Article

Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment

Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD 21224, USA.
NeuroImage (Impact Factor: 6.13). 07/2011; 59(1):212-7. DOI: 10.1016/j.neuroimage.2011.07.056
Source: DBLP

ABSTRACT Recent genetic and proteomic studies demonstrate that clusterin/apolipoprotein-J is associated with risk, pathology, and progression of Alzheimer's disease (AD). Our main aim was to examine associations between plasma clusterin concentration and longitudinal changes in brain volume in normal aging and mild cognitive impairment (MCI). A secondary objective was to examine associations between peripheral concentration of clusterin and its concentration in the brain within regions that undergo neuropathological changes in AD. Non-demented individuals (N=139; mean baseline age 70.5 years) received annual volumetric MRI (912 MRI scans in total) over a mean six-year interval. Sixteen participants (92 MRI scans in total) were diagnosed during the course of the study with amnestic MCI. Clusterin concentration was assayed by ELISA in plasma samples collected within a year of the baseline MRI. Mixed effects regression models investigated whether plasma clusterin concentration was associated with rates of brain atrophy for control and MCI groups and whether these associations differed between groups. In a separate autopsy sample of individuals with AD (N=17) and healthy controls (N=4), we examined the association between antemortem clusterin concentration in plasma and postmortem levels in the superior temporal gyrus, hippocampus and cerebellum. The associations of plasma clusterin concentration with rates of change in brain volume were significantly different between MCI and control groups in several volumes including whole brain, ventricular CSF, temporal gray matter as well as parahippocampal, superior temporal and cingulate gyri. Within the MCI but not control group, higher baseline concentration of plasma clusterin was associated with slower rates of brain atrophy in these regions. In the combined autopsy sample of AD and control cases, representing a range of severity in AD pathology, we observed a significant association between clusterin concentration in the plasma and that in the superior temporal gyrus. Our findings suggest that clusterin, a plasma protein with roles in amyloid clearance, complement inhibition and apoptosis, is associated with rate of brain atrophy in MCI. Furthermore, peripheral concentration of clusterin also appears to reflect its concentration within brain regions vulnerable to AD pathology. These findings in combination suggest an influence of this multi-functional protein on early stages of progression in AD pathology.

0 Followers
 · 
178 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intracranial volume (ICV) is an important normalization measure used in morphometric analyses to correct for head size in studies of Alzheimer Disease (AD). Inaccurate ICV estimation could introduce bias in the outcome. The current study provides a decision aid in defining protocols for ICV estimation in patients with Alzheimer disease in terms of sampling frequencies that can be optimally used on the volumetric MRI data, and the type of software most suitable for use in estimating the ICV measure. Two groups of 22 subjects are considered, including adult controls (AC) and patients with Alzheimer Disease (AD). Reference measurements were calculated for each subject by manually tracing intracranial cavity by the means of visual inspection. The reliability of reference measurements were assured through intra- and inter- variation analyses. Three publicly well-known software packages (Freesurfer, FSL, and SPM) were examined in their ability to automatically estimate ICV across the groups. Analysis of the results supported the significant effect of estimation method, gender, cognitive condition of the subject and the interaction among method and cognitive condition factors in the measured ICV. Results on sub-sampling studies with a 95% confidence showed that in order to keep the accuracy of the interleaved slice sampling protocol above 99%, the sampling period cannot exceed 20 millimeters for AC and 15 millimeters for AD. Freesurfer showed promising estimates for both adult groups. However SPM showed more consistency in its ICV estimation over the different phases of the study. This study emphasized the importance in selecting the appropriate protocol, the choice of the sampling period in the manual estimation of ICV and selection of suitable software for the automated estimation of ICV. The current study serves as an initial framework for establishing an appropriate protocol in both manual and automatic ICV estimations with different subject populations.
    BMC Bioinformatics 04/2015; 16 Suppl 7:S8. DOI:10.1186/1471-2105-16-S7-S8 · 2.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Clusterin protein in plasma has been found to differentiate between people with and without cognitive changes. However, these findings are not conclusive, despite the clusterin gene variations repeatedly being linked to increased risk for dementia, in particular Alzheimer's disease (AD).Method We analysed the level of clusterin in platelet and plasma in 25 subjects with a clinical diagnosis of AD and 26 subjects with no cognitive impairment.ResultsIn the current study, we report that the levels of both plasma and platelet clusterin are similar between AD and cognitively intact individuals. Clusterin plasma and platelet levels, as well as the plasma/platelet clusterin ratio, were not affected by age, gender, cognitive impairment and/or overt behavioural symptomatology, including presence of hallucinations and delusions, as well as depression. However, the plasma/platelet clusterin ratio was positively associated in with the Neuropsychiatric Inventory measures of agitation, apathy, irritability and motor aberrant behaviour in AD subjects.Conclusion Previous inconsistencies in reported blood clusterin levels may be a result of underlying non-cognitive symptoms in people with AD. Our findings need now to be replicated in larger group of dementia subjects.
    International Journal of Geriatric Psychiatry 04/2015; 30(4). DOI:10.1002/gps.4145 · 3.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intracranial volume (ICV) is a standard measure often used in morphometric analyses to correct for head size in brain studies. Inaccurate ICV estimation could introduce bias in the outcome. The current study provides a decision aid in defining protocols for ICV estimation across different subject groups in terms of sampling frequencies that can be optimally used on the volumetric MRI data, and type of software most suitable for use in estimating the ICV measure. Four groups of 53 subjects are considered, including adult controls (AC, adults with Alzheimer's disease (AD), pediatric controls (PC) and group of pediatric epilepsy subjects (PE). Reference measurements were calculated for each subject by manually tracing intracranial cavity without sub-sampling. The reliability of reference measurements were assured through intra- and inter- variation analyses. Three publicly well-known software packages (FreeSurfer Ver. 5.3.0, FSL Ver. 5.0, SPM8 and SPM12) were examined in their ability to automatically estimate ICV across the groups. Results on sub-sampling studies with a 95 % confidence showed that in order to keep the accuracy of the inter-leaved slice sampling protocol above 99 %, sampling period cannot exceed 20 mm for AC, 25 mm for PC, 15 mm for AD and 17 mm for the PE groups. The study assumes a priori knowledge about the population under study into the automated ICV estimation. Tuning of the parameters in FSL and the use of proper atlas in SPM showed significant reduction in the systematic bias and the error in ICV estimation via these automated tools. SPM12 with the use of pediatric template is found to be a more suitable candidate for PE group. SPM12 and FSL subjected to tuning are the more appropriate tools for the PC group. The random error is minimized for FS in AD group and SPM8 showed less systematic bias. Across the AC group, both SPM12 and FS performed well but SPM12 reported lesser amount of systematic bias.
    Neuroinformatics 03/2015; DOI:10.1007/s12021-015-9266-5 · 3.10 Impact Factor