Joint pattern analysis applied to PET DAT and VMAT2 imaging reveals new insights into Parkinson's disease induced presynaptic alterations

Abstract

Most neurodegenerative diseases are known to affect several aspects of brain function, including neurotransmitter systems, metabolic and functional connectivity. Diseases are generally characterized by common clinical characteristics across subjects, but there are also significant inter-subject variations. It is thus reasonable to expect that in terms of brain function, such clinical behaviors will be related to a general overall multi-system pattern of disease-induced alterations and additional brain system-specific abnormalities; these additional abnormalities would be indicative of a possible unique system response to disease or subject-specific propensity to a specific clinical progression. Based on the above considerations we introduce and validate the use of a joint pattern analysis approach, canonical correlation analysis and orthogonal signal correction, to analyze multi-tracer PET data to identify common (reflecting functional similarities) and unique (reflecting functional differences) information provided by each tracer/target. We apply the method to [ 11 C]-DTBZ (VMAT2 marker) and [ 11 C]-MP (DAT marker) data from 15 early Parkinson's disease (PD) subjects; the behavior of these two tracers/targets is well characterized providing robust reference information for the method's outcome. Highly significant common subject profiles were identified that decomposed the characteristic dopaminergic changes into three distinct orthogonal spatial patterns: 1) disease-induced asymmetry between the less and more affected dorsal striatum; 2) disease-induced gradient with caudate and ventral striatum being relatively spared compared to putamen; 3) progressive loss in the less affected striatum, which correlated significantly with disease duration ( p < 0.01 for DTBZ, p < 0.05 for MP). These common spatial patterns reproduce all known aspects of these two targets/tracers. In addition, orthogonality of the patterns may indicate different mechanisms underlying disease initiation or progression. Information unique to each tracer revealed a residual striatal asymmetry when targeting VMAT2, consistent with the notion that VMAT2 density is highly related to terminal degeneration; and a residual DAT disease-induced gradient in the striatum with relative DAT preservation in the substantia nigra. This finding may be indicative either of a possible DAT specific early disease compensation and/or related to disease origin. These results demonstrate the applicability and relevance of the joint pattern analysis approach to datasets obtained with two PET tracers; this data driven method, while recapitulating known aspects of the PD-induced tracer/target behaviour, was found to be statistically more robust and provided additional information on (i) correlated behaviors of the two systems, identified as orthogonal patterns, possibly reflecting different disease-induced alterations and (ii) system specific effects of ...

Cardiac sympathetic innervation and vesicular storage in pure autonomic failure

“…Positron-emitting analogs of the VMAT2 inhibitor tetrabenazine (e.g., 18 F-dihydrotetrabenazine, 11 C-dihydrotetrabenazine) might have been an alternative to 11 C-MRB, since VMAT2 ligands have been used successfully in several studies to assess intraneuronal vesicular uptake in the brain; [36][37][38] however, these agents also cannot distinguish a vesicular storage defect from denervation; moreover, there seems to be relatively little cardiac compared to brain uptake of 18 F-dihydrotetrabenazine in humans. 39 Perspective If the present estimate were correct that there is an approximately 40% loss of cardiac sympathetic nerves in PAF, then in order to account for drastic myocardial NE deficiency in PAF the majority of residual nerves would have to be dysfunctional-"sick-but-not-dead."…”

“…Positron‐emitting analogs of the VMAT2 inhibitor tetrabenazine (e.g., 18 F‐dihydrotetrabenazine, 11 C‐dihydrotetrabenazine) might have been an alternative to 11 C‐MRB, since VMAT2 ligands have been used successfully in several studies to assess intraneuronal vesicular uptake in the brain; 36‐38 however, these agents also cannot distinguish a vesicular storage defect from denervation; moreover, there seems to be relatively little cardiac compared to brain uptake of 18 F‐dihydrotetrabenazine in humans 39 …”

Positron emission tomography/computed tomography dual imaging using 18-fluorine flurodeoxyglucose and 11C-labeled 2-β-carbomethoxy-3-β-(4-fluorophenyl) tropane for the severity assessment of Parkinson disease

“…DAT imaging can assess the location, density, and function of DAT lesions and determine the severity of PD. [ 22 – 23 ] In PD patients, given that the degeneration and attrition of the dopaminergic neurons in the substantia nigra are usually accompanied by a reduction in the amount and function of DAT on the presynaptic membrane, a reduced uptake of the contrast medium by the striatum indicates a decline in the DAT function. Studies [ 24 – 25 ] have noted the binding of 11 C-CFT to DAT with high specificity in the basal ganglia of PD patients.…”

Dopamine transporter imaging in neurodegenerative movement disorders: PET vs. SPECT

“…Regarding imaging of the pre-synaptic dopaminergic system, more targets exist than just the DAT. PET radioligands for the vesicular monoamine transporter (VMAT2) or aromatic l-amino acid decarboxylase (AADC) are available and widely used as imaging tools for PD [4,6,64]. SPECT tracers for the same targets are not available.…”