The bioenergetic status relates to dopamine neuron loss in familial PD with PINK1 mutations.

Mutations in the PINK1 gene cause autosomal recessive familial Parkinson's disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous ((31)P) and proton ((1)H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA K(i) values correlated positively with MI (r = 0.879, p<0.001) and inversely with β-ATP (r = -0.784, p = 0.008) and GPC concentrations (r = -0.651, p = 0.030) in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance

¹H MRSI data of the PINK1 study cohort compared to age-matched healthy controls.

<p>Data are given as mean (1SD). 95% CI = 95% confidence interval.</p

³¹P MRSI data of the PINK1 study cohort compared to age-matched healthy controls.

<p>Data are given as mean (1SD). 95% CI = 95% confidence interval. Bold data with an asterisk mark values outside of the 2SD range of controls.</p

Correlation of MRSI and PET findings in the putamen.

<p>Across the entire study cohort with either a single heterozygous (n = 9, open circles) or two homozygous PINK1 mutations (n = 2, black triangles), the mean putaminal FDOPA K_i values (min⁻¹) determined by PET correlated positively with MRSI-measured MI levels (r = 0.879, p<0.001) (a), but inversely with ATP (r = −0.784, p = 0.008) (b) and GPC concentrations (r = −0.651, p = 0.030) (c). Spearman rank correlation, p-values give the significance level. The dashed horizontal lines set the upper and lower limits of the 2SD range in healthy controls. Note that we found concentrations above the upper limit for GPC in both and for ATP in one of the homozygous mutation carriers.</p

Correlation of striatal FDOPA-PET K_i values with selected putaminal MRSI data given for all PINK1 mutation carriers (n = 11) and for individuals with heterozygous mutations only (n = 9).

<p>r = Spearman rank correlation coefficient; n.s. = not significant.</p

Calculated MRSI data of the PINK1 study cohort compared to age-matched healthy controls.

<p>Data are given as mean (1SD). 95% CI = 95% confidence interval. Bold data with an asterisk mark values outside of the 2SD range of controls.</p