**2.1 CNS pathophysiology of NE system in PD**

#### **2.1.1 Neuroanatomical evidence in PD patients**

As early as 1917, noradrenergic neurons originating from the LC were reported to be severely deteriorated in patients suffering from PD (Tretiakoff et al., 1917; Fornai et al.,

Pathophysiology of Non-Dopaminergic Monoamine

**2.1.2 Mechanism(s) of NE loss** 

**2.2 Non-motor symptoms** 

result of motor impairments.

**2.2.1 NE loss and non-motor symptoms** 

Systems in Parkinson's Disease: Implications for Mood Dysfunction 529

The mechanisms underlying NE loss like DA neurodegeneration remain to be elucidated. However, NE neurons are susceptible to the same insults that affect DA neurons such as oxidative stress, neuroinflammation, protein misfolding and neurotoxin-induced cell death. For example, Yavich et al. (2006) demonstrated that mice expressing a pathogenic mutation of α-synuclein have abnormal compartmentalization and metabolism of both DA and NE. In addition, it is well known that monoamines have a tendency to auto-oxidize leading to oxidative stress and neuronal cell loss (Chiueh et al., 2000; Maker et al., 1986); and the aforementioned abnormal compartmentalization of NE may make LC neurons vulnerable to oxidative stress. Genetic mutations in Parkin, a genotype found in PD, also make LC neurons vulnerable to cell death. Studies in mice have demonstrated that Parkin mutations lead to loss of LC neurons (Von Coelln et al., 2004) likely via protein misfolding and dysregulation of the ubiquitous-proteasome system. This is a compelling finding since alterations in the expression of proteasome activators have been shown to correlate with neuronal loss in SNpc and the LC. Poor expression of proteasome activators correlated with neuronal cell loss in the LC and regions expressing normal levels of the proteasome activators did not suffer from neuronal degeneration (McNaught et al., 2010). Finally, NE neurons are also susceptible to neurotoxin-induced apoptosis. For example, in the experimental 6-hydroxydopamine (6-OHDA) model of PD, administration of desipramine, a NE transporter (NET) inhibitor, infers protection to NE neurons. Since DA and NE transporters share homology in structure and display common affinity for several substrates, it is likely that NET takes up the same neurotoxins that affect DA neurons in sporadic PD. Collectively these factors could make the LC neurons vulnerable to damage in both genetic and sporadic models of PD. More studies that shed light on the neurodegenerative processes in the LC are necessary to better understand the progression of PD. Moreover, neuroprotective strategies directed toward LC neurons may be warranted since loss of LC neurons makes the DA neurons more vulnerable to neurodegeneration.

Although motor symptoms of PD are widely acknowledged hallmarks of this neurodegenerative disease, there exists compelling evidence for the presence of psychiatric complications, such as depression, anxiety and psychotic symptoms (Bosboom et al., 2004). Loss of dopaminergic and noradrenergic innervation has been associated with psychiatric complications such as depression (Remy et al., 2005) and anxiety (Stein et al., 1990; Lauterbach et al., 2003). Cognitive and mood dysfunction has been reported in >50% of PD patients. In patients with early PD, depression (40%), apathy (27%), and anxiety (27%) are widely reported (Aarsland et al., 2009) and it is notable that these non-motor symptoms are identified as the most important and devastating feature contributing towards poverty of quality of life (McKinlay et al., 2008; Schrag, 2006). Moreover, the incidence of depression and anxiety in PD exceeds not only rates within the normal population but also other neurological disorders (Weintraub et al., 2003), with anxiety disorders, such as off-period panic attacks and specific phobias, have been reported in nearly 40% of PD patients (Lauterbach, 2005). Collectively these findings lead to the important observation that depression and anxiety are likely a result of neuropathological processes rather than as a

2007). In a landmark study by Hornykiewicz et al., (1960), direct biochemical evidence supported these initial findings, by showing the loss of both NE neurons and NE content in several brain regions in PD, including the caudate nucleus and putamen (Ehringer and Hornykiewicz, 1960).

Neuropathological evidence in post-mortem tissue of PD patients ranges from observation of Lewy bodies (LB) within single NE cells and cytoplasmic neurofibrillary tangles (NT) to a loss of neurons in the LC (Mann, 1983). Patt and Gerhard (1993), using a variant of the Golgi method, found that medium-sized LC neurons containing neuromelanin granules were most affected in PD patients (Patt and Gerhard, 1993) correlating with loss of synaptic spines, a reduction in dendritic length, swollen perikarya and apoptosis. Bertrand et al., (1997) reported the presence of glial proliferation along with extracellular neuromelanin granules around dying NE neurons. Post-mortem studies carried out in PD patients have established a loss of approximately 70% of NE neurons when compared to age-matched controls (Bertrand et al., 1997; Zarow et al., 2003). Interestingly, the NE neuronal loss was greater in the LC compared to cholinergic loss in the nucleus basalis and dopaminergic loss in the SNpc in Alzheimer and PD patients, respectively (Zarow et al., 2003). Of note, the loss of LC neurons observed in PD patients is not homogenous as there appears to be a disease specific and regional pattern to degeneration in the LC. For example, German and co-workers (1992) observed that in PD patients with no dementia complications, the degeneration was consistent throughout the rostral and caudal portion of the LC, whereas, in PD patients with dementia, the cell loss occurred more severely in the rostral portion of the LC nucleus. These findings have led to the postulation that LC degeneration patterns could be used to classify and differentiate between various sub-groups of PD patients. Comprehensive evidence by Braak and colleagues have found that, in PD patients, the degeneration of NE neurons progressed from lower brain stem regions, like the LC, to more rostral areas, like the SNpc (Braak and Braak, 2000; Braak et al., 2003).

Biochemical evidence obtained from post-mortem and ante-mortem studies in PD patients suggests that NE levels in multiple brain regions, including the motor cortex, hippocampus, striatum, substantia nigra and hypothalamus, are significantly decreased (Gesi et al., 2000). Interestingly, brain regions that are innervated by NE nuclei other than LC are relatively spared from NE loss.

Accumulating evidence strongly suggests that the loss of NE neurons originating from the LC is a very important aspect of the pathophysiology of PD and contributes to the progression of PD, deleteriously affecting the survival of DA neurons. For example, various experimental studies have demonstrated that prior loss of NE innervation increases the vulnerability of the DA neurons to a further neurotoxic insult (Fornai et al., 1995; Mavridis et al., 1991). Conversely, it has been established that increased NE stimulation is neuroprotective against 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced induced neurotoxicity (Kilbourn et al., 1998; Rommelfanger et al., 2004). Thus, it appears that NE may play a neurotrophic role acting as a neuroprotective mechanism for DA neurons. This was corroborated by Tong and colleagues (2006) who found an inverse relationship between intact NE innervation and DA loss in PD patients. Collectively, these findings suggest that the loss of LC neurons precedes and facilitates the subsequent damage to nigrostriatal DA neurons.

Therefore, since NE is known to act as a modulator of the dopaminergic system in various brain regions, the loss of NE appears to be a very critical event in the timeline of PD.
