Faculty Bibliography

Transcranial Alternating Current Stimulation (tACS) is a promising noninvasive electrical stimulation therapy for neuropsychiatric diseases. Invasive neuromodulation using alternating current has been efficacious for drug-resistant epilepsy, but it is associated with surgical and medical complications. We aimed to explore the safeness and effectivity on seizure frequency reduction of two tACS protocols against placebo in patients with multifocal refractory epilepsy. This was a randomized, double-blinded, placebo-controlled clinical trial with 3-arm parallel-group (placebo, 30 min/2 mA daily sessions for 3 days [tACS-30], and 60 min/2 mA weekday sessions [tACS-60]). The main outcome was considered a change in reducing seizure frequency at 2 months after the intervention. Secondary outcomes were the apparition of any adverse effects during follow-up. At the second month, we observed a nonsignificant reduction in the seizure frequency in the placebo (7.3 ± 40.4%, p > 0.05) and the tACS-60 (26 ± 37.7%, p > 0.05). While the tACS-30 group showed a nonsignificant increase in seizure frequency (63.6 ± 155.3%, p > 0.05). No changes were statistically different from the placebo group. Otherwise, participants experienced only minor adverse events - the most common being an initial local transient tingling sensation (21%). This pilot study of tACS raises no severe safety issues, but provides negligible evidence for efficacy using this brief treatment protocol. Therefore, more studies are warranted testing different parameters to further verify the safety and effectivity of tACS in multifocal epilepsy.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Loneliness is common and its prevalence is rising. The relationship of loneliness with subsequent dementia and the early preclinical course of Alzheimer disease and related dementia (ADRD) remains unclear. Thus, the primary objective of this study was to determine the association of loneliness with 10-year all-cause dementia risk and early cognitive and neuroanatomic imaging markers of ADRD vulnerability. METHODS:Retrospective analysis of prospectively collected data from the population-based Framingham Study cohorts (09/09/1948-12/31/2018). Eligible participants had loneliness assessed and were dementia-free at baseline. Loneliness was recorded using the Center for Epidemiologic Studies Depression Scale; defined conservatively as feeling lonely ≥3 days in the past week. The main outcomes were incident dementia over a 10-year period, cognition, and MRI brain volumes and white-matter injury. RESULTS:Of 2308 participants (mean age, 73 [SD, 9] years; 56% women) who met eligibility in the dementia sample, 14% (329/2308) developed dementia; 6% (144/2308) were lonely. Lonely (versus not lonely) adults had higher 10-year dementia risk (age-, sex-, and education-adjusted hazard ratio, 1.54; 95% CI, 1.06-2.24). Lonely participants younger than age 80 without APOE ε4 alleles had a three-fold greater risk (adjusted hazard ratio, 3.03; 95% CI, 1.63-5.62). Among 1875 persons without dementia who met eligibility in the cognition sample (mean age, 62 [SD, 9] years; 54% women), loneliness associated with poorer executive function, lower total cerebral volume, and greater white-matter injury. DISCUSSION/CONCLUSIONS:Over 10 years of close clinical dementia surveillance in this cohort study, loneliness was associated with increased dementia risk; this tripled in adults whose baseline risk would otherwise be relatively low based on age and genetic risk, representing a majority of the US population. Loneliness was also associated with worse neurocognitive markers of ADRD vulnerability, suggesting an early pathogenic role. These findings may have important clinical and public health implications given observed loneliness trends. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that loneliness increases the 10-year risk of developing dementia.

Although the Uniform Determination of Death Act (UDDA) has served as a model statute for 40 years, there is a growing recognition that the law must be updated. One issue being considered by the Uniform Law Commission's Drafting Committee to revise the UDDA is whether the text "all functions of the entire brain, including the brainstem" should be changed. Some argue that the absence of diabetes insipidus indicates that some brain functioning continues in many individuals who otherwise meet the "accepted medical standards" like the American Academy of Neurology's. The concern is that the legal criteria and the medical standards used to determine death by neurological criteria are not aligned. We argue for the revision of the UDDA to more accurately specify legal criteria which align with the medical standards: brain injury leading to permanent loss of a) the capacity for consciousness, b) the ability to breathe spontaneously, and c) brainstem reflexes. We term these criteria "neuro-respiratory criteria" and show that they are well-supported in the literature for physiological and social reasons justifying their use in the law.

Seizure risk is 10-fold higher in Alzheimer's disease patients than the general population, yet the mechanisms underlying this susceptibility and the effects of seizures on Alzheimer's disease are poorly understood. To elucidate our proposed bidirectional relationship between Alzheimer's disease and seizures, we studied Alzheimer's disease human brain samples (n = 34) and found that patients with a history of seizures (n = 14) had increased β-amyloid and tau pathology, and upregulation of the mechanistic target of rapamycin (mTOR) pathway compared to cases without known seizure history (n = 20). To establish whether seizures could accelerate Alzheimer's disease progression, we induced chronic hyperexcitability in the 5XFAD Alzheimer's disease mouse model by kindling with the chemoconvulsant pentylenetetrazol and observed that 5XFAD mice displayed higher seizure severity compared to wild type. Furthermore, kindled seizures exacerbated later cognitive impairment, Alzheimer's disease neuropathology and mTORC1 activation. Finally, we demonstrate that administration of the mTOR inhibitor rapamycin following kindled seizures rescued enhanced remote and long-term memory deficits associated with earlier kindling and prevented the seizure-induced increases in Alzheimer's disease neuropathology. These data demonstrate an important link between chronic hyperexcitability and progressive Alzheimer's disease pathology and suggest a mechanism whereby rapamycin may serve as an adjunct therapy to attenuate Alzheimer's disease progression.

Somatostatin (SS) is a peptide hormone with diverse physiological roles. By investigating a deep-water clade of fish-hunting cone snails, we show that predator-prey evolution has generated a diverse set of SS analogs, each optimized to elicit specific systemic physiological effects in prey. The increased metabolic stability, distinct SS receptor activation profiles, and chemical diversity of the venom analogs make them suitable leads for therapeutic application, including pain, cancer, and endocrine disorders. Our findings not only establish the existence of SS-like peptides in animal venoms but also serve as a model for the synergy gained from combining molecular phylogenetics and behavioral observations to optimize the discovery of natural products with biomedical potential.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT_856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM-treated mice demonstrated a CD4 T cell-mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node-like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.

BACKGROUND:Little information is available regarding technical challenges with the new lower profile Woven EndoBridge (WEB 17) system intended for smaller aneurysms. METHODS:We report illustrative cases of technical complications encountered with 2 anterior communicating artery aneurysms treated by the WEB 17 system requiring rescue stenting in both cases, discussing technical nuances regarding potential reasons for the encountered failures along with management plan. RESULTS:Over a span of 1 year (January 2021 to January 2022), 45 WEB embolization procedures were performed at 2 institutions. Two procedures were complicated by abrupt change in orientation of the WEB device immediately after detachment from the delivery wire. In the first case, abrupt angulation with subsequent migration and prolapse out of the aneurysm sac into the distal right anterior cerebral artery was encountered with unsuccessful retrieval despite multiple attempts using a variety of devices, eventually requiring rescue stenting. A similar sudden orientation change was noted in the second case with partial prolapse from the aneurysm sac similarly bailed out by intracranial stenting. Both patients recovered to preprocedural baseline with no permanent deficits and eventually were discharged home. CONCLUSIONS:Intrasaccular WEB 17 embolization may be technically challenging in smaller wide-necked aneurysms with acute aneurysm-parent artery angulation with abrupt changing of WEB device orientation after detachments with device migration and prolapse into the parent vessel requiring rescue stenting. Proper WEB 17 device sizing and vigilance in the transition phase between the end of deployment and detachment windows of the procedure are paramount to treatment success. Routine use of antiplatelets in cases of anatomical aneurysms that are anticipated to be challenging might be a useful strategy if bailout stenting is needed.

BACKGROUND:The chronic disease burden among African Americans has continued to rise. Although racial disparities in chronic disease risk are well documented, the role of chronic stress in risk disparities among racial and ethnic minorities is not well understood. This systematic review of studies reporting on the relationship between chronic stress, education, and/or income, and biomarkers of chronic stress (allostatic load and telomere length) longitudinally among African Americans, seeks to contribute to this knowledge gap. OBJECTIVE:To use the existing literature to both examine the strength of two objective biomarkers--telomere length and allostatic load--as measures of the overactivation of physiological stress processes in African American adults; and determine if existing studies used these two biomarkers to assess the relationship between chronic stress, income and level of educational attainment among African Americans longitudinally. METHODS:In order to identify English-language articles published prior to October 11, 2021, a comprehensive search strategy was developed using five databases: PubMed/Medline, EMBASE, Web of Science Plus, Global Health (Ovid), and PsycINFO. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was used to record progress on the comprehensive search for studies reporting on allostatic load and/or telomere length biomarkers longitudinally within all bodily fluids and chronic stress among African American adults. RESULTS:In total, 7 studies met the search criteria; 902 were excluded. Thus, less than 1% of all studies reporting on biomarkers of chronic stress longitudinally included African Americans. Each of the 7 studies described the relationship between telomere length and/or allostatic load among African Americans and chronic stress, education, and/or income. Higher chronic stress levels and experiences of racial discrimination were associated with telomere shortening while lower income and higher chronic stress levels were associated with an increase in allostatic load among African Americans. DISCUSSION/CONCLUSIONS:Given the limited number of studies reporting on the association between allostatic load, telomere length, and/or the relationship between both in assessing chronic stress severity longitudinally among African American populations, it is impossible to determine whether one biomarker has greater predictive value than the other. However, based on the literature included in this review, higher chronic stress levels and experiences of racial discrimination were associated with shorter telomere length, while lower income and higher chronic stress levels are associated with an increase in allostatic load among African Americans. CONCLUSION/CONCLUSIONS:These data illustrate a gap in the literature on the relationship between the biomarkers of telomere length and allostatic load combined as a potential measure for chronic stress among African Americans. To our knowledge, none the current literature describes the relationship between telomere length and allostatic load longitudinally among African American adults. As the field strives to develop a "gold standard" for measuring chronic stress, the combination of these biomarkers needs to be the subject of scientific inquiry and thus, fully examined. Future longitudinal studies among African Americans are needed to better understand which biomarker, or combination of biomarkers will provide the most accurate measure of physiological stress processes.

BACKGROUND AND AIMS:We highlight the peripheral neurologic complications of coronavirus disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an ongoing global health emergency. METHODS:We evaluated twenty-five patients admitted to the COVID-19 Recovery Unit (CRU) at New York-Presbyterian Weill Cornell University Medical Center after intensive care hospitalization with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), whom neurology was consulted for weakness and/or paresthesias. All patients were clinically evaluated by a neuromuscular neurologist who performed electrodiagnostic (EDX) studies when indicated. Magnetic resonance imaging (MRI) of the affected regions, along with nerve and muscle biopsies were obtained in select patients to better elucidate the underlying diagnosis. RESULTS:We found fourteen out of twenty-five patients with prolonged hospitalization for COVID-19 infection to have peripheral neurological complications, identified as plexopathies, peripheral neuropathies and entrapment neuropathies. The other eleven patients were not found to have peripheral neurologic causes for their symptoms. Patients with peripheral neurological complications often exhibited more than one type of concurrently. Specifically, there were four cases of plexopathies, nine cases of entrapment neuropathies, and six cases of peripheral neuropathies, which included cranial neuropathy, sciatic neuropathy, and multiple mononeuropathies. CONCLUSIONS:We explore the possibility that the idiopathic peripheral neurologic complications could be manifestations of the COVID-19 disease spectrum, possibly resulting from micro-thrombotic induced nerve ischemia.

The World Trade Center Environmental Health Center (WTC EHC), is a federally designated clinical center of excellence for surveillance and treatment of WTC disaster exposed community members (WTC Survivors). Cognitive impairment (CI) has been extensively described in WTC responders and a concern for progressive impairment in all WTC disaster exposed groups has been raised. Cognitive status, however, has not been systematically characterized in the WTC Survivor population. We describe cognitive status in a subgroup of the Survivor population referred for mental health evaluation (N = 480) in the WTC EHC as measured by scores on the Montreal Cognitive Assessment (MoCA) instrument, and examine their association with WTC exposures and individual-level covariates including PTSD and depression screening inventory scores. In regression analyses, probable cognitive impairment (MoCA score < 26) was found in 59% of the study subjects and was significantly associated with age, race/ethnicity, education, income, depression and PTSD scores. Being caught in the dust cloud on 11 September 2011 was significantly associated with cognitive impairment even after controlling for the above. These data suggest an association with cognitive dysfunction in WTC Survivors with exposure to the toxic dust/fumes and psychological stress from the 9/11 terrorist attack and warrant further systematic study.