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Arch Gen Psychiatry. Author manuscript; available in PMC Jun 9, 2009.
Published in final edited form as:
PMCID: PMC2693405
NIHMSID: NIHMS115518
Influence of Cognitive Status, Age, and APOE-4 Genetic Risk on Brain FDDNP Positron-Emission Tomography Imaging in Persons Without Dementia
Gary W. Small, MD,1,4,5 Prabha Siddarth, PhD,1 Alison C. Burggren, PhD,1 Vladimir Kepe, PhD,2 Linda M. Ercoli, PhD,1 Karen J. Miller, PhD,1 Helen Lavretsky, MD,1 Paul M. Thompson, PhD,3 Greg M. Cole, PhD,3,4 S. C. Huang, PhD,2 Michael E. Phelps, PhD,2 Susan Y. Bookheimer, PhD,1 and Jorge R. Barrio, PhD2
1 Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
2 Departments of Molecular and Medical Pharmacology, University of California, Los Angeles
3 Department of Neurology, University of California, Los Angeles
4 Alzheimer’s Disease Center, University of California, Los Angeles
5 Center on Aging, David Geffen School of Medicine, University of California, Los Angeles
Correspondence: Gary W. Small, MD, Semel Institute, 760 Westwood Plaza, Ste 88-201, Los Angeles, CA 90024 (gsmall/at/mednet.ucla.edu)
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.
Neurodegeneration associated with aging progresses along a continuum,1 but it has been categorized according to the degree of cognitive impairment. In normal aging, mild memory concerns with minimal objective cognitive deficits have been observed in nearly half of people by 50 years of age.2 Such awareness of memory changes is usually stable and not a risk factor for future cognitive decline.3 Mild cognitive impairment (MCI) is a more advanced form of age-related cognitive decline in which people notice memory changes and neuropsychological tests often confirm problems with delayed recall, although non–memory-related cognitive domains may also be impaired.4 People experiencing this transitional state between normal aging and dementia are still able to live independently, but they have an increased risk for developing dementia. A recent study that followed patients with MCI for 30 months reported conversion rates to Alzheimer disease (AD) ranging from 27% to 49%, depending on the subtype of MCI.5 The prevalence of MCI may be as high as 19% in people older than 65 years and 29% in those older than 85 years.6 When cognitive decline interferes with daily functioning and impairs not just memory but other mental abilities, dementia is often diagnosed.7 Alzheimer disease, which accounts for most cases, is insidious in its onset and progressive in its course.8 The prevalence of AD in individuals aged 71 years and older approaches 10%,9 and by 85 years has been reported to be as high as 50%.10
Age is the strongest known risk factor for AD. The estimated annual incidence of AD in a community-based sample ranged from 0.6% for people aged 65 to 69 years to 8.4% for those 85 years and older.11 In a meta-analysis of 23 studies,12 the incidence of AD increased exponentially with age until 90 years.
In addition to cognitive status and age, many genetic and nongenetic13 factors contribute to the risk for developing AD. For the common forms of late-onset AD, the major genetic risk is associated with the apolipoprotein E (APOE) gene on chromosome 19, which has 3 allelic variants (2, 3, and 4) and 5 common genotypes (2/3, 3/3, 2/4, 3/4, and 4/4). The APOE-4 allele increases risk and decreases the average age of dementia onset in a dose-related fashion (ie, AD risk is lowest for the 3/3 genotype, higher for the 3/4 genotype, and highest for the 4/4 genotype),14 while APOE-2 lowers the risk.15
Because APOE-4 accounts for only part of the genetic risk for AD, family history of dementia, regardless of whether an individual is an APOE-4 carrier, may increase the risk for developing AD. People with a first-degree relative with dementia have a 10% to 30% increased risk of developing the disorder,16 although a recent investigation reported that family history of dementia was associated with increased risk of dementia and AD only in APOE-4 carriers.17
Less education also appears to increase the risk for AD.18 Although this association suggests that the cognitive stimulation resulting from higher education protects the brain,19 other factors may explain the higher risk of dementia in people with less education including unhealthy lifestyles, lower cognitive reserve,20 and higher prevalence of small vascular lesions.21
In patients with AD, 2 proteins, β-amyloid (in senile plaques) and tau (in neurofibrillary tangles), accumulate abnormally in the brain in a predictable spatial pattern; however, these proteins also appear to accumulate before people develop dementia and increase gradually with age.22,23 For a definitive diagnosis of AD, high cerebral concentrations of amyloid senile plaques and tau neurofibrillary tangles must be present in the brain at autopsy.8
Newly developed small molecule tracers used in conjunction with positron emission tomography (PET) have made it possible to obtain measures of these abnormal protein deposits in living people.2426 For example, the amyloid-binding radiotracer Pittsburgh Compound B has been used with PET imaging to demonstrate significantly greater cortical Pittsburgh Compound B retention in patients with AD vs controls.24
Our group has developed a small molecule, 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl} ethylidene)malononitrile (FDDNP), for use as an in vivo chemical marker of cerebral amyloid and tau proteins.26 This molecule and its parent compound, DDNP, are both fluorescent and may be used with confocal fluorescence microscopy to clearly visualize plaques and tangles in vitro in brain specimens of patients with AD.27 Initial studies have found that global FDDNP-PET binding (average of temporal, parietal, posterior cingulate, and frontal regions) in MCI is intermediate between controls with normal cognition and patients with AD, and that subjects who progress clinically over time show corresponding increases in FDDNP signal.28 Moreover, 3-dimensional cortical surface projection images of FDDNP-PET show patterns remarkably similar to those expected from autopsy studies demonstrating regional brain accumulation patterns of plaques and tangles.1,22,28
In this study, we determined whether previously reported risk factors for developing a clinical diagnosis of AD were also associated with plaque and tangle accumulation as measured with FDDNP-PET binding in volunteers without dementia. We hypothesized that several established risk factors, including impaired cognitive status, older age, APOE-4 genetic risk for AD, family history of dementia, and lower educational achievement would be associated with increased regional cerebral FDDNP-PET binding.
SUBJECTS AND CLINICAL ASSESSMENTS
We performed neuropsychiatric evaluations, cognitive assessments, and PET scanning on 63 volunteers without dementia from a larger longitudinal study.28 Subjects were recruited through study advertisements regarding mild memory concerns, media coverage, and referrals from physicians and families. Although all subjects had mild memory concerns, patients with any form of dementia were excluded. Also excluded were individuals taking medications that might affect cognition, such as sedatives, or those taking nonsteroidal antiinflammatory drugs, which bind to amyloid plaques and may affect FDDNP binding values.27
Subjects had screening laboratory tests and structural imaging scans (3-dimensional magnetic resonance imaging [MRI] or computed tomography [CT]) to rule out other causes of cognitive impairment (eg, stroke, tumor)8 and for coregistration with PET scans for region-of-interest image analyses. Computed tomography scans instead of MRI were performed on 4 subjects because they could not tolerate MRI (eg, owing to claustrophobia, metal in body). Subjects with vascular lesions on the MRI or CT scan were excluded from the study. In addition to the Mini-Mental State Examination29 and Hamilton Rating Scale for Depression,30 a neuropsychological test battery31 was administered to assess 5 cognitive domains: (1) memory, including logical memory, selective reminding, and complex figure recall; (2) language, including Boston naming and letter and category fluency; (3) attention and information-processing speed, including Trail Making A, Stroop Color (Kaplan version), and Digit Symbol; (4) executive functioning, including Trail Making B, Stroop Interference (Kaplan version), Wisconsin card sort, and perseverative errors; and (5) visuospatial, including block design, complex figure copy, and visual retention.
To diagnose MCI, we used standard diagnostic criteria for amnestic MCI (ie, memory impairment without other cognitive impairments), which include (1) patient awareness of a memory problem, preferably confirmed by another person; (2) memory impairment detected with standard assessment tests; and (3) ability to perform normal daily activities.4 For a broad definition of MCI, we also used guidelines to identify subjects with other MCI subtypes, including those with memory impairment and additional cognitive deficits.32 The diagnosis was corroborated by clinical judgment4 and included subjects with MCI who scored 1 SD or more less than age-corrected norms, as this threshold for impairment yields high sensitivity for predicting dementia.33 To balance increased sensitivity with specificity, we required impairment on at least 2 neuropsychological tests within 1 of the 5 cognitive domains.34 Subjects in the MCI group did not meet diagnostic criteria for AD,7,8 and the presence of memory concerns was documented using a standardized subjective memory instrument (Memory Functioning Questionnaire)35 and clinical interview.
Volunteers with 1 or more first-degree relatives (ie, sibling or parent) with AD or dementia were classified as having a positive family history of dementia. Prior educational achievement was quantified according to years and months completed, beginning with elementary school (ie, first grade).
All clinical assessments were performed within 4 weeks of scanning procedures, and clinicians were blinded to the results of FDDNP-PET scans. Written informed consent was obtained in accordance with the University of California, Los Angeles Human Subjects Protection Committee procedures. Cumulative radiation dosimetry for all scans was below the mandated maximum annual dose and in compliance with state and federal regulations. Two minor adverse events occurred during PET scanning: one subject developed minor bruises at venipuncture sites, and another subject experienced a transient headache.
GENETIC ANALYSIS
All DNA was obtained from blood samples. The APOE genotypes were determined using standard techniques as previously described.14 Genetic data were available for 72 subjects.
SCANNING AND IMAGE ANALYSIS PROCEDURES
As previously described, FDDNP was prepared at very high specific activities (>37 gigabecquerel [GBq]/μmol).26,28 All scans were performed with the ECAT HR or EXACT HR+ tomograph (Siemens-CTI, Knoxville, Tennessee) with subjects supine and with the imaging plane parallel to the orbitomeatal line. A bolus of FDDNP (320–550 megabecquerel [MBq]) was injected via an indwelling venous catheter, and consecutive dynamic PET scans were performed for 2 hours. Scans were decay corrected and reconstructed using filtered back-projection (Hann filter, 5.5 mm full-width at half-maximum) with scatter and measured attenuation correction. The resulting images contained 47 contiguous slices with plane separation of 3.37 mm (ECAT HR) or 63 contiguous slices with plane separation of 2.42 mm (EXACT HR+). Results did not differ significantly according to the scanner used.
The FDDNP binding data were quantified using Logan graphical analysis with the cerebellum as the reference region for time points between 60 and 125 minutes.28,36 The slope of the linear portion of the Logan plot is the relative distribution volume, which is equal to the distribution volume of the tracer in a region of interest divided by that in the reference region. The relative distribution volume parametric images were generated and analyzed using regions of interest traced on the coregistered MRI or CT scans for left and right parietal, medial temporal (limbic regions including hippocampus, parahippocampal areas, and entorhinal cortex), lateral temporal, posterior cingulate, and frontal regions, as previously described.28 Each regional relative distribution volume or binding value was expressed as an average of left and right regions. Rules for region-of-interest drawing were based on the identification of gyral and sulcal landmarks with respect to the atlas of Talairach and Tournoux.37 All PET scans were read and regions of interest drawn by individuals who were blinded to clinical assessments and genotype. Repeat scans performed on the same 2 subjects within several weeks indicated stability of these measures (≤3% SD of regional values).
STATISTICAL ANALYSIS
Data were screened for outliers and normality assumptions. Descriptive statistics were computed for the entire sample and for the MCI and control subjects separately. The t test was used to compare the continuous variables of cognitive groups and χ2 tests were used for categorical variables. General linear models were used to determine which variables— age, APOE-4 status, family history, education, and cognitive status (MCI vs normal)—were associated with regional FDDNP binding in the entire sample. We first included all of these risk factors as predictors in the general linear model. We then computed the final model by deleting the risk factors that did not contribute significantly. All tests were 2-tailed, and a significance level of P=.05 was used for all inferences.
Subjects were middle-aged or older (range, 47–87 years; mean [SD] age, 66.8 [10.7] years) and educated (mean [SD] education, 17.0 [2.9] years). They showed minimal impairment on cognitive testing (mean [SD] Mini-Mental State Exam scores, 28.7 [1.5]), and 44 (59%) had a family history of dementia in at least 1 first-degree relative. Of the 36 patients with MCI, 17 showed memory impairment consistent with amnestic MCI and 19 had amnestic MCI plus deficits in other cognitive areas. The memory symptoms of all other subjects were normal for their age. Of the 72 subjects with genetic data, 34 (47%) were APOE-4 carriers (Table). Of these, 4 subjects were homozygotes (4/4 genotype).
Table
Table
Demographic and Clinical Characteristics
For all regions of interest studied, cognitive status (ie, diagnosis of MCI vs normal aging) was associated with increased FDDNP binding (medial temporal F1,67=6.04, P<.02; lateral temporal F1,68=8.34, P <.005; parietal F1,70=7.46, P <.008; posterior cingulate F1,70=3.83, P <.05; and frontal F1,68=9.27, P <.003). Older age was associated with increased lateral temporal FDDNP binding (F1,68=5.41, P <.02). Subjects’ APOE-4 status was associated with higher frontal FDDNP binding; APOE-4 carriers showed more binding than noncarriers (F1,68=3.93, P<.05).
In the MCI group, older age was associated with increased medial temporal (F1,29=4.08, P <.05)(Figure) and lateral temporal (F1,34=6.73, P <.01) FDDNP binding, and APOE-4 carriers had more medial temporal FDDNP binding than noncarriers (F1,29=5.22, P <.03). In the group without MCI, APOE-4 carriers had more frontal FDDNP binding than noncarriers (F1,37=4.40, P <.04).
Figure
Figure
Medial temporal 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) binding correlated with age in persons with mild cognitive impairment (MCI) (r=0.35, P<.03; solid line) but not in those without (dotted (more ...)
Family history of dementia and years of educational achievement were not associated with increased FDDNP binding values. No associations between Hamilton Depression Scale scores and FDDNP binding were found.
These findings indicate that impaired cognitive performance, older age, and APOE-4 genetic risk for AD are associated with increased brain FDDNP-PET binding in persons without dementia. Moreover, the degree of cognitive impairment (ie, normal aging vs MCI) appears to influence the interactions among risk factors. For example, in the MCI group, APOE-4 carriers show higher medial temporal FDDNP binding, whereas in normal aging, APOE-4 carriers demonstrate higher frontal binding. Overall, the results are consistent with our hypotheses and with previous clinical and postmortem studies demonstrating a relationship between such risk factors and amyloid plaque and tau tangle formation in the brain. By contrast, the other risk factors we tested, family history of dementia and prior years of education, were not found to be associated with higher FDDNP binding values.
Brain deposition of plaques and tangles follows a pattern in which tau tangles accumulate initially in the entorhinal cortex in normal aging and then spread to medial temporal regions as MCI develops; concentrations of medial temporal tangles become intermediate between those of normal aging and AD.22,23,38 The finding in our study that APOE-4 status was associated with FDDNP binding in the medial temporal region of patients with MCI is interesting in light of autopsy studies showing that this region is among the earliest to demonstrate increased plaque and tangle accumulation.22,23,38 Also, neuritic and diffuse plaques and tangles in patients with MCI are widely distributed throughout the neocortex and limbic structures.38 This spatial pattern and progression of abnormal protein accumulation may be consistent with an interaction between plaque and tangle accumulation. At some critical point in neurodegeneration, β-amyloid peptides may accelerate age-related tangle accumulation, which would otherwise progress relatively slowly with age.23 Tangle load has been associated with cognitive decline in older individuals, but plaque load has not consistently demonstrated such an association.38 The findings that FDDNP binds both plaques and tangles, particularly in the medial temporal lobe, may explain, in part, the association between higher FDDNP binding values and impaired cognitive function. Moreover, the regional pattern of FDDNP binding appears consistent with plaque and tangle accumulation patterns observed in autopsy studies.22,23,28,38
This is the first study to explore and demonstrate that a genetic risk for AD is associated with increased FDDNP-PET binding in persons without dementia. These results are consistent with previous neuropathological studies demonstrating increased plaque and tangle formation in middle-aged andolderAPOE-4 carriers without dementia.39,40 For example, in a study of persons without dementia who died between the ages of 50 and 93 years, APOE-4 carriers showed a pre-mature appearance of β-amyloid and neurofibrillary tangles.40 By contrast, autopsy studies of patients with AD find that APOE-4 heterozygotes do not show increased plaque and tangle accumulation, whereasAPOE-4 homozygotes do show increased accumulation.41 Thus, the effect of the APOE-4 allele on cerebral plaque and tangle formation may only occur early in the course of neurodegeneration.
Clearly APOE-4 lowers the age of clinical dementia onset, but surprisingly, several studies do not demonstrate acceleration of clinical progression of the disease in APOE-4 carriers.4246 Consistent with such findings, APOE-4 has been reported to accelerate transitions from normal aging to MCI, but not from MCI to dementia.4649 While controversial, these results suggest that APOE-4 may have a larger effect on a central precipitating event like amyloid plaque deposition, arguably a poor correlate of clinical progression or initial pathology in medial temporal regions, as observed in this study with FDDNP.
Previous autopsy studies of individuals without dementia ranging from young adults to elderly persons also have demonstrated that plaque and tangle formation is age-related.22,50 Other research has demonstrated interactions among these various risk factors. For example, APOE-4 carrier status may lead to increased tangle accumulation in relatively young age groups. In an autopsy study of asymptomatic younger adults (mean age, 38 years), tangle formation was significantly greater in APOE-4 carriers compared with controls.51 Sex may also modify the effect of APOE-4 on the deposition of AD brain pathology; in a study of 729 brains examined by routine autopsy, an association between the APOE-4 allele and plaques was found only for women aged between 60 and 79 years, whereas the association was found for men in all age groups.52 In the present study, we did not find sex to be associated with greater FDDNP binding.
Subjective memory concerns and minimal decline in memory ability compared with young adults are expected with normal aging.2 Although cognitive impairment is a risk factor for dementia, it is also a consequence of the brain lesions causing AD. The results of this study suggest that in vivo measures of plaques and tangles are associated with increased cognitive impairment, but other factors besides plaques and tangles can contribute to cognitive impairment including cerebrovascular disease and head trauma.53,54
Revised research criteria for the diagnosis of AD have been proposed.55 These criteria include the presence of early episodic memory impairment along with 1 or more abnormal biomarker such as molecular neuroimaging with PET or cerebrospinal fluid analysis of β-amyloid or tau proteins. Our findings that FDDNP binding patterns differ according to the degree of cognitive impairment (ie, normal aging vs MCI) suggest that FDDNP-PET might be a useful tool in applying such revised research diagnostic criteria. Additional studies clarifying the patterns of FDDNP binding and other molecular imaging techniques in AD, MCI, and normal aging will likely have an effect on the use of such diagnostic criteria.
Family history of dementia was not associated with higher FDDNP binding values. Previous studies have found that family history of dementia increases the risk for neurodegeneration56 and is associated with subsequent cognitive decline57 and lower scores on neuropsychological testing.58 Family history of dementia is an established risk factor for AD,59 but not all studies have confirmed such a risk.60,61 Moreover, the effect of family history on risk for dementia may be age-dependent—some studies have found the effect in persons older than 75 years,62 while other reports suggest that the effect of familial or genetic factors on dementia risk diminishes with increasing age.17 Misclassification in the assessment of dementia history and cohort effects (ie, relatives may be more likely to report dementia in siblings than in parents) may also diminish the accuracy of family history estimates. The relatively small sample size also may explain why family history was not associated with increased FDDNP binding values.
This small sample also may explain why we did not find prior educational achievement to influence our results. In addition, the lack of variance in years of education in these subjects may have minimized any effect of education in the present analysis. Other methodological issues could have influenced these results as well, including partial volume effects63 and use of a relatively educated sample who may not be representative of the general population.
Despite such limitations, these results, that FDDNP-PET may be an informative biological marker for people at risk for dementia, are encouraging. An important potential application of emerging technologies such as FDDNP-PET is in early detection of neurodegeneration. Our finding that greater FDDNP binding is associated with increased cognitive impairment in individuals without dementia suggests that this approach might be useful in detecting people at risk for dementia, which would also be useful for identifying candidates for clinical trials of prevention treatments. These results suggest that in future clinical trials using FDDNP-PET, stratifying subject groups according to APOE-4 carrier status, age, and cognitive status may be an informative strategy.
Acknowledgments
Funding/Support: This study was supported by grants P01-AG024831, AG13308, P50 AG 16570, MH/AG58156, MH52453, AG10123, and M01-RR00865 (General Clinical Research Centers Program) from the National Institutes of Health; contract DE-FC03-87-ER60615 from the Department of Energy; the Rotary CART Fund; the Fran and Ray Stark Foundation Fund for Alzheimer’s Disease Research; the Ahmanson Foundation; the Larry L. Hill-blom Foundation; the Lovelace Foundation; the Judith Ole-nick Elgart Fund for Research on Brain Aging; the John D. French Foundation for Alzheimer’s Research; and the Tamkin Foundation. No company provided support of any kind for this study.
Additional Contributions: The authors also thank Andrea Kaplan, MD, Deborah Dorsey, RN, Gwendolyn Byrd, MD, and Teresann Crowe-Lear, MD, for help in subject recruitment, data management, and study coordination, and Gerald Timbol and Anasheh Halabi for help in image processing.
Footnotes
Previous Presentations: Presented at the Annual Scientific Meeting of the American College of Neuropsychopharmacology; December, 2007; Boca Raton, Florida.
Financial Disclosure: The University of California, Los Angeles, owns a US patent (6,274,119) titled “Methods for Labeling β-Amyloid Plaques and Neurofibrillary Tangles” that uses the approach outlined in this article and has been licensed to Siemens. Drs Small, Huang, Cole, and Barrio reported that they are among the inventors, have received royalties, and will receive royalties on future sales. Dr Small reports having served as a consultant and/or having received lecture fees from Abbott, Brainstorming Co, Dakim, Eisai, Forest, Myriad Genetics, Novartis, Ortho-McNeil, Pfizer, Radica, Siemens, and Verus Med, as well as having received stock options from Dakim. Dr Lavretsky reports having received lecture fees from Eisai, Janssen, and Pfizer and having received a grant from Forest. Dr Huang reports having received lecture fees from Glaxo Smith Kline. Dr Barrio reports having served as a consultant and having received lecture fees from Nihon Medi-Physics Co, Bristol-Meyer Squibb, PETNet Pharmaceuticals, and Siemens. Drs Ercoli, Siddarth, Burggren, Kepe, Miller, Thompson, Phelps, and Bookheimer have no financial conflicts of interest.
1. Small GW, Bookheimer SY, Thompson PM, Cole GM, Huang S-C, Kepe V, Barrio JR. Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol. 2008;7(2):161–172. [PMC free article] [PubMed]
2. Larrabee GJ, Crook TH. Estimated prevalence of age-associated memory impairment derived from standardized tests of memory function. Int Psychogeriatr. 1994;6(1):95–104. [PubMed]
3. Jorm AF, Christensen H, Korten AE, Henderson AS, Jacomb PA, Mackinnon A. Do cognitive complaints either predict future cognitive decline or reflect past cognitive decline? a longitudinal study of an elderly community sample. Psychol Med. 1997;27(1):91–98. [PubMed]
4. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256(3):183–194. [PubMed]
5. Fischer P, Jungwirth S, Zehetmayer S, Weissgram S, Hoenigschnabl S, Gelpi E, Krampla W, Tragl KH. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology. 2007;68(4):288–291. [PubMed]
6. Lopez OL, Jagust WJ, DeKosky ST, Becker JT, Fitzpatrick A, Dulberg C, Breitner J, Lyketsos C, Jones B, Kawas C, Carlson M, Kuller LH. Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study. Arch Neurol. 2003;60(10):1385–1389. [PubMed]
7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4. Washington, DC: American Psychiatric Association; 1994.
8. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939–944. [PubMed]
9. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, Willis RJ, Wallace RB. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1–2):125–132. [PMC free article] [PubMed]
10. Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, Hebert LE, Hennekens CH, Taylor JO. Prevalence of Alzheimer’s disease in a community population of older persons: higher than previously reported. JAMA. 1989;262(18):2551–2556. [PubMed]
11. Hebert LE, Scherr PA, Beckett LA, Albert MS, Pilgrim DM, Chown MJ, Funkenstein HH, Evans DA. Age-specific incidence of Alzheimer’s disease in a community population. JAMA. 1995;273(17):1354–1359. [PubMed]
12. Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology. 1998;51(3):728–733. [PubMed]
13. Small GW. What we need to know about age related memory loss. BMJ. 2002;324 (7352):1502–1505. [PMC free article] [PubMed]
14. Corder EH, Saunders AM, Strittmatter WJ, Schmechel D, Gaskell P, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–923. [PubMed]
15. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7(2):180–183. [PubMed]
16. van Duijn CM, Clayton D, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Mortimer JA. Familial aggregation of Alzheimer’s disease and related disorders: a collaborative re-analysis of case-control studies: EURODEM Risk Factors Research Group. Int J Epidemiol. 1991;20(suppl 2):S13–S20. [PubMed]
17. Huang W, Qiu C, von Strauss E, Winblad B, Fratiglioni L. APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study. Arch Neurol. 2004;61(12):1930–1934. [PubMed]
18. Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Influence of education and occupation on the incidence of Alzheimer’s disease. JAMA. 1994;271(13):1004–1010. [PubMed]
19. Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002;287(6):742–748. [PubMed]
20. Ngandu T, von Strauss E, Helkala EL, Winblad B, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. Education and dementia: what lies behind the association? Neurology. 2007;69(14):1442–1450. [PubMed]
21. Del Ser T, Hachinski V, Merskey H, Munoz DG. An autopsy-verified study of the effect of education on degenerative dementia. Brain. 1999;122(pt 12):2309–2319. [PubMed]
22. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259. [PubMed]
23. Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol. 1999;45(3):358–368. [PubMed]
24. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–319. [PubMed]
25. Verhoeff NP, Wilson AA, Takeshita S, Trop L, Hussey D, Singh K, Kung HF, Kung MP, Houle S. In-vivo imaging of Alzheimer disease β-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry. 2004;12(6):584–595. [PubMed]
26. Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, Read S, Satyamurthy N, Petric A, Huang SC, Barrio JR. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer’s disease. Am J Geriatr Psychiatry. 2002;10(1):24–35. [PubMed]
27. Agdeppa ED, Kepe V, Petri A, Satyamurthy N, Liu J, Huang SC, Small GW, Cole GM, Barrio JR. In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile. Neuroscience. 2003;117(3):723–730. [PubMed]
28. Small GW, Kepe V, Ercoli L, Siddarth P, Miller K, Bookheimer SY, Lavretsky H, Burggren AC, Cole G, Vinters HV, Thompson PM, Huang S-C, Satyamurthy N, Phelps ME, Barrio JR. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006;355(25):2652–2663. [PubMed]
29. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–198. [PubMed]
30. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62. [PMC free article] [PubMed]
31. Lezak M, Howieson D, Loring D. Neuropsychological Assessment. 4. New York, NY: University Press; 2004.
32. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004;256(3):240–246. [PubMed]
33. de Jager CA, Budge MM. Stability and predictability of the classification of mild cognitive impairment as assessed by episodic memory test performance over time. Neurocase. 2005;11(1):72–79. [PubMed]
34. Busse A, Hensel A, Gühne U, Angermeyer MC, Riedel-Heller SG. Mild cognitive impairment: long-term course of four clinical subtypes. Neurology. 2006;67 (12):2176–2218. [PubMed]
35. Gilewski MJ, Zelinski EM. Questionnaire assessment of memory complaints. In: Poon LW, editor. Handbook for Clinical Memory Assessment of Older Adults. Washington, DC: American Psychological Association; 1986. pp. 93–107.
36. Logan J, Fowler J, Volkow N, Wang G, Ding Y, Alexoff D. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;16(5):834–840. [PubMed]
37. Talairach J, Tournoux P. Coplanar Stereotaxic Atlas of the Human Brain: Three-Dimensional Proportional System: an Approach to Cerebral Imaging. New York, NY: Thieme; 1988.
38. Petersen RC, Parisi JE, Dickson DW, Johnson KA, Knopman DS, Boeve BF, Jicha GA, Ivnik RJ, Smith GE, Tangalos EG, Braak H, Kokmen E. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol. 2006;63(5):665–672. [PubMed]
39. Ohm TG, Scharnagl H, März W, Bohl J. Apolipoprotein E isoforms and the development of low and high Braak stages of Alzheimer’s disease-related lesions. Acta Neuropathol. 1999;98(3):273–280. [PubMed]
40. Warzok RW, Kessler C, Apel G, Schwarz A, Egensperger R, Schreiber D, Herbst EW, Wolf E, Walther R, Walker LC. Apolipoprotein E4 promotes incipient Alzheimer pathology in the elderly. Alzheimer Dis Assoc Disord. 1998;12(1):33–39. [PubMed]
41. Tiraboschi P, Hansen LA, Masliah E, Alford M, Thal LJ, Corey-Bloom J. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology. 2004;62(11):1977–1983. [PubMed]
42. Kleiman T, Zdanys K, Black B, Rightmer T, Grey M, Garman K, Macavoy M, Gelernter J, van Dyck C. Apolipoprotein E epsilon4 allele is unrelated to cognitive or functional decline in Alzheimer’s disease: retrospective and prospective analysis. Dement Geriatr Cogn Disord. 2006;22(1):73–82. [PubMed]
43. Hoyt BD, Massman PJ, Schatschneider C, Cooke N, Doody RS. Individual growth curve analysis of APOE epsilon 4-associated cognitive decline in Alzheimer disease. Arch Neurol. 2005;62(3):454–459. [PubMed]
44. Murphy GM, Jr, Taylor J, Kraemer HC, Yesavage J, Tinklenberg JR. No association between apolipoprotein E epsilon 4 allele and rate of decline in Alzheimer’s disease. Am J Psychiatry. 1997;154(5):603–608. [PubMed]
45. Dal Forno G, Rasmusson DX, Brandt J, Carson KA, Brookmeyer R, Troncoso J, Kawas CH. Apolipoprotein E genotype and rate of decline in probable Alzheimer’s disease. Arch Neurol. 1996;53(4):345–350. [PubMed]
46. Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locascio JJ, Perls TT, Lipsitz LA, Hyman BT. Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer’s disease. Ann Neurol. 1996;39(1):62–70. [PubMed]
47. Tyas SL, Salazar JC, Snowdon DA, Desrosiers MF, Riley KP, Mendiondo MS, Kryscio RJ. Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study. Am J Epidemiol. 2007;165(11):1231–1238. [PMC free article] [PubMed]
48. Amieva H, Letenneur L, Dartigues JF, Rouch-Leroyer I, Sourgen C, D’Alchée-Birée F, Dib M, Barberger-Gateau P, Orgogozo JM, Fabrigoule C. Annual rate and predictors of conversion to dementia in subjects presenting mild cognitive impairment criteria defined according to a population-based study. Dement Geriatr Cogn Disord. 2004;18(1):87–93. [PubMed]
49. Kryscio RJ, Schmitt FA, Salazar JC, Mendiondo MS, Markesbery WR. Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology. 2006;66(6):828–832. [PubMed]
50. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18(4):351–357. [PubMed]
51. Ghebremedhin E, Schultz C, Braak E, Braak H. High frequency of apolipoprotein E epsilon4 allele in young individuals with very mild Alzheimer’s disease-related neurofibrillary changes. Exp Neurol. 1998;153(1):152–155. [PubMed]
52. Ghebremedhin E, Schultz C, Thal DR, Rüb U, Ohm TG, Braak E, Braak H. Gender and age modify the association between APOE and AD-related neuropathology. Neurology. 2001;56(12):1696–1701. [PubMed]
53. Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ. Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol. 2008;64(2):168–176. [PMC free article] [PubMed]
54. Van Den Heuvel C, Thornton E, Vink R. Traumatic brain injury and Alzheimer’s disease: a review. Prog Brain Res. 2007;161:303–316. [PubMed]
55. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734–746. [PubMed]
56. Prince M, Cullen M, Mann A. Risk factors for Alzheimer’s disease and dementia: a case-control study based on the MRC elderly hypertension trial. Neurology. 1994;44(1):97–104. [PubMed]
57. Persson G, Skoog I. Subclinical dementia: relevance of cognitive symptoms and signs. J Geriatr Psychiatry Neurol. 1992;5(3):172–178. [PubMed]
58. La Rue A, O’Hara R, Matsuyama SS, Jarvik LF. Cognitive changes in young-old adults: effect of family history of dementia. J Clin Exp Neuropsychol. 1995;17(1):65–70. [PubMed]
59. Fratiglioni L, Ahlbom A, Viitanen M, Winblad B. Risk factors for late-onset Alzheimer’s disease: a population-based, case-control study. Ann Neurol. 1993;33(3):258–266. [PubMed]
60. Tyas SL, Manfreda J, Strain LA, Montgomery PR. Risk factors for Alzheimer’s disease: a population-based, longitudinal study in Manitoba, Canada. Int J Epidemiol. 2001;30(3):590–597. [PubMed]
61. Lindsay J, Laurin D, Verreault R, Hébert R, Helliwell B, Hill GB, McDowell I. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol. 2002;156(5):445–453. [PubMed]
62. Silverman JM, Smith CJ, Marin DB, Mohs RC, Propper CB. Familial patterns of risk in very late-onset Alzheimer disease. Arch Gen Psychiatry. 2003;60(2):190–197. [PubMed]
63. Aston JA, Cunningham VJ, Asselin MC, Hammers A, Evans AC, Gunn RN. Positron emission tomography partial volume correction: estimation and algorithms. J Cereb Blood Flow Metab. 2002;22(8):1019–1034. [PubMed]