[123I]-IBVM SPECT imaging of cholinergic systems in multiple system atrophy: A specific alteration of the ponto-thalamic cholinergic pathways (Ch5–Ch6)

Abstract

We evaluated in vivo the integrity of brain cholinergic pathways in Multiple System Atrophy (MSA) and the relationship between cholinergic dysfunction and motor disturbances, by measuring the vesicular acetylcholine transporter (VAChT) expression using Single Photon Emission Computed Tomography (SPECT) and [123I]-iodobenzovesamicol ([123I]-IBVM).MethodsNine patients with probable MSA and 12 healthy volunteers underwent a dynamic [123I]-IBVM SPECT–CT scan and a magnetic resonance imaging (MRI) scan. All patients were examined with the Unified MSA Rating Scale (UMSARS; subscale I = activities of daily living (ADL), II = motor and IV = disability). CT and MRI images were used to register the dynamic SPECT image to the Montreal Neurological Institute brain template, which includes the regions of interest (ROI) of striatum and Ch1 (medial septum nucleus-hippocampus), Ch4 (nucleus basalis of Meynert-cortex) and Ch5–Ch6 (pedunculopontine and laterodorsal tegmental nuclei-thalamus) cholinergic pathways. For each ROI, pharmacokinetic modeling of regional time activity curves led to the calculation of [123I]-IBVM to VAChT binding potential (BPND) value, proportional to VAChT expression.ResultsWhen compared to controls, BPND values for MSA in Ch5–Ch6 were significantly decreased in both the pedunculopontine–laterodorsal nuclei and the thalamus (p = 0.004 and p = 0.006, respectively). Additionally, thalamus BPND values were correlated with UMSARS ADL (p = 0.006), motor (p = 0.002) and disability (p = 0.02) sub-scores. UMSARS motor subscale items 13 (postural instability) and 14 (gait) were also correlated with thalamus BPND values (p = 0.04).ConclusionCh5–Ch6 are the most affected cholinergic pathways in MSA at both cell bodies and thalamic cholinergic terminals. These results underscore the relevant role of [123I]-IBVM SPECT for improving our understanding of the pathophysiology in MSA.

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

“…Increased cerebellar lactate peaks measured in 1 H MR spectroscopy could contribute to distinguish SCA2 from MSA-C [165]. Moreover, SPECT and PET data point out possible: (1) hypometabolism in cerebellum, middle cerebellar peduncle, pons and putamen, (2) presynaptic nigrostriatal dopaminergic denervation, and (3) alteration of the cholinergic (Ch5–Ch6) projections from pedunculopontine and laterodorsal tegmental nuclei to the thalamus correlated with motor and disability impairments [166, 167]. In conclusion, no MRI abnormality seems to be specific of MSA-C. A combined MRI and dopamine receptor imaging with [123I]-IBZM-SPECT reported a more severe cerebellar and brainstem atropy with MSA-C than MSA-P, while the loss of dopamine receptor was identical in both groups [168].…”

Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter

“…[19-22] Among the benzovesamicol analogues shown in Figure 1 , 5-( N -methyl-amino)benzovesamicol ( 3 , MABV) and N -ethyl-fluoroacetamidobenzovesamicol ( 4 , NEFA) are more potent inhibitors and more selective for VAChT versus σ receptors than vesamicol. [23] Furthermore, the single-photon emission computerized tomography (SPECT) radiotracer (-)-5-[ 123 I]iodo-benzovesamicol ([ 123 I] 5 , [ 123 I]IBVM) was used for mapping cholinergic terminals in the human brain [7-9, 24-27] although quantification of peak uptake in the target regions required at least 6 hr post-injection (p.i.). Although SPECT is a useful tool for studies of ligands with slow kinetic processes,[28] PET offers higher spatial resolution and sensitivity for clinical studies of ligands with more rapid pharmacokinetics.…”

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

“…In some studies of MSA, however, a-synuclein-immunoreactive NCI have been observed in the DG (Takeda et al 1997;Wakabayashi et al 1998). Consistent with these conclusions, imaging studies suggest significantly less atrophy of the temporal lobe and HC in CBD (Markus et al 1995;Seritan et al 2004), DLB (Barber et al 2001), PD (Rektorova et al 2014;Lee et al 2013), PSP (Saini et al 2013), and MSA (Mazere et al 2013). However, in PD-Dem, using MRI source-based morphometry, atrophy of temporal lobes and HC has been observed in some cases (Rektorova et al 2014).…”