Brain Advance Access originally published online on October 10, 2007
Brain 2007 130(11):2837-2844; doi:10.1093/brain/awm238
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ß-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease
1School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, 2Department of Nuclear Medicine, Centre for PET, Austin Health, Heidelberg, 3Centre for Neurosciences, University of Melbourne, 4The Mental Health Research Institute, Parkville, 5Cogstate Pty Ltd, Melbourne, Victoria, Australia, 6Departments of Radiology and Psychiatry, University of Pittsburgh, PA, USA and 7Department of Medicine, Austin Health, University of Melbourne, Victoria, Australia
Correspondence to: Christopher Rowe, Department of Nuclear Medicine, Centre for PET, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia E-mail: christopher.rowe{at}austin.org.au
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Summary |
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ß-amyloid (Aß) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Aß burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Aß burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Aß burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Aß plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Aß deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Aß deposition are warranted.
Key Words: memory performance; Alzheimer's disease; mild cognitive impairment; beta-amyloid; PET imaging
Abbreviations: AD, Alzheimer's disease; MCI, mild cognitive impairment; SUV, standardized uptake value
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Received June 29, 2007. Revised August 14, 2007. Accepted September 5, 2007.
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Introduction |
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ß-Amyloid (Aß) deposition in the brain is implicated in the pathogenesis of Alzheimer's disease (AD) and is central to current aetiological theories (Masters and Beyreuther, 2006
). While a strong relationship is evident between neurofibrillary tangles and cognition, consensus has not been reached on the relationship between Aß burden and cognition (Cummings, et al., 1996; Nagy et al., 1996; Bartoo et al., 1997; Kanne et al., 1998; Mufson et al., 1999; Bussière et al., 2002; Giannakopoulos et al., 2003; Guillozet, et al., 2003; Thomas et al., 2005; Markesbery et al., 2006; Prohovnik et al., 2006).
Most research into Aß burden and cognition has focused on people with dementia, despite evidence for a long preclinical phase preceding the diagnosis of AD. Subtle cognitive deficits are present up to 9 years before dementia is diagnosed (Amieva et al., 2005) and neuropathological studies in Down syndrome have demonstrated cortical Aß plaques decades before the usual onset of dementia that almost invariably develops in these individuals (Beyreuther et al., 1992). Neuropathological studies have also documented moderate numbers of Aß plaques in the cerebral cortex of more than a quarter of nondemented persons aged over 75 years, equivalent to the prevalence of dementia at age 85 years (Ferri et al., 2005), suggesting that neuropathological changes precede the clinical expression of AD by many years (Price and Morris, 1999; Bennett et al., 2006).
Mild cognitive impairment (MCI) is considered a transitional stage between healthy aging (HA) and AD (Petersen et al., 2001), although up to 40% of people meeting the criteria for MCI do not develop overt clinical dementia (Busse et al., 2006a). The degree of neuropathological change in MCI is variable, with many demonstrating AD-like pathological features (Markesbery et al., 2006; Petersen et al., 2006), but the relationship between Aß burden and cognition in MCI is not well understood.
While post-mortem studies provide a comprehensive assessment of the neuropathologic changes at the time of death, conclusions from such studies can be limited by substantial delays between cognitive assessment and death in patients with AD, and the advanced age at death of non-demented cases (Bennett et al., 2006). New Aß-specific PET radiotracers allow quantitative analysis of Aß burden in vivo and can therefore overcome such limitations. The best validated of these radiotracers is ‘Pittsburgh Compound-B’ (11C-PIB; Klunk et al., 2004), a carbon-11-labelled derivative of the thioflavin-T amyloid dye, that binds with high affinity and high specificity to neuritic Aßplaques (Klunk et al., 2003). 11C-PIB-PET studies in AD have shown robust cortical binding (Klunk et al., 2004; Kemppainen et al., 2006), and correlations with the rate of cerebral atrophy (Archer et al., 2006), parietotemporal hypometabolism (Edison et al., 2007), and decreased CSF Aß42 (Fagan et al., 2006).
The current study utilizes 11C-PIB-PET to investigate the relationship between Aß burden and concurrent cognitive performance, and finds a strong relationship between PIB binding and episodic memory impairment in HA and MCI participants, but not in those with AD.
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Methods |
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Participants
The study included 31 participants with mild to moderate AD, 33 people with MCI, and 32 asymptomatic volunteers from a healthy ageing study. Participants were excluded if they were not fluent in English, Mini-Mental State Examination (MMSE) was less than 12, or there was a history of acquired brain injury or alcoholism. Written informed consent was obtained prior to participation. The relevant committees at Austin Health and Monash University granted ethics approval. All AD participants met NINCDS-ADRDA criteria for probable AD (McKhann et al., 1984
). All MCI participants met the following recently published consensus criteria: (i) clinical opinion that they were neither normal nor demented, (ii) subjective report of decline over time with objective evidence of impairment, (iii) no significant functional loss (Winblad et al., 2004). Participants were classified based on their clinical history, presentation and neuropsychological assessment where objective impairment was regarded as at least one neuropsychological test score falling 1.5 SD or more below relevant normative data. On neuropsychological assessment, 24 of the MCI participants had objective memory impairment (amnestic MCI), six had objective cognitive impairment without memory impairment (non-amnestic MCI) and three were classified as MCI based on self and reliable informant report of progressive decline (termed here ‘subjective MCI’). The subjective MCI participants had evidence of premorbid superior cognitive abilities but current cognitive performance in the average or low average range. Most of the HA participants (91%) were recruited from the longitudinal healthy ageing study being conducted at the Mental Health Research Institute of Victoria (Weaver Cargin et al., 2006). In all participants, apolipoprotein-E (ApoE) genotype was determined by PCR amplification of genomic DNA.
As shown in Table 1, groups were well matched for age, years of education and gender. HA were less likely to have an ApoE 
4 allele (Fisher's exact test = 0.004) and more likely to have a first-degree relative with AD (Fisher's exact test = 0.009) compared with MCI and AD participants. Characteristics of MCI participants are also shown in Table 1. Non-amnestic MCI cases were younger than those with amnestic MCI and all were male.
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Neuropsychological assessment
Participants were administered the MMSE (Folstein et al., 1975
), 30-item Boston Naming Test (BNT; Saxton et al., 2000), Digit Span forwards [DSp(f)] and backwards [DSp(b)] and Digit Symbol-Coding (DS-C) from the Wechsler Adult Intelligence Scale – Third edition (WAIS-III; Wechsler, 1997), California Verbal Learning Test – Second edition (CVLT-II; Delis et al., 2000), Rey Complex Figure Test (RCFT; Meyers and Meyers, 1995), letter fluency (Benton, 1968) and category fluency tasks. A composite episodic memory score was calculated by taking the average of the z scores (generated using the HA group as the reference) for RCFT (30 min) long delay and CVLT-II long delay. A composite non-memory cognition score was designed to examine participants’ average performance on tasks not involving episodic memory. This was calculated by taking the average of the z scores for the BNT, letter fluency, category fluency, DSp(f), DSp(b), DS-C and RCFT copy.
Neuroimaging
All participants had a 3D spoiled gradient echo (SPGR) T1-weighted MRI for screening and co-registration with the PET images. Within 11 ± 22 days of the neuropsychological assessment, participants also had a 11C-PIB-PET scan, as previously described (Rowe et al., 2007). PET standardized uptake value (SUV) data acquired 40–70 min post-PIB injection were summed and normalized to the cerebellar cortex SUV, resulting in a region to cerebellar ratio termed the SUV ratio (SUVR). The cerebellar cortex was used as a reference region as it is relatively devoid of senile plaques and shows no PIB binding in controls or AD (Price et al., 2005; Rowe et al., 2007). Regions of interest (ROI) were drawn on the individual MRI and transferred to the co-registered PET images. Neocortical Aß burden was expressed as the average SUVR of the area-weighted mean for the following cortical ROIs: frontal (consisting of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal regions), superior parietal, lateral temporal, lateral occipital and anterior and posterior cingulate. No correction for partial volume was applied to the PET data.
The data were further analysed using a receiver operating characteristic curve to establish the most accurate cut-off value to distinguish AD from HA. This approach generated a cut-off value for 11C-PIB SUVR of 1.6, which was used to categorize participants into those with ‘AD-like’ (PIB-positive, SUVR >1.6) images or those with ‘HA-like’ (PIB-negative, SUVR 
1.6) images.
Statistical analysis
Data were analysed using SPSS software (version 11). Differences between groups for binomially distributed data were assessed using 
2 tests. Independent sample t-tests were used to compare means of AD and HA to MCI, and to compare means within the MCI subgroups. Pearson's correlations were used to assess bivariate relationships. A series of multiple regression analyses were conducted to examine the possible mediating effect of diagnosis on the relationship between PIB binding and cognition. Moderated regression was also conducted to examine whether the relationship between PIB binding and memory differed across groups. Diagnosis was dummy coded using two variables: AD (participants with AD were coded 1, HA or MCI were coded 0) or HA (HA were coded 1, AD or MCI were coded 0). The interactions between PIB binding and group (AD x PIB; HA x PIB) were calculated by first centering the variables and then multiplying them together (Aiken and West, 1991). Age, gender and education were controlled in all analyses.
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Results |
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ß-Amyloid burden
HA participants demonstrated significantly lower neocortical PIB binding than did MCI participants (P < 0.001), who in turn demonstrated significantly lower binding than AD participants (P < 0.001), as shown in Fig. 1. As Levene's test for homogeneity of variance was violated a corrected t value was computed to correct for heterogeneity of variance. Ninety-seven percent of AD cases were PIB-positive, compared with 61% of MCI and 22% of HA. The PIB scans with the median SUVR of the AD group, and the PIB-positive and negative divisions of the MCI and HA groups are shown in Fig. 2. All six of the non-amnestic MCI participants had a PIB-negative scan, whereas 18 (75%) of the amnestic subgroup and 2 (67%) of the subjective subgroup were PIB-positive. As shown in Table 1, 80% of MCI participants with a PIB-positive scan carried an ApoE
4 allele, compared to only 23% of those with a PIB-negative scan (P = 0.003 by Fisher's exact test).
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Cognition
As shown in Table 1, HA participants had higher composite scores for both memory and non-memory cognition than MCI participants, who in turn had significantly higher composite scores than AD participants. As expected by definition, the amnestic MCI subgroup demonstrated worse episodic memory than did the non-amnestic MCI subgroup, as shown in Table 1. The composite episodic memory score for PIB-positive MCI participants was 2.7 SD below HA, compared with 1.1 SD below in PIB-negative MCI participants. There were no differences between these MCI subgroups on the non-memory composite score.
Similarly, within the HA group, participants with a PIB-positive scan performed 0.8 SD worse on the composite episodic memory score than those with a PIB-negative scan (P = 0.023), but there were no differences on the composite non-memory score.
ß-Amyloid burden and cognition
PIB binding had a strong negative relationship with composite episodic memory (r = –0.73, P < 0.001), and a moderate negative correlation with composite non-memory cognition (r = –0.50, P < 0.001). Figure 3 demonstrates that AD cases cluster in the region of high PIB binding with low episodic memory scores, conversely, HA cases cluster around the region of low PIB binding with high episodic memory scores, while participants with MCI are distributed across the spectrum.
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We conducted a series of multiple linear regression analyses to examine whether diagnosis could explain the associations of PIB binding with episodic memory and with non-memory cognition, controlling for age, education and gender. The first set of analyses demonstrated that increased PIB binding was related to being diagnosed with AD (ß = 0.60, P < 0.001) and not being diagnosed as a HA (ß = –0.59, P < 0.001). Impaired memory performance was related to increased PIB binding (ß = –0.67, P < 0.001), being diagnosed with AD (ß = –0.27, P < 0.001), and not being diagnosed as a HA (ß = 0.58, P < 0.001). In a model combining both PIB binding and diagnosis, the relationship between memory performance and PIB binding had diminished, but was still significant (ß = –0.30, P < 0.001). Thus, diagnosis only partly explained the relationship between PIB binding and memory. The same method of analysis applied to non-memory cognition and PIB binding demonstrated a less robust negative correlation (ß = –0.50, P < 0.001) that was eliminated when diagnosis was controlled (ß = –0.01, P = 0.91).
Pearson correlations for each group showed a strong relationship between episodic memory and PIB binding in MCI (r = –0.60, P < 0.001) and HA (r = –0.38, P = 0.034), but not in AD (r = 0.04, P = 0.85), as shown in Fig. 4. The correlation in MCI persisted when only amnestic MCI were included (r = –0.46, P = 0.023). There was also a strong correlation when all non-demented (MCI and HA) PIB-positive cases were included (r= –0.51, P = 0.006).
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Comparison of Pearson correlations can be misleading, however, when the variance of the independent variable—episodic memory in this case—differs between groups (Baron and Kenny, 1986
). To address this issue, we conducted a moderated regression with episodic memory as the criterion variable and the following predictors: age, gender, education, PIB binding, diagnostic variables and the interaction between each of the diagnostic variables and PIB binding. Moderation is indicated by a significant interaction (Aiken and West, 1991). There was no significant effect of the HA x PIB product term (ß = 0.06, P = 0.41). There was, however, a strong trend (ß = 0.14, P = 0.056) for an effect of the AD x PIB product term. This trend supports the results of the Pearson correlations and tentatively suggests that there is a different relationship between PIB binding and memory in AD compared with nondemented participants (MCI and HA), when age, gender and education are controlled. We explored the nature of this trend further by deriving equations from the standardized ß values in regression analysis to represent the relationship between PIB binding and memory in AD compared with MCI and HA. These equations demonstrated a stronger negative relationship between PIB binding and episodic memory in the nondemented groups (ß = –0.25), compared with AD (ß = –0.12). |
Discussion |
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Aß burden, assessed in vivo by 11C-PIB PET, was related strongly and inversely to episodic memory performance, but this differed between groups. A much stronger relationship was evident in the HA and MCI participants than in those with AD. Other cognitive functions had a weaker relationship to Aß burden, which disappeared when diagnosis was controlled. The stronger relationship of AD-related pathological changes to episodic memory compared with other cognitive domains is consistent with previous post-mortem research (Nagy et al., 1996
; Thomas et al., 2005; Bennett et al., 2006). All the non-amnestic MCI participants had a PIB-negative scan, compared to only 25% of the amnestic MCI cases.
ß-Amyloid distribution and episodic memory networks
Although a central role for the medial temporal lobe (MTL) in episodic memory function is well established (Cohen and Eichenbaum, 1993; Squire and Zola, 1996), Aß deposition does not occur there early or in abundance (Braak and Braak, 1991; Edison et al., 2007). This poses questions about the basis of the association between Aß distribution and episodic memory impairment. The MTL may be particularly sensitive to the neurotoxic effect of Aß (Roder et al., 2003; Resende et al., 2007), either directly or through Aß-induced neurofibrillary tangles, which are known to correlate with memory impairment in established AD (Nagy et al., 1996; Guillozet et al., 2003; Bennett et al., 2004). Alternatively, memory impairment may be related to the presence of soluble Aß oligomers in the MTL (Klein, 2006), which 11C-PIB-PET is not thought to detect. It is also plausible to postulate that Aß is related to memory performance through its effect on other parts of the memory network. Specifically, the posterior cingulate demonstrates hypometabolism (Minoshima et al., 1997; Buckner et al., 2005), atrophy (Buckner et al., 2005) and Aß deposition early in AD (Buckner et al., 2005; Mintun et al., 2006), and has been implicated in memory processes by virtue of its anatomical (Nestor et al., 2004; Buckner et al., 2005) and functional MTL connections (Buckner et al., 2005; Johnson et al., 2006).
ß-Amyloid burden and memory in HA and MCI
Despite documentation of Aß in non-demented cases, only one previous study (Guillozet et al., 2003) examined the relationship between Aß burden, memory and non-memory cognition in non-demented participants. They reported no relationship between any of the cognitive tasks and Aß plaque density, but the sample was small (5 HA, 3 MCI). In contrast, with a much larger sample, we found a strong relationship between Aß (as measured by PIB binding) and concurrent episodic memory performance in both HA and MCI. This is consistent with a recent report from a large post mortem study of reduced memory performance in HA participants who had AD neuropathologic changes at autopsy (Bennett et al., 2006). Together with the findings of a preferential relationship with memory, the earliest and most predictive cognitive change detectable in AD, these results suggest that Aß deposition is an early event in the pathological process of AD.
In addition, we found that our PIB-positive MCI subgroup were more likely to carry an ApoE 4 allele and demonstrate worse memory impairment (resembling AD) compared with the PIB-negative MCI subgroup. These characteristics are indicative of early AD and suggest the PIB-positive MCI group represent preclinical AD. Our rate of PIB positive scans in MCI is also in accord with the expected proportion that will develop AD (Busse et al., 2006a). Although our longitudinal follow-up assessments are not complete, 18-month follow-up data has been obtained on 5 of the 33 MCI participants. These consist of three PIB-positive amnestic MCI participants who have all converted to AD, a PIB-negative amnestic MCI participant who has shown stable cognitive functioning and a PIB-positive subjective MCI participant who has developed objective cognitive impairment and now meets criteria for amnestic MCI. Forsberg et al. (in press, Neurobiology of Aging) also report conversion of PIB-positive but not PIB-negative MCI cases to AD over an 8-month follow-up period. As none of our non-amnestic MCI participants had PIB-positive scans, we hypothesize that the aetiology of their cognitive problems may include depression (Aggarwal et al., 2005), dementia where Aß deposition is not a feature (e.g. frontotemporal dementia; Rowe et al., 2007), or they may prove to be part of the 5–10% who have stable MCI, or the 20% who revert to apparent normality (Busse et al., 2006b).
One of the limitations of our study is the high proportion (50%) of HA participants with a family history of dementia. This represents a selection bias, with many of our HA participants volunteering because they had a family member with dementia, and is somewhat concerning given that family history is one of the primary risk factors for AD (Blacker and Tanzi, 1998; Zekanowski et al., 2004). It could mean that our HA group have an increased risk of developing dementia compared to healthy elderly individuals randomly recruited from the population, and that they may be more likely to have a PIB-positive (‘AD-like’) scan.
ß-Amyloid burden and memory in AD
In contrast to the strong relationship between PIB binding and memory in MCI and HA, a much weaker relationship was found in AD. Some studies have reported a relationship between Aß and memory in AD (Nagy et al., 1996; Kanne et al., 1998; Thomas et al., 2005; Edison et al., 2007), but the relationships are inconsistent and disappear when different pathological criteria are used (Nagy et al., 1996; Edison et al., 2007), or are only present after particular corrections (Kanne et al., 1998). Our data suggest that by the time dementia has developed and AD can be diagnosed, Aß deposition is well advanced and the relationship between Aß and memory has reached a plateau. This finding raises several possibilities. It may be that the continued presence of a given level of amyloid progressively destroys cell function, with accelerating cognitive decline as all reserve function is exhausted. Alternatively, factors such as ischaemic neuronal damage, perhaps due to microvascular amyloid angiopathy, may contribute to acceleration of cognitive decline in people with AD.
Methodological explanations for the observed lack of correlation between PIB binding and memory impairment in AD include the restricted range of dementia severity in our study (MMSE 22.7 ± 3.6) and ‘floor’ effects with cognitive testing. Almost all our AD participants had very low scores on the episodic memory tasks, limiting the range of results and therefore possibly obscuring a correlation. With less demanding tasks, however, we also found no correlation between performance and Aß burden in the AD group (e.g. for MMSE, r = –0.08, P = 0.68). Our findings accord with a recent report that PIB binding does not change significantly in AD over a 2-year period, even in participants with significant cognitive decline between scans (Engler et al., 2006). Of interest, Nagy et al. (1996) found that the relationship between Aß and memory in AD was best represented by a square root function, lending support to our idea of a relationship that plateaus.
In conclusion, our study shows that Aß deposition is associated with impaired episodic memory in non-demented individuals, providing support for the proposal that Aß imaging can detect the preclinical phase of AD. Further longitudinal study is required to confirm this interpretation. These findings have implications for the timing of potential anti-amyloid therapeutics, suggesting that such therapy should be evaluated in mildly symptomatic or asymptomatic individuals with increased brain Aß burden to assess the potential for the prevention of dementia.
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Footnotes |
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8Present address: Macquarie Centre for Cognitive Science (MACCS), Macquarie University, Sydney, NSW, Australia
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Acknowledgements |
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Unrestricted educational research grants were provided from Neurosciences Victoria, Austin Hospital Medical Research Foundation, and the Commonwealth Government of Australia Department of Health and Ageing. The authors wish to acknowledge the valued assistance of David Darby for recruitment of healthy elderly participants, Sylvia Gong and Graham O’Keefe in image acquisition and processing, Tiffany Cowie for ApoE genotyping, and Uwe Ackermann, Henri Tochon-Danguy, and Clare Smith for synthesis of PIB. Funding to pay the Open Access publication charges for this article was provided by the Commonwealth Government of Australia Department of Health & Ageing.
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References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Bennett DA. Mild cognitive impairment in different functional domains and incident Alzheimer's disease. J Neurol Neurosurg Psychiatry (2005) 76:1479–84.
Aiken LS, West SG. Multiple regression: testing and interpreting interactions. (1991) Newbury Park, CA: Sage Publications.
Amieva H, Jacqmin-Gadda H, Orgogozo J-M, Le Carret N, Helmer C, Letenneur L, et al. The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study. Brain (2005) 128:1093–101.
Archer HA, Edison P, Brooks DJ, Barnes J, Frost C, Yeatman T, et al. Amyloid load and cerebral atrophy in Alzheimer's disease: an 11C-PIB positron emission tomography study. Ann Neurol (2006) 60:145–7.[CrossRef][ISI][Medline]
Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol (1986) 51:1173–82.[CrossRef][ISI][Medline]
Bartoo GT, Nochlin D, Chang D, Kim Y, Sumi SM. The mean Aß load in the hippocampus correlates with duration and severity of dementia in subgroups of Alzheimer disease. J Neuropathol. Exp Neurol (1997) 56:531–40.
Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology (2006) 66:1837–44.
Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol (2004) 61:378–84.
Benton A. Differential behavioral effects of frontal lobe disease. Neuropsychologia (1968) 6:53–60.[CrossRef][ISI]
Beyreuther K, Dyrks T, Hilbich C, Monning U, Konig G, Multhaup G, et al. Amyloid precursor protein (APP) and beta A4 amyloid in Alzheimer's disease and Down syndrome. Prog Clin Biol Res (1992) 379:159–82.[Medline]
Blacker D, Tanzi RE. The genetics of Alzheimer disease: current status and future prospects. Arch Neurol (1998) 55:294–6.
Braak H, Braak E. Neuropathological staging of Alzheimer related changes. Acta Neuropathol (Berl) (1991) 82:239–59.[CrossRef][Medline]
Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci (2005) 25:7709–17.
Busse A, Angermeyer MC, Riedel-Heller SG. Progression of mild cognitive impairment to dementia: a challenge to current thinking. Br J Psychiatry (2006a) 189:399–404.
Busse A, Hensel A, Gühne U, Angermeyer MC, Riedel-Heller SG. Mild cognitive impairment: long-term course of four clinical subtypes. Neurology (2006b) 67:2176–85.
Bussière T, Friend PD, Sadeghi N, Wicinski B, Lin GI, Bouras C, et al. Stereological assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer's disease. Neuroscience (2002) 112:75–91.[CrossRef][ISI][Medline]
Cohen NJ, Eichenbaum H. Memory, amnesia, and the hippocampal system. (1993) Cambridge: The MIT Press.
Cummings BJ, Pike CJ, Shankle R, Cotman CW. ß-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease. Neurobiol Aging (1996) 17:921–33.[CrossRef][ISI][Medline]
Delis DC, Kramer JH, Kaplan E, Ober BA. CVLT-II: California Verbal Learning Test Second Edition Adult Version. (2000) San Antonio, TX: The Psychological Corporation.
Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, et al. Amyloid, hypometabolism, and cognition in Alzheimer disease: An [11C] PIB and [18F] FDG PET study. Neurology (2007) 68:501–8.
Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, et al. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain (2006) 129:2856–66.
Fagan AM, Mintun MA, Mach RH, Lee S, Dence CS, Shah AR, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aß42 in humans. Ann Neurol (2006) 59:512–9.[CrossRef][ISI][Medline]
Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet (2005) 366:2112–7.[CrossRef][ISI][Medline]
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) 12:189–98.[CrossRef][ISI][Medline]
Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2007 (in press), doi:10.1016/j.neurobiolaging. 2007.03.029. [epub ahead of print: May 10, 2007].
Giannakopoulos P, Herrmann FR, Bussière T, Bouras C, Kövari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology (2003) 60:1494–500.[CrossRef]
Guillozet AL, Weintraub S, Mash DC, Mesulam MM. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol (2003) 60:729–36.
Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL, et al. Activation of brain regions vulnerable to Alzheimer's disease: the effect of mild cognitive impairment. Neurobiol Aging (2006) 27:1604–12.[CrossRef][ISI][Medline]
Kanne SM, Balota DA, Storandt M, McKeel DW Jr, Morris JC. Relating anatomy to function in Alzheimer's disease: neuropsychological profiles predict regional neuropathology 5 years later. Neurology (1998) 50:979–85.
Kemppainen NM, Aalto S, Wilson IA, Nagren K, Helin S, Brück A, et al. Voxel-based analysis of PET amyloid ligand [11C] PIB uptake in Alzheimer disease. Neurology (2006) 67:1575–80.
Klein WL. Synaptic targeting by Aß oligomers (ADDLS) as a basis for memory loss in early Alzheimer's disease. Alzheimers Dement (2006) 2:43–55.[CrossRef]
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Ann Neurol (2004) 55:306–19.[CrossRef][ISI][Medline]
Klunk WE, Wang Y, Huang G-F, Debnath ML, Holt DP, Shao L, et al. The binding of 2-(4'-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J Neurosci (2003) 23:2086–92.
Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR. Neuropathologic substrate of mild cognitive impairment. Arch Neurol (2006) 63:38–46.
Masters CL, Beyreuther K. Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Aß amyloid pathway. Brain (2006) 129:2823–9.
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 department of health and human services task force on Alzheimer's disease. Neurology (1984) 34:939–44.
Meyers JE, Meyers KR. Rey Complex Figure Test and Recognition Trial. (1995) Odessa: Psychological Assessment Resources Inc.
Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol (1997) 42:85–94.[CrossRef][ISI][Medline]
Mintun MA, LaRossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology (2006) 67:446–52.
Mufson EJ, Chen E-Y, Cochran EJ, Beckett LA, Bennett DA, Kordower JH. Entorhinal cortex ß-amyloid load in individuals with mild cognitive impairment. Exp Neurol (1999) 158:469–90.[CrossRef][ISI][Medline]
Nagy Z, Jobst KA, Esiri MM, Morris JH, King EM-F, MacDonald B, et al. Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer's disease: clinicopathologic correlations using three sets of pathologic diagnostic criteria. Dementia (1996) 7:76–81.[ISI][Medline]
Nestor PJ, Scheltens P, Hodges JR. Advances in early detection of Alzheimer's disease. Nat Rev Neurosci (2004) 5:s34–41.[CrossRef]
Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive impairment. Arch Neurol (2001) 58:1985–92.
Petersen RC, Parisi JE, Dickson DW, Johnson KA, Knopman DS, Boeve BF, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol (2006) 63:665–72.
Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, et al. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab (2005) 25:1528–47.[CrossRef][ISI][Medline]
Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol (1999) 45:358–68.[CrossRef][ISI][Medline]
Prohovnik I, Perl DP, Davis KL, Libow L, Lesser G, Haroutunian V. Dissociation of neuropathology from severity in late-onset Alzheimer disease. Neurology (2006) 66:49–55.
Resende R, Pereira C, Agostinho P, Vieira AP, Malva JO, Oliveira CR. Susceptibility of hippocampal neurons to Aß peptide toxicity is associated with perturbation of Ca2+ homeostasis. Brain Res (2007) 1143:11–21.[CrossRef][ISI][Medline]
Roder S, Danober L, Pozza MF, Lingenhoehl K, Wiederhold K-H, Olpe HR. Electrophysiological studies on the hippocampus and prefrontal cortex assessing the effects of amyloidosis in amyloid precursor protein 23 transgenic mice. Neuroscience (2003) 120:705–20.[CrossRef][ISI][Medline]
Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging ß-amyloid burden in aging and dementia. Neurology (2007) 68:1718–25.
Saxton J, Ratcliff G, Munro CA, Coffey E, Becker JT, Fried L, et al. Normative data on the Boston Naming Test and two equivalent 30-item short forms. Clin Neuropsychol (2000) 14:526–34.[CrossRef][ISI][Medline]
Squire LR, Zola SM. Structure and function of declarative and nondeclarative memory systems. Proc Natl Acad Sci USA (1996) 93:13515–22.
Thomas A, Ballard C, Kenny RA, O'Brien J, Oakley A, Kalaria R. Correlation of entorhinal amyloid with memory in Alzheimer's and vascular but not Lewy body dementia. Dement Geriatr Cogn Disord (2005) 19:57–60.[ISI][Medline]
Weaver Cargin J, Maruff P, Collie A, Masters C. Mild memory impairment in healthy older adults is distinct from normal aging. Brain Cogn (2006) 60:146–55.[CrossRef][ISI][Medline]
Wechsler D. WAIS-III administration and scoring manual. (1997) San Antonio, TX: Psychological Corporation.
Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund L-O, et al. Mild cognitive impairment - beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med (2004) 256:240–6.[CrossRef][ISI][Medline]
Zekanowski C, Religa D, Graff C, Filipek S, Kuznicki J. Genetic aspects of Alzheimer's disease. Acta Neurobiol Exp (Wars) (2004) 64:19–31.[Medline]
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