Biomarkers
Our researchers use multiple modalities to model brain trajectories from normal aging to dementia with an important focus on the discovery of biofluid biomarkers of diseases to set up the clinical trials of the future in Alzheimer's disease and other neurodegenerative disorders. They aim to close the gap between discovery science and clinical intervention by developing tools that allow better risk stratification, early detection, and impactful clinical interventions. Studies underway are investigating the full spectrum of pathologies and syndromes including Alzheimer's disease, genetic vascular neurodegeneration (CADASIL), frontotemporal degeneration, and Lewy body disorders. These studies are enabling the discovery of disease signatures using biological samples, imaging techniques, clinical phenotypes, and advanced analytical methods, including artificial intelligence and machine learning.

Drug Discovery and Therapeutic Interventions
At the Icahn School of Medicine at Mount Sinai, we are developing therapeutic strategies targeting the removal of senescent microglia to foster neuroprotection during aging and to arrest the progression of neurodegenerative diseases. Clinical trials are being conducted to investigate the efficacy of an AbO-neutralizing peptide and an amyloid precursor protein small interfering oligonucleotide in treating Alzheimer's disease and cerebral amyloid angiopathy. Efforts are also being made to identify potential preventative and therapeutic interventions that target multiple disease mechanisms simultaneously to increase the likelihood of clinical success.

Genetics
Our researchers are at the forefront of investigating the genetic underpinnings of Alzheimer's disease and related dementias. The Department is actively involved in a multi-center "family-based study" that aims to unravel the genetic and other mechanisms affecting families with a history of these conditions. A key initiative in this area is the National Institute on Aging- Alzheimer's Disease Family Based Study (NIA-AD FBS). This comprehensive study seeks to identify risk factors associated with the development of Alzheimer's disease and related dementias through the collection of data and genotyping of participating families. The NIA-AD FBS focuses on identifying, evaluating, and following individuals with Alzheimer's disease and other dementias, as well as both affected and unaffected family members.

Specifically, the study targets families with a history of Alzheimer's disease and related dementias, particularly those diagnosed by specialists such as neurologists or gerontologists. Participants contribute to this vital research by providing blood samples, medical records, and detailed family history information. Some participants may also undergo clinical examinations by neurologists and brief neuropsychological testing to evaluate memory and cognitive skills.

The information gathered from this study is instrumental in helping researchers identify genetic factors that contribute to these diseases. By focusing on family-based studies, our researchers aim to uncover inherited genetic variations that may increase susceptibility to Alzheimer's disease and related dementias, potentially leading to new avenues for early detection, prevention, and treatment strategies.

Molecular Mechanisms and Pathology
Our faculty is investigating the role of autophagy in microglia and its impact on cellular senescence and neurodegeneration. They aim to elucidate the neuroprotective mechanisms conferred by autophagy and understand how dysfunctional autophagy contributes to the pathogenesis of Alzheimer's and Parkinson's diseases. We are also focusing on understanding the molecular mechanisms underlying Alzheimer's disease, including the propagation of pathological tau through interconnected neural networks, the heterogeneous clinical presentation and progression of the disease, and the vulnerability of excitatory neurons to tau pathology in susceptible brain regions. Single nucleus RNA-sequencing is being utilized to study primary supranuclear palsy, a primary tauopathy disorder, to gain insights into its molecular mechanisms.

Additionally, our researchers are investigating the role of the major glutamate transporter EAAT2 deficiency and the major Alzheimer's disease genetic risk factor APOE e4 in relation to tau biology and blood-brain barrier disruption. Efforts are also being made to dissect the pathogenic mechanisms underlying the onset and progression of Alzheimer's disease and depression, with the goal of identifying potential preventative and therapeutic interventions targeting these mechanisms.

Mouse Models and Novel Mice
Significant contributions have been made at the Icahn School of Medicine at Mount Sinai in the development and characterization of novel mouse models for Alzheimer's disease research. These include the Dutch APP^E693Q mouse, which demonstrates that amyloid beta oligomers are sufficient to cause behavioral deficits in the absence of plaques, fibrils, synthetic peptides, or intracerebral injections. Our team has also created mice expressing an unusual Familial Alzheimer's Disease (FAD) mutant presenilin 1, a mutation in the PSEN1 gene, as well as mice modeling deficiency in the SORCS1 type 2 diabetes gene, and mice deficient in or overexpressing microglial molecules in the TREM2/DAP12 (TYROBP) pathway. These models have been instrumental in advancing our understanding of the molecular mechanisms underlying Alzheimer's disease. Collaborations with computational neuroscientists for multi-omics analysis have enabled the characterization of these novel mouse models and the study of the potential role of infectious agents in Alzheimer's disease.

Researchers working on Alzheimer’s disease and other cognitive disorders include:

• Michelle Ehrlich, MD
• Fanny Elahi, MD, PhD
• Samuel Gandy, MD, PhD
• Alison Goate, DPhil
• Trey Hedden III, PhD
• Estevana Isaac, MD
• Monica Rivera Mindt, PhD
• Georges Naasan, MD
• Ana Pereira, MD
• Jun Wang, PhD
• Zhenyu Yue, PhD

The Department’s researchers are actively investigating the role of the autonomic nervous system in regulating immune function and its potential implications for individuals living with HIV. They aim to elucidate the pathways connecting autonomic dysfunction to inflammation in people living with HIV compared to those without the condition. Prior research has indicated that vagal dysfunction is associated with small intestinal bacterial overgrowth and signs of inflammation in the blood of HIV-positive individuals. The research focuses on the gastrointestinal tract as a key site of interest in this context. Additionally, we are exploring potential therapeutic interventions, such as the use of pyridostigmine, a drug that can increase levels of acetylcholine, the neurotransmitter of the vagus nerve, and non-invasive vagal nerve stimulation, to determine if these approaches can provide beneficial effects for individuals living with HIV and experiencing autonomic dysfunction-related inflammation.

We are also studying whether the autonomic nervous system plays a role in the transition from episodic pain conditions, such as migraine, to chronic pain conditions, which have a tremendous impact on patients’ daily lives. As part of this work, we seek to understand how wearable devices can provide insights into autonomic dysfunction remotely.

Autonomic disorder researchers include:

• Bridget Mueller, MD, PhD
• Jessica Robinson-Papp, MD, MS

An interesting electroencephalogram (EEG) pattern called Brief Ictal Rhythmic Discharges (BIRDs) in both critically ill and non-critically ill adults has been identified and is a key focus area for our epilepsy researchers. In critically ill adults, BIRDs correlated with high seizure risk, worse functional outcomes, and higher acute brain injury risk. In non-critically ill adults, all patients with BIRDs had epilepsy, which was more likely to be drug-resistant, and scalp EEG seizure onsets co-localized to BIRDs. This pattern has been suggested as a scalp EEG biomarker for seizure activity and seizure onset zone, providing valuable insights for diagnosis and treatment.

As part of our work with the Mount Sinai Epilepsy Center, our researchers are developing a seizure prediction machine learning algorithm capable of detecting a hidden interval of time, called the "pre-seizure" period, approximately 10 minutes before a seizure is detectable by scalp or intracranial EEGs. Preliminary analysis has shown that deep learning algorithms can detect surface-negative seizures that are not electrographically visible on scalp EEG but are visible intracranially. The goal is to develop an algorithm that can be used to design wearable devices, such as watches or headbands, that may trigger a warning ahead of a seizure and enable people with epilepsy to move to safe areas before a seizure episode and/or take emergency medication, thus reducing their risk of trauma from falls or accidents and improving their overall quality of life.

Our team is conducting a proof-of-concept study to investigate the safety, efficacy, and clinical usability of a sub-anesthetic dose of IV Racemic Ketamine in the treatment of drug-resistant epilepsy in an outpatient setting. Anesthetic doses of ketamine have been successfully used in treating patients with refractory and super-refractory status epilepticus, with less significant adverse events. The research leverages the sustained anti-depressant effect seen in patients with treatment-resistant depression who received repeated ketamine infusions. The study expects a similar sustained effect with a 50 percent seizure reduction in seizure frequency 28 days post-infusion, potentially leading to reduced medication requirements over time. This is significant for a population that has already failed high doses of two or more anti-seizure medications and typically has their medications increased over time. An additional benefit is the potential for fewer adverse events with possible reduced dosing, as there is currently no anti-seizure medication with a similar mechanism of action available to epilepsy patients.

Epilepsy researchers include:

• Leah Blank, MD, MPH
• Madeline Fields, MD
• Lara Marcuse, MD
• James Young, MD, PhD
• Ji Yeoun (Jenna) Yoo, MD

Researchers at the Icahn School are part of the Early Phase Pain Investigation Clinical Network (EPPIC-Net), a consortium of centers dedicated to accelerating the development of non-addictive treatments for pain. As a site in this consortium, Mount Sinai offers patients the opportunity to participate in clinical trials aimed at finding innovative solutions for pain management. Within EPPIC-Net, researchers are leading a multicenter clinical trial of a new therapeutic targeting pain associated with diabetic peripheral neuropathy, focusing on understanding the underlying mechanisms and developing effective treatments for this debilitating condition.

We are working to understand the causes of medically unexplained pain and fatigue, which are associated with illnesses such as chronic fatigue syndrome (CFS), fibromyalgia, and long COVID. One study aims to understand the relationship between effort and the development of post-exertional malaise, a common symptom in CFS and long COVID, by monitoring symptoms over time and determining how symptom worsening relates to physical exertion through the use of two cardiac stress tests performed a day apart. Another study focuses on determining if brain imaging in patients with long COVID severe enough to fulfill criteria for CFS differs from CFS patients whose illness was not related to COVID infection.

Researchers are also collecting spinal fluid from chronic fatigue syndrome patients to further their work in identifying biomarkers that can aid in the diagnosis of CFS. Additionally, they are initiating a trial of non-invasive vagus nerve stimulation in long COVID patients who meet the criteria for CFS, with the goal of determining if this treatment can improve the health-related quality of life for these patients.

Improving palliative care delivery for patients with primary malignant brain tumors, with the long-term goal of enhancing the quality of life for both patients and their families is another research focus within the Department. Using quantitative and qualitative methods, our team has identified gaps in care and barriers to palliative care delivery for this population. The ultimate goal is to conduct clinical trials of palliative care interventions, including both primary palliative care delivered by neuro-oncology teams with disease-specific expertise and close relationships with patients, and specialty palliative care delivered by interdisciplinary teams with advanced training in the field.

Researchers at the David S. and Ruth L. Gottesman Center for Headache Treatment and Translational Research recognize that a migraine is more than just a headache. Non-painful symptoms, including fatigue, memory disturbances, and changes in mood, are common, especially in patients with frequent migraines. Current projects at the headache center focus on determining the role of the autonomic nervous system and the hypothalamic-pituitary-gonadal axis in migraine pathophysiology. Through this work, we aim to accelerate the development of precision medicine-based treatment approaches that alleviate both the painful and non-painful symptoms of this debilitating illness.

Headache, pain, chronic fatigue, and palliative care researchers include:

• Rita (Caroline) Crooms, MD, MPH
• Mohamed Waleed Elshorafa, MD
• Jasmin Jean, MD, MPH
• Bridget Mueller, MD, PhD
• Benjamin Natelson, MD
• Jessica Robinson-Papp, MD, MS

Health technologies, e-health, and big data have an ever-expanding role in facilitating the collection of patient-reported outcomes and the implementation of knowledge into practice. Knowledge translation research is aligned with the triple aim of improving the patient experience, improving population health, and reducing health care costs. Our researchers are evaluating the effect of health care processes and interventions on the health of individuals and populations, as well as pioneering new approaches to fill the knowledge-to-action gap at all levels of neurological care. We are working to address a broad range of patient-related outcomes, ensure that patients are correctly diagnosed using the best and most accurate technologies, that they are referred in a timely manner, and that they receive evidence-based, cost-effective treatment and quality of care.

Health outcomes and knowledge translation researchers include:

• Leah Blank, MD, MPH
• Benjamin Kummer, MD
• Laura Stein, MD, MPH

Within the Department of Neurology at the Icahn School of Medicine at Mount Sinai, our researchers are focused on predicting clinically impactful outcomes, disease phenotyping, and accelerating diagnosis in time-sensitive neurological conditions using artificial intelligence (AI) and machine learning techniques. Notable projects include using computer vision to diagnose neurological spells, deep learning to accelerate the diagnosis of perfusion abnormalities in acute stroke, AI to detect the presence of cerebrovascular disease in acute stroke activations, and physical activity monitoring to phenotype post-stroke outcomes.

In addition to AI and machine learning applications, we are evaluating the health service impacts of asynchronous teleneurology, such as eConsults and remote physiologic/activity monitoring. By studying the effectiveness and efficiency of these telemedicine solutions, we aim to identify ways to improve access to specialized neurological care, particularly for patients in underserved areas or those with mobility limitations.

Health Services and Neuro-Informatics researchers include:

• Benjamin Kummer, MD

Our team of researchers are focused on understanding the development of cognitive and psychological difficulties in adults by combining neuropsychological assessments with MRI measures of brain structure and function. The research goals encompass three main areas: 1) investigating the neural, neuropsychological, and behavioral correlates of various types of stress, such as childhood adversity, chronic stress, and social discrimination, in adults; 2) identifying the neural mechanisms responsible for HIV-related neuropsychological impairments; and 3) revealing the neural mechanisms through which childhood adversity contributes to increased neurocognitive and neuropsychiatric symptoms in adults living with HIV.

Neuroanatomy and neuroimaging researchers in the Department are also employing a multimodal approach to investigate the relationship between brain function and cognition in aging and neurodegenerative disease. By integrating multiple brain markers from neuroimaging, including PET markers of amyloid, tau accumulation, and dopamine transmission, alongside cognitive testing, researchers aim to identify potential preclinical Alzheimer's-related neuropathology in otherwise normal older individuals. The integration of various neuroimaging modalities and cognitive assessments enables researchers to uncover the complex interplay between brain pathology, neurotransmitter systems, and cognitive performance, ultimately leading to a better understanding of the early stages of neurodegenerative processes and the development of targeted interventions to maintain cognitive health in aging populations.

Neuroanatomy and neuroimaging researchers include:

• Uraina Clark, PhD
• Trey Hedden III, PhD

At the Icahn School, neurocritical care researchers evaluate novel strategies for managing patients with severe acute brain injuries (SABI), such as acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and status epilepticus. Current trials aim to identify and validate new interventions and management strategies to improve outcomes for patients with SABI. Researchers are also leveraging innovative technologies to provide compassionate care from triage to recovery for SABI, creating a strong partnership between academics and industry. They have launched trials to evaluate smart ambulances for interhospital transfers to make transfers for stroke patients safer and more efficient and assess a novel non-invasive monitor to objectively evaluate delirium and depth of sedation.

Neurology faculty have also collaborated with the Department of Artificial Intelligence (AI) to develop and validate an AI-based algorithm for predicting raised intracranial pressure using various physiological waveforms. These innovative approaches seek to improve patient care and outcomes by creating a more supportive and personalized environment in the ICU and harnessing the power of AI to predict and manage critical neurological conditions.

Neurocritical care researchers include:

• Neha Dangayach, MD

Our team of researchers is conducting observational and longitudinal studies of nervous system disorders in people with HIV (PWH). They maintain the largest multidisciplinary neuroHIV cohort in New York City and have the largest brain donation program/research resource in the United States for PWH. These studies focus on elucidating the pathogenesis of brain disorders caused by HIV and its comorbidities, such as substance use disorders, metabolic diseases, and the effects of therapy. We also study the effects of HIV on the autonomic nervous system and chronic pain disorders in PWH. By leveraging these unique research resources and collaborations, investigators aim to gain a comprehensive understanding of the complex interplay between HIV, comorbidities, and nervous system disorders.

Neuro-infectious disease researchers are also examining the impact of immune reconstitution inflammatory syndrome on the brain in individuals with HIV. Immune reconstitution inflammatory syndrome is a condition that can occur in some people with HIV after starting antiretroviral therapy, characterized by a paradoxical worsening of preexisting infections or the emergence of new symptoms. This research aims to elucidate the pathogenesis of immune reconstitution inflammatory syndrome in the central nervous system and to identify potential predictors and management strategies for this condition.

Neuro-infectious disease researchers include:

• Uraina Clark, PhD
• Monica Rivera Mindt, PhD
• Susan Morgello, MD
• Allison Navis, MD
• Jessica Robinson-Papp, MD, MS

Our neuro-ophthalmology researchers are leading major multisite NORDIC trials, including the first study to establish therapy and management guidelines for idiopathic intracranial hypertension. Additionally, we are conducting the first trial on acute neuroprotection for optic nerve injury, potentially revolutionizing treatment approaches for this condition.

Our team is pioneering new research in optical imaging of the optic nerve in intracranial hypertension, ischemic optic nerve injury, and optic neuritis. We are employing deep learning approaches to analyze imaging of swollen optic nerves, pushing the boundaries of diagnostic capabilities. Researchers have also expanded research into artificial intelligence for analyzing visual fields, fundus photos, and optical coherence evaluations of conditions causing optic nerve head swelling.

Our neuro-ophthalmology researchers are an integral part of the new Clinical Neuroscience Informatics and Innovation Center, an initiative aimed at expanding the use of AI for clinical neurological disorders. Through NIH and foundation grants, our researchers are working to determine risk factors and identify changes that reflect outcomes and potential therapies in various neuro-ophthalmic conditions.

Investigators are working to improve conscious control over movement of neurologically weakened parts of the body. Using interventions such as electrical spinal stimulation, magnetic brain stimulation, targeted physical exercises, new uses for old drugs, and more, researchers improve the quality of life for people with spinal cord injury and amyotrophic lateral sclerosis.

Spinal cord injury researchers are also studying neural repair after spinal cord and nerve root injuries, with a special interest in reversing neurological impairments after cauda equina and conus medullaris forms of spinal cord injury. They apply regenerative medicine tools and approaches, including intramedullary transplantation of human neural stem cells to replace degenerating motor and autonomic neurons after spinal cord injury in experimental models.

A team of researchers are evaluating novel biomarker candidates for improved predictions of vital signs using artificial intelligence/machine learning strategies in translational research and clinical studies of autonomic dysregulation after spinal cord injury. They are also performing high-resolution imaging studies, including transmission electron microscopy, for comprehensive mapping of peripheral nervous system projectomes to guide refinement of clinical neuromodulation strategies.

Additionally, they are developing novel tools to refine and automate ultrastructural studies of nerve fibers and facilitate predictions of their nerve conduction and recruitment properties by incorporating non-trivial mathematics to establish correlations between nerve fiber ultrastructure and function.

Spinal cord injury researchers include:

• Noam Harel, MD, PhD
• Leif Havton, MD, PhD

Neurology faculty are investigating treatments and therapies for Mal de Débarquement Syndrome, a chronic and debilitating balance disorder characterized by a persistent false sensation of non-spinning self-motion, such as rocking, swaying, bobbing, or being pulled in a particular direction. Additional research efforts center on improving the diagnosis and development of treatment for neurological disorders manifesting with dizziness and imbalance. Researchers have completed two clinical trials, one on treatment in vestibular migraine and the other on improving the diagnostic accuracy of acute dizziness. These studies aim to enhance the management and outcomes for patients experiencing these debilitating symptoms. Researchers are planning additional clinical trials to disseminate and implement protocols to improve the diagnosis and optimize the management of dizziness and imbalance, ensuring that evidence-based approaches are widely adopted in clinical practice.

In addition to clinical trials, researchers continue to investigate genetic defects underlying rare undiagnosed disorders manifesting with dizziness and imbalance. By identifying the genetic basis of these conditions, researchers aim to develop targeted therapies and improve diagnostic accuracy for patients with these challenging and often overlooked disorders.

Researchers working on neuro-ophthalmology and vestibular disorders include:

• Joanna Jen, MD, PhD
• Mark Kupersmith, MD
• Sergei Yakushin, PhD