Tracking the decline in cerebral glucose metabolism in persons and laboratory animals at genetic risk for Alzheimer's disease

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Abstract

Brain imaging methods can be used to track declines in the cerebral metabolic rate for glucose (CMRgl) in the absence of symptoms in persons and laboratory animals at risk for Alzheimer's disease (AD). In fluorodeoxyglucose (FDG) positron emission tomography studies, late middle-aged, cognitively normal carriers of a common Alzheimer's susceptibility gene (the apolipoprotein E ε4 allele) had progressively reduced CMRgl in the same regions of the brain as patients with Alzheimer's dementia. In an FDG autoradiography study, transgenic mice carrying two copies of an Alzheimer's gene (a mutation in the amyloid precursor protein gene) had a similar CMRgl pattern, including progressively reduced CMRgl in the posterior cingulate cortex. Functional brain imaging techniques could be used to help bridge the gap between studies of patients with Alzheimer's dementia, cognitively normal persons at genetic risk for AD, and suitable laboratory animals. By providing a potential indicator of AD, these techniques could help clarify disease mechanisms and screen candidate treatments in at least some transgenic mice, and they could efficiently test the potential of candidate Alzheimer's prevention therapies in persons at genetic risk for the disorder.

Introduction

Alzheimer's disease (AD) is the most common form of cognitive impairment in older persons. As the population ages, the disorder is expected to take a growing toll on affected persons, their families, and the public health system. Brain imaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), find characteristic and progressive abnormalities in patients with Alzheimer's dementia, some of which can be detected prior to the onset of symptoms. This article reviews our use of brain imaging techniques to track declines in the cerebral metabolic rate for glucose (CMRgl) in the absence of symptoms in cognitively normal persons and transgenic mice at genetic risk for AD. It considers how these techniques could be used to help clarify disease mechanisms and screen candidate treatments in transgenic mice and other suitable laboratory animals, and it considers how they could be used to efficiently test the potential of treatments to prevent AD in cognitively normal persons at genetic risk for the disorder.

In Section 2, we briefly consider the clinical features and escalating toll of AD; we cite progress in the scientific understanding, treatment, and potential prevention of the disorder; we indicate the need for techniques to track AD in the absence of symptoms; and we illustrate how different brain imaging methods are being used in the study of AD. In Section 3, we review our cross-sectional comparisons of fluorodeoxyglucose (FDG) PET and volumetric MRI data in cognitively normal apolipoprotein E (APOE) ε4 homozygotes and non-carriers, our cross-sectional and longitudinal comparisons of FDG PET data in cognitively normal APOE ε4 heterozygotes and non-carriers, and our comparisons of FDG autoradiographic data in transgenic mice overexpressing a mutant form of the human amyloid precursor protein (APP) and non-transgenic mice; and we consider how these and other brain imaging techniques could be used to track AD, help understand disease mechanisms, and help identify candidate treatments in the absence of symptoms.

Alzheimer's dementia is characterized by a gradual and continuing decline in memory and other cognitive functions [1], [2], [3]. The syndrome may begin with a monosymptomatic progressive amnesic syndrome, popularly termed mild cognitive impairment (MCI), or as a polysymptomatic syndrome with elements of aphasia, apraxia, agnosia, and impaired executive functions. Associated episodes of delirium may occur in response to certain medications, illnesses, stressors, and environmental changes. In the advanced stages of the illness, patients may be extremely confused, bedridden, incontinent, and unable to feed themselves. In addition to cognitive impairment, most patients with Alzheimer's dementia develop other behavioral disturbances, which are a common source of caregiver distress and the most common reason for nursing home placement. Non-cognitive behavioral features include suspiciousness, paranoia, delusions, hallucinations, wandering or pacing, verbal or physical aggression, apathy or social withdrawal, repeating rituals, depression, inappropriate or unsafe behaviors (e.g. impaired driving), incontinence, and a decline in personal hygiene. While the duration of illness varies greatly, it commonly lasts about 8–10 years. AD shortens life expectancy and is the fourth leading cause of death in the United States [4]. Some deaths are attributable to intervening illnesses indirectly related to AD (e.g. pneumonia and sepsis), some are attributable to falls and other accidents, and others are due to terminal complications of the disorder (e.g. inanition and aspiration).

While AD has a devastating impact on the affected person, it often takes an extraordinary toll on the person's family. Family caregivers often feel helpless, frustrated, and physically exhausted, and almost half become clinically depressed [5]. They may need to deplete their savings before the affected person is eligible to receive financial assistance for long-term care.

According to one community survey, Alzheimer's dementia afflicts about 10% of those over the age of 65 and almost half of those over the age of 85 years [6]. According to a 1990 estimate, the annual cost associated with each person with Alzheimer's dementia is about $47 000 per year [7]. As the population ages, the prevalence of this disorder is projected to quadruple in the next 50 years [8]: By then the prevalence of Alzheimer's dementia could grow from 4 to 16 million cases (with no adjustment for any increase in the patients’ life expectancy) and the annual cost of the disorder could grow from 188 to 752 million dollars per year (with no adjustment for inflation) in the United States alone [9]. An Alzheimer's prevention therapy is needed to avert a catastrophic public health problem.

Even if a prevention therapy were only modestly helpful, it would provide an extraordinary public health benefit. While prevalence and incidence estimates depend on the techniques used to identify and screen subjects, the severity criterion used to identify persons with dementia, and the percentage of persons with dementia considered to have AD, studies consistently find that the prevalence and incidence of Alzheimer's dementia doubles every 5 years between 65 and 85 years of age [10]. For this reason, it has been suggested that a prevention therapy that delayed the mean onset of Alzheimer's dementia by only 5 years might reduce the risk of the disorder by half [11].

Scientific progress in the last few years has raised the hope of identifying treatments to halt the progression and prevent the onset of AD.

First, researchers continue to characterize the cascade of molecular events which lead to the major histopathological features of the disorder: neuritic plaques, which contain extra-cellular deposits of amyloid β-peptides (Aβ); neurofibrillary tangles, which contain the hyperphosphorylated form of the intracellular, microtubule-associated protein, tau; and a loss of neurons and synapses [3], [12], [13]. These molecular events provide targets for the development of promising new treatments. For instance, Aβ has been postulated to trigger a cascade of events that are involved in the pathogenesis of AD [13], [14]. This cascade is thought to include the sequential cleavage of the β-amyloid precursor protein (APP) into Aβ peptides by β-secretase and γ-secretase, the aggregation of Aβ peptides, the entry of calcium into neurons, complement activation and low-grade inflammation, excitatory and oxidative events, and other potentially toxic molecular events [14]. To the extent that Aβ and one or more of its consequences are necessary for the development of AD (i.e. not just a byproduct of the disorder), the inhibition of inhibitors of β- or γ-secretase, calcium-channel blockers, anti-inflammatory medications, antioxidants, and other interventions have the potential to decrease the risk, delay the onset, or attenuate the progression of Alzheimer's dementia.

Second, researchers continue to characterize the genetic risk factors and gene products which account for many cases of AD [3], [15], [16], [17], [18], [19], [20], [21], [22], [23]. Patients with Trisomy 21 (Down's syndrome) have an abundance of neuritic plaques after the age of 40 and about 75% have dementia after the age of 60 [3], [10]. To date, researchers have identified at least 11 mutations of the APP gene on chromosome 21, at least 81 mutations of the presenilin 1 (PS1) gene on chromosome 14, and at least six mutations of the presenilin 2 (PS2) gene on chromosome 1 which account for most cases of AD with an early onset of dementia (typically prior to the age of 60) and autosomal dominant inheritance [15] (http://molgen-www.uia.ac.be/ADMutations). In addition to these relatively rare ‘AD genes,’ researchers have identified ‘AD susceptibility genes’ that account for many cases of AD with a late onset of dementia (usually after the age of 60) with or without a reported family history of dementia. The best established AD susceptibility gene is the APOE ε4 allele, which appears to account for about half of AD cases [16], [17], [24]. In addition, one or more loci on chromosome 12 (which may or may not include the gene for α2-macroglobulin) and a locus on chromosome 10 (which appears to be near the gene for insulin degrading enzyme) may account for many other cases of late-onset AD [19], [20], [21], [22], [23]. These genetic loci and other candidate genes remain to be confirmed and better characterized. (Mutations of the gene for tau on chromosome 17 have been linked to frontotemporal dementia with Parkinsonism (FTPD-17), a less common, familial disorder characterized by the widespread deposition of neurofibrillary tangles in the absence of neuritic plaques [15], [25], [26] (http://www.alzforum.org/members/research/tau/tau_references.html)).

The APOE gene is especially relevant to our human brain imaging studies. This gene has three major alleles, ε2, ε3, and ε4. While the ε3 allele is the most common variant, the ε4 allele is found in about one fourth of the population [30]. In comparison with the ε3 allele, the ε2 allele is associated with a lower risk of AD and a later age at dementia onset [18]. In contrast, the ε4 allele is associated with a higher risk of AD and an earlier age at dementia onset, and persons with two copies of this allele have a particularly high risk of Alzheimer's dementia [16], [17], [23]. Brain imaging studies of cognitively normal persons with this common AD susceptibility gene have the potential to track disease progression and efficiently screen candidate prevention therapies.

Interestingly, the three well-established AD genes and the implicated locus on chromosome 10 are each associated with an elevation in plasma levels of Aβ (particularly a form of this peptide with 42 amino acids), providing additional support for the role of amyloid in the pathogenesis of AD [14], [23]. Indeed, PS1 and PS2 are homologous proteins which appear to play critical roles in the cleavage of APP by γ-secretase [14]. While the APOE ε4 is not associated with an elevation in plasma levels of Aβ, the APOE E4 isoform has been suggested to serve as a pathological chaperone for the aggregation of Aβ [27]. Conversely, it has been suggested that the APOE isoforms associated with a lower risk of AD (i.e. E2 and E3) may inhibit Aβ-induced cytotoxicity [28], and that they may preferentially bind to tau, preventing hyperphosphorylation [29].

Together, these genetic discoveries promise to provide a better understanding of the molecular events involved in the pathogenesis of AD, the development of genetically engineered laboratory animals (e.g. mice with one or more transgenes, knockouts, and their combinations), and the identification of persons at risk for AD. Our brain imaging studies capitalize on the study of persons and laboratory animals at genetic risk for AD.

Third, researchers continue to identify treatments with the potential to treat and prevent AD. For instance, indirect evidence suggests that several commonly used medications and dietary supplements (e.g. estrogen-replacement therapy [31], [32], anti-inflammatory medications [33], [34], and vitamin E [35]) might decrease the risk, delay the onset, or attenuate the progression of AD.

While estrogen replacement therapy does not appear to attenuate the progression of Alzheimer's dementia [36], it continues to have promise in AD prevention. Several epidemiological studies find that estrogen replacement therapy is associated with a decreased risk and delayed onset of Alzheimer's dementia [31], [32]. Estrogen and other reproductive hormones have several neurobiological effects that are potentially relevant to the treatment or prevention of AD, and we recently found that short-term treatment with a combination of estrogen and methyltestosterone in healthy post-menopausal women was associated with increased cerebral glucose metabolism in brain regions that are preferentially affected in patients with Alzheimer's dementia and cognitively normal persons at genetic risk for AD [37]. The Women's Health Initiative Memory Study (WHIMS) has enrolled more than 7500 women 65–79 years of age in a 10-year randomized, double-blind, placebo-controlled study to test the ability of estrogen replacement therapy to decrease the risk of ‘all-cause’ dementia [38].

Similarly, while prednisone does not appear to attenuate the progression of Alzheimer's dementia [39], other inflammatory medications continue to be studied in patients with Alzheimer's dementia and may have more promise in the prevention of AD. Neuropathological studies find that AD is associated with low-grade inflammation and several epidemiological studies find that anti-inflammatory medications are associated with a decreased risk of Alzheimer's dementia [33], [34]. Promising prevention medications include the non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and the cyclooxygenase-2 (COX-2) inhibitors, which may be associated with fewer gastric and renal problems. This year, the AD Anti-inflammatory Primary Prevention Trial (ADAPT) will begin to enroll about 2900 cognitively normal persons over the age of 70 in a randomized, double-blind, placebo-controlled study to test the efficacy of naproxen (Aleve, an NSAID) and celecoxib (Celebrex, a COX-2 inhibitor) in the prevention of Alzheimer's dementia.

Oxidative changes have been postulated to play roles in the pathogenesis of AD and normal aging. In a study of patients with Alzheimer's dementia, the anti-oxidants vitamin E and selegiline (an inhibitor of monoamine oxidase B activity) delayed the onset of nursing home placement [35]. The AD Cooperative Study is conducting a 3-year, randomized, double-blind, placebo-controlled trial of vitamin E and the cholinesterase inhibitor donepezil (Aricept) in about 720 patients with MCI, who in one study developed Alzheimer's dementia at the rate of about 12% per year [40]. (While cholinesterase inhibitors are thought to attenuate the progression of AD symptoms [41], [42], [43], [44], there is suggestive evidence that cholinergic compounds might attenuate the progression of AD pathology: patients treated later in the course of their illness may have more significant cognitive impairment than those who are treated earlier [44], treatment with a muscarinic agonist decreases cerebrospinal fluid levels of total Aβ [45], and experimental cholinergic denervation in rabbits leads to vascular Aβ deposition [46].)

Finally, the pharmaceutical industry has begun to develop several innovative treatments, which have enormous potential in the treatment and prevention of Alzheimer's dementia. β-secretase has been identified [47]; compounds that functionally inhibit γ-secretase continue to be developed [48], [49], and some of these compounds are in the early stages of testing. In transgenic mice containing a human AD gene, immunization with a synthetic form of Aβ prevents the formation of amyloid plaques when administered in young animals, and it attenuates the formation and promotes the clearance of amyloid plaques when administered to older animals [50]. Passively administered antibodies have similar effects [51]. Aβ immunization is now being tested in Phase 1 clinical trials to confirm its safety (e.g. the absence of autoimmune effects) and determine the optimal regimen needed to produce adequate antibody titers. Other potential ‘plaque busters’ could bind to and inhibit the aggregation of Aβ monomers [14]. To the extent the amyloid is necessary for the development of AD and the treatments are well tolerated, these compounds have the potential to halt the progression and prevent the onset of Alzheimer's dementia.

While researchers are making remarkable progress in the effort not only to treat but also to prevent AD, an important problem remains: How can one identify an effective primary prevention therapy without losing a generation of persons along the way? While case-control studies of treatments like estrogen replacement therapy and anti-inflammatory medications are promising, findings can be confounded by selection bias. For instance, it remains possible that the use of these interventions could be related to educational level, which is independently related to a lower risk of Alzheimer's dementia; there could also be differences in the ability of patients and controls to recollect prior medication use.

Randomized, placebo-controlled trials are needed to establish the efficacy of a candidate prevention therapy. However, it would require thousands of research subjects, many years, and great expense to determine whether or when cognitively normal persons treated with a candidate primary prevention therapy develop Alzheimer's dementia. As previously noted, the Women's Health Initiative Memory Study has enrolled more than 7500 post-menopausal women over the age of 65 in a 10-year randomized, double-blind, placebo-controlled study to test the ability of estrogen replacement therapy to decrease the risk of ‘all-cause’ dementia [38]. While the investigators understand that women might require treatment at a younger age (i.e. sooner after menopause) for estrogen replacement therapy to decrease the risk of Alzheimer's dementia, it would require too many research subjects, too many years, and an enormous amount of money to determine whether or when cognitively normal women treated in their 50s develop Alzheimer's dementia.

One way to reduce the sample sizes and study duration required to assess the efficacy of a candidate prevention therapy is to conduct what might be considered a secondary prevention study in patients with MCI, who have an increased risk of dementia [40]. Clinical trials in MCI patients are already being employed to evaluate the ability of certain treatments to attenuate cognitive decline and conversion to Alzheimer's dementia. While this strategy is extremely important, it still remains possible that subjects would require treatment at an earlier age or at an earlier preclinical stage of AD for a candidate prevention therapy to exert its most beneficial effects. Indeed, it is possible that some treatments might effectively prevent the onset of AD even if they are relatively ineffective after the onset of the disorder.

We have been using brain imaging techniques to track the changes in brain function and brain structure that precede the onset of any cognitive impairment in persons at genetic risk for AD. Assuming these CMRgl declines are related to the predisposition to AD, we suggest that this paradigm could be used to efficiently test the potential of candidate Alzheimer's prevention therapies.

Section snippets

Overview

Several brain imaging techniques have been used by researchers to assist in the diagnosis, early detection, and tracking of AD and other dementias. Functional imaging techniques include PET, single photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS), and functional MRI (fMRI). Structural imaging techniques include MRI and computed tomography (CT). In this section, we briefly review applications of PET and structural MRI to the scientific study of AD.

When used to

Transgenic mouse brain imaging studies

In order to understand the pathogenesis of AD and identify promising treatments, it would be helpful to have a marker of the disease in small laboratory animals. Transgenic mice containing one or more AD genes develop some of the histopathological features of AD, including amyloid plaques, neuritic dystrophy, synaptic loss, and gliosis [108], [109], [110], [111], [112], [113], [114], [115]. While transgenic mice have great promise, uncertainties remain about the extent to which they provide a

Conclusion

Brain imaging techniques could be used to help bridge the gap between studies of patients with Alzheimer's dementia, cognitively normal persons at genetic risk for AD, and suitable laboratory animals. In at least one transgenic mouse line, these techniques could help clarify disease mechanisms and screen candidate treatments, helping the pharmaceutical industry select which treatments to test in expensive clinical trials. In persons with at least one common AD susceptibility gene, these

Acknowledgements

This study was supported by grants from the National Institutes of Health (MH57899-01A1), the Samaritan and Mayo Clinic Foundations, and the Arizona Center for Alzheimer's Disease Research.

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