No abstract

Exposure to high levels of manganese (Mn) is known to produce a complex neurological syndrome with psychiatric disturbances, cognitive impairment, and parkinsonian features. However, the neurobiological basis of chronic low-level Mn exposure is not well defined. We now provide evidence that exposure to levels of Mn that results in blood Mn concentrations in the upper range of environmental and occupational exposures and in certain medical conditions produces widespread Mn accumulation in the nonhuman primate brain as visualized by T1-weighted magnetic resonance imaging. Analysis of regional brain Mn distribution using a "pallidal index equivalent" indicates that this approach is not sensitive to changing levels of brain Mn measured in postmortem tissue. Evaluation of longitudinal 1H-magnetic resonance spectroscopy data revealed a significant decrease (p = 0.028) in the N-acetylaspartate (NAA)/creatine (Cr) ratio in the parietal cortex and a near significant decrease (p = 0.055) in frontal white matter (WM) at the end of the Mn exposure period relative to baseline. Choline/Cr or myo-Inositol/Cr ratios did not change at any time during Mn exposure. This indicates that the changes in the NAA/Cr ratio in the parietal cortex are not due to changes in Cr but in NAA levels. In summary, these findings suggest that during chronic Mn exposure a significant amount of the metal accumulates not only in the basal ganglia but also in WM and in cortical structures where it is likely to produce toxic effects. This is supported by a significantly decreased, in the parietal cortex, NAA/Cr ratio suggestive of ongoing neuronal degeneration or dysfunction.

The peripheral benzodiazepine receptor (PBR) has been used as a sensitive marker to visualize and measure glial cell activation associated with various forms of brain injury and inflammation. Previous studies have shown that increased PBR levels following brain injury are specific to areas expressing activated glial cells. However, the contribution of glial cell types responsible for the increases in PBR levels following brain injury is not well defined. In the present study, we used a murine model of cuprizone-induced demyelination to broaden the application of PBR as a marker of brain injury and to validate the relationship between PBR levels and glial cell types. C57BL/6J mice were maintained on a cuprizone-containing or control diet and sacrificed at specific time points after initiation of treatment. Quantitative autoradiography of the PBR-selective ligand [(3)H]-(R)-PK11195 and [(125)I]-(R)-PK11195 showed that increased PBR levels were associated with the degree of demyelination assessed by Black-Gold histochemistry and activation of glial cells assessed by glial fibrillary acidic protein (GFAP) immunohistochemistry for astrocytes and CD11b (Mac-1) for microglia. Our findings indicate that brain PBR levels increased as a function of dose and duration of cuprizone treatment and it was detectable prior to observable demyelination. Increased PBR levels were associated with the degree of demyelination and temporal activation of glial cell types in different anatomical regions. In the corpus striatum, we found a close anatomical correlation between microglial activation and increased PBR levels in demyelinating fibre tracts. In the deep cerebellar nuclei, the temporal increases in PBR paralleled demyelination and microglia and astrocyte activation. On the other hand, in the corpus callosum there was an apparent temporal shift in the increase in PBR levels by different glial cell types from an early and predominantly microglial contribution to a late microglial and astrocytic response. High-resolution emulsion autoradiography of [(3)H]-(R)-PK11195 binding to PBR coupled with GFAP or Mac-1 immunohistochemistry showed that demyelination-induced increases in PBR levels were co-localized to both microglia and astrocytes. These findings support the notion that PBR is a sensitive and specific marker for the in vitro and in vivo visualization and quantification of neuropathological changes in the brain.

We used positron emission tomography (PET) to measure the earliest change in dopaminergic synapses and glial cell markers in a chronic, low‐dose MPTP non‐human primate model of Parkinson’s disease (PD). In vivo levels of dopamine transporters (DAT), vesicular monoamine transporter‐type 2 (VMAT2), amphetamine‐induced dopamine release (AMPH‐DAR), D2‐dopamine receptors (D2R) and translocator protein 18 kDa (TSPO) were measured longitudinally in the striatum of MPTP‐treated animals. We report an early (2 months) decrease (46%) of striatal VMAT2 in asymptomatic MPTP animals that preceded changes in DAT, D2R, and AMPH‐DAR and was associated with increased TSPO levels indicative of a glial response. Subsequent PET studies showed progressive loss of all pre‐synaptic dopamine markers in the striatum with expression of parkinsonism. However, glial cell activation did not track disease progression. These findings indicate that decreased VMAT2 is a key pathogenic event that precedes nigrostriatal dopamine neuron degeneration. The loss of VMAT2 may result from an association with α‐synuclein aggregation induced by oxidative stress. Disruption of dopamine sequestration by reducing VMAT2 is an early pathogenic event in the dopamine neuron degeneration that occurs in the MPTP non‐human primate model of PD. Genetic or environmental factors that decrease VMAT2 function may be important determinants of PD.