Progression of monoaminergic dysfunction in Parkinson's disease: A longitudinal ¹⁸F-dopa PET study

Abstract

Post-mortem and neuroimaging studies in Parkinson's disease (PD) have shown involvement of the brain serotoninergic, noradrenergic and cholinergic pathways alongside the characteristic degeneration of nigrostriatal dopamine neurons. The rate of progression of the degenerative process in these extrastriatal areas is still unclear.

We used ¹⁸F-dopa PET, a marker of aromatic aminoacid decarboxylase activity in monoaminergic neurons, to assess longitudinal changes in tracer uptake in brain noradrenergic, serotoninergic and extrastriatal dopaminergic structures over a 3-year period in a group of early PD patients.

Ten PD patients had ¹⁸F-dopa PET twice: at baseline and again after 37.1 ± 21.5 months follow up. A standard object map was used to extract tracer influx constants (Ki) in 11 striatal and extrastriatal regions.

Progressive decreases in ¹⁸F-dopa Ki occurred over the follow-up period in the majority of the investigated areas, the fastest annual declines occurring in putamen (8.1%), locus coeruleus (7.8%), and globus pallidus interna (7.7%). Caudate and hypothalamus showed 6.3% and 6.1% annual Ki declines, respectively. At baseline, some structures showed increased levels of ¹⁸F-dopa uptake in PD compared to controls (internal pallidum, locus coeruleus), indicating possible compensatory upregulation of monoamine turnover. These increased levels had normalised (globus pallidus interna) or become subnormal (locus coeruleus) at follow-up suggesting exhaustion of these mechanisms within the first years of disease.

Loss of monoaminergic function in extrastriatal regions, as reflected by¹⁸F-dopa PET, is delayed and occurs independently from nigrostriatal degeneration. When assessing the efficacy of novel neuroprotective agents on nigrostriatal dysfunction in PD, ¹⁸F-dopa PET could provide supplementary information concerning function of extrastriatal monoaminergic structures.

Introduction

Parkinson's disease (PD) targets the nigrostriatal dopaminergic system causing progressive denervation. The presence of α-synuclein- and ubiquitin-positive Lewy bodies and Lewy neurites in surviving nigral neurons is considered its pathological hallmarks. However, neuropathological studies and biochemical and neuroimaging findings in PD patients have documented the occurrence of significant concomitant degeneration in non-dopaminergic pathways, including serotonin, noradrenaline, and acetylcholine containing neurons (Halliday et al., 1990, Gesi et al., 2000, Hirsch et al., 2003, Kish et al., 2008). Dysfunction of these systems could contribute to the motor symptoms of PD [loss of raphe serotonin HT1A binding is reported to be associated with parkinsonian tremor (Doder et al., 2003)] and also plays a significant role in the development of non-motor features such as sleep disorders, fatigue, dementia, and depression, so providing possible targets for pharmacological interventions to treat these symptoms.

Current knowledge concerning rates of disease progression in non-dopaminergic structure is limited. Based on patterns of abnormal immunostaining for α-synuclein, it has been suggested that Lewy bodies and Lewy neurites first appear in the medullary dorsal nucleus of the vagus and the pathology then ascends to involve non-dopaminergic brainstem structures in the pons, such as the locus coeruleus and median raphe, antedating by several years the involvement of the substantia nigra in the midbrain and the appearance of the classical motor signs. Lewy body pathology then progressively extends in a rostral direction to involve the nucleus basalis, the forebrain, and, in the final stages, the neocortex (Braak et al., 2004). However, while the pathology of PD may be ascending in nature, the associated dysfunction is highly variable from structure to structure and the rate of disease progression in individual non-dopaminergic regions and in extrastriatal dopaminergic structures remains unclear. Additionally, the relationship between decline in striatal function in PD and dysfunction in extra-striatal areas remains to be clarified.

¹⁸F-dopa PET, a marker of monoaminergic nerve terminal function, has been extensively used to evaluate severity and progression of presynaptic nigrostriatal dysfunction in PD. Striatal uptake of ¹⁸F-dopa, which reflects aromatic amino acid decarboxylase activity (AADC), correlates well with nigral cell counts and striatal tyrosine hydroxylase activity in both human cases and in primates with MPTP induced parkinsonism (Snow et al., 1993, Pate et al., 1993). Longitudinal studies with serial ¹⁸F-dopa PET have shown that the mean annual rate of ¹⁸F-dopa uptake decline in PD patients ranges from 8% to 12% of the baseline value in the putamen and 4% to 6% in the caudate compared with an annual decline less than 1% in normal volunteers (Vingerhoets et al., 1994, Morrish et al., 1996, Morrish et al., 1998, Nurmi et al., 2001, Nurmi et al., 2003).

In non-dopaminergic structures, ¹⁸F-dopa is taken up by the large neutral aminoacid transporter and decarboxylated by AADC in serotonin and noradrenaline terminals so providing an index of function of these terminals (Brown et al., 1999, Moore et al., 2003). In this report, we have used serial ¹⁸F-dopa PET to assess rates of progression of serotoninergic, noradrenergic, and extrastriatal dopaminergic dysfunction in patients with early PD. Changes over time in ¹⁸F-dopa uptake in extra-striatal structures were then compared with the rates of progression of striatal dysfunction in the same patients in order to better elucidate the time-course of the different aspects of the neurodegenerative process in PD.