Study offers window into human behavior, brain disease

UCSF scientists have identified a cell population that is a primary target of the degenerative brain disease known as frontotemporal dementia, which is as common as Alzheimer’s disease in patients who develop dementia before age 65.

Because the cells arose only recently in evolutionary history—in a common ancestor of great apes and humans—and are particularly abundant in humans, the finding supports the concept that evolution has rendered the human brain vulnerable to disease, including frontotemporal dementia, and, possibly, disorders such as autism and schizophrenia, the researchers say.

In addition, because the disease erodes aspects of social behavior and emotions - self awareness, moral reasoning and empathy - that are highly developed in humans, the finding suggests that the cells may play a role in what makes humans “human,” they say.

The finding is reported in the December 22 on-line issue of Annals of Neurology.

The cells, known as von Economo neurons, were first comprehensively described in 1925 by their Romanian-Austrian namesake, who determined that the unusually shaped cells—large, cigar-shaped and tapered at each end, with only a few dendritic processes extending away from them - were localized in only two regions of the frontal lobes.

The cells received only limited attention in the ensuing years, but in the meantime scientists determined that the brain regions in which von Economo neurons arise—the anterior cingulate and frontoinsular cortex—are key targets of frontotemporal dementia. And in 1999, a team of U.S. scientists made the surprising discovery that, among primates, von Economo neurons were seen only in great apes and humans. 

In the current study, the UCSF team set out to explore whether von Economo neurons could be the target of FTD.

Working in the laboratory of senior author Stephen J. DeArmond, MD, PhD, UCSF professor of pathology, they compared the numbers of von Economo neurons and neighboring neurons in the anterior cingulate cortex, looking specifically at brain tissue from three sets of deceased patients—seven who had no neurological disease, five who had Alzheimer’s disease and seven who had frontotemporal dementia.

The results were striking. In frontotemporal dementia, there was early, severe and selective loss of von Economo neurons compared to control subjects. In Alzheimer’s disease,  von Economo neurons were not significantly depleted.

“This finding provides new insight into how frontotemporal dementia erodes the brain at the cellular level,” says the first author of the study, William Seeley, MD, UCSF instructor of neurology and a clinician-scientist at the UCSF Memory and Aging Center.

Progress has been made in illuminating some of the genetic and molecular aspects of the disease - two mutated genes are associated with most inherited forms of the disease and major misprocessed proteins have been identified - but “discoveries at the genetic and molecular level do not yet explain why specific populations of neurons are dying,” he says.

“This observation gives us a new window into the early and cell-specific degenerative process, and we can use this window to better understand disease pathogenesis.”

The team, led by Seeley, is currently trying to study von Economo neuron-rich regions in living patients using neuroimaging. They also are studying VENs, themselves, in autopsy studies using neuropathological techniques.

As FTD is a disease for which there is as yet no disease-modifying therapy, studies of von Economo neurons could provide new strategies.
Why the cells are vulnerable is still a mystery, says Seeley. But given the fact that they are evolutionarily new, the explanation may be that there are still “kinks” in the genetic programming of the neuronal circuits.

“VENs probably help us in some wonderful way, which would explain why natural selection has pushed their rapid evolution in humans,” he says. “Still, in the context of FTD, something about VENs makes them vulnerable.”

Notably, cell-specific degeneration is a unifying feature of all the neurodegenerative diseases. Dopamine-producing neurons in the substantia nigra region of the brain deteriorate in Parkinson’s disease, motor neurons of the spinal cord and motor cortex degenerate in ALS and specific memory-forming medial temporal lobe neurons die in early Alzheimer’s disease.

“We hope to add von Economo neurons to that list,” says Seeley. “It’s a pretty important list to fill in, but for FTD there just hasn’t been a good candidate until now. We think we’ve found it, and that is the most exciting part of the discovery for those of us who treat patients.”

At the same time, he says, the finding “gives us a sense that we might be able to start to figure out what makes us unique as humans, what makes our brains different from those of other species. And that’s pretty exciting, too.”

Bruce Miller, MD, the A.W. & Mary Margaret Clausen Distinguished Professor of Neurology, director of the UCSF Memory and Aging Center and a co-author of the study, concurs.

“The social and behavioral skills that you lose in frontotemporal dementia are so characteristically human, or at least strongly associated with higher primates,” he reflects.

“I think it’s fascinating from an evolutionary perspective that we have these new neurons that are involved in social behavior that are selectively vulnerable in the second major degenerative disorder.”

Notably, VENs are located in regions of the brain that are in a good position to transmit raw emotional signals to other brain centers. In addition, VENs have characteristics that suggest they play a role in analyzing sparse inputs and sending rapid output signals, further supporting the idea that they may impact behavior.

It’s possible, says Seeley, that scientists will be able to figure out what these neurons normally do. But it won’t be easy.

“These are such abstract brain capacities we’re talking about…It’s not like analyzing movement of your right arm or color vision. We’re talking about understanding how we read others’ minds. The philosopher in me sees the opportunity to really learn something interesting about human nature, here.”

Still, he says, “It’s the neurologist in me that brings me to work everyday, and as a neurologist what I want is to help cure the disease.”

Co-authors of the study were Danielle A. Carlin, BA, and Marcelo N. Macedo, BS, of the UCSF Memory and Aging Center; Clarissa Bush, BS, of the De Armond neuropathology research lab, and John M. Allman, PhD, of California Institute of Technology.

The study was funded by the National Institutes of Health, the Larry L. Hillblom Foundation and the Gordon and Betty Moore and David and Lucile Packard Foundations.

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.