Magnetic resonance spectroscopy in Parkinson s disease and parkinsonian syndromes

Transcription

1 Magnetic resonance spectroscopy in Parkinson s disease and parkinsonian syndromes Mario Rango a,b Andrea Arighi a Piero Biondetti b Barbara Barberis b Cristiana Bonifati a,b Fabio Blandini c Claudio Pacchetti c Emilia Martignoni d,e Nereo Bresolin a Giuseppe Nappi c,f a Department of Neurology and b Magnetic Resonance Spectroscopy Center, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy c Interdepartmental Research Centre for Parkinson s Disease (CRIMP), IRCCS C. Mondino Institute of Neurology Foundation, Pavia, Italy d IRCCS S. Maugeri Foundation, Scientific Institute of Veruno, Italy e University A. Avogadro of East Piedmont, Novara, Italy f Department of Neurology and Otorhinolaryngology, University of Rome La Sapienza, Italy Corresponding author: Dr Mario Rango Clinica Neurologica IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via F. Sforza, Milan - Italy mariocristia@yahoo.it Received: November 2006 Accepted for publication: January 2007 Summary This paper looks at the use of magnetic resonance spectroscopy (MRS) for diagnostic and research purposes in Parkinson s disease and parkinsonian syndromes. The review considers both proton MRS (1H MRS) and phosphorus MRS (31 P MRS) studies. MRS is useful for diagnostic purposes, helping to differentiate Parkinson s disease from other parkinsonian syndromes. Even more usefully, MRS can be used for non invasive in vivo human research. KEY WORDS: brain, magnetic resonance spectroscopy, Parkinson s disease. Introduction Parkinson s disease (PD) is a common neurodegenerative disorder (1), probably due to combinations of environmental and genetic factors (2,3). In addition to the loss of neurons, including dopaminergic neurons in the substantia nigra pars compacta, a further morphological hallmark of PD is the presence of Lewy bodies and Lewy neuritis (4). The formation of these proteinaceous inclusions involves the interaction of several proteins, including α-synuclein, synphilin-1, parkin and UCH-L1. In animals, PD does not arise spontaneously, therefore characteristic and specific functional changes have to be mimicked artificially through the application of neurotoxic agents or through genetic manipulations. There is thus a real need for techniques allowing direct, in vivo, non-invasive investigation of patients with PD. Magnetic resonance spectroscopy (MRS) is one such technique, providing a tool for investigating many pathophysiological aspects of the condition (i.e., alterations of brain energetics, brain biochemistry and brain biophysics), which could be helpful diagnostically (5). The main MRS techniques are proton MRS (1H MRS) and phosphorus MRS (31P MRS). Indeed, clinical studies have concentrated mainly on metabolites containing hydrogen (1H MRS) and phosphorus (31P MRS), studying single, localized volumes of brain tissue, even as small as 1 ml(5). 1H MRS: compounds detectable in vivo In vivo 1H MRS visualizes signals from carbon-bound, non-exchangeable protons, showing the highest information density in the spectral region from 1 to 5 ppm (5). The principal metabolites detected by 1H MRS include N-acetylaspartate (NAA), an amino acid which, in adults, is present almost exclusively in neurons (it is absent in mature glial cell cultures and tumors of glial cell origin) and is therefore is used as an expression of neuronal integrity (6,7), choline-containing compounds (such as metabolites involved in phospholipid membrane synthesis), creatine (including phosphocreatine) as an internal reference standard, and lactate as an indicator of anaerobic glycolysis. Moreover, several other compounds and neurotransmitters can be studied, such as glutamate, glutamine, gaba, myoinositol (5). Although the function of NAA is unknown, a number of studies have shown a reduction of NAA in conditions in which neuronal or axonal loss is known to occur pathologically. Thanks to technical improvements in spectroscopy over the past few years, it is now possible to study single localized brain volumes as small as 1 ml. The majority of MRS studies have, to date, used metabolite ratios to quantify changes in individual compounds. The peak of creatine/phosphocreatine has most frequently been used to this end because theoretically these two compounds are in chemical equilibrium and therefore their total amount would be expected to remain constant even in disease states. It is known, however, that the total creatine-phosphocreatine con- Functional Neurology 2007; 22(2):

2 M. Rango et al. centration can change in different pathologies thus making interpretation of ratios difficult. It is possible, however, to carry out absolute quantification of metabolites present in millimolar concentrations (8-10). 1H MRS in Parkinson s disease and parkinsonian syndromes Single-voxel techniques It is still difficult to differentiate clinically between the various parkinsonian syndromes (4). About a quarter of patients diagnosed with idiopathic Parkinson s disease (IPD) during their lifetime have another neuropathological diagnosis at postmortem. Furthermore, neuropathologically confirmed cases of progressive supranuclear palsy (PSP) have been variously misdiagnosed, in life, as IPD, multiple system atrophy (MSA), corticobasal degeneration, and Alzheimer s disease. Similarly, MSA may be confused with PSP (4). In the early days of application of MRS in PD, Holshouser et al. (11) conducted a large multicenter 1H MRS study of 151 patients with IPD. Spectra were collected from a volume localized to the basal ganglia with 80-90% of the volume localized to the striatum. In this study no significant reduction in the NAA/creatine ratio was observed in the IPD group compared to the controls. The authors noted a decrease in the NAA/choline ratio in the older IPD patients and concluded that their findings may indicate a slight decrease in NAA or, alternatively, increased levels of choline and creatine in this subgroup. In a 1H MRS study of five IPD patients by Clarke et al. (12), absolute quantification of metabolites showed no significant difference in the absolute millimolar concentration of metabolites, including NAA, choline, and creatine. Furthermore, there was no significant change in the concentration of glutamine or glutamate in the basal ganglia (12). Davie and colleagues (9) carried out 1H MRS localized to the lentiform nucleus in patients with asymmetrical, levodoparesponsive IPD, and patients with clinically probable MSA, who were subdivided into striatonigral and olivopontocerebellar atrophy variants. No significant differences were observed between the IPD patients and controls. The MSA patients, however, showed a significant reduction in the absolute levels of NAA and in the NAA/creatine ratio in the lentiform nucleus compared with controls. This was most striking in the striatonigral patients. Lemmens et al. (13) showed that the reduction in the NAA/creatine ratio observed in five clinically probable MSA patients was present symmetrically in both putamen. The same authors showed no significant difference in the NAA/creatine ratio in a group of IPD patients. There was, however, a significant reduction of NAA/choline ratios in drug-naive IPD patients compared with a treated group and a control group. None of the studies published to date have looked for correlations with pathology. Mitochondrial dysfunction There is much interest in the hypothesis that IPD is causally linked to mitochondrial dysfunction (14-21). However, none of the studies have demonstrated elevated lactate levels in the basal ganglia in IPD. Bowen et al. (22) performed 1H MRS considering a large volume of brain (27 ml) centered on the occipital lobe in 14 patients with IPD. The authors demonstrated a significant group increase in lactate in the IPD patients compared with healthy controls. In particular, this increase was most striking in a subgroup of four parkinsonian patients with dementia. However, the authors also found elevated lactate levels in several controls. The detection of lactate by 1H MRS in healthy controls is well established. It must be borne in mind that lactate levels may be increased by functional stimulation (23). This has been demonstrated both in the occipital cortex and in the basal ganglia. The presence of a dementing process in patients diagnosed as IPD raises the possibility of an alternative diagnosis, such as Lewy body dementia. A study in patients with suspected vascular ischemic parkinsonism failed to show an elevated lactate signal in the striatum (24). A study by Davie et al. (25) in three former professional boxers with parkinsonism unresponsive to levodopa showed significantly reduced concentrations of NAA in the lentiform nucleus but no evidence of lactate production. Other findings Federico et al. (26) found, in five patients with PSP, a significant reduction of NAA/creatine and NAA/choline ratios in the lentiform nucleus compared with eight patients with IPD and nine age-matched controls. Again, no significant abnormalities were observed in the IPD patients. A study by Davie et al. (27) in a group of nine patients with PSP showed an absolute reduction in the concentration of NAA in the lentiform nucleus. Chemical shift techniques One limitation of single volume spectroscopy is that it provides information from only one area of the brain in any given examination. The ability to look at several areas of the brain simultaneously and to measure metabolite changes in vivo offers exciting opportunities for research into many movement disorders. Therefore, a more recent advance has been the development of techniques that allow multislice 1H MRS imaging (1H-MRSI) (5). This involves simultaneous acquisition of signal from several brain slices. Each slice consists of many individual volumes (usually a matrix) with each volume being 1 ml or less in size. Lowresolution images can also be produced for each of the individual metabolites. It is therefore possible to create images of NAA, and thus to provide information on neuronal loss throughout the brain. Tedeschi and colleagues applied this technique to patients with IPD, PSP, and corticobasal degeneration (CBD) (28). In the PSP patients they showed specific metabolite changes in the brainstem, centrum semiovale, frontal lobe, precentral cortex, and lentiform nucleus. In the CBD patients, significant changes were detected in the centrum semiovale, lentiform nucleus, and parietal lobe. The patients with IPD, however, showed no specific differences from controls in any of the regions studied. More recently O Neill et al. (29) investigated 10 patients with PD and 13 age-matched, healthy control subjects by 76 Functional Neurology 2007; 22(2): 75-79

3 MRS in Parksinson s disease and parkinsonian syndromes magnetic resonance imaging and 1H MRS of the substantia nigra, basal ganglia, and cerebral cortex. Compared to controls, the PD patients had approximately 24% lower creatine content in the region of the substantia nigra and smaller volumes of the putamen (11%), globus pallidus (16%), and prefrontal cortex (6%). No other significant between-group differences were found in nine regions examined. This is the only study reporting a decrease of creatine in parkinsonian patients. High magnetic field The development of 1H MRS at higher magnetic field strengths may result in a more important role for 1H MRS as an imaging tool in the differential diagnosis of parkinsonian disorders, as has been shown by a recent study applying single-voxel 1H MRS to multiple brain regions, including the putamen, pontine base and cerebral white matter at 3.0 T in 24 patients with MSA compared to 11 patients with PD and 18 controls (30). Significant NAA/creatine reductions have been shown in the pontine base both of patients with cerebellar variant of MSA (MSA-C) and of patients with MSA with predominant parkinsonism (MSA-P), while putaminal NAA/creatine was reduced only in the patients with MSA-P. Eight of the 11 MSA-P patients (as opposed to none of the PD or control group subjects) were classified correctly by combining individual NAA/creatine reductions in the pontine base and in the putamen. These results suggest that combined assessment of NAA/creatine in the pontine base and putamen may be effective in differentiating MSA-P from PD (on the basis of high specificity of reduced NAA/creatine in the pontine base and in the putamen in patients with MSA-P) (30). Lewy body disease Kantarci et al. (31) recently studied several patients with different kinds of dementia. These patients included 20 with dementia with Lewy bodies (DLB) in whom choline/creatine ratios were found to be elevated, whereas NAA was unchanged. Previously, Molina et al. (32) studied 12 patients with DLB and a control group. In comparison with the control group, the DLB patients showed significantly lower mean choline/creatine, NAA/creatine, and glutamate-glutamine/creatine ratios in the white matter, while their myoinositol/creatine and myoinositol/naa ratios did not differ from those of the control group. In the gray matter, no significant differences were found between the two groups. Therefore, further studies in DLB are needed to further clarify this matter. Parkinson s disease and solvent exposure All in all, the results provided by a number of spectroscopic studies seem to vary somewhat. This may be partly due to different technical approaches, which have been refined over time, to different quantitation methods and, perhaps more likely, to differences in the selection of the patients. It is now quite clear that the clinical expression and also the pathological substrate of PD may show marked differences (4,33). For example, some patients with PD have a history of chronic exposure to hydrocarbon solvents (1). Chronic exposure to hydrocarbon solvents has been proposed as a risk factor for more severe forms of PD with earlier onset of symptoms and reduced response to dopaminergic therapy. A direct correlation between disease severity and degree of exposure has previously been shown. However, in previous MRS studies, past exposure to solvents has not usually been among patient inclusion criteria. Very recently, Rango et al. (34) studied seven PD patients with solvent exposure (two with lowdegree exposure and five with high-degree exposure), 10 unexposed PD patients matched for sex, age and Hoehn and Yahr scale (=3 in the on phase), and 10 unexposed PD patients matched for sex, age and levodopa daily intake instead of disease severity (these patients were Hoehn and Yahr scale =3.5 in the on phase). Twenty normal subjects without previous exposure to hydrocarbon solvents and matched for age and sex with the exposed patients were studied for comparison. The purpose of the study was to assess neuronal degeneration in the striatum of exposed vs unexposed PD patients. The authors investigated whether neuronal damage/loss was detectable in the lentiform nucleus measuring NAA levels by 1H MRS. Multiple single-voxel MRS water-suppressed spectra were also obtained from the white matter and the occipital lobe. They found that NAA was normal in the lentiform nucleus of patients with low exposure as well as in patients with no exposure, whereas it was decreased in PD patients with high exposure. White matter and occipital lobe NAA content was normal both in exposed and in unexposed PD patients. The authors concluded that clinical expression is more severe in PD patients with a high degree of previous solvent exposure because of the associated postsynaptic damage to the nigrostriatal pathway. 31P MRS Information detectable in vivo 31P MRS provides information predominantly about intracellular energy metabolism. This capacity to provide detailed information about the rate of intracellular energy metabolism makes it a sensitive indicator of impaired oxidative metabolism. Phopshocreatine content, ATP, monophosphoesters, diphosphoesters, inorganic phosphate, free magnesium content, and intracellular ph can all be measured simultaneously by this technique which, as a result, is especially suitable for investigating mitochondrial function. Indeed, 31P MRS has been used as a diagnostic test in established mitochondrial diseases. 31P MRS in Parkinson s disease and parkinsonian syndromes Mitochondrial function and Parkinson s disease Athough there exists some evidence for a mitochondrial impairment in PD, it has not been possible, so far, to Functional Neurology 2007; 22(2):

4 M. Rango et al. demonstrate in vivo mitochondrial dysfunction in the human brain of PD patients. In a 31P MRS study of resting muscle in 28 IPD patients, a significant group increase of resting inorganic phosphate relative to phosphocreatine was demonstrated in the IPD patients compared with controls, suggesting a generalized mitochondrial disorder in PD (35). Recently, Rango et al. (36) used the high temporal and spatial resolution 31P MRS technique that they had previously developed in normal subjects and in patients with mitochondrial diseases to study mitochondrial function by observing high energy phosphates (HEPs) and intracellular ph (ph) in the visual cortex of 20 patients with PD and 20 normal subjects at rest, during, and after visual activation. In the normal subjects, HEPs remained unchanged during activation but rose significantly (by 16%) during recovery, and ph increased during visual activation with a slow return to rest values. In the PD patients, HEPs were within the normal range at rest and did not change during activation, but fell significantly (by 36%) in the recovery period; ph did not reveal a homogeneous pattern, displaying a wide spread of values. The authors concluded that energy imbalance in conditions of increased oxidative metabolism, i.e., the postactivation phase, discloses a mitochondrial dysfunction that is present in the brain of patients with PD even in the absence of overt clinical manifestations, as in the visual cortex. This is in agreement with their previous findings in patients with mitochondrial disease without clinical CNS involvement. The heterogeneity of the physicochemical environment (that is, ph) suggests various degrees of subclinical brain involvement in PD. 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