Cerebrospinal fluid to brain transport of manganese in a non-human primate revealed by MRI

Abstract

Manganese overexposure in non-human primates and humans causes a neurodegenerative disorder called manganism thought to be related to an accumulation of the metal in the basal ganglia. Here, we assess changes in the concentration of manganese in regions of the brain of a non-human primate (the common marmoset, Callithrix jacchus) following four systemic injections of 30 mg/kg MnCl 2 ·H 2 0 in the tail vein using T 1 -weighted magnetic resonance imaging (MRI) and compare these to changes in the rat following the same exposure route and dose. The doses were spaced 48 hours apart and we imaged the animals 48 hours after the final dose. We find that marmosets have significantly larger T 1 -weighted image enhancements in regions of the brain compared to rats, notably in the basal ganglia and the visual cortex. To confirm this difference across species reflects actual differences in manganese concentrations and not variations in the MRI properties of manganese, we measured the longitudinal relaxivity of manganese (χ 1 ) in the in vivo brain and found no significant species' difference. The high manganese uptake in the marmoset basal ganglia and visual cortex can be explained by CSF-brain transport from the large lateral ventricles and we confirm this route of uptake with time-course MRI during a tail-vein infusion of manganese. There is also high uptake in the substructures of the hippocampus that are adjacent to the ventricles. The large manganese accumulation in these structures on overexposure may be common to all primates, including humans.

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

“…According to a recent study, such differential distribution of manganese in the brain can be explained by preferential manganese transport via cerebrospinal fluid (CSF) and thus a higher manganese uptake in the brain structures adjacent to the ventricles (Bock et al, 2008a). Manganese-enhanced tissue contrast in cortical regions has been also reported in animals by several investigators, yet using much higher manganese concentrations than used in the present study (Bissig and Berkowitz, 2009;Bock et al, 2009;Silva et al, 2008).…”

“…Contrary to numerous toxicological studies, there is a common consensus in the existing MEMRI literature that rodents do not develop serious behavioral abnormalities or neural deficits following manganese exposure (Bissig and Berkowitz, 2009;Bock et al, 2008a;Yu et al, 2005). Unfortunately, MRI studies do not necessarily include a formal behavioral test and an assessment of potential toxic effects of manganese is usually limited to a rather subjective general observation of animal behavior in the home cage.…”

“…This dose range, however, is likely to produce such adverse side effects as depressed general activity, somnolence, transient weight loss, skin irritation, bleeding or necrosis at the injection site (Bock et al, 2008a;Bock et al, 2008b;Silva et al, 2004). Differential sensitivity to manganese at cellular, physiological or behavioral levels is not surprising.…”

“…One possible way to decrease manganese toxicity while keeping MRI-detectable levels of the ion, is to avoid transient high concentrations by slowly infusing larger volumes of diluted manganese using, for instance, osmotic pumps (Canals et al, 2008). Also, fractionated MEMRI has been suggested as an improved method of systemic manganese delivery by means of repeated administration of relatively low (30 mg/kg) doses of manganese with 48 h interval between injections (Bock et al, 2008a). However, the behavioral consequences of different administration protocols have never been studied in detail.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…In the brain, transthyretin is uniquely secreted by choroid plexus epithelial cells into the CSF in a continuous manner and throughout life [117], allowing long-term diffusion within the neuropil. Periventricular cellular uptake from CSF followed by retrograde transport also occurs, as exemplified for manganese [4,12]. Circumventricular organs (CVOs) which are either sensing or secreting organs interacting with the peripheral blood are juxtaposed to CSF spaces and a specific CSF-CVO dialogue takes place across the tanycytes bordering the CSF side of CVOs [65,95].…”