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Original Contribution |

Brain Single-Photon Emission Computed Tomography and Magnetic Resonance Imaging in Machado-Joseph Disease FREE

Elba C. S. C. Etchebehere, MD; Fernando Cendes, MD, PhD; Iscia Lopes-Cendes, MD, PhD; Juliana A. Pereira; Mariana C. L. Lima, MD; Carla R. Sansana; Cleide A. M. Silva; Maria F. A. G. Camargo; Allan O. Santos, MD; Celso D. Ramos, MD; Edwaldo E. Camargo, MD, PhD
[+] Author Affiliations

From the Division of Nuclear Medicine, Departments of Radiology (Drs Etchebehere, Lima, Santos, Ramos, and E. E. Camargo and Mmes Pereira and Sansana), Neurology (Dr Lopez-Cendes), and Genetics (Dr Lopes-Cendes and Mrs M. F. A. G. Camargo), and the Research Commission, School of Medical Sciences (Mrs Silva), Campinas State University, UNICAMP, Campinas, Brazil.


Arch Neurol. 2001;58(8):1257-1263. doi:10.1001/archneur.58.8.1257.
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Published online

Background  Machado-Joseph disease (MJD) is one of the most frequently encountered spinocerebellar ataxias. However, few reports on brain single-photon emission computed tomographic (SPECT) imaging (BSI) with hexylmethylpropylene amineoxine labled with technetium Tc 99m and magnetic resonance imaging (MRI) have been performed for the evaluation of patients with MJD.

Objectives  To investigate possible abnormalities with BSI and MRI in patients with MJD and to correlate these findings with the duration of symptoms; cerebellar, extrapyramidal, and pyramidal syndromes; and the molecular characteristics of the MJD mutation.

Patients and Methods  Twelve patients (8 males and 4 females [mean age, 39 years]) with genetically proven MJD were studied. The patients underwent BSI and MRI on the same day. Brain SPECT imaging was performed after an intravenous injection of 99mTc–hexylmethylpropylene amineoxine. The transaxial, coronal, and sagittal BSIs obtained were submitted to visual and semiquantitative analyses. Magnetic resonance imaging was obtained in a 2-T system with coronal, sagittal, transaxial, and 3-dimensional (volumetric) acquisitions. The volumes of the cerebellar hemispheres and vermis were calculated. Control groups for BSI (22 female and 20 male subjects [mean age, 33 years]) and MRI (13 female and 4 male subjects [mean age, 32.2 years]) were included for comparison.

Results  Correlation was observed between the perfusion abnormalities identified by visual analysis in the BSI with the structural abnormalities observed on MRI in the parietal lobes and vermis. Brain SPECT imaging identified (by visual analysis) more perfusion abnormalities in the inferior portion of the frontal lobes, mesial and lateral portions of the temporal lobes, basal ganglia, and cerebellar hemispheres. Magnetic resonance imaging identified more abnormalities in the pons and superior portions of the frontal lobes. Olivary atrophy was identified by MRI. Semiquantitative analysis showed a statistically significant difference of perfusion in the inferior and superior portions of the frontal lobes, lateral portion of the temporal lobes, parietal lobes, left basal ganglia, cerebellar hemispheres, and vermis when compared with the control group. A significant difference was noted between the vermis and cerebellar volumes on MRI when compared with the control group. A significant relationship was observed between the perfusion of the left parietal lobe (P = .05) and extrapyramidal syndrome. There was a tendency toward an inverse relationship between the duration of symptoms and the perfusion of the cerebellar hemispheres (ρ = −0.37; P = .24) and volume of the vermis (ρ = −0.30; P = .34); between the length of the expanded (CAG)nrepeat and the perfusion of the left parietal lobe (ρ = −0.32; P = .36), vermis (ρ = −0.28; P = .43), and pons (ρ = −0.28; P = .42). A direct association was observed between the length of the expanded (CAG)n repeat and the perfusion of the lateral portion of the right temporal lobe (ρ = 0.67; P = .03).

Conclusions  Brain SPECT imaging and MRI were capable of identifying subclinical abnormalities in individuals with MJD. These findings may be helpful for a better understanding of the pathophysiology of this disease.

Figures in this Article

MACHADO-JOSEPH disease (MJD) is one of the most frequently encountered spinocerebellar ataxias. Machado-Joseph disease was first described in 1972 by Nakano et al1 in a Portuguese-American family, which descended from Guilherme Machado, and emigrated from the Azores to Massachusetts. Since then, the disease has been described in other countries.27

Patients with MJD frequently display progressive cerebellar ataxia, external ophthalmoplegia, pyramidal and extrapyramidal syndromes, distal muscular atrophy, eyelid retraction, and twitching of the face and tongue.8 Early manifestations of the disease occur in affected individuals between the ages of 25 and 55 years (mean age, 40 years). In 1993, Takiyama et al9 localized the MJD gene in chromosome 14q. In 1994, Kawagushi et al10 identified the genetic defect as an expansion of a repetitive sequence of a CAG trinucleotide (or [CAG]n repeat). With modern molecular genetic technology, it is possible to establish the diagnosis of MJD with high sensitivity and specificity.6,11

There are only a few reports on brain single-photon emission computed tomographic (SPECT) imaging (BSI) with hexylmethylpropylene amineoxine radiolabeled with technium Tc 99m (99mTc-HMPAO) and magnetic resonance imaging (MRI) for the evaluation of patients with MJD. Most of these studies were performed before genetic testing was available.12 Brain SPECT imaging with 99mTc-HMPAO is a sensitive method for evaluating cerebral perfusion with the advantage of a lower cost when compared with positron emission tomographic scans.

The objectives of this study were to evaluate neuronal perfusion and function in patients with MJD who underwent visual and semiquantitative BSI analyses and visual and volumetric MRI analyses, and to determine the possible relationship between BSI and MRI abnormalities with the duration of the disease and the length of expanded CAG repeat.

Twelve patients (8 males, 4 females) from 5 families in the state of São Paulo, Brazil, with genetically proven MJD were studied. Ages ranged from 22 to 67 years (mean age, 39 years). All patients were required to sign an informed consent for the genetic analysis, BSIs, and MRIs. Both BSIs and MRIs were performed on the same day. The length of the CAG repeat was obtained in 10 of the 12 patients studied. Table 1lists the characteristics of the 12 patients, according to sex, age, duration of the disease, signs and symptoms, magnitude of cerebellar ataxia, and length of the expanded (CAG)n repeat. The duration of the disease was determined from the moment the patient first noted the clinical manifestation of ataxic gait. Ataxic abnormalities were classified as follows: 1 indicates mild; 2, mild to moderate; 3, moderate to severe; and 4, severe.

Table Graphic Jump LocationTable 1. Characteristics of the Patients With Machado-Joseph Disease (MJD)*

The control group for BSI consisted of 42 normal volunteers (22 females, 20 males) whose ages ranged from 22 to 66 years (mean age, 33 years). The control group for the MRI studies consisted of 17 normal volunteers (13 females, 4 males) whose ages ranged from 21 to 62 years (mean age, 32.2 years).

GENETIC ANALYSIS OF PATIENTS WITH MJD

Genomic DNA was isolated from peripheral lymphocytes through conventional methods. The fragment containing the (CAG)n repeat of the MJD gene was amplified by polymerase chain reaction using the primers MJD52 and MJD25. Polymerase chain reaction was performed in a final volume of 12.5 µL, containing 100 ng of genomic DNA, 10mM of Tris-hydrochloride (pH, 8.8), 15mM of magnesium chloride, 50mM of potassium chloride, 2% formamide, 250µM of dCTP, dGTP and dTTP, each, 25µM of adenosine triphosphate, 1.5 µCi of radiolabled [35S]dATP, 100 ng of each primer and 1 U of Taq polimerase. The DNA was denaturated at 94°C for 5 minutes, after 32 cycles at 94°C for 1 minute, 60°C for 1 minute, and 72°C for 5 minutes, followed by a final extension at 72°C for 5 minutes.

To determine the size of the allele, the products of the polymerase chain reaction were analyzed in gels of polyacrylamide at 6% in parallel with a marker of molecular weight and visualized through autoradiography. The size of the alleles was determined by comparison with a sequence of the marker and the numbers converted into units of CAG repeat (N), using the equation N = [(T − 121)/3], where T is the size of the fragments in base pairs, assuming that the variation of the size of the polymerase chain reaction product occurred in the repetitive CAG repeat.

BSI STUDIES

Brain SPECT imaging was performed using 99mTc-HMPAO. Patients were intravenously injected with 99mTc-HMPAO 15 minutes after preparation of the radioactive material. Patients and control subjects were required to remain resting in a dark quiet room for 10 minutes. While at rest, they received an intravenous injection of 30 mCi of 99mTc-HMPAO and were required to rest for 10 additional minutes.

Brain SPECT images were acquired in a scintillation camera equipped with a fan beam collimator. Sixty images were acquired, at 6°-intervals for a total of 360°. Images were normalized, a Metz filter and attenuation correction were applied. The images were reconstructed in the transaxial, coronal, and sagittal planes.

MRI STUDIES

Magnetic resonance images were obtained in a 2-T system. Acquisition was performed in the coronal, sagittal, and transaxial planes and in 3-dimensional mode (volumetric). Sagittal T1-weighted spin-echo images were used to guide the acquisition plane of the other images (slice thickness, 6 mm; tip angle, 180°; repetition time, 430 milliseconds; echo time, 12 milliseconds; acquistion matrix, 200 × 350 pixels; and field of view, 25 × 25 cm). T2-weighed fast spin-echo images were obtained (slice thickness, 4 mm; tip angle, 120°; repetition time, 5800 milliseconds; echo time, 129 milliseconds; acquistion matrix, 252 × 320 pixels; and field of view, 18 × 18 cm). Three-dimensional acquisition was obtained on the sagittal plane, gradient-echo T1-weighted (slice thickness, 1.5 mm; tip angle, 35°; repetition time, 22 milliseconds; echo time, 9 milliseconds; acquistion matrix, 256 × 220 pixels; field of view, 230 × 250 cm; and pixel size, 1 × 1). Volumetric analyses of the cerebellar hemispheres and vermis were performed using a semiautomatic manual drawing.

ANALYSIS OF BSI AND MRI STUDIES

Two nuclear medicine physicians (E.C.S.C.E. and E.E.C.) performed visual and semiquantitative analyses of BSIs. One neuroradiologist (F.C.) performed visual and quantitative analyses of MRIs.

Visual analysis of BSI was performed using a 4-grade hypoperfusion scale from normal to severely abnormal, using brain perfusion of the control group as reference. The perfusion abnormalities were graded as follows: 1, normal or mildly abnormal; 2, mild to moderately abnormal; 3, moderate to severely abnormal; and 4, severely abnormal. Semiquantitative analysis of BSI was performed using the thalami as reference, by placing regions of interest (ROIs) on the cerebral and cerebellar cortices. Counts per pixel of each ROI were obtained, divided by counts per pixel of the thalami, and compared with the control group.

Visual analysis of MRIs was performed using the same 4-grade scale from normal to severely abnormal. Quantitative analysis of MRI was performed by placing ROIs on the cerebral and cerebellar cortices. The volume of each ROI was obtained and compared with the control group.

In both the BSI and MRI studies, the regions analyzed were the frontal lobes (inferior and superior portions), the temporal lobes (lateral and mesial portions), the parietal lobes, the cerebellar hemispheres, vermis, and pons. On BSIs the basal ganglia and primary visual cortex were also analyzed. The inferior olives were evaluated on MRIs.

STATISTICAL ANALYSIS

To compare the variables measured between groups the Mann-Whitney test was applied. To verify associations or compare proportions the χ2 or the Fisher exact test were performed. Statistical significance was set at P<.05. To identify the magnitude of relationship between 2 measures, Spearman linear correlation coefficient was applied. To verify the concordance between BSI and MRI, the κ coefficient was applied.

Analysis of the length of the expanded (CAG)n repeat was not performed in 2 patients (patients 6 and 11) because they belong to the same family as patient 1, who was genotyped and positive for the MJD mutation (Table 1). In patients with MJD, the expanded (CAG)n repeat ranged from 68 to 78. No statistical significance was noted for age distribution differences between the controls and the patients with MJD (P = .09, Mann-Whitney test for BSI; P = .09, Mann-Whitney test for MRI).

VISUAL ANALYSIS OF BSI AND MRI

Table 2 gives the κ coefficients obtained for the visual analyses of BSI and MRI in the 12 patients with MJD. Correlation was excellent between BSI and MRI abnormalities in the vermis and good correlation in the parietal lobes. There was no correlation between the BSI and MRI abnormalities in other areas, and in general, the abnormalities were more severe on BSI than on MRI. Brain SPECT imaging identified more functional abnormalities in the inferior portion of the frontal lobes, temporal lobes (mesial and lateral portions), and cerebellar hemispheres. Magnetic resonance imaging identified more structural abnormalities in the pons and superior portion of the frontal lobes. Hypoperfusion of the basal ganglia was observed on BSI. Atrophy of the olives was identified in most patients on MRI and was not, because of the limitations of the method, for those studied using BSI. Perfusion of the primary visual cortex was normal in all patients except for patient 5 who presented hypoperfusion of this region on BSI but in whom this region was normal on MRI.

Table Graphic Jump LocationTable 2. Correlation Between the Visual Analyses of BSI and MRI in Patients With Machado-Joseph Disease*

No significant relationship was observed between the magnitude of the ataxia and perfusion abnormalities of the cerebellar hemispheres or vermis in the patients with MJD. No correlation was observed between the magnitude of the ataxia and the anatomical abnormalities of the cerebellar hemispheres (P = .93, Fisher exact test for BSI; P = .54, Fisher exact test for MRI) or vermis (P = .54, Fisher exact test for BSI; P = .68, Fisher exact test for MRI) in the patients with MJD. In general, the BSI and MRI abnormalities in the vermis and cerebellar hemispheres were more severe than the magnitude of the ataxia. The exceptions were BSI and MRI abnormalities in the vermis of patients 7, 8, and 11. The magnitude of ataxia was more severe than the perfusion and anatomical abnormalities in the cerebellar hemispheres in 5 patients (patients 5, 7-9, and 11).

SEMIQUANTITATIVE ANALYSIS OF BSI

Table 3 gives the mean (SD) of semiquantitative analysis of perfusion data for the controls and patients with MJD. A statistically significant difference in perfusion was observed in the inferior and superior portions of the frontal lobes, lateral portion of the temporal lobes, parietal lobes, cerebellar hemispheres, left basal ganglia, and vermis of the patients with MJD compared with the controls. No statistically significant difference in perfusion between the groups was observed in the mesial portion of the temporal lobes, right basal ganglia, anterior portion of the cingulate gyrus, pons, and primary visual cortex.

Table Graphic Jump LocationTable 3. Values Obtained From Semiquantitative Analysis of the Cerebral and Cerebellar Cortices Perfusion Data in Patients With Machado-Joseph Disease (MJD) and Control Subjects

No significant difference was observed between the duration of the disease and perfusion of the vermis (Spearman ρ = 0.10, P = .77). There was a tendency toward an inverse relationship between cerebellar hemisphere perfusion and the duration of symptoms (Spearman ρ = −0.37, P = .24).

There was a direct relationship between cerebellar syndrome and the perfusion of the vermis and cerebellar hemispheres. Extrapyramidal and pyramidal syndromes were correlated with the perfusion of the frontal, temporal, and parietal lobes and the basal ganglia. A statistically significant relationship was observed between the perfusion of the left parietal lobe (P = .05) and the presence of extrapyramidal syndrome.

Table 4 gives the Spearman association coefficients and P values between the length of the expanded (CAG)n repeat and the perfusion abnormalities on BSI. There was a tendency toward an inverse association between the hypoperfusion of the left parietal lobe, vermis, and pons and the length of the expanded (CAG)n repeat. A direct association was observed between the length of the expanded (CAG)n repeat and the perfusion of the lateral portion of the right temporal lobe.

Table Graphic Jump LocationTable 4. Correlation Between Length of the Expanded (CAG)n Repeat and Perfusion Abnormalities on BSI*
MRI VOLUMETRIC ANALYSIS

Patients with MJD presented marked reduction of the vermis and cerebellar volumes, with a statistically significant difference when compared with the controls (P = .004 and .001, respectively, Mann-Whitney test). Figure 1 compares the volumes of the vermis and cerebellar hemispheres, respectively, between both study groups. There was a tendency toward an inverse relationship between the duration of the disease and the volume of the vermis (Spearman ρ = −0.30, P = .34). No statistically significant difference was observed between the volume of the cerebellar hemispheres and the duration of the disease (Spearman ρ = −0.25, P = .42) or the length of the expanded (CAG)n repeat (Spearman ρ = −0.07, P = .85), as well as between the length of the expanded (CAG)n repeat and the volume of the vermis (Spearman ρ = −0.15, P = .69).

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Figure 1.

Vermis (A) and cerebellar hemisphere (B) volumes on magnetic resonance imaging of a patient with Machado-Joseph disease (MJD) and a normal volunteer.

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SEMIQUANTITATIVE BSI vs VOLUMETRIC MRI

No correlation was observed between the perfusion of the vermis and the volume of the vermis (P = .81, Spearman linear correlation test) as well as the perfusion of the cerebellar hemispheres and the volume of the cerebellar hemispheres (P = .33, Spearman linear correlation test). Figure 2 shows the percentage of volume loss of vermis and cerebellar hemispheres on MRI and perfusion loss on BSI, respectively.

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Figure 2.

Percentage of volume loss of vermis (A) and cerebellar hemispheres (B) on magnetic resonance imaging (MRI) and hypoperfusion on brain single-photon emission computed tomography (BSI).

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The percentage loss for BSI and MRI was calculated by the following equation:

Percentage of Loss = {[Patient − Control (Mean Value of the Control Group)]/Control (Mean Value of the Control Group)} × 100%.

There was a tendency to identify more perfusion abnormalities than volumetric abnormalities, since the percentage of loss was greater on BSI than on MRI. Overall, BSI detected more functional abnormalities than MRI detected structural abnormalities, as seen in the vermis of patients 1 through 6, 10, and 12 (Figure 3 and Figure 4).

Place holder to copy figure label and caption
Figure 3.

Brain single-photon emission computed tomographic imaging (BSI) of a normal volunteer (A) and of a patient with Machado-Joseph disease (B). Note the hypoperfusion of the vermis (arrow), the parietal lobe (arrowhead), and the inferior portion of the frontal lobe (dotted arrow) in the patient with Machado-Joseph disease.

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Place holder to copy figure label and caption
Figure 4.

Brain single-photon emission computed tomographic imaging (BSI) (A) and magnetic resonance imaging (B) of a patient with Machado-Joseph disease. C, The BSI of a normal volunteer. The BSI of the patient shows marked hypoperfusion of the vermis (arrows), while on magnetic resonance imaging the vermis is normal (dotted arrows). The BSI of the normal volunteer shows normal perfusion of the vermis (arrowhead).

Graphic Jump Location

There are a few reports on BSI1215 and MRI findings16,17 in patients with MJD. Magnetic resonance imaging has demonstrated atrophy of the pons, olives, cerebellar hemispheres, vermis,16 temporal and frontal lobes, and globus pallidus.17 To our knowledge, this report is the first to describe perfusion abnormalities in patients with MJD who undergo BSI using 99mTc-HMPAO.

Positron emission tomographic studies with different radiolabeled tracers such as 18F-dopamine (FD),11 C-raclopride (RAC), and 18F-fluorodeoxyglucose (FDG) have been performed in patients with MJD. Shinotoh et al,18 in 1997, demonstrated variable uptake of FD and normal uptake of RAC in the striatum of these patients, which did not correlate with the phenotype, length of the expanded (CAG)n repeat, duration, or age of onset of symptoms. Reduced FDG metabolism in the cerebellum,19 brainstem, striatum, and cerebral cortex in patients with MJD has also been described.20 Positron emission tomographic studies of patients with MJD21 have contributed to identifying cortical lesions not identified by anatomical imaging modalities. Unfortunately, positron emission tomographic scanners are unavailable in most nuclear medicine laboratories. Brain SPECT imaging with 99mTc-HMPAO has the advantage of lower cost and high sensitivity in identifying brain perfusion abnormalities.

In this study, the thalami were used as a reference because in many neuropathological,22,23 anatomical,16,17 and functional12,14,15,18,20,21,24 studies, these structures have been reported as normal. Despite the description of the uptake reduction of 123I-iomazenil in the thalami of 4 patients with MJD by Ishibashi et al,13 this is the only finding in the literature. The same authors, while evaluating regional cerebral blood flow with this tracer, did not observe perfusion abnormalities in the thalami.

Brain SPECT imaging may have underestimated pons abnormalities because of the size of this structure, which is difficult to visualize because of the resolution of the scintillation camera. Underestimation of abnormalities in the superior portion of the frontal lobes may have been due to the intense perfusion of the anterior portion of the cingulate gyrus, producing a partial volume effect.

Ataxia was present in all patients and, therefore, the perfusion and structural findings in the cerebellar hemispheres and vermis are important. Patients with grade 4 ataxia had grade 3 or 4 hypoperfusion of the vermis, while the cerebellar hemispheres were less affected, indicating that the ataxia was mainly of the trunk and not appendicular. In patients 2 through 4 and 6 the severity of hypoperfusion of the vermis was greater than the magnitude of the ataxia observed. Also, patient 4 had hypoperfusion grade 2 of the vermis while atrophy was graded as 1 on MRI. This may represent preclinical, functional abnormalities preceding structural damage. These findings suggest that BSI may be more useful in the early stages of disease for identification of preclinical functional changes before structural damages occur. Hypoperfusion and atrophy of the cerebellar hemispheres and vermis encountered in these patients are in agreement with the neuropathologic findings in patients with MJD.22 This may be related not only to the deaferentation of the dento-rubro-thalamo-cortical-ponto-cerebellar pathway, but to atrophy of the superior and medial cerebellar peduncles, and the anterior and posterior spinocerebellar tracts, structures known to be affected in patients with MJD. Vermis hypoperfusion and atrophy may be caused by neuronal loss in the anterior and posterior spinocerebellar tracts and the Clark column.

The percentage volume loss of the cerebellar hemispheres on MRI and of hypoperfusion on BSI did not correlate. This is probably because of the high sensitivity of BSI for detecting functional abnormalities before anatomical changes occur. Taniwaki et al20 observed hypometabolism of FDG in the cerebral and cerebellar cortices of patients with MJD while little or no structural abnormalities were found on MRI. Takahashi et al14 noted a reduction of the regional cerebral blood flow in the cerebellum of 2 patients with MJD who had no concomitant atrophy, which agrees with the findings in this study: patients 5, 8 through 10, and 12 had more hypoperfusion than atrophy. These authors also noted severe cerebellar atrophy with the normal regional cerebral blood flow in 1 patient, which was also seen in the present study: patients 3, 4, 7, and 11 showed more signs of atrophy than hypoperfusion.

Hypoperfusion of the frontal lobes, observed in these patients, may be due to deaferentation of 2 anatomical pathways: the dento-rubro-thalamo-cortical-ponto-cerebellar (dopaminergic pathway); or the pathway originating from the cerebellar hemispheres that sends connections to the thalami and from there to the frontal cortex. Hypoperfusion and atrophy of the parietal lobes may be caused by deafferentation of the synapses originating from the frontal lobes or from the association pathway of the parietal cortex with the cerebellum through the nuclei in the base of the pons. Hypoperfusion and atrophy of the temporal lobes may also be due to deafferentation of the communication pathways with the frontal lobes and parietal lobes. It may also be due to deafferentation of the mesocortical limbic pathway secondary to lesions in the ventral tegmentum of the mesencephalon, causing reduction of the function of the mesial portion of the temporal lobes. Botez et al12 and Taniwaki et al20 described hypoperfusion with 99mTc-HMPAO and hypometabolism with FDG, respectively, in the frontal, temporal, and parietal lobes. Ishibashi et al,13 using 123I-iomazenil, noted hypoperfusion of the left temporal lobe. Murata et al17 identified atrophy mainly in the frontal and temporal lobes, pons, and cerebellum of patients with MJD. These findings may be valuable for a better understanding of the pathways of the corticocerebellar connections and may explain behavioral changes that occur in these patients.

Left basal ganglia hypoperfusion may be caused by lesion of the substantia nigra with consequent deafferentation of the afferent and efferent fibers of the striatum. Hypometabolism of these structures has been described.13,15,18,20

Olivary atrophy was identified on MRI in most patients in this study. Lesion of this structure has not been described as a characteristic finding of patients with MJD22 although this has been previously described.16,25

The tendency toward an inverse relationship between the duration of the disease and cerebellar perfusion and volume of the vermis did not reach statistical significance probably because of the size of the population studied. The presence of extrapyramidal syndrome correlated with hypoperfusion of the left parietal lobe. There was also a tendency toward an inverse relationship between the length of (CAG)n repeat and perfusion of the left parietal lobe, vermis, and pons; and a direct relationship with the perfusion of the lateral portion of the right temporal lobe. To our knowledge, this is the first study to correlate the length of the expanded (CAG)n repeat with BSI abnormalities using 99mTc-HMPAO or MRI.

Despite the report by Takiyama et al22 that the cerebral cortex of patients with MJD is almost never affected, it is clearly evident that cortical lesions do occur and can be identified by BSI and MRI. Cortical hypoperfusion may be caused by deafferentation of anatomical pathways and not necessarily mean that anatomical lesions in these cortical regions actually exist. There may be a reduction of cortical function because of a lesion in the cerebellum and brainstem.

The evaluation of the regional cerebral metabolism is a noninvasive method capable of identifying preclinical changes and an objective marker of the disease activity. The genetic abnormality may produce functional abnormalities seen before any anatomical changes have occurred. Other studies using BSI with 99mTc-HMPAO in a larger population of patients with MJD would be important to test the power of this method in identifying abnormalities early in the course of the disease. This method may be of value for a better understanding of the pathways of the corticocerebellar connections in these patients and may eventually be used to identify patients who would be adequate candidates for therapeutic interventions and to evaluate response to treatment. Follow-up BSI and MRI of patients with MJD should be performed to evaluate disease progression and to eventually give an insight on patient prognosis.

Accepted for publication February 26, 2001.

Corresponding author and reprints: Elba C. S. C. Etchebehere, MD, Serviço de Medicina Nuclear, Hospital das Clínicas da UNICAMP, Caixa Postal 6142, 13081-970 Campinas, Brazil (e-mail: elba@mn-d.com).

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Takiyama  YOyanagi  SKawashima  S  et al A clinical and pathologic study of a large Japanese family with Machado-Joseph disease tightly linked to the DNA markers on chromosome 14q. Neurology.1994;44:1302-1308.
Robitaille  YLopes-Cendes  IBecher  MRouleau  GClark  AW The neuropathology of CAG repeat diseases: review and update of genetic and molecular features [review]. Brain Pathol.1997;7:901-926.
Soong  BWLiu  RS Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease. J Neurol Neurosurg Psychiatry.1998;64:499-504.
Haberhausen  GDamian  MSLeweke  FMüller  U Spinocerebellar ataxia, type 3 (SCA3) is genetically identical to Machado-Joseph disease (MJD). J Neurol Sci.1995;132:71-75.

Figures

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Figure 1.

Vermis (A) and cerebellar hemisphere (B) volumes on magnetic resonance imaging of a patient with Machado-Joseph disease (MJD) and a normal volunteer.

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Figure 2.

Percentage of volume loss of vermis (A) and cerebellar hemispheres (B) on magnetic resonance imaging (MRI) and hypoperfusion on brain single-photon emission computed tomography (BSI).

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Figure 3.

Brain single-photon emission computed tomographic imaging (BSI) of a normal volunteer (A) and of a patient with Machado-Joseph disease (B). Note the hypoperfusion of the vermis (arrow), the parietal lobe (arrowhead), and the inferior portion of the frontal lobe (dotted arrow) in the patient with Machado-Joseph disease.

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Figure 4.

Brain single-photon emission computed tomographic imaging (BSI) (A) and magnetic resonance imaging (B) of a patient with Machado-Joseph disease. C, The BSI of a normal volunteer. The BSI of the patient shows marked hypoperfusion of the vermis (arrows), while on magnetic resonance imaging the vermis is normal (dotted arrows). The BSI of the normal volunteer shows normal perfusion of the vermis (arrowhead).

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Tables

Table Graphic Jump LocationTable 1. Characteristics of the Patients With Machado-Joseph Disease (MJD)*
Table Graphic Jump LocationTable 2. Correlation Between the Visual Analyses of BSI and MRI in Patients With Machado-Joseph Disease*
Table Graphic Jump LocationTable 3. Values Obtained From Semiquantitative Analysis of the Cerebral and Cerebellar Cortices Perfusion Data in Patients With Machado-Joseph Disease (MJD) and Control Subjects
Table Graphic Jump LocationTable 4. Correlation Between Length of the Expanded (CAG)n Repeat and Perfusion Abnormalities on BSI*

References

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Yen  TCLu  CSTzen  KY  et al Decreased dopamine transporter binding in Machado-Joseph disease. J Nucl Med.2000;41:994-998.
Lopes-Cendes  ISilveira  IMaciel  P  et al Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease. Arch Neurol.1996;53:1168-1174.
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Gilman  SSt Laurent  RTKoeppe  RAJunck  LKluin  KJLohman  M A comparison of cerebral blood flow and glucose metabolism in olivopontocerebellar atrophy using PET. Neurology.1995;45:1345-1352.
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Soong  BWCheng  CLiu  RSShan  D Machado-Joseph disease: clinical, molecular and metabolic characterization in Chinese kindreds. Ann Neurol.1997;41:446-452.
Takiyama  YOyanagi  SKawashima  S  et al A clinical and pathologic study of a large Japanese family with Machado-Joseph disease tightly linked to the DNA markers on chromosome 14q. Neurology.1994;44:1302-1308.
Robitaille  YLopes-Cendes  IBecher  MRouleau  GClark  AW The neuropathology of CAG repeat diseases: review and update of genetic and molecular features [review]. Brain Pathol.1997;7:901-926.
Soong  BWLiu  RS Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease. J Neurol Neurosurg Psychiatry.1998;64:499-504.
Haberhausen  GDamian  MSLeweke  FMüller  U Spinocerebellar ataxia, type 3 (SCA3) is genetically identical to Machado-Joseph disease (MJD). J Neurol Sci.1995;132:71-75.

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