NEUROREPORT
NEUROCHEMISTRY
Magnetic resonance spectroscopic study of Alzheimer’s disease and frontotemporal dementia/Pick complex Masahito Miharaa,b, Noriaki Hattoria, Kazuo Abeb, Saburo Sakodab and Tohru Sawadaa a
BF Research Institute, Inc. and bDepartment of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Correspondence and requests for reprints to Masahito Mihara MD, Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565- 0871, Japan Tel: + 816 6879 3571; fax: + 816 6879 3579; e-mail:
[email protected] Received 5 January 2006; accepted10 January 2006
Disease-speci¢c metabolic changes in Alzheimer’s disease and frontotemporal dementia/Pick complex were examined by proton magnetic resonance spectroscopy at 3.0 T. Spectra were acquired from posterior and anterior cingulate cortices and the parieto-occipital and frontal white matter. This study included eight Alzheimer’s disease patients, 10 frontotemporal dementia/Pick complex patients and 14 healthy volunteers. N-acetylaspartate/creatine + phosphocreatine ratio was reduced in the posterior cingulate cortex in the Alzheimer’s disease and frontotemporal dementia/
Pick complex patients. The Alzheimer’s disease patients, however, showed a posterior dominant decrease, whereas the frontotemporal dementia/Pick complex patients showed a frontal predominant decrease. These di¡erent distributions of metabolic changes may represent the underlying pathological processes in each disease. Our standardized protocol of proton magnetic resonance spectroscopy measurement may be helpful in di¡erentiating c 2006 these dementia subtypes. NeuroReport 17:413^ 416 Lippincott Williams & Wilkins.
Keywords: Alzheimer’s disease, corticobasal degeneration, frontotemporal dementia, magnetic resonance spectroscopy, myoinositol, N-acetylaspartate, Pick’s disease, progressive supranuclear palsy
Introduction
Proton magnetic resonance spectroscopy (1H-MRS) is a useful tool for the noninvasive evaluation of brain metabolites, including N-acetylaspartate (NAA), creatine + phosphocreatine (Cr), choline-containing compounds (Cho) and myoinositol (mI). This technique has been used for evaluating neurodegenerative dementias [1–3], which include various pathological entities such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB) and other disorders. The clinical diagnosis of these dementia subtypes was based on the proposed consensus clinical criteria for each disease [4–7]. Distinguishing between these dementia subtypes by clinical examination alone, particularly in the early stage, however, continues to be difficult. Moreover, recent clinicopathological studies have revealed that there are clinical and pathological overlaps among these dementia subtypes [8], and coining of the term ‘FTD/Pick complex’, comprising FTD, CBD, PSP and primary progressive aphasia, has been proposed [5,9]. Although pharmacological treatment of dementia patients has not been satisfactory, recent meta-analyses have shown that treatment with cholinesterase inhibitors could be beneficial for AD patients [10]. Thus, early discrimination of AD patients from patients with FTD/Pick complex has
become more important than the precise differentiation of dementia subtypes. Previous studies using 1H-MRS reported decreased NAA and/or increased mI levels in the posterior cingulate cortex and the temporal lobes in AD patients [1–3,11], and decreased NAA and/or increased mI levels in the frontal lobe in FTD patients [1]. Moreover, decreased NAA levels in the frontal lobe and putamen was reported in the PSP and CBD patients [12]. It is, however, confusing that decreased NAA levels in the posterior cingulate cortex were also reported in FTD patients [11,13]. In this study, we performed 1 H-MRS measurements with a relatively simple protocol using multivoxel measurements, including those of the posterior cingulate cortex and frontal lobe, and tried to detect disease-specific distributions of metabolites that are useful in distinguishing between AD and the FTD/Pick complex.
Methods This study comprised 18 patients with dementia and 14 agematched healthy controls. Dementia was seen in eight patients with AD (five men and three women), six patients with FTD (four men and two women), three patients with PSP (all men) and one patient with CBD (women). The AD, FTD and PSP patients were diagnosed on the basis of the
c Lippincott Williams & Wilkins 0959- 4965 Vol 17 No 4 20 March 2006 413 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
NEUROREPORT published criteria [4,6,7]. The CBD patient was diagnosed by the presence of progressive dopa-resistant hemiparkinsonism with hemi-cortical atrophy based on magnetic resonance imaging [14]. The FTD, PSP and CBD patients were included within the FTD/Pick complex group. Fourteen controls (five men and nine women) had no neuropsychological disease or major medical histories that might have interfered with our study. The mean ages (7SD) of the controls, AD and FTD/Pick complex groups were 60.778.6, 69.1710.0 and 65.975.7 years, respectively; there were no significant differences in the ages among these groups. The mean disease durations of the AD and FTD/Pick complex groups were 45 months (range: 14–93 months) and 52 months (range: 11–159 months), respectively. All patients were evaluated by several neuropsychological examinations including the minimental state examination (MMSE) and Wechsler’s adult intelligence scale revised [15]. Informed consents, which were approved by the Institutional Review Board of BF Research Institute and Osaka University Graduate School of Medicine, were obtained from each patient or caregiver. Magnetic resonance imaging and magnetic resonance spectroscopy Magnetic resonance imaging and 1H-MRS were performed by a 3.0-T whole-body system (Signa VH/i, GE Medical Systems, Milwaukee, Wisconsin, USA) using a standard quadrature head coil. T1-weighted images were acquired with three-dimensional inversion recovery fast spoiled gradient recalled echo pulse (3D IRfSPGR) sequence and the parameters were as follows: repetition time (TR), 10 ms; echo time (TE), 3.7 ms; flip angle, 151; inversion time, 600 ms; matrix, 256 192; field of view, 200 mm 200 mm; and slice thickness, 1.3 mm (spatial resolutions were thus 0.78 mm 1.04 mm 1.3 mm). Localized 1H-MRS data were acquired with point resolved spectroscopy sequence and the following parameters: TR, 6000 ms; TE, 25 ms; bandwidth, 2500 Hz; number of data points, 2048; and excitations, 64. Four 8.0 cm3 (2.0 cm 2.0 cm 2.0 cm) volumes of interest (VOIs) were located as follows (Fig. 1): the posterior cingulate VOI (PC VOI) was placed symmetrically around the midline, including mainly the posterior cingulate cortex and precuneus. The parieto-occipital VOI (PO VOI) was placed in the parieto-occipital white matter adjacent to or including a small portion of the posterior horn of the left lateral ventricle. The anterior cingulate VOI (AC VOI) was placed symmetrically around the midline, including mainly the anterior cingulate cortex. The frontal VOI (Fr VOI) was placed in the frontal white matter adjacent to or including a small portion of the anterior horn of the left lateral ventricle. Local magnetic field homogeneity was optimized manually with 3-plane linear gradient shimming, and the mean (7SD) of the full-width at half-maximum of the unsuppressed water peak was 6.3870.49 Hz. The scan time of each VOI was 7 min and 24 s, and the total scan time, including the anatomical scan, was approximately 50 min. Data analysis The MRS data were evaluated using the LCModel software [16]; this analyses the spectrum as a linear combination of model spectra of the metabolites that were acquired from solutions containing each metabolite. The metabolite ratio of
MIHARA ETAL.
NAA, Cho and mI was calculated using Cr as an internal reference. In order to investigate differences in the spatial distribution of the metabolites, we calculated the anterior/ posterior ratio of the metabolites (A/P[Met]), which was defined as the metabolite ratio in the Fr VOI divided by the metabolite ratio in the PC VOI (([Met]Fr/[Cr]Fr)/([Met]PC/ [Cr]PC)). Therefore, a low A/P[Met] indicated that the metabolites decreased predominantly in the anterior side or increased predominantly in the posterior side. Statistical analysis Each metabolite ratio, age of the participant and the results of the neuropsychological examinations were analysed using unpaired t-test or one-way ANOVA followed by post-hoc analysis with Bonferroni’s correction. In all analyses, Po0.05 was considered significant.
Results No significant differences were observed in the scores of MMSE (maximum score was 30) or total intelligence quotient (IQ) between the AD and FTD/Pick complex groups. The MMSE scores of the two groups were 15.476.6 and 20.774.8, and the total IQ scores were 79.7718.2 and 76.6716.3, respectively. Table 1 shows the metabolite ratios in the four VOIs of each group. The NAA/Cr ratios in the PC VOI of both the AD and FTD/Pick groups were lower than those of the controls. The NAA/Cr ratios in the AC and Fr VOIs were lower in the FTD/Pick group than those in the controls. In addition, the NAA/Cr ratio in the Fr VOI was lower in the FTD/Pick group than that in the AD group. The Cho/Cr ratio in the Fr VOI of the FTD/Pick group was lower than that in the controls. The mI/Cr ratios in the PC and Fr VOIs of the FTD/Pick group were higher than those of the controls, and the mI/Cr ratio in the Fr VOI was higher in FTD/Pick group than in the AD group.
Table 1 Metabolite ratios to Cr in four VOIs of the control and dementia groups Control
AD
FTD/Pick
NAA/Cr PC PO AC Fr
1.1470.07 1.2970.11 1.1270.08 1.3170.13
0.9770.06** 1.1470.14 1.0370.08 1.2870.19
0.9970.14** 1.1770.19 1.0070.13* 1.0070.28**, $
Cho/Cr PC PO AC Fr
0.1870.01 0.2770.04 0.2670.03 0.3370.04
0.1870.03 0.2470.03 0.2470.04 0.2970.06
0.1870.02 0.2570.03 0.2570.02 0.2670.04**
mI/Cr PC PO AC Fr
0.6970.06 0.7070.07 0.7470.08 0.7370.07
0.7270.09 0.7270.14 0.7170.12 0.7870.10
0.7970.21* 0.8270.16 0.8370.18 1.0170.31**, $
AD, Alzheimer’s disease, FTD/Pick, FTD/Pick complex; NAA, N-acetylaspartate; Cr, creatinine + phosphocreatinine; mI, myo-inositol; PC, posterior cingulate cortex; PO, parieto-occipital white matter; AC, anterior cingulate cortex; Fr, Frontal white matter; VOI, volume of interest. *Po0.05 to control; **Po0.005 to control; $Po0.05 to AD.
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NEUROREPORT
MRS OF AD AND FTD/PICKCOMPLEX
Table 2 Anterior/posterior ratio of the metabolites of the control and dementia groups (mean7SD)
A/PNAA A/PCho A/PmI
3
Control
AD
FTD/Pick
1.1570.12 1.8870.21 1.0770.15
1.3370.17 1.6170.21 1.0970.11
1.0170.23$$ 1.4970.35** 1.2970.24*
4 AD, Alzheimer disease; FTD/Pick, FTD/Pick complex; A/P, anterior/posterior ratio; NAA, N-acetylaspartate; mI, myo-inositol. *Po0.05 to control; **Po0.005 to control; $$Po0.005 to AD.
Discussion 2 1
4 2
3 1
Fig. 1 The location of the 4 volumes of interests (VOIs). The ¢gure indicates the location of the four 8 cm3 (2 cm 2 cm 2 cm) VOIs on theT1weighted image of an Alzheimer’s disease patient: (1) posterior cingulate cortex (PC VOI); (2) parieto-occipital VOI (PO VOI); (3) anterior cingulate VOI (AC VOI); (4) frontal VOI (Fr VOI).
Table 2 shows A/P[Met] in the controls and the patient groups. The AD group showed a higher A/P[NAA] ratio than the FTD/Pick group. The A/P[NAA] ratio of the AD group tended to be higher than that of the controls, although it was not statistically significant (P¼0.088). The FTD/Pick group showed a lower A/P[Cho] ratio and a higher A/P[mI] ratio than the controls.
Consistent with previous studies, our results showed a decreased NAA/Cr ratio in the posterior cingulate cortex in both the AD group [1–3,11] and the FTD/Pick group [11,13]. The anterior/posterior ratio, however, demonstrated a different distribution of the NAA/Cr ratio, that is, the A/ P[NAA] ratio in the AD group was relatively higher than that in the FTD/Pick group. As NAA exists almost exclusively in neurons [17] and the NAA/Cr ratio is considered to decrease following neuronal cell death or neuronal dysfunction, the different distributions of the NAA/Cr ratio were considered to reflect different distributions of degenerative processes in AD and the FTD/Pick complex. The results of previous positron emission tomography (PET) studies, which reported decreased glucose metabolism in the posterior cingulate cortex in early AD [18] and decreased glucose metabolism in the anterior cingulate cortex and the frontal lobe in FTD and PSP [19], were also in agreement with this hypothesis. Our results demonstrated that apart from the decreased NAA/Cr ratio, the increased mI/Cr ratio and decreased Cho/Cr ratio in the frontal lobe were also characteristic findings of the FTD/Pick group. The A/P ratio also showed different distributions of the mI/Cr and Cho/Cr ratios. The frontal dominant increase in the mI/Cr ratio and decrease in the Cho/Cr ratio in the FTD/Pick group may be useful in distinguishing between the AD and FTD/Pick groups. Although the precise role of mI is not clear, the increased mI/Cr ratio may reflect glial proliferation because mI is located mainly in the glial cells [20,21]. Previous pathological studies have reported that gliosis with neuronal cell loss was one of the major pathological changes in the FTD/ Pick complex [22], which further supports this inference. Increased mI/Cr ratio has been reported in AD [1–3]; however, our results could not demonstrate a significantly increased mI/Cr ratio. A limited number of participants and the selection of TR and TE in our study may partly explain this discrepancy [23]. The Cho peak detected by 1H-MRS includes free glycerophosphorylcholine and phosphocholine, which are highly concentrated in oligodendrocytes, and an increased Cho peak was observed in the activated turnover of the membrane [20]. The changes in the Cho/Cr ratio in dementia, as mentioned in previous studies, have been inconsistent [3]. It is possible that the decreased Cho/Cr ratio indicates an increased Cr concentration and/or a decreased Cho concentration. Although both neurons and glial cells contain Cr, its concentration is particularly higher in astrocytes [24]. Therefore, the frontal predominant decrease in the Cho/Cr ratio together with the increased mI/Cr ratio in the FTD/Pick complex might be partly explained by the glial proliferation without obvious
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NEUROREPORT demyelination, which is the characteristic pathology of the FTD/Pick complex [22]. 1 H-MRS at a higher magnetic strength field has a higher signal-to-noise ratio and improves spectral resolution. Some investigators have, however, mentioned that decreased transverse relaxation time and increased magnetic susceptibility may minimize advantages of a higher magnetic strength field [25]. Kentarci and colleagues [2] compared the diagnostic performances by 1H-MRS by using 1.5 and 3.0 T systems and demonstrated increased intersubject variability in the ratio of metabolites. Overall, our results demonstrated that our protocol, which included the A/P ratio, may be useful in detecting characteristic distributions of the metabolites in AD and the FTD/Pick complex. In this study, we measured four VOIs, and the total scan time was approximately 50 min. The total scan time, however, appears to be longer for patients with dementia. For clinical convenience, the total scan time of our protocol can be shortened to approximately 30 min by eliminating the measurement in the PO and AC VOIs. Further studies are necessary to evaluate the diagnostic accuracy and reliability of the shorter study protocol. Conclusion Using a 3.0 T MR system, we could detect disease-specific distributions of metabolite changes. These characteristic metabolic changes in each disease may represent the underlying pathological features of the disease. Our study included a limited number of patients. Further studies are necessary to evaluate the correlation between the MRS findings and the pathological changes. This standardized protocol of 1H-MRS with 3.0 T MR system is, however, expected to detect disease-specific metabolic markers and be useful for early differentiation of dementia subtypes, which may also contribute to earlier initiation of pharmacological therapies to patients with AD.
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Acknowledgements We thank the staff at the BF Research Institute, Department of Medical Informatics, Meiji University of Oriental Medicine, for data acquisition and analysis. We also thank staff at Osaka University Hospital and Department of Neurology, Osaka University Graduate school of Medicine, for providing clinical information on the patients.
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