| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | RSS | TABLE OF CONTENTS |
|
|
|
||||||||
|
||||||||||
Clinical Investigations |
1 Department of Nuclear Medicine, Rouen University Hospital, Henri Becquerel Center, Laboratoire Universitaire Quantification en Imagerie Fonctionnelle, Rouen, France
2 Department of Neurology, Rouen University Hospital, Rouen, France
3 Department of Neurology, Reims University Hospital, Reims, France
4 Department of Biostatistics, Rouen University Hospital, Rouen, France
5 Department of Nuclear Medicine, Nime University Hospital, Nime, France
6 Service Hospitalier Frédéric Joliot, Commissariat à l’Energie Atomique–Direction des Sciences du Vivant–Orsay, France
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
Key Words: primary progressive aphasia • SPECT • MRI • neuropsychologic examination
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
The role of morphologic cerebral imaging by tomodensitometry (TDM) or MRI is first to eliminate a tissue or vascular lesion, which could produce an acquired progressive aphasia (4). Moreover, they may reveal asymmetric focal atrophy in the dominant hemisphere (5). TDM is considered less sensitive than MRI to show focal atrophy (6). In the series of Westbury and Bub (7), including 112 patients with PPA, an important incidence of structural abnormalities was reported, no matter what type of aphasia was studied. In 104 MRI studies, 84% of unilateral or bilateral cortical abnormalities were observed. In 56%, a cortical left hemispheric atrophy was observed, in particular in the perisylvian region and in the temporal lobe. A left frontal atrophy was observed in a few cases (n = 9) and a parietal atrophy was observed in only 1 case. Among the 38 MRI studies with bilateral atrophy (43%), temporal (n = 6), frontal (n = 6), and perisylvian (n = 4) involvement was more frequent. In semantic dementia, atrophy predominates in the pole and in the inferolateral part of the left temporal lobe (3,8–11). In contrast, the hippocampus and parahippocampal gyrus appeared normal at the onset of the illness (12). A bilateral extension of atrophy has previously been suggested (8,11,13). In the nonfluent PPA, a unilateral (4,9,14–18) or bilateral (19–22) perisylvian or frontal atrophy has been demonstrated. Also, atrophy is sometimes more diffuse in the left frontotemporoparietal cortex (9,17,23,24). Isolated left temporal atrophy has rarely been mentioned (4,17).
Functional cerebral imaging with PET or SPECT generally shows larger abnormalities than morphologic ones. This phenomenon is explained by the deafferentation of the region connected to the atrophic areas or by neuronal loss not visible on morphologic imaging (4,6). Major parts of functional imaging studies have been case reports or small series ranging from 2 to 13 patients. These studies were performed with 18F-FDG PET or with 99mTc-hexamethylpropyleneamine oxime (HMPAO) SPECT. They often showed a decrease in metabolism or perfusion in the left hemisphere, including temporal, frontal, or parietal lobes and, more specifically, in the left Broca or Wernicke cortex. Tyrrell et al. (9,19) have observed a decrease in metabolism in the right hemisphere, but only in patients with long-evolution duration (6 and 8 y). Right frontal abnormalities have been observed in nonfluent aphasia (3,10,25). Right temporal hypoperfusion has been observed by Sinnatamby et al. (6) but only in 1 patient with PPA associated with a visual agnosia. Recently, San Pedro et al. (26) reported a right temporal hypoperfusion in 2 right-handed women with long- evolution duration (7 y). These studies show that few series exist regarding functional imaging in patients with PPA. They frequently correspond to case reports that did not provide information in a homogeneous group of patients.
The aims of our study in patients with PPA was (a) to evaluate the perfusion changes using SPECT imaging, (b) to correlate SPECT and clinical symptoms, and (c) to compare SPECT and morphologic imaging.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
These patients had PPA defined according to Mesulam and Weintraub criteria (2). All patients presented a progressive alteration of language for >2 y without dementia (normal visual memory and visuoconstructive capacity).
Performance on nonverbal intelligence tests was assessed by the Raven’s Colored Progressive Matrices (PM47) and the visual memory subtest of the Wechler Memory Scale (WMS) (immediate reproduction of nonsignificant drawings). Accuracy of response for both tests had to be in the range of normality. Moreover, visuospatial relations had to be as follows: normal Rey Complex Figure test in copy and standard mark for age 
7 y at the Weschler Adult Intelligence Scale (WAIS) test. This threshold was determined from previously published results.
Neurologic examination and cerebral imaging were performed to exclude cerebral lesions. General examination and vitamin B12, folic acid, and thyroid- stimulating hormone dosages were obtained to exclude general pathology. For all patients, the delay between neuropsychologic examination and cerebral imaging was <6 mo.
Control Subjects
Patients were compared with 12 control subjects (8 women, 4 men; mean age ± SD, 74.1 ± 3.9 y) followed in the French prospective Eugeria study (27) regarding neuropsychologic evaluation in the elderly. In these patients, the Mini Mental Score Examination (MMSE) (28), a Computerized Cognitive Examination (29) repeated all years over 3 y, remained normal (MMSE 29/30). Morphologic imaging (MRI or CT) was normal in 12 control subjects. The control subjects were significantly older than the patients (74.3 ± 4.2 y vs. 65.1 ± 8.2 y; F = 13.97; P = 0.0006).
Language Examination
Two major parts of the language were explored: lexicosemantic comprehension and arthric realization. Results of language examination and patient grouping are presented in Table 1.
|
The 29 patients were divided into 2 groups, according to existence (or not) of lexicosemantic disorders (LS+ and LS-, respectively). LS+ patients were those who obtained marks inferior or equal to the mean minus 2 SDs at the semantic category classification test or at the verbal word pairment test. Patients 9–23 were included in the LS+ subgroup, and patients 1–8 and 24–29 were in the LS- subgroup.
Arthric Disorders.
Arthric realization was evaluated using 3 tests: articulation agility, arthric realization (BDAE tests 08 and 06, respectively), and repetition of 110 words. For this task, results were expressed as the ratio (%) between phonetic errors and total errors. For each word, a mistake was considered as phonetic when it consisted of transforming the phoneme with simplification (change without stopping between 2 phonemes) or of total deterioration. Phoneme moves, accentuations, and elisions were not considered as phonetic errors.
Patients were divided into 2 other groups according to existing (or not) arthric disorders (A+ and A-, respectively). Patients 1–10, included in the A+ group, showed word repetition impairment, regardless of the level of phonetic mistakes. Patients 11–29, included in the A- group, made no phonetic error for the same task.
SPECT
SPECT was performed on all 29 patients and 12 control subjects in a double-head gamma camera (DST; Sopha Medical Vision International) equipped with ultra-high-resolution, parallel-hole collimators. SPECT was performed 15 min after intravenous injection of 1,000 MBq 99mTc-HMPAO (n = 22 patients and control subjects) or 1 h after intravenous injection of 1,000 MBq 99mTc-ethylcysteinate dimer (ECD) (n = 7 patients) under conditions of low light and sound. The subject’s head was safely positioned in an adjustable head folder. For each SPECT study, 64 angular views of 60 s each were obtained through a 360° circular orbit (64 angular views by head). The data were recorded in a 128 x 128 matrix. SPECT images were reconstructed from projection data using the filtered backprojection algorithm with a 0.5 cutoff-frequency Hann filter and a software zoom of 2 (matrix, 128 x 128 x 128; voxel size, 1.7 x 1.7 x 1.7 mm). No attenuation correction was performed. SPECT full width at half maximum at the center was 7.4 mm in air (gyration radius, 12.5 cm). The acquisition and reconstruction parameters that were used have proven to be the best adapted for standard brain SPECT studies in clinical practice in our department (30).
Reconstructed brain slices were reoriented according to the bicommissural line (anterior commissure–posterior commissure [AC–PC]) with validated software. First, the AC–PC line was defined on SPECT images from the linear regression of 4 internal landmarks (frontal pole, inferior limit of the anterior corpus callosum, subthalamic point, and occipital pole). Second, the SPECT position of the AC and PC points on the AC–PC line were automatically determined from measurements made on hard copies of MR images of all patients. Finally, a proportional Talairach’s grid was automatically drawn on each axial SPECT image. The mean displacement between the estimated accuracy of the AC and PC localization have been shown to be inferior to the pixel size and represent a maximum error of <5 mm in the cortex localization. Intra- and intercomparisons of the method have been reported (31).
Eighteen cortical region of interest (ROIs) and 1 thalamic ROI were defined on each hemisphere, using stereotactic coordinates of the Talairach and Tournoux atlas (32). Segmentation was performed with the software previously described. The regions and anatomic boundaries of the ROIs are presented in Figure 1.
|
MRI
Axial MRI slices were obtained using a 0.5- or 1.5-T MR scanner. Each subject was positioned so that MRI axial slices were parallel to the bicommissural line (AC–PC; 18 patients) or parallel to the orbitomeatal line (9 patients), which was verified on a midsagittal image. T1-weighted, 3-mm-thick axial slices were obtained throughout the whole brain. Two patients underwent TDM. The delay between SPECT and MRI was 3.5 ± 8.6 mo.
For the 29 patients, atrophy was quantified on 16 cortical ROIs of each cerebral hemisphere similar to those defined for SPECT (except for the calcarine region). ROIs were drawn on the axial slices by the same observer to improve reproducibility.
For each ROI, the atrophy was estimated on 1–3 axial slices by 3 observers, SPECT being blind. The atrophy was classified by the observers in 5 grades: absence of atrophy, 0; doubtful, 1; slightly, 2; significant, 3; severe, 4. Discrepancies were resolved by consensus. Finally, patients with grade 0 and grade 1 were grouped as nonatrophic (Atrop-), and patients with grades 2–4 were grouped as atrophic (Atrop+). MRI or TDM of the 12 control patients was normal and included in a third group (group C).
Data Analysis
The mean ± SD was used for descriptive statistics. For each ROI, the PI was compared between male versus female and between ECD versus HMPAO. For each ROI, the PI was correlated with age and duration of PPA evolution. Comparisons were performed using an unpaired t test, and correlations were performed using regression analysis. P 
0.01 was considered significant. The Bonferroni post hoc test was performed for multiple tests when necessary.
All comparisons were performed for each ROI using ANOVA. First, the PI was compared between the 29 patients and the 12 control subjects. Second, the PI was compared between patients with (n = 15) or without (n = 14) lexicosemantic disorders and control subjects (n = 12) and between patients with (n = 10) or without (n = 19) arthric disorders and control subjects (n = 12). Third, the PI was compared between patients with (Atrop+) or without atrophy (Atrop-) and control subjects (n = 12). P 0.01 was considered significant. The Bonferroni post hoc test was performed for multiple tests when necessary.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
The PI was not statistically different between men and women, whatever the ROI studied. The PI was not significantly different between patients studied with ECD or HMPAO, whatever the ROI studied. For this reason, patients studied with HMPAO and with ECD were pooled in the entire study. No correlation was found between the PI and the evolution duration whatever the ROI studied.
Comparison of PI in Patients and Control Subjects
In comparison with control subjects, the PI was significantly decreased in the left lateral temporal region, Wernicke region, and parietal lobe and in the right lateral temporal region (Table 2). These regions and their percentage of decrease in comparison with control subjects are summarized in Figure 2.
|
|
|
|
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
Twenty-nine patients with PPA were compared with 12 control subjects. Only patients with Mesulam and Weintraub criteria were included in the study (2). Dementia was excluded with a specific neuropsychologic test (Table 1), and structural abnormalities, such as tumor, were excluded with an MRI or CT scan. The control group was selected from the Eugeria study of cognitive aging (27).
Two commercially available tracers of perfusion were used: HMPAO (22 patients and 12 control subjects) and ECD (7 patients). These 2 tracers are chemical microspheres, and their intracerebral uptake is correlated with regional CBF measured by a reference method—that is, a PET scan or the microsphere method. However, their intracellular mechanism of uptake is different. Patterson et al. (33) have shown a relative decrease in the PI on the posterior cortex with HMPAO compared with ECD. For this reason, patients were initially compared with regard to the tracer used. No significant difference was observed between the 2 tracers for all 38 ROIs—in particular, in the posterior region, basal ganglia, or cerebellum. For this reason, all patients were pooled in the study.
Cerebral systematization was determined regarding cerebral regions implicated in language. CBF was evaluated by a PI. The normalization by the cerebellum activity was used because no significant CBF abnormalities have been reported in the cerebellum in patients with PPA. Moreover, the PI was similarly calculated in the 12 control subjects, allowing the comparison of patients and control subjects without utilization of an asymmetry index.
Atrophy was evaluated by 3 observers blindly to SPECT, a method that has been shown to be reproducible (6,34,35). Among the 29 patients, atrophy was quantified from 0 to 4. Regarding the small number of patients in the groups, regions with scores of 0 and 1 were grouped (Atrop-) and regions with scores of 2–4 were also grouped (Atrop+). Because MRI was performed in different centers, digital MRI was not available and SPECT–MRI registration was not performed in the study.
The comparison of PI between patients and control subjects showed that PIs were significantly decreased in the left (-11%) and right (-5%) lateral temporal region, left Wernicke region (-7%), and parietal lobe (-6%) (Fig. 2). This result indicates that the left temporal and parietal cortex are affected in PPA, which is an agreement with previous studies (6,9,34,36) or case reports (8,10,25). By contrast, only a small number of published cases showing a right lateral temporal lesion are available. This may be explained by the methodologic analysis. First, with a visual analysis it is difficult to show a small decrease in perfusion (5% in our study). Second, the majority of studies used the right and left asymmetry ratio, which makes the analysis of perfusion or metabolism in the right hemisphere difficult. Thus, our analysis using both the cortex-to-cerebellum ratio and the comparison with control patients clearly demonstrates the bilateral temporal involvement in PPA.
Fluent-versus-nonfluent aphasia classification was not used. This classification depends on the mean length of sentences. Thompson et al. (37) have shown that patients with nonfluent aphasia may produce sentences of normal length. Therefore, we grouped our patients on the basis of arthric and lexicosemantic performance criteria.
The comparison between patients with and without lexicosemantic disorders showed that patients with lexicosemantic disorders (LS+) have a significant decrease in the PI in the left temporal region (lateral temporal, medial temporal, temporopolar, Wernicke), left parietal lobe, left Broca region, and the right lateral temporal region (Fig. 3). These results demonstrate that lexicosemantic disorders correspond to a large process, involving the bitemporal cortex, left parietal lobe, and posteroinferior frontal cortex.
Patients without lexicosemantic disorders (LS-) have a significant decrease in the PI in the right and left lateral temporal region. This group (LS-) included patients without arthric disorders, who may develop fluent aphasia. This finding suggests that LS- and A- patients who did not have lexicosemantic disorders already had a decrease in CBF in the bitemporal cortex.
Patients with lexicosemantic disorders (LS+) have a significant decrease in the PI in the left medial and lateral temporal cortex in comparison with patients without lexicosemantic disorders (LS-). These results show the implication of the left temporal cortex in patients with lexicosemantic disorders in the PPA.
The comparison of patients with (A+) or without (A-) arthric disorders showed that no significant difference between arthric patients (A+) and control subjects was observed. There was no tendency toward a decrease in the PI in the left external frontal cortex (P = 0.24) or in the left Broca region (P = 0.20). This result is in contrast with previous studies (16,19) and is probably explained by the large SDs of the PI in this small group of patients (n = 10). This finding may be explained by the fact that our patients probably had less severe disease than in other studies.
Patients without arthric disorders (A-) have a significant decrease in the PI in the left lateral temporal cortex in comparison with A+ patients and control subjects. Therefore, patients without arthric disorders (A-) are in the majority of patients with lexicosemantic disorders (Table 1), who are generally described as having large left temporal abnormalities (38).
In degenerative dementia, and particularly in lobar atrophy, the decrease in CBF is secondary to the decrease in metabolism, which is secondary to a neuronal loss or deafferentation. The PI measured in our study is a composite index showing all of these phenomena. For this reason, we investigated the relative importance of atrophy in the decrease in the PI.
In this study, the PI was compared between atrophic (Atrop+), nonatrophic (Atrop-), and control subjects (C). The PI was significantly different in the 3 groups in 5 regions: right lateral temporal, left temporopolar, lateral temporal, Wernicke, and parietal lobe (Table 5).
The determination of atrophy in the right lateral temporal region allowed classification of only 3 patients with atrophy. Therefore, because of the small number of patients in this group, a conclusion regarding comparison of patients with and without atrophy and between patients with atrophy and control subjects were not possible. However, comparison between patients without atrophy and control subjects showed a 5% decrease in the PI in patients without atrophy. These results demonstrate that without right cortical atrophy on MRI, SPECT may show a decrease in the PI in patients in comparison with control subjects. These results confirm the ability of SPECT in PPA to show functional abnormalities in the absence of morphologic abnormality.
In the left temporopolar region, comparison between nonatrophic patients and control subjects did not show a significant difference, suggesting that, without structural abnormalities, the PI is normal in this region. However, the PI in the left temporopolar region significantly decreased in atrophic patients in comparison with nonatrophic patients (6%) and control subjects (7%).
In the left lateral temporal region, the PI significantly decreased in atrophic patients in comparison with nonatrophic patients (8%) and in comparison with control subjects (13%). Moreover, there is a hypoperfusion in nonatrophic patients (7%) in comparison with control subjects. Results obtained in the left parietal lobe show a significantly decrease in the PI in atrophic patients in comparison with nonatrophic patients (7%) and in comparison with control subjects (12%). Moreover, there is a hypoperfusion in nonatrophic patients (5%) in comparison with control subjects (5%). Therefore, in the left lateral temporal region and in the parietal lobe, atrophy corresponded to a decrease in the PI. Moreover, the decrease in the PI preceded structural abnormalities.
In the left Wernicke cortex, comparison between nonatrophic and atrophic patients and between nonatrophic patients and control subjects did not show a significant difference of the PI. The decrease in the PI is about 5% for the 2 comparisons. Absence of a significant result is probably explained by the SD in the Atrop+ group (±0.08) and in the Atrop- group (±0.07). However, the PI significantly decreased in the Atrop+ group in comparison with control subjects, which shows that, in this region, the PI decrease seems to be related to atrophy.
|
CONCLUSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
For correspondence or reprints contact: Pierre Vera, MD, PhD, Nuclear Medicine Department, Henri Becquerel Center, 1 rue d’Amiens, 76000 Rouen, France.
E-mail: pierre.vera{at}rouen.fnclcc.fr
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  C. Cruchaga, M. A. Fernandez-Seara, M. Seijo-Martinez, L. Samaranch, E. Lorenzo, A. Hinrichs, J. Irigoyen, C. Maestro, E. Prieto, J. M. Marti-Climent, et al. Cortical Atrophy and Language Network Reorganization Associated with a Novel Progranulin Mutation Cereb Cortex, August 1, 2009; 19(8): 1751 - 1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.K. Panegyres, M. McCarthy, A. Campbell, N. Lenzo, M. Fallon, and J. Thompson Correlative Studies of Structural and Functional Imaging in Primary Progressive Aphasia American Journal of Alzheimer's Disease and Other Dementias, May 1, 2008; 23(2): 184 - 191. [Abstract] [PDF]
|
|
|
|
 |
|
 J. D. Rohrer, W. D. Knight, J. E. Warren, N. C. Fox, M. N. Rossor, and J. D. Warren Word-finding difficulty: a clinical analysis of the progressive aphasias Brain, January 1, 2008; 131(1): 8 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Le Rhun, F. Richard, and F. Pasquier Natural history of primary progressive aphasia Neurology, September 27, 2005; 65(6): 887 - 891. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | RSS | TABLE OF CONTENTS |
| JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY | THE JOURNAL OF NUCLEAR MEDICINE |
