Background and ObjectivesUnderstanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.MethodsWe present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.ResultsDonanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52–0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33–0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52–0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58–0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, −0.14 [95% CI –0.24 to −0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%–40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59–0.91; p = 0.005).DiscussionThese results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.Trial Registration InformationClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.

Background and ObjectivesMost of the research in Parkinson disease (PD) has been conducted in White populations. There is a gap in the understanding of PD in other racial/ethnic groups, such as Asian Americans (AAs) and Native Hawaiians or Pacific Islanders (NHPIs). Therefore, we aimed to test the feasibility of a longitudinal cohort and understand attitudes and barriers to research participation in a pilot study of AA, NHPI, and White patients with PD in Hawai’i.MethodsWe conducted a prospective pilot study of AA, NHPI, and White patients with PD, without dementia, to compare characteristics between racial groups' self-reported quality of life (QoL), interest in participating in research, health care utilization, and barriers to accessing health care, at baseline and 6-month follow-up visits. This was a single-center study completed at the Parkinson's and Movement Disorder Center at The Queen's Medical Center in Honolulu, Hawai’i from March 2023 to June 2024.ResultsOf 146 patients screened for eligibility, 79 completed study enrollment (mean 68.8 years, male = 59%). Demographics, PD history, and questionnaires from baseline and follow-up visits were analyzed for 78 participants (AA = 27, NHPI = 26, White = 25), with 1 participant who dropped out. Differences were found between groups' household income, comfort with technology, and awareness of advanced PD therapies. There was no significant difference between groups' self-reported QoL, barriers to PD care, and attitudes toward clinical research.DiscussionAA and NHPI patients with PD in this study were no less apt to participate in research compared with White patients with PD. Although there were no significant differences in the variables evaluated among different racial subgroups, our results warrant further research.

Background and ObjectivesPlasma biomarkers provide new tools for evaluating patients with mild cognitive impairment (MCI) for Alzheimer disease (AD) pathology. Such tools are needed for anti-amyloid therapies that require efficient and accurate diagnostic evaluation to identify potential treatment candidates. This study sought to develop and evaluate the clinical performance of a multimarker combination of plasma beta-amyloid 42/40 (Aβ42/40), ptau-217, and APOE genotype to predict amyloid PET positivity in a diverse cohort of patients at a memory clinic and evaluate >4,000 results from “real-world” specimens submitted for high-throughput clinical testing.MethodsStudy participants were from the 1Florida AD Research Center. Demographics, clinical evaluations, and amyloid PET scan data were provided along with plasma specimens for model development in the intended-use cohort (MCI/AD: n = 215). Aβ42/40 and ApoE4 proteotype (reflecting high-risk APOE ɛ4 alleles) were measured by mass spectrometry and ptau-217 by immunoassay. A likelihood score model was determined for each biomarker separately and in combination. Model performance was optimized using 2 cutpoints, 1 for high and 1 for low likelihood of PET positivity, to attain ≥90% specificity and sensitivity. These cutpoints were applied to categorize 4,326 real-world specimens and an expanded cohort stratified by cognitive status (normal cognition [NC], MCI, AD).ResultsFor the intended-use cohort (46.0% prevalence of PET positivity), a combination of Aβ42/40, ptau-217, and APOE4 allele count provided the best model with a receiver operating characteristic area under the curve of 0.942 and with 2 cutpoints fixed at 91% sensitivity and 91% specificity, yielding a high cutpoint with 88% positive predictive value and 87% accuracy and a low cutpoint with 91% negative predictive value and 85% accuracy. Incorporating the APOE4 allele count also reduced the percentage of patients with indeterminate risk from 15% to 10%. The cutpoints categorized the real-world clinical specimens as having 42% high, 51% low, and 7% indeterminate likelihood of PET positivity and differentiated between NC, MCI, and AD dementia cognitive status in the expanded cohort.DiscussionCombining plasma biomarkers Aβ42/40, ptau-217, and APOE4 allele count is a scalable approach for evaluating patients with MCI for suspected AD pathology.

Background and ObjectivesStereoelectroencephalography (SEEG) is increasingly used worldwide for epilepsy presurgical evaluation. A data-driven view of SEEG practice evolution is lacking for any world region. We aimed to perform a nationwide survey of SEEG use in Australian adult epilepsy centers. We predicted that the proportion of nonlesional MRI cases, number of electrodes, and radiofrequency thermocoagulation (RF-TC) use would increase over time.MethodsAll epilepsy centers in Australia undertaking SEEG in patients older than 16 years at any time were invited to participate in a nationwide survey. Data were retrospectively and/or prospectively collected on patient demographics and SEEG exploration. Descriptive statistics were used.ResultsA total of 281 SEEG explorations were performed in 8 centers from 2012 until 2023, 278 of which (99%) are reported here. A definite epileptogenic MRI lesion was present in 30.6% with no overall significant growth in the proportion of nonlesional cases (χ² [1, N = 278] = 0.067, p = 0.79), although this varied per center. Patients identifying as Indigenous Australians comprised 1.6% of this national SEEG survey vs an estimated national indigenous population of 3.8%. The median number of electrodes increased from 8 in 2012 to 15 in 2023. A total of 174 patients (62.6%) were offered resective surgery after SEEG. Surgery was performed with 1-year follow-up in 114, of whom 72.8% were seizure-free at the last follow-up. The presence/absence of an MRI lesion was not associated with postoperative seizure-free outcomes (χ² [1, N = 114] = 0.06, p = 0.80). RF-TC use differed between centers and evolved, with a crossover to the majority use of RF-TC occurring 5 years after regulatory approval.DiscussionThis comprehensive nationwide and regional survey of SEEG practice comprises full ascertainment of all centers and allows analysis of changes in practice over time. Whole cohort results show a high proportion of nonlesional MRI cases achieving satisfactory surgical outcomes and evolution to increased RF-TC use. Indigenous access to SEEG seems to be lower than expected, consistent with broader health care access issues for this population group. Nationwide collaboration on SEEG data provides a basis for analysis of practice at the individual center and state and national levels to optimize health care planning and sharing of expertise.

BackgroundHuntington disease (HD) is a genetic neurodegenerative disorder. Given the focus on motor manifestations, nonmotor symptoms are frequently underappreciated in clinical evaluations, despite frequently contributing to primary functional impairment.Recent FindingsA diagnosis of motor-onset as the definition of manifest symptoms misrepresents the complex nature of HD presentation. Despite recent attempt to integrate nonmotor diagnostic criteria, practical guidelines are necessary to inform clinical diagnosis. We propose an HD diagnostic framework and staging system that prioritizes genetic testing, integrates motor and nonmotor symptom considerations in the determination of clinical disease onset and severity, and acknowledges the secondary role of clinically indicated diagnostic assessments, incorporating the broad symptom profiles observed in clinical practice.Implications for PracticeThe proposed diagnostic criteria more accurately reflect the presentation of HD and provide greater opportunities for health care professionals to provide appropriate clinical care guidelines for adults with gene-expanded HD.

Background and ObjectivesMechanical thrombectomy (MT) improves outcomes for acute ischemic stroke (AIS) due to large vessel occlusion, but is time sensitive and requires specialized infrastructure. Professional organizations and certification bodies have promulgated minimum procedural volume standards for centers and for individual proceduralists but it is unclear whether enforcing these requirements would decrease geographic access to MT. Therefore, we sought to evaluate the potential impact of applying a minimum procedural volume threshold on geographic access to MT.MethodsWe identified all hospital discharges for stroke where an MT procedure was performed at any nonfederal hospital in Florida in 2019 using statewide hospital discharge data. We then generated geographic service area maps based on prespecified ground transport distances for the subset of hospitals that performed at least 1 MT and for those that performed at least 15 MTs that year, the minimum volume threshold required for thrombectomy capable and comprehensive stroke centers by the Joint Commission. Then, using zip code centroids and patient-level discharge hospital data, we computed the proportion of patients with AIS who lived within each of the generated service areas.ResultsA total of 105 of 297 hospitals performed MT; of those, 51 (17%) were low-volume centers (1–14 MTs/year) and 54 (18%) were high-volume centers (≥15 MTs/year). High-volume centers accounted for nearly 95% of all MTs performed in the state. Most patients hospitalized with AIS (87%) lived within 20 miles (or an estimated as a 1-hour driving time) of a hospital that performed at least 1 MT, and all (100%) lived within 115 miles (or estimated as 3-hour driving time). Setting a minimum MT volume threshold of 15 would decrease the proportion of stroke patients living within 1-hour driving time of an MT center from 87% to 77%.DiscussionIn 2019, most Florida stroke patients lived within a 1-hour ground transport time to a center that performed at least 1 MT and all lived within 3-hour driving time of an MT center, irrespective of whether a minimum procedural volume threshold of 15 cases per year was applied or not.

Background and ObjectivesIn health care, large language models such as Generative Pretrained Transformers (GPTs), trained on extensive text datasets, have potential applications in reducing health care disparities across regions and populations. Previous software developed for lesion localization has been limited in scope. This study aims to evaluate the capability of GPT-4 for lesion localization based on clinical presentation.MethodsGPT-4 was prompted using history and neurologic physical examination (H&P) from published cases of acute stroke followed by questions for clinical reasoning with answering for “single or multiple lesions,” “side,” and “brain region” using Zero-Shot Chain-of-Thought and Text Classification prompting. GPT-4 output on 3 separate trials for each of 46 cases was compared with imaging-based localization.ResultsGPT-4 successfully processed raw text from H&P to generate accurate neuroanatomical localization and detailed clinical reasoning. Performance metrics across trial-based analysis for specificity, sensitivity, precision, and F1-score were 0.87, 0.74, 0.75, and 0.74, respectively, for side; 0.94, 0.85, 0.84, and 0.85, respectively, for brain region. Class labels within the brain region were similarly high for all regions except the cerebellum and were also similar when considering all 3 trials to examine metrics by case. Errors were due to extrinsic causes—inadequate information in the published cases, and intrinsic causes—failures of logic or inadequate knowledge base.DiscussionThis study reveals capabilities of GPT-4 in the localization of acute stroke lesions, showing a potential future role as a clinical tool in neurology.

Background and ObjectivesRepresentation of persons from marginalized racial and ethnic groups in Parkinson disease (PD) trials has been low, limiting the generalizability of therapeutic options for individuals with PD. Two large phase 3 randomized clinical trials sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), STEADY-PD III and SURE-PD3, screened participants from overlapping Parkinson Study Group clinical sites under similar eligibility criteria but differed in participation by underrepresented minorities. The goal of this research is to compare recruitment strategies of PD participants belonging to marginalized racial and ethnic groups.MethodsA total of 998 participants with identified race and ethnicity consented to STEADY-PD III and SURE-PD3 from 86 clinical sites. Demographics, clinical trial characteristics, and recruitment strategies were compared. NINDS imposed a minority recruitment mandate on STEADY-PD III but not SURE-PD3.ResultsTen percent of participants who consented to STEADY-PD III self-identified as belonging to marginalized racial and ethnic groups compared to 6.5% in SURE-PD3 (difference = 3.9%, 95% confidence interval [CI] 0.4%–7.5%, p value = 0.034). This difference persisted after screening (10.1% of patients in STEADY-PD III vs 5.4% in SURE-PD 3, difference = 4.7%, 95% CI 0.6%–8.8%, p value = 0.038).DiscussionAlthough both trials targeted similar participants, STEADY-PD III was able to consent and recruit a higher percentage of patients from racial and ethnic marginalized groups. Possible reasons include differential incentives for achieving minority recruitment goals.Trial Registration InformationThis study used data from The Safety, Tolerability, and Efficacy Assessment of Isradipine for Parkinson Disease (STEADY-PD III; NCT02168842) and the Study of Urate Elevation in Parkinson’s Disease (SURE-PD3; NCT02642393).

BackgroundEXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures.MethodsAfter completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3–15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR).ResultsOf 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2–36.1; N = 352) at week 18, 46.6% (95% CI, 40.9–52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7–65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5–36.1) at week 18, 46.7% (95% CI, 40.2–54) at 1 year, and 56.9% (95% CI, 50–68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5–35.2; N = 361) at week 18, 38.8% (95% CI, 33.7–44.1; N = 358) at 1 year, and 41% (95% CI, 34.6–47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock).ConclusionsSustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns.Classification of evidenceThis study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.