Clinical Neuroscience

[Diffusion MRI measured white matter microstructure as a biomarker of neurodegeneration in preclinical Huntington’s disease]

KINCSES Tamás Zsigmond1,2, SZABÓ Nikoletta2,1, TÓTH Eszter3,1, ZÁDORI Dénes1, FARAGÓ Péter1, NÉMETH Dezsõ4, JANACSEK Karolina4, BABOS Magor5, KLIVÉNYI Péter1, VÉCSEI László6,1

NOVEMBER 30, 2013

Clinical Neuroscience - 2013;66(11-12)

[Background - Huntington’s disease is a progressive neurodegenerative disease, genetically determined by CAG trinucleotide expansions in the IT15 gene. The onset of the symptoms is related to the number of CAG triplets. Because the patients are asymptomatic in the early phase of the disease, in vivo biomarkers are needed to follow up the neurodegeneration and to test putative neuroprotective approaches. One such promising biomarker is the diffusion MRI measured microstructural alteration of the white matter. Methods - Seven presymtomatic, mutation carriers and ten age-matched healthy controls were included in the study. Diffusion parameters were compared between groups and correlated with measures describing neurodegeneration. In order to reduce the possible misregistration bias due to atrophy the analysis was restricted to the core of each fibre bundles as defined by maximal fractional anisotropy (Tract- Based Spatial Statistics). Results - Decreased fractional anisotropy, along with increased mean, parallel and perpendicular diffusivity was found in white matter tracts, mainly in the corpus callosum. An inverse correlation was detected between the fractional anisotropy and neurodegeneration score (derived from the number of CAG triplets and the patient age) from the areas of the left precentral gyrus, frontal lobe, corpus callosum and the capsula extrema. Altered diffusion parameters are promising biomarkers of the neurodegeneration in Huntington’s disease.]

AFFILIATIONS

  1. Department of Neurology, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged
  2. International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic
  3. International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czech Republic
  4. Department of Clinical Psychology and Addiction, Institute of Psychology, Eötvös Loránd University, Budapest
  5. Euromedic Hungary Ltd., Szeged
  6. Neuroscience Research Group of the Hungarian Academy of Sciences and University of Szeged

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[Goals - The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) involves the accumulation of endogenous and exogenous toxic substances. The disruption of the proper functioning of certain transporters in the blood-brain barrier and in the blood-cerebrospinal fluid barrier in PD would accompany to that accumulation. Although there is an emerging role of the dysfunction of multidrug resistance-associated proteins (MRPs), members of ATP-binding cassette (ABC) transporter superfamily, in neurodegenerative disorders, there is only a few available data as regards PD. So the aim of our study was the assessment of the role of certain MRPs (1,2,4 and 5) in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Methods - Following the intraperitoneal administration of silymarin (with MRP1, 2, 4 and 5 inhibitory effects), naringenin (with MRP1, 2 and 4 stimulatory effects), sulfinpyrazone (with MRP1, 4 and 5 inhibitory and MRP2 stimulatory effects) and allopurinol (with MRP4 stimulatory effect) in doses of 100 mg/kg, 100 mg/kg, 100 mg/kg and 60 mg/kg, respectively, for one week before and after the administration of MPTP in C57B/6 mice in acute dosing regimen, the striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid has been measured using high-performance liquid chromatography. Results - Although the results of these experiments showed that neither of these substances exerted significant influence on MPTP-induced striatal depletion of dopamine and its metabolites, naringenin exerted a slight prevention of dopamine decrease, while allopurinol considerably enhanced the MPTP-induced lethality in mice. The explanation of these findings would be that the stimulation of MRP1- and MRP2-mediated transport of glutathione conjugates of toxic substances may have slight beneficial effects, while stimulation of MRP4-mediated efflux of brain urate, which has an important antioxidant potency, may worsen the effects of oxidative stress.]

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