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.

Applied Neuroscience Research Group CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Neurology Faculty of Medicine Albert Szent Györgyi Clinical Centre University of Szeged Szeged Hungary

Department of Neurology University Hospital LMU Munich Munich Germany

Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar India

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Psychiatry and Psychotherapy University Hospital LMU Munich Munich Germany

Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Scientific Instruments of the Czech Academy of Sciences Brno Czech Republic

Multi modal and Functional Neuroimaging Group CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

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