Mintun, M. A. et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67, 446-452

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Neurology (Impact Factor: 8.29). 09/2006; 67(3):446-52. DOI: 10.1212/01.wnl.0000228230.26044.a4
Source: PubMed


Beta-amyloid (Abeta) plaques are the hallmark of Alzheimer disease (AD). A PET imaging tracer that binds to Abeta plaques in vivo, N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]PIB for "Pittsburgh Compound-B"), has significantly higher binding in subjects diagnosed with dementia of the Alzheimer type (DAT) compared to nondemented controls. The authors used this imaging technique to investigate whether abnormal binding occurs in clinically normal individuals, prior to the development of cognitive changes.
Forty-one nondemented subjects (age range 20 to 86 years) and 10 patients with DAT (age range 66 to 86 years) underwent [(11)C]PIB PET scanning. Regions of interest were drawn on the MRI over the cerebellar, prefrontal, lateral temporal, occipital, gyrus rectus, precuneus, and striatal cortex. Binding potential values (BPs), proportional to the density of [(11)C]PIB-Abeta binding sites, were calculated using the Logan graphical analysis and the cerebellar cortex for a reference tissue.
Patients with DAT had elevated BP values vs nondemented subjects (p < 0.0001). Four of the 41 nondemented subjects had elevated cortical BP values and their BP values as a group were not significantly different from the DAT subjects' BP values. Two of these four nondemented subjects had [(11)C]PIB uptake, both visually and quantitatively, that was indistinguishable from the DAT subjects.
Elevated [(11)C]PIB binding in nondemented subjects suggests that [(11)C]PIB amyloid imaging may be sensitive for detection of a preclinical Alzheimer disease state. Longitudinal studies will be required to determine the association of elevated [(11)C]PIB binding and risk of developing dementia of the Alzheimer type.

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    • "Clinical characterization alone leaves open the likelihood of inclusion of non-AD cognitively impaired subjects and normal subjects with pre-clinical AD biomarker profiles. Our findings support both scenarios , with perhaps ∼30% of the MCI/AD group misdiagnosed based on the combination of CSF and PET imaging results and aligned to previous studies that have found 30% of cognitively normal subjects over 60 years of age display abnormal AD biomarkers [7] [8] [26] [40] or plaques [26] [27] [28]. Therefore , our observations support the recommendation that each laboratory establish CSF analyte reference ranges for their own use in clinical dementia assessments and for the identification of individuals for AD clinical trials, emphasizing the need to utilize HC that have undergone optimal characterization [20] [21] [41]. "
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    ABSTRACT: Background: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). Objective: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Methods: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. Results: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity. Conclusions: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.
    Journal of Alzheimer's disease: JAD 09/2015; 48(1):175-187. DOI:10.3233/JAD-150247 · 4.15 Impact Factor
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    • "MCBP values ! 0.18 are considered abnormally elevated [27] "
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    ABSTRACT: Dementia in Parkinson disease (PD) is associated with abnormal accumulation of proteins, including β-amyloid, in cortical regions. High cognitive reserve capacity may protect cognition from β-amyloid and delay the onset of dementia. We tested the cognitive reserve theory in PD by determining whether educational attainment, a proxy for cognitive reserve, modifies the correlation between cortical β-amyloid accumulation and cognitive impairment. PD participants (N = 155) underwent MRI to quantify brain volume and [(11)C] PiB PET imaging to quantify fibrillar β-amyloid deposition. Mean cortical binding potentials (MCBP) were calculated for each participant, with higher scores indicating more fibrillar β-amyloid. Global cognitive function was assessed using the Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE). Multiple linear regression analysis was used to determine whether education modified the relationship between MCBP and cognitive function after controlling for brain volume. MCBP interacted with educational attainment to predict scores on each of the cognitive outcome measures (ps ≤ 0.02). Post-hoc analysis revealed that the effect of MCBP on cognitive function changed once the level of education reached 16 years. For participants with less than16 years of education (n = 68), higher MCBP correlated with worse cognitive function, with MCBP accounting for 8-30% of the variance in MMSE and CDR scores (ps ≤ 0.02). For participants with at least 16 years of education (n = 87), MCBP did not correlate with MMSE or CDR scores (R(2)s < 0.02, ps ≥ 0.17). These findings provide support for the cognitive reserve theory in PD and suggest that education may protect PD patients' cognition against cortical β-amyloid pathology. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 05/2015; 21(8). DOI:10.1016/j.parkreldis.2015.05.020 · 3.97 Impact Factor
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    • "One particularly interesting finding has been that up to 30% of individuals who are cognitively 'normal' have been found to have AD-related pathology, and this number has been found in post-mortem studies as well as in in vivo amyloid imaging and CSF assay studies (e.g. see Aizenstein et al., 2008; Knopman et al., 2003; Mintun et al., 2006; Price & Morris, 1999; Savva et al., 2009; Shaw et al., 2009). In addition, some studies have documented the deposition rate of amyloid in the brain of individuals who are initially cognitively normal. "
    Dementia 05/2015; 14(3):285-97. DOI:10.1177/1471301214562135 · 0.91 Impact Factor
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