Background: The purpose of this study was to evaluate the safety and efficacy of low-intensity tFUS under the threshold for BBB disruption in patients with AD. In addition, we assessed changes in the regional cerebral metabolic rate of glucose (rCMRglu) using F-18 fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and cognitive function after tFUS. Methods: Eight AD patients were recruited. We applied low-intensity tFUS to the right hippocampus for 3 minutes using an image-guided tFUS system. For multi-modal neuroimaging guidance, MRI and CT data were spatially co-registered using the maximization of normalized mutual information. The subjectspecific coordinates of the hippocampus in the right hemisphere were identified as the tFUS target location. Results: Radiological evidence of contrast enhancement associated with BBB opening was not found in neither the visual inspection nor the ICA of the DCE-MRI data. No adverse events were observed during the hospitalization and follow-up outpatient visits for 5 to 24 months. The immediate recall and recognition memory on the SVLT were significantly improved after the sonication. The PET analysis showed the increased level of rCMRglu in the right hippocampus. Conclusions: Application of low-intensity tFUS to the hippocampus with MB did not open blood brain barrier but increased hippocampal glucose metabolism and memory function.

Background: Recent evidence shows that epileptiform activity (EA) in sleep can present early in Alzheimer’s Disease (AD) with faster cognitive decline. Existing literature examining sleep, AD and seizures is mostly qualitative. We conducted a systematic review to quantify the sleep stage most associated with EA in AD and amnestic mild cognitive impairment (aMCI)Methods: We searched MEDLINE and Embase using MeSH terms: “Alzheimer’s Disease” AND “Epilepsy” OR “Seizures’’ AND “Sleep” OR “REM” (rapid eye movement sleep). We extracted data to determine the EA distribution across sleep stages. We averaged percentages across studies. If a study had AD and aMCI subgroups, we averaged percentages to represent that study. Results: 4/14 articles had quantitative sleep stage EA data from a total of 111 AD or aMCI patients. Most EA occurred in the non-REM stage (N2; 36.1±17.8%). EA next most frequently occurred in slow-wave sleep (SWS; 34.1±9.9%), N1 (15.5±6.7%), and REM (14.4±11.6%). Conclusions: N2 and slow-wave sleep were most associated with sleep EA in AD or aMCI. This suggests the importance of therapeutic interventions that may decrease N2 and slow-wave sleep and increase REM. Future studies could explore whether it is the quantity or quality of the N2 and slow-wave sleep that is associated with EA.

Background: In Parkinson’s disease (PD), mounting evidence implicates degeneration of cholinergic systems in cognitive and gait decline. The Nucleus Basalis of Meynert (NBM) is a major cholinergic nucleus with widespread cortical projections. We hypothesized that atrophy of the NBM is correlated with cognitive phenotypes and gait measures in PD. Methods: Subjects from the COMPASS-ND study (20 controls and 79 PD patients) were studied. Clinical measures included cognitive diagnosis (MCI, dementia) and quantitative gait parameters with dual task gait. Manual region of interest measurement of the NBM was performed on T1 MRI scans. NBM volumes were analyzed against clinical measures. Results: PD-MCI and PD-dementia patients had greater dual task costs to gait speed when performing serial 7s (mean difference -12%, p=0.02; -11%, p=0.04) and animal fluency tasks (mean difference -9%, p=0.02; -15%, p<.001) compared to controls. Reduced normalized NBM volume was associated with PD-MCI (mean difference 0.34, p=0.04) and PD-dementia (mean difference 0.55, p<0.001) phenotypes. NBM volume was weakly correlated with gait velocity (r2 0.06, p=0.01) and dual task cost to gait velocity with animal fluency (r2 0.06, p=0.02). Conclusions: NBM atrophy is associated with cognitive decline in PD and may be responsible for cognitive aspects of gait performance.

Background: There are many cognitive tests that detect mild cognitive impairment (MCI) and dementia such as the Montreal Cognitive Assessment (MoCA) and Rowland Universal Dementia Assessment Scale (RUDAS). The comparative performance of these screening tests for identifying MCI and dementia is unknown. Methods: The MoCA and RUDAS were administered during baseline visits for patients in the Calgary Neurosciences Program. Those that enrolled in the Prospective Registry of Persons with Memory Symptoms (PROMPT) had their scores related to their final clinical diagnosis. Cut-off scores of 26 for the MoCA and 22 for the RUDAS were used to indicate a positive result. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of both cognitive scores were compared. Results: The sensitivity, specificity, PPV, NPV, and accuracy of the MoCA (n = 125) was 89.3%, 72.7%, 93.9%, 59.3%, and 86.4%, respectively. The sensitivity, specificity, PPV, NPV, and accuracy of the RUDAS (n = 125) was 47.6%, 100%, 100%, 29.0%, 56.8%, respectively. Conclusions: In patients with cognitive complaints presenting to a specialist clinic, the MoCA was more sensitive and accurate than the RUDAS for a final clinician diagnosis of mild cognitive impairment or dementia when using the standard cut-offs.

Background: Saskatchewan’s Rural and Remote Memory Clinic (RRMC) has provided post-diagnostic virtual dementia care for approximately 19 years. In response to the COVID-19 pandemic and a new need for remote dementia diagnosis, we developed a virtual, team-based, interdisciplinary (neurology, neuropsychology, nursing), diagnostic memory clinic (vRRMC). We evaluated patient and caregiver satisfaction with the new virtual clinic. Methods: Semi-structured telephone interviews were conducted with rural vRRMC patients (n=7), caregivers (n= 13), and one patient/caregiver dyad. Ages of respondents ranged from 40 to 70 years old (60% female). Level of diagnosed cognitive dysfunction ranged from subjective cognitive impairment to major neurocognitive disorder. Respondents saved an average of 460 km of travel compared to a trip to Saskatoon. Results: Thematic analysis of responses revealed universal satisfaction with the virtual model. The technology training sessions, offered prior to the first vRRMC visit, was described as important for satisfaction. Analysis of preference for future visits revealed more nuance; some preferred in-person visits and planned to travel for future appointments post-pandemic, while others preferred to maintain the virtual model due to perceived travel burden (cost, time, and inconvenience). Conclusions: When clinically appropriate, virtual diagnostic memory clinics should persist as an option post pandemic for families who experience high travel burden.

Background: Within the IMPACT-AD BC study, we sought to address the gap in knowledge around how the use of Alzheimer’s disease (AD) CSF biomarker testing impacts clinical management. Methods: IMPACT-AD BC (NCT05002699, impactAD.org) is an observational, longitudinal study examining the role of AD CSF biomarker testing (i.e., amyloid-beta and tau proteoforms) in medical and personal decision-making, and health economics. For medical decision-making, physicians completed surveys on patient management plans before and after receiving the biomarker findings. Overall change in management was assessed as a composite measure of changes in the use of: (i) AD symptomatic medications, (ii) other dementia-relevant medications, (iii) diagnostic procedures, and (iv) referrals or counselling. Results: Of the 142 participants, 66% were determined to have CSF biomarker profiles on the AD continuum. Overall change in management was observed in 89% of patients, with the greatest changes by category being: diagnostic procedures > referrals and counselling > AD symptomatic medications > other dementia-relevant medications. Conclusions: The use of AD CSF biomarker testing increases diagnostic confidence and aids in medical decision-making. Notably, the addition of biomarker testing leads to a reduction in the use of other diagnostic procedures, helps optimize pharmacotherapy and results in increased physician-patient/family member counselling.

Background: There is a pressing need to monitor the cognitive outcomes of patients undergoing deep brain stimulation (DBS) for movement disorders, despite the prevalence of pre-operative cognitive evaluations. Previous research has demonstrated the potential for DBS to induce reversible cognitive decline, highlighting the need for post-operative cognitive monitoring. Methods: To address this issue, the present study sought to improve upon the existing Autonomous Cognitive Examination through the development of a 5-minute web-based exam. This examination leverages the capacity of machine-learning algorithms to evaluate complex multimodal inputs, including cognitive and movement disorders, and is made available through a web-based platform for physicians to administer to their patients. Results: The outcome of this study was the development of a cognitive evaluation platform, which enables physicians to administer and view results of a brief cognitive examination with sensitivity to multiple domains of cognition, including movement disorders. The web-application based screening examination is easily accessible and can be used on any device. Conclusions: This web-based cognitive examination offers a crucial solution for monitoring longitudinal cognition in high-risk patient populations undergoing DBS for movement disorders. Its ability to assess complex multimodal inputs has broad applications beyond movement disorders and serves as a valuable tool for detecting cognitive decline.

Background: To enrich our understanding of the impact of Alzheimer’s disease (AD) CSF biomarker testing on patients and caregivers, we examined these perspectives within the IMPACT-AD BC study. Methods: IMPACT-AD BC (NCT05002699, impactAD.org) is an observational, longitudinal study examining the impact of AD CSF biomarker testing (i.e., amyloid-beta and tau proteoforms) on personal and medical utility, and health economics. Patients underwent AD biomarker testing as part of medical care (n=142), and for the personal utility arm, a subset of patients (n=34), and their ‘care partner’ (n=31), were interviewed post-biomarker disclosure to understand their decision-making to undergo testing and the impact of learning the test results. Results: The primary consideration in patients’ decision to undergo testing was the desire for diagnostic clarity (63%). After biomarker result disclosure, patients’ positive feelings stemmed largely from having greater diagnostic certainty (55%) and the ability to plan for the future (23%), including making financial changes (58%) and care plans (21%). Care partners conveyed that biomarker testing provided needed information to help plan for the future and spurred them to connect with community resources. Conclusions: Patients and care partners value the diagnostic clarity from AD biomarker testing and use the information to make informed future plans.

Background: The Montreal Cognitive Assessment (MoCA) and Rowland Universal Dementia Assessment Scale (RUDAS) are tests used to detect mild cognitive impairment (MCI) and dementia. However, it has been suggested that the MoCA may not be appropriate for diverse populations, and that the relatively newer RUDAS may be better suited as a universal cognitive test. Methods: The MoCA and RUDAS were administered at baseline visits for participants enrolled in the Prospective Registry of Persons with Memory Symptoms (PROMPT). Test scores were compared for patients with different levels of educational attainment, first language, and race using the Kruskal-Wallis test. Results: The difference in MoCA (0.029) and RUDAS (0.0041) scores between patients with different levels of educational attainment (n = 141) was significant. The difference in MoCA (0.62) and RUDAS (0.78) scores between patients with a different first language (n = 141) was not significant. The difference in MoCA (0.64) and RUDAS (0.96) scores between patients of different race (n = 141) was not significant. Conclusions: The difference between MoCA and RUDAS scores remained consistent regardless of level of educational attainment, first language and race. The results suggest that the RUDAS may not be more appropriate than the MoCA in detecting MCI and dementia across diverse populations.

Background: CT angiogram of the head and neck (CTA) is not part of the routine work-up of status epilepticus (SE), which could miss acute ischemic stroke (AIS) as the cause. We hypothesized that healthcare savings from early treatment of otherwise undiagnosed AIS would be greater than the cost of adding a routine CTA for work-up of SE (all comers). Methods: The total number of patients presenting to ER with SE (defined as seizure/epilepsy+hospital admission), and the subgroup who were diagnosed with a new ischemic stroke, or received a CTA were retrospectively calculated at the Ottawa Hospital between 2010-2019. CTA costs, and savings of early treatment of AIS were obtained from the Department of Radiology and literature review, respectively. Results: 727 individuals presented with SE. 3% (n=22) had a new ischemic stroke-of these, 95% (n=21) did not receive a CTA (considered missed AIS). Assuming CTA could help detect every case of ischemic stroke missed this could result in 2.27 additional strokes caught early/year, and assuming if all thrombolysis candidates this would net cost $7,967/year (vs no acute treatment), or if all thrombolysis+thrombectomy candidates would net save $19,823/year (vs thrombolysis alone). Conclusions: Routine CTA in SE in the ER has potential to result in healthcare savings.

Background: The incidence of drug resistant epilepsy (DRE) is around 30% patients with epilepsy. Vagus nerve stimulation (VNS) is offered to patients who are not candidates for epilepsy resective surgery, however the results of lesional cases has not been explored previously Methods: The study was a retrospective cohort study that involved patients with DRE implanted with VNS at the Epilepsy program at Western University, Ontario. We classified our VNS cohort based on brain imaging of lesional (L) and nonlesional (NL) epilepsy. Results: The median age was 31.8 years, 70.69% were females. The VNS-L group average age was 31.8 years and the NL 35.2 years. The most common abnormality was nodular heterotropias 31.34% (n=9). 16 patients underwent palliative procedures before the VNS implantation, 12 in VNS-L and 4 in VNS-NL. The median period of follow-up was 69.97 months. 62% of the VNS-L group had a seizure reduction of 50% or greater, compared to 41.38% in the VNS-NL group. Seizure freedom was 10.34% in VNS-L, compared to 6.99% in VNS-NL. Conclusions: This is the first study reporting the outcome of VNS in lesional cases. Our results suggest that VNS in lesional cases is effective. However, a large multicenteric study is needed.

Background: This study assessed the importance of mode of administration relative to other treatment attributes when selecting a preventive migraine therapy. Methods: Cross-sectional study among Canadian adults diagnosed with migraine with ≥5 monthly migraine days and tried ≥2 prescription migraine treatments (any kind/duration). Preferences for treatments varying in the following attributes were evaluated via a discrete choice experiment: speed of efficacy (effective in 24hr/1wk/3mo), duration of efficacy (wears off never/1wk/2 wks before next dose), mode of administration (infusion/auto-injection/cranial injections), administration setting (clinic/home), and administration frequency (1mo/3mo). Attribute-level preference weights were estimated using Hierarchical Bayes modeling. Results: Of 200 respondents, 142 experienced episodic migraine and 58 experienced chronic migraine. Preference weights confirmed that respondents’ most preferred treatments were those that provided fast and long-lasting efficacy (effective in 24hr = 0.59; wears off never = 1.07) and were offered via infusion (0.58) or auto-injection (0.47) over intracranial injection (-1.04). Respondents reported being moderately willing to receive infusions in either a home or clinic setting (1-6 Likert scale from “not at all” to extremely” willing). Conclusions: Second to speed and duration of efficacy, respondents were most concerned with mode of administration when selecting their preferred migraine preventive, suggesting that physicians should consider patient preferences in treatment decision-making.

Background: This analysis reports the impact of eptinezumab on work productivity and daily activities in patients with migraine and prior preventive treatment failures. Methods: The DELIVER study (NCT04418765) randomized adults with migraine and documented evidence of 2-4 prior preventive treatment failures to receive eptinezumab 100mg, 300mg, or placebo (IV every 12 weeks). At baseline and every 4 weeks, patients completed the migraine-specific 6-question Work Productivity Activity Impairment (WPAI:M) questionnaire (7-day recall). Changes from baseline in WPAI subscores were predefined secondary endpoints and analyzed without control for multiplicity. Results: The full analysis set included 890 patients (100mg, n=299; 300mg, n=293; placebo, n=298). Mean baseline WPAI subscores indicated a negative impact of migraine on work productivity and normal daily activities. Beginning at first post-baseline assessment at Week 4 and through Week 24, eptinezumab demonstrated larger reductions than placebo in absenteeism (P<0.05), presenteeism (P<0.001), work productivity loss (P<0.001), and activity impairment (P<0.001) subscores. Conclusions: In adults with migraine and prior preventive treatment failures, eptinezumab treatment robustly improved migraine-related absenteeism, presenteeism, work productivity loss, and activity impairment as early as Week 4 and throughout the study.

Background: This post hoc analysis of the PROMISE-2 data provides an assessment of the total preventive migraine efficacy of eptinezumab over 24 weeks in patients with a dual diagnosis of chronic migraine (CM) and medication overuse headache (MOH). Methods: PROMISE-2 was a double-blind, placebo-controlled, phase 3 study of eptinezumab (NCT02974153) over 24 weeks. Endpoints analyzed here include changes in MMDs, changes in monthly days of AHM use (total and class-specific), percentage of patients below thresholds for CM and MOH, and assessments patient-reported outcomes (PROs). Results: 40.2% patients with CM also had a diagnosis of MOH at baseline. Mean changes from baseline in MMDs during Weeks 1–12 were -8.4 and -8.6 in eptinezumab 100 mg and 300 mg treatment groups, respectively (vs 16.7 at baseline), compared with -5.4 in the placebo group (P<0.0001 vs placebo for both doses). Total monthly AHM use also decreased with eptinezumab. For all 24 weeks, 51.1% (100 mg) and 54.4% (300 mg) of eptinezumab-treated patients were below the ICHD thresholds for diagnosis of CM, compared with 32.4% of patients receiving placebo. Conclusions: This subgroup analysis of patients with a dual diagnosis of CM and MOH suggests that eptinezumab treatment resulted in greater improvements overall compared with placebo.

Background: In DELIVER, eptinezumab reduced migraine frequency and was well tolerated in patients with migraine and prior preventive treatment failures. This analysis evaluated changes in patient-reported outcomes (PROs). Methods: DELIVER (NCT04418765; phase 3b double-blind study) randomized adults with migraine and 2-4 prior preventive treatment failures to eptinezumab or placebo every 12 weeks. The assessed PROs included EuroQol 5-Dimensions 5-Levels visual analogue scale (EQ-5D-5L VAS); 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), most bothersome symptom (MBS), and Migraine-Specific Quality of Life Questionnaire (MSQ, v2.1). Results: Patients received eptinezumab 100mg (n=299), 300mg (n=294), or placebo (n=298). Mean changes from baseline to Wk12 in EQ-5D-5L VAS scores were 2.0 (100mg, P=0.0007) and 4.4 (300mg, P<0.0001) versus -3.1 (placebo), and were maintained or further improved to Wk24 (2.0, 5.2, -2.8, respectively). Mean baseline HIT-6 total scores were ~66.4, with mean changes of -6.9 (100mg, P<0.0001) and -8.5 (300mg, P<0.0001) versus -3.1 (placebo) at Wk12 that were further improved through Wk24 (-8.9 and -9.9 vs -3.9). PGIC, MBS, and MSQ domain scores showed greater improvement for eptinezumab than placebo. Conclusions: In adults with migraine and prior preventive treatment failures, eptinezumab robustly improved health-related quality of life and migraine-related burden over 24 weeks versus placebo.

Background: Saccade and pupil responses are potential neurodegenerative disease biomarkers due to overlap between oculomotor circuitry and disease-affected areas. Instruction-based tasks have previously been examined as biomarker sources, but are arduous for patients with limited cognitive abilities; additionally, few studies have evaluated multiple neurodegenerative pathologies concurrently. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with Alzheimer’s disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, progressive supranuclear palsy, or Parkinson’s disease (PD). Patients (n=274, age 40-86) and healthy controls (n=101, age 55-86) viewed 10 minutes of frequently changing video clips without instruction while their eyes were tracked. We evaluated differences in saccade and pupil parameters (e.g. saccade frequency and amplitude, pupil size, responses to clip changes) between groups. Results: Preliminary data indicates low-level behavioural alterations in multiple disease cohorts: increased centre bias, lower overall saccade rate and reduced saccade amplitude. After clip changes, patient groups generally demonstrated lower saccade rate but higher microsaccade rate following clip change to varying degrees. Additionally, pupil responses were blunted (AD, MCI, ALS) or exaggerated (PD). Conclusions: This task may generate behavioural biomarkers even in cognitively impaired populations. Future work should explore the possible effects of factors such as medication and disease stage.

Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder associated with cognitive, psychiatric, and motor dysfunction. As a potential behavioural biomarker, experimental tasks assessing motor learning may thus provide a reasonable assay of HD onset and progression. The saccadic adaptation paradigm is a non-invasive, accessible method of assessing rapid learning in the oculomotor system. Evidence demonstrates that the thalamus and basal ganglia are important loci for saccadic adaptation, also known to exhibit neurodegenerative pathology before the onset of clinically observable symptoms in HD. Methods: 26 early symptomatic HD patients (Total Functional Capacity Score ≥ 10/13) and sex/age-matched controls were tested on a standard saccadic adaptation task. Eye movements were measured using infrared oculography. Learning dynamics of how quickly the participants adapted their saccade metrics were analysed using state learning models. Results: Initial findings demonstrate that the learning dynamics of HD patients are slower and more variable with respect to saccade amplitude compared to controls. Conclusions: These results demonstrate that motor learning dynamics as captured by a saccadic adaptation task reveal early motor dysfunction in HD, thus providing a discriminating tool to detect early pathological changes in HD patients. Further work is needed regarding applications as a biomarker for disease progression.

Background: The Canadian Guideline for Parkinson Disease (PD) indicates clozapine and quetiapine are considered the only safe antipsychotics for people with PD, to avoid potentially exacerbating motor symptoms. In response to safety events in our centre, we explore contraindicated antipsychotic prescriptions being administered to hospital inpatients with PD to determine common factors and develop approaches to prevent future occurrences. Methods: Following a privacy impact analysis, the Interior Health Quality Improvement & Patient Safety Office identified inpatients at Kelowna General Hospital, between December 2018 and June 2021, with a coded diagnosis of PD. Pharmacy medication order and dispensing data were cross-referenced to determine patients exposed to a contraindicated antipsychotic for further chart analysis. Results: Of the 140 admissions with a PD diagnosis, 17 had at least one contraindicated antipsychotic prescribed or dispensed (12.1%). Loxapine (7) and haloperidol (6) were the most frequently prescribed. This occurred despite a diagnosis of PD being noted on admission in 14 cases, and 13 cases were known to be taking levodopa. Conclusions: These results demonstrate additional safety measures are needed to reduce the frequency of contraindicated antipsychotic prescriptions in this population. We propose developing a stepwise plan for behaviour de-escalation and pharmacological management.

Background: People with parkinsonian syndromes (PPS) in advanced stages deal with a wide range of highly impactful motor and non-motor problems, including dementia, hallucinations, falls, and dysautonomia. Care planning becomes difficult and unpredictable. In addition, while healthcare providers focus on reducing symptom burden, PPS and carepartners deal with difficult emotions such as demoralization and grief. At those stages, multidisciplinary care becomes imperative. In October 2022 we launched Advanced Care Team for Parkinson’s (ACT-PD), a clinical research program whose goals include advanced care planning, symptoms management and emotional support. Methods: Our primary outcomes are changes in quality of life (QoL-AD), carepartner burden (ZBI-12) and patient satisfaction. The team involves neurology, palliative nursing, social-work, psychology, and spiritual care. Every three months, participants meet the team in person or virtually. In two hours, they address tailored concerns, complemented with phone calls as required. Accordingly, participants complete assessments. Results: In its first 4 months, ACT-PD included 40 PPS and 40 carepartners. Preliminary results show that the first visit with ACT-PD resulted in a 30% reduction in carepartner burden and 28% of improvement in patients’ QoL. Conclusions: Even in early phases, this novel patient and carepartner-centered approach improves QoL and reduces carepartner burden in PPS in advanced disease stages.

Background: Pain is a frequent symptom in Parkinson’s disease (PD), and the therapeutic alternatives are scarce. The goal of this trial was to assess the effects of botulinum toxin type A (BTXA) in the treatment of foot dystonia in PD. Methods: Randomized placebo-controlled trial (RCT) (double-blind parallel-group study) evaluating the safety and efficacy of BTXA for PD-related painful foot dystonia using 100 units of BTXA/placebo, followed by an open-label phase. The primary outcome was a change in pain on the King’s Parkinson’s disease Pain scale and on a visual analogue scale at 6, 12 and 24 weeks. Secondary outcomes included the percentage of responders, clinical global impression, MDS-UPDRS, PDQ-39 scores, and adverse events. Results: 40 subjects were screened and 33 were enrolled. The RCT blind will be opened in March 2023 after the final study visit and data will be available for presentation at the June 2023 conference. The current open-label phase has revealed a preliminary that the toxin is safe and effective in reducing pain in PD-related foot dystonia with 84% of participants noticing a significant benefit. Conclusions: According to our preliminary data, targeted BTXA injections are a safe and effective treatment in patients with foot dystonia and PD.