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DOI: 10.1148/radiol.2443061128
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(Radiology 2007;244:832-837.)
© RSNA, 2007

Neuroradiology

Quantitative Magnetization Transfer Imaging in Alzheimer Disease1

Basil H. Ridha, MRCP, Daniel J. Tozer, PhD, Mark R. Symms, PhD, Katherine C. Stockton, MSc, Emma B. Lewis, PhD 2, Musib M. Siddique, PhD, David G. MacManus, MSc, Martin N. Rossor, MD, FRCP, Nick C. Fox, MD, FRCP, and Paul S. Tofts, DPhil

1 From the Dementia Research Centre (B.H.R., K.C.S., E.B.L., M.M.S., M.N.R., N.C.F.), NMR Research Unit (D.J.T., D.G.M., P.S.T.), and Department of Clinical and Experimental Epilepsy (M.R.S.), Institute of Neurology, University College London, 8-11 Queen Square, London, WC1N 3BG, England. Received June 29, 2006; revision requested August 31; revision received October 25; accepted November 22; final version accepted February 7, 2007. N.C.F. and M.N.R. supported by Alzheimer's Research Trust and Medical Research Council. D.J.T. supported by Multiple Sclerosis Society of Great Britain and Northern Ireland. Address correspondence to B.H.R. (e-mail: bridha{at}dementia.ion.ucl.ac.uk).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively measure magnetization transfer (MT) parameters, along with established atrophy parameters, in patients with Alzheimer disease (AD) and in age- and sex-matched control subjects.

Materials and Methods: Participants provided informed consent, and additional assent was obtained from next of kin of all patients with AD. The study was approved by the local ethics committee. Fourteen patients with AD (seven men; mean age, 67.2 years ± 6.5 [standard deviation]) and 14 control subjects (nine men; mean age, 65.5 years ± 9.4) underwent volumetric T1-weighted magnetic resonance and MT imaging. Whole-brain and total hippocampal volumes were adjusted for total intracranial volume. MT images were processed to derive four fundamental parameters in the hippocampal region by using the two-pool model of the MT phenomenon. Pearson correlation coefficients were used to assess the association between volumetric and MT parameters and Mini-Mental State Examination (MMSE) results. Logistic regression models were used to investigate whether combinations of parameters associated with MMSE could help provide better group discrimination.

Results: Patients with AD had significantly reduced whole-brain (P = .001) and total hippocampal (P < .001) volumes compared with those of control subjects. Two MT parameters were significantly reduced in the hippocampal region of patients: 1/(RAT2A)—that is, ratio of relaxation times of free proton pool, where RA equals 1/T1A and is the inverse of the longitudinal relaxation time of the free proton pool (P = .01)—and Formula , which equals fb/[RA(1 – fb)], where fb is the restricted proton fraction (P < .001). Among patients with AD, whole-brain volume and hippocampal Formula were correlated with MMSE results. When both parameters were included in a logistic regression model, only hippocampal Formula was significantly associated with case-control status (P = .03).

Conclusion: Certain MT parameters may serve as useful biomarkers of AD.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
At a microscopic level, Alzheimer disease (AD) is characterized by neuronal loss, gliosis, and deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles, which eventually lead to macroscopic atrophy. The pathologic process, particularly that involved in deposition of neurofibrillary tangles, typically affects medial temporal lobe structures before spreading to involve neocortical regions (1). The development of magnetic resonance (MR) imaging techniques sensitive to the characteristic pathologic features of AD would be helpful in the establishment of the diagnosis of AD and in the assessment of the effectiveness of disease-modifying agents.

Most MR imaging studies on AD have focused on the demonstration of atrophy of medial temporal lobe structures such as the hippocampus and entorhinal cortex, which reflects their early involvement, and whole-brain volume as a summation of global neurodegeneration (2–5). However, measurement of atrophy does not take into account the important microstructural alterations that accompany—and may well precede—volume loss. In addition, manual segmentation, particularly of medial temporal lobe structures, is labor intensive and subject to interrater variability.

Magnetization transfer (MT) imaging helps to investigate the relationship between free protons and those bound to macromolecular structures (6). MT parameters depend on the local chemical and biophysical environment of macromolecules and therefore may allow more accurate detection and quantification of histologic changes that occur as a result of the disease process.

MT ratio has been used as an overall measure of the MT phenomenon, and its value has been investigated in several neurologic diseases, including AD (7–10). However, MT ratio is a composite measure, which can be heavily imager and sequence dependent; this makes comparisons between studies difficult (11), although this difficulty can be reduced (12). Quantitative analysis of MT imaging results allows the derivation of more fundamental parameters of the MT phenomenon that reflect the intrinsic biophysical properties of brain tissue and are potentially independent of the details of the acquisition pulse sequence.

A two-pool mathematical model of the MT phenomenon initially proposed by Henkelman et al (13) and modified by Ramani et al (14) has been developed to derive several fundamental and quantitative parameters of the MT phenomenon. Results of application in patients with multiple sclerosis have revealed a decrease in the fraction of restricted protons (fb)—potentially those in macromolecules such as myelin—and an increase in the transverse relaxation time of the restricted protons (T2B) in multiple sclerotic lesions (15,16). These parameters may also prove to be sensitive markers of AD pathologic features. To our knowledge, the value of quantitative analysis of MT imaging results has not been assessed in AD. Thus, the purpose of our study was to prospectively measure MT parameters, along with established atrophy parameters, in patients with AD and in age- and sex-matched control subjects.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Patients and Control Subjects
From August 2003 to April 2004, 14 consecutive patients with AD (seven men; mean age, 67.2 years ± 6.5 [standard deviation]) and 14 healthy control subjects (nine men; mean age, 65.5 years ± 9.4) were recruited into the study. All patients met the diagnostic criteria for probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association criteria (17). Neurologically healthy spouses or friends of patients were asked to participate as control subjects. The study was approved by the local ethics committee. All participants signed an informed consent form, and additional assent was obtained from next of kin of all patients with AD. The Mini-Mental State Examination (MMSE) (18) was performed in all participants as a global bedside measure of their cognitive function.

MR Imaging Protocol
Imaging was performed with a 1.5-T unit (Signa; GE Medical Systems, Waukesha, Wis) with software (Horizon, version 5.8; GE Medical Systems). Volumetric T1-weighted coronal MR images were obtained by using a three-dimensional inversion-recovery prepared fast spoiled gradient-echo technique (frequency- and phase-encoding matrix, 256 x 256; field of view, 24 x 18 cm; repetition time msec/echo time msec/inversion time msec, 14/5.4/650; flip angle, 15°; number of signals acquired, one; section thickness, 1.5 mm), which yielded 124 contiguous sections.

For MT imaging, a two-dimensional spoiled gradient-echo sequence was performed (frequency- and phase-encoding matrix, 128 x 256 [reconstructed as 256 x 256]; field of view, 24 x 24 cm; 1140/12; flip angle, 25°; number of signals acquired, 0.75 [ie, partial filling of k-space]; section thickness, 5 mm). Ten separate data sets were acquired at differing MT pulse offset frequencies and amplitudes, which resulted in 10 MT weightings (D.G.M., 8 years of experience) (Table 1). Twenty-eight contiguous transverse sections, which resulted in whole-brain coverage, were acquired. The entire MT data set was acquired in approximately 15 minutes. To minimize examination time, T1 maps were not acquired.


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  		Table 1. Flip Angle, Amplitude, and Offset Frequency of MT Pulse Sequences

 
Volumetric MR Image Analysis
Volumetric T1-weighted MR images were transferred to workstations (Sun Microsystems, Mountain View, Calif) and were analyzed by using the Medical Image Display and Analysis System (19). Images were presented to the rater (K.C.S.) in random order, and all analyses were performed with the rater blinded to participant details. The brain was first "extracted" from skull, scalp, and other soft tissue by using a semiautomated iterative morphologic technique. The brain volume of interest was then checked and manually edited where necessary to obtain a whole-brain volume (K.C.S., 2 years of experience) (19).

Total intracranial volume was calculated according to a previously described protocol (K.C.S.) (20). This was used to normalize brain volume for differences in head size between individuals (21). Whole-brain volumes were standardized to the mean total intracranial volume of the control subjects. The standardization was performed by using the slope of the relationship between whole-brain volume and total intracranial volume estimated from a linear regression model that related whole-brain volume to total intracranial volume, with both variables on logarithmic scales.

For hippocampal volume measurements, all images were first registered to a standard brain template by using a six-degrees-of-freedom algorithm to reduce any variability in landmarks used in delineating the hippocampus (22). Each hippocampus was manually traced by using multiple views to include the cornu ammonis, gyrus dentatus, and subiculum (B.H.R., 4 years of experience) (23). Total (right plus left) hippocampal volumes were calculated and adjusted to the mean total intracranial volume of the control subjects (24). The standardization was similar to whole-brain volume adjustment as described above.

Quantitative Analysis of MT Images
The second and subsequent MT-weighted data sets were registered to the first one by using a mutual information algorithm (25). Volumes of interest were outlined in the left (mean volume, 3.2 mL; range, 1.0–7.6 mL) and right (mean volume, 3.1 mL; range, 1.1–7.9 mL) hippocampal regions and in parietal white matter (mean volume, 3.2 mL; range, 1.6–6.1 mL) as a control region in the transverse plane of the first MT data set (B.H.R.) (Fig 1). These volumes of interest were copied onto the other nine coregistered MT data sets.


Figure 1
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  		Figure 1: Left and right hippocampal regions outlined in transverse plane of first MT data set generated by using two-dimensional spoiled gradient-echo sequence (1140/12; flip angle, 25°; amplitude, 185 radian·sec–1; flip angle, 212°; offset frequency, 1000 Hz) in patient with AD.

 
The modified two-pool model was fitted to the data with a super-Lorentzian line shape for the restricted protons (D.J.T., 4 years of experience) (15,26,27). Four MT parameters were derived.

1. Formula , where g is an imager-dependent scaling factor and Formula is the magnetization of the free proton pool, was derived.

2. 1/(RAT2A), which is the ratio of the relaxation time of the free proton pool and RA, which equals 1/T1A and is the inverse of the longitudinal relaxation time of the free proton pool, was derived.

3. Formula , in seconds, which equals fb/[RA(1 – fb)], where fb is the restricted proton fraction, defined as Formula /[( Formula + Formula )] ( Formula is the magnetization of the restricted proton pool), was derived. We have introduced this new parameter, Formula , for convenience. In a situation where RA hardly varies and fb is less than 1, Formula is linearly related to fb.

4. T2B, the transverse relaxation time of the restricted proton pool in microseconds, was derived.

The mean value of each MT parameter was calculated in each volume of interest. Whole-brain maps of MT parameters were not calculated because of a problem with the pulse sequence (27). Although the signal loss due to this error was recoverable, the signal-to-noise ratio was not considered high enough to enable us to perform pixel-by-pixel investigations.

Statistical Analysis
Demographic, clinical, and imaging data of patients with AD and control subjects were compared by using the two-sample t test, except for sex comparisons, for which the Fisher exact test was used. Pearson correlation coefficients (r values) were used to investigate the association between MMSE results and the various volumetric and MT parameters among patients with AD. Logistic regression models were used to investigate whether combinations of parameters associated with the MMSE could help provide better discrimination between patient and control groups. A P value of less than .05 was considered to indicate a significant difference. Software (SPSS, version 11.5, 2002; SPSS, Chicago, Ill) was used to calculate mean MT values in the volumes of interest. The rest of the analysis was performed by using a different software (Intercooled, version 8, 2003; Stata, College Station, Tex).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Demographic and Clinical Data
Patients with AD and control subjects were matched for age (P = .56) and sex (P = .70). Patients had significantly lower MMSE scores than did control subjects (P < .001) (Table 2).


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  		Table 2. Demographic, Clinical, and Imaging Data

 
Volumetric MR and MT Imaging Data
Patients had significantly reduced mean adjusted whole-brain volume (1030 mL ± 84 vs 1139 mL ± 63, P = .001) and total hippocampal volume (4.22 mL ± 0.76 vs 5.76 mL ± 0.42, P < .001) compared with those of control subjects (Table 2).

There were no significant differences between corresponding left and right MT parameters in the regions of the hippocampus or parietal white matter (all P values > .05). For simplicity, for each MT parameter, the mean of the left and right MT values was calculated for hippocampal and parietal white matter regions. Patients with AD had significantly lower mean 1/RAT2A (16.9 ± 6.9 vs 23.0 ± 4.6, P = .01) and Formula (0.030 second ± 0.003 vs 0.039 second ± 0.004, P < .001) in the hippocampal region, but not in parietal white matter (both P values > .05). There were no significant differences between the two groups in Formula or T2B parameters (all P values > .05) (Table 2).

Only adjusted whole-brain volume (Fig 2) and hippocampal Formula were significantly correlated with MMSE scores among patients with AD (r = 0.52, P = .05 and r = 0.55, P = .04, respectively). Therefore, both whole-brain volume and hippocampal Formula were included in a logistic regression model with case-control status (0 = patient with AD, 1 = control subject). The model showed that hippocampal Formula was independently significantly associated with case-control status (P = .03), whereas whole-brain volume was not (P = .42). This suggests that measurement by using the combination of brain volume and hippocampal Formula is no better than measurement by using hippocampal Formula alone in the differentiation of patients with AD from control subjects.


Figure 2A
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  		Figure 2a: Scatterplots of relationship between MMSE scores and (a) adjusted brain volume and (b) mean hippocampal fb among patients with AD and control subjects.

 

Figure 2B
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  		Figure 2b: Scatterplots of relationship between MMSE scores and (a) adjusted brain volume and (b) mean hippocampal fb among patients with AD and control subjects.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
To our knowledge, our study represents the first application of quantitative analysis of MT imaging results in AD; MT imaging is a technique that could reflect the microstructural changes that accompany the pathologic process in AD. The analysis was based on a mathematical model of two pools of protons: those in free water, such as those present in the interstitial or intracellular fluid, and those restricted within macromolecular structures—typically, phospholipid bilayers forming cell membranes and intracellular organelles.

The parameter Formula was reduced in the hippocampal regions of patients with AD compared with that in control subjects. This could have two possible origins: (a) a decrease in fb, the fraction of the restricted proton pool, or (b) an increase in RA, the inverse of longitudinal relaxation time of the free proton (T1A), which corresponds to a decrease in T1A. Although T1, which could then be related to RA (which equals 1/T1A) (26), was not directly measured, it is unlikely to decrease because it has been shown to increase with worsening dementia severity (27,28). Thus, an increase in RA is unlikely. Not acquiring T1 maps was a limitation of this study because the effects of fb and T1A cannot be separated in the Formula parameter. However, it seems reasonable that fb should be reduced because of either a reduction in the number of restricted protons due to microstructural destruction or an increase in free water due to gliosis.

The parameter 1/(RAT2A), the ratio of relaxation time of the free proton pool, was also decreased in the hippocampal regions of patients with AD compared with that in control subjects. Because RA (which equals 1/T1A) is unlikely to increase, this parameter is assumed to represent an increase in the transverse relaxation time of free protons (T2A), which suggests a further increase in the freedom of motion within the free proton pool. A limited number of studies on T2 relaxometry have to date provided conflicting results on whether T2 increases (29,30), decreases (31), or remains unchanged (32) in the hippocampal region of patients with AD. Direct measurements of T1 and T2, in addition to MT parameters, are needed to explain this finding. However, the lack of association of hippocampal 1/(RAT2A) with MMSE results suggests that it may be a weaker biomarker of AD progression than Formula .

There was a nonsignificant trend for mean hippocampal T2B to be increased among patients with AD compared with control subjects. Results of a previous study (15) found T2B to be significantly increased in multiple sclerotic lesions. Further studies with larger subject groups are required to assess whether the observed trend becomes significant. If shown to be significant, this finding could reflect tissue disintegration within the restricted proton pool, which results in increased freedom of motion.

The significant differences found in MT parameters in the hippocampal region were not found in parietal white matter, which was used here as a control region for comparison. Because AD pathologic progression typically affects the hippocampus and then spreads to other cortical regions, the regional differences may reflect the differential involvement of hippocampal and parietal white matter in AD pathologic progression. Further studies are required to confirm this finding, because white matter is known to be eventually involved in AD, probably as a result of wallerian degeneration of axons from dying cortical neurons (33).

Total hippocampal and whole-brain volumes were significantly reduced among patients with AD compared with control subjects. However, total hippocampal volume was not significantly associated with MMSE scores, whereas whole-brain volume was. Hippocampal volume measurement is more labor intensive and more subject to interrater variability than whole-brain volume measurement. The lack of association between total hippocampal volume and MMSE scores may reflect extensive functional damage to the hippocampus, a structure primarily involved with day-to-day memory, by the time AD is established clinically. On the other hand, whole-brain volume may represent global reserve for remaining cognitive function, as measured with the MMSE, in the moderate stages of the disease.

Results of previous studies (5) have shown that the rate of whole-brain atrophy was significantly increased in AD, which makes it an objective tool for tracking disease progression in longitudinal studies. It remains to be tested whether rates of change in MT parameters would prove to be sensitive biomarkers of AD disease progression. Results of our cross-sectional pilot study found the measurement of the MT parameter Formula in the hippocampal region to be at least as good as whole-brain volume measurement in the display of correlation with MMSE results among patients with AD and in the differentiation of patient and control groups.

There were limitations to our study. The sample sizes were small, and no histologic confirmation was available. T1 maps were not acquired because of time limitations, so we can only hypothesize as to what underlies the reduction in mean hippocampal Formula and 1/(RAT2A). In addition, calculation of MT parameters was restricted to volume-of-interest analysis because whole-brain maps of MT parameters could not be reliably calculated.

Results of our pilot study in patients with clinically established AD suggest that measurement of certain quantitative parameters of MT imaging may serve as potential biomarkers of the disease. Larger studies are needed to confirm our findings in AD and for comparison with other dementias. In our opinion, application of serial quantitative MT imaging to patient groups with early AD and mild cognitive impairment seems warranted.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
We thank Riitta Kukkastenvehmas, MSc, and Philippa Bartlett, DCR (R), for their help with this study. We thank Chris Frost, MA, for valuable statistical advice. We particularly thank the patients and their caretakers who participated in this study.


   FOOTNOTES
 

Abbreviations: AD = Alzheimer disease • MMSE = Mini-Mental State Examination • MT = magnetization transfer

2 Current address: University of Surrey, Guildford, England. Back

Authors stated no financial relationship to disclose.

Author contributions:Guarantors of integrity of entire study, B.H.R., P.S.T.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, B.H.R., M.R.S., P.S.T.; clinical studies, M.R.S., E.B.L., D.G.M.; statistical analysis, B.H.R., D.J.T., P.S.T.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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