Magnetic Resonance Imaging Features of the Nigrostriatal System: Biomarkers of Parkinson's Disease Stages?

INTRODUCTION: Magnetic resonance imaging (MRI) can be used to identify biomarkers in Parkinson's disease (PD); R2* values reflect iron content related to high levels of oxidative stress, whereas volume and/or shape changes reflect neuronal death. We sought to assess iron overload in the nigrostriatal system and characterize its relationship with focal and overall atrophy of the striatum in the pivotal stages of PD. METHODS: Twenty controls and 70 PD patients at different disease stages (untreated de novo patients, treated early-stage patients and advanced-stage patients with L-dopa-related motor complications) were included in the study. We determined the R2* values in the substantia nigra, putamen and caudate nucleus, together with striatal volume and shape analysis. We also measured R2* in an acute MPTP mouse model and in a longitudinal follow-up two years later in the early-stage PD patients. RESULTS: The R2* values in the substantia nigra, putamen and caudate nucleus were significantly higher in de novo PD patients than in controls. Early-stage patients displayed significantly higher R2* values in the substantia nigra (with changes in striatal shape), relative to de novo patients. Measurements after a two-year follow-up in early-stage patients and characterization of the acute MPTP mouse model confirmed that R2* changed rapidly with disease progression. Advanced-stage patients displayed significant atrophy of striatum, relative to earlier disease stages. CONCLUSION: Each pivotal stage in PD appears to be characterized by putative nigrostriatal MRI biomarkers: iron overload at the de novo stage, striatal shape changes at early-stage disease and generalized striatal atrophy at advanced disease.

Self-perceived and actual ability in the functional reach test in patients with Parkinson's disease.

Falls frequently occur during daily activities such as reaching for an object in patients with Parkinson's disease (PD). Misjudgment is also reported to be one of the circumstances that lead to falls. The functional reach test is an indicator of dynamic balance. The primary objective was to establish whether there is a difference between self-perceived and actual ability to perform the functional reach test in patients with PD who have never fallen. Three groups of participants (all with no history of falls) were studied: young adults, elderly adults and PD patients. The participants first estimated their maximum reaching distance (but without performing the action, i.e. as a motor imagery task) and then actually performed the functional reach test (i.e. as a motor task). No significant overestimation or underestimation was observed. The reaching distance was lower in PD than in the two other groups. There were no differences between PD patients and elderly adults in terms of the forward centre of pressure displacement. Seven PD patients reported a fall in the year following the experiment. The fallers had a longer history of disease. Finally, PD patients adequately estimated their ability in the functional reach test and did not adopt an "at risk" strategy and appeared to be quite conservative (as were healthy elderly adults) in their postural control behavior. Ability to estimate self-performance is preserved in PD patients with no clinical impairments of postural control although they are at risk of future falls.

Auditory cueing of gait initiation in Parkinson's disease patients with freezing of gait.

OBJECTIVE: Impaired gait initiation (GI) in patients with advanced Parkinson's disease (PD) is a typical functional sign of akinesia. Failure to initiate the first step is frequently presented by patients with freezing of gait (FOG) and is often considered a sub-type of freezing. The literature on the effects of cueing of GI preparation and execution remains controversial. Our objective was to establish whether auditory cueing improves the preparation and/or execution of GI in PD patients with a history of FOG. METHODS: We recorded first-step preparation and execution in 30 PD patients with confirmed FOG under two randomised conditions: self-triggered (ST) gait and gait cued by a sound beep in off- and on-dopa conditions. Anticipatory postural adjustments (APAs) were evaluated by monitoring the trajectory of the centre of pressure. RESULTS: We compared the patients with 30 patients without history of FOG and 30 healthy controls (HCs). l-Dopa only slightly improved the characteristics of APAs in freezers but was effective to improve gait hypokinesia. Auditory cueing was effective in improving step preparation in freezers, who showed adequate APAs more frequently. As seen with HCs and patients without FOG, patients released their APAs more quickly when auditory cueing was applied. However, cueing did not have a significant effect on step length. Clinically, auditory cueing also improved start hesitation in freezers. CONCLUSIONS: Auditory cueing improved step preparation but not step execution in PD patients. SIGNIFICANCE: A failure to link step preparation and execution during GI may explain the poor first-step execution seen in PD freezers.

Targeting chelatable iron as a therapeutic modality in Parkinson's disease.

AIMS: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. RESULTS: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. INNOVATION: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. CONCLUSIONS: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.