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Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease.

ABSTRACT: Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer's disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using the postmortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression patterns in MCI are not an extension of aging, and for the most part, are not intermediate between aged controls and AD. Functional enrichment analysis of significant genes revealed prominent upregulation in MCI brains of genes associated with anabolic and biosynthetic pathways (notably transcription, protein biosynthesis, protein trafficking, and turnover) as well as mitochondrial energy generation. In addition, many synaptic genes showed altered expression in MCI, predominantly upregulation, including genes for central components of the vesicle fusion machinery at the synapse, synaptic vesicle trafficking, neurotransmitter receptors, and synaptic structure and stabilization. These data suggest that there is a rebalancing of synaptic transmission in the MCI brain. To investigate if synaptic gene expression levels in MCI were related to cognitive function, Pearson correlation coefficient between the Mini Mental State Examination (MMSE) and region-specific messenger RNA expression were computed for MCI cases. A number of synaptic genes showed strong significant correlations (r > 0.8, p < 0.01) most notably in the entorhinal cortex, with fewer in the hippocampus, and very few in neocortical regions. The synaptic genes with highly significant correlations were predominantly related to synaptic transmission and plasticity, and myelin composition. Unexpectedly, we found that gene expression changes that facilitate synaptic excitability and plasticity were overwhelmingly associated with poorer MMSE, and conversely that gene expression changes that inhibit plasticity were positively associated with MMSE. These data suggest that there are excessive excitability and apparent plasticity in limbic brain regions in MCI, that is associated with impaired synaptic and cognitive function. Such changes would be predicted to contribute to increased excitability, in turn leading to greater metabolic demand and ultimately progressive degeneration and AD, if not controlled.

SUBMITTER: Berchtold NC

PROVIDER: S-EPMC4067010 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease.

Berchtold Nicole C NC Sabbagh Marwan N MN Beach Thomas G TG Kim Ronald C RC Cribbs David H DH Cotman Carl W CW

Neurobiology of aging 20140402 9

Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer's disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using the postmortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression pa ...[more]

PMID: 24786631

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Project description:BackgroundAll cells accumulate insoluble protein aggregates throughout their lifespan. While many studies have characterized the canonical disease-associated protein aggregates, such as those associated with amyloid plaques, additional, undefined proteins aggregate in the brain and may be directly associated with disease and lifespan.MethodsA proteomics approach was used to identify a large subset of insoluble proteins in the mild cognitively impaired (MCI) and Alzheimer's disease (AD) human brain. Cortical samples from control, MCI, and AD patients were separated into detergent-soluble and detergent-insoluble fractions, and high-resolution LC/MS/MS technology was used to determine which proteins became more insoluble in the disease state. Bioinformatics analyses were used to determine if the alteration of protein aggregation between AD and control patients was associated with any specific biological process. Western blots were used to validate the proteomics data and to assess the levels of secondary protein modifications in MCI and AD.ResultsThere was a stage-dependent increase in detergent-insoluble proteins, with more extreme changes occurring in the AD cohort. Glycolysis was the most significantly overrepresented gene ontology biological process associated with the alteration of protein aggregation between AD and control patients. It was further shown that many low molecular weight proteins that were enriched in the AD brain were also highly aggregated, migrating on SDS-PAGE far above their predicted molecular masses. Glucose-6-phosphate isomerase, ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCHL1/PARK5), and the DNA damage repair enzyme KU70 were among the top insoluble proteins identified by proteomics and validated by Western blot to be increased in the insoluble fractions of both MCI and AD brain samples.ConclusionsDiverse proteins became more detergent-insoluble in the brains of both MCI and AD patients compared to age-matched controls, suggesting that multiple proteins aggregate in these diseases, likely posing a direct toxic insult to neurons. Furthermore, detergent-insoluble proteins included those with important biological activities for critical cellular processes such as energetics, proteolysis, and DNA damage repair. Thus, reduced protein solubility likely promotes aggregation and limits functionality, reducing the efficiency of multiple aspects of cell physiology. Pharmaceutical interventions that increase autophagy may provide a useful therapeutic treatment to combat protein aggregation.

Project description:BackgroundLeukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time.MethodsThis longitudinal observational study used data from the National Alzheimer's Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models.ResultsIn AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = -0.200 [-0.380, -0.019] points/year, n = 800) and AD dementia (B = -0.321 [-0.597, -0.046] points/year, n = 604) as measured by CDR Sum of Boxes.ConclusionsThe use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.

Project description:A sensitive marker for monitoring progression of early Alzheimer's disease would help to develop and test new therapeutic strategies. The present study is aimed at investigating brain metabolism changes over time, as a potential monitoring marker, in patients with amnestic mild cognitive impairment, according to their clinical outcome (converters or non-converters), and in relation to their cognitive decline. Seventeen amnestic mild cognitive impairment patients underwent magnetic resonance imaging and 18FDG-positron emission tomography scans both at inclusion and 18 months later. Baseline and follow-up positron emission tomography data were corrected for partial volume effects and spatially normalized using magnetic resonance imaging data, scaled to the vermis and compared using SPM2. 'PET-PAC' maps reflecting metabolic per cent annual changes were created for correlation analyses with cognitive decline. In the whole sample, the greatest metabolic decrease concerned the posterior cingulate-precuneus area. Converters had significantly greater metabolic decrease than non-converters in two ventro-medial prefrontal areas, the subgenual (BA25) and anterior cingulate (BA24/32). PET-PAC in BA25 and BA24/32 combined allowed complete between-group discrimination. BA25 PET-PAC significantly correlated with both cognitive decline and PET-PAC in the hippocampal region and temporal pole, while BA24/32 PET-PAC correlated with posterior cingulate PET-PAC. Finally, the metabolic change in BA8/9/10 was inversely related to that in BA25 and showed relative increase with cognitive decline, suggesting that compensatory processes may occur in this dorso-medial prefrontal region. The observed ventro-medial prefrontal disruption is likely to reflect disconnection from the hippocampus, both indirectly through the cingulum bundle and posterior cingulate cortex for BA24/32, and directly through the uncinate fasciculus for BA25. Altogether, our findings emphasize the potential of 18FDG-positron emission tomography for monitoring early Alzheimer's disease progression.

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Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease.

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Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease.

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