Diffusion kurtosis imaging detects the time‐dependent progress of pathological changes in the oral rotenone mouse model of Parkinson's disease

Abstract

Clinical diagnosis of Parkinson's disease (PD) occurs typically when a substantial proportion of dopaminergic neurons in the substantia nigra (SN) already died, and the first motor symptoms appear. Therefore, tools enabling the early diagnosis of PD are essential to identify early‐stage PD patients in which neuroprotective treatments could have a significant impact. Here, we test the utility and sensitivity of the diffusion kurtosis imaging (DKI) in detecting progressive microstructural changes in several brain regions of mice exposed to chronic intragastric administration of rotenone, a mouse model that mimics the spatiotemporal progression of PD‐like pathology from the ENS to the SN as described by Braak's staging. Our results show that DKI, especially kurtosis, can detect the progression of pathology‐associated changes throughout the CNS. Increases in mean kurtosis were first observed in the dorsal motor nucleus of the vagus (DMV) after 2 months of exposure to rotenone and before the loss of dopaminergic neurons in the SN occurred. Remarkably, we also show that limited exposure to rotenone for 2 months is enough to trigger the progression of the disease in the absence of the environmental toxin, thus suggesting that once the first pathological changes in one region appear, they can self‐perpetuate and progress within the CNS. Overall, our results show that DKI can be a useful radiological marker for the early detection and monitoring of PD pathology progression in patients with the potential to improve the clinical diagnosis and the development of neuroprotective treatments.

Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein

“…Interestingly, when compared to WT mice, we observed that ASYN KO mice showed a poorer performance in the rotarod test even before exposure to rotenone. In WT mice, exposure to rotenone normally leads to impair motor function and a significant decrease in the number of dopaminergic TH + neurons in rotenone-exposed mice when compared to vehicle-treated mice [11,12,16]. Whereas there seems to be a disconnection between the normal number of TH + neurons in the SNc and the reduced performance in the rotarod test, these results would be in accordance with previous observations.…”

“…To investigate the role of ASYN in this progression, we exposed 1-yo ASYN KO mice (B6;129×1- Snca tm1Rosl /J, Jackson Laboratories) to orally administered rotenone or vehicle for 2 and 4 months (experimental timeline in Figure 1). WT (C57BL/6) mice where used as a control for the genetic background (results already published, see Figure 3 in [16]). In ASYN KO mice, the number of TH + neurons was comparable to the number of dopaminergic neurons in the SNpc of WT mice and, contrary to what was observed in WT mice, orally administered rotenone did not induce changes in the number of TH + neurons in the SN even after 4 months of rotenone exposure (see Figure 2A-F).…”

“…The WT mice were treated following the same experimental design. Details on the experimental conditions and the results obtained can be found here [16]. Exclusion criteria included sickness (unrelated to rotenone exposure), persistent weight loss or death before the end of experiment and no mice needed to be excluded from the study.…”

“…Carboxymethylcellulose solution 2% with 1.25% chloroform was used as a vehicle in control animals. This animal model was generated in parallel to 1-year old WT mice (protocol and results published in [16]) by administration via intragastric gavage 5 days per week for 2 or 4 months (see Supplementary Figure 2). The oral administration was always performed during the morning hours between 09:00 and 11:00 AM.…”

Non-Reproducibility of Oral Rotenone as a Model for Parkinson’s Disease in Mice

“…Nevertheless, the majority of oral rotenone-PD studies claimed the model as suitable [ 21 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 33 , 34 , 35 , 37 , 43 , 44 , 58 , 59 ]. Some of these studies used different solvents, such as sunflower oil 4% or 2% carboxymethylcellulose with 1.25% chloroform, which likely affects absorption [ 59 , 60 , 61 , 62 ] but not so much first-pass metabolism. According to SwissADME prediction ( , accessed on 6 September 2022), GI absorption is per se high, and rotenone is substrate and inhibitor of cytochrome P450 enzymes.…”