Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

Abstract

The choice of reference region in positron emission tomography (PET) human brain imaging of the vesicular monoamine transporter 2 (VMAT2), a marker of striatal dopamine innervation, has been arbitrary, with cerebellar, whole cerebral, frontal, or occipital cortices used. To establish whether levels of VMAT2 are in fact low in these cortical areas, we measured VMAT2 protein distribution by quantitative immunoblotting in autopsied normal human brain (n = 6). Four or five species of VMAT2 immunoreactivity (75, 55, 52, 45, 35 kDa) were detected, which were all markedly reduced in intensity in nigrostriatal regions of patients with parkinsonian conditions versus matched controls (n = 9 to 10 each). Using the intact VMAT2 immunoreactivity, cerebellar and cerebral neocortices had levels of the transporter > 100-fold lower than the VMAT2-rich striatum and with no significant differences among the cortical regions. We conclude that human cerebellar and cerebral cortices contain negligible VMAT2 protein versus the striatum and, in this respect, all satisfy a criterion for a useful reference region for VMAT2 imaging. The slightly lower PET signal for VMAT2 binding in occipital (the currently preferred reference region) versus cerebellar cortex might not therefore be explained by differences in VMAT2 protein itself but possibly by other imaging variables, for example, partial volume effects.

Effects of anesthetics on vesicular monoamine transporter type 2 binding to 18 F-FP-(+)-DTBZ: a biodistribution study in rat brain

“…As expected, and consistent with the results reported by MP Kung et al [18], 18 F-FP-(+)-DTBZ displayed high concentration in the striatum and moderate uptake in the hippocampus, giving high ST/CB and moderate HP/CB value (Fig 1). In addition, we found there was no significant difference of 18 F-FP-(+)-DTBZ concentration among the frontal, occipital, temporal and parietal cortex in rat brain (data not shown), which was consistent with VMAT2 distribution in human brain [23]. The uptake of the striatum and hippocampus reached transient equilibrium during 60-120 min post 18 F-FP-(+)-DTBZ injection, giving stable ratios of tissue/CB (Fig 1).…”

Low levels of astroglial markers in Parkinson’s disease: relationship to α-synuclein accumulation

“…Findings in the striatum and frontal cortex of PD were largely negative although there were indications (e.g., GFAP aggregation and vimentin truncation) of astroglial activation in the caudate and frontal cortex at least in some of the patients, which is consistent with some literature ((Mythri et al , 2011; Charron et al , 2014), but see (Banati et al , 1998; Mirza et al , 2000)). In the SN, in which nigral neuronal damage was roughly comparable amongst the three disorders by qualitative neuropathological assessment (Supplementary Table 1) and by similar extent of loss of the vesicular monoamine transporter 2 (VMAT2) in SN (Tong et al , 2011a) and dopamine in the striatum (Tong et al , 2010), there was only a trend for increased levels of one of the markers (vimentin) in PD, whereas concentrations of one or more glial markers were significantly above-normal in the other conditions. Interestingly, for GFAP, presently the most commonly used astroglial marker, levels of this marker (total, LMW, and HMW) in about half of the PD cases were actually below the lowest value of the controls.…”

Serotonin and molecular neuroimaging in humans using PET

“…Lowest levels were observed in white matter regions such as the corpus callosum and internal capsule as well as cerebellar regions (Tong et al 2011).…”