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Selective Neuronal Death Targets Unique Human-Ape Cells In Frontotemporal Dementia

ARTICLE IN BRIEF

  • ✓ Researchers report that von Economo neurons seen only in humans and great apes — and perhaps humpback whales as well — are early targets in frontotemporal dementia.

The selective neurodegeneration of frontotemporal dementia (FTD) erodes the traits that make us most human, including social and emotional self-awareness, moral reasoning, and the ability to empathize. Despite this selectivity, no single cell type has been implicated in the disease.

But now, researchers have found that neurons seen only in humans and great apes — and perhaps humpback whales as well — are early targets in FTD (Ann Neurol 2006;60:600–667). While the exact functions of these cells are still unknown, they are prominent in the same cerebral regions that govern social behavior, suggesting they may be the key to understanding both the pathogenesis and the clinical features of this most human of brain diseases.

VON ECONOMO NEURONS

“Von Economo neurons” (VENs) were first described in the nineteenth century by Constantin von Economo (1876–1931), an Austrian neurologist, anatomist, and pathologist, memorialized for his description of encephalitis lethargica (“von Economo's” disease). He first described the neurons in the human brain, where they are localized to the anterior cingulate cortex (ACC) and the fronto-insula (FI), areas associated with social and emotional functions. They are more numerous in the right hemisphere than in the left, also in keeping with what is known about lateralization of social and emotional behavior.

The large, cigar-shaped neurons with relatively simple architecture and little dendritic branching form clusters oriented perpendicularly to the surface of the cortex and project to unknown targets beyond the ACC and FI. VENs arise in the brain late in development, and are fully populated by the fourth year of life.

While they have been known for more than one hundred years, not until 1999 was a remarkable discovery made about their distribution in the animal kingdom: Out of all the major primates, from prosimians to humans, VENs are found only in humans and the great apes (gorillas, orangutans, and chimpanzees), and are much more abundant in humans than in apes.

SELECTIVE TARGET OF NEURODEGENERATION

Taking together their anatomic distribution, developmental pattern, and evolutionary restriction, these patterns suggest that VENs likely subserve the social and emotional functions that distinguish humans and great apes from other primates. This hypothesis has now received further support from the surprising discovery that VENs are an early and selective target of neurodegeneration in frontotemporal dementia.

Figure

Dr. William Seeley: “Von Economo neurons are exquisitely sensitive to the FTD pathologic process. Our findings suggest that selective VEN loss is a defining feature of FTD [frontotemporal dementia].”

“We'd been thinking for a while that frontotemporal dementia was, through its deficits, trying to tell us something about human uniqueness,” said William Seeley, MD, lead author on the new study. “Now we believe we've identified a specific cell type that is highly susceptible to neurodegeneration in frontotemporal dementia.” Dr. Seeley is an instructor at the Memory and Aging Center in the department of neurology at the University of California-San Francisco.

Dr. Seeley's intellectual curiosity was piqued when, as a first-year dementia fellow, he first heard of VENs in a lecture by John Allman, PhD, a professor of biology at the California Institute of Technology.

“These neurons seemed tailor-made as a candidate for frontotemporal dementia. Different ideas crystallized at that point,” he said, leading him and Dr. Allman to the Armed Forces Institute of Pathology brain bank. They compared the brain of a Pick disease patient with an Alzheimer disease patient, and immediately saw a difference in the loss of von Economo neurons. They then expanded their sample to those included in the current study, which compared seven FTD brains, five AD brains, and seven control brains. Strikingly, he said, “we found exactly the same numbers as in the original comparison.”

Their analysis showed that in layer five of the ACC and FI, FTD patients had a 74 percent reduction in VENs, while non-VEN neighboring neurons were insignificantly reduced. The same pattern was seen in both pathologic subtypes of FTD, Pick disease, and FTLD-U (frontotemporal lobar degeneration with ubiquitinated inclusions).

“Von Economo neurons are exquisitely sensitive to the FTD pathologic process,” Dr. Seeley said. “Our findings suggest that selective VEN loss is a defining feature of FTD.”

In contrast, Alzheimer disease brains showed only nonsignificant reductions in VENs compared to healthy brains, and non-VEN neighbors were equally targeted. Dr. Seeley noted that AD patients often retain “social graces” until late in the disease, while in FTD, self-awareness, empathy, and behavioral control are lost early. These capacities have been previously associated with the ACC and FI, and Dr. Seeley's results suggest that VENs may play a large role in carrying out these functions, although, he cautioned, “that is completely speculative at this point.”

“I hope this finding will lead to a better understanding of the pathogenesis of the disease,” he said. Making that more challenging is that lower primates used as lab models don't have VENs, and great apes are no longer the subjects of neurologic experiments.

IMPORTANCE OF DISCOVERY

VENs make up such a small fraction of brain neurons — only 2 percent of all neurons within layer 5 of the ACC and FI — that current neuroimaging techniques cannot isolate them. Nonetheless, Dr. Seeley said, the knowledge of their importance may lead others to try to refine these techniques. Meanwhile, work has begun to try to map the networks that VENs are part of, and to pinpoint the cerebral targets of their projections.

This discovery of a role for von Economo neurons in FTD is both surprising and important, according to Marsel Mesulam, MD, director of the Cognitive Neurology and Alzheimer's Disease Center at Northwestern University Medical School. “This study helps us understand two big questions: what is unique about human brains, and how the selectivity of frontotemporal dementia is established. It could lead to some interesting insights.”

“There are many things we still have to know,” he said, including more about their chemistry, development, genetics, and connectivity. And, of course, to what extent this selectivity is confirmed by additional studies.

“These neurons are intriguing, because they reflect something unique in human brains. The discovery that von Economo neurons are selectively targeted in FTD is a complete surprise — it is not the sort of thing you could have easily predicted.”

Underscoring the fascination of this discovery, it was reported in November 2006 that VEN-like neurons have been found in the brain of the humpback whale, which, more than any other marine species, appears to have a complex social structure.

REFERENCES

• WW Seeley, DA Carlin, SJ DeArmond, et al. Early frontotemporal dementia targets neurons unique to apes and humans. Ann Neurol 2006;60:600–667.
    • Allman JM, Watson KK, Hakeem AY, et al. Intuition and autism: a possible role for Von Economo neurons. Trends Cogn Sci 2005;9:367–373.
      • Hof PR, Estel Van Der Gucht E. Structure of the cerebral cortex of the humpback whale, Megaptera novaeangliae (Cetacea, Mysticeti, Balaenopteridae). Anatom Rec Part A 2006; E-pub 27 Nov 2006.