Parkinson Kinetic Graph : Are Motor Fluctuations in Parkinson Disease Related with Disease Duration ?

Introduction: The Parkinson’s KinetiGraph (PKG) is a digital measurement system for motor fluctuations (FS). The aim of this study is to investigate whether FS, measured by the PKG, are associated with disease duration of Parkinson’s Disease (PD) patients. Material and Methods: 172 PD were included. PKG measurements, clinical data and disease duration were collected. Patients were categorized in four disease duration categories (0 5 years, 6 7 years, 8 11 years and ≥12 years). Kruskal-Wallis and Mann-Whitney U tests were used for statistical analysis. Results: The mean age of the patients is 69.2 years (SD ± 8.13). Disease duration varies between 1 and 28 years. Significant difference was found between the four disease categories in FS (p = 0.050); between group 1 3, p = 0.005. Conclusions: As expected, FS measured by PKG increase during disease progression in PD. In advanced disease stages, FS stabilise, indicating that PKG is the most useful in early and moderate stages of PD.


Introduction
Motor fluctuations (FS) are frequently seen during progression in Parkinson Disease (PD) patients [1] [2].Therapeutic interventions are focused on minimising FS [3] [4].The degree of motor symptoms combined with the degree of disability experienced by patients determines therapeutic decisions.This decision is based on the amount of disturbance/disability the patient is experiencing, but an effective monitoring of these complications is missing.
The severity of these FS used to be measured by clinical rating scales or diaries [3].However, these methods have numerous limitations, including inter-rater subjectivity and inability to measure the motor state of the patient continuously [3] [4].
Recently, the Parkinson's KinetiGraph (PKG) has been developed to measure bradykinesia (BKS), dyskinesia (DKS) and FS almost continuously [3].The aim of this study is to investigate whether the assessment of FS measured by PKG, is correlated with disease duration.

Material and Methods
The PKG is a method that collects movement data by an accelerometer placed around the wrist of the most severely affected side of PD patients [3].Individual scores of BKS, DKS and as a result FS are being calculated [5].
The sample size consists of data from all PD patients with a successful PKG

Results
In total, data of 215 patients who were measured in the period of December 2014 to May 2016 were collected.Of these 215 patients, 18 patients were measured twice and 3 patients were measured three times resulting in a total of 239 measurements.Of these patients, 41 patients with in total 48 measurements met the exclusion criteria and were excluded.Therefore, the statistical analysis is performed on 174 patients with a total of 191 measurements.Of one patient, the disease duration was not known.Table 1 presents the patient characteristics.
Results of the analysis of the variables, subdivided by disease duration are shown in Table 2.
A tendency for a reverse parabolic configuration was found in the FS: a deflecting rising curve between the first three categories and a descending curve between the third and fourth category.There was a significant difference found between the categories (p = 0.050).A significant increase in FS was found between the first and third category (p = 0.005), followed by a slight decrease in the fourth category.

Discussion
Using the PKG, a significant increase in FS was found during disease progression in PD patients.This is in accordance with several studies that found a positive relation in frequency between motor complications (FS and dyskinesias) and disease progression (set by clinical rating scales) [7].However, in our study, FS tend to decrease in the most advanced stages of PD.This is in line with previous studies which described a spontaneous "resolution" or a "remission" of dyskinesia and FS during the later or end stages of PD, without any reduction in levodopa treatment and/or in the dose of anti-Parkinson drugs [8] [9].Papapetropoulos et al. mentioned a decrease in dopaminergic receptor density and post-synaptic degeneration with disease progression as a possible explanation for the resolution [8].We have to take in consideration, that late stage PD patients use significant more walking aid.This could be an explanation for a decline in FS in later stages of PD.When patients use a walker, the wrist is more stable than when walking without.This fixation can have a negative influence on the primary variables.
Surprisingly, no difference in BKS between groups was found.As a result, FS are completely dependent by DKS.We had expected to find lower BKS early in the course of the disease.Possibly, an effective BKS treatment was set in all groups, or the occurrence of DKS was more pronounced in later stages compared to the early stages.Another explanation can be that the PKG is not sensitive enough to measure this difference in BKS.
As expected, the distribution of levodopa intake (times a day) was different between the categories [10].In later stages of PD, levodopa is more frequently used with shorter intervals.Although, not significant, a tendency for increased amounts of levodopa was seen during disease progression, probably to minimise FS [7].
However, in the most advanced PD patients, a slightly decrease in levodopa amount was seen, suggesting that the maximum beneficial level of levodopa was reached.Probably, using supra-maximal levodopa, minimal response was reached and more adverse effects were present [9] [11] [12] [13].On the other hand, other Parkinson medications were more used in later phases of PD.
*For statistical analysis see Table2.

Table 2 .
Disease duration divided in four categories.