From July 11, 2013 August 20, 2014, we collected 77 brains through the DC and VA Medical Examiners Offices. During this time, part of the brain collection was transferred to the Lieber Institute on Brain development (LIBD) as part of the Material Transfer Agreement (MTA) and as a result the total number of brains in the NIMH collection diminished as compared with the last fiscal year (from 1,204 to 929). Our collection consists now of brain tissues from 929 subjects. The breakdown by diagnosis is as follows: ADHD 7 Anxiety 3 Autism 4 Bipolar disorder 87 Controls (non-psychiatric) 301 Major depression 182 Neurological disorders 14 Schizophrenia 180 Substance abuse 13 Other 30 Not yet characterized 108 The major focus of our studies is schizophrenia (SZ), which involves cognitive deficits, negative symptoms, and psychosis, usually starting in late adolescence or early adulthood. The recent discovery of genetic variations associated with SZ not only speaks to a significant component of the etiology, but allows for increased understanding of the neuropsychology, neuroimaging, and neuropathology of the disorder. Postmortem human brain studies guided by genetic advances are a valuable, if not essential component, in elucidating the cellular and molecular pathophysiology of SZ. Improved understanding of a genetic component in SZ may enhance diagnostic abilities and hopefully, lead to new treatments. Postmortem human brain studies are limited by the quality and quantity of the specimens. Brain Procurement: The number of brains collected per year has remained relatively constant for the past ten years and we have become very selective in choosing cases. The entire collection has undergone a case-by-case review leading to a reduction in the number of brains for study. Selected cases all have informed audiotaped consent from the next-of-kin at time of donation, with extensive medical records available for review. Interviews with the next-of-kin, adds clinical information. The tissue is screened for macro- and microscopic neuropathology, and multiple screens are performed for RNA and protein integrity. Toxicological screens are conducted for substances of abuse, and prescribed psychotropic medications. Clinical Review and Characterization: Informed consent for research on the brain and related tissue samples from the next-of-kin is obtained at or before the time of autopsy includes the brain, blood, and hair specimen (for toxicology) as well as permission to obtain medical records. Next-of-kin are interviewed with a 14-item telephone-screening questionnaire. The next-of-kin are advised that they will receive a follow-up interview in greater depth within several months. This in-depth interview relies upon three screening devices: a SCID (First et al., 1997), a modified psychological autopsy (Kelly and Mann, 1996) and a modified version of the DEAD (Diagnostic Evaluation after Death) (Zalcman et al., 1983) to collect relevant clinical information from the next-of-kin in order to enhance our diagnostic classification. The ME offices provide demographic information (age, gender, race, etc.), a police report, interviews with the next-of-kin, and relevant medical personnel and witnesses, toxicology screens, and a general autopsy report that includes the cause and manner of death. The ME offices perform toxicology screens in the vast majority of cases. If toxicology screens are not performed or inadequate in terms of the extent of the substances measured, we have contracted a laboratory to complete the screens. An extensive review of clinical records and all other available information is conducted by trained HBCC personnel and independently reviewed by two board certified psychiatrists. If the latter agree on diagnosis, the case is formally reviewed at a diagnostic conference attended by the two psychiatrists, the neuropathologist, the clinical interview team, and the social worker and study coordinator who records a final diagnostic description according to DSM-IVR (APA, 2000) into the database. If the two psychiatrists disagree, a third board certified psychiatrist reviews the case independently prior to the diagnostic conference. No final DSM-IVR diagnosis is assigned at the diagnostic conference unless two psychiatrists concur on diagnoses. Similar rigor is used in designating normal control subjects who must have no history of psychiatric or neurological disorders, no history of significant substance abuse or dependence, a negative toxicology screen at autopsy, and a neuropathological screen free from abnormalities. Nicotine use has been carefully reviewed and is not an exclusionary criterion for normal control subjects. The neuropathological screening involves two components, a macro- and microscopic examination and inspection. A board certified neuropathologist conducts the macroscopic examination at time of tissue collection, weighing and inspecting the whole brain, upper cervical spinal cord, pituitary and pineal glands, dura, and intracranial vasculature. The microscopic examination involves sectioning and staining tissue from the frontal, temporal, and occipital poles, the posterior hippocampus, and the cerebellar vermis, looking for evidence of neurodegeneration or other pathological processes. Sections are routinely stained to reveal neurofibrillary tangles and neuritic plaques that are counted to apply Khachaturian criteria to establish the neuropathological diagnosis of AD (Khachaturian, 1985). Sections are taken from any region that shows signs of macroscopic pathology, such as an apparent infarct or abscess, for additional neuropathological analysis. A formal macro- and microscopic neuropathology report is written from the information obtained from these examinations. Screening for Molecular Biology Studies: The following procedures have been performed on every brain prior to study inclusion: a. Measurement of tissue pH from homogenized cerebellar hemispheric tissue. b. Measurement of mRNA expression of a panel of putatively constitutively expressed genes (such as actin, B2M, GUSB) by quantitative PCR c. Extraction of total RNA using Qiagen RNAeasy kits d. Quantitative analysis of total RNA integrity (RIN) and 28S to 18S ratios using capillary electrophoresis on a Bioanalyzer 2100 (Agilent, Inc.). e. Acceptable postmortem intervals (PMI) in human brain for each protein studied with Westerns or ELISAs are inferred from rat studies investigating the PMI when protein levels for that protein significantly decline (Halim et al., 2003). f. To determine effects of medications in the human studies of mRNA and protein expression, we are using brain tissue from rats chronically treated with various doses of antipsychotic drugs (haloperidol and clozapine) (Lipska et al., 2001,2003). g. From these screening measurements, we have developed exclusionary criteria for the use of human brain tissue in our experiments: tissue pH <6.00, PMI >60 hours, RIN <5.0. h. The vast majority of our cases (over 90%) come from ME offices, and few, if any, of our brains come from patients who have died with prolonged agonal states. The latter is clearly associated with low pH and increased RNA degradation (Tomita et al., 2004).

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICMH002903-08
Application #
8940170
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
Zip Code
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