Brain fluorodeoxyglucose PET in adrenoleukodystrophy
Ettore Salsano, MD Giorgio Marotta, MD Valentina Manfredi, PsyD Anna Rita Giovagnoli, MD Laura Farina, MD Mario Savoiardo, MD† Davide Pareyson, MD Riccardo Benti, MD Graziella Uziel, MD
Correspondence to Dr. Salsano: [email protected]
ABSTRACT
Objective: To investigate the cerebral glucose metabolism in subjects with X-linked adrenoleukodystrophy (X-ALD) by using brain [18F]-fluorodeoxyglucose PET (FDG-PET).
Methods: Cross-sectional study in which 12 adults with various forms of X-ALD underwent clinical evaluation and brain MRI, followed by brain FDG-PET, neuropsychological assessment, and personality and psychopathology evaluation using the Symptom Checkist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory-III (MCMI-III). Results: When compared to healthy control subjects (n 5 27) by using Statistical Parametric Mapping 8 software, the patients with X-ALD—with or without brain MRI changes—showed a pattern of increased glucose metabolism in frontal lobes and reduced glucose metabolism in cerebellum and temporal lobe areas. On single case analysis by Scenium software, we found a similar pattern, with significant (p , 0.02) correlation between the degree of hypermetabolism in the frontal lobes of each patient and the corresponding X-ALD clinical scores. With respect to personality, we found that patients with X-ALD usually present with an obsessive-compulsive personality disorder on the MCMI-III, with significant (p , 0.05) correlation between glucose uptake in ventral striatum and severity of score on the obsessive-compulsive subscale.
Conclusions: We examined cerebral glucose metabolism using FDG-PET in a cohort of patients with X-ALD and provided definite evidence that in X-ALD the analysis of brain glucose metabolism reveals abnormalities independent from morphologic and signal changes detected by MRI and related to clinical severity. Brain FDG-PET may be a useful neuroimaging technique for the characterization of X-ALD and possibly other leukodystrophies. Neurology® 2014;83:981–989 GLOSSARY ALMN 5 adrenoleukomyeloneuropathy; AMN 5 adrenomyeloneuropathy; BBB 5 blood-brain barrier; BR 5 base rate; C-ALD 5 cerebral adrenoleukodystrophy; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, fourth edition; FDG 5 fluorodeoxyglucose; FDR 5 false discovery rate; MCMI-III 5 Millon Clinical Multiaxial Inventory-III; OCPD 5 obsessive-compulsive personality disorder; SCL-90-R 5 Symptom Checkist-90-Revised; SPM 5 Statistical Parametric Mapping; X-ALD 5 X-linked adrenoleukodystrophy.
Supplemental data at Neurology.org
X-linked adrenoleukodystrophy (X-ALD)—caused by ABCD1 mutations—encompasses a wide spectrum of clinical phenotypes, ranging from the childhood-onset, rapidly progressive cerebral form to completely asymptomatic individuals late in life.1–3 Adrenomyeloneuropathy (AMN) is the most common adult-onset form of X-ALD and is characterized by symptoms limited to the spinal cord and peripheral nerves. About 55% of patients with AMN have very slow progression, and brain MRI remains normal (“pure” AMN) or shows corticospinal tract involvement. The remaining 45% can show lobar cerebral white matter involvement (adrenoleukomyeloneuropathy [ALMN]), which might become severely progressive.1 Rarely, X-ALD presents during adolescence or adulthood with neuropsychological symptoms followed by neurologic deficits (cerebral adrenoleukodystrophy [C-ALD]). In these cases, the demyelinating lobar involvement is present from the start of the disease, which has rapid progression, like the childhood cerebral form.4 †Deceased. From the Departments of Clinical Neurosciences (E.S., D.P.), Diagnostics and Applied Technology (V.M., A.R.G., L.F., M.S.), and Child Neurology (G.U.), Fondazione IRCCS, Istituto Neurologico “C. Besta,” Milano, Italy; and Department of Nuclear Medicine (G.M., R.B.), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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Table 1
Clinical features of the 12 adults with different forms of adrenoleukodystrophy investigated by brain FDG-PET Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
8
11
8
Patient 7
Patient 8
Patient 9
Patient 10
Patient 11
Patient 12
18
5
Neurology 83 September 9, 2014
Schooling, y
8
8
18
13
12
8
13
ABCD1 mutation
c.443A.G; c.242insCCTGCGGCT; p.Asn148Ser p.R80_L81insLLR
IVS312T.A exon8-10del
exon810del
Exon710del
c.1631A.G; p.Gln544Arg
c.293C.T; p. Ser98Leu
c.1165C.T; p.Arg389Cys
c.454C.T; c.1015T.G; p.Arg152Cys p.Trp339Gly
c.1165C.T; p.Arg389Cys
Age at onset of neurologic symptoms, y
14
18
20
20
25
21
25
33
43
NA
NA
NA
Age at evaluation, y
24
37
35
24
32
24
37
34
45
27
56
62
AdolC-ALD
AC-ALD
ALMN
AMN
AMN
AMN
AMN
AMN
AMN
Addison-only phenotype
Asymptomatic Asymptomatic
Adrenal failure
Yes
Yes
No
Yes
Yes
Yes (early)
Yes (early)
Yes
No
Yes
No
No
Initial neurologic symptoms
Behavioral Depression and cognitive decline
Gait difficulties
Gait difficulties
Impotence
Gait difficulties
Gait difficulties
Gait difficulties
Calf muscle cramps, urinary urge incontinence
NA
NA
NA
Gaitb
Normal
Spastic ataxic 2
Spastic 3
Spastic ataxic 2
Spastic ataxic 2
Spastic ataxic 1
Spastic 2
Spastic 3
Spastic ataxic 1 Normal
Normal
Normal
Ambulation Indexc
0
4
7
4
4
2
3
7
2
0
0
0
Muscle toned
Normal
3
3
2
2
1
2
3
1
Normal
Normal
Normal
31
41
41
41
41
41
41
41
31
21
21
41
1
2
a
X-ALD form
Clinical features at evaluation
Tendon reflexes e
Normal
1
2
2
2
Normal
2
Normal
Normal
Normal
Bladder function
Normal
Urge incontinence
Neurogenic bladder
Urgency
Urge Urge Urgency incontinence incontinence
Urgency
Urge incontinence
Normal
Normal
Normal
Other symptoms
Manic-like behaviorf
Bipolar disorder, visual and hearing loss
Visual loss
Manic-like behavior, pain in the legs, fecal urgency, impotence
Pain in the legs
No
Lower leg numbness
Pain in the legs
Impotence, pain in the legs
No
No
No
Motor function (0–6)
0
4
5
4
4
2
2
5
2
0
0
0
Bladder functions (0– 3)
0
2
3
2
2
2
2
2
2
0
0
0
Sensory symptoms or pain in the legs (0–3)
0
2
2
2
2
2
2
2
2
0
0
0
Cerebral functions (0–12)h
6
9
6
3
0
0
0
3
0
0
0
0
Total score (0–24)
6
17
16
11
8
6
6
12
6
0
0
0
X-ALD brain MRI severity scorei
13.5
14
10
0.5
5
3
0.5
0.5
0.5
0
0.5
0
Vibration sense
ALD Clinical Scoreg
Abbreviations: ALD 5 adrenoleukodystrophy; FDG 5 fluorodeoxyglucose; MCMI-III 5 Millon Clinical Multiaxial Inventory-III; NA 5 not applicable; X-ALD 5 X-linked adrenoleukodystrophy. a AC-ALD 5 adult cerebral X-ALD; AdolC-ALD 5 adolescent cerebral X-ALD; ALMN 5 adrenoleukomyeloneuropathy; AMN 5 adrenomyeloneuropathy.
Gait: 1 5 abnormal without support; 2 5 with support; 3 5 wheelchair-bound. The Ambulation Index is a 10-point scale to assess mobility by evaluating the time and degree of assistance for walking 25 feet (8 m).32 d Ashworth scale: 0 5 normal muscle tone; 1 5 slight increase in tone giving a “catch” when limb is flexed or extended; 2 5 more marked increase in tone but limb still easily flexed; 3 5 considerable increase in tone, passive movement difficult; 4 5 limb rigid in flexion or extension.33 e Vibration sense: 1 5 decreased in feet; 2 5 absent in feet and lowered in lower legs; 3 5 lowered in at least upper legs and absent in lower legs.34 f At the time of MCMI-III administration, the manic-like behavior was well-controlled by valproic acid.28 g The ALD Clinical Score is a clinical measure of disability specifically conceived for X-ALD.4 h Personality disorders as assessed by MCMI-III were not considered psychiatric symptoms. i The maximum X-ALD brain MRI severity score, which was proposed specifically for X-ALD,10 is 34; a score $1 is considered abnormal. c
b
PET using 2-[18F]-fluoro-2-deoxy-D-glucose (FDG-PET) has rarely been used to examine cerebral glucose metabolism in X-ALD, and only a few reports of single cases have been published so far.5–9 Notably, a patient with AMN presented with multifocal brain and cerebellar hypometabolism despite the lack of MRI signal changes.8 This discrepancy suggests that X-ALD may be characterized by metabolic brain abnormalities detectable by FDG-PET and independent from signal abnormalities detected by standard MRI. The aim of this study is to assess the presence of metabolic brain abnormalities in adults with different forms of X-ALD by using FDGPET and to examine their correlation with clinical, personality, and brain MRI features. METHODS Patients. We recruited 12 adult ($18 years) Italian participants (mean age: 36 years; range: 24–62 years) with both biochemically and genetically confirmed X-ALD, followed at the IRCCS Foundation, “C. Besta” Neurological Institute, Milan, Italy. The selection of patients was not random and was aimed at including different forms of X-ALD. The clinical features and brain MRI findings of each patient are summarized in table 1. The MRI severity score, proposed specifically for X-ALD,10 was calculated by 2 neuroradiologists (L.F. and M.S.) experienced in X-ALD. Mild to moderate global cerebral atrophy was present in 3 patients only (patients 1, 2, and 3), whereas selective frontal, temporal, or cerebellar atrophy was not evident in any of the patients.
Neuropsychological assessment. Cognitive functions were assessed using a standardized battery of neuropsychological tests for the evaluation of the most relevant domains of cognition. Briefly, the Attentive Matrices, Weigl’s Sorting, Street’s Completion, Corsi’s Blocks Span and Digit Span, Word Fluency on phonemic or semantic cue, Short Story, Rey’s Complex Figure Copying and Delayed Reproduction, Trail Making Test A and B, and Raven’s Colored Progressive Matrices tests were used to assess selective attention, categorization of visuospatial stimuli and shifting, visual perception, spatial and verbal memory span, word finding, verbal and visuospatial memory, constructive praxis, visuomotor coordination speed and divided attention, and abstract reasoning.11–16 Personality and psychopathology assessment. The Symptom Checklist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory-III (MCMI-III) were administered with the supervision of a psychologist (V.M.) for assessing the presence of DSM-IV Axis I clinical syndromes and DSM-IV Axis II personality disorders. The SCL-90-R is a 90-item selfreport (multidimensional symptom) inventory that explores 9 symptom dimensions of psychopathology, such as depression and anxiety. The 90 items in the questionnaire are scored on a 5-point Likert scale, ranging from “not at all” (0) to “extremely” (4) for indicating the rate of occurrence of each symptom.17 The MCMI-III is a self-report inventory composed of 175 true/false items assessing personality disorders and clinical syndromes related to the DSM-IV classification. It yields raw scores on 24 scales (10 clinical syndrome and 14 personality disorder scales), which are converted into base rate (BR) scores, which take into
account the prevalence of the particular personality pattern or psychiatric clinical syndrome in the target population. A BR score higher than 75 is considered to indicate the “presence of a trait,” while a BR score higher than 85 is considered to indicate definite presence of the personality pattern or clinical syndrome.18
Brain FDG-PET imaging and data analysis. FDG-PET imaging was performed using a Biograph Truepoint 64 PET/ CT scanner (Siemens, Erlangen, Germany) as routinely done at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy. Data were quantitatively analyzed using the Statistical Parametric Mapping (SPM) software, version 8 (Wellcome Department of Cognitive Neurology, London, UK) for group analysis, with false discovery rate (FDR) correction for multiple testing (p , 0.01) and age at PET scan as nuisance covariate, and using the software Scenium (Siemens Molecular Imaging) for single-participant analysis (appendix e-1 on the Neurology® Web site at Neurology.org). We used the software Scenium for single-participant analysis in order to corroborate the results obtained from group analysis by using SPM. Indeed, unlike SPM, Scenium is a straightforward and easy-to-do software solution that was conceived to compare the metabolic changes of a single participant with a predefined reference database of 30 normal participants. Correlation analysis. Correlation analyses were carried out using commercial software package SPSS for Windows 7.0 (SPSS UK, Surrey, UK). Standard protocol approvals, registrations, and patient consents. The study was in compliance with the Declaration of Helsinki principles and was approved by the institutional review boards, and all patients involved gave their written informed consent. RESULTS Neuropsychological findings. Cognitive functions were normal in 9 out of 12 patients (table e-1). Six of these 9 patients had AMN, 2 were asymptomatic, and 1 had adrenocortical insufficiency only. The 3 patients with pathologic cognition had C-ALD (n 5 2) or ALMN (n 5 1).
Psychopathological and personality features. No psycho-
pathology was demonstrated on the SCL-90-R, with the exception of patient 2 who had a pathologic score on the depression subscale. With respect to personality, all patients with X-ALD showed at least one personality disorder on the MCMI-III, i.e., the BR score was .85 on at least one MCMI-III subscale. Notably, the BR score was .85 for the obsessive-compulsive subscale in 9 out of 12 (75%). No questionnaire was considered “invalid” according to the inventory criteria. The mean BR scores and the corresponding confidence intervals are shown in figure 1 as error bar plots. Cerebral metabolic activity on FDG-PET. Group analysis.
Using SPM8, we first compared the brain 18PETFDG uptake at rest from 12 adult males with different forms of X-ALD with that from 27 age-matched healthy controls. We found that, compared with healthy controls, the patients with X-ALD had clusters of increased glucose metabolism in the middle and superior frontal gyri and in the anterior cingulate Neurology 83
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gyri, and clusters of reduced glucose metabolism in temporal gyri and cerebellum (p , 0.01, FDRcorrected) (figure 2; see table 2 for further details). Of note, brain MRI did not reveal any abnormality in these areas (i.e., frontal, temporal, and cerebellar cortex), except in patient 2 who had cerebellar white matter abnormalities, and similar changes in cerebral metabolic activity were found when we compared only the subjects with AMN (n 5 6) vs healthy controls. Single-participant analysis. Using Scenium software, we subsequently compared the brain 18PET-FDG uptake at rest of each patient with X-ALD with the reference database of 30 healthy controls. In particular, for each patient we calculated a z score on a voxelby-voxel basis and a mean z score for each anatomical region in the brain, such as frontal lobes and cerebellum, in order to indicate to what extent the patient scan differs from a scan that is considered normal. In agreement with the group analysis, we found that each patient with X-ALD had varying degrees of significant changes (i.e., z score .2 or ,22) in the glucose uptake of the frontal lobes, cerebellum, or both (figure 3). For instance, in patient 2 we found positive z scores of 6.3 and 6.8 in the left and right frontal lobes and negative z scores of 22.3 and 23.9 in the left and right cerebellum. We also found a significantly reduced metabolism (i.e., negative z score ,22) in the visual cortex of the 2 patients (patients 2 and 3) with visual disturbances and parieto-occipital white matter abnormalities on brain MRI (figure e-1). Eventually we observed no abnormal glucose metabolism in the context of the parietooccipital white matter abnormalities of patient 2, despite the presence of abnormal contrast enhancement, and no univocal change in the glucose metabolism in temporal lobes. Correlation between cerebral glucose metabolism and
We found a significant (p , 0.02) correlation between the degree of hypermetabolism of the frontal lobes (expressed as the z score calculated using the Scenium software) and the severity of the ALD clinical score (Pearson r 5 0.68 [left] and 0.67 [right]). This correlation was maintained when we excluded the 3 patients with overt MRI abnormalities (i.e., patients 1, 2, and 3). More importantly, we found a significant (p , 0.05) correlation between glucose uptake in ventral striatum and score on the MCMI-III obsessive-compulsive subscale (figure e-2) (Pearson r 5 0.86 [left] and 0.76 [right]). clinical and personality features.
DISCUSSION Brain FDG-PET can be used to indirectly investigate the gray matter function of the brain, as there is a link between gray matter glucose uptake and neuron activity, and it is considered 984
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a reliable,19 relatively easy to perform, and safe neuroimaging technique (e.g., in this study, each patient was exposed to approximately 3–4 mSv; for comparison, the limit of the International Commission on Radiological Protection for an occupational radiation worker is 20 mSv/year). So far, no systematic research has been conducted to evaluate cerebral gray matter glucose uptake in patients with X-ALD, although gray matter dysfunctions related to white matter damage and axonal or neuronal loss might be expected in X-ALD. In support of this, 3 cases of cerebral X-ALD investigated by brain FDG-PET revealed decreased glucose uptake (or hypometabolism) in posterior areas of the brain overlying the typical white matter abnormalities (in the occipital and parietal lobes).5–7 Moreover, 2 of them presented with hypermetabolism in the cerebral white matter areas, probably caused by the active process of neuroinflammation.5,7 This process was also investigated by PET using the 11C-[R]-PK11195 radioligand, which recognizes peripheral benzodiazepine receptors expressed by activated microglia in cases of neuroinflammation.20 Finally, the presence of hypometabolism of different cortical regions and cerebellum has been recently documented in one individual with AMN and one individual with the cerebello-brainstem form of X-ALD.8,9 Our study assessed cerebral glucose metabolism by using standard FDG-PET in a cohort of 12 adults with different forms of X-ALD, including 6 cases of AMN, 1 case of ALMN, 2 cases of C-ALD, 1 Addison-only phenotype, and 2 presymptomatic patients. On group comparison (X-ALD vs normal healthy controls), FDG-PET showed increased uptake within frontal areas and anterior cingulate cortex and decreased uptake in temporal areas and cerebellum (figure 2). This metabolic pattern seems to be characteristic of the disease and unrelated to the presence of brain MRI abnormalities. Indeed, this pattern was also present when only the subjects with AMN (i.e., without any brain MRI abnormality) were compared to normal healthy controls. The physiopathologic basis of this pattern of abnormal brain glucose metabolism in X-ALD is unknown. We hypothesize that it might be primarily caused by a cortical afferent dysfunction, which can be seen on FDG-PET images as “cortical diaschisis.” This hypothesis is supported by the fact that on brain MRI there was no atrophy restricted to frontal, temporal, or cerebellar cortex as possible structural correlate of glucose uptake abnormalities, and postmortem studies in cerebral X-ALD and AMN show that the gray matter, including cerebral and cerebellar cortex, is largely spared.21,22 On the other hand, cortical diaschisis is typically observed in cerebral pathologies associated with focal or diffuse damage of white matter, including vascular and traumatic brain injuries,23,24 and in our
Figure 1
Base rate scores on the Millon Clinical Multiaxial Inventory-III for the 12 adults with different forms of adrenoleukodystrophy
Base rate scores higher than 75 indicate “presence of a trait,” while base rate scores higher than 85 indicate definite presence of the personality pattern or clinical syndrome.
different cases of X-ALD there was no evident lesion in the white matter of frontal and temporal lobes, as well as in the white matter of cerebellum. Postmortem studies, however, show that there are varying degrees of dysmyelination, inflammatory demyelination, and axonal loss in the cerebral white matter of cerebral X-ALD and AMN, and even patients with “pure” AMN have microscopic foci of dysmyelination, with PAS 1 macrophages and varying degrees of oligodendrocyte reduction and axonal loss, although no macroscopic white matter lesion is observed.25 Therefore, it is plausible that in X-ALD there is some degree of cortical afferent dysfunction, even without clear correlation with MRI findings, because it may be from axonal degeneration, microscopic white matter changes, or both. Moreover, because the afferent cerebellar cortical connections, including the climbing and mossy fibers, are excitatory, it is tempting to speculate that their dysfunction leads to a reduced excitatory drive and therefore to a reduced glucose metabolism in the cerebellar cortex. In contrast, given the complex modulation of the frontal cerebral cortex activity, the frontal glucose hypermetabolism
might be a sign of increased activity of neuronal cells in response to disconnection. Such hyperactivation may be compensatory and may imply the recruitment of alternative networks,26 but it may also reflect the inability of patients with X-ALD to select appropriate neuronal circuits and to inhibit inappropriate ones. On single case analysis, we substantially confirmed the presence of frontal/cingulate-paracingulate hypermetabolism, cerebellar hypometabolism, or both in all cases, and we found that the relative increase of frontal lobe uptake is correlated with the severity of the disease, as assessed by the X-ALD clinical score.4 In agreement with this, unambiguous frontal hypermetabolism, cerebellar hypometabolism, or both were found in the 6 patients with AMN and in the remaining 3 patients with parieto-occipital white matter MRI abnormalities (2 cerebral forms and 1 ALMN), whereas only slightly increased glucose uptake in the anterior cingulate and paracingulate cortex (patient 10) or slightly decreased glucose uptake in the cerebellum (patients 11 and 12) was found in presymptomatic patients (figure 3). Neurology 83
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Figure 2
Cerebral glucose uptake pattern in X-linked adrenoleukodystrophy
On group comparison of 12 patients with X-linked adrenoleukodystrophy vs 27 healthy controls, brain fluorodeoxyglucose PET reveals a pattern characterized by glucose hypermetabolism (red color) in the frontal lobes and glucose hypometabolism (blue color) in the temporal lobe areas and cerebellar hemispheres (Statistical Parametric Mapping 8 group analysis).
Of note, an overt frontal hypermetabolism was found even in the patient with adult-onset cerebral X-ALD who had clear attentive/executive dysfunctions (patient 2, table e-1), suggesting that these neuropsychological deficiencies are related to an alteration of connections between neurons rather than an extensive loss of the frontal neuronal cells. Analogously, the
Table 2
Anatomic locations, side, spatial extent of the clusters in voxels, Montreal Neurological Institute (MNI) space coordinates of the statistical peaks, and z scores of the brain areas showing significant differences between patients with X-linked adrenoleukodystrophy (n 5 12) and healthy controls (n 5 27)
Side
MNI coordinates Cluster size z Score (x, y, z)
Frontal middle (and superior) gyrus
R
6,469
5.48
40, 14, 54
Frontal middle (and superior) gyrus
L
1,813
5.29
240, 6, 56
Anterior cingulate gyrus
L (and R)
273
4.30
26, 48, 22
Inferior temporal gyrus
L
915
5.56
236, 0, 238
Inferior temporal gyrus
R
976
5.07
48, 26, 228
Cerebellum
L (and R) 5,780
4.99
224, 264, 246
Anatomic locations Hypermetabolism
Hypometabolism
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presence of hypometabolism in the visual cortex of patients 2 and 3, who had visual disturbances, is likely due to the deafferentation of the visual cortex from the underlying parieto-occipital white matter abnormalities, as previously suggested.7 Finally, the lack of hypermetabolism in the parieto-occipital white matter of patient 2, despite the presence of pathologic contrast enhancement on brain MRI, strongly suggests that any abnormal increase of glucose uptake in the white matter is not related to damage to the blood-brain barrier (BBB) but rather to the presence of an abundant infiltrate of inflammatory cells. Indeed, unlike gadolinium, FDG passes freely through the BBB. Considering the close relationship between cognitive functions and cerebral glucose metabolism, we also assessed patients with X-ALD by using a battery of neuropsychological tests. In agreement with previous findings,22,27 we documented that cognitive functions are normal in patients with AMN, patients with Addison only, and presymptomatic patients, suggesting that the cortical abnormalities revealed by FDG-PET are unrelated to cognitive status. We also found that there are attentive/executive dysfunctions and memory deficits in the 3 patients with C-ALD and ALMN, but the location and type of FDG-PET abnormalities support the hypothesis that these neuropsychological deficits are from subcortical damage, or they are due—at least for the most part—to manic-like behavior (patient 1), depression (patient 2), and visual impairment (patients 2 and 3).28 Finally, we evaluated the presence of psychopathologic features and the personality of our patients with X-ALD. The psychobehavioral assessment using the SCL-90-R revealed only depression in one patient (patient 2), in agreement with his clinical history. In contrast, the personality assessment using the MCMI-III revealed an increased incidence of obsessive-compulsive personality disorder (OCPD) (9 patients out of 12 [75%]). The prevalence of OCPD in the general population as assessed by the MCMI-III is approximately 10%.29 Although a diagnosis of OCPD cannot be formulated on the basis of only the MCMI-III, it is interesting to note that we found a strong correlation between MCMI-III score on the OCPD subscale and glucose uptake in the ventral striatum, which has been associated with obsessivecompulsive behaviors.30 Therefore, as MCMI-III and FDG-PET studies were independently performed, we suggest that this disorder might be common in patients with X-ALD. If so, this personality profile could account for the rigidity, perfectionism, and control of patients with X-ALD and might favor their compliance with diagnostic tests and treatment regimens. There are some limitations to this study. The number of patients was limited because of the rarity of X-ALD and the need to obtain preliminary findings before planning larger, expensive studies with use of
Figure 3
FDG-PET images from 3 patients with different forms of adrenoleukodystrophy analyzed using Scenium software
On single-case analysis using Scenium software, brain FDG-PET revealed varying degrees of glucose hypermetabolism (red color) in the frontal lobes, glucose hypometabolism (azure color) in the cerebellar hemispheres, or both in all patients (n 5 12) with X-linked adrenoleukodystrophy (X-ALD). Color coding represents the z score of glucose uptake for the different brain regions in comparison with a database of healthy normal participants. The correspondence between the color and the z-score value is given in the palette located at the bottom of the figure. A z score .2 corresponds to abnormally high glucose metabolism, while a z score ,22 corresponds to abnormally low glucose metabolism (p , 0.05). The cortical views of 3 paradigmatic examples are shown in the figure: a case of cerebral adrenoleukodystrophy (CALD, patient 2) in the upper part, a case of adrenomyeloneuropathy (AMN, patient 6) in the middle part, and an asymptomatic patient (Asymp, patient 11) in the lower part. Intriguingly, we found a significant correlation between the degree of frontal lobe hypermetabolism and the X-ALD clinical score (Pearson r 5 0.68 for the left frontal lobe, and Pearson r 5 0.67 for the right frontal lobe [p , 0.02]).
FDG-PET. The patients were intentionally not randomly selected in order to explore a wide spectrum of X-ALD phenotypes, as in a recent study aimed at investigating the presence of small nerve fiber dysfunction in patients with X-ALD.31 Another bias may be the use of some drugs, including corticosteroids (i.e., cortisone acetate or hydrocortisone), baclofen, and in one case valproic acid, by some symptomatic patients. These drugs might influence FDG-PET data, but the pattern of abnormal brain glucose metabolism was also found in patients with no potentially modifying therapy; thus, we believe the data should be considered bona fide as independent from drug-related effects. Our findings provide definite evidence that brain FDG-PET can reveal and quantify functional abnormalities in the cerebral gray matter of patients with
different forms of X-ALD, including AMN. These functional abnormalities are independent from any morphologic and signal abnormalities detected by standard MRI, but they might be related to the clinical severity of the disease. Therefore, our observations lay the foundation for larger studies that might assess whether the abnormal brain glucose metabolism detected in X-ALD can be used as a surrogate clinical marker. FDG-PET can be a useful, but still underinvestigated, in vivo neuroimaging technique for the characterization of patients with X-ALD and possibly other hereditary leukoencephalopathies. AUTHOR CONTRIBUTIONS Dr. Ettore Salsano took the lead in drafting the manuscript and made substantial contributions to study concept and design, data acquisition, analysis and interpretation of data, and study coordination. Dr. Giorgio Marotta Neurology 83
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made substantial contributions to acquisition, analysis, and interpretation of data, and was involved in drafting the manuscript. Dr. Valentina Manfredi, Dr. Anna Rita Giovagnoli, Dr. Laura Farina, Dr. Mario Savoiardo, Dr. Davide Pareyson, and Dr. Riccardo Benti all made substantial contributions to acquisition, analysis, and interpretation of data, and were involved in revising the manuscript. Dr. Graziella Uziel was involved in revising the manuscript critically for important intellectual content and made substantial contributions to study concept and design and analysis and interpretation of data.
ACKNOWLEDGMENT The authors thank the patients and their families for their collaboration. This work is dedicated to our dear friend and colleague Mario Savoiardo, who unfortunately passed away during the review process of this article. His great knowledge and passion for neuroradiology together with his kindness and brilliant intuitions will survive in our memory.
12.
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14.
15.
STUDY FUNDING This work was partly supported by FP7 European Union Project “LeukoTreat” Grant HEALTH-F2-2010-241622.
16.
DISCLOSURE
17.
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
18. Received November 18, 2013. Accepted in final form June 11, 2014. REFERENCES 1. Semmler A, Köhler W, Jung HH, Weller M, Linnebank M. Therapy of X-linked adrenoleukodystrophy. Expert Rev Neurother 2008;8:1367–1379. 2. Dobyns WB, Filauro A, Tomson BN, et al. Inheritance of most X-linked traits is not dominant or recessive, just Xlinked. Am J Med Genet A 2004;129A:136–143. 3. Singh I, Pujol A. Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. Brain Pathol 2010; 20:838–844. 4. Koehler W, Sokolowski P. A new disease-specific scoring system for adult phenotypes of X-linked adrenoleukodystrophy. J Mol Neurosci 1999;13:247–252. 5. Volkow ND, Patchell L, Kulkarni MV, Reed K, Simmons M. Adrenoleukodystrophy: imaging with CT, MRI, and PET. J Nucl Med 1987;28:524–527. 6. Iinuma K, Haginoya K, Handa I, et al. Computed tomography, magnetic resonance imaging, positron emission tomography and evoked potentials at early stage of adrenoleukodystrophy. Tohoku J Exp Med 1989;159:195–203. 7. Bakheet S, Al-Essa M, Patay Z, et al. Cerebral fluorine-18 fluorodeoxyglucose positron emission tomographic findings in X-linked adrenoleukodystrophy. Clin Nucl Med 1999;24:364–365. 8. Renard D, Castelnovo G, Collombier L, Kotzki PO, Labauge P. Brain fludeoxyglucose F 18 positron emission tomography hypometabolism in magnetic resonance imaging-negative X-linked adrenoleukodystrophy. Arch Neurol 2011;68:1338–1339. 9. Kim JE, Choi KG, Jeong JH, Kang HJ, Kim HS. Diffuse cortical hypometabolism on (18)F-FDG-PET scan in a case of an adult variant cerebello-brainstem dominant form of ALD manifesting dementia. Parkinsonism Relat Disord 2012;18:210–212. 10. Loes DJ, Fatemi A, Melhem ER, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology 2003;61:369–374. 11. Spinnler H, Tognoni G. Standardizzazione e taratura italiana di test neuropsicologici. Ital J Neurol Sci 1987;6:1–120.
988
Neurology 83
September 9, 2014
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Orsini A, Grossi D, Capitani E, Laiacona M, Papagno C, Vallar G. Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children. Ital J Neurol Sci 1987;8:539–548. Novelli G, Papagno C, Capitani E, Laiacona M, Vallar G, Cappa SF. Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali. Arch Psicol Neurol Psichiatr 1986;47:447–506. Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A. Rey-Osterrieth complex figure: normative values in an Italian population sample. Neurol Sci 2002;22: 443–447. Giovagnoli AR, Del Pesce M, Mascheroni S, Simoncelli M, Laiacona M, Capitani E. Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci 1996;17:305–309. Basso A, Capitani E, Laiacona M. Raven’s coloured progressive matrices: normative data on 305 adult normal controls. Funct Neurol 1987;2:189–194. Derogatis LR. Administration, Scoring, and Procedures Manual for the SCL-90-R. Baltimore, MD: Clinical Psychometrics Research; 1977. Millon T, Davis R. MCMI-III: Millon Clinical Multiaxial Inventory-III Manual. Minneapolis, MN: National Computer Systems; 2006. Kumar A, Newberg A, Alavi A, Berlin J, Smith R, Reivich M. Regional cerebral glucose metabolism in latelife depression and Alzheimer disease: a preliminary positron emission tomography study. Proc Natl Acad Sci U S A 1993;90:7019–7023. Kumar A, Chugani HT, Chakraborty P, Huq AH. Evaluation of neuroinflammation in X-linked adrenoleukodystrophy. Pediatr Neurol 2011;44:143–146. Powers JM. Adreno-leukodystrophy (adreno-testiculoleukomyelo-neuropathic-complex). Clin Neuropathol 1985;4:181–199. Ferrer I, Aubourg P, Pujol A. General aspects and neuropathology of X-linked adrenoleukodystrophy. Brain Pathol 2010;20:817–830. Iglesias S, Marchal G, Viader F, Baron JC. Delayed intrahemispheric remote hypometabolism. Correlations with early recovery after stroke. Cerebrovasc Dis 2000;10: 391–402. Selwyn R, Hokenbury N, Jaiswal S, Mathur S, Armstrong RC, Byrnes K. Mild traumatic brain injury results in depressed cerebral glucose uptake: an 18FDG PET Study. J Neurotrauma 2013;23:1943–1953. Powers JM, DeCiero DP, Ito M, Moser AB, Moser HW. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol 2000;59:89–102. Morbelli S, Perneczky R, Drzezga A, et al. Metabolic networks underlying cognitive reserve in prodromal Alzheimer disease: a European Alzheimer disease consortium project. J Nucl Med 2013;54:894–902. Edwin D, Speedie LJ, Kohler W, Naidu S, Kruse B, Moser HW. Cognitive and brain magnetic resonance imaging findings in adrenomyeloneuropathy. Ann Neurol 1996;40:675–678. Salsano E, Gambini O, Giovagnoli AR, Farina L, Uziel G, Pareyson D. Effectiveness of valproate for the treatment of manic-like behavior in X-linked adrenoleukodystrophy. Neurol Sci 2012;33:1197– 1199.
29.
30.
31.
Grant BF, Hasin DS, Stinson FS, et al. Prevalence, correlates, and disability of personality disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. J Clin Psychiatry 2004;65: 948–958. Cilia R, Siri C, Marotta G, et al. Functional abnormalities underlying pathological gambling in Parkinson disease. Arch Neurol 2008;65:1604–1611. Horn MA, Nilsen KB, Jørum E, Mellgren SI, Tallaksen CM. Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy. Neurology 2014;82:1678–1683.
32.
33. 34.
Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 1983;308:173–180. Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis. Practitioner 1964;192:540–542. van Geel BM, Koelman JH, Barth PG, Ongerboer de Visser BW. Peripheral nerve abnormalities in adrenomyeloneuropathy: a clinical and electrodiagnostic study. Neurology 1996;46:112–118.
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Brain fluorodeoxyglucose PET in adrenoleukodystrophy Ettore Salsano, Giorgio Marotta, Valentina Manfredi, et al. Neurology 2014;83;981-989 Published Online before print August 6, 2014 DOI 10.1212/WNL.0000000000000770 This information is current as of August 6, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/11/981.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/06/WNL.0000000000 000770.DC1.html
References
This article cites 32 articles, 6 of which you can access for free at: http://www.neurology.org/content/83/11/981.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Leukodystrophies http://www.neurology.org//cgi/collection/leukodystrophies PET http://www.neurology.org//cgi/collection/pet
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Ettore Salsano, MD Giorgio Marotta, MD Valentina Manfredi, PsyD Anna Rita Giovagnoli, MD Laura Farina, MD Mario Savoiardo, MD† Davide Pareyson, MD Riccardo Benti, MD Graziella Uziel, MD
Correspondence to Dr. Salsano: [email protected]
ABSTRACT
Objective: To investigate the cerebral glucose metabolism in subjects with X-linked adrenoleukodystrophy (X-ALD) by using brain [18F]-fluorodeoxyglucose PET (FDG-PET).
Methods: Cross-sectional study in which 12 adults with various forms of X-ALD underwent clinical evaluation and brain MRI, followed by brain FDG-PET, neuropsychological assessment, and personality and psychopathology evaluation using the Symptom Checkist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory-III (MCMI-III). Results: When compared to healthy control subjects (n 5 27) by using Statistical Parametric Mapping 8 software, the patients with X-ALD—with or without brain MRI changes—showed a pattern of increased glucose metabolism in frontal lobes and reduced glucose metabolism in cerebellum and temporal lobe areas. On single case analysis by Scenium software, we found a similar pattern, with significant (p , 0.02) correlation between the degree of hypermetabolism in the frontal lobes of each patient and the corresponding X-ALD clinical scores. With respect to personality, we found that patients with X-ALD usually present with an obsessive-compulsive personality disorder on the MCMI-III, with significant (p , 0.05) correlation between glucose uptake in ventral striatum and severity of score on the obsessive-compulsive subscale.
Conclusions: We examined cerebral glucose metabolism using FDG-PET in a cohort of patients with X-ALD and provided definite evidence that in X-ALD the analysis of brain glucose metabolism reveals abnormalities independent from morphologic and signal changes detected by MRI and related to clinical severity. Brain FDG-PET may be a useful neuroimaging technique for the characterization of X-ALD and possibly other leukodystrophies. Neurology® 2014;83:981–989 GLOSSARY ALMN 5 adrenoleukomyeloneuropathy; AMN 5 adrenomyeloneuropathy; BBB 5 blood-brain barrier; BR 5 base rate; C-ALD 5 cerebral adrenoleukodystrophy; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, fourth edition; FDG 5 fluorodeoxyglucose; FDR 5 false discovery rate; MCMI-III 5 Millon Clinical Multiaxial Inventory-III; OCPD 5 obsessive-compulsive personality disorder; SCL-90-R 5 Symptom Checkist-90-Revised; SPM 5 Statistical Parametric Mapping; X-ALD 5 X-linked adrenoleukodystrophy.
Supplemental data at Neurology.org
X-linked adrenoleukodystrophy (X-ALD)—caused by ABCD1 mutations—encompasses a wide spectrum of clinical phenotypes, ranging from the childhood-onset, rapidly progressive cerebral form to completely asymptomatic individuals late in life.1–3 Adrenomyeloneuropathy (AMN) is the most common adult-onset form of X-ALD and is characterized by symptoms limited to the spinal cord and peripheral nerves. About 55% of patients with AMN have very slow progression, and brain MRI remains normal (“pure” AMN) or shows corticospinal tract involvement. The remaining 45% can show lobar cerebral white matter involvement (adrenoleukomyeloneuropathy [ALMN]), which might become severely progressive.1 Rarely, X-ALD presents during adolescence or adulthood with neuropsychological symptoms followed by neurologic deficits (cerebral adrenoleukodystrophy [C-ALD]). In these cases, the demyelinating lobar involvement is present from the start of the disease, which has rapid progression, like the childhood cerebral form.4 †Deceased. From the Departments of Clinical Neurosciences (E.S., D.P.), Diagnostics and Applied Technology (V.M., A.R.G., L.F., M.S.), and Child Neurology (G.U.), Fondazione IRCCS, Istituto Neurologico “C. Besta,” Milano, Italy; and Department of Nuclear Medicine (G.M., R.B.), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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Table 1
Clinical features of the 12 adults with different forms of adrenoleukodystrophy investigated by brain FDG-PET Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
8
11
8
Patient 7
Patient 8
Patient 9
Patient 10
Patient 11
Patient 12
18
5
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Schooling, y
8
8
18
13
12
8
13
ABCD1 mutation
c.443A.G; c.242insCCTGCGGCT; p.Asn148Ser p.R80_L81insLLR
IVS312T.A exon8-10del
exon810del
Exon710del
c.1631A.G; p.Gln544Arg
c.293C.T; p. Ser98Leu
c.1165C.T; p.Arg389Cys
c.454C.T; c.1015T.G; p.Arg152Cys p.Trp339Gly
c.1165C.T; p.Arg389Cys
Age at onset of neurologic symptoms, y
14
18
20
20
25
21
25
33
43
NA
NA
NA
Age at evaluation, y
24
37
35
24
32
24
37
34
45
27
56
62
AdolC-ALD
AC-ALD
ALMN
AMN
AMN
AMN
AMN
AMN
AMN
Addison-only phenotype
Asymptomatic Asymptomatic
Adrenal failure
Yes
Yes
No
Yes
Yes
Yes (early)
Yes (early)
Yes
No
Yes
No
No
Initial neurologic symptoms
Behavioral Depression and cognitive decline
Gait difficulties
Gait difficulties
Impotence
Gait difficulties
Gait difficulties
Gait difficulties
Calf muscle cramps, urinary urge incontinence
NA
NA
NA
Gaitb
Normal
Spastic ataxic 2
Spastic 3
Spastic ataxic 2
Spastic ataxic 2
Spastic ataxic 1
Spastic 2
Spastic 3
Spastic ataxic 1 Normal
Normal
Normal
Ambulation Indexc
0
4
7
4
4
2
3
7
2
0
0
0
Muscle toned
Normal
3
3
2
2
1
2
3
1
Normal
Normal
Normal
31
41
41
41
41
41
41
41
31
21
21
41
1
2
a
X-ALD form
Clinical features at evaluation
Tendon reflexes e
Normal
1
2
2
2
Normal
2
Normal
Normal
Normal
Bladder function
Normal
Urge incontinence
Neurogenic bladder
Urgency
Urge Urge Urgency incontinence incontinence
Urgency
Urge incontinence
Normal
Normal
Normal
Other symptoms
Manic-like behaviorf
Bipolar disorder, visual and hearing loss
Visual loss
Manic-like behavior, pain in the legs, fecal urgency, impotence
Pain in the legs
No
Lower leg numbness
Pain in the legs
Impotence, pain in the legs
No
No
No
Motor function (0–6)
0
4
5
4
4
2
2
5
2
0
0
0
Bladder functions (0– 3)
0
2
3
2
2
2
2
2
2
0
0
0
Sensory symptoms or pain in the legs (0–3)
0
2
2
2
2
2
2
2
2
0
0
0
Cerebral functions (0–12)h
6
9
6
3
0
0
0
3
0
0
0
0
Total score (0–24)
6
17
16
11
8
6
6
12
6
0
0
0
X-ALD brain MRI severity scorei
13.5
14
10
0.5
5
3
0.5
0.5
0.5
0
0.5
0
Vibration sense
ALD Clinical Scoreg
Abbreviations: ALD 5 adrenoleukodystrophy; FDG 5 fluorodeoxyglucose; MCMI-III 5 Millon Clinical Multiaxial Inventory-III; NA 5 not applicable; X-ALD 5 X-linked adrenoleukodystrophy. a AC-ALD 5 adult cerebral X-ALD; AdolC-ALD 5 adolescent cerebral X-ALD; ALMN 5 adrenoleukomyeloneuropathy; AMN 5 adrenomyeloneuropathy.
Gait: 1 5 abnormal without support; 2 5 with support; 3 5 wheelchair-bound. The Ambulation Index is a 10-point scale to assess mobility by evaluating the time and degree of assistance for walking 25 feet (8 m).32 d Ashworth scale: 0 5 normal muscle tone; 1 5 slight increase in tone giving a “catch” when limb is flexed or extended; 2 5 more marked increase in tone but limb still easily flexed; 3 5 considerable increase in tone, passive movement difficult; 4 5 limb rigid in flexion or extension.33 e Vibration sense: 1 5 decreased in feet; 2 5 absent in feet and lowered in lower legs; 3 5 lowered in at least upper legs and absent in lower legs.34 f At the time of MCMI-III administration, the manic-like behavior was well-controlled by valproic acid.28 g The ALD Clinical Score is a clinical measure of disability specifically conceived for X-ALD.4 h Personality disorders as assessed by MCMI-III were not considered psychiatric symptoms. i The maximum X-ALD brain MRI severity score, which was proposed specifically for X-ALD,10 is 34; a score $1 is considered abnormal. c
b
PET using 2-[18F]-fluoro-2-deoxy-D-glucose (FDG-PET) has rarely been used to examine cerebral glucose metabolism in X-ALD, and only a few reports of single cases have been published so far.5–9 Notably, a patient with AMN presented with multifocal brain and cerebellar hypometabolism despite the lack of MRI signal changes.8 This discrepancy suggests that X-ALD may be characterized by metabolic brain abnormalities detectable by FDG-PET and independent from signal abnormalities detected by standard MRI. The aim of this study is to assess the presence of metabolic brain abnormalities in adults with different forms of X-ALD by using FDGPET and to examine their correlation with clinical, personality, and brain MRI features. METHODS Patients. We recruited 12 adult ($18 years) Italian participants (mean age: 36 years; range: 24–62 years) with both biochemically and genetically confirmed X-ALD, followed at the IRCCS Foundation, “C. Besta” Neurological Institute, Milan, Italy. The selection of patients was not random and was aimed at including different forms of X-ALD. The clinical features and brain MRI findings of each patient are summarized in table 1. The MRI severity score, proposed specifically for X-ALD,10 was calculated by 2 neuroradiologists (L.F. and M.S.) experienced in X-ALD. Mild to moderate global cerebral atrophy was present in 3 patients only (patients 1, 2, and 3), whereas selective frontal, temporal, or cerebellar atrophy was not evident in any of the patients.
Neuropsychological assessment. Cognitive functions were assessed using a standardized battery of neuropsychological tests for the evaluation of the most relevant domains of cognition. Briefly, the Attentive Matrices, Weigl’s Sorting, Street’s Completion, Corsi’s Blocks Span and Digit Span, Word Fluency on phonemic or semantic cue, Short Story, Rey’s Complex Figure Copying and Delayed Reproduction, Trail Making Test A and B, and Raven’s Colored Progressive Matrices tests were used to assess selective attention, categorization of visuospatial stimuli and shifting, visual perception, spatial and verbal memory span, word finding, verbal and visuospatial memory, constructive praxis, visuomotor coordination speed and divided attention, and abstract reasoning.11–16 Personality and psychopathology assessment. The Symptom Checklist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory-III (MCMI-III) were administered with the supervision of a psychologist (V.M.) for assessing the presence of DSM-IV Axis I clinical syndromes and DSM-IV Axis II personality disorders. The SCL-90-R is a 90-item selfreport (multidimensional symptom) inventory that explores 9 symptom dimensions of psychopathology, such as depression and anxiety. The 90 items in the questionnaire are scored on a 5-point Likert scale, ranging from “not at all” (0) to “extremely” (4) for indicating the rate of occurrence of each symptom.17 The MCMI-III is a self-report inventory composed of 175 true/false items assessing personality disorders and clinical syndromes related to the DSM-IV classification. It yields raw scores on 24 scales (10 clinical syndrome and 14 personality disorder scales), which are converted into base rate (BR) scores, which take into
account the prevalence of the particular personality pattern or psychiatric clinical syndrome in the target population. A BR score higher than 75 is considered to indicate the “presence of a trait,” while a BR score higher than 85 is considered to indicate definite presence of the personality pattern or clinical syndrome.18
Brain FDG-PET imaging and data analysis. FDG-PET imaging was performed using a Biograph Truepoint 64 PET/ CT scanner (Siemens, Erlangen, Germany) as routinely done at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy. Data were quantitatively analyzed using the Statistical Parametric Mapping (SPM) software, version 8 (Wellcome Department of Cognitive Neurology, London, UK) for group analysis, with false discovery rate (FDR) correction for multiple testing (p , 0.01) and age at PET scan as nuisance covariate, and using the software Scenium (Siemens Molecular Imaging) for single-participant analysis (appendix e-1 on the Neurology® Web site at Neurology.org). We used the software Scenium for single-participant analysis in order to corroborate the results obtained from group analysis by using SPM. Indeed, unlike SPM, Scenium is a straightforward and easy-to-do software solution that was conceived to compare the metabolic changes of a single participant with a predefined reference database of 30 normal participants. Correlation analysis. Correlation analyses were carried out using commercial software package SPSS for Windows 7.0 (SPSS UK, Surrey, UK). Standard protocol approvals, registrations, and patient consents. The study was in compliance with the Declaration of Helsinki principles and was approved by the institutional review boards, and all patients involved gave their written informed consent. RESULTS Neuropsychological findings. Cognitive functions were normal in 9 out of 12 patients (table e-1). Six of these 9 patients had AMN, 2 were asymptomatic, and 1 had adrenocortical insufficiency only. The 3 patients with pathologic cognition had C-ALD (n 5 2) or ALMN (n 5 1).
Psychopathological and personality features. No psycho-
pathology was demonstrated on the SCL-90-R, with the exception of patient 2 who had a pathologic score on the depression subscale. With respect to personality, all patients with X-ALD showed at least one personality disorder on the MCMI-III, i.e., the BR score was .85 on at least one MCMI-III subscale. Notably, the BR score was .85 for the obsessive-compulsive subscale in 9 out of 12 (75%). No questionnaire was considered “invalid” according to the inventory criteria. The mean BR scores and the corresponding confidence intervals are shown in figure 1 as error bar plots. Cerebral metabolic activity on FDG-PET. Group analysis.
Using SPM8, we first compared the brain 18PETFDG uptake at rest from 12 adult males with different forms of X-ALD with that from 27 age-matched healthy controls. We found that, compared with healthy controls, the patients with X-ALD had clusters of increased glucose metabolism in the middle and superior frontal gyri and in the anterior cingulate Neurology 83
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gyri, and clusters of reduced glucose metabolism in temporal gyri and cerebellum (p , 0.01, FDRcorrected) (figure 2; see table 2 for further details). Of note, brain MRI did not reveal any abnormality in these areas (i.e., frontal, temporal, and cerebellar cortex), except in patient 2 who had cerebellar white matter abnormalities, and similar changes in cerebral metabolic activity were found when we compared only the subjects with AMN (n 5 6) vs healthy controls. Single-participant analysis. Using Scenium software, we subsequently compared the brain 18PET-FDG uptake at rest of each patient with X-ALD with the reference database of 30 healthy controls. In particular, for each patient we calculated a z score on a voxelby-voxel basis and a mean z score for each anatomical region in the brain, such as frontal lobes and cerebellum, in order to indicate to what extent the patient scan differs from a scan that is considered normal. In agreement with the group analysis, we found that each patient with X-ALD had varying degrees of significant changes (i.e., z score .2 or ,22) in the glucose uptake of the frontal lobes, cerebellum, or both (figure 3). For instance, in patient 2 we found positive z scores of 6.3 and 6.8 in the left and right frontal lobes and negative z scores of 22.3 and 23.9 in the left and right cerebellum. We also found a significantly reduced metabolism (i.e., negative z score ,22) in the visual cortex of the 2 patients (patients 2 and 3) with visual disturbances and parieto-occipital white matter abnormalities on brain MRI (figure e-1). Eventually we observed no abnormal glucose metabolism in the context of the parietooccipital white matter abnormalities of patient 2, despite the presence of abnormal contrast enhancement, and no univocal change in the glucose metabolism in temporal lobes. Correlation between cerebral glucose metabolism and
We found a significant (p , 0.02) correlation between the degree of hypermetabolism of the frontal lobes (expressed as the z score calculated using the Scenium software) and the severity of the ALD clinical score (Pearson r 5 0.68 [left] and 0.67 [right]). This correlation was maintained when we excluded the 3 patients with overt MRI abnormalities (i.e., patients 1, 2, and 3). More importantly, we found a significant (p , 0.05) correlation between glucose uptake in ventral striatum and score on the MCMI-III obsessive-compulsive subscale (figure e-2) (Pearson r 5 0.86 [left] and 0.76 [right]). clinical and personality features.
DISCUSSION Brain FDG-PET can be used to indirectly investigate the gray matter function of the brain, as there is a link between gray matter glucose uptake and neuron activity, and it is considered 984
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a reliable,19 relatively easy to perform, and safe neuroimaging technique (e.g., in this study, each patient was exposed to approximately 3–4 mSv; for comparison, the limit of the International Commission on Radiological Protection for an occupational radiation worker is 20 mSv/year). So far, no systematic research has been conducted to evaluate cerebral gray matter glucose uptake in patients with X-ALD, although gray matter dysfunctions related to white matter damage and axonal or neuronal loss might be expected in X-ALD. In support of this, 3 cases of cerebral X-ALD investigated by brain FDG-PET revealed decreased glucose uptake (or hypometabolism) in posterior areas of the brain overlying the typical white matter abnormalities (in the occipital and parietal lobes).5–7 Moreover, 2 of them presented with hypermetabolism in the cerebral white matter areas, probably caused by the active process of neuroinflammation.5,7 This process was also investigated by PET using the 11C-[R]-PK11195 radioligand, which recognizes peripheral benzodiazepine receptors expressed by activated microglia in cases of neuroinflammation.20 Finally, the presence of hypometabolism of different cortical regions and cerebellum has been recently documented in one individual with AMN and one individual with the cerebello-brainstem form of X-ALD.8,9 Our study assessed cerebral glucose metabolism by using standard FDG-PET in a cohort of 12 adults with different forms of X-ALD, including 6 cases of AMN, 1 case of ALMN, 2 cases of C-ALD, 1 Addison-only phenotype, and 2 presymptomatic patients. On group comparison (X-ALD vs normal healthy controls), FDG-PET showed increased uptake within frontal areas and anterior cingulate cortex and decreased uptake in temporal areas and cerebellum (figure 2). This metabolic pattern seems to be characteristic of the disease and unrelated to the presence of brain MRI abnormalities. Indeed, this pattern was also present when only the subjects with AMN (i.e., without any brain MRI abnormality) were compared to normal healthy controls. The physiopathologic basis of this pattern of abnormal brain glucose metabolism in X-ALD is unknown. We hypothesize that it might be primarily caused by a cortical afferent dysfunction, which can be seen on FDG-PET images as “cortical diaschisis.” This hypothesis is supported by the fact that on brain MRI there was no atrophy restricted to frontal, temporal, or cerebellar cortex as possible structural correlate of glucose uptake abnormalities, and postmortem studies in cerebral X-ALD and AMN show that the gray matter, including cerebral and cerebellar cortex, is largely spared.21,22 On the other hand, cortical diaschisis is typically observed in cerebral pathologies associated with focal or diffuse damage of white matter, including vascular and traumatic brain injuries,23,24 and in our
Figure 1
Base rate scores on the Millon Clinical Multiaxial Inventory-III for the 12 adults with different forms of adrenoleukodystrophy
Base rate scores higher than 75 indicate “presence of a trait,” while base rate scores higher than 85 indicate definite presence of the personality pattern or clinical syndrome.
different cases of X-ALD there was no evident lesion in the white matter of frontal and temporal lobes, as well as in the white matter of cerebellum. Postmortem studies, however, show that there are varying degrees of dysmyelination, inflammatory demyelination, and axonal loss in the cerebral white matter of cerebral X-ALD and AMN, and even patients with “pure” AMN have microscopic foci of dysmyelination, with PAS 1 macrophages and varying degrees of oligodendrocyte reduction and axonal loss, although no macroscopic white matter lesion is observed.25 Therefore, it is plausible that in X-ALD there is some degree of cortical afferent dysfunction, even without clear correlation with MRI findings, because it may be from axonal degeneration, microscopic white matter changes, or both. Moreover, because the afferent cerebellar cortical connections, including the climbing and mossy fibers, are excitatory, it is tempting to speculate that their dysfunction leads to a reduced excitatory drive and therefore to a reduced glucose metabolism in the cerebellar cortex. In contrast, given the complex modulation of the frontal cerebral cortex activity, the frontal glucose hypermetabolism
might be a sign of increased activity of neuronal cells in response to disconnection. Such hyperactivation may be compensatory and may imply the recruitment of alternative networks,26 but it may also reflect the inability of patients with X-ALD to select appropriate neuronal circuits and to inhibit inappropriate ones. On single case analysis, we substantially confirmed the presence of frontal/cingulate-paracingulate hypermetabolism, cerebellar hypometabolism, or both in all cases, and we found that the relative increase of frontal lobe uptake is correlated with the severity of the disease, as assessed by the X-ALD clinical score.4 In agreement with this, unambiguous frontal hypermetabolism, cerebellar hypometabolism, or both were found in the 6 patients with AMN and in the remaining 3 patients with parieto-occipital white matter MRI abnormalities (2 cerebral forms and 1 ALMN), whereas only slightly increased glucose uptake in the anterior cingulate and paracingulate cortex (patient 10) or slightly decreased glucose uptake in the cerebellum (patients 11 and 12) was found in presymptomatic patients (figure 3). Neurology 83
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Figure 2
Cerebral glucose uptake pattern in X-linked adrenoleukodystrophy
On group comparison of 12 patients with X-linked adrenoleukodystrophy vs 27 healthy controls, brain fluorodeoxyglucose PET reveals a pattern characterized by glucose hypermetabolism (red color) in the frontal lobes and glucose hypometabolism (blue color) in the temporal lobe areas and cerebellar hemispheres (Statistical Parametric Mapping 8 group analysis).
Of note, an overt frontal hypermetabolism was found even in the patient with adult-onset cerebral X-ALD who had clear attentive/executive dysfunctions (patient 2, table e-1), suggesting that these neuropsychological deficiencies are related to an alteration of connections between neurons rather than an extensive loss of the frontal neuronal cells. Analogously, the
Table 2
Anatomic locations, side, spatial extent of the clusters in voxels, Montreal Neurological Institute (MNI) space coordinates of the statistical peaks, and z scores of the brain areas showing significant differences between patients with X-linked adrenoleukodystrophy (n 5 12) and healthy controls (n 5 27)
Side
MNI coordinates Cluster size z Score (x, y, z)
Frontal middle (and superior) gyrus
R
6,469
5.48
40, 14, 54
Frontal middle (and superior) gyrus
L
1,813
5.29
240, 6, 56
Anterior cingulate gyrus
L (and R)
273
4.30
26, 48, 22
Inferior temporal gyrus
L
915
5.56
236, 0, 238
Inferior temporal gyrus
R
976
5.07
48, 26, 228
Cerebellum
L (and R) 5,780
4.99
224, 264, 246
Anatomic locations Hypermetabolism
Hypometabolism
986
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presence of hypometabolism in the visual cortex of patients 2 and 3, who had visual disturbances, is likely due to the deafferentation of the visual cortex from the underlying parieto-occipital white matter abnormalities, as previously suggested.7 Finally, the lack of hypermetabolism in the parieto-occipital white matter of patient 2, despite the presence of pathologic contrast enhancement on brain MRI, strongly suggests that any abnormal increase of glucose uptake in the white matter is not related to damage to the blood-brain barrier (BBB) but rather to the presence of an abundant infiltrate of inflammatory cells. Indeed, unlike gadolinium, FDG passes freely through the BBB. Considering the close relationship between cognitive functions and cerebral glucose metabolism, we also assessed patients with X-ALD by using a battery of neuropsychological tests. In agreement with previous findings,22,27 we documented that cognitive functions are normal in patients with AMN, patients with Addison only, and presymptomatic patients, suggesting that the cortical abnormalities revealed by FDG-PET are unrelated to cognitive status. We also found that there are attentive/executive dysfunctions and memory deficits in the 3 patients with C-ALD and ALMN, but the location and type of FDG-PET abnormalities support the hypothesis that these neuropsychological deficits are from subcortical damage, or they are due—at least for the most part—to manic-like behavior (patient 1), depression (patient 2), and visual impairment (patients 2 and 3).28 Finally, we evaluated the presence of psychopathologic features and the personality of our patients with X-ALD. The psychobehavioral assessment using the SCL-90-R revealed only depression in one patient (patient 2), in agreement with his clinical history. In contrast, the personality assessment using the MCMI-III revealed an increased incidence of obsessive-compulsive personality disorder (OCPD) (9 patients out of 12 [75%]). The prevalence of OCPD in the general population as assessed by the MCMI-III is approximately 10%.29 Although a diagnosis of OCPD cannot be formulated on the basis of only the MCMI-III, it is interesting to note that we found a strong correlation between MCMI-III score on the OCPD subscale and glucose uptake in the ventral striatum, which has been associated with obsessivecompulsive behaviors.30 Therefore, as MCMI-III and FDG-PET studies were independently performed, we suggest that this disorder might be common in patients with X-ALD. If so, this personality profile could account for the rigidity, perfectionism, and control of patients with X-ALD and might favor their compliance with diagnostic tests and treatment regimens. There are some limitations to this study. The number of patients was limited because of the rarity of X-ALD and the need to obtain preliminary findings before planning larger, expensive studies with use of
Figure 3
FDG-PET images from 3 patients with different forms of adrenoleukodystrophy analyzed using Scenium software
On single-case analysis using Scenium software, brain FDG-PET revealed varying degrees of glucose hypermetabolism (red color) in the frontal lobes, glucose hypometabolism (azure color) in the cerebellar hemispheres, or both in all patients (n 5 12) with X-linked adrenoleukodystrophy (X-ALD). Color coding represents the z score of glucose uptake for the different brain regions in comparison with a database of healthy normal participants. The correspondence between the color and the z-score value is given in the palette located at the bottom of the figure. A z score .2 corresponds to abnormally high glucose metabolism, while a z score ,22 corresponds to abnormally low glucose metabolism (p , 0.05). The cortical views of 3 paradigmatic examples are shown in the figure: a case of cerebral adrenoleukodystrophy (CALD, patient 2) in the upper part, a case of adrenomyeloneuropathy (AMN, patient 6) in the middle part, and an asymptomatic patient (Asymp, patient 11) in the lower part. Intriguingly, we found a significant correlation between the degree of frontal lobe hypermetabolism and the X-ALD clinical score (Pearson r 5 0.68 for the left frontal lobe, and Pearson r 5 0.67 for the right frontal lobe [p , 0.02]).
FDG-PET. The patients were intentionally not randomly selected in order to explore a wide spectrum of X-ALD phenotypes, as in a recent study aimed at investigating the presence of small nerve fiber dysfunction in patients with X-ALD.31 Another bias may be the use of some drugs, including corticosteroids (i.e., cortisone acetate or hydrocortisone), baclofen, and in one case valproic acid, by some symptomatic patients. These drugs might influence FDG-PET data, but the pattern of abnormal brain glucose metabolism was also found in patients with no potentially modifying therapy; thus, we believe the data should be considered bona fide as independent from drug-related effects. Our findings provide definite evidence that brain FDG-PET can reveal and quantify functional abnormalities in the cerebral gray matter of patients with
different forms of X-ALD, including AMN. These functional abnormalities are independent from any morphologic and signal abnormalities detected by standard MRI, but they might be related to the clinical severity of the disease. Therefore, our observations lay the foundation for larger studies that might assess whether the abnormal brain glucose metabolism detected in X-ALD can be used as a surrogate clinical marker. FDG-PET can be a useful, but still underinvestigated, in vivo neuroimaging technique for the characterization of patients with X-ALD and possibly other hereditary leukoencephalopathies. AUTHOR CONTRIBUTIONS Dr. Ettore Salsano took the lead in drafting the manuscript and made substantial contributions to study concept and design, data acquisition, analysis and interpretation of data, and study coordination. Dr. Giorgio Marotta Neurology 83
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made substantial contributions to acquisition, analysis, and interpretation of data, and was involved in drafting the manuscript. Dr. Valentina Manfredi, Dr. Anna Rita Giovagnoli, Dr. Laura Farina, Dr. Mario Savoiardo, Dr. Davide Pareyson, and Dr. Riccardo Benti all made substantial contributions to acquisition, analysis, and interpretation of data, and were involved in revising the manuscript. Dr. Graziella Uziel was involved in revising the manuscript critically for important intellectual content and made substantial contributions to study concept and design and analysis and interpretation of data.
ACKNOWLEDGMENT The authors thank the patients and their families for their collaboration. This work is dedicated to our dear friend and colleague Mario Savoiardo, who unfortunately passed away during the review process of this article. His great knowledge and passion for neuroradiology together with his kindness and brilliant intuitions will survive in our memory.
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STUDY FUNDING This work was partly supported by FP7 European Union Project “LeukoTreat” Grant HEALTH-F2-2010-241622.
16.
DISCLOSURE
17.
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
18. Received November 18, 2013. Accepted in final form June 11, 2014. REFERENCES 1. Semmler A, Köhler W, Jung HH, Weller M, Linnebank M. Therapy of X-linked adrenoleukodystrophy. Expert Rev Neurother 2008;8:1367–1379. 2. Dobyns WB, Filauro A, Tomson BN, et al. Inheritance of most X-linked traits is not dominant or recessive, just Xlinked. Am J Med Genet A 2004;129A:136–143. 3. Singh I, Pujol A. Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. Brain Pathol 2010; 20:838–844. 4. Koehler W, Sokolowski P. A new disease-specific scoring system for adult phenotypes of X-linked adrenoleukodystrophy. J Mol Neurosci 1999;13:247–252. 5. Volkow ND, Patchell L, Kulkarni MV, Reed K, Simmons M. Adrenoleukodystrophy: imaging with CT, MRI, and PET. J Nucl Med 1987;28:524–527. 6. Iinuma K, Haginoya K, Handa I, et al. Computed tomography, magnetic resonance imaging, positron emission tomography and evoked potentials at early stage of adrenoleukodystrophy. Tohoku J Exp Med 1989;159:195–203. 7. Bakheet S, Al-Essa M, Patay Z, et al. Cerebral fluorine-18 fluorodeoxyglucose positron emission tomographic findings in X-linked adrenoleukodystrophy. Clin Nucl Med 1999;24:364–365. 8. Renard D, Castelnovo G, Collombier L, Kotzki PO, Labauge P. Brain fludeoxyglucose F 18 positron emission tomography hypometabolism in magnetic resonance imaging-negative X-linked adrenoleukodystrophy. Arch Neurol 2011;68:1338–1339. 9. Kim JE, Choi KG, Jeong JH, Kang HJ, Kim HS. Diffuse cortical hypometabolism on (18)F-FDG-PET scan in a case of an adult variant cerebello-brainstem dominant form of ALD manifesting dementia. Parkinsonism Relat Disord 2012;18:210–212. 10. Loes DJ, Fatemi A, Melhem ER, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology 2003;61:369–374. 11. Spinnler H, Tognoni G. Standardizzazione e taratura italiana di test neuropsicologici. Ital J Neurol Sci 1987;6:1–120.
988
Neurology 83
September 9, 2014
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Orsini A, Grossi D, Capitani E, Laiacona M, Papagno C, Vallar G. Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children. Ital J Neurol Sci 1987;8:539–548. Novelli G, Papagno C, Capitani E, Laiacona M, Vallar G, Cappa SF. Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali. Arch Psicol Neurol Psichiatr 1986;47:447–506. Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A. Rey-Osterrieth complex figure: normative values in an Italian population sample. Neurol Sci 2002;22: 443–447. Giovagnoli AR, Del Pesce M, Mascheroni S, Simoncelli M, Laiacona M, Capitani E. Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci 1996;17:305–309. Basso A, Capitani E, Laiacona M. Raven’s coloured progressive matrices: normative data on 305 adult normal controls. Funct Neurol 1987;2:189–194. Derogatis LR. Administration, Scoring, and Procedures Manual for the SCL-90-R. Baltimore, MD: Clinical Psychometrics Research; 1977. Millon T, Davis R. MCMI-III: Millon Clinical Multiaxial Inventory-III Manual. Minneapolis, MN: National Computer Systems; 2006. Kumar A, Newberg A, Alavi A, Berlin J, Smith R, Reivich M. Regional cerebral glucose metabolism in latelife depression and Alzheimer disease: a preliminary positron emission tomography study. Proc Natl Acad Sci U S A 1993;90:7019–7023. Kumar A, Chugani HT, Chakraborty P, Huq AH. Evaluation of neuroinflammation in X-linked adrenoleukodystrophy. Pediatr Neurol 2011;44:143–146. Powers JM. Adreno-leukodystrophy (adreno-testiculoleukomyelo-neuropathic-complex). Clin Neuropathol 1985;4:181–199. Ferrer I, Aubourg P, Pujol A. General aspects and neuropathology of X-linked adrenoleukodystrophy. Brain Pathol 2010;20:817–830. Iglesias S, Marchal G, Viader F, Baron JC. Delayed intrahemispheric remote hypometabolism. Correlations with early recovery after stroke. Cerebrovasc Dis 2000;10: 391–402. Selwyn R, Hokenbury N, Jaiswal S, Mathur S, Armstrong RC, Byrnes K. Mild traumatic brain injury results in depressed cerebral glucose uptake: an 18FDG PET Study. J Neurotrauma 2013;23:1943–1953. Powers JM, DeCiero DP, Ito M, Moser AB, Moser HW. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol 2000;59:89–102. Morbelli S, Perneczky R, Drzezga A, et al. Metabolic networks underlying cognitive reserve in prodromal Alzheimer disease: a European Alzheimer disease consortium project. J Nucl Med 2013;54:894–902. Edwin D, Speedie LJ, Kohler W, Naidu S, Kruse B, Moser HW. Cognitive and brain magnetic resonance imaging findings in adrenomyeloneuropathy. Ann Neurol 1996;40:675–678. Salsano E, Gambini O, Giovagnoli AR, Farina L, Uziel G, Pareyson D. Effectiveness of valproate for the treatment of manic-like behavior in X-linked adrenoleukodystrophy. Neurol Sci 2012;33:1197– 1199.
29.
30.
31.
Grant BF, Hasin DS, Stinson FS, et al. Prevalence, correlates, and disability of personality disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. J Clin Psychiatry 2004;65: 948–958. Cilia R, Siri C, Marotta G, et al. Functional abnormalities underlying pathological gambling in Parkinson disease. Arch Neurol 2008;65:1604–1611. Horn MA, Nilsen KB, Jørum E, Mellgren SI, Tallaksen CM. Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy. Neurology 2014;82:1678–1683.
32.
33. 34.
Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 1983;308:173–180. Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis. Practitioner 1964;192:540–542. van Geel BM, Koelman JH, Barth PG, Ongerboer de Visser BW. Peripheral nerve abnormalities in adrenomyeloneuropathy: a clinical and electrodiagnostic study. Neurology 1996;46:112–118.
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Brain fluorodeoxyglucose PET in adrenoleukodystrophy Ettore Salsano, Giorgio Marotta, Valentina Manfredi, et al. Neurology 2014;83;981-989 Published Online before print August 6, 2014 DOI 10.1212/WNL.0000000000000770 This information is current as of August 6, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/11/981.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/06/WNL.0000000000 000770.DC1.html
References
This article cites 32 articles, 6 of which you can access for free at: http://www.neurology.org/content/83/11/981.full.html##ref-list-1
Subspecialty Collections
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