Faculty Bibliography

BACKGROUND:There is an increased effort to better understand neuropsychiatric symptoms of Alzheimer's disease (AD) as an important feature of symptomatic burden as well as potential modi- fiable factors of the disease process. Anxiety is one of the most common neuropsychiatric symptoms in Alzheimer's disease (AD). A growing body of work has emerged that addresses the epidemiology and biological correlations of anxiety in AD. OBJECTIVE AND METHODS/OBJECTIVE:Here, we review human studies in research and clinical cohorts that examined anxiety in AD. We focused on work related to prevalence across AD stages, correlation with established biomarkers, relationship with AD neuropathology and genetic risk factors, and impact on progression. RESULTS:Anxiety is prominent in the early stages and increases across the spectrum of functional stages. Biomarker relationships are strongest at the level of FDG-PET and amyloid measured via PET or cerebrospinal fluid analysis. Neuropathologically, anxiety emerges with early Braak stage tau pathology. The presence of the apolipoprotein E e4 allele is associated with increased anxiety at all stages, most notably at mild cognitive impairment. Anxiety portended a faster progression at all pre-dementia stages. CONCLUSION/CONCLUSIONS:This body of work suggests a close biological relationship between anxiety and AD that begins in early stages and influences functional decline. As such, we discuss future work that would improve our understanding of this relationship and test the validity of anxiolytic treatment as disease modifying therapy for AD.

BACKGROUND:The coronavirus disease 2019 (COVID-19) is a systemic entity that frequently implies neurologic features at presentation and complications during the disease course. We aimed to describe the characteristics and predictors for developing in-hospital neurologic manifestations in a large cohort of hospitalized patients with COVID-19 in Mexico City. METHODS:We analyzed records from consecutive adult patients hospitalized from March 15 to June 30, 2020, with moderate to severe COVID-19 confirmed by reverse transcription real-time polymerase chain reaction (rtRT-PCR) for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neurologic syndromes were actively searched by a standardized structured questionnaire and physical examination, confirmed by neuroimaging, neurophysiology of laboratory analyses, as applicable. RESULTS:We studied 1,072 cases (65% men, mean age 53.2±13 years), 71 patients had pre-existing neurologic diseases (diabetic neuropathy: 17, epilepsy: 15, history of ischemic stroke: eight, migraine: six, multiple sclerosis: one, Parkinson disease: one), and 163 (15.2%) developed a new neurologic complication. Headache (41.7%), myalgia (38.5%), dysgeusia (8%), and anosmia (7%) were the most common neurologic symptoms at hospital presentation. Delirium (13.1%), objective limb weakness (5.1%), and delayed recovery of mental status after sedation withdrawal (2.5%), were the most common new neurologic syndromes. Age, headache at presentation, preexisting neurologic disease, invasive mechanical ventilation, and neutrophil/lymphocyte ratio ≥9 were independent predictors of new in-hospital neurologic complications. CONCLUSIONS:Even after excluding initial clinical features and pre-existing comorbidities, new neurologic complications in hospitalized patients with COVID-19 are frequent and can be predicted from clinical information at hospital admission.

Background and Objective/UNASSIGNED:Posttraumatic stress disorder (PTSD) is a serious and frequently debilitating psychiatric condition that can occur in people who have experienced traumatic stessors, such as war, violence, sexual assault and other life-threatening events. Treatment of PTSD and traumatic brain injury (TBI) in veterans is challenged by diagnostic complexity, partially due to PTSD and TBI symptom overlap and to the fact that subjective self-report assessments may be influenced by a patient's willingness to share their traumatic experiences and resulting symptoms. Corticotropin-releasing factor (CRF) is one of the main mediators of hypothalamic pituitary adrenal (HPA)-axis responses in stress and anxiety. Methods and Results/UNASSIGNED:We analyzed serum CRF levels in 230 participants including heathy controls (64), and individuals with PTSD (53), TBI (70) or PTSD+TBI (43) by enzyme immunoassay (EIA). Significantly lower CRF levels were found in both the PTSD and PTSD+TBI groups compared to healthy control (PTSD vs Controls: P=0.0014, PTSD + TBI vs Controls: P=0.0011) and chronic TBI participants (PTSD vs TBI: P<0.0001PTSD + TBI vs TBI: P<0.0001) , suggesting a PTSD-related mechanism independent from TBI and associated with CRF reduction. CRF levels negatively correlated with PTSD severity on the CAPS-5 scale in the whole study group. Conclusions/UNASSIGNED:Hyperactivation of the HPA axis has been classically identified in acute stress. However, the recognized enhanced feedback inhibition of the HPA axis in chronic stress supports our findings of lower CRF in PTSD patients. This study suggests that reduced serum CRF in PTSD should be further investigated. Future validation studies will establish if CRF is a possible blood biomarker for PTSD and/or for differentiating PTSD and chronic TBI symptomatology.

Recently, Vesuna et al. proposed a novel circuit mechanism underlying dissociative states using optogenetics and pharmacology in mice in combination with intracranial recordings and electrical stimulation in an epilepsy patient. Specifically, the authors identified a posteromedial cortical delta-rhythm that underlies states of dissociation. In the following, we would like to critically review these findings in the context of the human literature on dissociation as well as highlight the challenges in translational neuroscience to link complex behavioral phenotypes in psychiatric syndromes to circumscribed circuit mechanisms.

Neurogenic orthostatic hypotension (nOH) is one of the most debilitating nonmotor symptoms in patients with Parkinson disease and other synucleinopathies. Patients with Parkinson disease and nOH suffer from more hospitalizations, emergency room visits, more telephone calls and e-mails to providers, and have a significantly shorter survival compared to patients with Parkinson disease and no nOH. Overall, health-related costs in patients with Parkinson disease and OH are 2.5-fold higher compared to patients with Parkinson disease without OH. Therefore, the development of effective therapies for patients with Parkinson disease and nOH should be a research priority. In recent years, better understanding of the pathophysiology of nOH has resulted in the identification of novel therapeutic targets and the development and approval of effective drug therapies, such as midodrine and droxidopa. We here review the design and endpoint selection for clinical trials of nOH in patients with Parkinson disease and other synucleinopathies, recapitulate the results of completed and ongoing clinical trials for nOH, and discuss common challenges and their potential remedies.
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Introduction: Activities of daily living (ADLs) are performed through a sequence of fundamental units of motion, called primitives. We previously observed that during ADLs, one upper extremity (UE) may engage two objects simultaneously, such as turning on a faucet while holding a toothbrush. These dual-object primitives (DOPs) may demand increased neural resources, as they likely entail the simultaneous execution of two motor plans. Skilled movement by the nondominant healthy UE or the paretic UE has also been found to require increased neural activity. We posited that performance of DOPs would exceed the neural resources available to the nondominant or paretic side, reducing their performance on these sides. We also predicted that the frequency of DOP performance by the paretic UE would relate to its degree of motor impairment.
Method(s): We studied 19 right-hand dominant healthy subjects (10M:9F; 62.0 +/- 13.6 years) and 43 premorbidly right-hand dominant stroke subjects (23M:20F; 24L:19R paretic; 57.5 +/- 14.5 years; 5.7 +/- 6.5 years post stroke). We evaluated subjects on the UE Fugl-Meyer Assessment (FMA) and videotaped their performance of a feeding and toothbrushing task. We analyzed the videos to extract the incidence and count of DOP performance by each UE. To control for dominance and paresis, we normalized DOP counts to the total number of primitives performed by the UE. We used two-tailed Fisher's Exact tests to compare the incidence of DOPs performed by each UE, and Spearman's correlation to examine the relationship between FMA score and DOP frequency.
Result(s): In healthy subjects, the incidence of DOPs was lower on the nondominant than dominant side (12/19 vs. 19/19; p<0.01). In stroke subjects, the incidence of DOPs was lower on the paretic than nonparetic side (19/43 vs. 43/43; p<0.01). The laterality of paresis did not affect whether that UE would perform DOPs (11/19 dominant paretic vs. 8/24 nondominant paretic; p=0.132). In stroke subjects, lower FMA scores were related to a lower frequency of DOP performance on their paretic UE (rho=0.368, p=0.015).
Discussion(s): Our results suggest that UE laterality and impairment may impact DOP performance in healthy and stroke subjects, respectively. DOPs were less commonly performed by the nondominant UE and the paretic UE, and worse impairment was associated with lower DOP performance. We speculate that engaging two objects simultaneously requires additional neural resources that are unavailable to the nondominant or injured motor network. It is conceivable that the return of DOP performance by the paretic UE may track with the availability of a recovered neural substrate.

Background/Objectives/UNASSIGNED:Little is known regarding the prevalence and predictors of prolonged cognitive and psychological symptoms of COVID-19 among community-dwellers. We aimed to quantitatively measure self-reported metrics of fatigue, cognitive dysfunction, anxiety, depression, and sleep and identify factors associated with these metrics among United States residents with or without COVID-19. Methods/UNASSIGNED:We solicited 1000 adult United States residents for an online survey conducted February 3-5, 2021 utilizing a commercial crowdsourcing community research platform. The platform curates eligible participants to approximate United States demographics by age, sex, and race proportions. COVID-19 was diagnosed by laboratory testing and/or by exposure to a known positive contact with subsequent typical symptoms. Prolonged COVID-19 was self-reported and coded for those with symptoms ≥ 1 month following initial diagnosis. The primary outcomes were NIH PROMIS/Neuro-QoL short-form T-scores for fatigue, cognitive dysfunction, anxiety, depression, and sleep compared among those with prolonged COVID-19 symptoms, COVID-19 without prolonged symptoms and COVID-19 negative subjects. Multivariable backwards step-wise logistic regression models were constructed to predict abnormal Neuro-QoL metrics. Results/UNASSIGNED:= 0.047), but there were no significant differences in quantitative measures of anxiety, depression, fatigue, or sleep. Conclusion/UNASSIGNED:Prolonged symptoms occurred in 25% of COVID-19 positive participants, and NeuroQoL cognitive dysfunction scores were significantly worse among COVID-19 positive subjects, even after accounting for demographic and stressor covariates. Fatigue, anxiety, depression, and sleep scores did not differ between COVID-19 positive and negative respondents.