Dr. Benzinger is currently a fourth-year Radiology Resident at the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO. She earned a bachelor's degree from Williams College and her MD and PhD degrees from the University of Chicago-Pritzker School of Medicine, Chicago, IL. After completing her residency, she will begin a Neuroradiology Fellowship at the Mallinckrodt Institute of Radiology.

Alzheimer's disease (AD) is an irreversible dementia of the elderly that has an insidious onset but eventually leads to severe debilitation and death. It currently affects more than 4 million people in the United States, and it is estimated that 14 million Americans will be afflicted by the year 2050. ^1,2 Given the aging population in the United States, the National Institutes of Health have designated research in AD to be an urgent priority. ¹ As new therapies for early intervention in AD become available, such as the vaccine trials currently under way, ³ the need for accurate, early diagnostic tools and the ability to assess response to therapy will become imperative. Radiologic imaging potentially holds the key to providing accurate, early diagnosis of this devastating disease. An overview of current routine, specialized, and research protocols for the imaging of AD is provided in Table 1.

Imaging of dementia: Conventional computed tomography and magnetic resonance imaging

Current recommendations from the American Academy of Neurology for the evaluation of patients with suspected AD call for a complete neurological assessment plus a computed tomographic (CT) or magnetic resonance imaging (MRI) scan. ² The current role of imaging is to exclude other causes of dementia, such as multiple infarctions (the second most common form of dementia), brain tumors, head trauma (acute, subacute, or chronic), normal pressure hydrocephalus, prion diseases, or inflammatory diseases (such as human immunodeficiency virus [HIV] encephalitis). The finding of diffuse atrophy, with enlargement of the ventricles and sulci, is suggestive of AD; however, this pattern of atrophy can also be seen in normal aging. In contrast, basal ganglia or thalamic strokes can lead to focal cortical atrophy. Atrophy limited to the frontal and temporal cortex is often found in frontotemporal dementia. Other diseases that may be identified at MRI, based upon the topological distribution of atrophy, include Pick's atrophy, corticobasal degeneration, Huntington's disease, and multisystem degeneration. ⁴

Periventricular white matter disease is another finding commonly seen in AD. It is manifested by decreased attenuation on CT and more readily by increased signal intensity on T2-weighted MRI. However, periventricular white matter disease may result from chronic microinfarctions and can be seen in patients with and without AD. ⁵

Most MRI protocols for initial evaluation of dementia also include diffusion-weighted imaging (DWI) sequences. There are no findings specific for AD on conventional DWI. However, DWI is helpful in the evaluation of stroke as a cause of the patient's dementia and to establish its chronicity. DWI is also helpful in exclusion of rare causes of dementia such as Cruetzfeldt-Jakob disease (CJD), a prion disease. In CJD, patients may present with increased signal on DWI in the basal ganglia and thalami (Figure 1). ^6-9 Conventional CT and MRI, even with the inclusion of DWI, currently offer little information specific to diagnosing AD, nor do they offer any prognostic information.

Specialized clinical imaging protocols

Nuclear medicine offers 2 examinations, single-photon-emission CT (SPECT) and positron emission tomography (PET), which may be useful in the diagnosis of AD. SPECT and PET can be used to evaluate global and regional metabolic and blood flow abnormalities. Specifically, patients with AD show symmetric, bilateral hypometabolism in the temporal and parietal lobes. ¹⁰ In contrast, multi-infarct dementia shows asymmetric, focal abnormalities, and frontal and temporal lobe dementias show hypometabolism limited to those lobes. ¹⁰ PET allows higher resolution and greater sensitivity than SPECT, whereas SPECT is more commonly available. A recently published meta-analysis of PET in AD found an overall sensitivity of 86% and a specificity of 86%, but suggested that clear parameters including patient selection, threshold values, and correlations with cognitive impairment must be established before PET can be routinely used in the evaluation of AD. ¹⁰ However, in cases in which early diagnosis of AD is critical (such as in trials for early administration of investigational therapeutics) or in cases in which the differential diagnosis is difficult, PET can be combined with careful clinical examination to improve diagnostic certainty. ⁵

Similarly, perfusion MR can be used to show areas of decreased cerebral blood flow and cerebral blood volume. Compared with SPECT, perfusion MR allows superior spatial resolution for distinguishing between multi-infarct dementia, which has multifocal, subcortical decreases in cerebral blood flow, and AD, which has generalized cortical decreases in cerebral blood flow. ¹¹ Perfusion MR has been found to show localized findings of decreased cerebral blood volume in the temporoparietal lobes with 90% sensitivity and 87% specificity in patients who have AD. ¹² More recent research using a transgenic mouse model of AD suggests that regional decreases in cerebral blood volume in the hippocampus, thalamus, and temporoparietal cortex may occur prior to the development of any neurological dysfunction or histopathologic evidence of AD. ¹³ However, like PET and SPECT, the clinical utility of perfusion MR in the diagnosis of AD is still undergoing evaluation and is currently limited to special cases.

Volumetric analysis has undergone more thorough evaluation than any other imaging technique in AD. Both CT and MRI, as well as autopsy correlation, show global atrophy in patients with AD. For a single patient, the amount of atrophy has not been shown to correlate with clinical dys-function. ¹⁴ However, in longitudinal studies, patients with AD have a higher rate of global atrophy than do age-matched controls. ¹⁵

MRI offers superior contrast resolution and, in some cases, higher spatial resolution than does CT and can be used to perform volumetric analysis of brain subregions. Temporal lobe structures are found to be more atrophic in patients with AD than in age-matched controls, with specific involvement of the hippocampus and entorhinal cortex early in AD. ^16-20 Multiple studies have reported that volumetric atrophy of the hippocampus is a sensitive indicator of AD. ^19,21-26 However, these examinations are limited in specificity, partly due to limitations in the ability to discriminate microstructural elements. Also, they have been difficult to correlate between centers and, despite the high sensitivity, have not become part of the routine MRI for dementia. However, Adachi and colleagues ²⁷ have recently developed a DWI approach to evaluate the hippocampus that very closely parallels the histopathologic findings at autopsy (Figure 2). ²⁷

The addition of DWI to clinical MRI has transformed the clinical evaluation of stroke, of which multi-infarct dementia is a part. The role of DWI in stroke is beyond the scope of this paper and has been extensively reviewed elsewhere. ^28,29 In the case of AD, DWI allows for improved MR contrast within the hippocampus (Figure 2).

Investigational imaging in dementia: Diffusion tensor magnetic resonance

Diffusion tensor imaging allows for quantitative evaluation of the rate and direction of water motion (Figure 3). The axonal organization of white matter tracts in the brain is such that water motion is limited in directions perpendicular to the axons. The rate of diffusion, or diffusivity, is measured by the apparent diffusion coefficient (ADC) (related to the "trace" image on clinical scanners). Directionality is measured by relative or fractional anisotropy (FA). The diffusion tensor is a mathematical model of diffusion in 3-dimensional (3D) space, where anisotropy is used to represent the shape of the tensor ellipsoid. To obtain this 3D information, we must apply diffusion gradients in a minimum of 6 directions (6 b -values). Measurements of anisotropy in individual voxels can be grouped to obtain estimates of the trajectories of fiber tracts, a process known as tractography (Figure 4). ³⁰

Tractography has shown losses of tract-count (number of fibers comprising a tract) and in the FA of the fibers within counts in frontal-occipi-tal and thalamo-frontal tracts in patients suspected of early AD (Figure 5). ³¹ This corresponds to quantitative electroencephalography (EEG) findings of a loss of coherence between the frontal and occipital lobes. ³²

White matter damage can also be assessed in AD by the placement of regions-of-interest (ROIs) in specific areas of the brain. White matter values of ADC and FA in a small cohort of AD patients have been established by Bozzali and colleagues. ^33,34 More recently, investigators at the University of Rochester used diffusion tensor MRI to evaluate the corpus callosum in AD and found a decrease in FA (Figure 6). Neuropsychological examinations of the same patients found a direct relationship between decreasing FA in the corpus callosum and cognitive decline. ³⁵ A recent, larger study established values of ADC and FA for young adults, elderly adults without dementia, and AD patients. ³⁶ In this study, researchers at Washington University found decreased FA in anterior white matter structures for elderly patients without dementia but in both anterior and posterior structures for elderly patients with AD (Figure 7).

The improved resolution and contrast of temporal lobe structures available with investigational diffusion MR sequences (Figure 2) also allows for quantitative diffusion tensor analysis of the hippocampus. In research presented at the 2004 meeting of the International Society for Magnetic Resonance in Medicine (ISMRM), Kantarci and colleagues ³⁷ followed-up 89 elderly individuals over a mean time period of 40 months with serial high-resolution hippocampal MRI and clinical examinations. They showed that ADC abnormalities in the hippocampus can be used to predict later development of mild cognitive impairment and AD. Specifically, those patients with amnestic mild cognitive impairment and an elevated baseline hippocampal ADC were more likely to convert to AD during the time of the study protocol, and baseline hippocampal ADC predicted future progression to AD with 70% sensitivity and 75% specificity.

Also at the 2004 ISMRM meeting, Samann and colleagues ³⁸ presented a template-derived histogram approach to this hippocampal ADC analysis. Using this semiautomated approach, patients with early AD can be separated from age-matched controls. This method holds great potential for clinical utility, as it allows for the type of streamlined analysis necessary in reviewing clinical MRIs.

Diffusion tensor MR also holds great potential in the diagnosis of Lewy body dementia. Like AD, Lewy body dementia is a fairly common form of dementia for which there are no specific imaging findings. It is very difficult to distinguish from AD by conventional imaging. SPECT studies of Lewy body dementia have found diffuse cortical hypoperfusion and hypometabolism involving the occipital lobe that is not present in AD patients. ^39,40 Similarly, Bozzali and colleagues ⁴¹ recently used diffusion tensor MR to show abnormal diffusivity and FA in the occipital lobes of patients with Lewy body dementia, providing further evidence that this technique will be increasingly useful in distinguishing among various forms of dementia.

Validation of diffusion tensor approaches to the diagnosis of dementia still relies upon clinical follow-up information, and whenever possible, postmortem correlation with imaging findings. Fortunately, diffusion tensor MR can be performed on fixed tissue samples. These postmortem correlations of imaging and histologic features offer ongoing validation of the imaging technique and remain a current area of research in dementia. ^42,43

Ongoing research also continues in the imaging of animal models of AD. Transgenic mouse models of AD are based upon overexpression of the amyloid precursor protein (APP), that gives rise to the β-amyloid plaques which, in excess, are pathognomonic for AD. These mice develop the classic AD plaques and progressive neurological decline found in AD patients. MR imaging studies of these mice allow for high-field (typically 4.7T and higher), high-resolution (<0.5 mm) in vivo and ex vivo imaging with direct histopathologic correlations. Recently, this approach has been used to identify age-dependent white matter injury in APP mice, ^44,45 to identify hippocampal changes in FA that precede the development of β-amy-loid plaques, ⁴⁶ and to correlate changes in cortical diffusively with expansion of the volume of extracellular space in APP mice. ⁴⁷

Other investigational uses of MRI in dementia

Further investigation into the utility of MR volumetrics, MR spectroscopy (MRS), perfusion MR, and functional MRI (fMRI) is ongoing. In the area of volumetric analysis, clinical utility has been limited due to the overlap of normal aging and AD. Recently, however, it has been reported that in individual patients followed-up with serial MR examinations, the rate of atrophy directly correlates with the progression of disease. ⁴⁸ This research has direct clinical applications, as whole-brain volumetric calculations can be easily applied to many of the clinical MR sequences currently in use. As patients return for MRI for other indications, a volumetric analysis could be added for those patients with suspected or diagnosed AD. Further research continues to establish parameters for volume loss in the hippocampus, the entorhinal cortex, and other temporal lobe structures.

MR spectroscopy is another technique that may be useful for the diagnosis of AD in difficult cases. In the setting of encephalopathy, MRS can be useful in differentiation of hepatic encephalopathy (elevated levels of glycine and glutamate ⁴⁹ and changes in levels of GABA ⁵⁰ ) and HIV encephalopathy (decreased N-acetylaspartate [NAA] and increased choline ⁵¹ levels). More recently, at 3T, MRS has been used to distinguish between AD, frontotemporal dementia, and progressive supranuclear palsy based upon ratios of NAA, choline, and myoinositol levels to creatine. ⁵²

Functional MRI utilizes changes in blood oxygenation to identify areas of brain activation. The difference in the fMRI signal between activated and nonactivated brain areas at 1.5T is small (2% to 4%) but significant. There are 3 main types of neuropsychologic tests currently under investigation with fMRI: Encoding of recent memory, simple cognitive tasks, and image memory. However, there are no clear standards available yet for the routine use of fMRI in patients with dementia. ⁵

Finally, a relatively new MR technique, T1ρ (T1-rho) imaging, offers a new alternative to standard T1, T2, and DWI contrast. T1ρ gives contrast that is somewhere between T1 and T2. T1ρ contrast is based upon the spin-lattice relation in the rotating frame of reference. At the 2004 meeting of the ISMRM, T1ρ was preliminarily reported to directly identify areas of β-amyloid plaque in an APP-mouse model of AD (manifested as loss of signal intensity on T1ρ images). ⁵³

Conclusion

Alzheimer's disease presents a diagnostic and prognostic dilemma for which new imaging techniques will need to emerge as progress on treatments continues. Current guidelines from the neurologic literature recommend routine CT and MRI examination of all patients with newly diagnosed dementia. Although there are many imaging modalities for AD currently under investigation, MRI offers a single, noninvasive examination allowing for the measurement of changes in multiple parameters. These include relaxation, water diffusivity, volumetric analysis, brain perfusion, metabolic analysis, and functional imaging. Diffusion tensor MR is emerging as a sensitive and specific tool for identifying patients with early and late AD and as a method for evaluating disease progression-information that will be critical to referring physicians as new pharmaceuticals become available.