The progression of Parkinson's disease (PD) seems to vary according to the disease stage, which greatly influences the management of PD patients. However, the underlying mechanism of progression in PD remains unclear. This study was designed to explore the progressive pattern of iron accumulation at different stages in PD patients. Sixty right-handed PD patients and 40 normal controls were recruited. According to the disease stage, 45 patients with Hoehn–Yahr stage ≤ 2.5 and 15 patients with Hoehn–Yahr stage ≥ 3 were grouped into early-stage PD (EPD) and late-stage PD (LPD) groups, respectively. The iron content in the cardinal subcortical nuclei covering the cerebrum, cerebellum and midbrain was measured using quantitative susceptibility mapping (QSM). The substantia nigra pars compacta (SNc) showed significantly increased QSM values in the EPD patients compared with the controls. In the LPD patients, while the SNc continued to show increased QSM values compared with the controls and EPD patients, the regions showing increased QSM values spread to include the substantia nigra pars reticulata (SNr), red nucleus (RN) and globus pallidus (GP). Our data also indicated that iron deposition was more significant in the GP internal segment (GPi) than in the GP external segment. No other regions showed significant changes in QSM values among the groups. Therefore, we were able to confirm a regionally progressive pattern of iron accumulation in the different stages of PD, indicating that iron deposition in the SNc is affected exclusively in the early stages of the disease, while the SNr, RN and GP, and particularly the GPi segment, become involved in advanced stages of the disease. This is a preliminary study providing objective evidence of the iron-related progression in PD. Copyright © 2016 John Wiley & Sons, Ltd.

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Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping

Parkinson's disease (PD) is histopa- thologically characterized by the loss of dopamine neu- rons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregu- lation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to 1) develop a diffusion tensor tractography pro- tocol for reliably tracking the nigrostriatal fibers on mul- ticenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; and 3) test whether abnormal integri- ties of the nigrostriatal fibers in PD patients are associ- ated with the severity of motor disability and putaminal dopamine binding ratios. Diffusion tensor tractography was performed on 50 drug-na€ ove PD patients and 27 healthy control subjects from the international multicen- ter Parkinson's Progression Marker Initiative. Tractogra- phy consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisot- ropy, along with radial and axial diffusivity of the nigro- striatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were asso- ciated with the degree of motor deficits in PD patients. Taken together, the findings imply that the diffusion ten- sor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD. V C 2015 International Parkinson and Movement Dis- order Society Key W ords: Parkinson's disease; MRI; diffusion ten- sor imaging; diffusion tensor tractography; nigrostriatal pathway

/pdf/diffusion-tensor-imaging-of-the-nigrostriatal-fibers-in-2z8vuc4mb1.pdf

Diffusion tensor imaging of the nigrostriatal fibers in Parkinson's disease.

Interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-α levels in CSF and serum in relation to the clinical diversity of Parkinson's disease.

https://www.archives-pmr.org/article/S0003-9993(11)00087-6/pdf

Freezing of gait and activity limitations in people with Parkinson's disease.

Background and purpose
There have been few long-term studies that have characterized and charted the clinical progression of Parkinson's disease (PD). This study was therefore undertaken to understand the natural clinical evolution of treated PD patients and to identify the variables that predict greater progression in these patients.

Methods
A longitudinal linear mixed model analysis of motor score progression was performed on 576 PD patients derived from the National Neuroscience Institute Movement Disorders Database. Clinical and demographic variables were taken at baseline and formed the subgroups for comparison (gender, age at diagnosis, subtype, Mini-Mental State Examination score and baseline motor score). Motor score progression was calculated at each patient follow-up time point as the difference between Unified Parkinson's Disease Rating Scale (UPDRS) motor score at baseline and follow-up scores.

Results
The overall annual motor score progression as measured by the change of UPDRS motor scores from baseline ranged from 0.62% to 3.67%. There are three distinct phases: improvement, stability, and steady progression. Patients returned to baseline score 2–2.5 years after diagnosis, with stability lasting to 7 years, followed by a period of steady progression. When analyzed longitudinally, male gender (P < 0.03), older age at diagnosis (P < 0.05), akinetic-rigid subtype (P < 0.04), cognitive impairment (P < 0.005) and lower baseline motor score (P < 0.04) were associated with greater progression of motor scores.

Conclusions
Our results show that, when measured clinically, motor progression was non-linear and that it occurred in distinct phases, all of which were affected by baseline demographic and clinical variables such as gender, age at diagnosis, disease subtype, cognitive status and baseline motor score.

Clinical evolution of Parkinson's disease and prognostic factors affecting motor progression: 9-year follow-up study.

This study was carried out to evaluate progression in Parkinson's disease (PD) by analyzing time taken to transit from one Hoehn and Yahr (HY whereas the median time taken to progress from stage 3 to 4 and 4 to 5 were 24 and 26 months, respectively. Cox regression analysis revealed that older age-at-diagnosis, longer PD duration, and higher Unified Parkinson's Disease Rating Scale (UPDRS) motor scores at baseline were associated with a significantly faster progression through various H&Y stages. Gender and ethnicity were not associated with disease progression. In conclusion, H&Y transition time is a useful measure of disease progression in PD and may be utilized in clinical studies evaluating therapeutic interventions and prognostic factors in PD.

Ying Jiao Zhao

Papers

Progression of Parkinson's disease as evaluated by Hoehn and Yahr stage transition times†