Mood and motor trajectories in Parkinson's disease: multivariate latent growth curve modeling.

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the loss of dopamine neurons in the midbrain. While PD was initially recognized as a purely motor disorder producing resting tremor, rigidity, bradykinesia and postural instability, the high prevalence of non-motor symptoms has led to its contemporary conceptualization as a neuropsychiatric disorder (Simuni & Sethi 2008). Non-motor symptoms of PD can include depression, apathy, anxiety, psychosis, and sleep disturbance, among several others. In PD, one of the major neuropathologic features is loss of dopaminergic input to the striatum, which disrupts cortico-basal ganglia-thalamocortical circuits (Bar-Gad & Bergman, 2001). The motor symptoms of PD result from dysfunction within the presumed motor loop, which comprises primary motor cortex, putamen, lateral globus pallidus interna, and the ventral lateral nucleus of the thalamus (Gibb, 1997). Parallel basal ganglia loops, however, contain cognitive and affective information flow as well (Alexander, DeLong & Strick, 1986; Middleton & Strick, 2000). The neurodegenerative process responsible for PD may also affect these non-motor loops, many of which refine signals originating in dorsolateral prefrontal, anterior cingulate, and orbitofrontal cortices. Dysfunction within these systems, which partially rely on midbrain dopaminergic input, may underlie certain cognitive and affective symptoms of PD (Obeso et al., 2008). However, there may be other neuroanatomical and neurochemical pathways also responsible for dysfunction. Depression is one of the most common non-motor features of PD, with average prevalence rates in cross-sectional studies in PD reaching 40% in most populations (Brown & Jahanshahi, 1995). The neurobiology of depression in PD is unclear, but one hypothesis involves degeneration of mesolimbic structures of the dopaminergic system, including the ventral tegmental area (VTA; Fibiger, 1984). The neuropatholophysiology of depression in PD is likely more complex, as studies using transcranial sonography have linked PD depression to morphological changes in non-dopaminergic brain regions (Becker et al., 1997; Walter, Skoloudik & Berg, 2009). Further evidence that pathological changes extend beyond those occurring within basal ganglia circuitry is the finding that the relationship between depressive and motor symptoms in PD is not clearly linear (Brown & Jahanshahi, 1995). Several studies have shown that symptoms can worsen and remit over time, with more severe symptoms at baseline predictive of potential depressive symptoms at follow-up (Brown et al., 1988; Ravina et al., 2009; Starkstein et al., 1992). Apathy refers to a lack of motivation and occurs in up to 60% of patients with PD (Leentjens et al., 2008; Marin, 1991). While apathy is a common symptom of depression, it can also manifest as an independent syndrome in up to 30% of patients with PD (Kirsch-Darrow et al., 2006). In contrast to the more heterogeneous neuropathophysiology implicated in PD depression, apathy has been consistently linked to fronto-striatal circuitry involving the anterior cingulate cortex and the striatum (Hama et al, 2007; Lavretsky et al., 2007). For example, patients with more severe apathy exhibit dopaminergic under-activity in the ventral striatum (Remy et al., 2005). Higher levels of apathy are associated with more severe parkinsonian motor symptoms in both PD and Alzheimer's disease (Oguru, et al., 2010; Pedersen et al., 2010; Starkstein et al., 2009). However, the precise relationship between clinical trajectories of motor and apathy symptoms in PD is unknown (Schrag, Jahanshahi & Quinn, 2001). To date, the course of these mood and motor symptoms in PD has not been examined longitudinally using a sophisticated modeling technique. The purpose of the present study was to compare the trajectories of motor, apathy, and depressive symptoms in a cohort of patients with PD followed by a single movement disorders center. Given evidence for stronger relationships between motor symptoms and apathy, as compared to depression, we predicted that both motor and apathy symptoms would worsen linearly. In contrast, we predicted non-linear changes in depressive symptoms based on prior studies suggesting a more complex (e.g., non-dopaminergic) neuropathophysiology of PD depression.