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.

Behavioral variant frontotemporal dementia (bvFTD) disrupts our most human social and emotional functions. Early in the disease, patients show focal anterior cingulate cortex (ACC) and orbital frontoinsula (FI) degeneration, accentuated in the right hemisphere. The ACC and FI, though sometimes considered ancient in phylogeny, feature a large bipolar projection neuron, the von Economo neuron (VEN), which is found only in humans, apes, and selected whales-all large-brained mammals with complex social structures. In contrast to bvFTD, Alzheimer disease (AD) often spares social functioning, and the ACC and FI, until late in its course, damaging instead a posterior hippocampal-cingulo-temporal-parietal network involved in episodic memory retrieval. These divergent patterns of functional and regional impairment remain mysterious despite extensive molecular-level characterization of bvFTD and AD. In this report, we further develop the hypothesis that VENs drive the regional vulnerability pattern seen in bvFTD, citing recent evidence from functional imaging in healthy humans, and also structural imaging and quantitative neuropathology data from bvFTD and AD. Our most recent findings suggest that bvFTD and AD target distinct, anticorrelated intrinsic connectivity networks and that bvFTD-related VEN injury occurs throughout the ACC-FI network. We suggest that the regional and neuronal vulnerability patterns seen in bvFTD and AD underlie the divergent impact of these disorders on recently evolved social-emotional functions.

The unique cognitive and behavioural manifestations of the non-AD dementias can be mistaken for psychiatric disorders. Improved detection of tauopathies and synucleinopathies and their differentiation from AD is possible.