Rani A. Sarkis

Bio: Rani A. Sarkis is an academic researcher from Brigham and Women's Hospital. The author has contributed to research in topics: Epilepsy & Medicine. The author has an hindex of 17, co-authored 51 publications receiving 826 citations. Previous affiliations of Rani A. Sarkis include Cleveland Clinic & American University of Beirut.

Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease

Abstract: The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.

Association of epileptiform abnormalities and seizures in Alzheimer disease.

Abstract: Objective To examine the relationship between scalp EEG biomarkers of hyperexcitability in Alzheimer disease (AD) and to determine how these electric biomarkers relate to the clinical expression of seizures in AD. Methods In this cross-sectional study, we performed 24-hour ambulatory scalp EEGs on 43 cognitively normal elderly healthy controls (HC), 41 participants with early-stage AD with no history or risk factors for epilepsy (AD-NoEp), and 15 participants with early-stage AD with late-onset epilepsy related to AD (AD-Ep). Two epileptologists blinded to diagnosis visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 9 epileptologists blinded to diagnosis was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG. Results Epileptiform abnormalities were seen in 53% of AD-Ep, 22% of AD-NoEp, and 4.7% of HC. Specific features of epileptiform discharges, including high frequency, robust morphology, right temporal location, and occurrence during wakefulness and REM, were associated with clinical seizures in AD. Multiple EEG biomarkers concordantly demonstrated a pattern of left temporal lobe hyperexcitability in early stages of AD, whereas clinical seizures in AD were often associated with bitemporal hyperexcitability. Frequent small sharp spikes were specifically associated with epileptiform EEGs and thus identified as a potential biomarker of hyperexcitability in AD. Conclusion Epileptiform abnormalities are common in AD but not all equivalent. Specific features of epileptiform discharges are associated with clinical seizures in AD. Given the difficulty recognizing clinical seizures in AD, these EEG features could provide guidance on which patients with AD are at high risk for clinical seizures.

Clinical and Neurophysiologic Characteristics of Unprovoked Seizures in Patients Diagnosed With Dementia

Abstract: Seizures are a common comorbid condition in patients with dementia, but their characteristics have been poorly described. The authors performed a retrospective chart review using ICD-9 diagnosis codes consistent with seizures and with dementia. Seventy-seven patients were identified. Average age at onset was 68.1 years for cognitive symptoms, 71.5 years for dementia, and 73.9 years for seizures. Seizures preceded or followed cognitive symptoms (4.3 years before and 18.7 years after). At last follow-up, 12% of patients continued to have seizures. Findings show that unprovoked seizures can precede or follow the onset of dementia, but these seizures are controlled with medications in the majority of patients.

Motivation and Cognitive Control: From Behavior to Neural Mechanism

Abstract: Research on cognitive control and executive function has long recognized the relevance of motivational factors. Recently, however, the topic has come increasingly to center stage, with a surge of new studies examining the interface of motivation and cognitive control. In the present article we survey research situated at this interface, considering work from cognitive and social psychology and behavioral economics, but with a particular focus on neuroscience research. We organize existing findings into three core areas, considering them in the light of currently vying theoretical perspectives. Based on the accumulated evidence, we advocate for a view of control function that treats it as a domain of reward-based decision making. More broadly, we argue that neuroscientific evidence plays a critical role in understanding the mechanisms by which motivation and cognitive control interact. Opportunities for further cross-fertilization between behavioral and neuroscientific research are highlighted.

Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention.

Abstract: Summary Sudden unexpected death in epilepsy (SUDEP) can affect individuals of any age, but is most common in younger adults (aged 20–45 years). Generalised tonic-clonic seizures are the greatest risk factor for SUDEP; most often, SUDEP occurs after this type of seizure in bed during sleep hours and the person is found in a prone position. SUDEP excludes other forms of seizure-related sudden death that might be mechanistically related (eg, death after single febrile, unprovoked seizures, or status epilepticus). Typically, postictal apnoea and bradycardia progress to asystole and death. A crucial element of SUDEP is brainstem dysfunction, for which postictal generalised EEG suppression might be a biomarker. Dysfunction in serotonin and adenosine signalling systems, as well as genetic disorders affecting cardiac conduction and neuronal excitability, might also contribute. Because generalised tonic-clonic seizures precede most cases of SUDEP, patients must be better educated about prevention. The value of nocturnal monitoring to detect seizures and postictal stimulation is unproven but warrants further study.

An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models.

Abstract: The identification of anti-NMDA receptor (NMDAR) encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.