Dataset Information

Cholecystokinin and Alzheimer's disease: a biomarker of metabolic function, neural integrity, and cognitive performance.

ABSTRACT: Cholecystokinin (CCK) is a satiety hormone that is highly expressed in brain regions like the hippocampus. CCK is integral for maintaining or enhancing memory and thus may be a useful marker of cognitive and neural integrity in participants with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD). Cerebrospinal fluid (CSF) CCK levels were examined in 287 subjects from the Alzheimer's Disease Neuroimaging Initiative. Linear or voxelwise regression was used to examine associations between CCK, regional gray matter, CSF AD biomarkers, and cognitive outcomes. Briefly, higher CCK was related to a decreased likelihood of having mild cognitive impairment or AD, better global and memory scores, and more gray matter volume primarily spanning posterior cingulate cortex, parahippocampal gyrus, and medial prefrontal cortex. CSF CCK was also strongly related to higher CSF total tau (R2 = 0.342) and p-tau-181 (R2 = 0.256) but not A?1-42. Tau levels partially mediated CCK and cognition associations. In conclusion, CCK levels may reflect compensatory protection as AD pathology progresses.

SUBMITTER: Plagman A

PROVIDER: S-EPMC6425756 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Cholecystokinin and Alzheimer's disease: a biomarker of metabolic function, neural integrity, and cognitive performance.

Plagman Alexandra A Hoscheidt Siobhan S McLimans Kelsey E KE Klinedinst Brandon B Pappas Colleen C Anantharam Vellareddy V Kanthasamy Anumantha A Willette Auriel A AA

Neurobiology of aging 20190109

Cholecystokinin (CCK) is a satiety hormone that is highly expressed in brain regions like the hippocampus. CCK is integral for maintaining or enhancing memory and thus may be a useful marker of cognitive and neural integrity in participants with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD). Cerebrospinal fluid (CSF) CCK levels were examined in 287 subjects from the Alzheimer's Disease Neuroimaging Initiative. Linear or voxelwise regression was used to examine associa ...[more]

PMID: 30739077

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Project description:BACKGROUND:Metabolic syndrome, the development of which is associated with high-caloric Western diet (HCD) intake, represent a risk factor for mild cognitive impairment (MCI) and dementia including Alzheimer's disease (AD) later in life. This study aimed to investigate the effect of diet-induced metabolic disturbances on white matter neuroinflammation and cognitive function in a transgenic (TG) Fischer 344 rat carrying a human ?-amyloid precursor protein (APP) gene with Swedish and Indiana mutations (APP21 TG), a model of pre-AD and MCI. METHODS:TG and wildtype (WT) rats received either a HCD with 40% kJ from fat supplemented with 20% corn syrup drink or a standard diet for 12 weeks. Body weight, caloric intake, and blood pressure were measured repeatedly. End-point changes in glucose and lipid metabolism were also assessed. Open field task was used for assessment of activity; Morris water maze was used to assess spatial learning and memory. Cerebral white matter microglia and astrocytes, hippocampal neurons, and neuronal synapses were examined using immunohistochemistry. RESULTS:Rats maintained on the HCD developed significant obesity, visceral adiposity, dyslipidemia, and hyperinsulinemia, but did not become hypertensive. Impaired glucose tolerance was observed only in WT rats on the HCD. Total microglia number, activated OX-6+ microglia, as well as GFAP+ astrocytes located predominantly in the white matter were greater in the APP21 TG rat model in comparison to WT rats. HCD-driven metabolic perturbations further exacerbated white matter microgliosis and microglia cell activation in the APP21 TG rats and led to detectable changes in spatial reference memory in the comorbid prodromal AD and metabolic syndrome group compared to WT control rats. Neuronal density in the CA1 subregion of the hippocampus was not different between the experimental groups. Synaptic density in the CA1 and CA3 hippocampal subregions was lower in the TG rats compared to WT rats; however, there was no additional effect of the co-morbidity on this measure. CONCLUSIONS:These results suggest that white matter neuroinflammation might be one of the possible processes of early interaction of metabolic syndrome with MCI and pre-AD and could be one of the early brain pathologies contributing to cognitive deficits observed in mild cognitive impairment and dementia, including AD cases.

Project description:Multiple biomarkers can capture different facets of Alzheimer's disease. However, statistical models of biomarkers to predict outcomes in Alzheimer's rarely model nonlinear interactions between these measures. Here, we used Gaussian Processes to address this, modelling nonlinear interactions to predict progression from mild cognitive impairment (MCI) to Alzheimer's over 3 years, using Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Measures included: demographics, APOE4 genotype, CSF (amyloid-β42, total tau, phosphorylated tau), [18F ]florbetapir, hippocampal volume and brain-age. We examined: (a) the independent value of each biomarker; and (b) whether modelling nonlinear interactions between biomarkers improved predictions. Each measured added complementary information when predicting conversion to Alzheimer's. A linear model classifying stable from progressive MCI explained over half the variance (R2 = 0.51, p < .001); the strongest independently contributing biomarker was hippocampal volume (R2 = 0.13). When comparing sensitivity of different models to progressive MCI (independent biomarker models, additive models, nonlinear interaction models), we observed a significant improvement (p < .001) for various two-way interaction models. The best performing model included an interaction between amyloid-β-PET and P-tau, while accounting for hippocampal volume (sensitivity = 0.77, AUC = 0.826). Closely related biomarkers contributed uniquely to predict conversion to Alzheimer's. Nonlinear biomarker interactions were also implicated, and results showed that although for some patients adding additional biomarkers may add little value (i.e., when hippocampal volume is high), for others (i.e., with low hippocampal volume) further invasive and expensive examination may be warranted. Our framework enables visualisation of these interactions, in individual patient biomarker 'space', providing information for personalised or stratified healthcare or clinical trial design.

Dataset Information

Cholecystokinin and Alzheimer's disease: a biomarker of metabolic function, neural integrity, and cognitive performance.

Publications

Cholecystokinin and Alzheimer's disease: a biomarker of metabolic function, neural integrity, and cognitive performance.

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