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Neuroradiology |
1 From the Departments of Diagnostic Radiology (K.K., C.R.J., Y.C.X., N.G.C.), Health Sciences Research (P.C.O., R.C.P.), Psychiatry and Psychology (G.E.S., R.J.I.), Neurology (B.F.B., E.K., R.C.P.), and Internal Medicine (E.G.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905. Received May 31, 2000; revision requested July 10; revision received August 11; accepted August 31. Supported by National Institutes of Health and National Institute on Aging grants AG11378, AG06786, and AG16574, and the Alzheimer’s Association. Address correspondence to C.R.J. (e-mail: jack.clifford@mayo.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Magnetic resonance images were obtained in 21 patients with Alzheimer disease, 19 patients with MCI, and 55 normally aging elderly control subjects without evidence of cognitive impairment. Regions of interest were drawn to compare the apparent diffusion coefficient (ADC) and the anisotropy index (AI) in frontal, parietal, temporal, occipital, anterior, and posterior cingulate white matter (WM), and the thalami and hippocampi.
RESULTS: Hippocampal ADC was higher in MCI and Alzheimer disease patients than in control subjects. ADC of the temporal stem and posterior cingulate, occipital, and parietal WM was higher in Alzheimer disease patients than in control subjects. Except for occipital AI, which was lower in MCI patients than in control subjects, there were no differences in AI among the three groups for any of the regions.
CONCLUSION: Hippocampal ADC was significantly different between control subjects and MCI patients, many of whom likely have preclinical Alzheimer disease. Elevation in hippocampal ADC may reflect early ultrastructural changes in the progression of Alzheimer disease.
Index terms: Alzheimer disease, 10.83, 1341.83 • Brain, MR, 13.121412, 13.121413, 13.121416, 13.12146 • Hippocampus, 1341.83 • Magnetic resonance (MR), diffusion study, 13.121412, 13.121413, 13.121416, 13.12146, 13.92 • Magnetic resonance (MR), tissue characterization, 13.121412, 13.121413, 13.121416, 13.12146, 13.92
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Pathologic changes in the cortical gray matter of the brain in Alzheimer disease are characterized by the accumulation of neurofibrillary tangles and senile plaques along with neuronal and synaptic loss that produce cerebral atrophy. The initial pathologic involvement has been shown to occur in the medial temporal lobes, and MR imaging–guided volumetry has depicted the early atrophy of the hippocampi in patients with mild Alzheimer disease (4,5). Besides the pathologic cortical conditions, white matter (WM) rarefaction with axonal damage and gliosis have been reported in patients with Alzheimer disease (6). With diffusion-weighted MR imaging, it is possible to quantify physiologic alterations in water diffusion resulting from microscopic structural changes that are not detectable with anatomic imaging.
The syndrome of mild cognitive impairment (MCI) resides within the cognitive continuum from normal aging to Alzheimer disease. MCI patients have a substantially higher rate of progression to Alzheimer disease (12%–15% per year) compared with cognitively normal elderly people (1%–2% per year) (7). Clinical criteria for the diagnosis of MCI have been established, and these patients are the primary study group in several national trials (7–9). Findings at diffusion-weighted MR imaging in the brains of patients with Alzheimer disease have been studied (10–12). We are not aware, however, of studies addressing the findings at diffusion-weighted MR imaging in patients with MCI.
In this study, we hypothesized that the magnitude of water diffusion measured with apparent diffusion coefficient (ADC) and the directionality of diffusion measured with the anisotropy index (AI) may be altered by the early ultrastructural changes caused by the pathologic process of Alzheimer disease. The purpose of this study was to characterize and compare the regional diffusivity of water in normally aging elderly people and patients with MCI or Alzheimer disease at different points along the cognitive continuum from normal aging to Alzheimer disease.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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3/4 and 4/4) were grouped as 4 carriers, and those with the genotypes 2/3 and 3/3 were grouped as 4 noncarriers. Subjects with the genotype 2/4 were not included in APOE analyses. Patients with MCI met the following criteria: (a) memory complaint, (b) normal general cognition, (c) normal activities of daily living, and (d) not demented (7). These patients had a Clinical Dementia Rating score of 0.5 with isolated memory impairment without deficits in other cognitive domains. This diagnosis of MCI represents a clinical judgment and is not based solely on fixed cutoff scores of psychometric tests.
Controls were defined as individuals who (a) were independently functioning community dwellers, (b) did not have active neurologic or psychiatric conditions, (c) had no cognitive complaints, (d) had a normal neurologic examination, and (e) were not taking any psychoactive medications in doses that would effect cognition.
MR Imaging and Diffusion-weighted Imaging
MR imaging and diffusion-weighted imaging studies were performed with a 1.5-T MR imager (Signa; GE Medical Systems, Milwaukee, Wis). After sagittal scout imaging, coronal T1-weighted images were obtained to be used as an anatomic reference for the placement of the regions of interest (ROIs). Special attention was paid to the symmetric positioning of the patient’s head. Single-shot, echo-planar, fluid-attenuated inversion recovery (FLAIR) diffusion-weighted MR imaging was performed in a coronal plane with repetition time msec/echo time msec/inversion time msec of 9,999/93/2,200, section thickness of 5 mm, section spacing of 2.5 mm, and field of view of 40 x 20 cm to cover the whole head. FLAIR imaging with constant magnetic induction field, or B0, of 0 sec/mm2 and diffusion-weighted MR imaging with B0 of 1,000 sec/mm2 in three orthogonal directions were performed in each section. With image analysis software (FUNCTOOL; GE Medical Systems), average ADC maps were computed pixel by pixel on the basis of the equation by Stejskal and Tanner (1).
Elliptic ROIs of 12–30 pixels (29.3–73.2 mm2) that concurrently appeared on the ADC maps were drawn on the FLAIR images (Fig 1). Eight pairs of ROIs were placed in each subject over the WM of the right and left frontal lobes, parietal lobes, occipital lobes, medial temporal lobes (temporal stem), anterior and posterior cingulate gyri, thalami, and hippocampi by the same investigator (K.K.), who was blinded to the clinical diagnoses of the subjects (Figs 1, 2).
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The temporal stem is defined as the WM connection between the temporal lobe and the frontal and parietal lobes (19). Because of the low spatial resolution of the FLAIR images, coronal T1-weighted images obtained with identical thickness and location were used as an anatomic reference for the placement and tracing of the ROI (Fig 1). AIs were calculated for every WM ROI: AI = ADCmax - ADCmin/ADCaverage (20).
Statistical Analyses
In the three clinical groups, differences in the mean ages, education (in years), and the MMSE scores were tested with rank sum tests, and sex differences were tested with 
2 tests. Differences in ADC and AI in the right and left hemispheres were tested with signed rank tests. The effects of age and sex on ADC and AI were tested in a single model by means of multiple regression analysis in controls only, as the data in controls should be free of the confounding effects of disease. The differences in the ADC and AI of the APOE 4 carriers and noncarriers were tested with rank sum tests in the three clinical groups independently. Between-group differences in ADC and AI were tested by means of multiple regression analysis. Differences with a P value less than .05 were considered significant. The sensitivity and specificity of diffusion-weighted MR imaging in distinguishing Alzheimer disease and MCI patients from controls were calculated at a fixed specificity of 80%.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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4 carrier-to-noncarrier ratios were higher in Alzheimer disease patients than in controls (P = .001) and higher in MCI patients than in controls (P = .004). The APOE 4 carrier-to-noncarrier ratios of MCI and Alzheimer disease patients were not different (P > .05). There was no correlation between the APOE genotype and ADC or AI in any of the ROIs in each clinical group. Except for higher right than left thalamic ADC (P = .001), we did not find any difference between ADC in ROIs from the right and left hemispheres in controls. Owing to this difference, right and left thalamic ADC were analyzed separately for all three clinical groups, and the homologous hemisphere values were combined for the remaining ROIs. We tested for the effects of age on ADC and AI in controls, and there was no association between age and ADC or AI in any of the ROIs (P > .05).
The mean plus or minus one SD for ADC obtained in each of the eight ROIs in controls and MCI or Alzheimer disease patients and the differences between the ADC of the three clinical groups are presented in Table 2. The only measurement that differed between controls and MCI patients was the hippocampal ADC, which was higher in MCI patients than in controls (P = .016) and was similar to that in Alzheimer disease patients. Although a similar trend was seen in the ADC from other ROIs, we did not find any difference between the ADC of MCI patients and controls in the remaining ROIs (P > .05). ADC was higher in Alzheimer disease patients than controls in the temporal stem (P = .014), occipital (P = .047), parietal (P = .004), and posterior cingulate WM (P = .001), and hippocampal (P = .001) ROIs (Table 2) (Fig 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In this study, the magnitude of water diffusion within the temporal stem, occipital, posterior cingulate, and parietal WM ROIs was greater in patients with Alzheimer disease than in controls and MCI patients. Our findings are in agreement with those in prior studies that revealed higher ADC in the temporal stem and parietal WM in Alzheimer disease patients compared with controls (11,12). The posterior cingulate gyrus is a part of the limbic system and is known to be involved early in the pathologic progression of Alzheimer disease, as has been demonstrated with functional imaging studies. Positron emission tomography, or PET (21,22), and single photon emission computed tomography, or SPECT (23), revealed decreased glucose metabolism and blood flow in the posterior cingulate gyrus and pericingular parietal cortex in preclinical Alzheimer disease patients and patients at risk for developing Alzheimer disease in comparison with normally aging elderly people.
With proton MR spectroscopy, an elevation in the myoinositol-to-creatine ratio has been identified in the posterior cingulate gyri in both patients with MCI and Alzheimer disease in comparison with elderly controls (24). The temporal stem serves as a conduit for temporal-to-extratemporal WM tracts within which the spatial orientation of the fibers are generally uniform. It was previously postulated that this increase in ADC reflects decreased fiber density, including the disruption and loss of axonal membranes or myelin (12).
Correlation of MR imaging findings with pathologic WM conditions in Alzheimer disease indicates that areas of periventricular hyperintensity are often related to the loss of myelinated axons and gliosis in the deep WM (25). WM rarefaction is associated with vascular risk factors, especially hypertension. Independent of periventricular changes, WM degeneration of secondary or Wallerian type has been identified to correlate with pathologic subjacent cortical conditions in Alzheimer disease (6,26). Findings in these studies suggest that two independent forms of WM degeneration may coexist in Alzheimer disease patients: periventricular WM disease, which is usually evident at MR imaging and is presumably vascular or ischemic in origin, and Wallerian type WM degeneration secondary to pathologic adjacent cortical neurodegenerative conditions. The WM regions we studied did not include areas of periventricular hyperintensity on FLAIR images. In light of the previous studies of the pathologic WM conditions in Alzheimer disease, the finding of increased diffusivity of water in the temporal stem and posterior cingulate, occipital, and parietal WM in Alzheimer disease patients suggests rarefaction of axons and myelin and can be explained on the basis of anterograde Wallerian degeneration.
A decrease in anisotropy in the temporal stem and parietal WM of Alzheimer disease patients has been reported (10–12). It was postulated that the decrease in anisotropy reflects decreased fiber density including loss of axonal membranes or myelin (12). Except for lower occipital AI in MCI patients than in controls, our data did not reveal any other differences in AI among controls and MCI or Alzheimer disease patients. This discrepancy may be related to a technical limitation in diffusion-weighted MR imaging that was also encountered by the previous investigators (11). Because AI is a measure of directionality of diffusion, it is highly sensitive to the variable orientation of the head with respect to the fixed geometry of the MR imaging system gradients.
In this study, the diffusion gradients were applied in the three logical orthogonal planes, which would cause a high degree of variability if all the subjects’ heads were not the same size and oriented the same way. This was apparent in our data as high variance in AI, which may be the reason we did not find a difference between the Alzheimer disease patients and controls, as reported by other groups (11,12). We calculated AI on the basis of only the trace of the diffusion tensor. Solving the entire tensor with rotationally invariant techniques and application of a higher number of diffusion gradients would overcome this problem (27).
In the controls, the ADC from the medial dorsal nuclei of thalami were higher on the right than the left side. This difference was not present in MCI or Alzheimer disease patients. There was however a trend of increased ADC in the left thalami of Alzheimer disease and MCI patients compared with controls that was not significant. Although such a difference has not been reported before, to our knowledge, our data from 53 normally aging elderly people is one of the largest series in the literature. Our data imply that a side-to-side structural difference normally exists, that is, the neurons and glial cells may be more densely packed in the medial dorsal nuclei of the left compared with the right thalami, so that the extracellular space is narrower and the diffusivity is less. However, we are not aware of any histologic studies that would support this idea.
Mean ADC was nearly always higher in MCI patients than in controls and lower than Alzheimer disease patients. However, only in the hippocampus did this trend reach significance. On the basis of prior longitudinal clinical studies, patients with MCI progress to Alzheimer disease at a rate of 12% per year (7). We can be fairly certain that a majority of our MCI patients had preclinical Alzheimer disease, but a smaller proportion with isolated memory problems may never progress to Alzheimer disease in their lifetime. Involvement of the hippocampus occurs very early during the pathologic progression of Alzheimer disease (4). Synapse and neuron loss, which coexist with pathologic neurofibrillary conditions, is present in the hippocampi of patients with preclinical Alzheimer disease who have isolated memory problems as in MCI (28–30). The increased diffusivity in the hippocampi of both MCI and Alzheimer disease patients is in agreement with the pathologic evolution of Alzheimer disease. It suggests expansion of the extracellular space owing to neuron loss. In addition, glial activation associated with neuritic senile plaques would also contribute to elevated ADC by producing an expansion of the extracellular space (31).
Diffusion of water in the hippocampi of Alzheimer disease patients has also been studied by other groups. One recent study showed higher ADC in the hippocampi of Alzheimer disease patients than in controls (11). Another study did not identify any difference between the hippocampal ADC of normally aging elderly people and Alzheimer disease patients (12). In both of these studies, however, the hippocampi were not traced to exclude the contributions from the cerebrospinal fluid but rather an ROI was placed over the hippocampi. Cerebrospinal fluid may contribute to ADC measurements: A previous study revealed higher ADC values from the cortical gray matter with a spin-echo diffusion sequence compared with an inversion-recovery diffusion sequence owing to contamination with the cerebrospinal fluid signal (32). Suppression of cerebrospinal fluid would be especially important in patients with Alzheimer disease, in whom the hippocampi are atrophic and partial volume averaging of cerebrospinal fluid may be present when relatively thick sections were used, as in diffusion-weighted MR imaging. Therefore, we used an echo-planar FLAIR pulse sequence for diffusion-weighted MR imaging to avoid contributions from the cerebrospinal fluid. Cerebrospinal fluid was not suppressed in the previous studies (11,12), which may be a reason for discrepant findings.
These data indicate that diffusion-weighted MR imaging may help identify early ultrastructural changes in the progression of Alzheimer disease. At our center, the accuracy for the clinical diagnosis of Alzheimer disease compared with the pathologic diagnosis is 81%. Furthermore, owing to the high degree of overlap between the ADC values of the three groups and low sensitivity in distinguishing Alzheimer disease and MCI patients from controls, our findings suggest limited value for clinical diagnosis in individual patients. However, measurements of ADC may be valuable in instances where group effects are of interest, such as drug trials. With longitudinal follow-up of MCI patients, we will be able to determine whether there is a correlation between the hippocampal ADC and the rate of progression to Alzheimer disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: ADC = apparent diffusion coefficient, FLAIR = fluid-attenuated inversion recovery, MCI = mild cognitive impairment, MMSE = Mini Mental State Examination, ROI = region of interest, WM = white matter
Author contributions: Guarantors of integrity of entire study, K.K., C.R.J.; study concepts and design, K.K., C.R.J.; literature research, K.K.; clinical studies, K.K., C.R.J., P.C.O., G.E.S., R.J.I., B.F.B., E.K., E.G.T., R.C.P.; data acquisition, K.K.; data analysis/interpretation, K.K., C.R.J., P.C.O.; statistical analysis, P.C.O., K.K.; manuscript preparation, K.K.; manuscript definition of intellectual content, K.K., C.R.J.; manuscript editing, K.K.; manuscript revision/review, K.K., C.R.J.; manuscript final version approval, all authors.
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