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Mapping correlations between ventricular expansion and CSF amyloid and tau biomarkers in 240 subjects with Alzheimer's disease, mild cognitive impairment and elderly controls

Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095-7332, USA.
NeuroImage (Impact Factor: 6.36). 03/2009; 46(2):394-410. DOI: 10.1016/j.neuroimage.2009.02.015
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ABSTRACT We aimed to improve on the single-atlas ventricular segmentation method of (Carmichael, O.T., Thompson, P.M., Dutton, R.A., Lu, A., Lee, S.E., Lee, J.Y., Kuller, L.H., Lopez, O.L., Aizenstein, H.J., Meltzer, C.C., Liu, Y., Toga, A.W., Becker, J.T., 2006. Mapping ventricular changes related to dementia and mild cognitive impairment in a large community-based cohort. IEEE ISBI. 315-318) by using multi-atlas segmentation, which has been shown to lead to more accurate segmentations (Chou, Y., Leporé, N., de Zubicaray, G., Carmichael, O., Becker, J., Toga, A., Thompson, P., 2008. Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer's disease, NeuroImage 40(2): 615-630); with this method, we calculated minimal numbers of subjects needed to detect correlations between clinical scores and ventricular maps. We also assessed correlations between emerging CSF biomarkers of Alzheimer's disease pathology and localizable deficits in the brain, in 80 AD, 80 mild cognitive impairment (MCI), and 80 healthy controls from the Alzheimer's Disease Neuroimaging Initiative. Six expertly segmented images and their embedded parametric mesh surfaces were fluidly registered to each brain; segmentations were averaged within subjects to reduce errors. Surface-based statistical maps revealed powerful correlations between surface morphology and 4 variables: (1) diagnosis, (2) depression severity, (3) cognitive function at baseline, and (4) future cognitive decline over the following year. Cognitive function was assessed using the mini-mental state exam (MMSE), global and sum-of-boxes clinical dementia rating (CDR) scores, at baseline and 1-year follow-up. Lower CSF Abeta(1-42) protein levels, a biomarker of AD pathology assessed in 138 of the 240 subjects, were correlated with lateral ventricular expansion. Using false discovery rate (FDR) methods, 40 and 120 subjects, respectively, were needed to discriminate AD and MCI from normal groups. 120 subjects were required to detect correlations between ventricular enlargement and MMSE, global CDR, sum-of-boxes CDR and clinical depression scores. Ventricular expansion maps correlate with pathological and cognitive measures in AD, and may be useful in future imaging-based clinical trials.

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Available from: Leslie M Shaw, Aug 18, 2015
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    • "Prior methods for ventricular segmentation have used semiautomated , automated (Chou et al., 2008), and single-atlas or multi-atlas methods (Chou et al., 2009). Here we segmented the ventricles with our modified multi-atlas approach (Gutman et al., 2013; Madsen et al., 2013). "
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    ABSTRACT: A recent genome-wide association meta-analysis showed a suggestive association between alcohol intake in humans and a common single nucleotide polymorphism in the ras-specific guanine nucleotide releasing factor 2 gene. Here, we tested whether this variant - associated with lower alcohol consumption - showed associations with brain structure and longitudinal ventricular expansion over time, across two independent elderly cohorts, totaling 1,032 subjects. We first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI1). Then, we assessed the generalizability of the findings by testing this polymorphism in a replication sample of 294 elderly subjects from a continuation of the first ADNI project (ADNI2) to minimize the risk of reporting false positive results. The minor allele - previously linked with lower alcohol intake - was associated with larger volumes in various cortical regions, notably the medial prefrontal cortex and cingulate gyrus in both cohorts. Intriguingly, the same allele also predicted faster ventricular expansion rates in the ADNI1 cohort at 1- and 2-year follow up. Despite a lack of alcohol consumption data in this study cohort, these findings, combined with earlier functional imaging investigations of the same gene, suggest the existence of reciprocal interactions between genes, brain, and drinking behavior.
    Frontiers in Aging Neuroscience 12/2013; 5:93. DOI:10.3389/fnagi.2013.00093 · 2.84 Impact Factor
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    • "A crucial question regards whether these atrophic processes in the brains of healthy elderly individuals are related to the cerebrospinal fluid (CSF) biomarkers b-amyloid 1-42 (Ab1-42) and tau proteins, potentially reflecting age-related neurodegenerative mechanisms. Depositions of extracellular plaques (Ab1-42) and intracellular neurofibrillary tangles (tau) are believed to play causative roles in neurodegeneration in Alzheimer's disease (AD; Goedert and Spillantini 2006; Spires-Jones et al. 2009a), and CSF levels of these biomarkers correlate with rates of atrophy and ventricular expansion (Hampel et al. 2005; de Leon et al. 2006; Chou et al. 2009; Schuff et al. 2009). However, it is unclear whether and to what extent these CSF biomarkers are related to neurodegenerative effects also in healthy elderly individuals. "
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    ABSTRACT: Reduced levels of beta-amyloid(1-42) (Abeta1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer's disease (AD), likely reflecting Abeta 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 Abeta1-42 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 Abeta1-42 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, Abeta1-42 was not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded that Abeta1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals but that reductions independent of CSF levels of Abeta1-42 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 Abeta1-42.
    Cerebral Cortex 09/2010; 20(9):2069-79. DOI:10.1093/cercor/bhp279 · 8.67 Impact Factor
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    • "CDF plots are commonly used by false discovery rate methods to assign overall significance values to statistical maps (Benjamini and Hochberg, 1995; Genovese et al. 2002; Storey, 2002). A significant correlation is declared if the CDF intersects the y ϭ 20x line (other than at the origin), i.e., critical p Ͼ 0, as this shows that the volume of suprathreshold statistics is more than 20 times that expected under null-hypothesis (Chou et al., 2009b; Hua et al., 2008a, 2009; Morra et al., 2009b). The critical p value refers to the point at where CDF plot intersects with the line y ϭ 20x, and this represents the highest statistical threshold for which at most 5% false positives are expected in the map. "
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    ABSTRACT: We set out to determine factors that influence the rate of brain atrophy in 1-year longitudinal magnetic resonance imaging (MRI) data. With tensor-based morphometry (TBM), we mapped the 3-dimensional profile of progressive atrophy in 144 subjects with probable Alzheimer's disease (AD) (age: 76.5 +/- 7.4 years), 338 with amnestic mild cognitive impairment (MCI; 76.0 +/- 7.2), and 202 healthy controls (77.0 +/- 5.1), scanned twice, 1 year apart. Statistical maps revealed significant age and sex differences in atrophic rates. Brain atrophic rates were about 1%-1.5% faster in women than men. Atrophy was faster in younger than older subjects, most prominently in mild cognitive impairment, with a 1% increase in the rates of atrophy and 2% in ventricular expansion, for every 10-year decrease in age. TBM-derived atrophic rates correlated with reduced beta-amyloid and elevated tau levels (n = 363) at baseline, baseline and progressive deterioration in clinical measures, and increasing numbers of risk alleles for the ApoE4 gene. TBM is a sensitive, high-throughput biomarker for tracking disease progression in large imaging studies; sub-analyses focusing on women or younger subjects gave improved sample size requirements for clinical trials.
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