Faculty Bibliography

Axial disorders, including postural deformities, postural instability, and gait disturbances, are among the most disabling symptoms of Parkinson's disease (PD). Equistasi®, a wearable proprioceptive stabilizer device, has been proposed as neurological rehabilitative device for this set of symptoms. To investigate the effects of the device on gait and balance, 24 participants affected by PD were enrolled in this crossover double-dummy, randomized, controlled study. Subjects were assessed four times before and after 8 weeks treatment with either active or placebo device; one-month wash-out was taken between treatments, in a 20-week timeframe. Gait analysis and instrumented Romberg test were performed with the aid of a sterofotogrammetric system and two force plates. Joint kinematics, spatiotemporal parameters of gait and center of pressure parameters were extracted. Paired T-test (p < 0.05) was adopted after evidence of normality to compare the variables across different acquisition sessions; Wilcoxon was adopted for non-normal distributions. Before and after the treatment with the active device, statistically significant improvements were observed in trunk flexion extension and in the ankle dorsi-plantarflexion. Regarding balance assessment, significant improvements were reported at the frequencies corresponding to vestibular system. These findings may open new possibilities on PD's rehabilitative interventions. Research question, tailored design of the study, experimental acquisition overview, main findings, and conclusions.

PD-1 is a critical therapeutic target in cancer immunotherapy and antibodies blocking PD-1 are approved for multiple types of malignancies. The phosphatase SHP2 is the main effector mediating PD-1 downstream signaling and accordingly attempts have been made to target this enzyme as an alternative approach to treat immunogenic tumors. Unfortunately, small molecule inhibitors of SHP2 do not work as expected, suggesting that the role of SHP2 in T cells is more complex than initially hypothesized. To better understand the perplexing role of SHP2 in T cells, we performed interactome mapping of SAP, an adapter protein that is associated with SHP2 downstream signaling. Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. This study suggests that ITK is a unique target in this pathway, and since ITK is a SHP2-dependent specific mediator of PD-1 signaling, the combination of ITK inhibitors with PD-1 blockade may improve upon PD-1 monotherapy in the treatment of cancer.

KEY POINTS/CONCLUSIONS:The corticoreticulospinal tract (CReST) is a descending motor pathway that reorganizes after corticospinal tract (CST) injury in animals. In humans, the pattern of CReST innervation to upper limb muscles has not been carefully examined in healthy individuals or individuals with CST injury. In the present study, we assessed CReST projections to an arm and hand muscle on the same side of the body in healthy and chronic stoke subjects using transcranial magnetic stimulation. We show that CReST connection strength to the muscles differs between healthy and stroke subjects, with stronger connections to the hand than arm in healthy subjects, and stronger connections to the arm than hand in stroke subjects. These results help us better understand CReST innervation patterns in the upper limb, and may point to its role in normal motor function and motor recovery in humans. ABSTRACT/UNASSIGNED:The corticoreticulospinal tract (CReST) is a major descending motor pathway in many animals, but little is known about its innervation patterns in proximal and distal upper extremity muscles in humans. The contralesional CReST furthermore reorganizes after corticospinal tract (CST) injury in animals, but it is less clear whether CReST innervation changes after stroke in humans. We thus examined CReST functional connectivity, connection strength, and modulation in an arm and hand muscle of healthy (n = 15) and chronic stroke (n = 16) subjects. We delivered transcranial magnetic stimulation to the contralesional hemisphere (assigned in healthy subjects) to elicit ipsilateral motor evoked potentials (iMEPs) from the paretic biceps (BIC) and first dorsal interosseous (FDI) muscle. We operationalized CReST functional connectivity as iMEP presence/absence, CReST projection strength as iMEP size and CReST modulation as change in iMEP size by head rotation. We found comparable CReST functional connectivity to the BICs and FDIs in both subject groups. However, the pattern of CReST connection strength to the muscles diverged between groups, with stronger connections to FDIs than BICs in healthy subjects and stronger connections to BICs than FDIs in stroke subjects. Head rotation modulated only FDI iMEPs of healthy subjects. Our findings indicate that the healthy CReST does not have a proximal innervation bias, and its strong FDI connections may have functional relevance to finger individuation. The reversed CReST innervation pattern in stroke subjects confirms its reorganization after CST injury, and its strong BIC connections may indicate upregulation for particular upper extremity muscles or their functional actions.

Purpose of Review/UNASSIGNED:In 2019, over 50 million Americans were expected to use wearables at least monthly. The technologies have varied capabilities, with many designed to monitor health conditions. We present a narrative review to raise awareness of wearable technologies that may be relevant to the field of neurology. We also discuss the implications of these wearables for our patients and briefly discuss issues related to researching new wearable technologies. Recent Findings/UNASSIGNED:There are a variety of wearables for neurologic conditions, e.g., stroke (for potential arrhythmia capture), epilepsy, Parkinson disease, and sleep. Research is being performed to capture the risk of neuropsychiatric relapse. However, data are limited and adherence to these wearables is often poorly studied. Summary/UNASSIGNED:The care of neurology patients may ultimately be improved with the use of wearable technologies. More research needs to examine efficacy and implementation strategies.

This study evaluated multiple previously-identified Continuous Performance Test-Third Edition (CPT-3) scores as embedded validity indicators (EVIs) among 201 adults undergoing neuropsychological evaluation for Attention-Deficit/Hyperactivity Disorder (ADHD) divided into valid (n = 169) and invalid (n = 32) groups based on seven criterion measures. Although 6/10 CPT-3 scores accurately detected invalidity, only two reached minimally acceptable classification accuracy of ≥0.70. The remaining four had unacceptably low accuracy (AUCs = 0.62-0.69) with 0.19-0.41 sensitivity at ≥0.90 specificity. Composite scores did not provide better classification accuracy than individual CPT-3 scores. In sum, CPT-3 individual and composite scores generally are not accurate PVTs among adults undergoing clinical evaluation for ADHD.

The ESM was updated in the original article to replace an incorrect version that was published with tracked changes notes.

INTRODUCTION/BACKGROUND:Many patients admitted to hospitals with acute trauma have positive serum blood alcohol levels. Published associations between alcohol use, injury patterns, and outcomes are inconsistent. We sought to further delineate the impact of alcohol use and alcohol withdrawal on hospital outcomes amongst acute trauma patients. METHODS:We performed a retrospective analysis of adult trauma patients hospitalized at a suburban level 1 trauma center between January 2015 and September 2019 with a blood alcohol level measurement and/or classification as alcohol withdrawal syndrome (AWS). Patients were separated into three groups: BAL ≤10 mg/dL, BAL >10 mg/dL, and alcohol withdrawal syndrome (AWS). RESULTS:Overall, 3896 patients met study criteria with 75.6% BAL ≤10, 23.2% BAL >10, and 1.2% AWS. The median age was significantly different (BAL ≤ 10: 59 years, BAL > 10: 44 years, AWS: 53.5 years). Alcohol withdrawal was experienced by patients with BAL ≤10 and BAL >10. While injury severity and mortality were similar across all 3 groups, AWS patients experienced significantly longer hospital and ICU lengths of stay, unplanned ICU admission, need for mechanical ventilation, and higher rates of complications. Patients with AWS had high rates of acute neuropsychiatric symptoms, complicating their management. CONCLUSIONS:Except for mortality, AWS patients experienced worse outcomes. The complex nature of alcohol withdrawal cases, including the possibility of developing AWS despite a negative BAL on admission, emphasizes the need for early assessment for alcohol withdrawal risk factors and input from specialists.

Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme β-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients.

BACKGROUND:Elevated systolic blood pressure (SBP) in the acute phase after endovascular therapy (EVT) is associated with worse outcome. However, the association between systolic blood pressure reduction (SBPr) and the outcome of EVT is not well understood. OBJECTIVE:To determine the association between SBPr and clinical outcomes after EVT in a prospective multicenter cohort. METHODS:A post hoc analysis of the Blood Pressure after Endovascular Stroke Therapy (BEST) prospective observational cohort study was carried out. SBPr was defined as the absolute difference between admission SBP and mean SBP in the first 24 hours after EVT. Logistic regression was used to assess the association between SBPr and poor functional outcome (modified Rankin Scale score 3-6) at 90 days. RESULTS:A total of 259/433 (58.5%) patients had poor outcome. SBPr was higher in the poor outcome group than in the good outcome group (26.6±27.4 vs 19.0±22.3 mm Hg; p<0.001). However, in adjusted models, SBPr was not independently associated with poor outcome (OR=1.00 per 1 mm Hg increase, 95% CI 0.99 to 1.01) or death (OR=0.9 per 1 mm Hg increase; 95% CI 0.98 to 1.00). No association remained when SBPr was divided into tertiles. Subgroup analyses based on history of hypertension, revascularization status, and antihypertensive treatment yielded similar results. CONCLUSION/CONCLUSIONS:The reduction in baseline SBP following EVT was not associated with poor functional outcomes. Most of the cohort (88%) achieved successful recanalization, and therefore, these results mainly apply to patients with successful recanalization.

Voluntary rapid eye movements (saccades) redirect the fovea toward objects of visual interest. The saccadic system can be considered as a dual-mode system: in one mode the eye is fixating, in the other it is making a saccade. In this review, we consider two examples of dysfunctional saccades, interrupted saccades in late-onset Tay-Sachs disease and gaze-position dependent opsoclonus after concussion, which fail to properly shift between fixation and saccade modes. Insights and benefits gained from bi-directional collaborative exchange between clinical and basic scientists are emphasized. In the case of interrupted saccades, existing mathematical models were sufficiently detailed to provide support for the cause of interrupted saccades. In the case of gaze-position dependent opsoclonus, existing models could not explain the behavior, but further development provided a reasonable hypothesis for the mechanism underlying the behavior. Collaboration between clinical and basic science is a rich source of progress for developing biologically plausible models and understanding neurological disease. Approaching a clinical problem with a specific hypothesis (model) in mind often prompts new experimental tests and provides insights into basic mechanisms.