Table 1 Changes in wake-active neuronal populations across aging and neurodegenerative disease

Orexinergic

Lateral Hypothalamus (LH)

•Cell loss(Kessler et al. 2011)(Brownell and Conti 2010)

•Cell loss (Fronczek et al. 2012)

•Cell loss (Thannickal et al. 2007)(Lessig et al. 2010)

•Decreased plasma orexin concentration (Çoban et al. 2013)

•Loss of fibers (Stanley and Fadel 2012)(Downs et al. 2007)(Zhang et al. 2005)

•Decreased CSF orexin concentration (Fronczek et al. 2012)

•Lewy Bodies (Fronczek et al. 2007)

•Decreased CSF orexin concentration in DLB (Wennström et al. 2012)

•Decreased responsiveness to orexin in projection areas (Stanley and Fadel 2012)

Noradrenergic

Locus Coeruleus (LC)

•Decreased noradrenaline reuptake at terminals (Shores et al. 1999)(Zhu et al. 2005)(Shirokawa et al. 2003)

•Cell loss (Brunnström et al. 2011)

•Cell loss (Brunnström et al. 2011)

•Loss of neuron pigmentation (Hoogendijk et al. 1995)

•Cell loss (Brunnström et al. 2011)

•Decreased DBH (Zhu et al. 2005)

•NFTs (Grudzien et al. 2007)

•Lewy Bodies (Seidel et al. 2014)

•Intracellular inclusion bodies (Iwanaga et al. 1997)

•Increased CHOP (Naidoo et al. 2011)

Cholinergic

Nucleus Basalis of Meynert (NBM)

•Cell loss (Wolf et al. 2014)(Grothe et al. 2012)

•Cell loss (Rogers et al. 1985)

•Cell loss (Rogers et al. 1985)(Grothe et al. 2014)(Iranzo et al. 2014)

•Intracellular inclusion bodies (Matsuoka et al. 2011)

•Decreased nicotinic receptor expression in cortex (Nordberg et al. 1992)(Uchida et al. 2013)

•NFTs (Rogers et al. 1985)(Iraizoz et al. 1999)

•Lewy Bodies (Rogers et al. 1985)

•Altered AMPA receptor expression(Ikonomovic et al. 2000)

Histaminergic

Tuberomammillary Nucleus (TMN)

•Elevated levels of CSF histamine metabolites (Prell et al. 1988)

•Cell loss (Nakamura et al. 1993)(Shan et al. 2012a)

•Lewy Bodies (Shan et al. 2012b)

•Decreased binding of cortex histamine receptors (Yanai et al. 1992)

•NFTs (Nakamura et al. 1993)

•Increased density of histaminergic fibers in SN (Anichtchik et al. 2000)

•Regional alterations in HDC expression (Shan et al. 2012a)

Serotonergic

Dorsal Raphe (DR)

•Region-specific alterations in 5-HT receptor expression (Rodríguez et al. 2012)(Marcusson et al. 1984)

•Cell loss (Chen et al. 2000)

•Cell loss (Halliday et al. 1990)

•Decreased CSF levels of 5-HT precursor tryptophan(Monaco et al. 1979)

•Cell loss (Yang and Schmitt 2001)

•NFTs (Chen et al. 2000)

•Lewy Bodies (Seidel et al. 2014)

•Reduced 5-HT1A and 5-HT2A receptor expression in cortex (Bowen et al. 2008)

•Decreased CSF 5-HT

•Decreased CSF 5-HT concentration(Tohgi et al. 1992)

concentration (Tohgi et al. 1993)

Decreased 5-HT receptor expression in cortex (Turner et al. 2005)

•Reduced SERT expression (Rodríguez et al. 2012)

•Decreased 5-HT receptor expression in cortex (Lai et al. 2005)

•Reduced 5-HT signaling throughout brain (Politis et al. 2012)

•Decreased 5-HT fiber density and aberrant morphology (van Luijtelaar et al. 1988)

Dopaminergic

Ventral Periaqueductal Gray (vPAG)

•NFTs (Parvizi et al. 2000)

•Cell loss (Benarroch et al. 2009)

•Lewy Bodies (Seidel et al. 2014)(Benarroch et al. 2009)

•Increased rates of dopamine metabolism (Kumakura et al. 2010)