Jellied Century-Old Brains Reveal Secrets of Mental Illness

preserved brain tissue from dementia patient who died in the 1930s. — Brain tissue mounted in blocks from an autopsy performed on a patient who had been diagnosed with a type of dementia and who died in 1931 at the Central Indiana Hospital for the Insane; the tissues are stored in the original specimen jar. Dr. Sandusky used minute samples from the tissue specimens.

(Image credit: George Sandusky, University of Indiana/Indiana Medical History Museum)

Among the bloodletting boxes, ether inhalers, kangaroo-tendon sutures and other artifacts stored at the Indiana Medical History Museum in Indianapolis are hundreds of scuffed-up canning jars full of dingy yellow liquid and chunks of human brains.

Until the late 1960s the museum was the pathology department of the Central Indiana Hospital for the Insane. The bits of brain in the jars were collected during patient autopsies performed between 1896 and 1938. Most of the jars sat on a shelf until the summer of 2010, when Indiana University School of Medicine pathologist George Sandusky began popping off the lids.

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Sandusky is not alone. Several research groups are now seeking ways to mine genetic and other information hidden in old, often forgotten tissue archives—a handful of which can be found in the U.S., along with many more in Europe. Several technical hurdles stand in the way, but if these can be overcome, the archives would offer several advantages. Beyond supplying tissues that can be hard to acquire at a time when autopsies are on the decline, the vintage brains are untainted by modern psychiatric drugs and are often paired with detailed clinical notes that help researchers make more accurate post hoc diagnoses.

About a dozen facilities in the U.S. today receive postmortem brain donations from people with schizophrenia; collectively, they hold about 700 brains, according to Joel Kleinman, chief of the section on neuropathology at the National Institute of Mental Health (NIMH). His institute's collection is one of the largest, with 232 brains. But getting access to these modern samples is not easy for everyone, he says. "These institutions collected them at great expense, and are not just going to give them up."

A few researchers have instead tapped into much older brain collections, especially for anatomical studies, such as measuring the relative size of white and gray matter or counting neurons. The National Museum of Health and Medicine in Silver Spring, Md., holds one such collection of old brains: thousands of decades-old human brain specimens, many of which originally came from Saint Elizabeth's Hospital, a psychiatric facility in Washington, D.C.

As proof of principle, Sandusky is first screening the DNA for a handful of genetic glitches that researchers have already linked to schizophrenia in blood studies. So far, the search for the genetic culprits of mental illness has been inconclusive and disappointing, pushing researchers to gather as much data as possible, which is one reason old overlooked brain collections are so valuable. He also plans to look for RNA, which is produced when genes are turned on. Whereas DNA analysis reveals genetic mutations written into a person's genome, RNA analysis reveals which genes are actively overexpressed or underexpressed compared with the general population.

The DNA could be interesting on its own, though. Researchers are learning that an individual's DNA is not always the same in blood cells and brain cells. For instance, sometimes large genomic deletions and duplications—called copy number variations, or CNVs—crop up in certain tissues after conception. Francine Benes, director of the Harvard Brain Tissue Resource Center, says she has found interesting CNV differences from one brain region to another in 20-year-old schizophrenia brains preserved in paraffin wax. These differences could reflect atypical brain development that might contribute to schizophrenia.

On the one hand, old clinical diagnoses do not line up with modern ones, which could make it difficult to compare data from old and new brains, according to several experts. On the other hand, century-old clinical records are often much more descriptive than modern ones. In the early 1900s patients were often confined to institutions and followed much more closely than are patients today, giving psychiatrists the chance to record intimate details. "For example, one record describes a female patient who, over the course of a couple of weeks, ate all of the fibers in a broom," Sandusky says.

"Some of the old cases are very good in terms of quality," says Manuel Graeber, chair of brain tumor research at the University of Sydney. In 1997 he found slides of 94-year-old brain tissue from the first described Alzheimer's patient stashed in a basement at the University of Munich. His team confirmed the telltale plaques and tangles of the disease and ran DNA tests on the tissue. "These were meticulous scientists. It's inspiring."