Neuropathology Division Strategic Plan 2016-2021
Overview
Brown University has made a long-term commitment to the development of neuroscience as an area of excellence. This is embodied in the formation of the multidisciplinary Brown Institute for Brain Science (BIBS), a unique union of the neuroscience, mathematics, engineering, and computer science programs. Lifespan Corporation, Brown University's affiliated hospital network, has also acknowledged its commitment to the development of clinical neuroscience through the establishment of the Norman Prince Neuroscience Institute (NPNI). New chairs have been recruited in neurosurgery, neurology, and psychiatry to further develop this goal in partnership with Brown University. Excellent brainimaging facilities are available on the Brown campusand within its affiliated hospitals. High Res, a state of the art morphometric image analysis facility, has been made available for use by Brown faculty.
Greater emphasisis being placed on the relevance of medical research to human disease by the National Institutes of Health and other external funding agencies. The development of translational medical researchis a major goal of Dr. Elias, the Dean at the Warren Alpert Medical School of Brown University. To facilitate translational research efforts among the faculty, a Dean's Award program for funding collaborations between hospital- and campus-based facultyhas been initiated.
The neuropathology division at Lifespan is in a unique position to spearhead future cellular and moleculartranslational neuroscience efforts at both Lifespan and Brown University by providing neuropathologic confirmation of the clinical diagnosis and by facilitating the optimization of diseased human tissues for use in translational studies.
Strength in Clinical Cellular and Molecular Neuropathology Services
Neurosurgical Service
Four staff neuropathologists provide operating room coverage for frozen sections at Rhode Island Hospital 24/7. We process approximately 500 neurosurgical specimens/year and perform 300 intraoperative consultations. Approximately 30 ophthalmic pathology specimens are included among the specimens received. In addition to providing intraoperative consultation, we also serve as major participants in both the adult and pediatric brain tumor boards responsible for patient treatment decisions.
We are extremely excited about the recent recruitment of Dr. Ziya Gokaslan, the Chief of Neurosurgery and a world expert on the treatment of spinal neoplasms. He plansto recruit a neurosurgeon with a clinical and research interest in brain tumors. Given Dr. Gokaslan's longstanding interest in culturing cells from spinal neoplasms, we have established a protocol for the rapid collection and preservation of both spinal and cerebral tumors. Tumor tissue for cell culture and snap freezing will be obtained from all cases in which there is an excess of tissue and an established diagnosis. This will be done through the existing departmental COBRE Cancer Center tumor bank under the directorship of Dr. Yakirevich. The neuropathology service will continue to play a major role in the collection of tumor tissue for special processing in accordance with specific protocols for clinical trials such as the DCVaxglioblastoma vaccine trial.
We anticipate the need to continue expanding our current testing for tumor molecular markers as new markers become available. In the past last 2-5 years, we have implemented tests for the loss of 1p/19q; methylation of MGMT promoter; IDH-1 mutation analysis; INI-1 loss; p53 index; BRAF mutation, and Ki-67 semi-quantitative proliferation index. Additional tests to consider for development include: EGFR vIII, isochromosome 17p, quantitative Ki-67 proliferation index; a medulloblastoma panel; ATRX;TERT;and H3-K27M.
We have a new director of molecular pathology, Dr. Nimesh Patel, whom we will work closely with to implement additional molecular testing on brain tumors, including brain tumor mutation panels similar to those currently in use for lung and colon carcinomas, as well as TERT promoter status, which has recently been shown to be associated with prognostication in gliomas. This molecular data will be interpreted and presented at all of the brain tumor boards.
Autopsy Service
We serve as neuropathology consultants for nearly all of the hospitals in south-eastern New England. In addition, we provide forensic consultation services for the Rhode Island Medical Examiners' Office and for medical examiners in several other states. Collectively, this amounts to 900 brains per year and includes a diverse mix of perinatal, pediatric, forensic, medical, surgical,and geriatric cases. Our goal is to complete all neuropathology reports in accordance with the College of American Pathology turnaround time guidelines for routine and complex cases. Autopsy tissues will also be processed for utilization in ongoing ophthalmic, neuromuscular,and small fiber neuropathy validation studies.
Neuromuscular Service
We are regional consultants for nerve and muscle biopsy specimens that are performed at the Lifespan Ambulatory Surgical Center and at other surgical centers throughout south-eastern New England. These specimens are often brought in on ice by special courier or retrieved directly from the OR at the time of surgery. They are then specially processed for histochemical enzyme staining, immunohistochemistry, and electron microscopy by our histology tech specialist. Approximately 150 muscle specimens and 20 nerve biopsy specimens are processed annually. We plan to expand our existing dystrophin-associated protein immunohistochemical panel and create separate panels for pediatric vs. adult myopathies. Other stains under consideration for future development include the myoadenylate deaminase stain and the nonspecific esterase stain. Although most molecular analyses are currently being outsourced, new molecular tests will be developed in conjunction with our Lifespan molecular laboratory and implemented in accordance with local demand and standard of care.
Dr. Anthony is in the process of validating novel morphometric techniques for better quantifying normal and diseased nerve and muscle pathology. In addition, Dr. Donahue is setting up and validating a quantitative protocol for assessing small fiber neuropathies on skin biopsies. Plans are underway to determine the best means for advertising and marketing these new morphometric capabilities.
Consultation Services
The Neuropathology Division provides consultation services for institutions across the country. Drs. Donahue and Stopa have served as consultants for the Brain Endowment Bank at the Miller School of Medicine of the University of Miami and have signed out many neurodegenerative disease cases. Dr. Donahue has done consultation forensic neuropathology work for Medical Examiner’s offices in Bergen County, New Jersey;Union County, New Jersey; and Tarrant County, Texas. Dr. Anthony has been a consultant in neuromuscular pathology for many institutions, including the University of South Alabama.
Lifespan/Brown Brain Tissue Resource Center
More than 4 million people in the United States have Alzheimer’s disease (AD). Risk factors include age, apolipoprotein E (APOE) ε4 alleles, head trauma, family history, low education level, and poor language ability. The late-onset sporadic form of AD has been associated with the presence of one or more APOE-ε4 alleles. Early-onset familial AD, comprising roughly 10% of cases, has been associated with 3 different gene mutations, including the amyloid precursor protein gene on chromosome 21, presenilin-1 (PS1) gene on chromosome 14, and the presenilin-2 (PS2) gene on chromosome 1.
The Brown Brain Bank was established at Rhode Island Hospital in 1993 to provide control and Alzheimer tissues to investigators engaged in dementia research at Brown University and numerous other academic institutions. We have organized the collection of control and dementia brains through the enthusiastic participation of the Rhode Island chapter of the Alzheimer's Association. Our primary goal is to establish accurate neuropathologic diagnoses on all brains submitted to the Brown Brain Bank using current and reliable diagnostic criteria. We accomplish this goal by documenting the histopathologic, immunocytochemical, and anatomic findings in all brains submitted for evaluation using the 2012 National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. In 2014, the impact of the Brown Brain Bank in providing quality control assessment of clinical diagnostic accuracy among dementia patients was recognized by Lieutenant Governor Elizabeth Roberts, who included it as an important resource forthe Rhode Island State Plan for Alzheimer's disease. Families that choose to donate are provided with a copy of the final neuropathology report and given the opportunity to discuss the significance of brain examination findings with staff physicians. We have also served as a neuropathology site for national and international Alzheimer clinical trials where patients involved in the trials eventually have their brains harvested and sent for tissue analysis. These include the Alzheimer’s Disease Neuroimaging Initiative (ADNI), GE Healthcare Study GE067-007 (comparing brain uptake of [18F]flutemetamol with brain neuritic plaque density determined postmortem), and Avid 18F-1451-A16 (designed to test the relationship between ante-mortem 18F-AV-1451 Positron Emission Tomography (PET) imaging and tau neurofibrillary pathology associated with Alzheimer's disease (AD), as measured at autopsy.)
Nancy Heath, our neuropathology tech specialist, is currently in the process of creating an electronic database of our inventory and transferring all specimens to improved Tupperware storage containers. Dr. Suzanne de la Monte is in the process of revising and streamlining our frozen tissue collection protocol by harvesting tissues more rapidly using punch biopsies on selected brain regions.
In addition to collecting brain tissues, we have also begun to collect frozen samples of choroid plexus and cerebrospinal fluid (CSF) in order to examine changes in CSF composition during aging and dementia, as well as in a cohort of patients with a history of normal pressure hydrocephalus.
Negotiations are underway with the Chiari and Syringomyelia Foundation to develop a national network for collecting tissues from patients with Ehlers-Danlos Syndrome. This rare syndrome has recently been found to be associated with spinal cord tethering abnormalities for reasons that remain unstudied.
Education Neuropathology Fellowship
The Neuropathology fellowship program at Brown Medical School has three primary goals:
To train career neuropathologists in clinical diagnostic skills through the use of gross, microscopic, and ultrastructural analyses of tissue samples obtained within a hospital setting, which offers a diverse and steady case mix and excellent support services.
To provide research skills by exposure to techniques and methodology that will enable the trainee to qualify, enter, and contribute in research fields or academic medicine.
To encourage dialogue, independent investigation, and interdisciplinary cooperation with other members of the pathology department, the department of clinical neurosciences, and various basic science departments within the medical school in order to create an intellectually stimulating environment.
Current fellowship applicants are individuals who have been previously trained in anatomic pathology, neurology, or neurosurgery. The program accepts one fellow per year from a pool of approximately 5-10 applicants. The American Board of Pathology now requires board eligibility in one of these three disciplines prior to obtaining board certification in neuropathology. The two-year neuropathology fellowship requires competence in a wide variety of diagnostic modalities (light microscopy, electron microscopy, immunohistochemistry etc.), as well as experience in basic research.
We have a strong fellowship with committed faculty and excellent material. We usually have two fellows at one time and are fully committed until 2017. The fellows actively participate in brain tumor, neuromuscular, and autopsy diagnosis. They also assist in preparing specimens for the Brown Brain/Biobank.
Goals include recruiting high-quality applicants to the fellowship program who will successfully pass the neuropathology boardsand have a strong record of scholarly achievement.
We will continue active recruitment for 2017 fellowship opening by advertising in journals and on websites advertising pathology jobs. We will identify strong and motivated medical students and residents who interview and encourage them to do their residency in our program and perform due diligence during interview process.
We will emphasize the importance to current fellows of establishing a “portfolio” of signed-out cases (autopsies and surgicals) and prepared didactic presentations. We will also encourage fellows to give as many didactic presentations as possible, such as during resident conferences.
We will work to improve the scholarly publication record of fellows by requiring a six-month block of time to pursue an area of basic neuroscience research. We will solicit from faculty any active research projects they have ongoing that the fellows might be able to take part in. We will also make fellows aware of opportunities in the Dept. of Neuroscience at Brown University. We will expect the submission of an abstract to the American Association of Neuropathologists (AANP) annual meeting.
Neuropathology Rotators
The neuropathology division has rotators from the pathology, neurology, and neurosurgery residency programs on a regular basis. Fourth-year medical students have also rotated through the division from time to time as part of their pathology elective, and Dr. Donahue is in the process of establishing a new neuropathology elective for either third- or fourth-year students. Rotators participate in the regularly-scheduled neuropathology curriculum, and they receive formal neuropathology syllabi. Fellows from the neurophysiology fellowship in the Dept. of Neurology regularly attend the weekly neuromuscular conference. We have also begun accepting 3rd-year medical students on a weekly longitudinal rotation as part of their neurology/psychiatry experience. Both the staff and fellows are actively involved in the teaching of these rotators.
Goals include giving the best possible educational experience to rotators but reminding them that the amount of effort that they put into the rotation will be directly proportional to the amount of knowledge and satisfaction that they get out of it.
We will obtain the schedule of rotators and distribute syllabi to them. Additional space within the department has been requested for these rotators, who currently share the space occupied by the neuropathology fellows. Rotators will be expected to answer the multiple choice questions in the syllabus to enhance their learning and then review their answers with Dr. Donahue. They are also welcome to come back after the rotation is over to review questions as needed.
We will encourage third-year medical students to restructure their schedules so that they can attend brain cutting conferences on Friday mornings in addition to attending sign-out in the afternoon once a week.
Neuropathology Conferences
In addition to the daily sign-out of neurosurgical cases, our division is responsible for formal multidisciplinary and intradepartmental conference coverage over the course of the week.
Monday: Neurosurgery Grand Rounds; Neurosurgery Didactic Conference; Adult Brain/Spine Tumor Board.
Tuesday: Neuropathology Consensus Conference; Brain Autopsy Sign-Out Conference.
Wednesday: Neurology/Neuropathology Grand Rounds; Neurology Radiology Conference; Children’s Neurodevelopment Conference; Memory Disorders Clinic Conference; Medical Examiner Brain Cutting.
Thursday: Pediatric Brain/Spine Tumor Board; Neuromuscular Pathology Conference; Neuropathology Didactic Conference/Journal Club; Epilepsy Conference; Fetal/Neonatal Brain Cutting Conference.
Friday: Brain Cutting Conference; Neurology Resident Conference (once/month).
Neuropathology fellows are actively involved in these conferences, including presenting the pathology at the tumor boards and assisting with the brain cuttings.
Goals include continuing to assist our clinical colleagues in other specialties while at the same time giving fellows ample opportunity to develop an academic “portfolio” by giving didactic presentations at these conferences.
We will divide up conference attendance responsibility among the staff so that every staff member does not have to attend every conference. We will strongly encourage or require fellows to give lectures at the monthly Neurology Resident Conference to enhance their “portfolio” of didactic presentations.
Topics for Neuropathology Grand Rounds will be chosen two weeks in advance to allow fellows the time necessary to work on the presentation.
At the didactic teaching sessions held every other week we will review selected topics in neuropathology chosen from standard textbooks and solicit interesting Journal Club articles from multiple staff for active discussion.
Warren Alpert Medical School of Brown University
Dr. Donahue is a co-director of Bio 3650A/3652 (Integrated Medical Sciences II: Brain Sciences) at the medical school and is also a lecturer and small-group leader in the course, for which he has received multiple Dean’s Teaching Excellence Awards and Certificates of Recognition. Dr. Stopa has been a long-time lecturer of neuropathology in that course, for which he has also received multiple Dean’s Teaching Excellence Awards and Certificates of Recognition. Dr. Anthony has just recently been added to the lecturer roster in the neuroanatomy section of that course. Dr. Donahue also participates in small groups in Bio 3662 (IMS III: Cardiovascular), Bio 3663 (IMS III: Pulmonary), and Bio 3673 (IMS IV: Gastroenterology), for which he has also received multiple Dean’s Teaching Excellence Awards and Certificates of Recognition. Goals include continuing these teaching responsibilities.
Strength in Research Programs in Cellular and Molecular Neuroscience
The Brown Institute for Brain Science (BIBS) offers a stimulating environment for basic neuroscience collaborations across different university departments including bioengineering, computer science and mathematics. It is closely affiliated with the Norman Prince Neuroscience Institute (NPNI) at Rhode Island Hospital that serves as the clinical arm of BIBS. The Division of Neuropathology facilitates translational research between these two institutes. It also serves as a liaison with other major national and international academic centers and biotechnology companies. Summaries of ongoing research within the division are as follows:
Basic Neuroscience
The Suprachasmatic Nucleus (SCN) and Circadian Rhythms.
In the early 1980s the existence of the SCN in humans remained controversial. Melatonin receptors were demonstrated in the human SCN confirming that both the human pineal gland and SCN had a functional relationship. Melatonin was later introduced as a treatment for circadian rhythm disorders. The carbocyanine dye DiIwas used to define the retinohypothalamic tract in human brain, a tract that directly relays information about photic stimulation from the retina to the SCN. For nearly 2 decades a cohort of dementia patients has been studied to determine how the changes in activity and core body temperature rhythms can be influenced by structural changes within the SCN to better understand the effects of dementia on circadian rhythmicity.