Table 1.

Clinical and preclinical anatomical and functional changes in NE/LC system and related cognitive symptoms of Alzheimer's disease, Parkinson's disease, ADHD, and schizophrenia.

	Alzheimer's disease	Parkinson's disease	ADHD	Schizophrenia
Functional/anatomical changes in NE/LC system	Decreased LC volume and cell numbers with a rostrocaudal gradient [27, 44, 99] Tau protein assembles in LC into neurofibrillary tangles starting in early adulthood [95, 96] Decreased CNS levels of NE [92, 93, 102–105] Impaired hippocampal neurogenesis [101] Impaired synaptic plasticity [104, 105]	General destruction of LC without pattern topography [27, 44, 99] α-synuclein accumulation in LC [120] Loss of protective effect of α2AR on NE/DA system [122, 123]	Imbalances in DA/NE monoamine systems [132] PI3Kγ deficiency [130, 131] Impairment of NE transmission in PFC [71, 135, 137, 138] Improvement in behavioral symptoms by modulators of NE transmission [8, 10, 134, 135] Dysregulation of signaling at the α2A receptor [71, 135, 137]	Orbitofrontal cortex in DISC1+/+ mice contain shorter tyrosine hydroxylase (TH) positive fibers compared to wild-type mice [165, 166] Impaired α1 receptor-dependent LTD [76] Decreased binding of adrenergic probe to β1AR [166, 173]
NE-related behavioral changes	Early sensory deficits: impaired olfactory discrimination [56, 124] Behavioral perseveration modulated by innervation of medial PFC [5, 7, 8, 53, 125, 126] Memory decline [18, 85, 104, 105, 124, 127]		Deficits in working memory, sustained attention, hyperactivity, impulsivity, behavioral flexibility [44, 134]	Positive symptoms associated with high NE state [142, 153–155, 169, 170] Impaired spatial working memory [158–161, 170]