-36d3-41bf-aa0e-f42ae53cdfdf","order_by":3,"name":"Sergiy Yakovenko","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Sergiy","middleName":"","lastName":"Yakovenko","suffix":""}],"badges":[],"createdAt":"2024-03-06 18:24:16","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4021983/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4021983/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52189998,"identity":"ee3eaf26-a331-4244-8630-5621022a0174","added_by":"auto","created_at":"2024-03-07 19:05:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90499,"visible":true,"origin":"","legend":"\u003cp\u003eVisuomotor processing schematic \u003cstrong\u003eA. \u003c/strong\u003eTwo stream theory \u003cstrong\u003eB. \u003c/strong\u003eTop-down visuomotor processing for gait modifications\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4021983/v1/7afd33c08b837fefc8c9537b.png"},{"id":52187910,"identity":"98b68cd9-54ff-4743-b6e7-2ccbcbef2dd1","added_by":"auto","created_at":"2024-03-07 18:57:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78563,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA. \u003c/strong\u003eTimeline of data collection. Following diagnosis, patient initiated a stable dose of Zoloft (25 mg) and Memantine (5 mg). Lecanamab was initiated 3 months post-diagnosis. The day prior to her first infusion, all pre-treatment gait assessments were collected. Patient received Lecanemab infusions on the standard schedule, every 2 weeks, and all repeat assessments occurred 12 days following the 3-month interval. This occurred at the 3, 6, and 9-month marks. \u003cstrong\u003eB.\u003c/strong\u003e Experimental set-up of patient with AD stepping over obstacles of different sizes.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4021983/v1/712acccb30efe5d9bc79adc3.png"},{"id":52187912,"identity":"cbde679d-1409-453c-a74c-daa6ed97e351","added_by":"auto","created_at":"2024-03-07 18:57:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":35929,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of available response time (ART) in patient with Alzheimer’s disease (AD) and neurotypical peers. From pre-treatment with Lecanemab to the first post-assessment at 3-months, there is a significant difference in ART in all obstacle heights and on both sides. This significance remains at each 3-month interval when compared to the pre-treatment ART, though changes are less so as time passes. When comparing ART in AD to neurotypical peers, there is a significant difference at baseline. There is no difference between the patient with AD and her neurotypical peers at the 6-month assessment and no difference persists at 9-months.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4021983/v1/6aac0c0b2c0b0aaa78f8a403.png"},{"id":52187913,"identity":"fc96ee62-56ba-489c-863e-9980fc64648a","added_by":"auto","created_at":"2024-03-07 18:57:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":84316,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of perception task results in Alzheimer’s disease (AD) and speed-matched neurotypical control (average preferred speed was 0.99 ± 0.17 m/s). \u003cstrong\u003eA)\u003c/strong\u003eProbability of detecting which leg is moving faster (%) vs interlimb speed difference (%). Speed difference is based on the participants’ preferred speed. Gray lines indicate individual speed-matched neurotypical participants, and black line is their average. The lines with brown gradient represent the longitudinal sessions of the AD participant, with the darkest brown indicating the pre-treatment session and the lightest brown indicating the most recent post-treatment session. \u003cstrong\u003eB) \u003c/strong\u003eBar graph showing the area under the curve (AUC) for the perception curves, shown in Panel A. The black bar represents the average of the neurotypical participants, with the whiskers representing standard deviation. AUC values were normalized to the cumulative maximum, with n.u. indicating normalized units.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4021983/v1/086d91e79319a85f0231da64.png"},{"id":52190526,"identity":"f19514a5-8bdd-406d-b5c9-44a8b97c079b","added_by":"auto","created_at":"2024-03-07 19:13:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":484845,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4021983/v1/3aad9b30-2dc1-4d4e-93e7-b5ed4cc11777.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eVisuomotor Control of Stepping over Obstacles Improves in Early Alzheimer’s Disease after Lecanemab Treatment: A Single Subject Case Series\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTargeting β-amyloid presents an appealing focus for prospective therapeutic interventions (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). β-amyloid accumulation in the brain, occurring up to two decades before the manifestation of clinical symptoms is a pathological hallmark of AD, with subsequent emergence of tau protein coinciding with symptom onset, such as decreased memory, repeating oneself, and getting lost (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Higher-order neurological processes that link sensorimotor functions are involved in the ability to plan movements and respond to environmental changes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Early gait dysfunction, particularly in the domain of obstacle avoidance, highlights the need to investigate the role of visuomotor behavior and processing in ambulation.\u003c/p\u003e \u003cp\u003eβ-amyloid accumulation interferes with neural processing through colocalized evidence of apoptosis (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), and interventions that address this mechanism are likely to maintain cognitive and motor cortical functions. Despite controversy surrounding the amyloid hypothesis, developing drugs to slow or delay the progression of AD has historically been the focus of research efforts (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The amyloid hypothesis posits that β-amyloid, the primary component of extracellular plaques discovered in the brains of individuals with AD, triggers the disease\u0026rsquo;s progression (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This includes inflammation, the formation of neurofibrillary tangles, and the eventual neuronal cell death and cognitive decline observed in individuals with AD (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlzheimer\u0026rsquo;s disease (AD) is a progressive neurodegenerative disorder primarily affecting older adults, resulting in cognitive decline, memory impairment and gait dysfunction (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Although AD is largely considered a cognitive disorder, the sensorimotor functions are also affected (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Among the various motor manifestations of AD, gait disturbances are prevalent and can significantly impact an individual\u0026rsquo;s mobility and overall quality of life (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Locomotion is one of the most vital behaviors that is tightly correlated with the quality of life and longevity; mobility deficits present in early AD may be closely related to the expected cortical disruption of visuomotor processing (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDisruptions in cortical processing, such as those seen in AD, can lead to deficits in locomotion and movement control. These deficits may manifest as gait disturbances, balance problems, or difficulties navigating in complex environments. Both the ventral and dorsal processing streams, spanning multiple cortical areas such as the prefrontal parietal cortex (PPC), premotor areas (premotor cortex - PM, supplementary motor area - SMA), and inferotemporal cortex (IT), have been implicated in visuomotor deficits. These areas are involved in processing the \"where\" and \"what\" aspects of visual inputs, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The classical model of visuomotor processing, originating from the discovery of corresponding cortical dorsal and ventral streams by Ungerleider et al. in 1983, initially proposed a clear dissociation between these streams. However, subsequent research has revealed that the distinction between the two streams may not be as rigid as initially thought, as demonstrated by asymmetric disruptions observed in patients with lesions causing spatial/optic ataxia or visual agnosia (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). For example, damage to the \"where\" stream not only leads to motor and cognitive impairments but also disrupts spatial attention and gaze (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). During more complex activities, such as navigating a cluttered environment or stepping over obstacles, the \u0026ldquo;what\u0026rdquo; pathway, or ventral stream, is primarily involved in object recognition and identification, providing information about the size, shape, and identity of the object. Additional regions in the \u0026ldquo;what\u0026rdquo; pathway contribute to determining how to interact with the recognized obstacle. The \u0026ldquo;where\u0026rdquo; pathway, or dorsal stream, as previously noted, is primarily involved in spatial processing and guiding action; this helps determine the location and spatial relationship of the object relative to the body (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Obstacle negotiation requires both the \u0026ldquo;what\u0026rdquo; and \u0026ldquo;where\u0026rdquo; pathways to work together, processing visual information during locomotion, allowing the individual to perceive the obstacle, determine their spatial location, and plan and execute appropriate motor responses to successfully navigate over or around them. Disruptions in either pathway may lead to movement planning and execution deficits, impacting one\u0026rsquo;s ability to successfully navigate through the environment. Cortical activity in balance and walking tasks may be decreased due to cortical atrophy affecting the motor cortical regions and corpus collosum, with the prefrontal cortex and basal ganglia most strongly affected (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In the case of neurological disease, locomotor control is impaired. Not only are the \u0026ldquo;what\u0026rdquo; and \u0026ldquo;where\u0026rdquo; pathways disrupted (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), but the ability to perceive limb speed may also be impaired (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Accurate perception of limb speed allows individuals to adjust step length and cadence accordingly, ensuring stable locomotion (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Visual cues, such as the speed of limb movement relative to the environment provide crucial input, and when combined with proprioceptive feedback from the muscles and joints, allows for additional fine-tuning of limb speed perception (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Furthermore, the thickness of cortical regions involved in the \u0026ldquo;what\u0026rdquo; and \u0026ldquo;where\u0026rdquo; visual processing streams may play a crucial role in the planning and execution of obstacle negotiation tasks (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Cortical thickness is closely linked to the functional integrity of these regions (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), affecting their abilities to process visual information and guide motor responses (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Specifically, alterations in cortical thickness in areas of the \"where\" pathway, such as the posterior parietal cortex, may impact spatial processing and the ability to perceive the location and orientation of obstacles in the environment (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Similarly, changes in cortical thickness in regions associated with the \"what\" pathway, such as the inferotemporal cortex, may influence object recognition and identification, affecting the ability to recognize obstacles and assess their properties (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNeurodegeneration is frequently measured through measurements of cortical thickness using structural magnetic resonance imaging (MRI) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Among individuals with late mild cognitive impairment, only three clusters showed significant atrophy compared with cognitively normal or early mild cognitive impairment- the left supramarginal gyrus, left middle, and inferior occipital gyrus. These areas are all located in the \u0026ldquo;where\u0026rdquo; pathway, associated with spatial processing and may impact obstacle negotiation (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Recently, larger study of individuals with AD showed decreased cortical thickness; volumes of various regions within the frontal lobes were compared to areas in the mesial temporal lobes, which are conventional biomarkers of memory deficits in AD (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). It was observed that the decrease in cortical thickness across frontal, parietal, and temporal regions provided a better explanation for performance variation than an individual structural measurement. Moreover, the reduced volume of brain regions has been shown to correlate with symptoms when these regions interact with one another (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). For instance, while the frontal lobe is traditionally associated with learning (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), learning performance was found to be enhanced through the interaction of the entorhinal cortex (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), known for its role in memory, navigation, and spatial perception. Other studies suggest that degeneration in the posteromedial parietal cortex, a structure responsible for the transformation of visual cues into motor action, may be a key indicator of AD risk (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Furthermore, it is suggested that motor tasks may serve as significant predictors of the transition from mild cognitive impairment to AD (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Functional MRI shows AD disrupts multiple pathways, including the thalamo-cortical, dorsal attention, visual, and sensorimotor pathways (\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Disruptions in cognitive and motor functions are prevalent among individuals with Alzheimer's disease (AD), particularly affecting visuomotor transformation\u0026mdash;an essential process guiding purposeful actions, including locomotion (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Vision plays a pivotal role in facilitating coordinated movements, particularly in intricate environments, by providing critical information on factors such as heading direction, object size, shape, and distance (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Previously, head orientation has been demonstrated to affect the choice of limb movements (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) and to predict turning behavior during walking on both straight and curved paths (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). For example, if an individual intends to turn their head to the right when walking, they are more likely to initiate limb movements that correspond to that direction such as stepping forward with their right leg, Further, to complete a turn to the right, their left leg will need to move faster than their right. This coordination between head orientation and limb movement is thought to be driven by the integration of sensory information from the visual, vestibular, and proprioceptive systems (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Visual input, including environmental information and obstacles, is processed to formulate and enact timely motor plans, such as stepping over obstacles. Typically, individuals plan two steps ahead, allowing themselves time to modify their gait pattern as needed (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Accurate stepping and locomotor strategies necessitate real-time adjustments for obstacle avoidance, constituting specialized tasks for these pathways that are susceptible to disruption (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Such disruption is likely to impede precise stepping and obstacle avoidance functions, essential for ensuring safe ambulation. During the seemingly simple task of stepping over an obstacle such as curb negotiation or stepping into the shower, requires the involvement of a top-down hierarchy to process visual information (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) and the integration of external environmental constraints and demands, alongside the neuromechanical dynamics defined by bottom-up organization (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). To avoid tripping or falling, the period of planning gait modification must be adequate; a shorter available period may result in a higher risk for falling, particularly among persons with mild cognitive impairment (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). The reaction time to obstacle presentation in self-paced locomotion can be used as a measure of sensory processing and planning. Here we report measures of obstacle negotiation response times and limb perception over time in a longitudinal case study focusing on a 75-year-old female diagnosed with AD and explore gait changes pre- and post-Lecanemab infusions over 9-months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePatient\u003c/span\u003e: A 75-year-old Caucasian female with a 4-year history of progressive memory loss and repetition during conversations, more notable over the prior 3 months, presented to the memory care clinic with her daughter. No fall history was noted, and the patient denied a fear of falling. The patient, unaware of her deficits, partook in a comprehensive evaluation including medical history, cognitive tests, neurological examinations, brain imaging, and lumbar puncture. Past medical history is significant for hypothyroidism, hypertension, hyperlipidemia, atrial fibrillation, and depression. Current medications include Eliquis, Metoprolol, Synthroid, Hydrochlorothiazide, Irbesartan, and Rosuvastatin. Neurological examination revealed 5/5 strength throughout bilateral upper and lower extremities and 23/30 on the Mini-Mental Status Examination (MMSE). On the Functional Gait Assessment (FGA), she scored 25/30, with difficulties noted with horizontal and vertical head turns during ambulation, walking with eyes closed, and ambulating backwards. MRI was abnormal, showing moderate bilateral parietal cortical atrophy and left greater than right perisylvian volume loss in temporal opercular region. Further, bilateral hippocampal volume loss and moderate left entorhinal cortical atrophy were evident. A lumbar puncture confirmed the presence of abnormal proteins in the cerebrospinal fluid, including Abeta42 at 1036 pg/mL, total tau 420 pg/mL, P-tau 43.3 pg/mL, and a p-tau/ABeta42 ratio of 0.042 (normal value\u0026thinsp;\u0026le;\u0026thinsp;0.023). APoE genotype is heterozygous, E3/E4. Based on the Unites States National Institute of Aging and the Alzheimer\u0026rsquo;s Association guidelines for diagnosis (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), this patient was diagnosed with AD. At diagnosis, Zoloft (25mg) and memantine (5mg) were prescribed, and she was scheduled to begin Lecanemab infusions every 2 weeks.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSession design\u003c/span\u003e: In this longitudinal study, we tracked sensorimotor performance in AD prior to initiation of and throughout anti-amyloid treatment. Motor performance was assessed overground with the functional gait assessment (FGA), a clinical test documenting postural stability and motor function during ambulation (i.e., stepping over obstacles, turning, stair negotiation, backward walking), as well as walking tasks on the split-belt treadmill (Bertec, Columbus, OH)\u0026mdash;standard gait analysis, limb speed perception accuracy and stepping over obstacles. All gait pre-testing was performed after initiation of Zoloft and memantine, but prior to Lecanemab infusions. At 3-months, Eliquis was discontinued, and a baby aspirin was initiated due to Lecanemab prescribing recommendations. There were no reported amyloid related imaging abnormalities throughout treatment. All procedures were approved by the institutional review board of West Virginia University (IRB #2210669796).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eControl group\u003c/span\u003e: To compare the performance to a neurotypical cohort, we recruited 3 age-matched females (75.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2y) to perform the same obstacle negotiation task (table 1). We tested the performance of the patient with AD relative to the neurotypical group using a two-way ANOVA to analyze the effect of obstacle type and group [neurotypical vs AD session (pre-treatment)] on available RT. The performance of the patient with AD over time was assessed using a two-way ANOVA to analyze the effect of obstacle type and AD session (pre-treatment vs. post-3 months vs. post-6 months vs. post- 9-months) on available RT. At 9-months, we tested the performance of the AD patient relative to the neurotypical group using a one-tailed t-test across all obstacle types. Analysis reveals a significant difference between the patient and her cohort pre-treatment; however, significant improvement toward matching her neurotypical cohort by 3 months, with no significant differences noted by 6 months, and enduring results at 9 months (table 1). Analysis of limb speed perception was performed with speed-matched neurotypical controls and a test of equivalence was performed to establish there was no difference between the groups, as well as no difference between the participant with AD pre- and post-treatment, indicating perception stability Step analysis was also performed on the stepping limb to categorize the stepping strategy: long step, short step, regular step, or kick step. Notably, the participant the AD was the only one to demonstrate a kick step as a strategy, and the neurotypical cohort had a greater proportion of short and long stepping strategies.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePsychometric Task\u003c/span\u003e: Throughout the session, the participant utilized a body weight support system (BWSS, Pneumex, Sandpoint, ID) with an overhead gantry without unloading for safety. While secured in the BWSS she walked on the tied-belt treadmill with different speeds and selected her preferred speed (PS). She maintained PS (0.9m/s) for 2 minutes, acclimating to treadmill walking. Next, lower visual field blocking glasses were donned and worn while she walked at her PS for 2 minutes, acclimating to treadmill walking under this condition. The split-belt paradigm was introduced during the interim 5-minute rest period. She was instructed to determine which leg was moving faster (left or right) without visual input (looking down). To minimize visual and auditory cues, she received automated cues to assess the speed difference (3s) as well as report limb speed perception (4s). No performance feedback was provided during the walking trial. Belt speed variations were randomized based on her PS, including 0%, \u0026plusmn;\u0026thinsp;2%, \u0026plusmn;\u0026thinsp;5%, \u0026plusmn;\u0026thinsp;20%, and \u0026plusmn;\u0026thinsp;30% variations of her PS. All responses and belt speed data from the instrumented treadmill were recorded and used to identify the just noticeable difference in limb speed and her perception accuracy. Before the experimental procedure, the participant performed 10 practice trials for familiarization with the split-belt treadmill paradigm. Following this, she had another 5-minute rest period before another 2-minute treadmill walking session at her PS in a symmetrical condition under typical conditions.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eObstacle Avoidance Task\u003c/span\u003e: Following another brief rest and explanation, the participant was asked to perform an obstacle negotiation task. Small obstacles were placed on the treadmill every 10 seconds during this task. Obstacles, standardized as 2 cm, 5 cm, and 10 cm blocks, were placed on the treadmill in a pseudo-randomized order between the height and belt sides. Seven repetitions were performed under each condition. While walking at 0.5m/s, the participant was asked to clear the obstacle without upper extremity support. We measured the response time, determined by the period between \u003cem\u003eblock placement\u003c/em\u003e and \u003cem\u003etoe off\u003c/em\u003e events for each obstacle type and side. Finally, the participant was asked to walk for 2 minutes at 1.0 m/s following a 5-minute rest period.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStatistics and Data Analysis\u003c/span\u003e: Custom-written MATLAB (The MathWorks, Inc., Natick, MA, United States) code was used to control the treadmill to impose desired speed differences and randomizations during all treadmill tasks, including the perception and obstacle negotiation tasks. Gait trials were also visually inspected using Adobe software for frame analysis to accurately determine the time of block placement, toe-off, and categorize stepping strategy. ANOVA and one-tailed t-test were used for the comparative analysis with the significance threshold set to 0.05.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAssessment of Perception in Psychometric Task\u003c/span\u003e: For each trial, participant response (i.e., left or right) was compared to the correct answer, and the percentage correct for each interlimb speed difference category was determined. The threshold for detecting the interlimb speed difference was determined by finding the last speed difference category to have a probability less than or equal to 50%. For all the speed difference categories prior to the threshold, the probability was adjusted to 50% to represent that the participant had a 50% probability of answering correctly based on chance. Plots of the probability of detecting which leg is moving faster versus the interlimb speed difference were made for pre- and post-medication sessions and speed-matched neurotypical controls. The area under the curve (AUC) for each session was determined using trapezoidal numerical integration to quantify both sensory and cognitive deficits. The sensory deficits would be expected in the larger thresholds in speed difference detection (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u0026ldquo;a\u0026rdquo;); cognitive deficits would be expected in the depression of probability of detection even at large values of speed differences (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u0026ldquo;b\u0026rdquo;). The AUC was normalized to the maximum area possible (100% probability x 30% speed difference). To account for the fact that one of the individual control sessions and the post-9-month session were recorded with 0%, 5%, 12.5%, 20%, and 30% speed differences while the rest of the sessions were recorded with 0%, 2%, 5%, 20%, and 30% speed differences, linear interpolation was used to fill in any missing speed difference categories for a given session.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBaseline and interval testing was obtained every 3 months throughout the initial 9 months of this participant\u0026rsquo;s treatment (table 1). Prior to Lecanemab infusion, MMSE score was 23/30, with difficulties with word recall, backward counting, and orientation. Overground walking assessment with the FGA had decreased performance in the areas of horizontal head turns, walking with eyes closed, and walking backwards, receiving an overall score of 25/30. Available RT at baseline 2.61 \u0026plusmn; 0.41s overall. The individual responses to obstacle type and stepping limb are reported in Table 1. Stepping strategy revealed a kick step strategy as the most utilized strategy (38%), as compared to the incidence of short step and long step strategies, particularly with the 10cm obstacles. Initial pre-infusion gait testing showed that while this patient could clear each obstacle successfully, her strategy for obstacle clearance ranged widely between obstacle height and side. The initial probability of detecting which leg was moving faster versus the interlimb speed difference was 76% using the AUC method.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1. Subject population and summary of test results participant with AD and neurotypical cohort. Stepping strategies: LS: long step, SS: short step, RS: regular step; KS: kick step\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cp\u003eFollowing 3-months of Lecanemab infusions, all metrics were re-evaluated. MMSE score improved to 27/30, with difficulties on world recall only. Overground walking assessment with the FGA revealed improvement to 28/30, noting ongoing difficulties with horizontal head turns (deviation out of bounds) and gait with eyes closed. Post 3-months, available RT decreased significantly in all areas, with overall available RT decreasing to 1.67 \u0026plusmn; 0.32s (see Table 1 for details). Stepping strategy continues to show a kick strategy as the most utilized strategy (40%), particularly with the 10cm obstacles. Limb speed detection abilities were maintained at this time (78%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollowing 6-months of Lecanemab infusions, MMSE score was maintained at 27/30, with difficulties on world recall only. Overground walking assessment with the FGA revealed improvement to 30/30. Post 6-months, decreased available RT persists in all areas, with overall available RT 1.48\u0026nbsp;\u0026plusmn; 0.39s (see Table 1 for details). Stepping strategy shifted: the long step strategy is now the most predominant strategy (36%), although the kick step strategy continues to be utilized frequently (24%). Limb speed detection abilities were slightly improved (80%) at this time.\u003c/p\u003e\n\u003cp\u003eAt 9-months post Lecanemab infusions, MMSE score improved to 29/30, with a single point lost on word recall, and FGA remained at 30/30. Post 9-months, decreased available RT endures, with overall available RT 1.50\u0026nbsp;\u0026plusmn; 0.39s (see Table 1 for details). Stepping strategy shifted again with a balance between the long step strategy (33%) and the kick step strategy (33%).\u0026nbsp;Results from the available RT during obstacle negotiation under all conditions from the pre-test (2, 5, and 10 cm blocks) indicate that treatment with Lecanemab may have influenced improved advanced gait skills with available RT decreasing in all conditions. Left and right-sided obstacle available RT significantly decreased overall from pre-treatment to 3-months and maintained improvements through the 9-month testing period (p\u0026lt;.001). All individual obstacle heights showed significant and enduring results (p\u0026lt;.001). Compared to her age and sex-matched neurotypical peers prior to treatment, available RT for this patient was significantly longer in all categories (p\u0026lt;.001). However, no significant difference was evident in any obstacle category at 9-months of treatment between this patient and her neurotypical peers as evaluated by a series of direct post-hoc comparisons (overall left 1.52 \u0026plusmn; 0.39s vs 1.44 \u0026plusmn; 0.35s, \u003cem\u003ep\u003c/em\u003e = .19; overall right 1.48 \u0026plusmn;0.34s vs 1.48 \u0026plusmn; 0.34s, \u003cem\u003ep\u003c/em\u003e = .42; 2cm left 1.64 \u0026plusmn; 0.41s vs 1.41 \u0026plusmn; 0.30s, \u003cem\u003ep\u003c/em\u003e = .06; 2cm right 1.51 \u0026plusmn; 0.45s vs 1.49 \u0026plusmn; 0.37s, \u003cem\u003ep\u003c/em\u003e = .15; 5cm left 1.39 \u0026plusmn; 0.50s vs 1.45 \u0026plusmn; 0.39s, \u003cem\u003ep\u003c/em\u003e = .36; 5cm right 1.49 \u0026plusmn; .46s vs 1.42 \u0026plusmn; 0.39s, .35; 10cm left 1.54 \u0026plusmn; .25s vs 1.48 \u0026plusmn; 0.36s, \u003cem\u003ep\u003c/em\u003e = .32, and 10cm right 1.45 \u0026plusmn; .32s vs 1.51 \u0026plusmn; 0.27s, \u003cem\u003ep\u003c/em\u003e = .32). Limb speed detection abilities were stable over 9-months (fig. 4) with no difference noted with equivalence testing using a 95% confidence interval for AUC. No difference was also noted between the patient with AD and neurotypical cohort. Further, compared with speed-matched neurotypical controls (n= 5, 54.6 \u0026plusmn; 5.41y), she remains within approximately 1 S.D. (79% \u0026plusmn; 5%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis described case of a 75-year-old patient with newly diagnosed AD and early intervention with Lecanemab may be interesting for the practice of physicians due to the current dearth of research on the role of monoclonal therapy on gait. Psychometric testing indicated that the disruption and subsequent recovery were not influenced by limb representation within control pathways. This reinforces the notion that Alzheimer\u0026apos;s disease affects the \u0026apos;where\u0026apos; dorsal stream pathway responsible for planning and coordinating frame transformations. These findings are noteworthy as, typically, in the absence of monoclonal therapy, we observe a decline in both cognition and overall function within a similar timeframe\u0026nbsp;(46).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGait disturbances in AD manifest as alterations in walking speed, stride length, and balance, often leading to an increased risk of falls and injuries (47,48). Managing these gait abnormalities can be challenging, often necessitating specialized interventions to enhance mobility and reduce the risk of falls. Older adults with poor motor function, particularly those with impaired balance and gait abnormalities, are at an increased risk of cognitive impairment, with gait disturbances being predictive of incident AD (13,49,50).\u003c/p\u003e\n\u003cp\u003eBefore receiving the Lecanemab infusion, the patient exhibited a behavior of waiting for the obstacle to approach her, resembling a \u0026apos;rusty water mill\u0026apos; scenario where she could see the obstacle. However, an apparent error in visual-motor transformation resulted in a delayed step-over. Because gait speed was constant, increased RT was acquired on the treadmill by moving toward the backmost area and decreasing step length to allow increased stability and afford trip avoidance. Post-infusion, the decreased available RT may be attributed to improved visuomotor processing rather than a product of learning due to the length of time between trials (3 months). Further, obstacle negotiation and successful walking rely on intact cognitive processes and accurate sensorimotor capabilities (51,52). As previously shown, reaction time increases with choice and decreases with learning (53). Here, learning chance was minimized through a computer-generated algorithm for random obstacle height and side of placement.\u003c/p\u003e\n\u003cp\u003eFurther, placing random obstacles is analogous to the patient being presented with an unanticipated obstacle. Unanticipated obstacles require higher levels of attention, visuospatial, and information processing, all skills associated with executive function, thus increasing the cognitive demand associated with motor planning (54). These unanticipated obstacles require quicker recruitment of cognitive resources, and inadequate sensorimotor planning may lead to increased available RT via a modified obstacle negotiation strategy.\u003c/p\u003e\n\u003cp\u003eStepping strategies for obstacle negotiation have been previously identified and defined as stride lengthening (crossing the obstacle via a lengthening cross step) or stride shortening during which the preceding step is shortened and the obstacle is crossed in the next step (55). In the case series, we also identified two additional strategies\u0026mdash;a kick step during which the knee was flexed, and the obstacle was allowed to pass underfoot, as well as a regular step during which the participant did not alter their preceding or crossing step to negotiate the obstacle. This observation was much like receiving full credit for obstacle negotiation on overground obstacle negotiation in the FGA. The kick step was only observed in the participant with AD and appeared to be an atypical obstacle negotiation strategy. This strategy, persisting throughout all phases of treatment, was frequently observed during the highest obstacle negotiations and may afford increased stability in dynamic situations, thus allowing improved trailing limb foot placement (24).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eStudying gait modifications in AD is an essential aspect of comprehensive research efforts to understand the progression of disease, improve early diagnosis, develop effective treatments, and enhance the overall care and management of individuals living with AD. Detecting early gait aberrations may provide valuable insights into the progression of the disease and its impact on a person\u0026rsquo;s functional abilities. Looking at it in the context of monoclonal therapy, research in gait assessment may help us better understand the underlying mechanisms and pathology of the disease and its impact on cortical visuomotor processing. Further, it may serve as a non-invasive biomarker to monitor disease progression and evaluate the effectiveness of monoclonal therapy and other potential treatments.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMcDade E, Cummings JL, Dhadda S, Swanson CJ, Reyderman L, Kanekiyo M, et al. Lecanemab in patients with early Alzheimer\u0026rsquo;s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res Ther. 2022 Dec 21;14(1):191.\u003c/li\u003e\n \u003cli\u003eKarran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. 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Hum Brain Mapp. 2012 May;33(5):1076\u0026ndash;88.\u003c/li\u003e\n \u003cli\u003eZheng W, Liu X, Song H, Li K, Wang Z. Altered Functional Connectivity of Cognitive-Related Cerebellar Subregions in Alzheimer\u0026rsquo;s Disease. Front Aging Neurosci. 2017 May 16;9:143.\u003c/li\u003e\n \u003cli\u003eGeorgopoulos AP, Grillner S. Visuomotor Coordination in Reaching and Locomotion. Science. 1989 Sep 15;245(4923):1209.\u003c/li\u003e\n \u003cli\u003eDrew T, Andujar JE, Lajoie K, Yakovenko S. Cortical mechanisms involved in visuomotor coordination during precision walking. Brain Res Rev. 2008 Jan;57(1):199\u0026ndash;211.\u003c/li\u003e\n \u003cli\u003eDancause N, Schieber MH. The impact of head direction on lateralized choices of target and hand. Exp Brain Res. 2010 Apr;201(4):821\u0026ndash;35.\u003c/li\u003e\n \u003cli\u003eHicheur H, Vieilledent S, Berthoz A. Head motion in humans alternating between straight and curved walking path: Combination of stabilizing and anticipatory orienting mechanisms. Neurosci Lett. 2005 Jul;383(1\u0026ndash;2):87\u0026ndash;92.\u003c/li\u003e\n \u003cli\u003ePatla A, Vickers J. How far ahead do we look when required to step on specific locations in the travel path during locomotion? Exp Brain Res. 2003 Jan 1;148(1):133\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eMaidan I, Shustak S, Sharon T, Bernad-Elazari H, Geffen N, Giladi N, et al. Prefrontal cortex activation during obstacle negotiation: What\u0026rsquo;s the effect size and timing? Brain Cogn. 2018 Apr;122:45\u0026ndash;51.\u003c/li\u003e\n \u003cli\u003eSobinov A, Yakovenko S. Model of a bilateral Brown-type central pattern generator for symmetric and asymmetric locomotion.\u003c/li\u003e\n \u003cli\u003ePieruccini-Faria F, Sarquis-Adamson Y, Montero-Odasso M. Mild Cognitive Impairment Affects Obstacle Negotiation in Older Adults: Results from \u0026ldquo;Gait and Brain Study.\u0026rdquo; Gerontology. 2018 Oct 12;65(2):164\u0026ndash;73.\u003c/li\u003e\n \u003cli\u003eDubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, et al. Clinical diagnosis of Alzheimer\u0026rsquo;s disease: recommendations of the International Working Group. Lancet Neurol. 2021 Jun;20(6):484\u0026ndash;96.\u003c/li\u003e\n \u003cli\u003eVan Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer\u0026rsquo;s Disease. N Engl J Med. 2023 Jan 5;388(1):9\u0026ndash;21.\u003c/li\u003e\n \u003cli\u003ePieruccini-Faria F, Black SE, Masellis M, Smith EE, Almeida QJ, Li KZH, et al. Gait variability across neurodegenerative and cognitive disorders: Results from the Canadian Consortium of Neurodegeneration in Aging (CCNA) and the Gait and Brain Study. 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Advancing age progressively affects obstacle avoidance skills in the elderly. Hum Mov Sci. 2005 Oct;24(5\u0026ndash;6):865\u0026ndash;80.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"West Virginia University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease, Lecanemab, Visuomotor, Gait disturbance, Obstacle negotiation, Functional outcomes,","lastPublishedDoi":"10.21203/rs.3.rs-4021983/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4021983/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eAlzheimer’s disease (AD), an incurable, progressive neurological disease, is the most common cause of dementia among older adults. While traditionally recognized for cognitive impairments, the emergence of gait disturbances presents a pivotal aspect of disease advancement, necessitating consideration of associated sensorimotor dysfunction. AD affects cortical visuomotor transformations, evidenced by diminished cortical thickness and altered reaction times in reaching tasks. Furthermore, eye-tracking studies have identified cognitive interference during visuomotor tasks, manifesting as increased saccadic movements and prolonged fixations, likely attributable to heightened cognitive demands. Although these findings support AD’s effects on the visuomotor transformation in locomotion, its diagnostic and assessment potential remains unexplored. Moreover, the recent use of monoclonal antibody therapies targeting β-amyloid show cognitive improvements, yet their efficacy in improving motor-related functional outcomes remains largely unexplored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003e In this case study, we present a 75-year-old female diagnosed with early AD treated with Lecanemab. We explore gait changes pre- and post-Lecanemab infusions over 9-months. Before treatment, the patient scored 23/30 on the Mini Mental State Examination (MMSE) and 25/30 on the Functional Gait Assessment (FGA). Visuomotor processing was assessed using treadmill locomotion with and without obstacles of different sizes. Response time was measured as the period between the obstacle presentation and the initiation of stepping over that obstacle at preferred walking speed maintained across sessions. Additionally, we assessed for potential disruption of embedded limb representation in planning pathways through psychometric testing of limb speed perception. Measurements were repeated every 3-months for 9-months. At 9-months, the patient scored a 29/30 on the MMSE and a 30/30 on the FGA. During advanced gait assessment, she cleared obstacles, with an overall RT of 1.50 ± .39s. Limb speed perception accuracy remained stable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eOur patient demonstrated disrupted visuomotor processing and execution functions during the treadmill obstacle avoidance task. Treatment 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.\u003c/p\u003e","manuscriptTitle":"Visuomotor Control of Stepping over Obstacles Improves in Early Alzheimer’s Disease after Lecanemab Treatment: A Single Subject Case Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-07 18:57:39","doi":"10.21203/rs.3.rs-4021983/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"461b239b-8753-47ef-8456-2b63a07ded4b","owner":[],"postedDate":"March 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":29178430,"name":"Neurology"}],"tags":[],"updatedAt":"2024-03-07T18:57:39+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-07 18:57:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4021983","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4021983","identity":"rs-4021983","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}