13 Proton MR Spectroscopy in Metabolic Disorders of the Central Nervous System
Nicola De Stefano and Marzia Mortilla
N. De Stefano, MD, PhD
Associate Professor, Department of Neurology and Behavioral Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy M. Mortilla, MD
Department of Radiology, Children Hospital Anna Meyer, Florence, Italy
CONTENTS
13.1 Introduction 195
13.2 Proton MRS Changes in Demyelinating and Dysmyelinating Diseases 195
13.3 Diagnostic-Specifi c MRS Changes in WM Disorders 199
13.4 Metabolic Changes Beyond MRI Lesions 202 13.5 Conclusions 206
References 206
13.1
Introduction
The advent of magnetic resonance (MR) imaging (MRI) has revolutionized the clinical approach to the evaluation of the metabolic disorders affecting the cerebral white matter and has contributed signifi - cantly to the expansion of these diseases. The clinical importance of MRI in the management of patients with metabolic disorders lies in its great sensitivity for detecting brain white matter lesions. However, in these disorders the detected lesions can be due to a variety of pathological processes and can be associ- ated with many different types of myelin abnormality (demyelinization, hypomyelinization, myelin rarefac- tion, etc.) (Kolodny 1993).
On clinical grounds, the diagnostic work-up of a given metabolic disease is particularly challenging.
This is due to both extreme variability of the clinical picture and heterogeneity of the underlying pathol- ogy. Unfortunately, the white matter lesions detected on MRI are often not characteristic enough to allow the diagnosis of these complex disorders (van der Knaap et al. 1991). Lack of specifi city of conventional MRI and its limitations in analyzing the nature of the lesions can account, at least in part, for the signifi cant amount of patients with focal or diffuse white matter
pathology that cannot fi t the criteria for any defi ned disorder (van der Knaap et al. 1991; Schiffmann and van der Knaap 2004).
In recent years, nonconventional MR techniques have been used to complement conventional MRI and overcome some of its limitations. Among these, MR spectroscopy (MRS) techniques have proven to offer additional information and have been particularly useful in patients with metabolic disorders as they can simultaneously provide chemical-pathological correlates of changes occurring within and outside visible MRI lesions. Thus, an expanding number of research groups have been using single-voxel pro- ton MRS and multivoxel MR spectroscopic imaging (MRSI) in vivo to study patients with metabolic dis- orders involving the cerebral white matter (Arnold and Matthews 1996; de Stefano et al. 2000b; van der Knaap 2001). These MRS techniques have dem- onstrated to increase diagnostic accuracy and the understanding of the evolution of pathology in many leukoencephalopathies. However, the increasing use of proton MRS techniques in white matter diseases also has revealed that most of the metabolic changes detected in these disorders are not disease-specifi c.
Metabolic changes of several white matter pa- thologies as detected by proton MRS techniques and their clinical interpretation are reported below. As mentioned before, the group of white matter diseases with inherited or acquired metabolic abnormalities is very heterogeneous and includes pathologies with different pathogenesis. Here, we will simply give an overview on MRS changes of the most frequently studied metabolic disorders affecting the cerebral white matter.
13.2
Proton MRS Changes in Demyelinating and Dysmyelinating Diseases
Myelinogenesis is a complex process that can be al-
tered by various hereditary metabolic defects result-
ing in disorders that are generically grouped under the term of leukodystrophies. This congenital failure in myelinogenesis is comprehensive of several mecha- nisms of myelin disruption such as hypomyelination, demyelination, myelin rarefaction, etc., and is due to very different genetic and biochemical abnormalities, most of which are still undefi ned (Kolodny 1993).
Proton MR spectra of the normal human brain at long echo time reveal four major resonances: a large signal from N-acetyl groups [mainly N-acetyl aspartate (NAA)], a smaller resonance from choline- containing phospholipids (Cho), a resonance from creatine and phosphocreatine (Cr), and a doublet from lactate (Lac) (Arnold and Matthews 1996).
Excellent spectra also can be obtained using short echo time measurements, which allow the detection of a greater number of metabolites [including lipids
and myo-inositol (mI)] (Arnold and Matthews 1996).
Changes in all of these metabolites can be seen within demyelinating lesions since the very early phase of the pathological process (de Stefano et al. 1995a) (Fig. 13.1a). Changes in the resonance in- tensity of Cho result mainly from increases in the steady state levels of phosphocholine and glycerol- phosphocholine, both membrane phospholipids released during active myelin breakdown. Increases in Lac are likely to refl ect the metabolism of infl am- matory cells. In large, acute demyelinating lesions, decreases in Cr can also be seen (de Stefano et al.
1995a). Short echo time spectra give evidence for transient increases in mI (Koopmans et al. 1993) and lipids (Narayana et al. 1998), also released dur- ing myelin breakdown.
Fig. 13.1a,b. Conventional brain MRI in transversal orientation and spectroscopic images of myo-inositol (mI), choline (Cho), creatine (Cr), N-acetylaspartate (NAA) and lactate (Lac) of a patient with a single giant demyelinating lesion during acute (a) and chronic (b) stages. a During the acute stage, images of the different metabolites show focal increases in mI, Cho and Lac and
a
b
decreases in NAA and Cr that co-localize with the MRI lesion. b The examination performed 15 months later shows a reduction of the MRI lesion and normalization of mI, Cho, Cr and Lac metabolic images. NAA shows a partial recovery
After the acute phase, metabolic modifi cations in the demyelinating lesion show a variable time course (de Stefano et al. 1995a) (Fig. 13.1b). Usually, reso- nance intensities of Cr and lipids return to normal within a few days. At this stage, small changes in Cr, due to changes in cellularity, can be found inside the demyelinating lesion (Davies et al. 1995). Resonance intensities of Lac show a progressive reduction over a period of weeks, whereas Cho and mI return to normal in months. The signal intensity of NAA re- mains decreased or may show a partial recovery (de Stefano et al. 1995b). Recovery of NAA may be re- lated to resolution of edema, increases in the diam- eter of previously shrunken axons that are secondary to remyelination and clearance of infl ammatory fac- tors, and reversible metabolic changes in neurons (de Stefano et al. 1995b).
In slowly progressive disorders, such as many leu- kodystrophies, the loss of myelin can be very slow and released membrane phospholipids might not ac- cumulate. Thus, MRS changes such as those detected in acute demyelination are not seen. In some cases, however, (i.e., adrenoleukodystrophy, Krabbe dis- ease) the high membrane turnover may cause long- term increases in Cho (Kruse et al. 1993; de Stefano et al. 2000a). In contrast, a decrease in Cho that is sec- ondary to hypomyelination or vacuolar myelinopa- thy can be detected in spongiform leukoencephalop- athies (van der Knaap et al. 1995, 1997; Austin et al.
1991; Grodd et al. 1990) or mitochondrial disorders (Matthews et al. 1993).
A number of brain MRS studies of patients with
white matter disorders have also shown changes in
the relative resonance intensity of mI. The function
of mI in the human brain is not clear, but increases of this metabolite seem to be related to the presence of white matter gliosis and appear consistently in disorders associated with impaired myelination such as adrenoleukodystrophy, metachromatic leukodys- trophies, phenylketonuria and Zellweger syndrome
(Bruhn et al. 1992; Johannik et al. 1994; Kruse et al.
1993; Tzika et al. 1993).
Finally, a constant fi nding of all metabolic dis- orders affecting the brain white matter is the large decrease in cerebral NAA (de Stefano et al. 2000b) (Fig. 13.2). As NAA is found almost exclusively in neu-
Fig. 13.3. Conventional brain MRI in transversal orientation (central-left panel) and spectroscopic image of lactate (La) rela- tive to a patient with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes during an acute attack of the disease (central-right panel). The grid of the spectroscopic volume of interest is shown in the transverse MRI. The conventional MR image shows the hyperintense signal in the right occipital region due to the recent stroke-like episode. Proton spectra from a voxel localized in the stroke-like region (circle) and in a homologous voxel of the contralateral hemisphere are also shown (square). The proton spectrum from a voxel localized to the stroke-like region shows a large decrease in N-acetylaspartate (NAA) and a striking increase in lactate. These changes are not found in the homologous voxel of the contralateral hemisphere
Fig. 13.2a,b. Conventional brain MRI in transversal orientation (a) and spec- troscopic image of N-acetylaspartate (NAA) (b) of a patient with unknown leukoencephalopathy. The volume of interest of the multivoxel spectroscopic examination is shown in both images. In the metabolic image of NAA (b), note the decreases of the metabolite co-local- ized (1) with the white matter abnor- malities on conventional MRI
a b
rons and their processes in mature brains decreases in this metabolite are interpreted as an index of axo- nal damage (Matthews et al. 1998; Bjartmar et al.
2002). This is most likely due to a secondary axonal dysfunction and/or loss, suggestive of the relevance of neuro-axonal damage in both demyelinating and dysmyelinating disorders. Recent studies suggest that NAA may provide a surrogate measure that can be relevant to clinical disability in patients with several white matter disorders (de Stefano et al. 2000b).
13.3
Diagnostic-Specifi c MRS Changes in WM Disorders
As already mentioned, most of the metabolic changes detected in white matter disorders are not disease- specifi c. However, in some specifi c circumstances, proton MRS can offer information useful for the dif- ferential diagnosis beyond what is currently available in routine clinical use or can even provide typical brain metabolic patterns characteristic of a given disorder.
As proton MRS can provide a specifi c and accu- rate interpretation of the pathological processes un-
derlying the white matter lesions, this can be used to differentiate brain lesions appearing similar on MRI.
Different pathophysiology might be seen, for exam- ple, in hypoxic-ischemic white matter lesions with a complex pathogenesis existing in rare metabolic con- ditions such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) (Dubeau et al. 2000). Patients with MELAS can show very large increases in levels of brain parenchymal Lac in the area of the acute stroke (Fig. 13.3). Also, large increases in brain parenchymal Lac can be found in the brain tissue even in patients without history of acute ischemic attack (Fig. 13.4). Thus, proton MRS fi ndings can allow for an accurate differentiation of this maternally inherited condition from any other acute and chronic cerebrovascular disorders.
In other very rare metabolic disorders such as eth- ylmalonic encephalopathy (Grosso et al. 2004) and cerebrotendinous xanthomatosis (de Stefano et al.
2001), the fi ndings of diffuse brain mitochondrial im- pairment have strongly contributed to the interpre- tation of the complex pathogenetic mechanisms of these disorders. In the fi rst case (Grosso et al. 2004), the diffuse MRS increase in brain Lac detected in a multi-voxel MRSI study (Fig. 13.5) was underlying a primary mitochondrial disorder, as later demon- strated by biochemical and genetic studies (Coburn
Fig. 13.4a,b. Conventional MRI of two el- derly patients (over 70 year of age) with hypertension, loss of memory, previous cerebral transitory ischemic attacks (a, b) and their proton MR spectra com- ing from voxels localized to the deep periventricular white matter (square and circle, respectively). The volume of interest of the multi-voxel spectroscopic examination is shown in both images. In both patients, conventional MRI shows periventricular lesions suggestive of leukoaraiosis. In one patient (right), there is high resonance intensity of lac- tate (LA) in the proton spectrum. This patient was subsequently diagnosed as having MELAS (mitochondrial en- cephalopathy with lactic acidosis and stroke-like episodes), despite a stroke- like episode never being reported in the clinical history. The other patient (left) does not show changes in lactate reso- nance intensity and was subsequently diagnosed as having initial cerebrovas- cular dementia
a b
a b
2004). In the latter condition (de Stefano et al. 2001), single-voxel proton MRS data (Fig. 13.6) add to mor- phological and biochemical evidence of mitochon- drial dysfunction (Federico et al. 1991; Dotti et al.
1995) (probably secondary to the toxic effect of high cholestanol and/or bile alcohol levels), suggesting the presence of a diffuse impairment of mitochondrial oxidative metabolism in patients with cerebrotendi- nous xanthomatosis.
There are also conditions in which proton MRS can provide typical brain metabolic patterns able to address the diagnosis. One example of a disease in which MRS provides a diagnostic pattern is a spon- giform leukoencephalopathy known as Canavan dis- ease. In this disorder, the defi ciency of the enzyme aspartoacylase (which breaks down NAA) is respon- sible for abnormally high levels of NAA in the brain, which can be considered pathognomonic (Austin et al. 1991; Grodd et al. 1990). Another characteristic metabolic MRS pattern has been shown recently in other spongiform leukoencephalopathies such as megalencephalic cystic leukoencephalopathy (MCL)
(Hanefeld et al. 1993; van der Knaap et al. 1995) and childhood ataxia with diffuse CNS hypomyelin- ation (CACH, also called vanishing white matter dis- ease) (Tedeschi et al. 1995; van der Knaap et al.
1997). In these disorders, conventional MRI fi ndings of extensive white matter abnormalities with spar- ing of central brain structures are seen together with a peculiar MRS pattern. This is characterized by the almost complete disappearance of all normally detected metabolites in the white matter, presence of small increases in Lac and sparing of gray mat- ter that is structurally and metabolically normal. In MCL, although MRS abnormalities tend to be more pronounced with increasing age, these are generally mild and the frontal white matter is signifi cantly less involved than other white matter regions (Fig. 13.7).
In patients with CACH disease, increases in glucose resonance intensities may also be present. This MRS metabolic profi le is perhaps due to little brain white matter tissue left and the great increase in extracel- lular spaces. In both diseases, white matter increases in Lac resonance intensities are small and inconstant
Fig. 13.6a,b. Single-voxel proton MR spectra relative to cerebral (a) and cerebellar (b) volume of interests of a normal control [left panels in (a) and (b)] and of a patient with cerebrotendinous xanthomatosis [right panels in (a) and (b)]. Note the cerebral and cerebellar increases in lac- tate in the patient’s spectra with respect to normal control
a b
Fig. 13.5a,b. Conventional T2-weighted MRI with the superimposed grid of spectroscopy voxels (a) and proton MR spectra corresponding to brain voxels located in the basal ganglia of both cerebral hemispheres (b) in a patient with ethylmalonic encephalopathy. Each spectrum shows large pathological signals at 1.33 ppm coming from the methyl doublet of lactate (Lac)
a b
suggesting that they might be due to a disturbance in Lac removal after accumulation of foamy macro- phages in pathologically active areas more than to a primary impairment of the oxidative metabolism. In any case, these MRS patterns appear to be suffi ciently specifi c to differentiate these spongiform leukoen- cephalopathies from other white matter disorders with similar clinical and radiological appearance.
As mentioned before, distinctive white mat- ter changes can also be seen in a number of mito- chondrial encephalopathies (Bardosi et al. 1987;
Burgeois et al. 1992; Leutner et al. 1994; Nakai et al. 1994). Signifi cant decreases in Cho have been observed in some mitochondrial encephalopathies even in the absence of white matter abnormality on conventional MRI (Arnold and Matthews 1996; de Stefano et al. 1995c). These are likely re- lated to be associated vacuolar myelinopathy which has been described pathologically in Kearns-Sayre syndrome and some of its variance (Matthews et al. 1993). Proton MRS studies also show decrease in NAA and increases in Lac relative resonance inten- sities in primitive mitochondrial encephalopathies (Matthews et al. 1993; Arnold and Matthews 1996). The latter, in particular, represents an impor- tant biochemical marker of these disorders. Lac levels are transiently increased in a number of acute patho- logical conditions associated with infl ammatory cells
(Arnold et al. 1992; Petroff et al. 1992; Arnold and Matthews 1996), but extensive pathological in- creases in Lac both within and outside of MRI lesions may be indicative of widespread energy failure asso- ciated with mitochondrial dysfunction (Matthews et al. 1993; de Stefano et al. 1995c). Accordingly, classical primitive mitochondrial such as pyruvate dehydrogenase defi ciency, Leigh’s and Kearns-Sayre syndromes show diffuse increases in brain parenchy- mal Lac (Fig. 13.8).
Other rare metabolic conditions also may provide diagnostic-specifi c proton MRS fi ndings. In the phe- nylketonuria, patients show a specifi c peak due to the elevated phenylalanine and proton MRS can be used in patients with this metabolic disorder to follow the infl ux of phenylalanine from blood into brain tissue as well as to monitor the response of diet therapy (Kreis et al. 1995; Pietz et al. 2003). In the leuko- encephalopathy associated with the disturbance of the metabolism of the polyols (van der Knaap et al. 1999), the diffuse decrease of all normally de- tected metabolites is associated with the increases of arabitol and sorbitol in both white and grey matter regions. In maple syrup disease, a relatively specifi c broad peak is detectable at 0.9 ppm. This region of the spectrum is usually attributed to lipids, but in maple syrup disease is believed to represent resonances of methyl protons from branched-chain amino-acids
Fig. 13.7a–c. Conventional FLAIR image and proton MR spectra corresponding to brain voxels located in the frontal white matter (a), periventricular white matter (b) and grey matter (c) in the MRI/MRSI examination performed in a patient with megalencephalic cystic leukoencephalopathy at 25 years of age. Loss of signals in all the metabolites normally detected with the long echo time multi-voxel MRSI method are evident in white matter voxels. These abnormalities are relatively mild in the frontal white matter (a) and more pronounced in the periventricular white matter (b). Moderate increases in Lac resonance intensity can be seen in both white matter regions. No abnormalities are evident in grey matter voxels (c)
a c
b
and branched-chain alpha-keto acids that accumu- late as a result of defective oxidative decarboxylation of leucine, isoleucine and valine (Jan et al. 2003). Also proton MRS studies on patients with Niemann-Pick type C disease have shown increased resonance in- tensity of the lipid region of the spectrum (Fig. 13.9), probably due, in this case, to a defective metabolism of cholesterol with ceramide accumulation (Sylvain et al. 1994; Battisti et al. 2003). In both maple syrup and Niemann-Pick type C disease, the abnormal broad peak detectable at 0.9 ppm seem to decrease with appropriate therapy (Jan et al. 2003; Sylvain et al. 1994).
Finally, specifi c metabolic syndromes have re- cently been revealed by using proton MRS. This is the case of the creatine defi ciency syndromes, which include defects in the guanidinoacetate methyltrans- ferase and in the arginine-glycine amidinotransfer- ase (Stockler et al. 1994; Schulze 2003), and the X-linked creatine defi ciency syndrome (Bizzi et al.
2002). In the fi rst two forms of the diseases, the Cr resonance intensity is undetectable in the brain on proton MRS, but cerebral levels of Cr do increase af- ter creatine supplementation. In the X-linked form of creatine defi ciency, as the metabolic defect is due to the transport of creatine into the central nervous system, patients are unresponsive to treatment and the Cr resonance intensity levels are unchanged af- ter creatine supplementation (Fig. 13.10). Another
condition with very specifi c proton MRS spectrum is the unique case of a child with minor developmen- tal delay and absence of cerebral NAA, in whom the most prominent peak of proton MRS at 2.02 ppm was undetectable (Martin et al. 2001). Both creatine defi ciency syndromes and the absence of NAA are characterized by mild or absent abnormalities on conventional MRI suggesting the unique potential of proton MRS in revealing metabolic abnormalities in MRI normal-appearing tissue.
13.4
Metabolic Changes Beyond MRI Lesions
As extensively reported in patients with multiple scle- rosis (Fu et al. 1998), also in patients with both he- reditary and acquired white matter disorders the de- tection of brain metabolic changes is not restricted to lesions (de Stefano et al. 2000b). Metabolic changes in normal-appearing white matter are usually less severe than those found inside the lesions and mostly consist in decreases in NAA and increases in Lac and Cho.
Because axons project through lesion volumes, any axonal dysfunction or loss should extend well beyond the borders of a lesion and into normal-appearing white matter, as an expression of anterograde and
Fig. 13.8a,b. Conventional MRI with the superimposed grid of spectroscopy voxels (a) and proton MR spectra corresponding to brain voxels located in the basal ganglia of both cerebral hemispheres (b) in a patient with pyruvate dehydrogenase defi ciency.
Each spectrum shows large pathological signals at 1.33 ppm coming from the methyl doublet of lactate (Lac)
a
bretrograde axonal degeneration. Thus, it should not be surprising that decreases in NAA can be observed beyond the borders of MS lesions as defi ned by T
2- weighted MRI. The analysis of serial multi-voxel proton MRSI studies from patients who present with large, solitary demyelinating lesions offers special op- portunities in this respect. These studies showed that decreases in NAA can be seen well outside the demy- elinating lesion (de Stefano et al. 1995a) and can be transiently evident even in homologous voxels of the hemisphere contralateral to the lesion (de Stefano et al. 1999).
Increases in Lac resonance intensities in the nor- mal-appearing brain tissue represent a biochemical characteristic of mitochondrial encephalopathies.
As mentioned before, Lac levels are transiently in- creased in a number of acute pathological conditions associated with infl ammation (Arnold et al. 1992;
Petroff et al. 1992), but pathological increases in Lac outside of MRI lesions may be indicative of wide- spread mitochondrial impairment (Matthews et al.
1993; de Stefano et al. 1995c).
Increases in Cho also could be detected in the nor- mal-appearing WM in several WM conditions. This is the case, for example, in patients with rare, inherited diseases such as adrenoleukodystrophy (Kruse et al.
1994) and adult-onset Krabbe disease (de Stefano et al. 2000a) (Fig. 13.11). In all of these cases, the detec-
Fig. 13.9a,b. Single voxel proton MR spectra relative to a normal control (a) and a patient with Niemann-Pick type C disease (b).
The spectra originate from homologous large volume of interest localized above the lateral ventricles and including grey and white matter of both cerebral hemispheres. Note the large decrease in N-acetyl aspartate and the increase in the lactate/lipids signals in the patient with Niemann-Pick type C disease respect to the normal control. Increases in lipids, rare in MR spectra at long echo times, are interpreted as due to ceramide accumulation
a b
Fig. 13.10a–c. Proton brain MR spectra of a patient with X- linked creatine defi ciency. The spectra show decreases in cre- atine resonance intensity (a), which remains unchanged after 3 months of oral creatine monohydrate supplementation at 400 mg/kg/day (b) and after 8 months of supplementation at 800 mg/kg/day (c). (Courtesy of Alberto Bizzi)
a
b
c
tion of metabolic changes in tissue appearing nor- mal on MRI should be interpreted as the fi rst sign of white matter pathology, not yet detectable by conven- tional MRI.
On the other hand, brain metabolic changes sometimes can be independent of the degree of abnormalities seen on conventional MRI. This can be found, for example, in CADASIL (cerebral auto- somal dominant arteriopathy with subcortical in- farcts and leukoencephalopathy) patients with mild and severe neurological impairment who can show similar white matter abnormalities on conventional MRI and, respectively, mild and severe brain meta- bolic abnormalities on multi-voxel proton MRSI (Fig. 13.12). Similarly, a single voxel study showed that this is also valid in other diseases such as in congenital muscular dystrophy where, in a patient
with no central nervous system impairment, the MRS metabolic pattern was normal despite the dif- fuse white matter abnormalities on conventional MRI (Fig. 13.13). This confi rms once again the lack of pathological specifi city of the white matter le- sions detected on conventional MRI and supports the hypothesis that brain lesions appearing similar on MRI may have a different pathophysiology and, as a consequence, different clinical relevance. In contrast, in both CADASIL and congenital muscular dystrophy as well as in other metabolic disorders cerebral levels of NAA correlated closely to patients’
clinical status (de Stefano et al. 2000b) suggesting that the widespread cerebral neuro-axonal dysfunc- tion and/or loss represents the most relevant mecha- nism of functional impairment in several metabolic disorders affecting the cerebral white matter.
Fig. 13.11a,b. Proton brain MRI/MRSI examination of a patient with adult-onset Krabbe disease. Conventional MRI examina- tion show abnormally high signal localized to the motor strips of both hemispheres. The volume of interest for spectroscopy is shown in the transverse MRI. Proton MRSI voxels were classifi ed as inside the lesion if they were entirely fi lled with abnormal MRI signal (a) and as outside the lesion if there was no abnormal MRI signal within the voxel and in adjacent voxels (b). Proton MRSI spectra from voxels [squares in (a) and (b)] show abnormal increases in choline resonance intensities
a
b
Fig. 13.12a,b. Proton brain MRI/MRSI examinations relative to two patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mild (a) and severe (b) neurological impairment, respectively.
Patients show similar white matter abnormalities on conventional MRI. In contrast, proton MRSI voxels localized in the deep white matter (squares) show metabolic changes which are independent of the degree of MRI white matter abnormalities and are very mild in the CADASIL patient with mild neurological impairment, and more pronounced in the CADASIL patient with severe clinical status
a b
Fig. 13.13a,b. Conventional MRI in transversal orientation (a) and the single voxel pro- ton MRS spectrum of a patient with congenital muscular dystrophy (b). The volume of interest for spectroscopy is shown in the transverse MRI. The conventional MR image shows diffuse white matter hyperintensity, but the MR spectrum is normal.
The patient, despite the diffuse cerebral white matter abnormalities, did not have CNS impairment
a
b13.5 Conclusions
Brain MRS provides chemical-pathological infor- mation that has the potential to improve both di- agnostic classifi cation and management of patients with metabolic disorders affecting the brain white matter. Metabolic indices provided by proton MRS and MRSI could be sensitive indicators of early neu- rological involvement, relevant to patients’ clinical status. A more extensive use of a combination of MR modalities including volumetric MRI, MRS and other nonconventional MR techniques might yield a more complete description of the dynamics responsible for pathological changes in this heterogeneous group of disorders and allow a more accurate evaluation of disease progression and response to therapy. A wider use of proton MRS techniques should be encour- aged in clinical studies of patients with metabolic disorders.
References
Arnold DL, Matthews PM (1996) Practical aspects of clinical applications of MRS in the brain. In: Young IR, Charles HC (eds) MR spectroscopy: clinical applications and tech- niques. Dunitz, London, pp 139-159
Arnold DL, Matthews PM, Francis GS, O’Connor J, Antel JP (1992) Proton magnetic resonance spectroscopic imaging for metabolic characterization of demyelinating plaques.
Ann Neurol 31:235-241
Austin SJ, Connelly A, Gadian DG, Benton JS, Brett EM (1991) Localized 1H NMR spectroscopy in Canavan’s disease: a report of two cases. Magn Reson Med 19:439-445
Bardosi A, Creutzfeldt W, DiMauro S, Felgenhauer K, Friede RL, Goebel HH et al (1987) Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial defi - ciency of cytochrome-c-oxidase. A new mitochondrial multisystem disorder. Acta Neuropathol 74:248-258 Battisti C, Tarugi P, Dotti MT, De SN, Vattimo A, Chierichetti
F et al (2003) Adult onset Niemann-Pick type C disease: a clinical, neuroimaging and molecular genetic study. Mov Disord 18:1405-1409
Bizzi A, Bugiani M, Salomons GS, Hunneman DH, Moroni I, Estienne M et al (2002) X-linked creatine defi ciency syndrome: a novel mutation in creatine transporter gene SLC6A8. Ann Neurol 52:227-231
Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD (2002) N- acetylaspartate is an axon-specifi c marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve. Ann Neurol 51:51-58 Bruhn H, Kruse B, Korenke GC, Hanefeld F, Hanicke W, Mer-
boldt KD et al (1992) Proton NMR spectroscopy of cerebral metabolic alterations in infantile peroxisomal disorders. J Comput Assist Tomogr 16:335-344
Burgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, Aicardi J (1992) Defi ciency in complex II of the respira- tory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome. Brain Dev 14:404-408
Coburn B (2004) A rare disorder, ethylmalonic encephalopa- thy, is caused by mutations in a mitochondrial protein. Clin Genet 65:460-462
Davies SE, Newcombe J, Williams SR, McDonald WI, Clark JB (1995) High resolution proton NMR spectroscopy of mul- tiple sclerosis lesions. J Neurochem 64:742-748
De Stefano N, Matthews PM, Antel JP, Preul M, Francis G, Arnold DL (1995a) Chemical pathology of acute demy- elinating lesions and its correlation with disability. Ann Neurol 38:901-909
De Stefano N, Matthews PM, Arnold DL (1995b) Reversible decreases in N-acetylaspartate after acute brain injury.
Magn Reson Med 34:721-727
De Stefano N, Matthews PM, Ford B, Genge A, Karpati G, Arnold DL (1995c) Short-term dichloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders. Neurology 45:1193-1198 De Stefano N, Narayanan S, Matthews PM, Francis GS, Antel JP,
Arnold DL (1999) In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 122:1933-1939
De Stefano N, Dotti MT, Mortilla M, Pappagallo E, Luzi P, Rafi MA et al (2000a) Evidence of diffuse brain pathology and unspecifi c genetic characterization in a patient with an atypical form of adult-onset Krabbe disease. J Neurol 247:226-228
De Stefano N, Narayanan S, Matthews PM, Mortilla M, Dotti MT, Federico A et al (2000b) Proton MR spectroscopy to assess axonal damage in multiple sclerosis and other white matter disorders. J Neurovirol 6 [Suppl 2]:121-129 De Stefano N, Dotti MT, Mortilla M, Federico A (2001) Mag-
netic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis.
Brain 124:121-131
Dotti MT, Manneschi L, Federico A (1995) Mitochondrial enzyme defi ciency in cerebrotendinous xanthomatosis. J Neurol Sci 129:106-108
Dubeau F, De SN, Zifkin BG, Arnold DL, Shoubridge EA (2000) Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedi- gree. Ann Neurol 47:179-185
Federico A, Dotti MT, Volpi N (1991) Muscle mitochondrial changes in cerebrotendinous xanthomatosis (letter). Ann Neurol 30:734-735
Fu L, Matthews PM, De Stefano N, Worsley KJ, Narayanan S, Fran- cis GS et al (1998) Imaging axonal damage of normal-appear- ing white matter in multiple sclerosis. Brain 121:103-113 Grodd W, Krageloh-Mann I, Petersen D, Trefz FK, Harzer K
(1990) In vivo assessment of N-acetylaspartate in brain in spongy degeneration (Canavan’s disease) by proton spec- troscopy (letter). Lancet 336:437-438
Grosso S, Balestri P, Mostardini R, Federico A, De SN (2004) Brain mitochondrial impairment in ethylmalonic encepha- lopathy. J Neurol 251:755-756
Hanefeld F, Holzbach U, Kruse B, Wilichowski E, Christen HJ, Frahm J (1993) Diffuse white matter disease in three chil- dren: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spec- troscopy. Neuropediatrics 24:244-248
Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM (2003) MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decom- pensation. Neuroradiology 45:393-399
Johannik K, Van Hecke P, Francois B, Marchal G, Smet MH, Jaeken J et al (1994) Localized brain proton NMR spectros- copy in young adult phenylketonuria patients. Magn Reson Med 31:53-57
Kolodny EH (1993) Dysmyelinating and demyelinating con- ditions in infancy (review). Curr Opin Neurol Neurosurg 6:379-386
Koopmans RA, Li DK, Zhu G, Allen PS, Penn A, Paty DW (1993) Magnetic resonance spectroscopy of multiple sclerosis:
in-vivo detection of myelin breakdown products (letter).
Lancet 341:631-632
Kreis R, Pietz J, Penzien J, Herschkowitz N, Boesch C (1995) Identifi cation and quantitation of phenylalanine in the brain of patients with phenylketonuria by means of local- ized in vivo 1H magnetic-resonance spectroscopy. J Magn Reson B 107:242-251
Kruse B, Barker PB, van Zijl PC, Duyn JH, Moonen CT, Moser HW (1994) Multislice proton magnetic resonance spectro- scopic imaging in X-linked adrenoleukodystrophy. Ann Neurol 36:595-608
Kruse B, Hanefeld F, Christen HJ, Bruhn H, Michaelis T, Hanicke W et al (1993) Alterations of brain metabolites in metachromatic leukodystrophy as detected by localized proton magnetic resonance spectroscopy in vivo. J Neurol 241:68-74
Leutner C, Layer G, Zierz S, Solymosi L, Dewes W, Reiser M (1994) Cerebral MR in ophthalmoplegia plus. AJNR Am J Neuroradiol 15:681-687
Martin E, Capone A, Schneider J, Hennig J, Thiel T (2001) Absence of N-acetylaspartate in the human brain: impact on neurospectroscopy? Ann Neurol 49:518-521
Matthews PM, Andermann F, Silver K, Karpati G, Arnold DL (1993) Proton MR spectroscopic characterization of differ- ences in regional brain metabolic abnormalities in mito- chondrial encephalomyopathies. Neurology 43:2484-2490 Matthews PM, de Stefano N, Narayanan S, Francis GS, Wolin-
sky JS, Antel JP et al (1998) Putting magnetic resonance spectroscopy studies in context: axonal damage and dis- ability in multiple sclerosis. Semin Neurol 18:327-336 Nakai A, Goto Y, Fujisawa K, Shigematsu Y, Kikawa Y, Konishi Y
et al (1994) Diffuse leukodystrophy with a large-scale mito- chondrial DNA deletion. Lancet 343:1397-1398
Narayana PA, Doyle TJ, Lai D, Wolinsky JS (1998) Serial proton magnetic resonance spectroscopic imaging, contrast-
enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 43:56- 71
Petroff OA, Graham GD, Blamire AM, al-Rayess M, Rothman DL, Fayad PB et al (1992) Spectroscopic imaging of stroke in humans: histopathology correlates of spectral changes.
Neurology 42:1349-1354
Pietz J, Lutz T, Zwygart K, Hoffmann GF, Ebinger F, Boesch C et al (2003) Phenylalanine can be detected in brain tissue of healthy subjects by 1H magnetic resonance spectroscopy. J Inherit Metab Dis 26:683-692
Schiffmann R, van der Knaap MS (2004) The latest on leuko- dystrophies. Curr Opin Neurol 17:187-192
Schulze A (2003) Creatine defi ciency syndromes. Mol Cell Bio- chem 244:143-150
Stockler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M et al (1994) Creatine defi ciency in the brain:
a new, treatable inborn error of metabolism. Pediatr Res 36:409-413
Sylvain M, Arnold DL, Scriver CR, Schreiber R, Shevell MI (1994) Magnetic resonance spectroscopy in Neimann-Pick disease type C: correlation with diagnosis and clinical responce to cholestyramine and lovastatin. Pediatric Neu- rology 10:228-232
Tedeschi G, Schiffmann R, Barton NW, Shih HH, Gospe SMJ, Brady RO et al (1995) Proton magnetic resonance spec- troscopic imaging in childhood ataxia with diffuse central nervous system hypomyelination. Neurology 45:1526-1532 Tzika AA, Ball WS Jr, Vigneron DB, Dunn RS, Nelson SJ, Kirks
DR (1993) Childhood adrenoleukodystrophy: assessment with proton MR spectroscopy. Radiology 189:467-480 Van der Knaap MS (2001) Magnetic resonance in childhood
white-matter disorders. Dev Med Child Neurol 43:705-712 Van der Knaap MS, Valk J, de Neeling N, Nauta JJ (1991) Pat- tern recognition in magnetic resonance imaging of white matter disorders in children and young adults. Neuroradi- ology 33:478-493
Van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts WF, Hoogenraad F et al (1995) Leukoencephalopa- thy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 37:324-334
Van der Knaap MS, Barth PG, Gabreels FJ, Franzoni E, Begeer JH, Stroink H et al (1997) A new leukoencephalopathy with vanishing white matter. Neurology 48:845-855
Van der Knaap MS, Wevers RA, Struys EA, Verhoeven NM, Pouwels PJ, Engelke UF et al (1999) Leukoencephalopathy associated with a disturbance in the metabolism of polyols.
Ann Neurol 46:925-928
