Medicine and Health Sciences Commons^™

Genome-Wide Mega-Analysis Identifies 16 Loci And Highlights Diverse Biological Mechanisms In The Common Epilepsies., Bassel Abou-Khalil, Pauls Auce, Andreja Avbersek, Melanie Bahlo, David J. Balding, Thomas Bast, Larry Baum, Albert J. Becker, Felicitas Becker, Bianca Berghuis, Samuel F. Berkovic, Katja E. Boysen, Jonathan P. Bradfield, Lawrence C. Brody, Russell J. Buono, Ellen Campbell, Gregory D. Cascino, Claudia B. Catarino, Gianpiero L. Cavalleri, Stacey S. Cherny, Krishna Chinthapalli, Alison J. Coffey, Alastair Compston, Antonietta Coppola, Patrick Cossette, John J. Craig, Gerrit-Jan De Haan, Peter De Jonghe, Carolien G.F. De Kovel, Norman Delanty, Chantal Depondt, Orrin Devinsky, Dennis J. Dlugos, Colin P. Doherty, Christian E. Elger, Johan G. Eriksson, Thomas N. Ferraro, Martha Feuch, Ben Francis, Andre Franke, Jacqueline A. French, Saskia Freytag, Verena Gaus, Eric B. Geller, Christian Gieger, Tracy Glauser, Simon Glynn, David B. Goldstein, Hongsheng Gui, Youling Guo, Kevin F. Haas, Hakon Hakonarson, Kerstin Hallmann, Sheryl Haut, Erin L. Heinzen, Ingo Helbig, Christian Hengsbach, Helle Hjalgrim, Michele Iacomino, Andrés Ingason, Jennifer Jamnadas-Khoda, Michael R. Johnson, Reetta Kälviäinen, Anne-Mari Kantanen, Dalia Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Heidi E. Kirsch, Robert C. Knowlton, Bobby P.C. Koeleman, Roland Krause, Martin Krenn, Wolfram S. Kunz, Ruben Kuzniecky, Patrick Kwan, Dennis Lal, Yu-Lung Lau, Anna-Elina Lehesjoki, Holger Lerche, Costin Leu, Wolfgang Lieb, Dick Lindhout, Warren D. Lo, Iscia Lopes-Cendes, Daniel H. Lowenstein, Alberto Malovini, Anthony G. Marson, Thomas Mayer, Mark Mccormack, James L. Mills, Nasir Mirza, Martina Moerzinger, Rikke S. Møller, Anne M. Molloy, Hiltrud Muhle, Mark Newton, Ping-Wing Ng, Markus M. Nöthen, Peter Nürnberg, Terence J. O’Brien, Karen L. Oliver, Palotie Palotie, Faith Pangilinan, Sarah Peter, Slavé Petrovski, Annapurna Poduri, Michael Privitera, Rodney Radtke, Sarah Rau, Philipp S. Reif, Eva M. Reinthaler, Felix Rosenow, Josemir W. Sander, Thomas Sander, Theresa Scattergood, Steven C. Schachter, Christoph J. Schankin, Ingrid E. Scheffer, Bettina Schmitz, Susanne Schoch, Pak C. Sham, Jerry J. Shih, Graeme J. Sills, Sanjay M. Sisodiya, Lisa Slattery, Alexander Smith, David F. Smith, Michael C. Smith, Philip E. Smith, Anja C.M. Sonsma, Doug Speed, Michael R. Sperling, Bernhard J. Steinhoff, Ulrich Stephani, Remi Stevelink, Konstantin Strauch, Pasquale Striano, Hans Stroink, Rainer Surges, K. Meng Tan, Liu Lin Thio, G. Neil Thomas, Marian Todaro, Rossana Tozzi, Maria S. Vari, Ellen P.G. Vining, Frank Visscher, Sarah Von Spiczak, Nicole M. Walley, Yvonne G. Weber, Zhi Wei, Judith Weisenberg, Christopher D. Whelan, Peter Widdess-Walsh, Markus Wolff, Wolking Wolking, Wanling Yang, Federico Zara, Fritz Zimprich

Department of Neurology Faculty Papers

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the …

Triggers, Protectors, And Predictors In Episodic Migraine., Michael J. Marmura

Department of Neurology Faculty Papers

PURPOSE OF REVIEW: A wide variety of triggers prompt attacks in episodic migraine. Although experimental triggers such as glyceryl trinitrate reliably produce migraine, natural triggers are much less predictable and vary in importance between individuals. This review describes the most common triggers in episodic migraine and provides strategies for managing them in clinical practice.

RECENT FINDINGS: Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned. Clinical studies have verified that fasting, premenstrual periods in …

Medial Temporal Lobe Functional Connectivity Predicts Stimulation-Induced Theta Power., E. A. Solomon, J. E. Kragel, R. Gross, B. Lega, M. R. Sperling, G. Worrell, S. A. Sheth, K. A. Zaghloul, B. C. Jobst, J. M. Stein, S. Das, R. Gorniak, C. S. Inman, S. Seger, D. S. Rizzuto, M. J. Kahana

Department of Neurology Faculty Papers

Focal electrical stimulation of the brain incites a cascade of neural activity that propagates from the stimulated region to both nearby and remote areas, offering the potential to control the activity of brain networks. Understanding how exogenous electrical signals perturb such networks in humans is key to its clinical translation. To investigate this, we applied electrical stimulation to subregions of the medial temporal lobe in 26 neurosurgical patients fitted with indwelling electrodes. Networks of low-frequency (5-13 Hz) spectral coherence predicted stimulation-evoked increases in theta (5-8 Hz) power, particularly when stimulation was applied in or adjacent to white matter. Stimulation tended …

Distinct Role Of Il-27 In Immature And Lps-Induced Mature Dendritic Cell-Mediated Development Of Cd4, Fang Zhou, Guang-Xian Zhang, A. M. Rostami

Department of Neurology Faculty Papers

Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4⁺ T cell-mediated immune responses have not yet been elucidated. Here we show that IL-27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS-stimulated DCs. IL-27 treatment facilitates development of the CD4⁺ CD127⁺3G11⁺ regulatory T cell subset …

Therapeutic Effect Of Rho Kinase Inhibitor Fsd-C10 In A Mouse Model Of Alzheimer's Disease., Qing-Fang Gu, Jie-Zhong Yu, Hao Wu, Yan-Hua Li, Chun-Yun Liu, Ling Feng, Guang-Xian Zhang, Bao-Guo Xiao, Cun-Gen Ma

Department of Neurology Faculty Papers

Fasudil, a Rho kinase (ROCK) inhibitor, effectively inhibits disease severity in a mouse model of Alzheimer's disease (AD). However, given its significant limitations, including a relatively narrow safety window and poor oral bioavailability, Fasudil is not suitable for long-term use. Thus, screening for ROCK inhibitor(s) that are more efficient, safer, can be used orally and suitable for long-term use in the treatment of neurodegenerative disorders is required. The main purpose of the present study is to explore whether FSD-C10, a novel ROCK inhibitor, has therapeutic potential in amyloid precursor protein/presenilin-1 transgenic (APP/PS1 Tg) mice, and to determine possible mechanisms of …

Bath-Related Headache, Aliza Kumpinsky, Stephanie J. Nahas

Department of Neurology Faculty Papers

PURPOSE OF REVIEW: The purpose of this review is to summarize the most up-to-date literature on bath-related headache, a rare disorder.

RECENT FINDINGS: Initially described in middle-aged Asian women, it is now reported in a wider demographic. More information is available about the pathophysiology of bath-related headache, including its classification as a subtype of reversible cerebral vasoconstriction syndrome (RCVS). Nimodipine can be effective in patients both with and without vasospasm. Bath-related headache is a rare form of thunderclap headache. Although its mechanism is still unclear, it is associated with vasospasm and RCVS. Controlled trials investigating the use of nimodipine and …

Neurological Complications Of Immune Checkpoint Inhibitors: What Happens When You 'Take The Brakes Off' The Immune System., Marinos Dalakas

Department of Neurology Faculty Papers

Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2-12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events …

Hypoglycemic, Hypolipidemic And Antioxidant Effects Of Iridoid Glycosides Extracted From: Corni Fructus: Possible Involvement Of The Pi3k-Akt/Pkb Signaling Pathway, Jiefang Kang, Chen Guo, Rodolfo Thome, Ning Yang, Yuan Zhang, Xing Li, Xiaoyan Cao

Department of Neurology Faculty Papers

Iridoid glycosides (CIG) are the major component of Corni fructus. In this work, we researched the antioxidative, hypoglycemic and lowering blood lipids effects of CIG on diabetic mice induced by a high-fat diet (HFD) and streptozotocin (STZ). Furthermore, to investigate the molecular mechanism of action, the phosphorylation and protein expression of phosphoinositide 3-kinase (PI3K) and its downstream proteins, such as insulin receptor (INSR), protein kinase B (Akt/PKB) and glucose transporter 4 (GLUT4) have been detected. The results showed that CIG significantly improved oral glucose tolerance in diabetic mice. Biochemical indices also revealed that CIG had a positive effect on lipid …

Carnosol Modulates Th17 Cell Differentiation And Microglial Switch In Experimental Autoimmune Encephalomyelitis, Xing Li, Li Zhao, Juan-Juan Han, Fei Zhang, Shuai Liu, Lin Zhu, Zhe-Zhi Wang, Guang-Xian Zhang, Yuan Zhang

Department of Neurology Faculty Papers

Medicinal plants as a rich pool for developing novel small molecule therapeutic medicine have been used for thousands of years. Carnosol as a bioactive diterpene compound originated from Rosmarinus officinalis (Rosemary) and Salvia officinalis, herbs extensively applied in traditional medicine for the treatment of multiple autoimmune diseases (1). In this study, we investigated the therapeutic effects and molecule mechanism of carnosol in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Carnosol treatment significantly alleviated clinical development in the myelin oligodendrocyte glycoprotein (MOG35–55) peptide-induced EAE model, markedly decreased inflammatory cell infiltration into the central nervous system and reduced …

Enhanced Co-Registration Methods To Improve Intracranial Electrode Contact Localization., Walter A. Hinds, Amrit Misra, Michael R. Sperling, Ashwini Sharan, Joseph I. Tracy, Karen A. Moxon

Department of Neurology Faculty Papers

Background: Electrode contact locations are important when planning tailored brain surgeries to identify pathological tissue targeted for resection and conversely avoid eloquent tissue. Current methods employ trained experts to use neuroimaging scans that are manually co-registered and localize contacts within ~2 mm. Yet, the state of the art is limited by either the expertise needed for each type of intracranial electrode or the inter-modality co-registration which increases error, reducing accuracy. Patients often have a variety of strips, grids and depths implanted; therefore, it is cumbersome and time-consuming to apply separate localization methods for each type of electrode, requiring expertise across …

Fasudil In Combination With Bone Marrow Stromal Cells (Bmscs) Attenuates Alzheimer's Disease-Related Changes Through The Regulation Of The Peripheral Immune System., Jiezhong Yu, Yuqing Yan, Qingfang Gu, Gajendra Kumar, Hongqiang Yu, Yijin Zhao, Chunyun Liu, Ye Gao, Zhi Chai, Jasleen Chumber, Bao-Guo Xiao, Guang-Xian Zhang, Han-Ting Zhang, Yuqiang Jiang, Cun-Gen Ma

Department of Neurology Faculty Papers

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)-homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 10

Enzyme Replacement Therapies: What Is The Best Option?, Azam Safary, Mostafa Akbarzadeh Khiavi, Rahimeh Mousavi, Jaleh Barar, Mohammad Rafi

Department of Neurology Faculty Papers

Despite many beneficial outcomes of the conventional enzyme replacement therapy (ERT), several limitations such as the high-cost of the treatment and various inadvertent side effects including the occurrence of an immunological response against the infused enzyme and development of resistance to enzymes persist. These issues may limit the desired therapeutic outcomes of a majority of the lysosomal storage diseases (LSDs). Furthermore, the biodistribution of the recombinant enzymes into the target cells within the central nervous system (CNS), bone, cartilage, cornea, and heart still remain unresolved. All these shortcomings necessitate the development of more effective diagnosis and treatment modalities against LSDs. …

Lateralized Hippocampal Oscillations Underlie Distinct Aspects Of Human Spatial Memory And Navigation., Jonathan Miller, Andrew J. Watrous, Melina Tsitsiklis, Sang Ah Lee, Sameer A. Sheth, Catherine A. Schevon, Elliot H. Smith, Michael R. Sperling, Ashwini Sharan, Ali Akbar Asadi-Pooya, Gregory A. Worrell, Stephen Meisenhelter, Cory S. Inman, Kathryn A. Davis, Bradley Lega, Paul A. Wanda, Sandhitsu R. Das, Joel M. Stein, Richard Gorniak, Joshua Jacobs

Department of Neurology Faculty Papers

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1-3-Hz "low theta" band increases when viewing subsequently remembered object-location pairs. In contrast, in …

Stroke Severity Affects Timing: Time From Stroke Code Activation To Initial Imaging Is Longer In Patients With Milder Strokes., Kimberly T. Kwei, John W. Liang, Natalie Wilson, Stanley Tuhrim, Mandip Dhamoon

Department of Neurology Faculty Papers

Optimizing the time it takes to get a potential stroke patient to imaging is essential in a rapid stroke response. At our hospital, door-to-imaging time is comprised of 2 time periods: the time before a stroke is recognized, followed by the period after the stroke code is called during which the stroke team assesses and brings the patient to the computed tomography scanner. To control for delays due to triage, we isolated the time period after a potential stroke has been recognized, as few studies have examined the biases of stroke code responders. This "code-to-imaging time" (CIT) encompassed the time …

Efficacy And Safety Of Eslicarbazepine Acetate Monotherapy In Patients Converting From Carbamazepine., Ladislav Pazdera, Michael R. Sperling, Jay H. Harvey, Maria C. Sam, Laura A. Strom, David Blum, Todd Grinnell, Hailong Cheng

Department of Neurology Faculty Papers

OBJECTIVE: To evaluate the influence of prior use of carbamazepine (CBZ) and other antiepileptic drugs (AEDs) with a putatively similar mechanism of action (inhibition of voltage-gated sodium channels; VGSCs) on seizure outcomes and tolerability when converting to eslicarbazepine acetate (ESL), using data pooled from 2 controlled conversion-to-ESL monotherapy trials (studies: 093-045, 093-046).

METHODS: Adults with treatment-resistant focal (partial-onset) seizures were randomized 2:1 to ESL 1600 or 1200 mg once daily. The primary efficacy endpoint was study exit (meeting predefined exit criteria related to worsening seizure control) versus an historical control group. Other endpoints included change in seizure frequency, responder rate, …

Effects Of Adjunctive Eslicarbazepine Acetate On Serum Lipids In Patients With Partial-Onset Seizures: Impact Of Concomitant Statins And Enzyme-Inducing Antiepileptic Drugs., Scott Mintzer, Robert T. Wechsler, Joanne B. Rogin, Barry E. Gidal, Matthias Schwab, Elinor Ben-Menachem, Mar Carreño, Patrício Soares Da Silva, Joana Moreira, Yan Li, David Blum, Todd Grinnell

Department of Neurology Faculty Papers

PURPOSE: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences.

SUBJECTS AND METHODS: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period.

KEY FINDINGS: In total, 426 and 1021 placebo- and ESL-treated …

Closed-Loop Stimulation Of Temporal Cortex Rescues Functional Networks And Improves Memory., Youssef Ezzyat, Paul A. Wanda, Deborah F. Levy, Allison Kadel, Ada Aka, Isaac Pedisich, Michael R. Sperling, Ashwini Sharan, Bradley C. Lega, Alexis Burks, Robert E. Gross, Cory S. Inman, Barbara C. Jobst, Mark A. Gorenstein, Kathryn A. Davis, Gregory A. Worrell, Michal T. Kucewicz, Joel M. Stein, Richard Gorniak, Sandhitsu R. Das, Daniel S. Rizzuto, Michael J. Kahana

Department of Neurology Faculty Papers

Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target …

Electrical Stimulation Modulates High Γ Activity And Human Memory Performance., Michal T. Kucewicz, Brent M. Berry, Vaclav Kremen, Laura R. Miller, Fatemeh Khadjevand, Youssef Ezzyat, Joel M. Stein, Paul Wanda, Michael R. Sperling, Richard Gorniak, Md, Kathryn A. Davis, Barbara C. Jobst, Robert E. Gross, Bradley Lega, S Matt Stead, Daniel S. Rizzuto, Michael J. Kahana, Gregory A, Worrell

Department of Neurology Faculty Papers

Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We …

Consensus Guidelines For Newborn Screening, Diagnosis And Treatment Of Infantile Krabbe Disease., Jennifer M. Kwon, Dietrich Matern, Joanne Kurtzberg, Lawrence Wrabetz, Michael H. Gelb, David A. Wenger, Can Ficicioglu, Amy T. Waldman, Barbara K. Burton, Patrick V. Hopkins, Joseph J. Orsini

Department of Neurology Faculty Papers

BACKGROUND: Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly …

Advances In The Diagnosis, Immunopathogenesis And Therapies Of Igm-Anti-Mag Antibody-Mediated Neuropathies., Marinos Dalakas

Department of Neurology Faculty Papers

Polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy is the most common paraproteinemic neuropathy, comprising a clinicopathologically and immunologically distinct entity. The clinical spectrum spans from distal paresthesias and mild gait imbalance to more severe sensory ataxia, with falls and a varying degree of distal sensorimotor deficits. In approximately 75% of patients, the monoclonal IgM immunoreacts with myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), or other peripheral nerve glycolipids that serve as antigens. These antibodies are considered pathogenic because IgM and complement are deposited on the myelin sheath, splitting the myelin lamellae, while adoptive transfer of patients' IgM into susceptible host …

Timing Of Vessel Imaging For Suspected Large Vessel Occlusions Does Not Affect Groin Puncture Time In Transfer Patients With Stroke., John W. Liang, Laura Stein, Natalie Wilson, Johanna T. Fifi, Stanley Tuhrim, Mandip S. Dhamoon

Department of Neurology Faculty Papers

BACKGROUND: Access to endovascular therapy (ET) in cases of acute ischemic stroke may be limited, and rapid transfer of eligible patients to hospitals with endovascular capability is needed.

OBJECTIVE: To determine the optimal timing of diagnostic CT angiography to confirm large vessel occlusion (LVO).

METHODS: Of 57 emergency department transfers to Mount Sinai Hospital (MSH) for possible ET from January 2015 through March 2016, 39 (68%) underwent ET, among whom 22 (56%) had CT angiography before transfer and 17 (44%) had CT angiography on arrival. We compared mean outside hospital arrival to groin puncture (OTG) time between the two groups …

Sex Differences In Outcomes After Stroke In Patients With Diabetes In Ontario, Canada., Mandip S. Dhamoon, John W. Liang, Limei Zhou, Melissa Stamplecoski, Moira K. Kapral, Baiju R. Shah

Department of Neurology Faculty Papers

BACKGROUND: Outcomes after stroke in those with diabetes are not well characterized, especially by sex and age. We sought to calculate the sex- and age-specific risk of cardiovascular outcomes after ischemic stroke among those with diabetes.

METHODS: Using population-based demographic and administrative health-care databases in Ontario, Canada, all patients with diabetes hospitalized with index ischemic stroke between April 1, 2002, and March 31, 2012, were followed for death, stroke, and myocardial infarction (MI). The Kaplan-Meier survival analysis and Fine-Gray competing risk models estimated hazards of outcomes by sex and age, unadjusted and adjusted for demographics and vascular risk factors.

RESULTS: …