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Original Article |

Influence of Cognitive Status, Age, and APOE-4 Genetic Risk on Brain FDDNP Positron-Emission Tomography Imaging in Persons Without Dementia FREE

Gary W. Small, MD; Prabha Siddarth, PhD; Alison C. Burggren, PhD; Vladimir Kepe, PhD; Linda M. Ercoli, PhD; Karen J. Miller, PhD; Helen Lavretsky, MD; Paul M. Thompson, PhD; Greg M. Cole, PhD; S. C. Huang, PhD; Michael E. Phelps, PhD; Susan Y. Bookheimer, PhD; Jorge R. Barrio, PhD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior (Drs Small, Siddarth, Burggren, Ercoli, Miller, Lavretsky, and Bookheimer), Departments of Molecular and Medical Pharmacology (Drs Kepe, Huang, Phelps, and Barrio) and Neurology (Drs Thompson and Cole), Alzheimer's Disease Center (Drs Small and Cole) and Center on Aging (Dr Small), David Geffen School of Medicine, University of California, Los Angeles.


Arch Gen Psychiatry. 2009;66(1):81-87. doi:10.1001/archgenpsychiatry.2008.516.
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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.

Figures in this Article

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 Graphic Jump LocationTable. 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).

Place holder to copy figure label and caption
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 line). The interaction between cognitive status and age was significant (F1,65 = 4.74, P < .03).

Graphic Jump Location

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 and older APOE-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 premature 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, whereas APOE-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.

Correspondence: Gary W. Small, MD, Semel Institute, 760 Westwood Plaza, Ste 88-201, Los Angeles, CA 90024 (gsmall@mednet.ucla.edu).

Submitted for Publication: January 16, 2008; final revision received June 21, 2008; accepted June 23, 2008.

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 VerusMed, 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 GlaxoSmithKline. 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.

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. Hillblom Foundation; the Lovelace Foundation; the Judith Olenick 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.

Previous Presentations: Presented at the Annual Scientific Meeting of the American College of Neuropsychopharmacology; December, 2007; Boca Raton, Florida.

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.

Small  GWBookheimer  SYThompson  PMCole  GMHuang  S-CKepe  VBarrio  JR Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol 2008;7 (2) 161- 172
PubMed
Larrabee  GJCrook  TH Estimated prevalence of age-associated memory impairment derived from standardized tests of memory function. Int Psychogeriatr 1994;6 (1) 95- 104
PubMed
Jorm  AFChristensen  HKorten  AEHenderson  ASJacomb  PAMackinnon  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
Petersen  RC Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256 (3) 183- 194
PubMed
Fischer  PJungwirth  SZehetmayer  SWeissgram  SHoenigschnabl  SGelpi  EKrampla  WTragl  KH Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology 2007;68 (4) 288- 291
PubMed
Lopez  OLJagust  WJDeKosky  STBecker  JTFitzpatrick  ADulberg  CBreitner  JLyketsos  CJones  BKawas  CCarlson  MKuller  LH Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study. Arch Neurol 2003;60 (10) 1385- 1389
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC American Psychiatric Association1994;
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  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
Plassman  BLLanga  KMFisher  GGHeeringa  SGWeir  DROfstedal  MBBurke  JRHurd  MDPotter  GGRodgers  WLSteffens  DCWillis  RJWallace  RB Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007;29 (1-2) 125- 132
PubMed
Evans  DAFunkenstein  HHAlbert  MSScherr  PACook  NRChown  MJHebert  LEHennekens  CHTaylor  JO Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported. JAMA 1989;262 (18) 2551- 2556
PubMed
Hebert  LEScherr  PABeckett  LAAlbert  MSPilgrim  DMChown  MJFunkenstein  HHEvans  DA Age-specific incidence of Alzheimer's disease in a community population. JAMA 1995;273 (17) 1354- 1359
PubMed
Jorm  AFJolley  D The incidence of dementia: a meta-analysis. Neurology 1998;51 (3) 728- 733
PubMed
Small  GW What we need to know about age related memory loss. BMJ 2002;324 (7352) 1502- 1505
PubMed
Corder  EHSaunders  AMStrittmatter  WJSchmechel  DGaskell  PSmall  GWRoses  ADHaines  JLPericak-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
Corder  EHSaunders  AMRisch  NJStrittmatter  WJSchmechel  DEGaskell  PCRimmler  JBLocke  PAConneally  PMSchmader  KESmall  GWRoses  ADHaines  JLPericak-Vance  MA Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994;7 (2) 180- 183
PubMed
van Duijn  CMClayton  DChandra  VFratiglioni  LGraves  ABHeyman  AJorm  AFKokmen  EKondo  KMortimer  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
Huang  WQiu  Cvon Strauss  EWinblad  BFratiglioni  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
Stern  YGurland  BTatemichi  TKTang  MXWilder  DMayeux  R Influence of education and occupation on the incidence of Alzheimer's disease. JAMA 1994;271 (13) 1004- 1010
PubMed
Wilson  RSMendes De Leon  CFBarnes  LLSchneider  JABienias  JLEvans  DABennett  DA Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA 2002;287 (6) 742- 748
PubMed
Ngandu  Tvon Strauss  EHelkala  ELWinblad  BNissinen  ATuomilehto  JSoininen  HKivipelto  M Education and dementia: what lies behind the association? Neurology 2007;69 (14) 1442- 1450
PubMed
Del Ser  THachinski  VMerskey  HMunoz  DG An autopsy-verified study of the effect of education on degenerative dementia. Brain 1999;122 (pt 12) 2309- 2319
PubMed
Braak  HBraak  E Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82 (4) 239- 259
PubMed
Price  JLMorris  JC Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 1999;45 (3) 358- 368
PubMed
Klunk  WEEngler  HNordberg  AWang  YBlomqvist  GHolt  DPBergström  MSavitcheva  IHuang  GFEstrada  SAusén  BDebnath  MLBarletta  JPrice  JCSandell  JLopresti  BJWall  AKoivisto  PAntoni  GMathis  CALångström  B Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55 (3) 306- 319
PubMed
Verhoeff  NPWilson  AATakeshita  STrop  LHussey  DSingh  KKung  HFKung  MPHoule  S In-vivo imaging of Alzheimer disease β-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry 2004;12 (6) 584- 595
PubMed
Shoghi-Jadid  KSmall  GWAgdeppa  EDKepe  VErcoli  LMSiddarth  PRead  SSatyamurthy  NPetric  AHuang  SCBarrio  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
Agdeppa  EDKepe  VPetri  ASatyamurthy  NLiu  JHuang  SCSmall  GWCole  GMBarrio  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
Small  GWKepe  VErcoli  LSiddarth  PMiller  KBookheimer  SYLavretsky  HBurggren  ACCole  GVinters  HVThompson  PMHuang  S-CSatyamurthy  NPhelps  MEBarrio  JR PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006;355 (25) 2652- 2663
PubMed
Folstein  MFFolstein  SEMcHugh  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
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed
Lezak  MHowieson  DLoring  D Neuropsychological Assessment. 4th ed. New York, NY University Press2004;
Winblad  BPalmer  KKivipelto  MJelic  VFratiglioni  LWahlund  LONordberg  ABäckman  LAlbert  MAlmkvist  OArai  HBasun  HBlennow  Kde Leon  MDeCarli  CErkinjuntti  TGiacobini  EGraff  CHardy  JJack  CJorm  ARitchie  Kvan Duijn  CVisser  PPetersen  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
de Jager  CABudge  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
Busse  AHensel  AGühne  UAngermeyer  MCRiedel-Heller  SG Mild cognitive impairment: long-term course of four clinical subtypes. Neurology 2006;67 (12) 2176- 2218
PubMed
Gilewski  MJZelinski  EM Questionnaire assessment of memory complaints. Poon  LWHandbook for Clinical Memory Assessment of Older Adults. Washington, DC American Psychological Association1986;93- 107
Logan  JFowler  JVolkow  NWang  GDing  YAlexoff  D Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16 (5) 834- 840
PubMed
Talairach  JTournoux  P Coplanar Stereotaxic Atlas of the Human Brain: Three-Dimensional Proportional System: an Approach to Cerebral Imaging.  New York, NY Thieme1988;
Petersen  RCParisi  JEDickson  DWJohnson  KAKnopman  DSBoeve  BFJicha  GAIvnik  RJSmith  GETangalos  EGBraak  HKokmen  E Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63 (5) 665- 672
PubMed
Ohm  TGScharnagl  HMärz  WBohl  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
Warzok  RWKessler  CApel  GSchwarz  AEgensperger  RSchreiber  DHerbst  EWWolf  EWalther  RWalker  LC Apolipoprotein E4 promotes incipient Alzheimer pathology in the elderly. Alzheimer Dis Assoc Disord 1998;12 (1) 33- 39
PubMed
Tiraboschi  PHansen  LAMasliah  EAlford  MThal  LJCorey-Bloom  J Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 2004;62 (11) 1977- 1983
PubMed
Kleiman  TZdanys  KBlack  BRightmer  TGrey  MGarman  KMacavoy  MGelernter  Jvan 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
Hoyt  BDMassman  PJSchatschneider  CCooke  NDoody  RS Individual growth curve analysis of APOE epsilon 4-associated cognitive decline in Alzheimer disease. Arch Neurol 2005;62 (3) 454- 459
PubMed
Murphy  GM  JrTaylor  JKraemer  HCYesavage  JTinklenberg  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
Dal Forno  GRasmusson  DXBrandt  JCarson  KABrookmeyer  RTroncoso  JKawas  CH Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease. Arch Neurol 1996;53 (4) 345- 350
PubMed
Gomez-Isla  TWest  HLRebeck  GWHarr  SDGrowdon  JHLocascio  JJPerls  TTLipsitz  LAHyman  BT Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease. Ann Neurol 1996;39 (1) 62- 70
PubMed
Tyas  SLSalazar  JCSnowdon  DADesrosiers  MFRiley  KPMendiondo  MSKryscio  RJ Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study. Am J Epidemiol 2007;165 (11) 1231- 1238
PubMed
Amieva  HLetenneur  LDartigues  JFRouch-Leroyer  ISourgen  CD'Alchée-Birée  FDib  MBarberger-Gateau  POrgogozo  JMFabrigoule  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
Kryscio  RJSchmitt  FASalazar  JCMendiondo  MSMarkesbery  WR Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006;66 (6) 828- 832
PubMed
Braak  HBraak  E Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18 (4) 351- 357
PubMed
Ghebremedhin  ESchultz  CBraak  EBraak  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
Ghebremedhin  ESchultz  CThal  DRRüb  UOhm  TGBraak  EBraak  H Gender and age modify the association between APOE and AD-related neuropathology. Neurology 2001;56 (12) 1696- 1701
PubMed
Troncoso  JCZonderman  ABResnick  SMCrain  BPletnikova  OO'Brien  RJ Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol 2008;64 (2) 168- 176
PubMed
Van Den Heuvel  CThornton  EVink  R Traumatic brain injury and Alzheimer's disease: a review. Prog Brain Res 2007;161303- 316
PubMed
Dubois  BFeldman  HHJacova  CDekosky  STBarberger-Gateau  PCummings  JDelacourte  AGalasko  DGauthier  SJicha  GMeguro  KO'brien  JPasquier  FRobert  PRossor  MSalloway  SStern  YVisser  PJScheltens  P Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6 (8) 734- 746
PubMed
Prince  MCullen  MMann  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
Persson  GSkoog  I Subclinical dementia: relevance of cognitive symptoms and signs. J Geriatr Psychiatry Neurol 1992;5 (3) 172- 178
PubMed
La Rue  AO’Hara  RMatsuyama  SSJarvik  LF Cognitive changes in young-old adults: effect of family history of dementia. J Clin Exp Neuropsychol 1995;17 (1) 65- 70
PubMed
Fratiglioni  LAhlbom  AViitanen  MWinblad  B Risk factors for late-onset Alzheimer's disease: a population-based, case-control study. Ann Neurol 1993;33 (3) 258- 266
PubMed
Tyas  SLManfreda  JStrain  LAMontgomery  PR Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada. Int J Epidemiol 2001;30 (3) 590- 597
PubMed
Lindsay  JLaurin  DVerreault  RHébert  RHelliwell  BHill  GBMcDowell  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
Silverman  JMSmith  CJMarin  DBMohs  RCPropper  CB Familial patterns of risk in very late-onset Alzheimer disease. Arch Gen Psychiatry 2003;60 (2) 190- 197
PubMed
Aston  JACunningham  VJAsselin  MCHammers  AEvans  ACGunn  RN Positron emission tomography partial volume correction: estimation and algorithms. J Cereb Blood Flow Metab 2002;22 (8) 1019- 1034
PubMed

Figures

Place holder to copy figure label and caption
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 line). The interaction between cognitive status and age was significant (F1,65 = 4.74, P < .03).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Demographic and Clinical Characteristics

References

Small  GWBookheimer  SYThompson  PMCole  GMHuang  S-CKepe  VBarrio  JR Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol 2008;7 (2) 161- 172
PubMed
Larrabee  GJCrook  TH Estimated prevalence of age-associated memory impairment derived from standardized tests of memory function. Int Psychogeriatr 1994;6 (1) 95- 104
PubMed
Jorm  AFChristensen  HKorten  AEHenderson  ASJacomb  PAMackinnon  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
Petersen  RC Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256 (3) 183- 194
PubMed
Fischer  PJungwirth  SZehetmayer  SWeissgram  SHoenigschnabl  SGelpi  EKrampla  WTragl  KH Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology 2007;68 (4) 288- 291
PubMed
Lopez  OLJagust  WJDeKosky  STBecker  JTFitzpatrick  ADulberg  CBreitner  JLyketsos  CJones  BKawas  CCarlson  MKuller  LH Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study. Arch Neurol 2003;60 (10) 1385- 1389
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC American Psychiatric Association1994;
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  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
Plassman  BLLanga  KMFisher  GGHeeringa  SGWeir  DROfstedal  MBBurke  JRHurd  MDPotter  GGRodgers  WLSteffens  DCWillis  RJWallace  RB Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007;29 (1-2) 125- 132
PubMed
Evans  DAFunkenstein  HHAlbert  MSScherr  PACook  NRChown  MJHebert  LEHennekens  CHTaylor  JO Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported. JAMA 1989;262 (18) 2551- 2556
PubMed
Hebert  LEScherr  PABeckett  LAAlbert  MSPilgrim  DMChown  MJFunkenstein  HHEvans  DA Age-specific incidence of Alzheimer's disease in a community population. JAMA 1995;273 (17) 1354- 1359
PubMed
Jorm  AFJolley  D The incidence of dementia: a meta-analysis. Neurology 1998;51 (3) 728- 733
PubMed
Small  GW What we need to know about age related memory loss. BMJ 2002;324 (7352) 1502- 1505
PubMed
Corder  EHSaunders  AMStrittmatter  WJSchmechel  DGaskell  PSmall  GWRoses  ADHaines  JLPericak-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
Corder  EHSaunders  AMRisch  NJStrittmatter  WJSchmechel  DEGaskell  PCRimmler  JBLocke  PAConneally  PMSchmader  KESmall  GWRoses  ADHaines  JLPericak-Vance  MA Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994;7 (2) 180- 183
PubMed
van Duijn  CMClayton  DChandra  VFratiglioni  LGraves  ABHeyman  AJorm  AFKokmen  EKondo  KMortimer  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
Huang  WQiu  Cvon Strauss  EWinblad  BFratiglioni  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
Stern  YGurland  BTatemichi  TKTang  MXWilder  DMayeux  R Influence of education and occupation on the incidence of Alzheimer's disease. JAMA 1994;271 (13) 1004- 1010
PubMed
Wilson  RSMendes De Leon  CFBarnes  LLSchneider  JABienias  JLEvans  DABennett  DA Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA 2002;287 (6) 742- 748
PubMed
Ngandu  Tvon Strauss  EHelkala  ELWinblad  BNissinen  ATuomilehto  JSoininen  HKivipelto  M Education and dementia: what lies behind the association? Neurology 2007;69 (14) 1442- 1450
PubMed
Del Ser  THachinski  VMerskey  HMunoz  DG An autopsy-verified study of the effect of education on degenerative dementia. Brain 1999;122 (pt 12) 2309- 2319
PubMed
Braak  HBraak  E Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82 (4) 239- 259
PubMed
Price  JLMorris  JC Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 1999;45 (3) 358- 368
PubMed
Klunk  WEEngler  HNordberg  AWang  YBlomqvist  GHolt  DPBergström  MSavitcheva  IHuang  GFEstrada  SAusén  BDebnath  MLBarletta  JPrice  JCSandell  JLopresti  BJWall  AKoivisto  PAntoni  GMathis  CALångström  B Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55 (3) 306- 319
PubMed
Verhoeff  NPWilson  AATakeshita  STrop  LHussey  DSingh  KKung  HFKung  MPHoule  S In-vivo imaging of Alzheimer disease β-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry 2004;12 (6) 584- 595
PubMed
Shoghi-Jadid  KSmall  GWAgdeppa  EDKepe  VErcoli  LMSiddarth  PRead  SSatyamurthy  NPetric  AHuang  SCBarrio  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
Agdeppa  EDKepe  VPetri  ASatyamurthy  NLiu  JHuang  SCSmall  GWCole  GMBarrio  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
Small  GWKepe  VErcoli  LSiddarth  PMiller  KBookheimer  SYLavretsky  HBurggren  ACCole  GVinters  HVThompson  PMHuang  S-CSatyamurthy  NPhelps  MEBarrio  JR PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006;355 (25) 2652- 2663
PubMed
Folstein  MFFolstein  SEMcHugh  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
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed
Lezak  MHowieson  DLoring  D Neuropsychological Assessment. 4th ed. New York, NY University Press2004;
Winblad  BPalmer  KKivipelto  MJelic  VFratiglioni  LWahlund  LONordberg  ABäckman  LAlbert  MAlmkvist  OArai  HBasun  HBlennow  Kde Leon  MDeCarli  CErkinjuntti  TGiacobini  EGraff  CHardy  JJack  CJorm  ARitchie  Kvan Duijn  CVisser  PPetersen  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
de Jager  CABudge  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
Busse  AHensel  AGühne  UAngermeyer  MCRiedel-Heller  SG Mild cognitive impairment: long-term course of four clinical subtypes. Neurology 2006;67 (12) 2176- 2218
PubMed
Gilewski  MJZelinski  EM Questionnaire assessment of memory complaints. Poon  LWHandbook for Clinical Memory Assessment of Older Adults. Washington, DC American Psychological Association1986;93- 107
Logan  JFowler  JVolkow  NWang  GDing  YAlexoff  D Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16 (5) 834- 840
PubMed
Talairach  JTournoux  P Coplanar Stereotaxic Atlas of the Human Brain: Three-Dimensional Proportional System: an Approach to Cerebral Imaging.  New York, NY Thieme1988;
Petersen  RCParisi  JEDickson  DWJohnson  KAKnopman  DSBoeve  BFJicha  GAIvnik  RJSmith  GETangalos  EGBraak  HKokmen  E Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63 (5) 665- 672
PubMed
Ohm  TGScharnagl  HMärz  WBohl  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
Warzok  RWKessler  CApel  GSchwarz  AEgensperger  RSchreiber  DHerbst  EWWolf  EWalther  RWalker  LC Apolipoprotein E4 promotes incipient Alzheimer pathology in the elderly. Alzheimer Dis Assoc Disord 1998;12 (1) 33- 39
PubMed
Tiraboschi  PHansen  LAMasliah  EAlford  MThal  LJCorey-Bloom  J Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 2004;62 (11) 1977- 1983
PubMed
Kleiman  TZdanys  KBlack  BRightmer  TGrey  MGarman  KMacavoy  MGelernter  Jvan 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
Hoyt  BDMassman  PJSchatschneider  CCooke  NDoody  RS Individual growth curve analysis of APOE epsilon 4-associated cognitive decline in Alzheimer disease. Arch Neurol 2005;62 (3) 454- 459
PubMed
Murphy  GM  JrTaylor  JKraemer  HCYesavage  JTinklenberg  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
Dal Forno  GRasmusson  DXBrandt  JCarson  KABrookmeyer  RTroncoso  JKawas  CH Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease. Arch Neurol 1996;53 (4) 345- 350
PubMed
Gomez-Isla  TWest  HLRebeck  GWHarr  SDGrowdon  JHLocascio  JJPerls  TTLipsitz  LAHyman  BT Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease. Ann Neurol 1996;39 (1) 62- 70
PubMed
Tyas  SLSalazar  JCSnowdon  DADesrosiers  MFRiley  KPMendiondo  MSKryscio  RJ Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study. Am J Epidemiol 2007;165 (11) 1231- 1238
PubMed
Amieva  HLetenneur  LDartigues  JFRouch-Leroyer  ISourgen  CD'Alchée-Birée  FDib  MBarberger-Gateau  POrgogozo  JMFabrigoule  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
Kryscio  RJSchmitt  FASalazar  JCMendiondo  MSMarkesbery  WR Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006;66 (6) 828- 832
PubMed
Braak  HBraak  E Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18 (4) 351- 357
PubMed
Ghebremedhin  ESchultz  CBraak  EBraak  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
Ghebremedhin  ESchultz  CThal  DRRüb  UOhm  TGBraak  EBraak  H Gender and age modify the association between APOE and AD-related neuropathology. Neurology 2001;56 (12) 1696- 1701
PubMed
Troncoso  JCZonderman  ABResnick  SMCrain  BPletnikova  OO'Brien  RJ Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol 2008;64 (2) 168- 176
PubMed
Van Den Heuvel  CThornton  EVink  R Traumatic brain injury and Alzheimer's disease: a review. Prog Brain Res 2007;161303- 316
PubMed
Dubois  BFeldman  HHJacova  CDekosky  STBarberger-Gateau  PCummings  JDelacourte  AGalasko  DGauthier  SJicha  GMeguro  KO'brien  JPasquier  FRobert  PRossor  MSalloway  SStern  YVisser  PJScheltens  P Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6 (8) 734- 746
PubMed
Prince  MCullen  MMann  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
Persson  GSkoog  I Subclinical dementia: relevance of cognitive symptoms and signs. J Geriatr Psychiatry Neurol 1992;5 (3) 172- 178
PubMed
La Rue  AO’Hara  RMatsuyama  SSJarvik  LF Cognitive changes in young-old adults: effect of family history of dementia. J Clin Exp Neuropsychol 1995;17 (1) 65- 70
PubMed
Fratiglioni  LAhlbom  AViitanen  MWinblad  B Risk factors for late-onset Alzheimer's disease: a population-based, case-control study. Ann Neurol 1993;33 (3) 258- 266
PubMed
Tyas  SLManfreda  JStrain  LAMontgomery  PR Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada. Int J Epidemiol 2001;30 (3) 590- 597
PubMed
Lindsay  JLaurin  DVerreault  RHébert  RHelliwell  BHill  GBMcDowell  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
Silverman  JMSmith  CJMarin  DBMohs  RCPropper  CB Familial patterns of risk in very late-onset Alzheimer disease. Arch Gen Psychiatry 2003;60 (2) 190- 197
PubMed
Aston  JACunningham  VJAsselin  MCHammers  AEvans  ACGunn  RN Positron emission tomography partial volume correction: estimation and algorithms. J Cereb Blood Flow Metab 2002;22 (8) 1019- 1034
PubMed

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