**4.3 Summary**

252 Etiology and Pathophysiology of Parkinson's Disease

To determine if the surviving LC noradrenergic neurons in AD subjects are demonstrating compensatory changes, several noradrenergic markers, similar to the markers used on the LC tissue of PD subjects, were assessed in the LC of subjects with AD. Work from my laboratory showed that the surviving noradrenergic neurons in the LC of AD and a related dementing disorder, dementia with Lewy body (DLB), showed compensatory changes. In subjects with dementia, the number of TH, DBH and NET mRNA positively labeled neurons in the LC are significantly reduced as compared to age-matched control subjects (Szot et al., 2000, 2006) and the degree of this LC neuronal loss corresponds to documented loss of noradrenergic neurons in AD by other laboratories (Bondareff et al., 1982; Chan-Palay & Asan, 1989; German et al., 1992; Mann et al., 1980; Marcyniuk et al., 1986; Tomlinson et al., 1981). The degree of LC noradrenergic neuronal loss determined by TH mRNA expression in AD subjects is verified by counting the number of TH-IR positive labeled neurons

Table 1. Changes in noradrenergic markers in the LC of PD subjects and subjects with

However, in AD, the surviving LC noradrenergic neurons exhibit increased TH mRNA expression/neuron as compared to age-matched control subjects (Szot et al., 2000, 2006), suggesting compensation. NET binding over cell body region in the LC of AD subjects is significantly reduced as compared to age-matched control subjects, and the loss of NET binding over the cell body region corresponds to the number of LC noradrenergic neurons in the LC (Szot et al., 2006). However, NET binding sites over the peri-LC dendritic zone in AD subjects is not significantly different from age-matched control subjects, despite the reduction in LC noradrenergic neurons positively labeled for NET mRNA (Szot et al., 2000, 2006). The normal amount of NET binding in the peri-LC dendritic zone of AD subjects indicates dendritic sprouting of the surviving LC neurons. TH-IR labeling in dendritic region of AD supports the notion of enhanced dendritic innervation around LC noradrenergic neurons in AD subjects observed with NET binding (McMillan et al., 2011), again indicating compensation of the surviving LC neurons in AD. In addition to the sprouting in the LC, the surviving LC neurons in AD exhibit axonal sprouting into the hippocampus and prefrontal cortex (Szot et al., 2006, 2007). The difference in the response of the surviving LC noradrenergic neurons in PD and AD is observed even concerning DBH mRNA expression/neuron. In PD, DBH mRNA expression/neuron is elevated (as

dementia as compared to appropriate control groups.

**4.2 Alterations in noradrenergic markers in LC** 

(McMillan et al., 2011).

It appears then the response of surviving LC noradrenergic neurons in AD, in regards to the noradrenergic markers measured, is completely different from the response of surviving LC noradrenergic neurons in PD (Table 1). These noradrenergic markers in AD suggest that noradrenergic function in AD subjects may not be reduced and may even exceed function in normal subjects, while in PD subject's noradrenergic function is reduced. This hypothesis is supported clinically. Orthostatic hypotension, a common non-motor symptom observed in PD due to reduced noradrenergic function, is not observed in AD subjects despite a similar degree of LC noradrenergic neuronal loss. A progression of noradrenergic function can be drawn between these two neurodegenerative disorders; at one of the spectrum PD represents the loss of LC noradrenergic neurons with reduced noradrenergic function, while AD represents the other end of the spectrum with the loss of LC noradrenergic neurons but enhanced noradrenergic function.
