Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Cerebrovascular reactivity (CVR) is a widely studied biomarker of cerebral hemodynamics, commonly used in risk stratification and treatment planning in patients with steno-occlusive disease (SOD). Conventional use relies on normalization of estimates to contralateral hemisphere reference values, which is unsuitable for bilateral or indeterminate distributions of disease. We report upon a custom data-driven approach leveraging random forest classifiers (RFc) to identify candidate voxels for normalization in order to facilitate interrogation outside conditions of known unilateral SOD MATERIALS AND METHODS: We retrospectively analyzed 16 patients with unilateral SOD who underwent acetazolamide-augmented BOLD-MRI and DSC perfusion. Three RFc models were trained using leave-one-out cross-validation (LOOCV) to identify candidate voxels brain-wide whose CVR were within 10% of the normal hemispheric median: i. all voxels; ii. gray matter only; and iii. white matter only. Model input features included time-to-maximum (Tmax), mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV) from contemporaneous DSC. The median model-predicted reference CVR (CVRref) was compared to ground-truth medians in LOOCV, and its impact on threshold-based volumetric classification of CVR reduction assessed. RESULTS:RFc models effectively predicted ground-truth CVR voxels, achieving median absolute percent differences of 12.8% (IQR: 5.0%-18.9%) using all voxels, 11.3% (IQR: 9.3%-16.1%) for gray matter, and 9.8% (IQR: 4.4%-16.9%) for white matter. Volumetric estimates of CVR reduction across thresholds for the models revealed excellent agreement between ground-truth and model estimates without statistically significant differences (p>0.01), excepting lowest white matter CVR thresholds. Model use in a small pilot deployment of bilateral SOD cases demonstrated the potential utility, enabling voxel-wise CVR assessment without reliance on contralateral reference. CONCLUSIONS:We present a novel data-driven approach for normalizing CVR maps in patients with bilateral or indeterminate SOD. Using an RFc, our method provides an individualized, brain-wide reference CVR, expanding the utility of CVR estimates beyond the typical constraints of unilateral disease, and with potential application to other, similarly constrained scenarios such as for SPECT or PET hemodynamic studies. ABBREVIATIONS/BACKGROUND:CVR = cerebrovascular reactivity; RFc = random forest classifier; SOD = steno-occlusive disease.

IMPORTANCE/UNASSIGNED:The Implantable Neurostimulator for the Treatment of Parkinson's Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). OBJECTIVE/UNASSIGNED:To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson's Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. INTERVENTION/UNASSIGNED:Bilateral STN-DBS for moderate to advanced PD. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. RESULTS/UNASSIGNED:A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-III improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.

IMPORTANCE/UNASSIGNED:Leptomeningeal metastasis (LM) is associated with limited survival and few treatment options. Photon involved-field radiotherapy (IFRT) is the most common radiotherapy treatment for patients with LM from solid tumors. OBJECTIVE/UNASSIGNED:To assess whether proton craniospinal irradiation (pCSI) would result in superior central nervous system progression-free survival (CNS-PFS) compared with IFRT. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A randomized, phase 2 trial of pCSI vs IFRT was conducted between April 16, 2020, and October 11, 2021, and included patients with non-small cell lung cancer and breast cancer with LM. Patients with other solid tumors were also enrolled in an exploratory pCSI cohort. INTERVENTION/UNASSIGNED:For the randomized groups, after stratifying by histology and systemic disease status, patients were assigned (2:1) to pCSI or IFRT. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary end point was CNS-PFS. Secondary end points included overall survival (OS). RESULTS/UNASSIGNED:Of 98 total patients, 72 individuals (73.5%) were female, and the median (IQR) age was 59 (50-65) years. A total of 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS-PFS was observed with pCSI compared with IFRT, leading to the early discontinuation of the trial. In this final analysis, a significant benefit was continually observed in CNS-PFS with pCSI (median, 8.2 months; 95% CI, 6.6-15.3) vs IFRT (median, 2.3 months; 95% CI, 1.2-4.0; P < .001). A statistically significant and clinically meaningful OS benefit with pCSI (median, 11.3 months; 95% CI, 7.5-18.3) vs IFRT (median, 4.9 months; 95% CI, 3.9-15.0; P = .04) was also observed. For the exploratory pCSI cohort (n = 35), the median CNS-PFS was 5.8 months (95% CI, 4.4-9.1) and OS was 7.0 months (95% CI, 5.4-10.6). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This randomized clinical trial that assessed the optimal radiotherapy treatment for LM found improved CNS-PFS and OS with pCSI compared with IFRT. The results suggest that pCSI should be considered when available. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04343573.

OBJECTIVE:Up to 30% of people with epilepsy are refractory to current antiseizure medications (ASMs). JNJ-40411813 is a positive allosteric modulator of metabotropic glutamate 2 receptor, a presynaptic glutamate release inhibitor, and was hypothesized to reduce glutamate-mediated neuronal toxicity through inhibition of excessive glutamate release during seizures. METHODS:This 12-week, double-blinded, placebo-controlled phase 2a study, which employed a rational polypharmacy approach using a novel time-to-event endpoint for epilepsy clinical trials, evaluated JNJ-40411813 (Cohort 1: 50/100 mg; Cohort 2: 100/200 mg) as adjunctive treatment for focal seizures in participants aged 18-64 years receiving levetiracetam or brivaracetam and ≤3 other ASMs. Participants were stratified as induced or noninduced based on treatment or no treatment with a cytochrome P450 3A4 enzyme-inducing ASM. The primary endpoint was time-to-baseline monthly seizure count. RESULTS:Cohorts 1 and 2 randomized 60 and 50 patients, respectively. No significant clinical benefits were observed in the median time (95% confidence interval [CI]) to reach the baseline monthly seizure count in Cohort 1 (JNJ-40411813: 34 days [27-48], placebo 32 days [28-37], hazard ratio [HR] = .75 [.41-1.38], p = .36) or Cohort 2 (JNJ-40411813: 38 days [28-48], placebo: 29 days [22-69], HR = .83 [.40-1.75], p = .63). Similarly, no clinical benefits of JNJ-40411813 were observed for any of the secondary endpoints. JNJ-40411813 displayed an acceptable safety profile; treatment-emergent adverse events were mild to moderate in severity and not treatment limiting. SIGNIFICANCE/CONCLUSIONS:JNJ-40411813 adjunctive to levetiracetam or brivaracetam showed no significant clinical benefit over placebo in reducing time-to-baseline monthly seizure count or improvement in other key measures in patients with focal onset seizures. The time-to-event study design was successful at reducing participant exposure to ineffective treatment. Despite an acceptable safety profile, the overall efficacy and benefit-risk assessment of JNJ-40411813 does not support its use for patients with focal seizures.

BACKGROUND/UNASSIGNED:Time-to-treatment goals for acute ischemic stroke (AIS) have substantially improved outcomes, yet similar metrics have not been studied in patients with intracerebral hemorrhage (ICH), where mortality rates are much higher. METHODS/UNASSIGNED:Multicenter, observational retrospective study of patients with ICH and AIS between January 1, 2017, and December 31, 2022, in 11 comprehensive stroke centers across the United States participating in Get With The Guidelines. We included patients with ICH who received antihypertensive therapy and anticoagulation reversal, and patients with AIS requiring intravenous thrombolytic and mechanical thrombectomy. The coprimary outcomes included (1) time-to-treatment and (2) the percentage of patients meeting current national time interval goals. Multivariable logistic regression models controlling for age, sex, race and ethnicity, time to arrival, National Institutes of Health Stroke Scale score, arrival systolic blood pressure, and admission international normalized ratio were constructed to assess the likelihood of patients with ICH being treated within goal compared with patients with AIS. Multivariable logistic regression models were constructed to assess the impact of treatment time on mortality or discharge disposition in patients with ICH. RESULTS/UNASSIGNED:<0.01) compared with those treated in >60 minutes. CONCLUSIONS/UNASSIGNED:Time-to-treatment for patients with ICH is significantly longer than for patients with AIS. Faster antihypertensive treatment times are associated with better discharge outcomes in patients with ICH.

Sound structures such as phonemes and words have highly variable durations. Therefore, there is a fundamental difference between integrating across absolute time (for example, 100 ms) versus sound structure (for example, phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. Here, to answer this question, we rescaled the duration of all speech structures using time stretching and compression and measured integration windows in the human auditory cortex using a new experimental and computational method applied to spatiotemporally precise intracranial recordings. We observed slightly longer integration windows for stretched speech, but this lengthening was very small (~5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing.

BACKGROUND:CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy (DEE) associated with multiple impairments and comorbidities. Outcome measures for disease-modifying clinical trials for DEEs should measurably capture a spectrum of caregiver priorities and be externally validated. METHODS:The International CDKL5 Clinical Research Network was the data source for this observational study. A Structural Equation Model was constructed with latent, exogenous variables related to observed clinical features to calculate a global severity score from the following assessments: the CDKL5 Clinical Severity Assessment-Clinician and -Caregiver, Communication and Symbolic Behavior Scales Developmental Profile Infant Toddler Checklist and the Sleep Disturbance Scale for Children. Quantitative EEG power was measured as a biomarker. The Quality of Life Inventory-Disability measured quality of life. RESULTS:Acceptable fit statistics for models were obtained using data from 206 subjects (median [range] age 6.8 [3 months to 40] years). Motor and communication measures were the most important weighted contributors to the global severity score which correlated well with the biomarker and quality of life to support external validation. CONCLUSIONS:The resultant global severity score provided evidence that the assessments formed a coherent set of measures that reliably and meaningfully captured the diversity of severity in CDD. The models illustrated how the symptoms form a measurable network of relationships which may be suitable as an outcome measure for CDD and DEEs more broadly in clinical trials.

INTRODUCTION/BACKGROUND:Sleep, depression, stress, and neighborhood support are independently linked to cognition, but how these factors interact when sleep quality is poor remains understudied. METHODS:We analyzed cross-sectional baseline data from 233 adults aged ≥ 65 years in the Aging Adult Brain Connectome study. Sleep quality, depressive symptoms, stress, and neighborhood support were assessed with validated scales, and cognition was measured using the Preclinical Alzheimer's Cognitive Composite (PACC). Models tested two- and three-way interactions, adjusting for sociodemographics. RESULTS:Poor sleep quality was associated with lower PACC scores (β = -0.57, p = 0.002). This association was even more pronounced in older adults who also had depressive symptoms (β = -0.09, p < 0.001) or increased stress (β = -0.31, p < 0.001). This effect was attenuated by greater neighborhood support (interaction estimates 0.007-0.021, all p ≤ 0.014). DISCUSSION/CONCLUSIONS:Poor sleep quality was associated with lower cognition, compounded by psychosocial burden and buffered by neighborhood support. HIGHLIGHTS/CONCLUSIONS:Poor sleep quality worsened late-life cognitive performance in older adults. Depressive symptoms and stress further worsened the effect of poor sleep on cognitive performance. Neighborhood support buffered negative sleep-psychosocial impacts on cognitive performance.

INTRODUCTION/BACKGROUND:The Neighborhoods Study (TNS) is a novel investigation of adverse social exposome and brain health leveraging 22 Alzheimer's Disease Research Centers (ADRCs). TNS aims to understand if the adverse social exposures increase Alzheimer's disease and related dementias (ADRD) risk. METHODS:TNS uses innovative methods to determine lifetime addresses of living (n = ≈ 3116) and brain bank cohorts (n = ≈ 8637). Addresses are linked to time-concordant adverse social exposome using the Area Deprivation Index (ADI) and summarized over time. Brain health measures are provided by the National Alzheimer's Coordinating Center. RESULTS:We highlight a general overview and methodology of TNS. Data collection is ongoing; however, preliminary findings indicate that the adverse social exposome is related to ADRD biomarkers, neuropathology, and cognitive function. DISCUSSION/CONCLUSIONS:TNS is the largest study of adverse social exposome and ADRD, using the ADRC network to build robust scientific consortia. Its findings will inform ADRD interventions, precision medicine, and policy. HIGHLIGHTS/CONCLUSIONS:The Neighborhoods Study (TNS) investigates adverse social exposome and brain health. TNS is a collaboration among 22 Alzheimer's Disease Research Centers. TNS will give insight on environmental and exposomal factors which may be modifiable. Participant lifetime addresses are linked to temporal adverse social exposome metrics. This study's findings will inform precision approaches to mitigate dementia risk.