Faculty Bibliography

INTRODUCTION/BACKGROUND:The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS:We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS:Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION/CONCLUSIONS:We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. HIGHLIGHTS/CONCLUSIONS:The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

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.

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.

Huntington's disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington's Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population. The TFC least-squares mean difference between pridopidine and placebo was -0.18 (95% confidence interval -0.49 to 0.14; P = 0.26). The cUHDRS least-squares mean difference between pridopidine and placebo was -0.11 (95% confidence interval -0.40 to 0.18; P = 0.45). Sensitivity analysis in a subgroup of participants not treated with antidopaminergic medications at any time demonstrated a consistent pattern favoring pridopidine across multiple measures, including TFC and cUHDRS. Notably, pridopidine 45 mg twice daily demonstrated a favorable safety and tolerability profile. Taken together, pridopidine has the potential to address a critical unmet need in HD. ClinicalTrials.gov identifier: NCT04556656 .

BACKGROUND AND OBJECTIVES/OBJECTIVE:While reductions in optical coherence tomography (OCT) pRNFL and ganglion cell-inner plexiform layer thicknesses have been shown to be associated with brain atrophy in adult-onset MS (AOMS) cohorts, the relationship between OCT and brain MRI measures is less established in pediatric-onset MS (POMS). Our aim was to examine the associations of OCT measures with volumetric MRI in a cohort of patients with POMS to determine whether OCT measures reflect CNS neurodegeneration in this patient population, as is seen in AOMS cohorts. METHODS:This was a cross-sectional study with retrospective ascertainment of patients with POMS evaluated at a single center with expertise in POMS and neuro-ophthalmology. As part of routine clinical care, patients with POMS are evaluated by a POMS expert and undergo volumetric brain MRI, including whole-brain (WB), subregional, and gray matter (GM) volume analyses. Patients with POMS are routinely referred to neuro-ophthalmology for evaluation that includes high-contrast visual acuity, color vision testing, and OCT. Generalized estimating equation (GEE) models, accounting for within-patient, intereye correlations (both eyes of each patient were included), MS disease duration, and disease-modifying therapy efficacy, were used to determine the relationship between visual pathway structure and function and volumetric MRI measures. RESULTS:= 0.015, respectively). DISCUSSION/CONCLUSIONS:Our results demonstrate that changes in visual pathway structures are associated with reductions in overall brain volume and GM volumes, as well as greater lesion and black hole burden. Collectively, our results emphasize the importance of visual assessment in POMS and suggest that OCT reflects overall CNS neurodegeneration in this cohort.

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.

BACKGROUND/UNASSIGNED:Fingolimod is an immunomodulatory drug that has shown promising effects in stroke treatment, including improvements in neurofunctional recovery and a reduction in infarct size. Fingolimod modulates the sphingosine-1-phosphate receptors, which leads to the internalization of sphingosine-1-phosphate receptors on T and B lymphocytes, thereby preventing their egress from secondary lymphoid organs. Here, we report a secondary analysis from the Stroke Preclinical Assessment Network trial. We assessed the effects of fingolimod versus vehicle on stroke outcomes to better evaluate its therapeutic potential. METHODS/UNASSIGNED:The animal population (n=409) comprised male and female animals treated with fingolimod or vehicle. We used 4 clinically relevant models: young healthy mice (10-12 weeks-old), aging mice (16±1 month-old), obesity induced-hyperglycemic mice fed with a high-fat diet for 12 weeks (16 weeks-old), and spontaneously hypertensive rats (16±1 weeks-old). Stroke was induced by the middle cerebral artery occlusion for 1 hour, followed by reperfusion. Animals received a total of 6 intraperitoneal injections of 0.5 mg/kg twice daily of fingolimod or vehicle. Functional outcomes in the corner test and foot-faults test were measured at days 7 and 28. Lesion size and brain morphometry were evaluated at days 2 and 30 by magnetic resonance imaging. RESULTS/UNASSIGNED:Overall, fingolimod did not improve morphological and functional outcomes. However, fingolimod effects varied depending on sex or the comorbidity model. Fingolimod promoted a better outcome in the corner test in aging females. In contrast, it favored a worse outcome in obesity-induced hyperglycemic mice at day 7. Despite having no effect on survival rates or lesion size, fingolimod attenuated the midline retraction at day 30 in aging males, consistent with less atrophy. CONCLUSIONS/UNASSIGNED:Although fingolimod did not significantly benefit the overall primary functional outcome, its effects varied with sex and comorbidity models, underscoring how the therapeutic potential of a particular drug can differ in a heterogeneous population.

Aim To compare the clinical outcome and in-hospital complication risk with chemotherapy and without chemotherapy in patients with inflammatory and immune myopathies (IIM). Methods We obtained data for IIM patients admitted to hospitals in the United States from 2017 to 2018 with a primary diagnosis of IIM using a large national database. We determined the rate and pattern of utilization of associated in-hospital outcomes of chemotherapy in this patient population. Results A total of 5,360 patients had IIM, of which 315 (5.8%) received chemotherapy for the underlying malignancies and 5,045 (94.2%) did not. No significant racial or gender discrepancies were observed between the two groups. Patients who received chemotherapy had more in-hospital complications, including sepsis [79 (25.1%) vs. 585 (11.6%), p<0.01] and acute kidney injury [75 (23.8%) vs. 665 (13.2%), p<0.01]. The number of deaths was higher in the chemotherapy group [125 (39.7%) vs. 190 (3.8%)]. Further analysis of patients who died in the chemotherapy group showed that myocardial infarction [20 (6.3%)] and pneumonia [45 (14.3%)] were the leading causes of death. Conclusion In hospitalization complications such as sepsis and acute kidney injury were higher in patients who received chemotherapy in IIM patients; however, patients who died had a higher risk of myocardial infarction and pneumonia, so routine cardiac and pulmonary evaluation should be done during hospitalization of this patient population.