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Neuroimaging and Early Diagnosis of Alzheimer Disease: A Look to the Future¹

¹ From the Departments of Radiology (J.R.P., R.E.C.) and Geriatric Medicine and Psychiatry (P.M.D.), Duke University Medical Center, Duke Hospital North, Rm 1513, Erwin Rd, Durham, NC 27710. Received September 28, 2001; revision requested December 3; revision received February 25, 2002; accepted March 14. J.R.P. supported by grants from the RSNA Research and Education Foundation and the National Institute of Aging (R01AG019728-01). P.M.D. supported by grants from the American Federation of Aging Research and the National Institutes of Health. Address correspondence to J.R.P. (e-mail: jeffrey.petrella@duke.edu).

View larger version (24K): [in a new window]   Figure 1a. Two theories of how damage occurs in AD. (a) From outside the cell, amyloid ß peptides secreted by brain cells are normally soluble, and any excess is cleared away. When these peptides become insoluble, however, they collect in the space between cells. Amyloid fibrils are "herded" together by chaperone proteins. The large plaques that form then damage brain cells and attract reactive cells, microglia and astrocytes, which cause further damage. (b) From inside the cell, tau proteins, which normally stabilize microtubules in brain cells, undergo abnormal chemical changes and assemble into spirals called paired helical filaments, thus creating tangles that disrupt cell functions and lead to cell death. (Images courtesy of Dr John Trojanowski and Dr Virginia M. Y. Lee, University of Pennsylvania Medical Center, Philadelphia.)

View larger version (21K): [in a new window]   Figure 1b. Two theories of how damage occurs in AD. (a) From outside the cell, amyloid ß peptides secreted by brain cells are normally soluble, and any excess is cleared away. When these peptides become insoluble, however, they collect in the space between cells. Amyloid fibrils are "herded" together by chaperone proteins. The large plaques that form then damage brain cells and attract reactive cells, microglia and astrocytes, which cause further damage. (b) From inside the cell, tau proteins, which normally stabilize microtubules in brain cells, undergo abnormal chemical changes and assemble into spirals called paired helical filaments, thus creating tangles that disrupt cell functions and lead to cell death. (Images courtesy of Dr John Trojanowski and Dr Virginia M. Y. Lee, University of Pennsylvania Medical Center, Philadelphia.)

View larger version (64K): [in a new window]   Figure 2. NINCDS/ADRDA (National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association) criteria (21) for probable AD. EEG = electroencephalogram.

View larger version (31K): [in a new window]   Figure 3. Over the clinical course of AD, patients will demonstrate progressive declines in functional ability that correlate with MMSE scores. In the preclinical phase, also called MCI, patients with MMSE score greater than 23 will demonstrate minimal impairment—generally, mild memory loss—while functioning normally and independently. The typical length of the MCI phase remains undetermined. Onset of mild AD is indicated by MMSE score of 20-23; these patients exhibit gradual alterations in cognition, function, behavior, and mood. Forgetfulness and repetitive questions are hallmarks; daily function begins to become impaired. In moderate AD (MMSE score of 10-19), cognitive impairments progressively deteriorate and now include short-term memory loss (eg, difficulty in recalling recent conversations, forgetting to keep appointments, inability to remember recent events). Patients begin to have trouble with verbal fluency; specifically, increasing difficulty in remembering the correct word. Severe stage is reached when MMSE scores decline to less than 10. At this point, patients exhibit behavioral changes that include agitation, delusion, aggression, wandering, and hallucination. Sleep patterns are altered, and the patient eventually becomes completely dependent on others for dressing, feeding, and bathing. The clinical progression from onset of mild AD to onset of severe AD, although variable, is about 10 years.

View larger version (68K): [in a new window]   Figure 4. NINDS-AIREN (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l’Enseignement en Neurosciences) criteria (24) for probable vascular dementia. ACA = anterior cerebral artery, CVD = cerebrovascular disease, PCA = posterior cerebral artery.

View larger version (69K): [in a new window]   Figure 5. Proposed criteria of McKeith et al (28) for probable dementia with Lewy bodies (DLB).

View larger version (23K): [in a new window]   Figure 6. Model of neural deficits in early AD. Neural connections associated with normal memory function involve frontal and temporal lobes. Somatosensory, visual, and auditory information proceed from primary and association cortex to prefrontal cortex, located in the posterior frontal lobe. This region plays a major role in executive function (ie, organizing and directing attention), as well as in working memory, acting as a "mental scratchpad" for short-term information needed to perform a task, such as dialing a phone number. Part of this information may be consolidated, branching to the medial temporal lobe region via the entorhinal cortex (medial temporal lobe) and into the hippocampal complex. Projections from the hippocampal complex can transfer long-term information back to prefrontal cortex. This back-and-forth pathway between prefrontal cortex and medial temporal lobes is known as the limbic loop and is considered important for emotional stability, learning and memory function, and regulation of autonomic and endocrine functions. It is precisely these areas that are particularly susceptible to the pathologic changes of AD (11). (Adapted, with permission, from reference 32.)

View larger version (11K): [in a new window]   Figure 7. Conceptual continuum of memory decline in early AD. Diagram demonstrates overlap between healthy control subjects and patients with MCI and between patients with mild AD and those with MCI.

View larger version (144K): [in a new window]   Figure 8a. Coronal T2-weighted fast spin-echo MR images (repetition time msec/echo time msec, 2,700/80) in (a, b) a patient with AD and (c, d) an age-matched control subject. (a, b) The patient with AD has severe bilateral hippocampal atrophy (arrows). Compare this with (c, d) normal hippocampus (arrows) in the control subject. Note that b is a close-up of a, and d is a close-up of c. (Images courtesy of Daniel P. Barboriak, MD, Duke University Medical Center, Durham, NC.)

View larger version (59K): [in a new window]   Figure 8b. Coronal T2-weighted fast spin-echo MR images (repetition time msec/echo time msec, 2,700/80) in (a, b) a patient with AD and (c, d) an age-matched control subject. (a, b) The patient with AD has severe bilateral hippocampal atrophy (arrows). Compare this with (c, d) normal hippocampus (arrows) in the control subject. Note that b is a close-up of a, and d is a close-up of c. (Images courtesy of Daniel P. Barboriak, MD, Duke University Medical Center, Durham, NC.)

View larger version (135K): [in a new window]   Figure 8c. Coronal T2-weighted fast spin-echo MR images (repetition time msec/echo time msec, 2,700/80) in (a, b) a patient with AD and (c, d) an age-matched control subject. (a, b) The patient with AD has severe bilateral hippocampal atrophy (arrows). Compare this with (c, d) normal hippocampus (arrows) in the control subject. Note that b is a close-up of a, and d is a close-up of c. (Images courtesy of Daniel P. Barboriak, MD, Duke University Medical Center, Durham, NC.)

View larger version (50K): [in a new window]   Figure 8d. Coronal T2-weighted fast spin-echo MR images (repetition time msec/echo time msec, 2,700/80) in (a, b) a patient with AD and (c, d) an age-matched control subject. (a, b) The patient with AD has severe bilateral hippocampal atrophy (arrows). Compare this with (c, d) normal hippocampus (arrows) in the control subject. Note that b is a close-up of a, and d is a close-up of c. (Images courtesy of Daniel P. Barboriak, MD, Duke University Medical Center, Durham, NC.)

View larger version (162K): [in a new window]   Figure 9. Coronal T1-weighted MR images demonstrate tracings of the hippocampus and parahippocampal gyrus in a 75-year-old female control subject (left) and 73-year-old woman with AD (right). Outlines of the amygdala and hippocampus are indicated in the bottom images.

View larger version (100K): [in a new window]   Figure 10a. T1-weighted MR images with color voxel compression mapping overlay in a 46-year-old man with familial AD. Images were obtained in (a) transverse, (b) coronal, and (c) sagittal planes over 30 months during which symptoms developed. Green and blue areas demonstrate interval volume loss, particularly in temporal lobes and in other neocortical areas. (Images courtesy of Nick C. Fox, MD, MRCP, National Hospital for Neurology and Neurosurgery, London, England.)

View larger version (100K): [in a new window]   Figure 10b. T1-weighted MR images with color voxel compression mapping overlay in a 46-year-old man with familial AD. Images were obtained in (a) transverse, (b) coronal, and (c) sagittal planes over 30 months during which symptoms developed. Green and blue areas demonstrate interval volume loss, particularly in temporal lobes and in other neocortical areas. (Images courtesy of Nick C. Fox, MD, MRCP, National Hospital for Neurology and Neurosurgery, London, England.)

View larger version (122K): [in a new window]   Figure 10c. T1-weighted MR images with color voxel compression mapping overlay in a 46-year-old man with familial AD. Images were obtained in (a) transverse, (b) coronal, and (c) sagittal planes over 30 months during which symptoms developed. Green and blue areas demonstrate interval volume loss, particularly in temporal lobes and in other neocortical areas. (Images courtesy of Nick C. Fox, MD, MRCP, National Hospital for Neurology and Neurosurgery, London, England.)

View larger version (107K): [in a new window]   Figure 11a. Three-dimensional model-based segmentation. Screenshot demonstrates elastic model-based segmentation of limbic structures, including amygdalae (green and yellow) and hippocampi (blue and red). (a) Segmentation is shown in three-dimensional surface rendering (bottom left) and two-dimensional overlay on T1-weighted MR images in three orthogonal planes (top left and right, bottom right). (b) Sagittal T1-weighted MR image demonstrates outline of hippocampus in green. (c) Hippocampus (yellow) and neighboring brain structures (blue, green, and red) are shown on three-dimensional volume rendering of the brain. (Images courtesy of Guido Gerig, PhD, University of North Carolina, Chapel Hill.)

View larger version (193K): [in a new window]   Figure 11b. Three-dimensional model-based segmentation. Screenshot demonstrates elastic model-based segmentation of limbic structures, including amygdalae (green and yellow) and hippocampi (blue and red). (a) Segmentation is shown in three-dimensional surface rendering (bottom left) and two-dimensional overlay on T1-weighted MR images in three orthogonal planes (top left and right, bottom right). (b) Sagittal T1-weighted MR image demonstrates outline of hippocampus in green. (c) Hippocampus (yellow) and neighboring brain structures (blue, green, and red) are shown on three-dimensional volume rendering of the brain. (Images courtesy of Guido Gerig, PhD, University of North Carolina, Chapel Hill.)

View larger version (119K): [in a new window]   Figure 11c. Three-dimensional model-based segmentation. Screenshot demonstrates elastic model-based segmentation of limbic structures, including amygdalae (green and yellow) and hippocampi (blue and red). (a) Segmentation is shown in three-dimensional surface rendering (bottom left) and two-dimensional overlay on T1-weighted MR images in three orthogonal planes (top left and right, bottom right). (b) Sagittal T1-weighted MR image demonstrates outline of hippocampus in green. (c) Hippocampus (yellow) and neighboring brain structures (blue, green, and red) are shown on three-dimensional volume rendering of the brain. (Images courtesy of Guido Gerig, PhD, University of North Carolina, Chapel Hill.)

View larger version (102K): [in a new window]   Figure 12a. FDG PET images demonstrate typical findings in (a-c) three patients with AD and (d) one patient with frontotemporal dementia. (a) Note bilateral parieto-occipital hypometabolism (arrows) in a 77-year-old woman with AD. (b) Bilateral parietal hypometabolism (arrows) is also noted in a 62-year-old woman with AD. (c) Changes may be asymmetric, as demonstrated in a 53-year-old woman with AD, with the metabolic defect (arrow) primarily on the left. (d) As shown in a patient with frontotemporal dementia, PET may help differentiate frontotemporal dementia from AD by demonstrating metabolic deficits (arrows) in the frontal and anterior temporal lobes (not shown).

View larger version (100K): [in a new window]   Figure 12b. FDG PET images demonstrate typical findings in (a-c) three patients with AD and (d) one patient with frontotemporal dementia. (a) Note bilateral parieto-occipital hypometabolism (arrows) in a 77-year-old woman with AD. (b) Bilateral parietal hypometabolism (arrows) is also noted in a 62-year-old woman with AD. (c) Changes may be asymmetric, as demonstrated in a 53-year-old woman with AD, with the metabolic defect (arrow) primarily on the left. (d) As shown in a patient with frontotemporal dementia, PET may help differentiate frontotemporal dementia from AD by demonstrating metabolic deficits (arrows) in the frontal and anterior temporal lobes (not shown).

View larger version (99K): [in a new window]   Figure 12c. FDG PET images demonstrate typical findings in (a-c) three patients with AD and (d) one patient with frontotemporal dementia. (a) Note bilateral parieto-occipital hypometabolism (arrows) in a 77-year-old woman with AD. (b) Bilateral parietal hypometabolism (arrows) is also noted in a 62-year-old woman with AD. (c) Changes may be asymmetric, as demonstrated in a 53-year-old woman with AD, with the metabolic defect (arrow) primarily on the left. (d) As shown in a patient with frontotemporal dementia, PET may help differentiate frontotemporal dementia from AD by demonstrating metabolic deficits (arrows) in the frontal and anterior temporal lobes (not shown).

View larger version (94K): [in a new window]   Figure 12d. FDG PET images demonstrate typical findings in (a-c) three patients with AD and (d) one patient with frontotemporal dementia. (a) Note bilateral parieto-occipital hypometabolism (arrows) in a 77-year-old woman with AD. (b) Bilateral parietal hypometabolism (arrows) is also noted in a 62-year-old woman with AD. (c) Changes may be asymmetric, as demonstrated in a 53-year-old woman with AD, with the metabolic defect (arrow) primarily on the left. (d) As shown in a patient with frontotemporal dementia, PET may help differentiate frontotemporal dementia from AD by demonstrating metabolic deficits (arrows) in the frontal and anterior temporal lobes (not shown).

View larger version (69K): [in a new window]   Figure 13. PET images comparing temporal lobe uptake of [18F]FDDNP (see text), an amyloid-binding radiotracer, and FDG, a marker of glucose metabolism, in a patient with AD (left) and a control subject (right). Note increased uptake and retention of [18F]FDDNP (arrowheads) in temporal lobes of the patient with AD, compared with those in control subject. The patient with AD still demonstrates typical findings of decreased temporal (arrows) and parietal (not shown) FDG uptake.

View larger version (193K): [in a new window]   Figure 14a. Transgenic mouse model of AD (tg2576). (a) Section from entorhinal cortex demonstrates in vivo labeling of amyloid plaques. Fluorescent labeling of plaques is seen after intravenous injection of (trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene, or BSB, an amyloid ß binding agent that crosses the blood-brain barrier. (Original magnification, x400.) (b) The same section was also immunostained with amyloid ß-specific antiserum 2332, as demonstrated in this light microscopy image. (Original magnification, x400.) (c) Digital overlay of a and b reveals high specificity of BSB plaque labeling. (Original magnification, x400.) (Adapted and reprinted, with permission, from reference 100.)

View larger version (203K): [in a new window]   Figure 14b. Transgenic mouse model of AD (tg2576). (a) Section from entorhinal cortex demonstrates in vivo labeling of amyloid plaques. Fluorescent labeling of plaques is seen after intravenous injection of (trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene, or BSB, an amyloid ß binding agent that crosses the blood-brain barrier. (Original magnification, x400.) (b) The same section was also immunostained with amyloid ß-specific antiserum 2332, as demonstrated in this light microscopy image. (Original magnification, x400.) (c) Digital overlay of a and b reveals high specificity of BSB plaque labeling. (Original magnification, x400.) (Adapted and reprinted, with permission, from reference 100.)

View larger version (199K): [in a new window]   Figure 14c. Transgenic mouse model of AD (tg2576). (a) Section from entorhinal cortex demonstrates in vivo labeling of amyloid plaques. Fluorescent labeling of plaques is seen after intravenous injection of (trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene, or BSB, an amyloid ß binding agent that crosses the blood-brain barrier. (Original magnification, x400.) (b) The same section was also immunostained with amyloid ß-specific antiserum 2332, as demonstrated in this light microscopy image. (Original magnification, x400.) (c) Digital overlay of a and b reveals high specificity of BSB plaque labeling. (Original magnification, x400.) (Adapted and reprinted, with permission, from reference 100.)

View larger version (111K): [in a new window]   Figure 15. Brain activation maps obtained during memory-activation task in patients at genetic risk for AD (carriers of apolipoprotein [Apo] 4 allele) compared with control subjects (apolipoprotein 3 carriers). Three-dimensional renditions of the brain surface are shown in gray, and colored areas indicate regions of significantly increased MR signal intensity during performance of memory task as compared with that during resting periods. Activation is seen in temporal and frontal regions in both groups; however, both the extent and intensity of activation are greater among the genetic risk group, which suggests compensatory brain function. (Adapted and reprinted, with permission, from reference 117.)

View larger version (104K): [in a new window]   Figure 16a. Multivoxel MR spectroscopic imaging in (a) a 62-year-old healthy volunteer and (b) an 80-year-old patient with AD. Sample spectra are shown from right temporal lobe (bottom left), left insula (top right) and left thalamus (bottom right). Note the increase in myo-inositol (Ino) and choline (Cho) levels and the decrease in NAA level (short arrows in b) in the right temporal lobe of the patient with AD, compared with those levels in the healthy volunteer, suggesting the presence of gliosis, increased membrane turnover, and neuronal loss in AD. (P)Cre = creatine and phosphocreatine. (Images courtesy of H. Cecil Charles, PhD, Duke University Medical Center, Durham, NC.)

View larger version (74K): [in a new window]   Figure 16b. Multivoxel MR spectroscopic imaging in (a) a 62-year-old healthy volunteer and (b) an 80-year-old patient with AD. Sample spectra are shown from right temporal lobe (bottom left), left insula (top right) and left thalamus (bottom right). Note the increase in myo-inositol (Ino) and choline (Cho) levels and the decrease in NAA level (short arrows in b) in the right temporal lobe of the patient with AD, compared with those levels in the healthy volunteer, suggesting the presence of gliosis, increased membrane turnover, and neuronal loss in AD. (P)Cre = creatine and phosphocreatine. (Images courtesy of H. Cecil Charles, PhD, Duke University Medical Center, Durham, NC.)