Early frontotemporal dementia targets neurons unique to apes and humans.
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 = 7), Alzheimer's disease (n = 5), and age-matched nonneurological control subjects (n = 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.


CONCLUSIONS
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.
Seeley
William W
WW
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. wseeley@memory.ucsf.edu
Carlin
Danielle A
DA
Allman
John M
JM
Macedo
Marcelo N
MN
Bush
Clarissa
C
Miller
Bruce L
BL
Dearmond
Stephen J
SJ
D000368:Aged; D002452:Cell Count; D016923:Cell Death; D048430:Cell Shape; D003704:Dementia / Q000473:pathology* / Q000503:physiopathology; D003712:Dendrites / Q000473:pathology; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D005625:Frontal Lobe / Q000473:pathology* / Q000503:physiopathology; D006179:Gyrus Cinguli / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000473:pathology* / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000145:classification / Q000473:pathology*; D013045:Species Specificity; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
D016875:tau Proteins