Striatal Dopamine Loss in Early Parkinson's Disease: Systematic Review and Novel Analysis of Dopamine Transporter Imaging

Abstract

Background Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50–80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly. Objective To quantify dopamine transporter (DaT) activity by neuroimaging in early PD. Methods Systematic review and novel analysis of DaT imaging studies in early PD. Results In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6). Conclusions Loss of striatal DaT activity in early PD is less at 35–45%, rather than the 50–80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.

Aging hastens locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

“…While PD is a multifactorial disease, with pathological changes including neuroinflammation, increased oxidative stress, and ubiquitin-proteasome system failure, the defining and distinctive pathology that leads to the disease is a loss of dopaminergic neurons in the SN (McDonald et al, 2018; Hartmann et al, 2004; McNaught et al, 2001; Hirsch et al, 2003). Regardless of whether PD is idiopathic or of familial origin, postmortem studies show a variable 50-90% DA cell loss in the SN, while >80% loss in the striatum is associated with the onset of characteristic motor phenotype (Kordower et al, 2013; Nybo et al, 2020; Mazumder et al, 2022; Heng et al, 2023). Arguably, rodent PD models must reflect the human nigrostriatal pathologies.…”

Striatal dopamine depletion drives disease progression and network topology aberrations specifically by impairing left M1 network

“…Striatal dopamine depletion is a key hallmark of PD and contributes to the development of both motor and non-motor symptoms. 5,7,8,10 The loss of midbrain dopamine neurons is associated with the impairment of initiation, speed, and fluidity of voluntary movement. 50 It is generally hypothesized that striatal dopamine depletion causes dysfunction of basal ganglia-thalamocortical circuit, which results in the occurrence of motor impairment in PD.…”

“…4 Dopamine transporter imaging using single-photon emission computed tomography (DAT-SPECT) is one of the most highly developed supplementary assessments for PD, which is utilized to indirectly measure DAT availability in straitum. 5,6 Striatal binding ratio (SBR) in striatum measured by DAT-SPECT has been demonstrated to be associated with motor manifestations, including rigidity, 7,8 resting tremor, 9 and bradykinesia. 8 Apart from its associations with motor symptoms, striatum SBR was also linked to multiple non-motor symptoms, such as RBD, 10 cognitive impairment, 10–13 anxiety, 10 apathy, 14 depression, 15,16 impulse control disorders, 17 sexual dysfunction, 18 urinary dysfunction, 19 cardiovascular dysfunction, 20 gastrointestinal dysfunction, 21 and olfaction loss.…”

Age-induced midbrain-striatum assembloids model early phenotypes of Parkinson’s disease

“…Before the onset of neuronal loss there is significant decrease of dopaminergic axons in the striatum. This reduction in dopaminergic axons is twice as pronounced in the striatum compared to the decrease in dopaminergic neuronal cells in the SNpc (Chung et al, 2020; Heng et al, 2023; L. H. Li et al, 2009; Tagliaferro & Burke, 2016). However, due to the research focus on the loss of neurons, which is the ultimate endpoint of the disease, the mechanisms of the retrograde dopaminergic axons’ degeneration from the striatum are still not understood (Tagliaferro & Burke, 2016).…”

“…Before the onset of neuronal loss there is significant decrease of dopaminergic axons in the striatum. This reduction in dopaminergic axons is twice as pronounced in the striatum compared to the decrease in dopaminergic neuronal cells in the SNpc (Chung et al, 2020;Heng et al, 2023;L. H. Li et al, 2009;Tagliaferro & Burke, 2016).…”