Brain Atrophy in Healthy Aging Is Related to CSF Levels of A 1-42

Center for the Study of Human Cognition, Department of Psychology, University of Oslo, Oslo, Norway.
Cerebral Cortex (Impact Factor: 8.67). 09/2010; 20(9):2069-79. DOI: 10.1093/cercor/bhp279
Source: PubMed


Reduced levels of β-amyloid1-42 (Aβ1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer’s disease (AD), likely
reflecting Aβ deposition in plaques and neuronal and axonal damage. It is not known whether these biomarkers are associated
with brain atrophy also in healthy aging. We tested the relationship between CSF levels of Aβ1-42 and tau (total tau and tau
phosphorylated at threonine 181) proteins and 1-year brain atrophy in 71 cognitively normal elderly individuals. Results showed
that under a certain threshold value, levels of Aβ1-42 correlated highly with 1-year change in a wide range of brain areas.
The strongest relationships were not found in the regions most vulnerable early in AD. Above the threshold level, Aβ1-42 was
not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded
that Aβ1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals
but that reductions independent of CSF levels of Aβ1-42 is common. Further research and follow-up examinations over several
years are needed to test whether degenerative pathology will eventually develop in the group of cognitively normal elderly
individuals with low levels of Aβ1-42.

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    • "Several nonlinear methods have been used to model the relationship between biomarkers and neuroimaging-derived measurements. For example, polynomial regression has been used to model agerelated atrophy in relation to CSF Ab levels using a quadratic term (Fjell et al., 2010). Other methods do not need to explicitly model the parametric form of the association: generalized additive models have been used to model the effect of aging (Schuff et al., 2012), splines to model the relationship between brain atrophy and CSF Ab levels (Insel et al., 2014), and local regression methods to track the evolution of several biomarkers in dominantly inherited AD as a function of the estimated years from expected symptom onset (Bateman et al., 2012). "
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    ABSTRACT: The progression of Alzheimer's disease (AD) is characterized by complex trajectories of cerebral atrophy that are affected by interactions with age and apolipoprotein E allele ε4 (APOE4) status. In this article, we report the nonlinear volumetric changes in gray matter across the full biological spectrum of the disease, represented by the AD-cerebrospinal fluid (CSF) index. This index reflects the subject's level of pathology and position along the AD continuum. We also evaluated the associated impact of the APOE4 genotype. The atrophy pattern associated with the AD-CSF index was highly symmetrical and corresponded with the typical AD signature. Medial temporal structures showed different atrophy dynamics along the progression of the disease. The bilateral parahippocampal cortices and a parietotemporal region extending from the middle temporal to the supramarginal gyrus presented an initial increase in volume which later reverted. Similarly, a portion of the precuneus presented a rather linear inverse association with the AD-CSF index whereas some other clusters did not show significant atrophy until index values corresponded to positive CSF tau values. APOE4 carriers showed steeper hippocampal volume reductions with AD progression. Overall, the reported atrophy patterns are in close agreement with those mentioned in previous findings. However, the detected nonlinearities suggest that there may be different pathological processes taking place at specific moments during AD progression and reveal the impact of the APOE4 allele. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Neurobiology of aging
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    • "This finding suggests that cortical amyloid is predictive of future cognitive decline and symptomatic AD. In addition, reduced CSF Aβ42 levels were associated with brain atrophy in cognitively normal individuals, but not in patients with AD.70,71 Preclinical AD is not benign, and Aβ aggregation seems to drive neurodegeneration in the preclinical phase.6 "
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    ABSTRACT: The pathophysiologic process of Alzheimer's disease (AD) begins years before the diagnosis of clinical dementia. This concept of preclinical AD has arisen from the observation of AD pathologic findings such as senile plaques and neurofibrillary tangles in the brains of people who at the time of death had normal cognitive function. Recent advances in biomarker studies now provide the ability to detect the pathologic changes of AD, which are antecedent to symptoms of the illness, in cognitively normal individuals. Functional and structural brain alterations that begin with amyloid-β accumulation already show the patterns of abnormality seen in individuals with dementia due to AD. The presence of preclinical AD provides a critical opportunity for potential interventions with disease-modifying therapy. This review focuses on the studies of antecedent biomarkers for preclinical AD.
    Preview · Article · Jun 2011 · Journal of Clinical Neurology
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    • "Hippocampal volume has also been found to be sensitive and specific for predicting 1-year conversion from MCI to probable AD (Calvini, et al., 2009, Chupin, et al., 2009, McEvoy, et al., 2009, Misra, et al., 2009, Nestor, et al., 2008, Querbes, et al., 2009, Risacher, et al., 2009). MRI studies of the ADNI cohort have also examined longitudinal change in brain volumes using ROI and whole-brain structural change techniques (e.g., Jacobian determinants, boundary shift integral), and have detected differences in annual change in whole brain volume, hippocampal volume, and ventricular volume as a function of baseline diagnostic group (AD, MCI, HC) (Evans, et al., 2009, Fjell, et al., 2010b, Ho, et al., 2009, Holland, et al., 2009, Hua, et al., 2009, Jack, et al., 2009, Leow, et al., 2009, McDonald, et al., 2009, McEvoy, et al., 2009, Misra, et al., 2009, Morra, et al., 2009, Nestor, et al., 2008, Schuff, et al., 2009) and of APOE ε4 genotype (Fjell, et al., 2010a, Morra, et al., 2009, Nestor, et al., 2008, Schuff, et al., 2009). Several studies have reported larger declines in whole brain and regional volumes, as well as larger ventricular volume increases in MCI to AD converters than MCI non-converters (Evans, et al., 2009, Leow, et al., 2009, Misra, et al., 2009, Nestor, et al., 2008). "
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    ABSTRACT: Atrophic changes in early Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) have been proposed as biomarkers for detection and monitoring. We analyzed magnetic resonance imaging (MRI) atrophy rate from baseline to 1 year in 4 groups of participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI): AD (n = 152), converters from MCI to probable AD (MCI-C, n = 60), stable MCI (MCI-S, n = 261), and healthy controls (HC, n = 200). Scans were analyzed using multiple methods, including voxel-based morphometry (VBM), regions of interest (ROIs), and automated parcellation, permitting comparison of annual percent change (APC) in neurodegeneration markers. Effect sizes and the sample required to detect 25% reduction in atrophy rates were calculated. The influence of APOE genotype on APC was also evaluated. AD patients and converters from MCI to probable AD demonstrated high atrophy APCs across regions compared with minimal change in healthy controls. Stable MCI subjects showed intermediate atrophy rates. APOE genotype was associated with APC in key regions. In sum, APC rates are influenced by APOE genotype, imminent MCI to AD conversion, and AD-related neurodegeneration.
    Full-text · Article · Aug 2010 · Neurobiology of aging
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