Validation of nigrostriatal positron emission tomography measures: critical limits

Abstract

Objective: Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.

Methods: Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells.

Results: Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001).

Interpretation: Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

FIGURE 1

There was flooring effect of striatal FD K_OCC ratio, DTBZ and CFT BP_ND ratio with nigral cell loss > 50%. There was a significant linear correlation between K_OCC or BP_ND and nigral cell count expressed in % of control side excluding those with > 50% nigral cell loss (Pearson: r²= 0.84, p<0.001; r²= 0.86, p< 0.001; r²= 0.87, p<0.001 respectively; n=10).

FIGURE 1

There was flooring effect of striatal FD K_OCC ratio, DTBZ and CFT BP_ND ratio with nigral cell loss > 50%. There was a significant linear correlation between K_OCC or BP_ND and nigral cell count expressed in % of control side excluding those with > 50% nigral cell loss (Pearson: r²= 0.84, p<0.001; r²= 0.86, p< 0.001; r²= 0.87, p<0.001 respectively; n=10).

FIGURE 1

There was flooring effect of striatal FD K_OCC ratio, DTBZ and CFT BP_ND ratio with nigral cell loss > 50%. There was a significant linear correlation between K_OCC or BP_ND and nigral cell count expressed in % of control side excluding those with > 50% nigral cell loss (Pearson: r²= 0.84, p<0.001; r²= 0.86, p< 0.001; r²= 0.87, p<0.001 respectively; n=10).

FIGURE 2

(A) Striatal dopamine measures had flooring effect with > 50% nigral cell loss. (B-D): There was a linear distribution of striatal dopamine (% control side) compared to striatal FD K_OCC, DTBZ and CFT BP_ND (% control side) with or without the clustered data points (Pearson’s correlation: r²= 0.95; r²= 0.94; r²= 0.94 respectively with p<0.001, n=16; r²= 0.84; r²= 0.85; r²= 0.86 respectively with p<0.001, n=10).

FIGURE 2

(A) Striatal dopamine measures had flooring effect with > 50% nigral cell loss. (B-D): There was a linear distribution of striatal dopamine (% control side) compared to striatal FD K_OCC, DTBZ and CFT BP_ND (% control side) with or without the clustered data points (Pearson’s correlation: r²= 0.95; r²= 0.94; r²= 0.94 respectively with p<0.001, n=16; r²= 0.84; r²= 0.85; r²= 0.86 respectively with p<0.001, n=10).

FIGURE 2

(A) Striatal dopamine measures had flooring effect with > 50% nigral cell loss. (B-D): There was a linear distribution of striatal dopamine (% control side) compared to striatal FD K_OCC, DTBZ and CFT BP_ND (% control side) with or without the clustered data points (Pearson’s correlation: r²= 0.95; r²= 0.94; r²= 0.94 respectively with p<0.001, n=16; r²= 0.84; r²= 0.85; r²= 0.86 respectively with p<0.001, n=10).

FIGURE 2

(A) Striatal dopamine measures had flooring effect with > 50% nigral cell loss. (B-D): There was a linear distribution of striatal dopamine (% control side) compared to striatal FD K_OCC, DTBZ and CFT BP_ND (% control side) with or without the clustered data points (Pearson’s correlation: r²= 0.95; r²= 0.94; r²= 0.94 respectively with p<0.001, n=16; r²= 0.84; r²= 0.85; r²= 0.86 respectively with p<0.001, n=10).

FIGURE 3

Right-left ratio of striatal uptake for each radiotracer expressed in % of control side strongly correlated with each of the other two (Pearson: r²=0.98, p<0.001).