Faculty Bibliography

AIMS/OBJECTIVE:Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. METHODS:Hippocampal H&E slides (n=67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by 9 blinded reviewers: 3 board-certified forensic pathologists, 3 neuropathologists, and 3 dual-certified neuropathologist/forensic pathologists. RESULTS:Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (SUDC 52.5%, controls 53.0%), with no difference by cause of death (COD) (p=0.16) or febrile seizure history (p=0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' kappa=0.014, p=0.47). Within reviewer groups, there were no findings more frequent in SUDC compared to controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p=0.41). CONCLUSIONS:The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal malformation associated with sudden death (HMASD). These findings underscore a need for larger studies to standardize evaluation of hippocampal findings, identify the range of normal variation and, changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.

BACKGROUND:Persistent cognitive symptoms have been reported following COVID-19 hospitalization. We investigated the relationship between demographics, social determinants of health (SDOH) and cognitive outcomes 6-months after hospitalization for COVID-19. METHODS:We analyzed 6-month follow-up data collected from a multi-center, prospective study of hospitalized COVID-19 patients. Demographic and SDOH variables (age, race/ethnicity, education, employment, health insurance status, median income, primary language, living arrangements, and pre-COVID disability) were compared between patients with normal versus abnormal telephone Montreal Cognitive Assessments (t-MOCA; scores<18/22). Multivariable logistic regression models were constructed to evaluate predictors of t-MoCA. RESULTS:Of 382 patients available for 6-month follow-up, 215 (56%) completed the t-MoCA (n = 109/215 [51%] had normal and n = 106/215 [49%] abnormal results). 14/215 (7%) patients had a prior history of dementia/cognitive impairment. Significant univariate predictors of abnormal t-MoCA included older age, ≤12 years of education, unemployment pre-COVID, Black race, and a pre-COVID history of cognitive impairment (all p < 0.05). In multivariable analyses, education ≤12 years (adjusted OR 5.21, 95%CI 2.25-12.09), Black race (aOR 5.54, 95%CI 2.25-13.66), and the interaction of baseline functional status and unemployment prior to hospitalization (aOR 3.98, 95%CI 1.23-12.92) were significantly associated with abnormal t-MoCA scores after adjusting for age, history of dementia, language, neurological complications, income and discharge disposition. CONCLUSIONS:Fewer years of education, Black race and unemployment with baseline disability were associated with abnormal t-MoCA scores 6-months post-hospitalization for COVID-19. These associations may be due to undiagnosed baseline cognitive dysfunction, implicit biases of the t-MoCA, other unmeasured SDOH or biological effects of SARS-CoV-2.

The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21-linked early-onset Alzheimer's disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26-72 years of age were to identify the magnitude of brain region-specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26-41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43-49, 51-59, and 61-72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26-41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43-49 years of age; a 28.0% maximum neuronal loss at 51-59 years of age; and a 11.0% minimum neuronal loss at 61-72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.

Brainstem nuclei dysfunction is implicated in sudden unexpected death in epilepsy. In animal models, deficient serotonergic activity is associated with seizure-induced respiratory arrest. In humans, glia are decreased in the ventrolateral medullary pre-Botzinger complex that modulate respiratory rhythm, as well as in the medial medullary raphe that modulate respiration and arousal. Finally, sudden unexpected death in epilepsy cases have decreased midbrain volume. To understand the potential role of brainstem nuclei in sudden unexpected death in epilepsy, we evaluated molecular signalling pathways using localized proteomics in microdissected midbrain dorsal raphe and medial medullary raphe serotonergic nuclei, as well as the ventrolateral medulla in brain tissue from epilepsy patients who died of sudden unexpected death in epilepsy and other causes in diverse epilepsy syndromes and non-epilepsy control cases (n = 15-16 cases per group/region). Compared with the dorsal raphe of non-epilepsy controls, we identified 89 proteins in non-sudden unexpected death in epilepsy and 219 proteins in sudden unexpected death in epilepsy that were differentially expressed. These proteins were associated with inhibition of EIF2 signalling (P-value of overlap = 1.29 × 10^-8, z = -2.00) in non-sudden unexpected death in epilepsy. In sudden unexpected death in epilepsy, there were 10 activated pathways (top pathway: gluconeogenesis I, P-value of overlap = 3.02 × 10^-6, z = 2.24) and 1 inhibited pathway (fatty acid beta-oxidation, P-value of overlap = 2.69 × 10^-4, z = -2.00). Comparing sudden unexpected death in epilepsy and non-sudden unexpected death in epilepsy, 10 proteins were differentially expressed, but there were no associated signalling pathways. In both medullary regions, few proteins showed significant differences in pairwise comparisons. We identified altered proteins in the raphe and ventrolateral medulla of epilepsy patients, including some differentially expressed in sudden unexpected death in epilepsy cases. Altered signalling pathways in the dorsal raphe of sudden unexpected death in epilepsy indicate a shift in cellular energy production and activation of G-protein signalling, inflammatory response, stress response and neuronal migration/outgrowth. Future studies should assess the brain proteome in relation to additional clinical variables (e.g. recent tonic-clonic seizures) and in more of the reciprocally connected cortical and subcortical regions to better understand the pathophysiology of epilepsy and sudden unexpected death in epilepsy.

BACKGROUND:Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways. METHODS AND FINDINGS/RESULTS:We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4-26; n = 10, Control, mean age 13.1, range 3-45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at <15% false discovery rate associated with coagulation system (p = 1.45x10-9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences. CONCLUSIONS:Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects. CLINICAL TRIALS REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT02451696.

High-resolution susceptibility weighted imaging (SWI) provides unique contrast to small venous vasculature. The conspicuity of these mesoscopic veins, such as deep medullary veins in white matter, is subject to change from SWI venography when venous oxygenation in these veins is altered due to oxygenated blood susceptibility changes. The changes of visualization in small veins shows potential to depict regional changes of oxygen utilization and/or vascular density changes in the aging brain. The goal of this study was to use WM venous density to quantify small vein visibility in WM and investigate its relationship with neurodegenerative features, white matter hyperintensities (WMHs), and cognitive/functional status in elderly subjects (N = 137). WM venous density was significantly associated with neurodegeneration characterized by brain atrophy (β = 0.046± 0.01, p < 0.001), but no significant association was found between WM venous density and WMHs lesion load (p = 0.3963). Further analysis of clinical features revealed a negative trend of WM venous density with the sum-of-boxes of Clinical Dementia Rating and a significant association with category fluency (1-min animal naming). These results suggest that WM venous density on SWI can be used as a sensitive marker to characterize cerebral oxygen metabolism and different stages of cognitive and functional status in neurodegenerative diseases.

BACKGROUND:Post-acute sequelae of COVID-19 (PASC) includes a heterogeneous group of patients with variable symptomatology, who may respond to different therapeutic interventions. Identifying phenotypes of PASC and therapeutic strategies for different subgroups would be a major step forward in management. METHODS:In a prospective cohort study of patients hospitalized with COVID-19, 12-month symptoms and quantitative outcome metrics were collected. Unsupervised hierarchical cluster analyses were performed to identify patients with: (1) similar symptoms lasting ≥4 weeks after acute SARS-CoV-2 infection, and (2) similar therapeutic interventions. Logistic regression analyses were used to evaluate the association of these symptom and therapy clusters with quantitative 12-month outcome metrics (modified Rankin Scale, Barthel Index, NIH NeuroQoL). RESULTS:Among 242 patients, 122 (50%) reported ≥1 PASC symptom (median 3, IQR 1-5) lasting a median of 12-months (range 1-15) post-COVID diagnosis. Cluster analysis generated three symptom groups: Cluster1 had few symptoms (most commonly headache); Cluster2 had many symptoms including high levels of anxiety and depression; and Cluster3 primarily included shortness of breath, headache and cognitive symptoms. Cluster1 received few therapeutic interventions (OR 2.6, 95% CI 1.1-5.9), Cluster2 received several interventions, including antidepressants, anti-anxiety medications and psychological therapy (OR 15.7, 95% CI 4.1-59.7) and Cluster3 primarily received physical and occupational therapy (OR 3.1, 95%CI 1.3-7.1). The most severely affected patients (Symptom Cluster 2) had higher rates of disability (worse modified Rankin scores), worse NeuroQoL measures of anxiety, depression, fatigue and sleep disorder, and a higher number of stressors (all P<0.05). 100% of those who received a treatment strategy that included psychiatric therapies reported symptom improvement, compared to 97% who received primarily physical/occupational therapy, and 83% who received few interventions (P = 0.042). CONCLUSIONS:We identified three clinically relevant PASC symptom-based phenotypes, which received different therapeutic interventions with varying response rates. These data may be helpful in tailoring individual treatment programs.

Background and Purpose/UNASSIGNED:The vascular tortuosity (VT) of the internal carotid artery (ICA), and vertebral artery (VA) can impact blood flow and neuronal function. However, few studies involved quantitative investigation of VT based on magnetic resonance imaging (MRI). The main purpose of our study was to evaluate the age and gender effects on ICA and VA regarding the tortuosity and flow changes by applying automatic vessel segmentation, centerline tracking, and phase mapping on MR angiography. Methods/UNASSIGNED:A total of 247 subjects (86 males and 161 females) without neurological diseases participated in this study. All subjects obtained T1-weighted MRI, 3D time-of-flight MR angiography, and 2D phase-contrast (PC) MRI scans. To generate quantitative tortuosity metrics from TOF images, the vessel segmentation and centerline tracking were implemented based on Otsu thresholding and fast marching algorithms, respectively. Blood flow and velocity were measured using PC MRI. Among the 247 subjects, 144 subjects (≤ 60 years, 49 males/95 females) were categorized as the young group; 103 subjects (>60 years, 37 males/66 females) were categorized as the old group. Results/UNASSIGNED:< 0.001). The age was observed to be positively correlated with the VT metrics. Compared to the males, the females demonstrated higher geometric indices within VAs as well as faster age-related vascular profile changes. After adjusting age and gender as covariates, maximum blood velocity is negatively correlated with geometric measurements. No association was observed between blood flux and geometric measures. Conclusions/UNASSIGNED:Vascular auto-segmentation, centerline tracking, and phase mapping provide promising quantitative assessments of tortuosity and its effects on blood flow. The neck arteries demonstrate quantifiable and significant age-related morphological and hemodynamic alterations. Moreover, females showed more distinct vascular changes with age. Our work is built upon a comprehensive quantitative investigation of a large cohort of populations covering adult lifespan using MRI, the results can serve as reference ranges of each decade in the general population.