Parkinsonism and Related Disorders 20 (2014) 545e548

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Sex differences in cerebral energy metabolism in Parkinson’s disease: A phosphorus magnetic resonance spectroscopic imaging study Nora Weiduschat a, Xiangling Mao a, M. Flint Beal b, Melissa J. Nirenberg c, Dikoma C. Shungu a, Claire Henchcliffe b, * a b c

Radiology, Weill Cornell Medical College, New York, NY 10021, United States Neurology, Weill Cornell Medical College, New York, NY 10021, United States Neurology, NYU School of Medicine, New York, NY 10016, United States

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 September 2013 Received in revised form 27 January 2014 Accepted 4 February 2014

Objective: To test the hypothesis that there are sex differences in cerebral energy metabolism in Parkinson’s disease (PD). Methods: Phosphorus magnetic resonance spectroscopy (31P MRS) was used to determine high-energy phosphate (phosphocreatine and ATP) and low-energy phosphate (free phosphate) levels in the striatum and temporoparietal cortical gray matter (GM) in 10 men and 10 women with PD, matched for age at onset, disease duration, and UPDRS scores. Results: In the hemisphere more affected by PD, both ATP and high energy phosphate (HEP: phosphocreatine þ ATP) content in striatum was 15% lower in men versus women with PD (p ¼ .050 and p ¼ .048, respectively). Similar decreases by 16% in ATP (p ¼ .023) and 12% in HEP (p ¼ .046) were observed in GM in men versus women with PD. In contrast, there were no detectable sex differences in ATP or HEP in healthy age-matched controls. Conclusions: Men with PD have lower levels of ATP and high energy phosphate than women in brain regions affected by PD. These findings suggest that there may be a greater burden of mitochondrial dysfunction in PD in men versus women with PD. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Parkinson’s disease Sex differences Magnetic resonance spectroscopy Biomarker Oxidative stress Mitochondrial dysfunction

1. Introduction Mitochondrial dysfunction contributes to the pathogenesis of Parkinson’s disease (PD) by impairing cerebral energy metabolism and calcium homeostasis, thereby increasing oxidative stress and facilitating apoptosis. Strong evidence for neuronal energy deficits consistent with mitochondrial dysfunction has been found both in preclinical PD models and in patients (for review, see Ref. [1]). Using phosphorus (31P) magnetic resonance spectroscopy (MRS), a noninvasive method to measure phosphate-containing compounds in vivo, cerebral adenosine triphosphate (ATP, high energy phosphate) reductions [2,3], free phosphate (Pi, low energy phosphate) elevations [4], and Pi/ATP elevations [3] have been * Corresponding author. Weill Cornell Medical College, 428 East 72nd Street, Suite 400, New York, NY 10021, United States. Tel.: þ1 212 746 2584. E-mail addresses: [email protected], [email protected] (C. Henchcliffe). http://dx.doi.org/10.1016/j.parkreldis.2014.02.003 1353-8020/Ó 2014 Elsevier Ltd. All rights reserved.

reported in PD, all supporting impaired energy metabolism. For the high energy phosphate compound phosphocreatine (PCr), both reductions [2] and elevations [3] have been described. In their study of 29 subjects with PD, Hattingen et al. found reduced PCr in the putamen bilaterally, both in early and advanced disease cohorts [2]. Another study reported an increased PCr/ATP ratio, which might have been due to PCr elevations, but also ATP decline [3]. Phosphorus MRS before, during and after visual stimulation revealed a HEP reduction by one-third in the visual cortex during the recovery period in PD, while HEP content rose by 16% in healthy controls [5]. Surprisingly, there are no reports on differences between men and women on cerebral energy metabolism in PD, despite established differences in the clinical presentation, incidence, risk factors and biomarkers in PD, along with the known effects of estrogen on mitochondria. To assess the relationship between female or male sex and brain energetics, we compared markers of brain energy metabolism as measured by 31P MRS in female and male PD study participants.

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2. Methods 2.1. Study subjects For this cross-sectional study, ten women and ten men fulfilling United Kingdom Parkinson’s Disease Society Brain Bank criteria were included. Recruitment was conducted through the Parkinson’s Disease and Movement Disorders Institute of Weill Cornell Medical College (WCMC). In addition, 12 age-matched healthy controls (5 female, 7 male) were enrolled. Study participants had to be able to give informed consent and be free of any ferromagnetic implants or devices that would preclude undergoing MRS (including neurostimulators). Exclusion criteria were diagnosis of any significant neurologic, psychiatric or medical disease other than PD. Clinical evaluation included the Unified Parkinson’s Disease Rating Scale (UPDRS) [6]. The WCMC Institutional Review Board approved the study protocol and each study participant gave written informed consent prior to enrollment. 2.2. MR data acquisition and processing MR experiments were conducted using a 3T GE EXCITE MR system (GE Medical Systems, Milwaukee, WI) with a double-quadrature, dual-tuned 1H/31P head coil (Clinical MR Solutions, Brookfield, WI) as previously described [7,8]. First, subjects underwent a three-plane, low-resolution scout imaging series and high-resolution standard axial T1-, T2- and spin density-weighted scans that were used to select the volumes of interest (VOI) for the MRS data acquisitions. Next, 31P MRS data were recorded from a single 30 mm slice with a nominal voxel size of 30  30  30 mm3. Spectra were acquired with a pulse sequence (“FIDCSI”) supplied by the instrument manufacturer consisting of a single slice-selective radiofrequency pulse, followed by a slice refocusing gradient and 1 ms long phase-encoding gradients, and using 14  14 phase-encoding steps, 8 excitations per phase-encoding step, a field-of-view of 420 mm, 2048 sample points, 5 kHz spectral width, and TR 1000 ms. Although our use of a relatively short TR (1000 ms) resulted in substantial saturation of all 31P resonances, this did not adversely affect the signal-to-noise ratio (Fig. 1). The raw

data matrix was zero-filled to 32  32 spatial points and then processed by standard 3D Fourier transformation to derive a spectrum for each voxel (Fig. 1). Metabolite peak areas were obtained using a robust and highly optimized public-domain LevenbergeMarquardt nonlinear least-squares IDL minimization routine to model the resonance peaks in the frequency domain (Fig. 1) as a linear combination of pseudo-Voigt functions, which enable more precise analysis of lineshapes that consist of mixtures of Lorentzian and Gaussian functions, as is often the case for in vivo spectra. Each metabolite was then expressed as a ratio relative to the root mean square of the background noise [7,8]. The levels for ATP and PCr were added yielding the HEP amount (ATP þ PCr ¼ HEP). Voxels encompassing the striatum and the temporoparietal gray matter (GM) were selected group comparisons. In the PD group, hemispheres were categorized as ipsilateral or contralateral to the more affected body side. In healthy volunteers, a mean value was calculated for each region using voxels from both hemispheres. 2.3. Statistical methods After testing for normality using ShapiroeWilk tests, metabolite concentrations in female and male PD patients were compared using independent sample t-tests (a  .05 without correction for multiple comparisons). To explore whether any difference observed between men and women with PD could also be found in healthy women and men, we repeated the comparisons for positive metabolites in the control group. The PD and HV groups as a whole were compared using independent sample t-tests. Statistical analyses were conducted using SPSS Statistics, version 18 (IBM, Chicago, IL).

3. Results Between the 10 female and 10 male PD participant groups, there were no statistically significant differences in disease

Fig. 1. (A) Prescription of the slice of interest for 31P MRSI scan. (B) Locations of (a) striatal and (b) parieto-temporal voxels of interest; the grid on the image depicts the voxel size after zerofilling the spatial matrix to 32  32 from 14  14. (C) Sample 31P MRSI grid demonstrating quality of spectra across several voxels of the brain. (D) [a] Identification of phosphate resonances in a typical spectrum: phosphomonoesters (PME); inorganic orthophosphate (Pi); phosphodiesters (PDE); phosphocreatine (PCr); adenosine triphosphate (ATP) comprising three phosphorus resonances. [b] “Best-fit” of the experimental spectrum in [a] to obtain the phosphate metabolite peak areas; [c] individual components of the model fit; and [d] residual of the difference between experimental and “best-fit” spectra. Baseline distortions in each spectrum, introduced by the large first-order phase corrections needed to account for the finite delay between the single slice-selective excitation pulse and signal acquisition, were removed by interpolation.

N. Weiduschat et al. / Parkinsonism and Related Disorders 20 (2014) 545e548

duration, age at onset and UPDRS (Table 1). Although the age of women (62  12 years) was numerically higher than that of men (53  10 years) this age difference was not statistically significant (p ¼ .091). Treatment status was comparable in the male and female groups, with 4 unmedicated participants in each group. Levodopa therapy was more common in the male group (4 versus 2 participants), while dopamine agonist treatment was more common in women. The healthy control group included 5 women and 7 men with a mean age of 54  12 years versus 61  10 years (p ¼ .23; Table 1). ATP content was significantly higher in women than men with PD in the striatum (48.7  8.6 versus 41.2  7.4, p ¼ .050) and GM (40.0  4.4 versus 33.7  6.7, p ¼ .023), contralateral to the more affected body side (Table 1). Likewise, striatal HEP concentration was higher in women than men with PD in both striatum (83.6  13.1 versus 71.5  12.5, p ¼ .048) and GM (72.6  9.9 versus 63.6  8.9, p ¼ .046). Neither ATP nor HEP levels in PD, in the hemisphere ipsilateral to the more affected side of the body, were significantly different between women versus men for the striatum (ATP: 49.1  9.9 versus 44.5  8.4, p ¼ .283; HEP: 82.5  15.2 versus 76.0  15.4, p ¼ .352) or GM (ATP 40.0  11.0 versus 38.1  10.6, p ¼ .708; HEP 73.6  16.9 versus 70.1  12.7, p ¼ .609). The numerically lower values of the high energy phosphate compound

Table 1 Clinical characteristics and MRS metabolite content in PD patients and healthy volunteers (HV). Male PD 53  10 4 unmedicated 4 levodopa  other 0 dopamine agonist 3 MAOB inhibitor Disease duration 32 Age at onset 52  10 UPDRS 22  11 Striatum contralateral ATP 41.2  7.4 HEP 71.5  12.5 PCr 30.3  6.9 Pi 7.9  2.5 Gray matter contralateral ATP 33.7  6.7 HEP 63.6  8.9 PCr 30.0  6.2 Pi 6.3  2.4 Striatum ipsilateral ATP 44.5  8.4 HEP 76.0  15.4 PCr 31.4  8.0 Pi 8.7  3.0 Gray matter ipsilateral ATP 38.1  10.6 HEP 70.1  12.7 PCr 32.0  6.3 Pi 6.7  1.6 Age Treatment status

Age (in years) Striatum ATP HEP PCr Pi Gray matter ATP HEP PCr Pi

Female PD

p-Value

62  12 4 unmedicated 2 levodopa  other 3 dopamine agonist 1 MAOB inhibitor 32 60  13 20  13

.091

.907 .142 .707

48.7  8.6 83.6  13.1 34.9  5.1 8.1  2.5

.050* .048* .105 .869

40.0  4.4 72.6  9.9 32.7  7.0 6.9  2.0

.023* .046* .374 .555

49.1  9.9 82.5  15.2 33.4  5.9 8.6  3.0

.283 .352 .538 .953

40.0  11.0 73.6  16.9 33.6  6.5 8.1  2.7

.708 .609 .573 .177

Male HV

Female HV

p-Value

61  10

54  12

.231

43.0  15.4 74.3  21.5 31.2  6.9 7.8  1.6

50.3  6.7 83.0  9.1 32.7  2.9 8.1  .8

.349 .418 .679 .635

32.3  10.4 63.0  14.3 30.7  4.7 7.2  1.4

36.9  4.2 67.6  5.5 30.8  3.4 6.3  1.2

.374 .510 .990 .281

Age, disease duration and age at onset are given in years. Metabolite concentration means and standard deviations are given in institutional units (i.u.). *p  .05.

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PCr in men with PD compared with women with PD did not reach statistical significance in any of the regions examined. Pi concentration in PD was not significantly different between male and female participants in any of the regions examined. Examination of ATP, PCr, and Pi content in the age-matched healthy control group did not reveal any sex-related differences in either region (Table 1). Comparing only female PD versus female HV, and male PD versus male HV, there were no detectable differences in any of the metabolites. Furthermore, the brain metabolites in the PD group as a whole were comparable to those in the healthy control group [7].

4. Discussion The findings of this study suggest that there may be sex-specific differences in brain energy metabolism in PD. We find that cerebral ATP concentration as measured by MRS is approximately 15% lower in men than in women with PD in brain regions known to be affected in PD, including both the striatum and the temporoparietal cortex. To our knowledge, this is the first study to investigate potential cerebral energy metabolism differences between men and women with PD. However, several MRS studies that included mostly men and did not stratify for sex have found lower HEP and/or increased Pi in PD compared with healthy controls [2e4]. There are a number of ways in which the metabolic differences that we have observed may relate to the higher incidence, earlier disease onset and faster progression, and more severe motor symptoms and cognitive impairment in men versus women with PD (reviewed in Ref. [9]). Men may be more vulnerable to PDrelated oxidative stress and mitochondrial dysfunction leading to ATP deficits, providing a potential mechanism for why antioxidants such as urate may be associated with lower PD risk and slower PD progression in men, but less so in women (for a metaanalysis, see Ref. [10]). Although estrogen augments mitochondrial function by enhancing oxidative phosphorylation and reducing ATPase activity [11], thus protecting from HEP decreases, eight of the ten women in this study were post-menopausal making this explanation unlikely. However, long-term effects of previous estrogen exposure, or sexual dimorphism in response to estrogen have been suggested as potential explanations for sex differences in the clinical phenotype of PD [12,13], and might potentially also underlie the observed sex-related metabolic differences in the disorder. The groups did not differ statistically in age, disease duration, UPDRS and age at onset. In this small sample size, statistical adjustment for confounders or subgrouping was not possible. Thus, given that numerical age in women with PD was greater than men with PD, and that age-related differences in metabolism have been reported, the possibility that age may have confounded results deserves consideration. Several lines of evidence argue against this possibility, however. First, increases in high energy phosphates with aging are only 5e10% of the magnitude of change we find in this study [14]. Second, the observed metabolic differences were not generalized across the two hemispheres. Our finding that ATP and HEP levels differed significantly only in the more affected hemisphere supports that this is specific to the disease process. Third, there were no observed differences between men and women for ATP or HEP in the healthy control group. In summary, this study has found that brain ATP and HEP levels are lower in men compared with women with PD. These findings underscore the need for further studies of sex-associated differences in PD pathogenesis, to improve understanding of etiopathogenesis, aid in sex-specific analyses in clinical trials, and facilitate personalized therapy for PD [9].

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Sex differences in cerebral energy metabolism in Parkinson's disease: a phosphorus magnetic resonance spectroscopic imaging study.

To test the hypothesis that there are sex differences in cerebral energy metabolism in Parkinson's disease (PD)...
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