Dataset Information

Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia.

ABSTRACT: Vascular pathology plays an important role in the development of cognitive decline and dementia. In this context, growth differentiation factor-15 (GDF-15) has been suggested to be a biomarker due to its regulatory roles in inflammatory and trophic responses during tissue injury. However, limited data exist on the associations of GDF-15 with either cerebrovascular disease (CeVD) burden or the spectrum of cognitive impairment. Therefore, we aimed to study peripheral levels of GDF-15 incognitive impairment no dementia (CIND) or Alzheimer disease (AD) subjects assessed for CeVD using a case-control cohort design, with cases recruited from memory clinics and controls from memory clinics and the community. All subjects underwent detailed neuropsychological assessment, 3-Tesla magnetic resonance imaging, and venous blood draw. Subjects were classified as CIND or AD based on clinical criteria, while significant CeVD was defined as the presence of cortical infarcts and/or 2 lacunes or more, and/or confluent white matter hyperintensities (WMHs) in 2 or more brain regions. A total of 324 subjects were included in the study, of whom 80 had no cognitive impairment, 144 CIND and 100with AD. Higher GDF-15 levels were significantly associated with disease groups, especially in the presence of CeVD, namely, CIND with CeVD (odds ratios [OR]: 7.21; 95% confidence interval [CI]: 2.14-24.27) and AD with CeVD (OR: 21.87; 95% CI: 2.01-237.43). Among the different CeVD markers, only WMH was associated with higher GDF-15 levels (OR: 3.97; 95% CI: 1.79-8.83). The associations between GDF-15 and cognitive impairment as well as with WMH remained significant after excluding subjects with cardiovascular diseases. In conclusion, we showed that increased GDF-15 may be a biomarker for CIND and AD in subjects with WMH.

SUBMITTER: Chai YL

PROVIDER: S-EPMC5370808 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia.

Chai Yuek Ling YL Hilal Saima S Chong Jenny P C JPC Ng Yan Xia YX Liew Oi Wah OW Xu Xin X Ikram Mohammad Kamran MK Venketasubramanian Narayanaswamy N Richards A Mark AM Lai Mitchell K P MKP Chen Christopher P CP

Medicine 20160801 33

Vascular pathology plays an important role in the development of cognitive decline and dementia. In this context, growth differentiation factor-15 (GDF-15) has been suggested to be a biomarker due to its regulatory roles in inflammatory and trophic responses during tissue injury. However, limited data exist on the associations of GDF-15 with either cerebrovascular disease (CeVD) burden or the spectrum of cognitive impairment. Therefore, we aimed to study peripheral levels of GDF-15 incognitive i ...[more]

PMID: 27537582

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Project description:White matter hyperintensities (WMHs) of presumed vascular origin are one of the most important neuroimaging markers of cerebral small vessel disease (CSVD), which are closely associated with cognitive impairment. The aim of this study was to elucidate the pathogenesis of WMHs from the perspective of inflammation and hypoperfusion mechanisms. A total of 65 patients with WMHs and 65 healthy controls were enrolled in this study. Inflammatory markers measurements [hypersensitive C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2)], cognitive evaluation, and pseudocontinuous arterial spin labeling (PCASL) MRI scanning were performed in all the subjects. The multivariate logistic regression analysis showed that Lp-PLA2 was an independent risk factor for WMHs. Cerebral blood flow (CBF) in the whole brain, gray matter (GM), white matter (WM), left orbital medial frontal gyrus [MFG.L (orbital part)], left middle temporal gyrus (MTG.L), and right thalamus (Tha.R) in the patients was lower than those in the controls and CBF in the left triangular inferior frontal gyrus [IFG.L (triangular part)] was higher in the patients than in the controls. There was a significant correlation between Lp-PLA2 levels and CBF in the whole brain (R = -0.417, p < 0.001) and GM (R = -0.278, p = 0.025), but not in the WM in the patients. Moreover, CBF in the MFG.L (orbital part) and the Tha.R was, respectively, negatively associated with the trail making test (TMT) and the Stroop color word test (SCWT), suggesting the higher CBF, the better executive function. The CBF in the IFG.L (triangular part) was negatively correlated with attention scores in the Cambridge Cognitive Examination-Chinese Version (CAMCOG-C) subitems (R = -0.288, p = 0.020). Our results revealed the vascular inflammation roles in WMHs, which may through the regulation of CBF in the whole brain and GM. Additionally, CBF changes in different brain regions may imply a potential role in the modulation of cognitive function in different domains.

Project description:Background and Purpose: Hemoglobin is one of the main proteins in erythrocytes. There are significant correlations between low hemoglobin and white matter hyperintensities (WMH) and cognitive impairment. This study explored whether erythrocytopenia has predictive value for vascular cognitive impairment (VCI) in patients with WMH. Method: We conducted a cross-sectional study of 302 patients, including 62 with cerebral small vessel disease and 240 with stroke. Basic demographic data and fasting blood were collected. First, all patients were divided into normal cognition (NC), mild VCI (mVCI), and severe VCI (sVCI) groups (subgroups later) based on cognitive behavior scores. Second, all patients were divided into mild WMH (mWMH) and severe WMH (sWMH) groups based on Fazekas scores. The differences in blood markers between different groups or subgroups with different cognitive levels were analyzed by univariate analysis. Then, binary logistic regression was used to analyze the diagnostic value of erythrocyte counts for VCI in the sWMH group, and ordinal logistic regression was used to analyze the predictive value of multiple variables for different cognitive levels. Results: Univariate analysis showed that erythrocytes, hemoglobin, high-sensitivity C-reactive protein, retinol binding protein and prealbumin were potential blood markers for different cognitive levels in sWMH patients. Among them, erythrocytopenia has good predictive value for the diagnosis of mVCI (AUC = 0.685, P = 0.008) or sVCI (AUC = 0.699, P = 0.003) in patients with sWMH. Multivariate joint analysis showed that erythrocytes were an independent protective factor reducing the occurrence of VCI in patients with sWMH (OR = 0.633, P = 0.045). Even after adjusting for age, there was still a significant difference (P = 0.047). Conclusion: Erythrocytes are an independent protective factor for VCI in patients with sWMH. Promoting hematopoietic function may have potential value for prevention of cognitive decline in patients with cerebrovascular disease.

Project description:White matter hyperintensities (WMH) are a key hallmark of subclinical cerebrovascular disease and are known to impair cognition. Here, we parcellated WMH using a novel system that segments WMH based on both lobar regions and distance from the ventricles, dividing the brain into a coordinate system composed of 36 distinct parcels ('bullseye' parcellation), and then investigated the effect of distribution on cognition using two different analytic approaches. Data from a well characterized sample of healthy older adults (58 to 84 years) who were free of dementia were included. Cognition was evaluated using 12 computerized tasks, factored onto 4 indices representing episodic memory, speed of processing, fluid reasoning and vocabulary. We first assessed the distribution of WMH according to the bullseye parcellation and tested the relationship between WMH parcellations and performance across the four cognitive domains. Then, we used a data-driven approach to derive latent variables within the WMH distribution, and tested the relation between these latent components and cognitive function. We observed that different, well-defined cognitive constructs mapped to specific WMH distributions. Speed of processing was correlated with WMH in the frontal lobe, while in the case of episodic memory, the relationship was more ubiquitous, involving most of the parcellations. A principal components analysis revealed that the 36 bullseye regions factored onto 3 latent components representing the natural aggrupation of WMH: fronto-parietal periventricular (WMH principally in the frontal and parietal lobes and basal ganglia, especially in the periventricular region); occipital; and temporal and juxtacortical WMH (involving WMH in the temporal lobe, and at the juxtacortical region from frontal and parietal lobes). We found that fronto-parietal periventricular and temporal & juxtacortical WMH were independently associated with speed of processing and episodic memory, respectively. These results indicate that different cognitive impairment phenotypes might present with specific WMH distributions. Additionally, our study encourages future research to consider WMH classifications using parcellations systems other than periventricular and deep localizations.

Project description:ImportanceAlthough white matter hyperintensities (WMHs) are associated with the risk for Alzheimer disease, it is unknown whether they represent an independent source of impairment or interact with known markers of disease.ObjectiveTo examine the degree to which WMHs predict aggressive cognitive decline among individuals with mild cognitive impairment, either independently or by modifying the effects of entorhinal cortex volume (ECV), a marker of Alzheimer disease-related neurodegeneration.Design, setting, and participantsThe Alzheimer's Disease Neuroimaging Initiative is a longitudinal study with 6-month follow-up visits. Three hundred thirty-two participants (mean [SD] age, 74.6 [7.4] years; 118 women) of a total of 374 participants diagnosed as having mild cognitive impairment were included. Participants were excluded if they did not have longitudinal data, apolipoprotein E genotype data, or had evidence of supratentorial infarct.Main outcomes and measuresA decline in Mini-Mental State Examination score of 3 points over 6 months or 6 points over 1 year between consecutive visits was defined as aggressive decline. White matter hyperintensity volume and ECV were entered as predictors in Cox proportional hazards models and Wilcoxon-Breslow tests to examine their impact on this outcome, adjusting for sex, age, education, and apolipoprotein E status.ResultsGreater WMH volume at baseline, apolipoprotein E ε4 status, and smaller ECV at baseline were associated with an increased risk for aggressive decline (hazard ratio [HR], 1.23; 95% CI, 1.05-1.43; P = .01 for WMH volume; HR, 1.49; 95% CI, 1.09-2.05; P = .04 for apolipoprotein E ε4 status; HR, 0.66; 95% CI, 0.55-0.79; P < .001 for ECV). White matter hyperintensity volume modified the effect of ECV on aggressive decline risk: individuals with high ECV and low WMH were at particularly low likelihood of decline (χ2 = 15, P = .001). Participants with Mini-Mental State Examination scores that declined by 3 or more points over 6 months or 6 or more points over 12 months were more likely to have converted to Alzheimer disease by the end of the follow-up period (χ2 = 82, P < .001).Conclusions and relevanceWhite matter hyperintensity burden and ECV predict rapid cognitive decline among individuals with mild cognitive impairment both additively and multiplicatively.

Project description:BackgroundAlbuminuria, a kidney marker of microvascular disease, may herald microvascular disease elsewhere, including in the brain.Study designCross sectional.Setting & participantsBoston, MA, elders receiving home health services to maintain independent living who consented to brain magnetic resonance imaging.PredictorUrine albumin-creatinine ratio (ACR).OutcomePerformance on a cognitive battery assessing executive function and memory by using principal components analysis and white matter hyperintensity volume on brain imaging, evaluated in logistic and linear regression models.ResultsIn 335 participants, mean age was 73.4 +/- 8.1 years and 123 participants had microalbuminuria or macroalbuminuria. Each doubling of ACR was associated with worse executive function (beta = -0.05; P = 0.005 in univariate and beta = -0.07; P = 0.004 in multivariable analyses controlling for age, sex, race, education, diabetes, cardiovascular disease, hypertension, medications, and estimated glomerular filtration rate [eGFR]), but not with worse memory or working memory. Individuals with microalbuminuria or macroalbuminuria were more likely to be in the lower versus the highest tertile of executive functioning (odds ratio, 1.18; 95% confidence interval, 1.06 to 1.32; odds ratio, 1.19; 95% confidence interval, 1.05 to 1.35 per doubling of ACR in univariate and multivariable analyses, respectively). Albuminuria was associated with qualitative white matter hyperintensity grade (odds ratio, 1.13; 95% confidence interval, 1.02 to 1.25; odds ratio, 1.15; 95% confidence interval, 1.02 to 1.29 per doubling of ACR) in univariate and multivariable analyses and with quantitative white matter hyperintensity volume (beta = 0.11; P = 0.007; beta = 0.10; P = 0.01) in univariate and multivariable analyses of log-transformed data. Results were similar when excluding individuals with macroalbuminuria.LimitationsSingle measurement of ACR, indirect creatinine calibration, and reliance on participant recall for elements of medical history.ConclusionsAlbuminuria is associated with worse cognitive performance, particularly in executive functioning, as well as increased white matter hyperintensity volume. Albuminuria likely identifies greater brain microvascular disease burden.

Dataset Information

Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia.

Publications

Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia.

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