Neurodegenerative disorders of the human frontal lobes

The frontal lobes play an integral role in human socioemotional and cognitive function. Sense of self, moral decisions, empathy, and behavioral monitoring of goal-states all depend on key nodes within frontal cortex. While several neurodegenerative diseases can affect frontal function, frontotemporal dementia (FTD) has particularly serious and specific effects, which thus provide insights into the role of frontal circuits in homeostasis and adaptive behavior. FTD represents a collection of disorders with specific clinical-pathologic correlates, imaging, and genetics. Patients with FTD and initial prefrontal degeneration often present with neuropsychiatric symptoms such as loss of social decorum, new obsessions, or lack of empathy. In those patients with early anterior temporal degeneration, language (particularly in patients with left-predominant disease) and socioemotional changes (particularly in patients with right-predominant disease) precede eventual frontal dysregulation. Herein, we review a brief history of FTD, initial clinical descriptions, and the evolution of nomenclature. Next, we consider clinical features, neuropathology, imaging, and genetics in FTD-spectrum disorders in relation to the integrity of frontal circuits. In particular, we focus our discussion on behavioral variant FTD given its profound impact on cortical and subcortical frontal structures. This review highlights the clinical heterogeneity of behavioral phenotypes as well as the clinical-anatomic convergence of varying proteinopathies at the neuronal, regional, and network level. Recent neuroimaging and modeling approaches in FTD reveal varying network dysfunction centered on frontal-insular cortices, which underscores the role of the human frontal lobes in complex behaviors. We conclude the chapter reviewing the cognitive and behavioral neuroscience findings furnished from studies in FTD related to executive and socioemotional function, reward-processing, decision-making, and sense of self.