Regional and areal patterns of cell vulnerability (manifested as cell death and neuron loss) and cell sensitivity (as revealed by the presence of intracytoplasmic inclusions) are described in patients with frontotemporal dementia (FTD) and FTD+ motor neuron disease (MND). This is followed by studies geared to learning about possible mechanisms involved in selective neuron loss and studies focused on recognizing the identity of vulnerable populations of local-circuit neurons and the impact of FTD on individual cells as well as on postsynaptic and presynaptic terminals in the frontal cortex. Neuron loss is not associated with increased vulnerability to nuclear DNA fragmentation, and nor is it accompanied by modifications in the expression of the proteins Bcl-2 and Bax, and transcription factors c-Fos and c-Jun, thus suggesting that these proteins are probably not involved in cell death in these disorders. In the frontal and temporal cortices, glutamatergic pyramidal cells and calbindin-D28k-immunoreactive GABAergic local-circuit neurons are lost in the upper cortical layers. Parvalbumin-immunoreactive cells are preserved. In addition, reduction of putative postsynaptic sites (as inferred from the decreased numbers of dendritic branches in both pyramidal and nonpyramidal neurons, and of dendritic spines in pyramidal cells) in remaining neurons of the upper layers, as well as reduction of presynaptic terminals (as suggested by the decreased expression of synaptic vesicle-associated proteins, synaptophysin, synaptotagmin, rab 3a and synapsin 1, and presynaptic plasma membrane proteins SNAP-25 and syntaxin 1) in the upper layers of the frontal cortex, but not of the posterior parietal cortex, demonstrate the combined devastating effects of FTD on cortico-cortical connections.