DOI: 10.1148/radiol.2262011600
(Radiology 2003;226:315-336.)
© RSNA, 2003
Neuroimaging and Early Diagnosis of Alzheimer Disease: A Look to the Future1
Jeffrey R. Petrella, MD,
R. Edward Coleman, MD and
P. Murali Doraiswamy, MD
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).
 |
ABSTRACT
|
|---|
Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. Current consensus statements have emphasized the need for early recognition and the fact that a diagnosis of AD can be made with high accuracy by using clinical, neuropsychologic, and imaging assessments. Magnetic resonance (MR) or computed tomographic (CT) imaging is recommended for the routine evaluation of AD. Coronal MR images can be useful to document or quantify atrophy of the hippocampus and entorhinal cortex, both of which occur early in the disease process. Both volumetric and subtraction MR techniques can be used to quantify and monitor dementia progression and rates of regional atrophy. MR measures are also increasingly being used to monitor treatment effects in clinical trials of cognitive enhancers and antidementia agents. Positron emission tomography (PET) and single photon emission CT offer value in the differential diagnosis of AD from other cortical and subcortical dementias and may also offer prognostic value. In addition, PET studies have demonstrated that subtle abnormalities may be apparent in the prodromal stages of AD and in subjects who carry susceptibility genes. PET ligands are in late-stage development for demonstration of amyloid plaques, and human studies have already begun. Functional MR–based memory challenge tests are in development as well.
© RSNA, 2003
Index terms: Alzheimer disease, 13.83 • Brain, CT, 13.12111 • Brain, function • Brain, MR, 13.121411, 13.121412, 13.121416, 13.12144, 13.12145 • Brain, radionuclide studies, 13.12162, 13.12163 • State of the Art
|
INTRODUCTION
|
|---|
Alzheimer disease (AD) is a progressive neurodegenerative disorder associated with disruption of neuronal function and gradual deterioration in cognition, function, and behavior (1). It is the most common cause of dementia in the elderly and affects approximately 2–4 million individuals in the United States and more than 30 million worldwide. Age is a strong risk factor, with the disease affecting approximately 8% of individuals over the age of 65 years and 30% over the age of 85 years in developed countries. The progression of AD is gradual, and the average patient lives 8–10 years after onset of symptoms. Thus, with the growth of the older population in developed nations, the prevalence of AD is expected to triple over the next 50 years (2). Female-to-male prevalence is 70%, likely related to increased life expectancy in women. The annual cost of the disease in the United States alone, including medical, long-term, and home care, as well as loss in productivity, is currently estimated at $100 billion (3). Not only is the financial burden substantial, but the psychologic and emotional burden on patients and their families is even greater.
With the recent availability of several effective pharmaceutical agents for treatment of AD symptoms, along with several new agents undergoing clinical trials, we are entering a new age in the treatment of AD. Current consensus statements have emphasized the need for early recognition; thus, there is an urgent need to develop sensitive markers that may serve as adjuncts to current clinical and neuropsychologic tests to facilitate detection and/or monitoring of early brain changes suggestive of AD. Such markers may also facilitate early-intervention studies to prevent or slow disease progression.
Conventional structural neuroimaging, such as computed tomography (CT) or magnetic resonance (MR), has long played a supportive role in the diagnosis of memory disorders and is recommended for the routine evaluation of AD. However, because structural changes may not be detected at visual inspection until late in the course of the disease, more contemporary structural imaging techniques, such as serial volumetric imaging and voxel compression subtraction, have emphasized a quantitative approach capable of aiding in detection of subtle changes not readily apparent on routine images obtained at a single time point. Likewise, functional imaging modalities that demonstrate physiologic changes in the brain, including positron emission tomography (PET), single photon emission CT (SPECT), and functional MR imaging, also have the potential to enable identification of more subtle pathologic changes earlier during the disease course and, therefore, may have equal or greater potential in comparison with structural imaging modalities such as CT and conventional MR imaging.
This article will address the evolving role of contemporary neuroimaging in the evaluation of memory disorders, particularly AD. The intent is to focus primarily on AD; therefore, discussion of other causes of dementia is presented, in less detail, for the purpose of differential diagnosis. We will begin by briefly describing the current understanding of the neuropathology and genetics of AD, because these will have a direct bearing on diagnosis and treatment. Second, we will discuss pathologic and clinical diagnosis of memory disorders, followed by a description of the current role of structural neuroimaging evaluation. Third, we will give the reader perspective on the potential role of functional imaging in the broader scheme of clinical diagnosis and conventional imaging. Last, we will address what future steps are required for the implementation of advanced imaging techniques as useful diagnostic tools for work-up in the patient with dementia.
|
PATHOLOGY AND ETIOLOGY
|
|---|
Over the past 2 decades, rapid advances have occurred in our molecular genetic and cell biologic understanding of the pathogenesis of AD. Pathologically, AD is characterized by damage to the large cortical neurons subserving cognition, initially in the temporal lobes and later in the remaining neocortex and association areas. Damage is believed to occur owing to mechanisms outside the neuron, as well as inside the neuron, and is characterized by the appearance of extracellular senile (amyloid) plaques and intracellular neurofibrillary tangles (4) (Fig 1). Much work over the past 2 decades has focused on these two pathologic components of the disease, with application of molecular genetic, biochemical, and morphologic techniques to study them in great detail (5).
View larger version (24K):
[in this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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.)
|
|
Senile Plaques
All patients with AD develop neuritic plaques, which are extracellular aggregations of amyloid protein intimately associated with dystrophic axons and dendrites (neurites), activated microglia, and reactive astrocytes. Aggregations of amyloid protein that lack altered neurites and glia are known as diffuse plaques and may be found in normal aging, as well as in degenerative diseases other than AD. The primary component of these plaques is the amyloid ß protein. This protein is characteristic of AD and structurally distinct from the amyloid-forming proteins found in systemic amyloidosis.
Release of amyloid ß protein results from abnormal cleavage of the amyloid precursor protein, a glycoprotein found in high concentrations in the cell membrane of virtually all mammalian cells but in especially high concentrations in neuronal cell membranes. The enzymes responsible for normal and abnormal cleavage of amyloid precursor protein (
, ß, 
secretases) have been described and targeted for drug therapy. Amyloid precursor protein is normally secreted by both brain and nonbrain cells into extracellular fluids throughout life. Increased production of amyloid ß protein leads to precipitation, aggregation, and progressive deposition in the form of plaques. Plaque buildup is thought to incite an inflammatory and/or oxidative response, leading to progressive disruption of neuronal function and injury in the hippocampal complex and cerebral cortex (6).
Recent evidence suggests that genetic alterations underlying familial AD result in increased production of amyloid ß protein (Table 1). Mutations in the gene for amyloid precursor protein, leading to abnormal cleavage, are located on chromosome 21 and are present in patients with the rare early-onset familial form of the disease. Cloning of these mutations has lead to increased production of amyloid ß protein in cell cultures, and plasma levels of amyloid ß protein are elevated in some mutation carriers, even presymptomatically. Mutations of the presenilin 1, or PS-1, and presenilin 2, or PS-2, genes, on chromosomes 1 and 14 respectively, are also associated with the early-onset familial form of AD. Moreover, postmortem studies in patients with trisomy 21 (Down syndrome) and in those who carry susceptibility genes for AD have shown that amyloid ß protein accumulation in the cortex is an early invariant event in AD pathology, sometimes occurring decades before symptoms become apparent (5). Given this evidence, current thinking suggests that AD may represent not a single disease entity but rather a syndrome resulting from different genetic determinants that lead to a common phenotype with amyloid deposition and neuronal degeneration in specific brain regions (6).
Neurofibrillary Tangles
Neurofibrillary tangles consist of intraneuronal bundles of paired helical filaments composed of an abnormal microtubule-associated protein known as tau. Virtually all brains of AD patients contain neurofibrillary tangles. Unlike the gene for amyloid precursor protein, however, there is no evidence of defects in the gene encoding for tau in patients with familial forms of AD. In fact, neurofibrillary tangles, consisting of similar forms of modified tau protein, are detected in other etiologically distinct diseases such as subacute sclerosing panencephalitis, Hallervorden-Spatz disease, Parkinson dementia complex, and dementia pugilistica. Despite the lack of a direct etiologic connection, the results of numerous studies have demonstrated elevated levels of tau protein in the cerebrospinal fluid of patients with AD, compared with those levels in age-matched control subjects.
At present, the molecular and etiologic relationship between plaques and tangles is not fully understood. The bulk of current data suggests that these two lesions might be formed independently of each other. In fact, the distribution and density of both diffuse and neuritic senile plaques have not been consistently shown to correlate with the presence or severity of dementia (7), whereas the total density of neurofibrillary tangles does (8,9). Indeed, some elderly individuals without dementia have as much plaque deposition as have those with severe dementia. However, the neuritic variety of plaque associated with dystrophic axons and dendrites and reactive glial cells appears to be a more specific feature of AD than is the neurofibrillary tangle. Furthermore, results of a number of in vitro and in vivo studies have shown amyloid ß protein to be directly toxic to neurons, leading to phosphorylation of tau protein, the principal component of neurofibrillary tangles (10).
Pathologic Progression
The insidious onset and gradual progression of symptoms in patients with AD are thought to parallel the progression of AD-related brain destruction from entorhinal cortex to hippocampus to neocortex (11). In typical cases, there initially is isolated impairment of learning and short-term memory, without alteration in other domains of cognition or consciousness. This is followed by changes in long-term memory, personality, orientation, and executive function. After cognitive losses, there are behavioral problems (eg, hallucinations, delusions). Finally, there is deterioration of language, visuospatial skills, and, eventually, motor function, which leads to loss of activities of daily living.
Three stages in the gradual evolution of plaque deposition have been described (11). Stage A is characterized by deposition in the basal temporal neocortex, or entorhinal cortex. There then is extension through the hippocampal formation in stage B, eventually leading to deposits in virtually all cortical areas, including the highly myelinated primary areas of the neocortex in stage C.
There are reported to be six stages in the evolution of neurofibrillary tangles (11). Stage I is defined by the appearance of neurofibrillary tangle–bearing neurons in the transentorhinal region, with progression to the entorhinal region and hippocampal formation in stage II. These stages represent the presymptomatic phase of the disease. Further progression leads to stages III and IV, which are characterized by severe involvement of the entorhinal region, amygdala, and hippocampal formation. This involvement leads to interruption of the limbic loop, which is responsible for data transfer back and forth between the neocortex and the hippocampal formation. In addition, there is also involvement of many subcortical nuclei with diffuse projections to the cortex, among them the cholinergic system of the basal forebrain, including the nucleus basalis of Meynert. Patients with disease at these stages may present with symptoms of mild cognitive impairment (MCI) or prodromal AD, although symptoms may be masked by a high cognitive-reserve capacity. In stage V, there is extension to all major regions of the cerebral cortex, from association areas into primary areas. In stage VI, even the primary sensory areas are severely involved, although the motor area continues to be relatively spared. Stages V and VI are generally characterized by severe dementia.
|
PATHOLOGIC DIAGNOSIS
|
|---|
AD is characterized pathologically by reductions in the number of large cortical neurons in temporal and frontal cortex and by the appearance of senile (amyloid) plaques and neurofibrillary tangles (4). In living subjects, only a provisional diagnosis of possible or probable AD may be made, by using clinical, laboratory, and imaging evidence. Definitive diagnosis of AD is made by means of pathologic examination of tissue derived from autopsy or brain biopsy. For this reason, criteria have been created to standardize the pathologic diagnosis.
In the past, the two most extensively used pathologic criteria have been the National Institute on Aging consensus criteria (1) and the Consortium to Establish a Registry for Alzheimer’s Disease, or CERAD, criteria (12). The National Institute on Aging criteria are based on subject age and clinical history, taking into account the number of senile plaques per high-power microscopy field and the presence of neurofibrillary tangles in specific regions of the neocortex, hippocampus, and subcortical gray matter. The CERAD criteria use only the presence and density of neuritic senile plaques in the neocortex for establishment of the diagnosis of AD. The density is classified as "sparse," "moderate," or "severe" and is then combined with the age of the subject to yield an age-related plaque score. The plaque score is integrated with clinical information for the diagnosis of "definite," "probable," or "possible" AD.
More recently, the National Institute on Aging–Reagan Institute criteria, based on the number of both plaques and tangles in the neocortex and the limbic and paralimbic regions, were introduced (13,14). These criteria essentially combined the CERAD criteria, which are based on plaque frequency, and the staging criteria of Braak and Braak (15), which are based on neurofibrillary tangle distribution and frequency. The possibility of coexisting pathologic conditions other than AD is also recognized.
Unfortunately, because these criteria place varying degrees of dependence on the number and type of senile plaques and neurofibrillary tangles in various sections of the brain, as well as on the presence of a clinical history of dementia, the same diagnosis may not be rendered at autopsy in a given patient (16). In a recent study (17), however, a good correlation was shown between the National Institute on Aging–Reagan Institute criteria and the previous two criteria. The National Institute on Aging–Reagan Institute criteria offer the possibility of better diagnostic refinement because of the recognition that dementia in the elderly may arise from more than one disorder. In dementia with Lewy bodies, for example, there may be considerable clinical and pathologic overlap with AD.
|
CLINICAL DIAGNOSIS
|
|---|
The accuracy of a clinical diagnosis of AD depends on the stage of disease and the clinical setting. In an academic memory-disorders clinic setting, the diagnostic accuracy can exceed 90% (18–20), while accuracy may be substantially lower in the general community setting where there is less consistency and reliance on established diagnostic criteria. In this section, we will briefly review the clinical criteria for diagnosing AD and other common dementias of old age. We will also present current treatment options.
Diagnostic Criteria
AD.—Clinical criteria used for a provisional diagnosis consist of the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria (21) (Fig 2) for possible or probable AD or the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria (22) for dementia of the Alzheimer type. Probable AD can be categorized as mild (early), moderate (middle), or severe (late) dementia. Clinical work-up includes a detailed history from the patient and/or an informant, a general physical and mental status examination, neurologic assessment, and objective tests such as the Mini-Mental State Examination (MMSE) to help assess cognitive dysfunction. In addition, tests are also available to quantify activities of daily living, behavioral dysfunction, and caregiver stress. Staging instruments such as the Clinical Dementia Rating Scale and the Global Deterioration Scale are frequently used in academic settings.
View larger version (64K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
Laboratory evaluation is performed to exclude medical diseases that may cause dementia (eg, hypothyroidism, vitamin B12 deficiency). Cerebrospinal fluid assays of amyloid ß-42 and tau protein have been shown to have high sensitivity (
80%) and moderate specificity for the diagnosis of AD but are not widely used in routine practice. Other tests such as plasma assays of amyloid, cerebrospinal assays of neurotransmitter metabolites, and urine-based assays of neural thread protein have not been widely accepted as providing diagnostic value. Genetic testing is discussed elsewhere in this article.
Although variants with atypical manifestations have been described, the diagnosis of AD requires memory impairment as the most prominent manifestation, with a deficit in one or more cognitive domains, including language, orientation, or executive functioning (ie, planning, organizing, abstracting). The course of the disease is variable but is characterized by gradual onset with progressive decline in memory, with initial sparing of sensory and motor function. The memory impairment may initially manifest itself as a deficit in learning or recall of new information, followed by loss of remote memory. Behavioral and psychologic disturbances (depression, delusions, wandering, paranoia, anxiety, sleep changes) also develop in virtually 100% of patients over the course of the disease (Fig 3). Differentiation from dementia associated with depression (pseudodementia) may be difficult.
View larger version (31K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
AD is characterized by cholinergic deficits. There are currently three cholinesterase inhibitors in wide use as treatments of choice. Such treatments improve or stabilize cognition, and some evidence suggests that early initiation of therapy may delay institutionalization (23). Many patients are also treated "off label" with vitamin E, ginkgo biloba, and psychotropic drugs.
Differential diagnosis with other forms of dementia.—In developed countries, AD accounts for approximately 50%–70% of all cases of dementia in the elderly. Diagnostic criteria require that AD be distinguished from other causes of dementia such as vascular dementia, frontotemporal dementia, dementia with Lewy bodies, normal-pressure hydrocephalus, depression-related cognitive impairment, and intracranial mass.
Vascular dementia, which accounts for about 15% of all dementias in the United States, can be distinguished from AD by its more sudden onset and association with vascular risk factors. Vascular dementia is characterized by a stepwise course with periods of stability followed by sudden decline in cognitive function. Patients may experience focal neurologic deficits after a sudden decline, such as slurred speech or sensorimotor dysfunction. Clinical criteria for diagnosis of probable vascular dementia were created in 1993 and are known as the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria (Fig 4) (24). The term vascular dementia is preferred over multiinfarct dementia, because the former is an acknowledgment of the many vascular causes that can contribute to dementia. Control of vascular risk factors is the treatment of choice. Cholinesterase inhibitors are also increasingly being used to treat vascular dementia.
View larger version (68K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
Frontotemporal dementia comprises a group of dementias (eg, Pick disease) and accounts for approximately 5%–10% of cases of dementia. Frontotemporal dementia is clinically characterized by behavioral and language disturbances that may precede or overshadow memory deficits. There currently is no treatment for this condition.
Normal-pressure hydrocephalus is characterized by a classic triad of gait disturbance (25), dementia, and incontinence. There is evidence that ventricular shunting in a select group of these patients may improve symptoms, provided either pronounced gait difficulty or the full triad are present; however, there is little effect in patients in whom dementia is the first or primary symptom (26,27).
Dementia with Lewy bodies is being diagnosed more frequently; study results have demonstrated that it is responsible for approximately 25% of dementias. The clinical manifestation may be similar to that of AD or the dementia associated with Parkinson disease. Patients typically present with one of three symptom complexes: detailed visual hallucinations, Parkinson-like symptoms, or alterations in alertness and attention (3). Pathologically, the disease is characterized by the presence of Lewy bodies in various regions of the hippocampal complex, subcortical nuclei, and neocortex, with a variable number of diffuse amyloid plaques; however, the neurites (axons and dendrites) and neurofibrillary tangles seen in AD are not seen in this disease. In 1996, consensus criteria were developed for the diagnosis of probable dementia with Lewy bodies (28) (Fig 5). Cholinesterase inhibitors are currently the treatment of choice for this condition.
MCI.—Increasing evidence now suggests that the early pathogenic process of AD is protracted and may extend over decades (29). This preclinical stage of AD appears to be separated into two stages: an extended "latent period," where there may be no observable symptoms of the disease, followed by a shorter "prodromal phase," where mild symptoms are observed but preclude a clinical diagnosis. The prodromal phase is characterized by progressive isolated memory deficit, a condition now increasingly being termed in research settings as MCI. In contrast to MCI, patients with mild AD have more prominent deficits in one or more other cognitive domains (eg, language, executive function), as well as in daily functioning, and their memory deficits are usually also more pronounced.
Results of neuropsychologic studies of early AD have demonstrated that specific patterns of recent memory impairment help distinguish between early-stage AD, normal aging, and other dementing conditions (30). Based on these and other data, research criteria have been developed for identification of patients with MCI ("prodromal AD"), and such criteria are currently being used for selecting patients for ongoing-intervention trials (31). Specifically, MCI is characterized by a prominent and relatively isolated impairment in so-called secondary memory, or memory for information after short delays. Patients with MCI may also have impairments of working memory. This deficit in patients with MCI is believed to be to caused by impaired acquisition or consolidation of new information into permanent memory stores, presumably related to damage to the medial temporal lobe and/or specific prefrontal–temporal lobe circuits (Fig 6).
View larger version (23K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.)
|
|
There is still some controversy about the definition of MCI. Some experts believe that MCI simply reflects a very mild form of AD and that virtually all patients with MCI may have pathologic changes of AD (33). Others believe that patients with MCI represent a more heterogenous group, with some proportion of subjects staying stable or even "reversing" back to normal and with some patients progressing to develop additional deficits and meeting criteria for AD.
Although the definition of MCI has differed somewhat from study to study, there are now several longitudinal investigations in subjects with MCI. Peterson (34) has followed up MCI subjects and demonstrated that, on average, approximately 40% of carefully characterized subjects with MCI will progress to meet criteria for AD over a 4-year period. At present, there is no reliable test to predict which subjects will convert or progress, although all of the aforementioned risk factors may play a role. Symptoms of forgetfulness can be ambiguous and easily confused with the benign forms of memory change associated with normal aging (35) (Fig 7). Thus, there is an urgent need to develop sensitive markers that may serve as adjuncts to current clinical and neuropsychologic tests to facilitate detection and/or monitoring of early brain changes suggestive of AD. Such markers may also facilitate early intervention studies to prevent or slow further neuronal loss.
View larger version (11K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
The criteria for identification and classification of subjects with MCI are evolving. Current criteria for identifying subjects with MCI for secondary prevention trials of AD usually depend on one or more of the following factors: (a) impaired memory performance on a normalized objective verbal memory delayed-recall test (eg, word list or paragraph); (b) recent history of symptomatic worsening in memory, supported by an informant; (c) normal or near-normal performance on global cognitive tests (eg, MMSE score > 24), as well as on an activities of daily living scale; (d) global rating of 0.5 (questionable dementia) on the Clinical Dementia Rating Scale, with a score of at least 0.5 on the memory scale; (e) absence of other factors that may better explain memory loss; and (f) presence of other risk factors such as family history, older age, and presence of the apolipoprotein 
4 allele. While these criteria may seem relatively easy to apply, questions still remain with regard to which of these criteria to use, which memory test(s) to use, what cutoffs to apply to determine impairment, and how to deal with fluctuations in performance.
Genetic Testing
Genetic testing can be performed by using numerous markers (Table 1), many of which facilitate a diagnosis of early-onset dementia. Mutations of the PS-1, PS-2, and amyloid precursor protein genes on chromosomes 1, 14, and 21, respectively, are associated with early onset of the familial—and extremely rare—form of AD. The only useful marker for the more common late-onset (sporadic form) dementia is the apolipoprotein allele on chromosome 19. Results of genetic studies have shown that the 4 allele is associated with a high incidence of AD, whereas the 2 allele may be a protective factor. The 3 allele is thought to represent no increased or decreased risk (36). Because the 4 allele is more prevalent in patients with AD, it may be useful for differential diagnosis in patients with memory disorders. However, it is currently not recommended as a predictor of prognosis in asymptomatic subjects. The 4 allele is found in about 30% of healthy subjects and is absent in approximately 30%–40% of patients with AD (37).
|
ROLE OF STRUCTURAL NEUROIMAGING
|
|---|
Conventional CT and MR Imaging
Conventional CT and MR imaging are used routinely in the work-up of patients with dementia; however, because of their low sensitivity and specificity for the diagnosis of AD, they are primarily used as an adjunct to help assess the degree of atrophy and rule out other causes of dementia such as normal-pressure hydrocephalus, vascular dementia, or intracranial mass. Currently, there is no reason to support CT over MR in the evaluation of patients with dementia, except in cases where MR is contraindicated or not readily available or affordable.
Standard MR pulse sequences at most centers consist of nonenhanced transverse spin-echo T1-weighted imaging to help assess the presence and degree of generalized (eg, AD) or focal (eg, cerebellar degenerative diseases, Pick disease, AD) atrophy (38,39). Transverse dual-echo long-repetition-time imaging, including proton-density and/or fluid-attenuated inversion-recovery and T2-weighted imaging, is also used in the assessment for periventricular and subcortical white matter hyperintensities; cortical or deep gray matter lacunar infarcts (vascular dementia); and periaqueductal, cerebellar, or dorsal thalamic changes (eg, alcohol-related dementia) (40). At centers where fast spin-echo rather than conventional spin-echo imaging is used, T2*-weighted or gradient-echo imaging may be needed to help assess the degree of iron deposition (eg, parkinsonian disorders) (41). T1-weighted and T2-weighted sequences may also be used to help assess for the presence of ventricular dilatation or intracranial mass. Thin-section (
3-mm-thick) coronal T1-weighted images obtained in a plane orthogonal to the long axis of the hippocampus are useful for assessment of the degree of medial temporal lobe and hippocampal atrophy.
AD.—Medial temporal lobe atrophy, particularly of the amygdala, hippocampus, and parahippocampal gyrus, can be seen with higher frequency on structural images in patients with AD (42,43). Early investigators used CT to assess cortical, cerebellar, and hippocampal atrophy on transverse images; however, the addition of the coronal imaging plane with MR provided better qualitative assessments of the hippocampal region (Fig 8). Studies in which T1-weighted MR imaging was used in evaluation of the anterior hippocampus have been particularly useful. Data from a study (44) with 222 subjects (controls and patients with various forms of dementia) in which a visual rating scale was used to assess temporal lobe atrophy suggest that sensitivities and specificities in the area of 85% may be obtained for patients with AD.
View larger version (144K):
[in this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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.)
|
|
Normal-pressure hydrocephalus.—Normal-pressure hydrocephalus, an idiopathic form of communicating hydrocephalus, is characterized by holoventricular enlargement out of proportion to sulcal enlargement. These findings are in contrast to the findings of generalized atrophy, where the degree of sulcal and ventricular prominence are concordant. Radionuclide cisternography, demonstrating activity within the ventricular system at 24 hours, has been used to help diagnose normal-pressure hydrocephalus and determine which patients are more likely to respond to shunting (45). MR imaging can also be useful in this regard. MR images may show the presence of high signal intensity in the periventricular and subcortical white matter on T2-weighted, proton-density, or fluid-attenuated inversion-recovery images; this high signal intensity has been thought to represent transependymal edema. These abnormalities may, however, represent small-vessel ischemic changes, reflecting the relationship between normal-pressure hydrocephalus and decreased blood flow in the periventricular white matter (46). The presence of a prominent flow void in the cerebral aqueduct has been shown to correlate well with a positive response to shunting (47). More recently, a number of groups have demonstrated increased aqueductal cerebrospinal fluid flow, as measured with quantitative cine phase-contrast MR imaging, as a good predictor of response to shunting (48,49).
Despite the existence of consistent imaging findings, it should be noted that the diagnosis of normal-pressure hydrocephalus is made primarily on the basis of clinical findings. Without a prior suspected clinical diagnosis, it is unlikely the diagnosis will be made on the basis of imaging results alone.
Vascular dementia.—Vascular dementia, or multiinfarct dementia, is often characterized by multiple areas of high signal intensity on T2-weighted, proton-density, or fluid-attenuated inversion-recovery MR images. The high signal intensity may be in white matter, basal ganglia, and/or thalamus. Focal infarcts or lacunae in strategic locations can also be associated with vascular dementia. Clinical onset of cognitive deficits is characterized by a stepwise decline, as opposed to the more continuous decline in AD. Periods of abrupt decline may be followed by stable periods. Patients typically have cerebrovascular risk factors, including male sex, smoking, hypertension, and/or diabetes. Clinical characteristics such as abrupt onset of symptoms of memory impairment, emotional lability, somatic complaints, and focal neurologic deficits, along with a history of stroke or transient ischemic attacks, often guide the clinician in making a diagnosis of vascular dementia.
Modern diagnostic criteria emphasize the importance of imaging to support a clinical diagnosis (24). This diagnosis cannot be made on the basis of imaging findings alone, as white matter hyperintensities or lacunae on MR images do not necessarily always lead to dementia or notable cognitive impairment. Although study results have associated cognitive impairment with MR hyperintensities, the nature and strength of these associations have varied from one study to another (44,50–52). This variability may be due in part to the confounding effects of high cognitive reserve or education level, which may mask a neurocognitive decline. The volume of white matter lesions does, however, correlate with the presence of cerebrovascular risk factors (53). Patients with AD may also have abundant white matter lesions, and there is often overlap between vascular dementia and AD, a so-called mixed dementia. Thus, the presence of white matter lesions on T2-weighted MR images should not be used to exclude a diagnosis of AD (3). Likewise, several strategically placed infarcts may be sufficient to cause symptoms of vascular dementia and should not be viewed as unimportant.
Quantitative Imaging of Atrophy
Quantitative measures of generalized cerebral atrophy were developed for both CT and MR imaging in an attempt to identify pathologic atrophy in early dementia, as distinguished from the atrophy of "normal" aging. Such approaches included linear and volumetric CT measurements of ventricles and subarachnoid spaces and MR imaging measurements of cerebrospinal fluid and gray and white matter volumes (54–56). Unfortunately, age-related atrophy in individuals without dementia also occurs, causing substantial overlap between the two groups and limiting the diagnostic utility of such measurements. Subsequent work focused on the medial temporal lobes, given that the pathologic substrate of AD is known to affect the hippocampus and anatomically related areas such as the entorhinal cortex at the earliest stages of the disease. Authors of early studies with CT who focused on this region applied a linear approach to measure medial temporal lobe atrophy (57,58) and a stereological approach to measure hippocampal volume (59). However, because of the small size and uneven shape of the hippocampus, as well as considerations of section thickness, the transverse CT approach turned out not to be well suited for volumetric assessment.
Quantitative hippocampal volume analysis with MR imaging turned out to be better than that with CT, given the superior soft-tissue contrast capabilities of MR, the lack of beam-hardening artifacts, and the multiplanar capability. Initial techniques used linear and area measurements. Subsequent techniques have used semiautomated computer algorithms to calculate hippocampal volumes. Authors of a number of initial studies describing MR-based volume measurements reported extremely high sensitivity in distinguishing patients with AD from elderly control subjects; however, many of these studies were flawed by imaging methods that were not state of the art, by variations in neuroanatomic boundary criteria, and by small and highly selected samples, which made extrapolation to diagnosis of AD in a general setting problematic (60). The most widely used volumetric technique is the semiautomated tracing-thresholding method, where a threshold is used to outline the high-contrast portions of the anatomic boundary and an interactive manual trace is used to outline the low-contrast portions (61). Using the tracing-thresholding method, Jack et al (62) reported a sensitivity of 82% and a specificity of 80% in discriminating patients with AD from control subjects in a study of 220 individuals (Fig 9).
View larger version (162K):
[in this window]
[in a new window]
[Download PPT slide]
|
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.
|
|
Difficulties with single measurements of generalized and regional atrophy include the large overlap in volume measurements between control and AD populations. Serial measurements may be more specific than single measurements for detecting differences between patients with AD and control subjects, as serial measurements are less affected by overlap between populations. Several groups have evaluated dementia populations by using serial volume measurements in various memory-specific brain regions, including the medial temporal lobes. Rates of hippocampal atrophy have correlated with cognitive status at baseline and with change in cognitive status over time. Jack et al (63) studied 22 subjects with probable AD and 22 age- and sex-matched control subjects. The annualized rate of hippocampal atrophy and temporal horn enlargement was approximately two times greater in patients with probable AD. More recently, in a study with 129 patients grouped according to probable AD, MCI, or age-matched control, Jack et al (64) showed that rates of hippocampal atrophy lie along a continuum from patients with AD to those with MCI to age-matched control subjects. Within the control and MCI groups, subjects who subsequently showed a decline had a significantly greater rate of atrophy than did those whose condition remained clinically stable.
The potential of serial volume measurements to aid in prediction of a subsequent development of AD and evaluation of the efficacy of therapeutic regimens in at-risk populations, particularly those with MCI (65,66), has been evaluated. Fox et al (67) used a voxel compression subtraction technique to assess serial volume changes in individual subjects. The technique uses scaling, interpolation, and a rigid body registration method to first bring the later and earlier images into subvoxel alignment. A nonlinear registration algorithm using a compressible viscous fluid model is then applied to track local cerebral losses and deformations, which are presented in the form of a color overlay map on the baseline anatomic image. Fox et al (67) recently reported use of voxel compression mapping to show progressive regional atrophy involving the temporoparietal cortex and medial temporal and posterior cingulate regions in four patients with autosomal dominant mutations for early onset AD, all of whom developed the disease over a 5–8-year follow-up (Fig 10). The same technique can be used to monitor the effects of therapeutic regimens in slowing the rate of brain atrophy. It has been estimated that detection of a 20% reduction in atrophy rate would require approximately 200 patients and 200 control subjects in a 1-year placebo-controlled drug trial (68).
View larger version (100K):
[in this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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.)
|
|
Despite its promise, the lack of availability of a completely automated method for segmenting small and irregular structures such as the hippocampus, as well as the time-consuming and labor-intensive nature of the current methods, limits widespread use of serial volume measurements in clinical practice at this time. Techniques for automated segmentation of structures such as the hippocampus are in development (69) and await more extensive testing before they can be used in routine clinical settings (Fig 11).
View larger version (107K):
[in this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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.)
|
|
|
ROLE OF FUNCTIONAL NEUROIMAGING
|
|---|
Conventional structural neuroimaging with CT or MR is recommended in the routine evaluation of patients with memory disorders, to exclude treatable causes such as normal-pressure hydrocephalus or intracranial mass. Functional imaging modalities, including SPECT and PET, also offer value in the differential diagnosis of dementia, particularly in distinguishing AD from vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and depression. Moreover, because structural changes occur late in the course of the disease, functional imaging modalities, including SPECT, PET, and functional MR imaging techniques, may have greater potential in identifying more subtle pathologic changes earlier during the disease course.
SPECT Imaging
Cerebral SPECT, which is based on brain uptake of a technetium 99m–based lipid-soluble radionuclide such as ethyl cysteinate dimer or hexamethylpropylene amine oxime, is a widely available technique for evaluation of brain perfusion with a rotating gamma camera. Although the technique does not yield absolute values for cerebral blood flow, it does yield semiquantitative or relative values for comparison within and between patients when normalization by cerebellar activity is used (70).
Patients with AD have typically demonstrated a relative paucity of activity in the temporoparietal regions, compared with the activity in control subjects. Results of several studies have also shown that the magnitude of the perfusion abnormality correlates with the severity of cognitive impairment (71). In a prospective study with histologic confirmation of over 200 dementia cases and 119 control cases (72), the technique was reported to enable differentiation of patients with AD from healthy control subjects with a high degree of sensitivity and specificity (89% and 80%, respectively). Moreover, the accuracy of a clinical diagnosis of AD is improved with the aid of this technique, especially in mild cases of dementia, or "possible AD." In a study with histologic confirmation in 70 patients with dementia and 85 control subjects (73), a positive SPECT scan increased the pretest probability from 84% to 92% in patients with a clinical diagnosis of "probable AD" and from 67% to 84% in patients with "possible AD." A negative SPECT scan decreased the probability from 84% to 70% in patients with "probable AD" and from 67% to 52% in patients with "possible AD."
SPECT imaging also aids in the differential diagnosis of patients with dementia. Numerous studies have been performed in patients with various forms of dementia, including AD, frontotemporal dementia, and vascular dementia, with demonstration of unique uptake patterns. The presence of a frontal or anterior perfusion deficit has been associated with frontotemporal dementia and not with AD. In one study (74) in which a simple decision rule based on discriminant analysis of SPECT data was applied, 20 patients with probable AD and 20 with probable frontotemporal dementia were evaluated. One hundred percent of patients with frontotemporal dementia and 90% of patients with AD were correctly classified. In another study (75) with 16 patients with frontotemporal dementia, 71 patients with other forms of dementia, and 28 control subjects, an anterior-to-posterior ratio was successfully used to classify patients with frontotemporal dementia from those with other forms of dementia and from control subjects with a sensitivity of 87.5% and a specificity of 78.6%. The effect of different SPECT uptake patterns at baseline on modification of the differential diagnosis was evaluated in a study (76) with 363 patients followed up for a median of 3 years. Patients were classified into disease groups on the basis of clinical criteria. A bilateral posterior perfusion abnormality was associated with AD, whereas a bilateral anterior abnormality was associated with frontotemporal dementia. A patchy uptake pattern significantly increased the odds of a patient having vascular dementia.
It has been suggested that dementia with Lewy bodies may demonstrate occipital hypoperfusion, differentiating it from AD (77). Recently, Lobotesis et al (78) studied 23 subjects with a clinical diagnosis of dementia with Lewy bodies that had been based on consensus criteria. SPECT measures of occipital and medial temporal perfusion enabled correct classification of 69% of all subjects, with 65% sensitivity and 87% specificity for dementia with Lewy bodies versus AD and controls.
Thus, results of numerous studies to date have demonstrated that SPECT imaging offers additional diagnostic value in the work-up of patients with dementia. The question remains as to the cost-effectiveness of this additional diagnostic value at this time. McMahon et al (79) recently examined this question by utilizing a decision model designed to calculate quality-adjusted life-years that accrue to hypothetical cohorts of patients at the time of presentation to an AD center. This model depended on the sensitivity and specificity of the standard diagnostic work-up, the effectiveness of current treatments, and the severity of disease. The authors concluded that addition of SPECT imaging to the diagnostic regimen was not cost-effective given currently available therapies (79).
The use of a temporoparietal hypoperfusion pattern on SPECT images to help predict the clinical onset of AD in at-risk populations has not been extensively studied. One study (80) in which 36 patients with MCI were followed up for 3 years failed to show a correlation between the presence of a SPECT abnormality at baseline examination and subsequent cognitive decline in MMSE score. The investigators in that study used visual inspection alone for evaluation of SPECT scans. Authors of another study (81), using a quantitative singular-value decomposition analysis of SPECT images in patients with MCI, demonstrated regional decreases in uptake in the medial temporal lobe and cingulate regions that were most prominent among patients with MCI who subsequently converted to AD over the 1- to 2-year follow-up. The same group (82) also demonstrated reduced perfusion in the hippocampal complex in asymptomatic subjects with the PS-1 gene mutation, as compared with that in control subjects and in the anterior and posterior cingulate gyrus, posterior parietal lobe, and anterior frontal lobe regions. The authors suggested that a distributed brain network pertaining to memory might be selectively affected in the earliest stages of the disease.
PET Imaging
PET has been used to study the brain’s metabolic uptake of fluorine 18 (18F)-labeled fluorodeoxyglucose (FDG) and blood flow in patients with dementia. PET has been performed at baseline, as well as during the performance of various cognitive tasks. Baseline PET studies have been successful in enabling differentiation of AD from other forms of dementia on the basis of the pattern of FDG uptake. Specifically, deficits in temporoparietal metabolism are typically seen in patients with AD and not in patients with other forms of dementia or in age-matched control subjects (Fig 12a, 12b). Asymmetry of the metabolic deficits is not uncommon (Fig 12c). There typically is sparing of the basal ganglia, thalamus, cerebellum, and primary sensorimotor cortex (83). The magnitude of these deficits correlates well with the degree of cognitive impairment.
View larger version (102K):
[in this window]
[in a new window]
[Download PPT slide]
|
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 this window]
[in a new window]
[Download PPT slide]
|
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).
|
|
TOP
ABSTRACT
INTRODUCTION
