Alzheimers Disease: Assessment Through Imaging
Judith Greif, RN, MS, APNC
*Family Nurse Practitioner, East Brunswick, New Jersey.
Address correspondence to: Judith Greif, RN, MS, APNC, Family Nurse Practitioner, 50 Central Avenue, East Brunswick, NJ 08816. E-mail: grifcommedical@aol.com.
Disclosure Statement: Ms Greif reports having no significant financial or advisory relationships with corporate organizations related to this activity.
ABSTRACT
Alzheimer’s disease (AD) is the most common form of chronic dementia among older individuals, affecting 60% to 80% of those diagnosed with a dementia disorder—estimated to be up to 4.5 million Americans at present and expected to increase almost 3-fold over the next 50 years due to increasing life expectancy. It is characterized by the insidious onset of memory impairment and cognitive disturbances, which lead to serious behavioral changes that preclude individuals from functioning in activities of daily living and ultimately results in their death. To date, clinicians and scientists have not developed a reliable diagnostic tool or cure for the disease. Treatments are symptom-based and short-lived. Having the capacity to diagnose AD early in its course through neuroimaging and to differentiate it from other forms of chronic and potentially more treatable dementias is important for maximizing the health and safety of the affected individual, as well as for long-term planning. Furthermore, pharmaceutical treatments are based on what is currently known about the pathophysiology of AD—something that has been studied in part through the use of various imaging techniques. Therefore, state-of-the-art neuroimaging through modalities, such as magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, and single photon emission computed tomography, may play important roles in improving the outcomes for patients with AD across the spectrum of this illness—from diagnosis to monitoring of treatment effects to the development of novel therapies.
Introduction
Alzheimer’s disease (AD) is the most common form of chronic dementia among older individuals, affecting 60% to 80% of those diagnosed with a dementia disorder—estimated to be up to 4.5 million Americans.1,2 The American Psychiatric Association has established various criteria for the diagnosis of dementia of the Alzheimer’s type, which is marked by multiple cognitive deficits. These include impaired memory and 1 or more additional cognitive disturbances that may encompass disturbances of language (aphasia), sensory-motor skills (agnosia or apraxia), or executive functioning (planning, organizing, sequencing, and abstract thinking; Table).3 These must be severe enough to interfere with normal activities of daily living (such as the ability to feed oneself, take care of personal hygiene, drive, or work).3 According to the Centers for Disease Control and Prevention’s National Center for Health Statistics, 7.5% of patients in home and hospice care in 2000 and 14% of nursing home residents in 1999 had AD as their primary diagnosis (a total of nearly 232 000 individuals).4 These individuals require supportive care, generally living 8 to 10 years with the diagnosis, and spending an average of 620 days in long-term care facilities.4 AD is also an important cause of mortality, resulting in 65 965 deaths annually (22.5 per 100 000), and it ranks as the seventh leading cause of death in the United States.2
Alzheimer’s disease has an insidious onset with slow cognitive decline; as more and more Americans are living longer, the prevalence of AD is expected to rise such that by the year 2050, the number of individuals with AD will increase by almost 3-fold to 13.2 million.1 The disease usually begins after age 60, and the numbers of affected individuals grows almost exponentially with advancing age. According to data from the National Institute of Aging, approximately 5% of men and women aged 65 to 74 have AD, 18.2% have AD by age 80, and 49.6% have the disease by age 90.2 More recent data from a 2007 study of 856 men and women aged 71 or older, who were surveyed between 2001 and 2003, found that 13.9% had some type of dementia, 9.7% had AD, and 2.4% had vascular dementia—another common cause of dementia related to stroke. In this National Institutes of Health study, AD accounted for approximately 70% of all dementia cases among people aged 71 and older. It was estimated that 5% of people aged 71 to 79, 24.2% of people aged 80 to 89, and 37.4% of those aged 90 or older had some type of dementia. The estimated rate of AD also rose greatly with advancing age—from 2.3% of people aged 71 to 79, to 18.1% of individuals aged 80 to 89, to 29.7% of those aged 90 or older.5 Although other risk factors include a family history, previous head injury, lower educational level, and female sex, as the statistics show, aging is the most important risk factor for AD. The female-to-male prevalence of 70% for AD simply may be a consequence of the relative longevity of women as compared to men.6,7
To date, there is no known cause or cure for AD, in addition to no laboratory or imaging test to definitively diagnose this condition. Traditionally, the diagnosis is founded on history and physical examination (neurologic and psychiatric evaluations), but cannot be confirmed until after death if an autopsy is performed and certain histopathologic changes are noted in the brain tissue (see “Understanding the Pathophysiology of AD” section). This review discusses the epidemiology, signs and symptoms, and pathophysiology of AD. Assessment through various imaging techniques, such as magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and single photon emission computed tomography (SPECT), will be emphasized because early diagnosis and monitoring of treatment effects from new and experimental therapies may hold the key to eventual cure.
Signs and Symptoms of AD
Alzheimer’s disease is generally diagnosed when individuals or, more commonly, their caregivers begin to notice cognitive and/or personality changes, psychiatric symptoms, problem behaviors, and/or a decline in the ability to perform routine daily tasks. For example, cognitive changes may include forgetfulness or disorientation to person, place, or time and/or difficulty with comprehension of written or oral communication. Loss of episodic memory (for events that took place at a specific time and place) is the earliest and most significant memory impairment. In addition, individuals may display inappropriate conduct. They may be overly friendly and flirtatious or conversely, they may be suspicious, withdrawn, and apathetic. Individuals may be depressed and suffer from anxiety and insomnia. Early on, these patients may be less capable of handling work or financial matters or may lose interest in recreational activities. In the later stages, individuals may experience hallucinations and paranoia; they may become agitated and violent or may wander away from home and perform other unsafe behaviors, such as leaving the stove on or driving recklessly.
In addition to abnormal behaviors, clinicians rely on findings from a physical examination to attempt to diagnose dementias such as AD. Although symptoms for many of the dementias may seem similar, sometimes findings from an objective examination may allow the clinician to pinpoint the cause of the dementia and treat it if it is reversible. (The differential diagnosis from other major chronic dementia syndromes include vascular dementia, dementia with Lewy bodies, Parkinson’s disease with dementia, Huntington’s disease, and frontotemporal dementia.) For example, vascular dementias may cause focal neurologic deficits secondary to the location of the infarct. As will be discussed, imaging studies may be instrumental in distinguishing underlying etiologies in various types of dementias.
A physical examination that focuses on cognitive skills is essential. For example, to test for aphasia, patients may be asked to name a body part or identify a common object, such as a book. Apraxia (motor memory) may be tested by requesting that the individual act out how to brush his teeth, whereas agnosia may be evaluated by placing a common object (a coin or a pen) in the person’s hands while their eyes are closed and asking them to identify the object. Individuals with AD may have trouble carrying out a series of simple tasks, such as following a radiologic technologist’s instructions to remove a garment, place it in a locker, put on a gown, and have a seat in the waiting area. The Mini-Mental Status Examination (MMSE) is frequently used to evaluate executive function, although it may not test higher order thinking, such as judgment.7-9 This is sometimes assessed by asking a question, such as, "What would you do if you were in a store and the fire alarm went off?"
Assuming reversible causes of dementia (such as anemia, infection [human immunodeficiency virus or neurosyphilis], vitamin deficiency, thyroid disease, and alcohol, drug, or heavy metal toxicities) have been ruled out through a variety of blood and urine studies, neuroimaging may be used to diagnose AD and other types of chronic dementia. Although no cure exists at this time, early diagnosis is important for maximizing the health and safety of the affected individual, long-term planning, and use of symptom-based treatments based on what is currently known about the pathophysiology of AD—something that has been studied through the use of various imaging techniques in addition to other laboratory studies. The greater our understanding is of the pathophysiology of AD, the more likely is the possibility of therapeutic interventions.
Understanding the Pathophysiology of AD
It has been just over 100 years since Alois Alzheimer first described the disease named for him, after he performed an autopsy on a woman who had died of an unusual mental illness, and he identified certain cardinal changes in her brain tissue now considered to be diagnostic pathologic signs of AD. Yet, despite extensive clinical research, as well as research conducted on the molecular and cellular levels, researchers and physicians still lack a complete picture of this devastating disease, which condemns people to a vegetative state and ultimately, is fatal. What is known, however, is that affected individuals have abnormal extracellular accumulations of a normal protein called β-amyloid,10 but this normal protein is transformed into a toxic form that then accumulates in formations called neuritic plaques that surround and kill neurons.10,11 This begins a secondary sequence of events including inflammation, excitotoxicity, and apoptosis (programmed cell death). In addition, intraneuronal accumulations of another protein, identified as Tau protein, cause another characteristic pathologic change noted in the brain: neurofibrillary tangles. It was neuritic plaques and neurofibrillary tangles that were first noted by Dr Alzheimer on autopsy. Today, these may also be identified with advanced imaging techniques. For example, PET scanning with 11C-labeled Pittsburgh Compound-B tracer, a novel substance that binds to β-amyloid, can highlight damaged areas of the brain in patients with AD.12 In addition, computed tomography (CT) and MRI techniques, among others, reveal areas of neuronal death and brain atrophy brought on by these accumulations of plaques and tangles. Correlation of affected brain regions with clinical signs and symptoms help to identify areas of the brain associated with specific cognitive functions, help to refine diagnosis, and assist in the development and tracking of therapeutic interventions.
Biochemical studies of the brains of patients affected by AD reveal deficits in an enzyme (choline acetyltransferase) responsible for synthesizing an important neurotransmitter, acetylcholine. (Neurotransmitters are chemicals responsible for conducting nerve impulses across a synapse [a gap] to another important structure, most commonly and in the case of AD, another neuron.) It has been hypothesized that patients’ symptoms derive from deficits in the neocortex (dorsal region of the cerebral cortex; Figure 1), in addition to a loss of cholinergic neurons in the nucleus basalis of Meynert (Figure 2).10,13,14 The cholinergic system appears to play a role in memory and cognition, and the loss of cholinergic neurotransmission in the cerebral cortex caused by degeneration of these nerve cells in the basal forebrain might be responsible for the significant decline of cognitive abilities noted among subjects with AD.10 Thus, this has become the basis for the only symptom-based treatment for AD—inhibition of the enzyme, cholinesterase, which is responsible for breaking down acetylcholine in the synapse. Today, pharmaceutical agents, such as tacrine, metrifonate, donepezil, rivastigmine, and galantamine (cholinesterase inhibitor or ChEI drugs), appear to delay symptom onset (for some patients) by approximately 6 months.15-17 Unfortunately, not all patients have shown any benefit from these drugs, and it is unclear why this is the case or who may best be served by taking them.
Figure 1. Medial View of the Major Subdivisions of the Cortex
Reprinted with permission from Brainviews. Medial View of the Major Subdivisions of the Cortex. Available at: http://www.brainviews.com/abFiles/DrwMedlobes.jpg. Accessed February 4, 2008.13
Figure 2. Structures of the Brain Involved in Memory
Dementia of the Alzheimer’s type involves loss of ACh activity, and cellular degeneration in the nucleus basalis of Meynert and the cortex. Nicotinic cholinergic neurons are especially depleted.
ACh = acetylcholine.
Reprinted with permission from Medical College of Georgia. Brain Function: Learning and Memory. Available at: http://www.lib.mcg.edu/edu/eshuphysio/program/section8/8ch14/s8c14_26.htm. Accessed February 4, 2008.14
Again, as with establishing a diagnosis, neuroimaging may prove very useful to scientists and clinicians for monitoring of treatment effects, because biochemical assays cannot easily be accomplished for substances affecting the brain; therefore, so-called surrogate outcomes must be established. Furthermore, imaging also may help to determine whether treatments are in any way protective or whether their use is strictly limited to delaying symptoms.10
Use of CT, MRI, and MRS to Diagnose AD
Even though consensus criteria have been developed and applied to attempt to differentiate clinically between the major types of dementia, when pathologic findings are used to establish a definitive diagnosis, the sensitivity and specificity of these clinical criteria have only proven to be accurate between 34% and 97% of the time,18 and even upon postmortem examination, there may be evidence of more than 1 type of brain pathology. Therefore, CT and MRI have been employed to attempt to identify abnormal areas of the brain in individuals, not only to allow early detection, but to tailor patient management according to the underlying etiology and type of dementia. The American Academy of Neurology recommends structural neuroimaging with either a noncontrast head CT or MRI in the routine initial evaluation of all patients with dementia.19 MRI can provide structural information, because it has the necessary spatial resolution and tissue contrast to be able to image several areas of the brain. MRI pulse sequences have also been improved, resulting in the ability to note tissue characteristics, water diffusion, and vascular perfusion. Furthermore, MRI is nonionizing radiation, which makes it safe and useful for multiple imaging studies, should they be necessary for longitudinal studies.20
A related technique, MRS, otherwise known as nuclear magnetic resonance, tracks cerebral metabolites as a function of various types of brain pathology found among those with specific types of dementia, including AD. For example, a study by Pettegrew et al revealed alterations in membrane phospholipid metabolism and high-energy phosphate metabolism.21 Patients with mild dementia had increased levels of phosphomonoesters, decreased levels of phosphocreatine (and probably adenosine diphosphate), and an increased oxidative metabolic rate when compared with control subjects. The authors also noted that as the dementia worsened, levels of phosphomonoesters decreased and levels of phosphocreatine and adenosine diphosphate increased. The changes in oxidative metabolic rate suggest that AD places the brain under energetic stress, and MRS may be a new tool useful for diagnosing the metabolic changes that occur in AD, in addition to tracking the response to therapy.21
More than 100 studies have examined the role of MRI in the diagnosis and monitoring of AD.20 These studies have generally found that, although there may be global brain atrophy, affected areas of the brain most frequently include the anterior, temporal, parietal, and frontal lobes and the hippocampus (Figure 3).22 Patients with AD generally have symmetrical temporal lobe atrophy (in contrast to asymmetric changes sometimes noted in other types of dementia).
Figure 3. MRI Images of Hippocampal Atrophy
Arrow highlights the body of the hippocampus. Image on right is from a patient with atrophy.
Reprinted with permission from de Leon et al. J Intern Med. 2004;256:205-223.22
The hippocampus is located in the medial temporal lobe and, along with the amygdala and parahippocampual gyrus, comprises the limbic system, which appears to play a role in emotions, behavior, and memory (Figure 4).23 It is the hippocampus that may be the most severely affected in patients with AD.20,24 It is important to note that hippocampal atrophy appears to be a normal consequence of aging; however, if specific criteria can be developed to determine what is normal at each age milestone, changes in hippocampal volumes may be useful in detecting AD at an early or even preclinical stage, and then in following the course of the disease and treatment response.25 Quantitative MRI is important to the evaluation of the hippocampus, specifically measurements of the width of temporal horns and perihippocampal cerebrospinal fluid spaces. Volume measurements (volumetric MRI) should also be performed, because several studies have correlated hippocampal volume atrophy with cognitive decline, as indicated by poor scores on the MMSE or another scale, the Clinical Dementia Rating.20,26-32 Finally, individuals who may have a genetic predisposition to AD because they carry the apo E € 4 allele, have been noted in some studies to have a smaller hippocampal volume on MRI studies—regardless of whether or not they had overt dementia.33-35 Other limbic structures (parahippocampal gyrus and amygdala) appear to atrophy in patients with AD according to volumetric MRI studies conducted and compared to normal elderly subjects.36-38
Figure 4. The Limbic System—2 Views
A, limbic system. B, limbic system (cross-coronal section).
Reprinted with permission from Huntington’s Outreach Project for Education, at Stanford. The HOPES Brain Tutorial. Limbic System. Available at: http://www.stanford.edu/group/hopes/basics/braintut/ab5.html. Accessed February 4, 2008.23
Another important structure in the temporal lobe that provides input to the hippocampus is the entorhinal cortex (Figure 5).39 Being able to image the entorhinal cortex of high-risk or symptomatic patients (and specifically access its volume on MRI) may hold the key to early detection and risk prediction for AD. This is because some pathologic studies of patients with known AD have revealed that neuronal loss and the presence of neurofibrillary tangles are not only most severe, but appear earliest in this region of the brain—even more so than in the hippocampus.40-42 Furthermore, like the hippocampus, the entorhinal cortex plays an important role in memory. The difficulty in performing volumetric assessments of this portion of the brain on MRI is that it is difficult to delineate the borders of this region and differentiate it from other anatomic structures in the area; thus measurements may be unreliable.20
Figure 5. Entorhinal Cortex
The entorhinal cortex, shown in red, is the layer of grey matter tissue on a specific subregion of the parahippocampal gyrus of the temporal lobe.
Reprinted with permission from Oregon Health & Science University. Entorhinal Cortex Analysis. Available at: http://www.ohsu.edu/alzheimers/images/brain/vol_entorhinal1.jpg. Accessed February 4, 2008.39
Most MRI studies of brain atrophy have found that neuronal loss is greater in the gray matter than in white matter, although its significance in terms of memory function is unclear.20,43,44 MRI has detected more so-called white-matter signal hyperintensities on T2-weighted images of patients with AD, especially in the periventricular region, and this may be as a result of the loss of myelinated axons in deep white matter and stripping of the ventricular lining.20 Along with atrophy in various regions of the brain, there may be enlargement of the ventricular and sulcal cerebrospinal fluid spaces. It has been noted by researchers that these brain anomalies may be associated with decreased scores on the MMSE.45-47
Functional MRI (fMRI) is a specific type of MRI that can be used to detect changes in brain hemodynamics (perfusion) that then may be used to map specific areas of the brain responsible for various cognitive functions, and in the case of AD, to look for relationships between hemodynamic patterns and mental decline. This type of MRI is based on the observation that blood flow increases in the brain at the site of neural activity. Specifically, deoxyhemoglobin is paramagnetic, and thus, the MRI can identify areas of reduction in deoxyhemoglobin that correspond to increases in blood flow.48 Several small studies have noted that fMRI may detect changes in regional cerebral blood flow in mild cognitive impairment (MCI) and early AD.49,50 fMRI has the advantage over other imaging modalities (such as SPECT and PET, which are discussed later in this review) in that the signal does not require injection of radioactive isotopes, it is quicker, and provides higher resolution.48
Tracking Disease Progression with Longitudinal MRI Studies
Along with making an initial diagnosis, MRI studies also may hold the key to tracking disease progression. This may be assessed either by looking at global or focal brain changes (eg, hippocampal atrophy or temporal horn enlargement) over time among patients with AD. A certain amount of brain atrophy is normal and expected among elderly patients. It is generally in the range of 0.05% to 0.41% annually, which is considerably less than what has been found among individuals with AD. Researchers report a loss of brain volume on serial MRIs of 1% to 2.8% per year for patients with AD, and this has correlated with measurements of cognitive decline, such as scores on the MMSE.51-55 For example, in one study by Jack et al, rates of atrophy of 4 different brain structures were examined in serial MRIs over a period of 1 to 2 years.37 Specfically, the hippocampus, entorhinal cortex, whole brain, and ventricle were studied in terms of atrophy rate, and this information was compared to clinical measurements of cognitive decline (MMSE) in normal elderly and amnestic patients with MCI. MCI is a condition that is marked by cognitive changes related to memory (amnestic) and/or language, reading, writing, attention, reasoning, and judgment that are not as severe as what is noted in AD, but has been associated with AD (in the case of amnestic MCI).56 The authors found that among individuals with MCI, there were higher rates of atrophy of the whole brain and ventricle, and this was associated with a higher likelihood of developing AD. This was also true in normal older subjects when there were higher rates of ventricular enlargement on structural MRI, indicating that brain atrophy rates may predict subsequent clinical conversion to AD (Figure 6).22,37
Figure 6. Ventricular Anatomy in Control vs Patients with AD
AD = Alzheimer’s disease.
Reprinted with permission from de Leon et al. J Intern Med. 2004;256:205-223.22
Later studies by Devanand et al evaluating the usefulness of high-resolution T1-weighted MRIs of the hippocampus and entorhinal cortex supported the finding that smaller volumes in these regions also predicted conversion to AD for patients with MCI,57 whereas Meyer et al determined that medical temporal atrophy, greater enlargement of temporal horns, and fewer vascular lesions differentiated AD from other dementias, such as Parkinson-Lewy body or vascular dementias.58
Single Photon Emission CT
The same regions notable on fMRI also may demonstrate decreased perfusion using SPECT or PET. SPECT provides 3-dimensional images using a gamma camera to record the distribution of a radionucleotide as the camera is rotated around the patient—generally for 360° (Figure 7).6 As with conventional CT scan, thin cross-sectional images are obtained over a period of approximately 15 or 20 minutes. The γ-emitting tracer used for functional brain imaging is technetium-99 m with hexamethylpropylene amine oxime. Again, as with fMRI, blood brain flow is tied to cognitive effects. Specifically, the tracer’s uptake indicates brain metabolism at specific regions within the brain, and this correlates to criteria established for making a clinical diagnosis of AD, in addition to differentiating it from other forms of dementia, with sensitivities ranging from 71% to 91%.59-63
Figure 7. Comparison of Brain Perfusion SPECT Results for Individuals with MCI Who Do/Do Not Convert to AD
Comparison of Z-score mapping results for brain perfusion SPECT for converters (from amnestic MCI to AD) and nonconverters over 3 years. A, for 56-year-old woman who converted from MCI to AD, high values characterizing decreases in rCBF (severity and extent) were seen even at baseline. These values were markedly elevated 3 years later. B, for 68-year-old man who did not convert from MCI to AD, low values for severity and extent were seen at baseline. These values were not elevated 3 years later.
AD = Alzheimer’s disease; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; rCBF = regional cerebral blood flow; SPECT = single photon emission computed tomography; X MMSE = mean score to MMSE at the initial study; X + 3 MMSE = score on MMSE at 3 years.
Reprinted with permission from Matsuda. J Nucl Med. 2007;48:1289-1300.6
Positron Emission Tomography
Postitron emission tomography is another imaging modality that has shown promise for contributing to the diagnosis of AD, as well as enabling the search for more effective treatments. Similar to SPECT, PET scans use the radionucleotide 18F-fluorodeoxyglucose (FDG18), which is injected and then monitored for its uptake. The rate of glucose uptake by brain tissue corresponds to regional brain metabolism and can detect abnormal alterations in patterns that may help to differentiate from a normal brain, as well as one type of dementing disorder from another (Figure 8). For example, AD and another type of dementia, frontotemporal dementia (FTD), both have an insidious onset of gradual, progressive cognitive decline, and although AD is marked by memory loss compared to the behavior and language issues that distinguish FTD, sometimes the 2 are misdiagnosed. This is important because these disorders have a different prognosis, and it is also important for families to be aware of a diagnosis of FTD, because this is associated with a genetic predisposition toward early dementia in affected families. In addition, treatment is different, because cholinergic drugs will not be effective in patients with FTD. Through the use of PET, researchers have been able to differentiate 2 distinct patterns of pathology as reflected by patterns of glucose hypometabolism. Specifically, AD causes hypometabolism predominantly in posterior brain regions compared to in anterior structures with FTD.64-66
Figure 8. PET Images of a Normal Brain and a Brain Affected by AD
Brain scans done with PET show how AD affects brain activity. The left image (A) shows a normal brain, whereas the right (B) is from a person with AD. The blue and black areas in the right image indicate reduced brain activity resulting from the disease.
AD = Alzheimer’s disease; PET = positron emission tomography.
Courtesy of Alzheimer’s Disease Education and Referral Center, National Institute on Aging.
Positron emission tomography scanning also has identified regional brain abnormalities in subjects with dementia that were confirmed using neuropathologic diagnosis.67 In this large study by Silverman et al, it also was noted that if a subject had a negative PET scan, the “pathologic progression of cognitive impairment was unlikely to occur over the next 3 years,” thus demonstrating the prognostic value of PET scanning as well.67 These data were collected based on comparisons made from subjects’ PET scans and autopsy findings.
A more practical application of the PET scan technique has been to differentiate known, clinically diagnosed patients with AD from normal subjects.64 For example, in 1 large study by Herholz et al, the sensitivity and specificity were both 93% when scientists used a diagnostic indicator of PET scan abnormality based on age-adjusted t statistics and an automated voxel-based procedure to analyze data from 110 normal controls and 395 patients with probable AD.68 In controls, FDG18 uptake declined significantly with age in the anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD, there was a decline of FDG uptake in the posterior cingulate, temporoparietal, and prefrontal association cortex that was based on the severity of the dementia. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging and may be useful as a biomarker for early AD.68
Indeed, with both SPECT and PET technologies, abnormalities in hypoperfusion and hypometabolism may precede clinical signs and symptoms and may be helpful in diagnosing at-risk individuals.69,70 Although it has a higher sensitivity and spatial resolution, drawbacks to the PET test include its expense, time requirement, and its need to use an invasive radionucleotide tracer. It also is not as readily available as MRI and SPECT and may not be reimbursable with some insurance carriers. Continued research is focused on the false-positive results that have occurred with FDG18.
Monitoring Treatment Effects
Critical to formulating an early diagnosis and monitoring disease progression is the ability to determine whether a novel therapy or one under consideration in a clinical trial is effective in slowing the progression—or ideally, in curing—AD. It was actually the observation that there was a link between a decrease in choline acetyltransferase activity and an increase in neuritic plaque counts that led to the development of the first AD drugs.71 Today, it is hoped that various neuroimaging techniques may hold the key to the monitoring of treatment effects. In particular, pharmacologic MRI, SPECT, and PET may be helpful in tracking the pharmacodynamic effects of ChEI drugs. After a treatment is administered, changes in various brain parameters may be assessed for a variety of scenarios, including different patients and different drug dosages. Neuroimaging also can provide information about acute and chronic changes in the brain, in addition to indicating how long it may take for a medication to have an effect, which patients may benefit from a particular treatment, and what may be the consequences of delaying treatment. It is believed that use of techniques, such as PET or SPECT, will be more sensitive than using more subjective cognitive assessment techniques that are subject to patient variables outside of drug efficacy, such as patient fatigue.10 As previously noted, fMRI, SPECT, and PET imaging have the capabilities of monitoring regional cerebral blood flow and brain metabolism; therefore, these tests can obtain direct measures of the effects of various treatments on these parameters. For example, studies using these techniques have identified increases in brain blood flow and glucose metabolism, restoration of nicotinic receptor function (in the hippocampus these play an important role in memory), and re-establishment of task-related regional brain activation in response to cognitive stimulation after treatment. Structured MRI studies have identified specific patient groups that have benefited from the effects of given ChEI drugs and have also led researchers to believe that some of these treatments may be neuroprotective rather than merely for symptom management.10
Conclusions
At this point in time, AD is a condition that lacks a definitive means of diagnosis and a cure. Yet, increasing life expectancy coupled with the significant risk factor of advancing age will continue to increase the number of individuals and caregivers who must cope with this extremely disabling and ultimately fatal illness. Although at this point neuroimaging should be used only as an adjunct along with well-established clinical criteria, history, and physical examination, PET, SPECT, and various applications of MRI, including fMRI and MRS, are making promising contributions to the field of AD research. For example, they provide anatomic data, such as indications of global and regional brain atrophy and neuronal death, but they also have the capability to identify specific tissue changes that occur with dementia. These include functional measurements of blood volume, blood flow, and metabolites. Other applications of MRI someday also may include assessments of T2 relaxation time and water diffusion (damaged cells allow water molecules to move throughout the brain more freely), but thus far, studies in these areas are inconclusive.20 New techniques in the area of PET imaging, such as voxel-based analysis and the use of 11C-labeled Pittsburgh Compound-B tracer, which binds to β-amyloid plaques, are under investigation and may be even more specific in identifying AD than the current use of labeled glucose, and may be able to identify the condition in its earlier stages.12,72,73
These and other recent advancements hold out hope for an earlier and more accurate diagnosis that differentiates various types of dementias more accurately than current tools. In addition, identification in presymptomatic stages or when patients have MCI will aid patients and families in seeking genetic counseling and long-term planning options. They also may be able to predict which patients with MCI will ultimately develop AD. Last, but not least, imaging may assist in following patients over time with serial studies to determine the efficacy of various treatments, both for individuals and in clinical trials.
There remain many unanswered questions and unsolved problems, such as whether these more costly, time-consuming, and sometimes invasive techniques contribute anything substantial to the clinical diagnostic criteria currently in use for AD and whether these will be useful in finding a cure. It also is not known whether neuroimaging with respect to treatment will help to determine when clinicians should intervene for maximum effect, whether certain populations will be identified who do not appear to respond to treatment, and whether providing treatment might cause harm in some cases. However, there is encouragement that neuroimaging may be able to determine whether treatments will help manage symptoms or whether they will be truly disease modifying. Continued research is needed to further increase the diagnostic and therapeutic sensitivity of these neuoimaging modalities.
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