Longitudinal decline in striatal dopamine transporter binding in Parkinson’s disease: Associations with apathy and anhedonia

Abstract

Background Motivational symptoms such as apathy and anhedonia are common in Parkinson's disease, respond poorly to treatment, and have been hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in Parkinson's disease, but the association has never been examined longitudinally. We investigated whether the progression of dopaminergic neurodegeneration was associated with emergent apathy and anhedonia symptoms in Parkinson's disease. Methods Longitudinal cohort study of 412 newly diagnosed Parkinson's disease patients followed over five years as part of the Parkinson's Progression Markers Initiative (PPMI) cohort. Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item geriatric depression scale (GDS-15) and part I of the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Dopaminergic neurodegeneration was measured using repeated ioflupane [123-I] single photon emission computed tomography imaging of striatal dopamine transporters (DAT). Results Linear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio(SBR) and apathy/anhedonia symptoms, which emerged as Parkinson's disease progressed (interaction: β = -0.09, 95%CI[-0.15 -0.03], p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average two years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) (β =-0.06, 95%CI[-0.13 0.01]) or motor symptoms indexed by the MDS-UPDRS part III (β =0.20, 95%CI[-0.25 0.65]). Conclusion The relationship between the progression of dopaminergic neurodegeneration and emergent apathy/anhedonia symptoms supports a central role for dopaminergic dysfunction in motivational symptoms in Parkinson's disease. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies.

Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson disease

“…A potential explanation for this pattern is that the MAO-B inhibitor mechanism of action is dependent on presynaptic striatal dopamine neuron integrity, whereas other medication classes, such as dopamine agonists, act postsynaptically. Our results support existing evidence that striatal dopamine dysfunction plays a crucial role in motivation and highlight the need for further understanding of the effect of different dopaminergic therapies on depressive symptoms as PD pathology progresses over time 16 .…”

“…As reported previously in this sample, DAT specific binding ratio (SBR) in participants with PD was, on average, around half that of healthy controls, and as expected, there was evidence of a marked decline over time (mean ± standard deviation (s.d.) percentage reduction from baseline: year 1, −9.7 ± 17.4%; year 2, −16.6 ± 17.7%; year 4, −26.6 ± 18.4%) 16 .…”

“…The 'interest-activity' symptom dimension in depression that includes loss of interest, diminished activity, fatigue and difficulty making decisions has been associated with poor outcome of antidepressant treatment in large prospective clinical studies 14 . People with PD report worse apathy and anhedonia when off dopaminergic medication 10,15 and loss of dopaminergic innervation of the striatum, as measured by single photon emission computed tomography (SPECT) dopamine transporter (DAT) imaging, is associated with emergent motivational symptoms in PD 16 .…”

Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson’s disease

“…Our results support existing evidence that striatal dopamine dysfunction plays a crucial role in motivation, and highlights the need for further understanding of the effect of different dopaminergic therapies on depressive symptoms as PD pathology progresses over time. 34 Optimisation of dopaminergic therapies is often the first strategy in the treatment of depression in PD. 35 However, at present the choice of dopaminergic therapy is largely guided by motor symptoms and potential side effects.…”

Apathy and Motivation: Biological Basis and Drug Treatment

“…Apathy in Parkinson's can often emerge following reduction in medication and is successfully treated with dopamine agonists (8,96,97). A robust negative relationship between reduced striatal dopamine transporter (DAT) levels, a measure of pre-synaptic dopaminergic projection integrity, and motivational symptoms emerges as the disease progresses, independent of depression or motor symptoms (98). In schizophrenia, antipsychotic dopamine antagonists exacerbate motivational deficits, and reduce dopaminergic transmission in the PFC, which has been associated with more severe apathy (99).…”