Non-human primate FOG develops with advanced parkinsonism induced by MPTP Treatment

Abstract

Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD) and other forms of parkinsonism. The anatomical or pathophysiological correlates are poorly understood largely due to the lack of a well-established animal model. Here we studied whether FOG is reproduced in the non-human primate (NHP) model of PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (Genus Macaca, n=29) were examined for the development of FOG, and the leg movements were recorded with accelerometry. The relationships between developing FOG and the animals' characteristics, the MPTP treatments, and the modeled outcomes were determined. In parkinsonian monkeys FOG developed frequently (48%) manifesting similar characteristics to those seen in PD patients. In addition, FOG episodes in the monkey were accompanied by leg trembling with the typical duration (2-10s) and frequency (~7 Hz). The development of NHP FOG was significantly associated with the severity of parkinsonism, as shown by high motor disability scores (≥ 20) and levodopa-induced dyskinesia scores (p=0.01 and p=0.04, respectively). Differences in demographics and MPTP treatments (doses, treatment duration, etc.) had no influence on NHP FOG occurrence, with the exception of gender that showed FOG predominance in males (p=0.03). The unique features of FOG in PD can be replicated in severely parkinsonian macaques, and this represents the first description of a FOG animal model.

Fig 1

Variability in the tremor associated with FOG in the MPTP-treated monkey. The oscillatory movements recorded with an accelerometer placed on the back of the leg during 3 episodes of tremor associated with FOG as examples of variability are shown in the three traces. The raster on top of each trace shows the detection of full phase oscillations above the threshold. The frequency and duration of the tremor were calculated on the constructed raster. Tremor frequencies in these episodes were: 6.0, 7.8, and 6.6 Hz from top to bottom traces, respectively. Tremor durations in these episodes are shown next to each raster.

Fig 2

Analysis of the evolution of FOG episodes in the MPTP-treated monkey. A and B, recordings of leg movements with an accelerometer placed on the back of the leg during the whole duration of FOG episodes (~15 s). Each episode (A and B) has regular oscillations corresponding to tremor before the end of freezing. The freezing episode showed in B also has some initial oscillatory movements that did not qualify as tremor according to the pre-established criteria. Also in B, the end of the freezing episode is followed by gait festination. The traces show raw accelerometry data. C and D, rate meters for the whole duration of the FOG episodes corresponding to A and B, respectively. The peaks correspond to the tremor periods towards the end of the freezing episode when walk restarts. Rate meters used the data produced after detection of full phase oscillations above the threshold. The graphs were constructed with a bin width of 500 ms, and smoothed using a Gaussian filter. E, distribution of FOG tremor frequencies. The graph shows the frequencies (Hz) found across 20 recordings of tremor, each in a separate FOG episode. The average rate in the recorded tremors was 7.07 Hz (±1.47 STD).