![]() ![]() There was significant heterogeneity between studies. ![]() Striatal dopaminergic activity in early unilateral PD. We applied the robust standard error method to account for repeat scans in the same individual and checked this with a sensitivity analysis using the generalized estimating equations method. ![]() Laterality was defined in PD cases according to predominant motor signs, with the right side being arbitrarily defined as contralateral when clinical signs were symmetrical. The loss of dopaminergic activity for each brain region was calculated for PD cases as a percentage in relation to average control values, following previous methods. A single scan was also available for age and sex‐matched healthy controls with no first‐degree relatives’ history of idiopathic PD. The imaging was performed at study entry and repeated 1, 2, and 4 years later. Striatal dopamine deficiency was quantified by DaT imaging following standard methods, as a ratio of specific to non‐specific isotope uptake, combined with visual assessment, using 123I‐FP‐CIT and single photon emission computed tomography (SPECT). Cases with a revised diagnosis by consensus committee were excluded ( ). PD patients were recruited with a recent clinical diagnosis, with a minimum of asymmetrical rest tremor and either bradykinesia or rigidity. All analyses were carried out in STATA16 using the metan command.Ĭlinical and Imaging Findings in Early PDĭata from the Parkinson's Progression Markers Initiative (PPMI) study were downloaded in February 2021 ( ). We also display the I‐squared statistic as a measure of heterogeneity.Īn assessment for bias that might result in over‐ or under‐estimation of the degree of dopaminergic loss from smaller studies was performed using funnel plots. In our forest plots we have reported both an inverse‐variance (IV) weighted fixed effect analysis and a DerSimonian‐Laird (DL) random effects analysis. We then carried out a meta‐analysis and displayed all the results in forest plots. Standard errors for the percentage difference were derived using the delta method. Using the brain region summary statistics for the PD cases and controls within each study, we calculated the percentage loss for the PD cases relative to controls. These scores were used to summarize the risk of bias, as well as any concerns raised regarding applicability (Supplementary Table S1). Any disagreements were resolved by discussion, or if necessary, by consultation with a third author (KG). Two reviewers (NH and NM) carried out independent assessment of the studies included, blinded to each other's scores. The methodological quality of each included study was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS‐2), which comprises four key domains: patient selection, index test, reference standard and flow and timing. PRISMA diagram of paper selection for the systematic review. We therefore aimed to synthesize available evidence and the new analysis, to define the extent of dopaminergic loss in the early stages of PD. We focused on findings in relation to duration from diagnosis, and to clinical staging of disease severity. Secondly, we analyzed imaging results from a large multi‐center prospective study in early PD, that followed a standardized protocol with detailed clinical information over the first 6 years after diagnosis of PD, to examine the extent to which these findings matched those from the systematic review. Firstly, we conducted a novel systematic review to assess DaT imaging during the first 6 years after PD diagnosis, to reach a more definitive estimate of the extent of dopamine loss than is possible from smaller individual studies. We used two approaches to address these issues. However, individual studies are generally small, usually single center, and have variation in patient selection, the extent of clinical data collected, and the imaging radiotracer used and method of analysis, all of which influence comparisons between studies, and limit generalizability of results. It was estimated from autopsy studies that 70–80% of striatal dopamine was already depleted by the time motor symptoms emerged,īut it has subsequently been argued that this is likely to be an overestimate, given the limited availability of early‐stage cases, selection bias, effects of tissue degradation after death, and other confounding factors.įunctional imaging studies allow for the measurement of presynaptic dopaminergic cell function during life, in larger numbers of cases, earlier in the disease process, and repeatedly, which increases precision in quantifying dopaminergic activity in early PD. ![]() Neuronal loss was greatest in the ventral tier of the substantia nigra (71–91%) and least in the dorsal tier (46–48%). Nigrostriatal dopaminergic cell loss in Parkinson's disease (PD) was originally assessed in autopsy studies. ![]()
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