Cortical hypoperfusion in Parkinson's disease assessed using arterial spin labeled perfusion MRI
Highlights
► Cortical perfusion is abnormal in Parkinson's disease. ► We evaluated perfusion abnormalities using ASL perfusion MRI. ► Absolute cortical perfusion is decreased in Parkison's disease. ► ASL has enough sensitivity to detect changes in absolute perfusion. ► We demonstrated artifacts introduced by global mean normalization.
Introduction
Cerebral perfusion disturbances have been observed in a variety of neurodegenerative and psychiatric disorders. Due to the well-known phenomenon of neurovascular coupling, changes in cerebral blood flow (CBF) can be directly related to regional metabolism and neural activity (Raichle, 1998). Thus, CBF measurements could potentially become biomarkers for early disease diagnosis, and also serve to follow up disease progression and treatment response.
Cerebral glucose consumption (CMRglc) and perfusion have been previously assessed in Parkinson's disease (PD) using positron emission tomography (PET) (Eckert et al., 2007), single photon emission computed tomography (SPECT) (Amorim et al., 2007) and, more recently, perfusion magnetic resonance imaging (MRI) (Melzer et al., 2011). Previous studies with PET and SPECT have found alterations in metabolism and perfusion in PD with a pattern of relative cortical decreases concurrent with subcortical increases extending into large areas of the basal ganglia and thalamus (Eckert et al., 2007). However, recent publications have questioned the presence of such subcortical increases, arguing that they are an artifact introduced by global mean normalization of the data (Borghammer et al., 2010, Borghammer et al., 2009a, Borghammer et al., 2009b). Normalization is commonly used in PET and SPECT studies and indeed required when absolute quantification is not feasible. Even when absolute quantification can be performed, both perfusion and glucose consumption measurements from PET and SPECT have great inter-individual variability with large coefficients of variation (Borghammer et al., 2008), which makes the detection of small between-group differences difficult. However, normalization to the global mean is only appropriate when there is no difference in global mean values between groups, an assumption that seems to be violated in comparisons of PD patients and healthy controls (Borghammer et al., 2010).
Although anatomical studies in experimental models of PD using 2-deoxyglucose (2DG) autoradiography have also reported increased metabolism in several subcortical and brainstem structures (see for review (Borghammer et al., 2009a, Obeso et al., 2008)), these structures are generally too small to be detected with the resolution achievable using conventional PET and SPECT cameras (Cassidy and Radda, 2005).
Arterial spin labeled (ASL) perfusion MRI (Detre et al., 1992, Williams et al., 1992) has been recently introduced as a non-invasive alternative for perfusion measurements in PD (Fernandez-Seara et al., 2009, Kamagata et al., 2011, Ma et al., 2010, Melzer et al., 2011). The ASL technique utilizes electromagnetically labeled arterial blood water as an endogenous tracer, yielding quantitative CBF measurements in well-characterized physiological units of mL·100 g− 1 min− 1. Recent technical advances in ASL have increased the sensitivity of the method and, as a result, absolute CBF measurements can now be obtained with high reliability in both young and elderly subjects (Xu et al., 2010). Using quantitative ASL methods, a recent study has reported absolute perfusion decreases in PD in diverse cortical areas, while subcortical perfusion appeared preserved (Melzer et al., 2011). This study, while being the largest study of perfusion in PD to date, involved a heterogeneous group of patients that also included patients with dementia.
In the current study, an optimized ASL technique (Fernandez-Seara et al., 2008a) has been used to quantify absolute CBF in a homogeneous group of early-to-moderate PD patients and age-matched healthy controls. We hypothesized that perfusion alterations in PD would consist in cortical decreases and that those alterations could be detected using statistical parametric mapping analysis with this technique. In addition, comparisons of relative CBF values were also carried out to evaluate the effect of global mean normalization.
Section snippets
Subjects
Twenty-five early to moderate stage PD patients without dementia and thirty-four healthy age-matched controls participated in the study, approved by the Ethics Research Committee of the University of Navarra, after signing a written informed consent. The healthy volunteers had no past or present history of neurological or psychiatric disorders. The patients had been diagnosed with idiopathic Parkinson's disease according to the United Kingdom Parkinson's Disease Society Brain Bank criteria (
CBF quantification
The calculated whole brain mean CBF in the control group was 38.9 ± 6.2 mL·100 g− 1 min− 1 (mean ± standard deviation). In the patient group, the mean CBF was 36.9 ± 6.5, a value reduced by 5.1% with respect to the control group. However, the linear regression analysis showed that group was not a significant predictor of whole brain mean CBF (p = 0.196).
Parkinson's disease related perfusion deficits
The voxel-wise analysis of absolute CBF maps revealed areas of hypoperfusion in the cortex of PD patients. These areas are listed in Table 2 and depicted in
Discussion
Assessment of absolute cerebral perfusion in PD using the ASL technique yielded a pattern of cortical perfusion deficit, affecting frontal, parietal and occipital areas. Our results largely confirm prior studies of perfusion and metabolism measuring absolute CBF or CMRglc (Berding et al., 2001, Bohnen et al., 1999, Hu et al., 2000, Mito et al., 2005). In particular, they are mostly in agreement with the recent study of Melzer et al.(2011) that evaluated perfusion using ASL in a large and
Conclusions
The results of the current study contribute to identify the true pattern of perfusion alterations in Parkinson's disease. This could have an impact on our understanding of the pathological features of the disease progression. Our results support the hypothesis that cortical perfusion and metabolism are reduced in PD, even at the early disease stages, earlier than most other previous studies have suggested. In addition, this work demonstrates that the ASL technique has enough sensitivity to
Disclosure/conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the Spanish Ministry of Science and Innovation (grants SAF2008-00678 and RYC-2010-07161) and by the Navarra Government Health Department (grant 17/2008 GN Salud). M. Aznárez-Sanado was supported by a grant from the Navarra Government Education Department.
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