Aims

The current study sought to explore the relationship between state and trait anxiety and delayed verbal memory performance in APOE-4 carriers and noncarriers who were aged 50 years and above.

Materials & methods

The study was a retrospective analysis of 267 participants aged 50 years and above who had completed genetic testing for APOE status, the State-Trait Anxiety Inventory, and a comprehensive neuropsychological battery that included three delayed verbal memory measures (Wechsler Memory Scale – 3rd Edition, Logical Memory and Verbal Pairs subtests and the Buschke Selective Reminding Test).

Results

An inverse relationship was found between state anxiety and delayed verbal memory performance. No difference in level of anxiety was found between APOE-4 carriers versus noncarriers.

Conclusion

State anxiety, but not trait anxiety, was found to have an inverse relationship with delayed verbal memory performance. For example, as self-reported state anxiety increased, delayed verbal memory scores decreased. This relationship did not appear to be influenced by the presence or absence of the APOE-4 allele.

In vivo detection of Alzheimer's disease (AD) neuropathology in living patients using positron emission tomography (PET) in conjunction with high affinity molecular imaging probes for β-amyloid (Aβ) and tau has the potential to assist with early diagnosis, evaluation of disease progression, and assessment of therapeutic interventions. Animal models of AD are valuable for exploring the in vivo binding of these probes, particularly their selectivity for specific neuropathologies, but prior PET experiments in transgenic mice have yielded conflicting results. In this work, we utilized microPET imaging in a transgenic rat model of brain Aβ deposition to assess [F-18]FDDNP binding profiles in relation to age-associated accumulation of neuropathology. Cross-sectional and longitudinal imaging demonstrated that [F-18]FDDNP binding in the hippocampus and frontal cortex progressively increases from 9 to 18 months of age and parallels age-associated Aβ accumulation. Specificity of in vivo [F-18]FDDNP binding was assessed by naproxen pretreatment, which reversibly blocked [F-18]FDDNP binding to Aβ aggregrates. Both [F-18]FDDNP microPET imaging and neuropathological analyses revealed decreased Aβ burden after intracranial anti-Aβ antibody administration. The combination of this non-invasive imaging method and robust animal model of brain Aβ accumulation allows for future longitudinal in vivo assessments of potential therapeutics for AD that target Aβ production, aggregation, and/or clearance. These results corroborate previous analyses of [F-18]FDDNP PET imaging in clinical populations.

We evaluate an automated approach to the cortical surface mapping (CSM) method of VOI analysis in PET. Although CSM has been previously shown to be successful, the process can be long and tedious. Here, we present an approach that removes these difficulties through the use of 3D image warping to a common space. We test this automated method using studies of FDDNP PET in Alzheimer's disease and mild cognitive impairment. For each subject, VOIs were created, through CSM, to extract regional PET data. After warping to the common space, a single set of CSM-generated VOIs was used to extract PET data from all subjects. The data extracted using a single set of VOIs outperformed the manual approach in classifying AD patients from MCIs and controls. This suggests that this automated method can remove variance in measurements of PET data and can facilitate accurate, high-throughput image analysis.

Objectives

To determine the neuropathological load in the living brain of nondemented adults with Down syndrome using positron emission tomography with 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) and to assess the influence of age and cognitive and behavioral functioning. For reference, [18F]FDDNP binding values and patterns were compared with those from patients with Alzheimer disease and cognitively intact control participants.

Design

Cross-sectional clinical study.

Participants

Volunteer sample of 19 persons with Down syndrome without dementia (mean age, 36.7 years), 10 patients with Alzheimer disease (mean age, 66.5 years), and 10 controls (mean age, 43.8 years).

Main Outcome Measures

Binding of [18F]FDDNP in brain regions of interest, including the parietal, medial temporal, lateral temporal, and frontal lobes and posterior cingulate gyrus, and the average of all regions (global binding).

Results

The [18F]FDDNP binding values were higher in all brain regions in the Down syndrome group than in controls. Compared with the Alzheimer disease group, the Down syndrome group had higher [18F]FDDNP binding values in the parietal and frontal regions, whereas binding levels in other regions were comparable. Within the Down syndrome group, age correlated with [18F]FDDNP binding values in all regions except the posterior cingulate, and several measures of behavioral dysfunction showed positive correlations with global, frontal, parietal, and posterior cingulate [18F]FDDNP binding.

Conclusions

Consistent with neuropathological findings from postmortem studies, [18F]FDDNP positron emission tomography shows high binding levels in Down syndrome comparable to Alzheimer disease and greater levels than in members of a control group. The positive associations between [18F]FDDNP binding levels and age as well as behavioral dysfunction in Down syndrome are consistent with the age-related progression of Alzheimer-type neuropathological findings in this population.

Previous functional magnetic resonance imaging (MRI) studies in healthy subjects with the apolipoprotein E 4 (APOE-4) genetic risk for Alzheimer’s disease have shown increased activation during memory task performance in broadly distributed cortical regions. These findings have been hypothesized to reflect compensatory recruitment of intact brain regions that presumably result from subtle neural dysfunction reflecting incipient disease. In this study, we used high-resolution functional MRI in APOE-4 carriers and non-carriers to measure activity in hippocampal subregions (CA fields 1, 2, 3; dentate gyrus [DG], and subiculum) and adjacent medial temporal lobe (parahippocampal and entorhinal) subregions. We found reduced left CA2, 3 and dentate gyrus (CA23DG) activity in cognitively intact APOE-4 carriers. These results suggest that reduced neural activity in hippocampal subregions may underlie the compensatory increase in extra hippocampal activity in people with a genetic risk for Alzheimer’s disease prior to the onset of cognitive deficits.

Wavelet analysis is developed as a preprocessing tool for use in removing background information from near-infrared (near-IR) single-beam spectra before the construction of multivariate calibration models. Three data sets collected with three different near-IR spectrometers are investigated that involve the determination of physiological levels of glucose (1-30 mM) in a simulated biological matrix containing alanine, ascorbate, lactate, triacetin, and urea in phosphate buffer. A factorial design is employed to optimize the specific wavelet function used and the level of decomposition applied, in addition to the spectral range and number of latent variables associated with a partial least-squares calibration model. The prediction performance of the computed models is studied with separate data acquired after the collection of the calibration spectra. This evaluation includes one data set collected over a period of more than six months. Preprocessing with wavelet analysis is also compared to the calculation of second-derivative spectra. Over the three data sets evaluated, wavelet analysis is observed to produce better-performing calibration models, with improvements in concentration predictions on the order of 30% being realized relative to models based on either second-derivative spectra or spectra preprocessed with simple additive and multiplicative scaling correction. This methodology allows the construction of stable calibrations directly with single-beam spectra, thereby eliminating the need for the collection of a separate background or reference spectrum.

Amyloid plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer’s disease (AD), begin accumulating in the healthy human brain decades before clinical dementia symptoms can be detected. There is great interest in how this pathology spreads in the living brain and its association with cognitive deterioration. Using MRI-derived cortical surface models and four-dimensional animation techniques, we related cognitive ability to positron emission tomography (PET) signal from 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP), a molecular imaging probe for plaques and tangles. We examined this relationship at each cortical surface point in 23 older adults (10 cognitively intact, 6 with amnestic mild cognitive impairment, 7 with AD). [18F]FDDNP-PET signal was highly correlated with cognitive performance, even in cognitively intact subjects. Animations of [18F]FDDNP signal growth with decreased cognition across all subjects (http://www.loni.ucla.edu/~thompson/FDDNP/video.html) mirrored the classic Braak and Braak trajectory in lateral temporal, parietal, and frontal cortices. Regions in which cognitive performance was significantly correlated with [18F]FDDNP signal include those that deteriorate earliest in AD, suggesting the potential utility of [18F]FDDNP for early diagnosis.

People with the apolipoprotein-Eε4 (APOE-4) genetic risk for Alzheimer’s disease show morphologic differences in medial temporal lobe regions when compared to non-carriers of the allele. Using a high-resolution MRI and cortical unfolding approach, our aim was to determine the rate of cortical thinning among medial temporal lobe subregions over the course of 2 years. We hypothesized that APOE-4 genetic risk would contribute to longitudinal cortical thickness change in the subiculum and entorhinal cortex, regions preferentially susceptible to Alzheimer’s disease related pathology. Thirty-two cognitively intact subjects, mean age 61 years, 16 APOE-4 carriers, 16 non-carriers, underwent baseline and follow-up MRI scans. Over this relatively brief interval, we found significantly greater cortical thinning in the subiculum and entorhinal cortex of APOE-4 carriers when compared to non-carriers of the allele. Average cortical thinning across all medial temporal lobe subregions combined was also significantly greater for APOE-4 carriers. This finding is consistent with the hypothesis that carrying the APOE-4 allele renders subjects at a higher risk for developing Alzheimer’s disease.

This review summarizes the scientific talks presented at the conference “Therapeutics for Cognitive Aging,” hosted by the New York Academy of Sciences and the Alzheimer’s Drug Discovery Foundation on May 15, 2009. Attended by scientists from industry and academia, as well as by a number of lay people—approximately 200 in all—the conference specifically tackled the many aspects of developing therapeutic interventions for cognitive impairment. Discussion also focused on how to define cognitive aging and whether it should be considered a treatable, tractable disease.

Objective

Structural brain changes appear years before the onset of Alzheimer’s disease, the leading cause of dementia late in life. Determining risk factors for such presymptomatic brain changes may assist in identifying candidates for future prevention treatment trials. In addition to the e4 allele of the apolipoprotein E gene (APOE-4), the major known genetic risk factor, a family history of Alzheimer’s disease also increases the risk to develop the disease, reflecting yet unidentified genetic and, perhaps, nongenetic risks. The authors investigated the influence of APOE-4 genotype and family history risks on cortical thickness in medial temporal lobe subregions among volunteers without cognitive impairment.

Method

High-resolution magnetic resonance imaging (MRI) and a cortical unfolding method were performed on 26 subjects (APOE-4 carriers: N =13; noncarriers: N =13) with at least one first-degree relative with Alzheimer’s disease and 25 subjects (APOE-4 carriers: N =12; noncarriers: N =13) without this risk factor. All subjects (mean age: 62.3 years [SD=10.7]; range=38–86 years) were cognitively healthy.

Results

Family history of Alzheimer’s disease and APOE-4 status were associated with a thinner cortex in the entorhinal region, subiculum, and adjacent medial temporal lobe subfields. Although these associations were additive, family history of Alzheimer’s disease explained a greater proportion of the unique variance in cortical thickness than APOE-4 carrier status.

Conclusions

APOE-4 carrier status and family history of Alzheimer’s disease are independently associated with and contribute additively to hippocampal cortical thinning.

The spatial correlations between the brain's default mode network (DMN) and the brain regions known to develop pathophysiology in Alzheimer's disease (AD) have recently attracted much attention. In this paper, we compare results of different functional and structural imaging modalities, including MRI and PET, and highlight different patterns of anomalies observed within the DMN. Multitracer PET imaging in subjects with and without dementia has demonstrated that [C-11]PIB- and [F-18]FDDNP-binding patterns in patients with AD overlap within nodes of the brain's default network including the prefrontal, lateral parietal, lateral temporal, and posterior cingulate cortices, with the exception of the medial temporal cortex (especially, the hippocampus) where significant discrepancy between increased [F-18]FDDNP binding and negligible [C-11]PIB-binding was observed. [F-18]FDDNP binding in the medial temporal cortex—a key constituent of the DMN—coincides with both the presence of amyloid and tau pathology, and also with cortical areas with maximal atrophy as demonstrated by T1-weighted MR imaging of AD patients.

Purpose

The aim of this study was to investigate the longitudinal positron emission tomography (PET) metabolic changes in the elderly.

Procedures

Nineteen nondemented subjects (mean Mini-Mental Status Examination 29.4 ± 0.7 SD) underwent two detailed neuropsychological evaluations and resting 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)-PET scan (interval 21.7 ± 3.7 months), baseline structural 3T magnetic resonance (MR) imaging, and apolipoprotein E4 genotyping. Cortical PET metabolic changes were analyzed in 3-D using the cortical pattern matching technique.

Results

Baseline vs. follow-up whole-group comparison revealed significant metabolic decline bilaterally in the posterior temporal, parietal, and occipital lobes and the left lateral frontal cortex. The declining group demonstrated 10–15% decline in bilateral posterior cingulate/precuneus, posterior temporal, parietal, and occipital cortices. The cognitively stable group showed 2.5–5% similarly distributed decline. ApoE4-positive individuals underwent 5–15% metabolic decline in the posterior association cortices.

Conclusions

Using 3-D surface-based MR-guided FDG-PET mapping, significant metabolic changes were seen in five posterior and the left lateral frontal regions. The changes were more pronounced for the declining relative to the cognitively stable group.

Entorhinal cortex (ERC) volume in adults with mild cognitive impairment has been shown to predict prodromal Alzheimer's disease (AD). Likewise, neuronal loss in ERC has been associated with AD, but not with normal aging. Because ERC is part of a major pathway modulating input to the hippocampus, structural changes there may result in changes to cognitive performance and functional brain activity during memory tasks. In 32 cognitively intact older adults, we examined the relationship between left ERC thickness and functional magnetic resonance imaging (fMRI) activity during an associative verbal memory task. This task has been shown previously to activate regions that are sensitive to aging and AD risk. ERC was manually defined on native space, high resolution, oblique coronal MRI scans. Subjects having thicker left ERC showed greater activation in anterior cingulate and medial frontal regions during memory retrieval, but not encoding. This result was independent of hippocampal volume. Anterior cingulate cortex is directly connected to ERC, and is, along with medial frontal cortex, implicated in error detection, which is impaired in AD. Our results suggest that in healthy older adults, processes that engage frontal regions during memory retrieval are related to ERC structure.

Vascular problems increase Alzheimer’s disease (AD) risk, but the nature of this relationship remains unclear. Older adults having genetic risk for AD show regionally increased functional magnetic resonance imaging (fMRI) activity during memory, possibly representing compensation for a genetically induced neural deficit. We investigated whether vascular health risks, which similarly could lead to neuropsychological deficits, also showed increased fMRI activity during a memory task performed by 30 cognitively intact, primarily normotensive older adults (mean age = 61). Vascular risk measures included systolic blood pressure (sBP), body mass index (BMI), and total cholesterol. Higher sBP and BMI (but not total cholesterol) were significantly correlated with increased activation in posterior cingulate cortex and frontal, temporal, and parietal regions. In posterior cingulate and parietal cortices, these relationships were evident even within sBP and BMI ranges considered normal, and were independent of hippocampal volume. Our results are similar to those in prior AD risk research, and suggest that fMRI reveals an abnormal response to cognitive processes in cognitively intact older adults with increased vascular risk.

Head movement during a PET scan (especially, dynamic scan) can affect both the qualitative and quantitative aspects of an image, making it difficult to accurately interpret the results. The primary objective of this study was to develop a retrospective image-based movement correction (MC) method and evaluate its implementation on dynamic [18F]-FDDNP PET images of cognitively intact controls and patients with Alzheimer’s disease (AD).

Methods

Dynamic [18F]-FDDNP PET images, used for in vivo imaging of beta-amyloid plaques and neurofibrillary tangles, were obtained from 12 AD and 9 age-matched controls. For each study, a transmission scan was first acquired for attenuation correction. An accurate retrospective MC method that corrected for transmission-emission misalignment as well as emission-emission misalignment was applied to all studies. No restriction was assumed for zero movement between the transmission scan and first emission scan. Logan analysis with cerebellum as the reference region was used to estimate various regional distribution volume ratio (DVR) values in the brain before and after MC. Discriminant analysis was used to build a predictive model for group membership, using data with and without MC.

Results

MC improved the image quality and quantitative values in [18F]-FDDNP PET images. In this subject population, medial temporal (MTL) did not show a significant difference between controls and AD before MC. However, after MC, significant differences in DVR values were seen in frontal, parietal, posterior cingulate (PCG), MTL, lateral temporal (LTL), and global between the two groups (P < 0.05). In controls and AD, the variability of regional DVR values (as measured by the coefficient of variation) decreased on average by >18% after MC. Mean DVR separation between controls and ADs was higher in frontal, MTL, LTL and global after MC. Group classification by discriminant analysis based on [18F]-FDDNP DVR values was markedly improved after MC.

Conclusion

The streamlined and easy to use MC method presented in this work significantly improves the image quality and the measured tracer kinetics of [18F]-FDDNP PET images. The proposed MC method has the potential to be applied to PET studies on patients having other disorders (e.g., Down syndrome and Parkinson’s disease) and to brain PET scans with other molecular imaging probes.

Objectives

Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that may be associated with mild cognitive impairment or mood and anxiety symptoms years before the dementia diagnosis. To address this issue, we obtained positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl} ethylidene) malononitrile (FDDNP), a molecule that binds to amyloid plaques and neurofibrillary tangles, to determine whether symptoms of depression and anxiety in non-demented subjects were associated with increased FDDNP-PET binding values.

Methods

Forty-three middle-aged and elderly volunteers received clinical and FDDNPPET assessments. Subjects were non-demented - 23 of them were diagnosed with MCI, and 20 were cognitively normal. Subjects with a diagnosis of major depression or an anxiety disorder were excluded. Correlations between standardized measures of depressive and anxiety symptoms and regional FDDNP binding values were calculated.

Results

The MCI and comparison subjects did not differ by the depression and anxiety scores. In the MCI group, depression correlated with lateral temporal, and trait anxiety correlated with posterior cingulate FDDNP binding. In the comparison group, depression correlated with medial temporal, and trait anxiety scores correlated with medial temporal , and frontal FDDNP binding.

Discussion

This is the first report to demonstrate a relationship between the severity of depression and anxiety symptoms and FDDNP binding values in non-demented middle age and older individuals. The results suggest a relationship between relatively mild mood symptoms and biomarkers of cerebral amyloid and tau deposition and vary according to degree of cognitive impairment. The presence of MCI may signify different pathophysiological mechanisms underlying mood and anxiety symptoms.

Background

The ε4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer’s disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer’s disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition.

Methods

We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE ε4 allele and 14 were homozygous for the APOE ε3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later.

Results

Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer’s disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE ε4 allele than among the carriers of the APOE ε3 allele. During periods of recall, the carriers of the APOE ε4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (±SD) number of activated regions throughout the brain (15.9±6.2 vs. 9.4±5.5, P=0.005) than did carriers of the APOE ε3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory.

Conclusions

Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer’s disease and may predict a subsequent decline in memory.

Purpose

Subcortical white matter is known to be relatively unaffected by amyloid deposition in Alzheimer’s disease (AD). We investigated the use of subcortical white matter as a reference region to quantify [18F]FDDNP binding in the human brain.

Methods

Dynamic [18F]FDDNP PET studies were performed on 7 control subjects and 12 AD patients. Population efflux rate constants (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {k\prime_2} $$\end{document}) from subcortical white matter (centrum semiovale) and cerebellar cortex were derived by a simplified reference tissue modeling approach incorporating physiological constraints. Regional distribution volume ratio (DVR) estimates were derived using Logan and simplified reference tissue approaches, with either subcortical white matter or cerebellum as reference input. Discriminant analysis with cross-validation was performed to classify control subjects and AD patients.

Results

The population estimates of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {k\prime_2} $$\end{document} in subcortical white matter did not differ significantly between control subjects and AD patients but the variability of individual estimates of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {k\prime_2} $$\end{document} determined in white matter was lower than that in cerebellum. Logan DVR showed dependence on the efflux rate constant in white matter. The DVR estimates in the frontal, parietal, posterior cingulate, and temporal cortices were significantly higher in the AD group (p<0.01). Incorporating all these regional DVR estimates as predictor variables in discriminant analysis yielded accurate classification of control subjects and AD patients with high sensitivity and specificity, and the results agreed well with those using the cerebellum as the reference region.

Conclusion

Subcortical white matter can be used as a reference region for quantitative analysis of [18F]FDDNP with the Logan method which allows more accurate and less biased binding estimates, but a population efflux rate constant has to be determined a priori.

Technological advances have led to greater use of both structural and functional brain imaging to assist with the diagnosis of dementia for the increasing numbers of people with cognitive decline as they age. In current clinical practice, structural imaging (CT or MRI) is used to identify space-occupying lesions and stroke. Functional methods, such as PET scanning of glucose metabolism, could be used to differentiate Alzheimer’s disease from frontotemporal dementia, which helps to guide clinicians in symptomatic treatment strategies. New neuroimaging methods that are currently being developed can measure specific neurotransmitter systems, amyloid plaque and tau tangle concentrations, and neuronal integrity and connectivity. Successful co-development of neuroimaging surrogate markers and preventive treatments might eventually lead to so-called brain-check scans for determining risk of cognitive decline, so that physicians can administer disease-modifying medications, vaccines, or other interventions to avoid future cognitive losses and to delay onset of disease.

Purpose

The aim of this study was to investigate the longitudinal positron emission tomography (PET) metabolic changes in the elderly.

Procedures

Nineteen nondemented subjects (mean Mini-Mental Status Examination 29.4 ± 0.7 SD) underwent two detailed neuropsychological evaluations and resting 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)-PET scan (interval 21.7 ± 3.7 months), baseline structural 3T magnetic resonance (MR) imaging, and apolipoprotein E4 genotyping. Cortical PET metabolic changes were analyzed in 3-D using the cortical pattern matching technique.

Results

Baseline vs. follow-up whole-group comparison revealed significant metabolic decline bilaterally in the posterior temporal, parietal, and occipital lobes and the left lateral frontal cortex. The declining group demonstrated 10–15% decline in bilateral posterior cingulate/precuneus, posterior temporal, parietal, and occipital cortices. The cognitively stable group showed 2.5–5% similarly distributed decline. ApoE4-positive individuals underwent 5–15% metabolic decline in the posterior association cortices.

Conclusions

Using 3-D surface-based MR-guided FDG-PET mapping, significant metabolic changes were seen in five posterior and the left lateral frontal regions. The changes were more pronounced for the declining relative to the cognitively stable group.

Objective

Because anti-inflammatory drugs may delay cognitive decline and influence brain metabolism in normal aging, the authors determined the effects of the cyclooxygenase-2 inhibitor, celecoxib, on cognitive performance and regional cerebral glucose metabolism in nondemented volunteers with mild age-related memory decline.

Design

Randomized, double-blind, placebo-controlled, parallel group trial with 18-months of exposure to study medication.

Setting

University research institute.

Participants

Eighty-eight subjects, aged 40–81 years (mean: 58.7, SD: 8.9 years) with mild self-reported memory complaints but normal memory performance scores were recruited from community physician referrals, media coverage, and advertising. Forty subjects completed the study.

Interventions

Daily celecoxib dose of 200 or 400 mg, or placebo.

Main Outcome Measures

Standardized neuropsychological test battery and statistical parametric mapping (SPM) of FDG-PET scans performed during mental rest.

Results

Measures of cognition showed significant between-group differences in executive functioning (F [1, 30] = 5.06, p = 0.03) and language/semantic memory (F [1, 31] = 6.19, p = 0.02), favoring the celecoxib group compared with the placebo group. Concomitantly, FDG-PET scans demonstrated bilateral metabolic increases in prefrontal cortex in the celecoxib group in the vicinity of Brodmann’s areas 9 and 10, but not in the placebo group. SPM analyses of the PET data pooled by treatment arm corresponded to a 6% increase in activity over pretreatment levels (p = 0.01, after adjustment for multiple comparisons).

Conclusions

These results suggest that daily celecoxib use may improve cognitive performance and increase regional brain metabolism in people with age-associated memory decline.

Context

Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease that accumulate in the brains of people without dementia years before they develop dementia. Positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), which binds to plaques and tangles in vitro, demonstrate increased cerebral binding in patients with Alzheimer disease compared with cognitively intact controls. Here we investigated whether known risk factors for Alzheimer disease and dementia are associated with FDDNP-PET binding.

Objective

To determine if impaired cognitive status, older age, apolipoprotein E-4 (APOE-4) genetic risk for Alzheimer disease, family history of dementia, and less education are associated with increased regional cerebral FDDNP-PET binding.

Design

Cross-sectional clinical study.

Setting

A university research institute.

Participants

Volunteer sample of 76 middle-aged and older persons without dementia (mean age, 67 years) including 36 with mild cognitive impairment. Of the 72 subjects with genetic data, 34 were APOE-4 carriers.

Main Outcome Measures

The FDDNP-PET signal in brain regions of interest, including medial and lateral temporal, posterior cingulate, parietal, and frontal.

Results

For all regions studied, cognitive status was associated with increased FDDNP binding (P<.02 to .005). Older age was associated with increased lateral temporal FDDNP binding. Carriers of APOE-4 demonstrated higher frontal FDDNP binding than noncarriers. In the mild cognitive impairment group, age was associated with increased medial and lateral temporal FDDNP binding, and APOE-4 carriers had higher medial temporal binding than noncarriers.

Conclusions

Impaired cognitive status, older age, and APOE-4 carrier status are associated with increased brain FDDNP-PET binding in persons without dementia, consistent with previous clinical and postmortem studies associating these risk factors with amyloid plaque and tau tangle accumulation. Stratifying subject groups according to APOE-4 carrier status, age, and cognitive status may therefore be an informative strategy in future clinical trials using FDDNP-PET.

Diagnosis of Alzheimer's disease is often missed or delayed in clinical practice; thus, methods to improve early detection would provide opportunities for early intervention, symptomatic treatment, and improved patient function. Emerging data suggest that the disease process begins years before clinical diagnostic confirmation. This paper reviews current research focusing on methods for more specific and sensitive early detection using measures of genetic risk for Alzheimer's disease and functional brain imaging. This approach aims to identify patients in a presymptomatic stage for early treatment to delay progressive cognitive decline and disease onset.