Early frontotemporal dementia targets neurons unique to apes and humans

Abstract

Objective: Frontotemporal dementia (FTD) is a neurodegenerative disease that erodes uniquely human aspects of social behavior and emotion. The illness features a characteristic pattern of early injury to anterior cingulate and frontoinsular cortex. These regions, though often considered ancient in phylogeny, are the exclusive homes to the von Economo neuron (VEN), a large bipolar projection neuron found only in great apes and humans. Despite progress toward understanding the genetic and molecular bases of FTD, no class of selectively vulnerable neurons has been identified. Methods: Using unbiased stereology, we quantified anterior cingulate VENs and neighboring Layer 5 neurons in FTD (n ϭ 7), Alzheimer's disease (n ϭ 5), and age-matched nonneurological control subjects (n ϭ 7). Neuronal morphology and immunohistochemical staining patterns provided further information about VEN susceptibility. Results: FTD was associated with early, severe, and selective VEN losses, including a 74% reduction in VENs per section compared with control subjects. VEN dropout was not attributable to general neuronal loss and was seen across FTD pathological subtypes. Surviving VENs were often dysmorphic, with pathological tau protein accumulation in Pick's disease. In contrast, patients with Alzheimer's disease showed normal VEN counts and morphology despite extensive local neurofibrillary pathology. Interpretation: VEN loss links FTD to its signature regional pattern. The findings suggest a new framework for understanding how evolution may have rendered the human brain vulnerable to specific forms of degenerative illness.Ann Neurol 2006;60:660 -667 Primate brain evolution has led to increasing frontal encephalization, hemispheric functional lateralization, and maturational delay. At the level of neuronal morphology, however, little differentiates humans from even our distant mammalian ancestors. Von Economo neurons (VENs) provide a notable exception. These large bipolar projection neurons are a unique feature of great apes and humans.

The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans

“…The number of VENs is significantly greater in the postnatal brains relative to the neonatal brains. The percentage of total neurons that are VENs is relatively stable in adulthood (see Tables 2, 3) and is similar to the percentages observed by Seeley et al (2006). Figure 9 illustrates the ratio between the number of VENs in the right hemisphere and that in the left.…”

“…The VENs are also reduced in FI ). In contrast, Seeley et al (2006Seeley et al ( , 2007 found that the VENs were not significantly reduced in Alzheimer's dementia (AD) although a reduction had been reported in an earlier study which did not use stereological methods (Nimchinsky et al 1995). Rankin et al (2006) systematically investigated the capacity for empathic concern in a large population of neurological patients and found that this capacity was greatly reduced in FTD patients; while this capacity was variably expressed in Alzheimer's patients it was not significantly reduced relative to neurologically normal controls.…”

“…Seeley et al (2006Seeley et al ( , 2007Seeley 2008) found in a stereological study that the VENs are specifically and selectively attacked in the early stages of the behavioral variant of fronto-temporal dementia (FTD), in which empathy, social awareness, and self-control are severely diminished. The VEN population of ACC is reduced by an average of 74% in these patients, and many of the surviving VENs are severely dysmorphic.…”

“…The VEN population of ACC is reduced by an average of 74% in these patients, and many of the surviving VENs are severely dysmorphic. The destruction of the VENs in FTD results, in different patients, from one of two distinct molecular mechanisms related to abnormal isoforms of the tau protein or to abnormal expression in the cytoplasm of VENs of the DNA-binding protein TDP-43 (Seeley et al 2006;Seeley 2008). The VENs are also reduced in FI ).…”

Prosocial deficits in behavioral variant frontotemporal dementia relate to reward network atrophy

“…Highly social species (e.g., elephants, great apes, and dolphins) that exhibit prosocial behaviors such as giving, targeted helping, and consolation behaviors are also those that are capable of complex social‐cognitive acts such as mirror self‐recognition (Seeley & Sturm, 2006). These species are also united in that they have relatively large proportions of von Economo neurons, large neurons that are important for integrating socioemotional cues, which are also especially vulnerable in bvFTD (Seeley et al., 2006). Future work that relates the integrity of these specialized neurons to the degradation of prosociality in bvFTD will help to delineate the biology of these exceptional behaviors.…”