Deep Brain Stimulation of the Pedunculopontine Nucleus for Alzheimer's Disease

Determined by assessing recruitment trends. The effectiveness of recruitment strategies will be assessed by monitoring the rate at which eligible participants are enrolled.

To ensure procedural consistency across participants, adherence to the study protocol will be systematically monitored. Any protocol deviations will be documented and evaluated for their potential impact on study outcomes, ensuring the reliability and reproducibility of findings

Participant retention will be assessed through an analysis of attrition rates, with particular attention to identifying the causes of dropout.

Exit interviews will be conducted with participants and their caregivers to gather quantitative and qualitative information on their subjective experience and evaluation of the study intervention. Quantitative feedback on six items assessing satisfaction (e.g., understanding of study protocol, follow-up schedule manageability, likelihood of participating in future studies with same procedure) are measured on a a 5-point Likert scale (1 - "Very Dissatisfied" to 5 - "Very Satisfied"). Total score on quantitative items ranges from 6 - 30, with a higher score representing a more positive participant and caregiver evaluation of the study intervention.

Possible adverse events (AEs), serious adverse events (SAEs), or unanticipated problems related to the DBS device, related surgery and/or stimulation will be closely monitored and managed as per standard of care and definitions and classifications set forth in the following subsections.

An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational devices or procedures.

An SAE is an event that:

Led to death; Led to serious deterioration in the health of the subject Led to foetal distress, foetal death or a congenital abnormality or birth defect Could have led to death or a serious deterioration were it to recur.

All AEs will be assessed by the study team using The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 published by the U.S. Department of Health and Human Services (November 27, 2019) grading system. For AEs not included in the CTCAE defined grading system, the following guidelines will be used to describe severity:

Grade 1, Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated;

Grade 2, Moderate; minimal, local or non-invasive intervention indicated; limiting age- appropriate instrumental activities of daily life (ADL)*;

Grade 3, Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL**;

Grade 4, Life-threatening consequence; urgent intervention indicated; or

Grade 5, Death related to AE.

Team will determine AE's causality based on categories below:

Definitely Related - There is clear evidence to suggest a causal relationship, and other possible contributing factors can be ruled out.

Probably Related - There is evidence to suggest a causal relationship, and the influence of other factors is unlikely.

Possibly Related - There is some evidence to suggest a causal relationship (e.g., the event occurred within a reasonable time. However, other factors may have contributed to the event (e.g., the participant's clinical condition, other concomitant events).

Unlikely to be related - A clinical event whose temporal relationship to implantation/use of the study device makes a causal relationship improbable and in which other drugs, devices or underlying disease provides plausible explanations.

Not Related - The AE is completely independent of implantation/use of the study device, and/or evidence exists that the event is definitely related to another etiology.

The outcome of the AE will be defined according to the following:

Recovered/ Resolved: The event has fully resolved at the end of the study*;

Recovering/ Resolving: The event is improving but has not fully resolved at the end of the study*;

Recovered/ Resolved with sequelae: The event has resolved, but retained pathological conditions resulting from the prior disease or injury;

Not recovered/ not resolved: The event is ongoing at the end of the study*;

Fatal: This event is determined to be the cause of death; and

Unknown: Outcome information could not be obtained.

GO power spectral density and synchrony will be assessed using scalp EEG and MEG during DBS-PPN "on" and "off" epochs. These recordings will be collected during resting-state periods. Increases in gamma activity during the "on" state will be evaluated to determine the effectiveness of DBS-PPN in entraining GO rhythms.

Theta-gamma coupling will be measured using EEG and MEG recordings during the n-back task, which engages working memory and cognitive flexibility. Comparisons will be made between "on" and "off" states of DBS-PPN to evaluate whether stimulation enhances coupling and improves task performance. Theta-gamma coupling captures the interaction between slower theta rhythms (4-8 Hz) and faster GOs.

Working memory performance will be assessed using the n-back task during EEG and MEG recordings. Performance on the n-back task is measured by computing participants' accuracy (% of correct response) across trials, with higher measures indicating greater working memory performance.

Cognitive assessments will be employed to correlate the anticipated effects of DBS-PPN with improvements in cognitive performance. The CDR-SB will be used to provide a more granular assessment of cognitive and functional performance. It evaluates six domains, including memory, orientation, and problem-solving, and generates a total score that better captures subtle changes in disease severity. Each domain on the CDR is rated on a 5-point scale (0 = no impairment, 0.5 = questionable impairment, 1 = mild impairment, 2 = moderate impairment, 3 = severe impairment). The CDR-SB score is the total score across the domains and ranges from 0-18, with 18 indexing greater severity of cognitive impairment.

The ADAS-Cog assesses task performance in cognitive domains such as memory, language, and praxis, and is sensitive to detecting cognitive changes over time. Performance on each domain is scored from 0 - 5, with 5 indexing more severe cognitive impairment. The ADAS-Cog score is a summation of scores across the domains, and ranges from 0 to 70, with higher scores indicating more severe cognitive impairment.

The MoCA is a 30-item screening tool designed to detect early cognitive impairments across multiple domains. The MoCA consists of 12 tasks, each corresponding to a specific domain of cognitive impairment. Points are allocated for correct task performance and summed to compute the MoCA score. Lower scores index more severe cognitive dysfunction. MoCA scores range from 0 to 30, and the threshold score for normal cognitive functioning is 26 or above.

The NPI assesses behavioral and neuropsychiatric symptoms frequently observed in AD, such as agitation, depression, and apathy. It is administered through a structured interview with caregivers, who report on symptom presence, symptom severity (3-point scale, 1 "mild" - 3 "severe") and distress caused by symptoms (5-point scale, 0 "Not distressing at all" - 5 "Very Severely"), making it sensitive to treatment-related changes. The domain score is calculated by multiplying the distress and severity score. The total NPI score is calculated by adding all domain scores, with higher scores reflecting greater symptoms associated with AD. Total NPI score can range from 0 to 144.

The SDI expands upon the sleep-related item from the NPI. It captures the frequency (5-point scale, 0 "not present" - 4 "daily"), severity (4-point scale, 0 "not present" - 3 "marked), and caregiver burden of sleep disturbances through caregiver reports. The SDI Total score is calculated by multiplying the average frequency score by the average severity score. The SDI Total score ranges from 0-12, with higher scores indicating greater sleep disturbance.

The QoL-AD is a validated tool designed to assess quality of life in individuals with Alzheimer's disease. It consists of both patient and caregiver versions, capturing perceptions of physical health, social interaction, and emotional well-being. Each item is answered on a scale of 1 "poor" to 4 "Excellent". Scores on all 13 items are summed to compute the total QoL-AD score (ranging from 13-52), where higher scores index a greater QoL.