**1. Introduction**

246 Etiology and Pathophysiology of Parkinson's Disease

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#### **1.1 Dopaminergic neuronal loss in Parkinson's disease**

Parkinson's disease (PD) is a neurological disorder that affects approximately 2% of the elderly population, and as our population continues to age, the incidence will only increase (Singh et al., 2007). PD is commonly characterized by various motor deficits including tremor, rigidity and bradykinesia (Singh et al., 2007). The cause of these motor symptoms is the loss of dopaminergic neurons in the substantia nigra pars compacta (SN) and reduced dopamine (DA) levels in the striatum (Damier et al., 1999; Gibb, 1991; Gibb and Lee, 1991). However, the appearance of PD symptoms does not occur until 70-80% of the dopaminergic neurons are lost. In the progression of this disorder, the loss of dopaminergic neurons is not observed until Stage 3 (out of 6 Stages) of the disorder (Braak et al., 2003a, 2003b, 2006).

#### **1.2 Noradrenergic neuronal loss in Parkinson's disease**

Of course a great deal of research has focused on the dopaminergic system in PD because loss of neurons in the SN is responsible for PD symptoms; however, PD is represented by multiple systems failing. During the earlier stages of the disorder, non-motor preclinical symptoms are observed. These preclinical symptoms include hyposmia (Berendse et al., 2001, Ponsen et al., 2004), REM-sleep disorder (Boeve et al., 2003, Scheneck et al., 2003), depression (Leentjens et al., 2003; Mayeux et al., 1992; Slaughter et al., 2001) and autonomic dysfunction such as orthostatic hypotension (Mathias, 1998; Ziemssen & Reichmann, 2007). These preclinical symptoms are attributed to neuropathological changes in neurotransmitter systems other than the SN dopaminergic nervous system. One neurotransmitter system that may be responsible for these early non-motor symptoms is the noradrenergic nervous system (Goldstein et al., 2011; Itoi & Sugimoto, 2010; Lopez-Munoz & Alamo, 2009; Mathias, 1998; Osaka & Matsumura, 1994; Ziegler et al., 1977). The presence of these symptoms would indicate an alteration in the noradrenergic nervous system is occurring early in the progression of PD. Postmortem examination of PD tissue demonstrates a significant loss of noradrenergic neurons in the locus coeruleus (LC); this loss is equal to or greater than the neuronal loss observed in the SN (Bertrand et al., 1997; Cash et al., 1987; Chan-Palay & Asan, 1989; Hornykiewicz & Kish, 1987; Marien et al., 2004; McMillan et al., 2011; Patt & Gerhard,

The Noradrenergic System is a Major Component in Parkinson's Disease 249

Fig. 1. Catecholamine biosynthesis and production of catecholamine knockout mice.

The loss of LC noradrenergic neurons in PD subjects should result in changes in NE levels at the various forebrain regions it innervates and the degree of loss should depend on the amount of LC innervation the region receives as compared to lateral tegmental groups. In PD subjects, there are reduced NE levels in the cortex, hypothalamus and cerebellum (Gasper et al., 1984, 1991; Kish et al., 1984; Shannak et al., 1994). TH- and DBHimmunoreactivity (IR) are also reduced in the cortex of PD subjects (Gasper et al., 1991). The reduction in neurotransmitter content and synthesizing enzymes in PD subjects can be attributed to the loss of noradrenergic innervation to these areas associated with the loss of LC noradrenergic neurons. The cortex, as indicated above, receives sole innervation from the LC, so changes in LC neuronal number would have a major impact in this region (Aston-Jones et al., 1995; Jones & Moore, 1977; Loughlin et al., 1986a, b; Mason & Fibiger, 1970; Moore & Bloom, 1979; Olsen & Fuxe, 1971; Ungerstedt, 1971; Waterhouse et al., 1983). Presently, the consequence of LC noradrenergic neuronal loss in PD on NE tissue content in

In contrast to terminal NE content in forebrain regions, NE levels in the LC of PD subjects does not appear to be different from controls (Cash et al., 1987). Examining different noradrenergic markers in the surviving LC neurons in PD subjects indicates the noradrenergic neurons are not compensating for the loss of surrounding neurons or terminal NE. The number of TH and DBH mRNA positively labeled neurons in the LC of PD subjects are significantly reduced as compared to age-matched control subjects (Szot, 2000, 2006; McMillan et al., 2011) and corresponds to the documented loss of noradrenergic neurons by other laboratories (Bertrand et al., 1997; Cash et al., 1987; Chan-Palay & Asan, 1989; Hornykiewicz & Kish, 1987; Marien et al., 2004; McMillan et al., 2011; Patt & Gerhard, 1993; Zarow et al., 2003). The degree of LC noradrenergic neuronal loss determined by TH and DBH mRNA expression in PD subjects is verified by counting the number of LC TH-IR positive labeled neurons (McMillan et al., 2011). TH mRNA expression/neuron of the

**3. Consequence of LC neuronal loss in PD 3.1 Alterations in terminal noradrenergic markers** 

the dopaminergic SN region is unknown.

**3.2 Alterations in noradrenergic markers in LC** 

1993; Zarow et al., 2003). The loss of LC noradrenergic neurons also precedes the loss of dopaminergic neurons in the progression of PD (Braak et al., 2003b, 2006), correlating to the time that preclinical noradrenergic non-motor symptoms appear.
