Faculty Bibliography

Automatic assessment of impairment and disease severity is a key challenge in data-driven medicine. We propose a framework to address this challenge, which leverages AI models trained exclusively on healthy individuals. The COnfidence-Based chaRacterization of Anomalies (COBRA) score exploits the decrease in confidence of these models when presented with impaired or diseased patients to quantify their deviation from the healthy population. We applied the COBRA score to address a key limitation of current clinical evaluation of upper-body impairment in stroke patients. The gold-standard Fugl-Meyer Assessment (FMA) requires in-person administration by a trained assessor for 30-45 minutes, which restricts monitoring frequency and precludes physicians from adapting rehabilitation protocols to the progress of each patient. The COBRA score, computed automatically in under one minute, is shown to be strongly correlated with the FMA on an independent test cohort for two different data modalities: wearable sensors (ρ = 0.814, 95% CI [0.700,0.888]) and video (ρ = 0.736, 95% C.I [0.584, 0.838]). To demonstrate the generalizability of the approach to other conditions, the COBRA score was also applied to quantify severity of knee osteoarthritis from magnetic-resonance imaging scans, again achieving significant correlation with an independent clinical assessment (ρ = 0.644, 95% C.I [0.585,0.696]).

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at 8 Centers (7-US based and 1 European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive, and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB, and 23% to MSA). Faster phenoconversion from study enrollment to any diagnosis was associated with urinary and sexual dysfunction [HR 5.9, 95%CI: 1.6-22, and HR: 3.6, 95%CI: 1.1-12] followed by subtle motor signs [HR: 2.7, 95%CI: 1.2-6], trouble swallowing [HR 2.5, 95%CI: 1.4-4.5], and changes in speech [HR:2.4, 95%CI:1.1-4.8] at enrollment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95%CI: 1.1-5.9, ) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95%CI: 1.2-38). Patients with a younger age of PAF onset [HR: 11, 95%CI: 2.6-46], preserved olfaction [HR: 8.7, 95%CI: 1.7-45], anhidrosis [HR: 1.8, 95%CI: 1-3.1, p=0.042], and severe urinary problems [HR 1.6, 95%CI: 1-2.5, p=0.033] were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95%CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9%-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

IMPORTANCE/OBJECTIVE:This pilot study evaluates a remote strategy-based intervention for individuals with multiple sclerosis who experience everyday memory impairments. The intervention can potentially inform cognitive rehabilitation for this population. OBJECTIVE:To investigate the feasibility and efficacy of an intervention (TELE-Self-GEN) to determine whether it can alleviate everyday memory impairments of individuals with multiple sclerosis. DESIGN/METHODS:Pretest-posttest. SETTING/METHODS:Community. PARTICIPANTS/METHODS:Ten adults with multiple sclerosis. INTERVENTION/METHODS:Six synchronous treatment sessions were delivered online via Zoom. The treatment protocol embedded a memory strategy (self-generated learning) within a metacognitive framework, including self-awareness and self-management strategies. The treatment emphasizes when and how self-generation should be used. OUTCOME/RESULTS:Measurements assessed feasibility and participants' satisfaction with the intervention and its delivery method, as well as memory, everyday memory, and functional performance. RESULTS:Participants expressed high satisfaction with the virtual treatment, highlighting its convenience as a key factor. Treatment resulted in improvements in memory performance, perceived memory ability in daily life, and functional performance. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Results provide initial proof of concept in the utilization of a remotely delivered, strategy-based treatment approach to improve memory performance and functional abilities. The pilot data support a larger randomized clinical trial of the TELE-self-GEN. Plain-Language Summary: The results of this pilot study highlight the promising potential of TELE-self-GEN for people with multiple sclerosis (MS), who face memory challenges every day. This remotely delivered, strategy-based occupational therapy treatment approach, TELE-self-GEN, has the potential to significantly improve functional memory. The study participants reported improvements in their memory performance, perceived memory ability in daily life, and functional performance. These encouraging results serve as a foundation for more extensive clinical trials using TELE-self-GEN for people with MS.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Precise localization of the dentatorubrothalamic (DRT) tract can facilitate anatomic targeting in MRI-guided high-intensity focused ultrasound (HIFU) thalamotomy and thalamic deep brain stimulation for tremor. The anatomic segment of DRT fibers adjacent to the ventral intermediate nucleus of the thalamus (VIM), referred to as the rubral wing (RW), may be directly visualized on the fast gray matter acquisition T1 inversion recovery. We compared reproducibility, lesion overlap, and clinical outcomes when reconstructing the DRT tract using a novel anatomically defined RW region of interest, DRT-RW, to an existing tractography method based on the posterior subthalamic area region of interest (DRT-PSA). METHODS:We reviewed data of 23 patients with either essential tremor (n = 18) or tremor-predominant Parkinson's disease (n = 5) who underwent HIFU thalamotomy, targeting the VIM. DRT tractography, ipsilateral to the lesion, was created based on either DRT-PSA or DRT-RW. Volume sections of each tract were created and dice similarity coefficients were used to measure spatial overlap between the 2 tractographies. Post-HIFU lesion size and location (on postoperative T2 MRI) was correlated with tremor outcomes and side effects for both DRT tractography methods and the RW itself. RESULTS:DRT-PSA passed through the RW and DRT-RW intersected with the ROIs of the DRT-PSA in all 23 cases. A higher percentage of the RW was ablated in patients who achieved tremor control (18.9%, 95% CI 15.1, 22.7) vs those without tremor relief (6.7%, 95% CI% 0, 22.4, P = .017). In patients with tremor control 6 months postoperatively (n = 12), those with side effects (n = 6) had larger percentages of their tracts ablated in comparison with those without side effects in both DRT-PSA (44.8, 95% CI 31.8, 57.8 vs 24.2%, 95% CI 12.4, 36.1, P = .025) and DRT-RW (35.4%, 95% CI 21.5, 49.3 vs 21.7%, 95% CI 12.7, 30.8, P = .030). CONCLUSION/CONCLUSIONS:Tractography of the DRT could be reconstructed by direct anatomic visualization of the RW on fast gray matter acquisition T1 inversion recovery-MRI. Anatomic planning is expected to be quicker, more reproducible, and less operator-dependent.

Comprehensive understanding of venous anatomy is a key factor in the approach to a multitude of conditions. Moreover, the venous system has become the center of attention as a new frontier for treatment of diseases such as idiopathic intracranial hypertension (IIH), arteriovenous malformation (AVM), pulsatile tinnitus, hydrocephalus, and cerebrospinal fluid (CSF) venous fistulas. Its knowledge is ever more an essential requirement of the modern brain physician. In this article, the authors explore the descriptive and functional anatomy of the venous system of the CNS in 5 subsections: embryology, dural sinuses, cortical veins, deep veins, and spinal veins.

INTRODUCTION/BACKGROUND:We examined whether hypertension (HTN) was associated with Alzheimer's disease-related biomarkers in cerebrospinal fluid (CSF) and how changes in blood pressure (BP) related to changes in CSF biomarkers over time. METHODS:A longitudinal observation of cognitively healthy normotensive subjects (n = 134, BP < 140/90, with no antihypertensive medication), controlled HTN (n = 36, BP < 140/90, taking antihypertensive medication), and 35 subjects with uncontrolled HTN (BP ≥ 140/90). The follow-up range was 0.5to15.6 years. RESULTS:Total tau (T-tau) and phospho-tau181 (P-tau 181) increased in all but controlled HTN subjects (group×time interaction: p < 0.05 for both), but no significant Aβ42 changes were seen. Significant BP reduction was observed in uncontrolled HTN, and it was related to increase in T-tau (p = 0.001) and P-tau 181 (p < 0.001). DISCUSSION/CONCLUSIONS:Longitudinal increases in T-tau and P-tau 181 were observed in most subjects; however, only uncontrolled HTN had both markers increase alongside BP reductions. We speculate cumulative vascular injury renders the brain susceptible to relative hypoperfusion with BP reduction. HIGHLIGHTS/CONCLUSIONS:Over the course of the study, participants with uncontrolled HTN at baseline showed greater accumulation of CSF total tau and phospho-tau181 (P-tau 181) than subjects with normal BP or with controlled HTN. In the group with uncontrolled HTN, increases in total tau and P-tau 181 coincided with reduction in BP. We believe this highlights the role of HTN in vascular injury and suggests decline in cerebral perfusion resulting in increased biomarker concentrations in CSF. Medication use was the main factor differentiating controlled from uncontrolled HTN, indicating that earlier treatment was beneficial for preventing accumulations of pathology.

BACKGROUND AND OBJECTIVES/UNASSIGNED:In a retrospective study evaluating the diagnostic approach of definitive neurological infections at a tertiary referral center, we assessed the time to diagnosis from presentation, number of diagnostic tests ordered, and modality of etiologic diagnosis. METHODS/UNASSIGNED:A total of 111 confirmed clinical cases of neurological infections from 2010-2018 were reviewed. Definitive neuroinfectious diagnoses were defined by positive cerebrospinal (CSF) polymerase chain reaction (PCR)/antigen, CSF culture, CSF antibody, serology, or pathology tests. RESULTS/UNASSIGNED:< .001). DISCUSSION/UNASSIGNED:Given the high morbidity and mortality of neuroinfectious disease, specifically meningitis and encephalitis, efficient diagnostic testing is imperative to facilitate the most appropriate clinical course of action with special attention to the specific patient population.

BACKGROUND AND PURPOSE/UNASSIGNED:Sleep disturbance after hemorrhagic stroke (intracerebral or subarachnoid hemorrhage) can impact rehabilitation, recovery, and quality of life. We sought to explore preclinical and clinical factors associated with sleep disturbance after hemorrhagic stroke assessed via the Quality of Life in Neurological Disorders (Neuro-QoL) short form sleep disturbance inventory. METHODS/UNASSIGNED:We telephonically completed the Neuro-QoL short form sleep disturbance inventory 3-months and 12-months after hemorrhagic stroke for patients >18-years-old hospitalized between January 2015 and February 2021. We examined the relationship between sleep disturbance (T-score >50) and social and neuropsychiatric history, systemic and neurological illness severity, medical complications, and temporality. RESULTS/UNASSIGNED:= .046). CONCLUSION/UNASSIGNED:This exploratory analysis did not demonstrate a sustained relationship between any preclinical or clinical factors and sleep disturbance after hemorrhagic stroke. Larger studies that include comparison to patients with ischemic stroke and healthy individuals and utilize additional techniques to evaluate sleep disturbance are needed.