Insulin is differentially related to cognitive decline and atrophy in Alzheimer's disease and aging

We assessed the relationship of insulin resistance with cognitive decline and brain atrophy over two years in early Alzheimer's disease (AD, n=48) and nondemented controls (n=61). Intravenous glucose tolerance tests were conducted at baseline to determine insulin area-under-the-curve (AUC). A standard battery of cognitive tasks and MRI were conducted at baseline and 2-year follow-up. In nondemented controls, higher baseline insulin AUC was associated with 2-year decline in global cognitive performance (beta=-0.36, p=0.005). In early AD, however, higher insulin AUC was associated with less decline in global cognitive performance (beta=0.26, p=0.06), slower global brain atrophy (beta=0.40, p=0.01) and less regional atrophy in the bilateral hippocampi and cingulate cortices. While insulin resistance is associated with cognitive decline in nondemented aging, higher peripheral insulin may have AD-specific benefits or insulin signaling may be affected by systemic physiologic changes associated with AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Are optimal levels of testosterone associated with better cognitive function in healthy older women and men?

Background

Sex steroids can positively affect the brain and from this it would follow that high levels of sex steroids could be associated with better cognitive function in older men and women.

Methods

This Healthy Ageing Study sample comprised of 521 older participants (51% women) without dementia at baseline, with an age range from 64 to 94 years. Testosterone and sex hormone binding globulin were measured using the automated Immulite 2000 and analyzed in association with baseline memory, global cognitive function and decline (assessed using the Mini-Mental Status Examination or MMSE) and controlling for potential confounds such as age, education, vascular disease, smoking, diabetes, thyroid function, and body mass index.

Results

In healthy older men and women, optimal levels of testosterone were associated with better MMSE scores at baseline. Follow-up analyses indicated that in men, low testosterone levels (OR = .94, 95% CI = .88 to 1.00) were a risk factor for a sharp cognitive decline after 2 years, perhaps indicative of dementia. Associations were independent of covariates and baseline MMSE. Conversely, women at risk for a sharp drop in cognitive function showed some evidence for higher calculated free testosterone levels at baseline.

Conclusions

Results replicate earlier cross-sectional findings that high levels of sex steroids are not associated with better cognitive function in older people. In men, age accelerated endocrinological change could be associated with dementia pathology.

General significance

These data do not support increasing testosterone levels to prevent cognitive decline in men and women over 65 years of age.     

A Subset of Cerebrospinal Fluid Proteins from a Multi-Analyte Panel Associated with Brain Atrophy,Disease Classification and Prediction in Alzheimer’s Disease

In this exploratory neuroimaging-proteomic study, we aimed to identify CSF proteins associated with AD and test their prognostic ability for disease classification and MCI to AD conversion prediction. Our study sample consisted of 295 subjects with CSF multi-analyte panel data and MRI at baseline downloaded from ADNI. Firstly, we tested the statistical effects of CSF proteins (n = 83) to measures of brain atrophy, CSF biomarkers, ApoE genotype and cognitive decline. We found that several proteins (primarily CgA and FABP) were related to either brain atrophy or CSF biomarkers. In relation to ApoE genotype, a unique biochemical profile characterised by low CSF levels of Apo E was evident in ε4 carriers compared to ε3 carriers. In an exploratory analysis, 3/83 proteins (SGOT, MCP-1, IL6r) were also found to be mildly associated with cognitive decline in MCI subjects over a 4-year period. Future studies are warranted to establish the validity of these proteins as prognostic factors for cognitive decline. For disease classification, a subset of proteins (n = 24) combined with MRI measurements and CSF biomarkers achieved an accuracy of 95.1% (Sensitivity 87.7%; Specificity 94.3%; AUC 0.95) and accurately detected 94.1% of MCI subjects progressing to AD at 12 months. The subset of proteins included FABP, CgA, MMP-2, and PPP as strong predictors in the model. Our findings suggest that the marker of panel of proteins identified here may be important candidates for improving the earlier detection of AD. Further targeted proteomic and longitudinal studies would be required to validate these findings with more generalisability.     

CSF Biomarkers and Neuropsychological Profiles in Patients with Cerebral Small-Vessel Disease

Despite existing criteria, differential diagnosis of Vascular Dementia (VD) and Alzheimer''s disease (AD) remains difficult. The aim of this study is to figure out cognitive and biomarker profiles that may help to distinguish between VD, AD and AD + Cerebral Small Vessel Disease (CSVD). We examined a cohort of patients with CSVD (n = 92). After stratification of cognitive impaired patients (n = 59) using the standard CSF beta-amyloid 42/40 ratio cut-off point of 0.975, we obtained two groups which differed with respect to several features: 32 patients with normal beta-amyloid 42/40 ratio (>0.975) showed markedly impaired blood-brain-barrier function as indicated by an elevated albumin ratio (median 8.35). They also differed in cognitive profiles when compared to 27 patients with AD typical beta-amyloid ratio and normal albumin ratio. We also enrolled an additional group of patients with AD (no significant CSVD on MRI, n = 27) which showed no impairment of the blood-brain-barrier. We showed a negative correlation between the albumin ratio and executive cognitive function (p = 0.016) and a negative correlation between memory function and typical AD markers like Tau (p = 0.004) and p181-Tau (p = 0.023) in our cohort. We suppose that the group of patients with normal beta-amyloid ratio represents VD while patients in the other groups represent AD+CSVD and pure AD. Our results support the idea that a dysfunction of the blood-brain-barrier might be contributing factor in the development of cognitive decline in CSVD as it seems to be of more importance than the severity of white matter lesions.     

Clinical value of plasma pentraxin 3 levels for predicting cardiac troponin elevation after percutaneous coronary intervention

Aims

Post-procedural myocardial necrosis manifested by elevated cardiac troponin T (cTnT) often complicates percutaneous coronary intervention (PCI). Plasma pentraxin 3 (PTX3) levels are increased in patients with arterial inflammation and especially unstable angina pectoris (UAP). This study tested whether plasma PTX3 levels can predict post-PCI cTnT elevation.

Main methods

We evaluated 94 consecutive patients with AP and normal pre-PCI cTnT levels who underwent PCI. Pre-PCI virtual histology-intravascular ultrasound was performed to assess culprit plaque composition. Plasma PTX3 and serum hs-CRP levels were measured pre-PCI. Patients were divided into 2 groups according to presence (Group I, n = 34) or absence (Group II, n = 60) of post-PCI cTnT elevation > 3 × the upper limit of normal at 24 h after PCI.

Key findings

Plasma PTX3 (4.06 ± 2.05 ng/ml vs 2.17 ± 1.02 ng/ml, p < 0.001), serum hs-CRP levels (0.25 ± 0.03 vs 0.16 ± 0.03 mg/dl, p = 0.048), plaque burden (80.9 ± 5.3 vs 75.4 ± 10.6%, p = 0.047), presence of positive remodeling (59 vs 25%, p = 0.034), and percent necrotic core area (19.0 ± 7.4 vs 14.0 ± 5.9%, p = 0.046) were significantly higher in Group I than in Group II. Receiver-operating characteristic curve analysis showed that with a best cut-off value of 2.83 ng/ml, plasma PTX3 level (AUC 0.823) predicted post-PCI cardiac TnT elevation better than did serum hs-CRP level (AUC 0.618). Multiple logistic regression analysis showed that plasma PTX3 level was the most independent predictor of post-PCI cardiac cTnT elevation (OR: 2.65; 95% CI: 1.56–10.1; p = 0.003).

Significance

Plasma PTX3 level may be a useful marker for predicting post-PCI cardiac cTnT elevation, which is associated with inflammatory status of culprit lesions.     

The MTMR9 rs2293855 polymorphism is associated with glucose tolerance,insulin secretion,insulin sensitivity and increased risk of prediabetes

Background

Polymorphism of rs2293855 in gene MTMR9 has been associated with obesity and metabolic syndrome. We aim to study the association of rs2293855 with type 2 diabetes mellitus (T2DM) intermediate phenotypes in a Han Chinese population.

Methods

The polymorphism was genotyped in 838 Han Chinese individuals using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS); all participants underwent a 75 g oral glucose tolerance test (OGTT); associations between the polymorphism and glucose tolerance, indices of insulin secretion and indices of insulin sensitivity were analyzed.

Results

The frequency of genotypes and alleles differed significantly between normal glucose tolerance and prediabetes (P = 0.043 and P = 0.009, respectively). The GG homozygous presented higher fasting plasma glucose (P = 0.009), higher 2-hour plasma glucose (P = 0.024) and higher glucose area under the curve (AUC, P = 0.01). Moreover, the G allele of rs2293855 was associated with glucose intolerance (fasting glucose, P = 0.012; glucose AUC, P = 0.006; 2-h glucose, P = 0.024); it is also associated with decreased indices of insulin sensitivity (fasting insulin, P = 0.043; insulin sensitivity index composite, P = 0.009; homeostasis model assessment of insulin resistance, HOMA-IR, P = 0.008) and decreased indices of insulin secretion (HOMA of beta cell function, HOMA-B, P = 0.028; insulinogenic index, P = 0.003). In addition, the minor allele G was also associated with increased risk of prediabetes (OR = 1.463, 95%CI: 1.066–2.009, P = 0.018).

Conclusions

Polymorphism of rs2293855 in MTMR9 is associated with measures of glucose tolerance, indices of insulin secretion and indices of insulin sensitivity. We also suggest that allele G is likely to increase the risk of prediabetes by influencing both insulin secretion and insulin sensitivity.     

Aβ(42) induced MRI changes in aged rabbit brain resembles AD brain

Alzheimer’s disease is the most common form of dementia and is structurally characterized by brain atrophy and loss of brain volume. Aβ is one of the widely accepted causative factors of AD. Aβ deposition is positively correlated with brain atrophy in AD. In the present study, structural brain imaging techniques such as Magnetic Resonance Imaging (MRI) were used to measure neuroanatomical alterations in Alzheimer’s disease brain. MRI is a non-invasive method to study brain structure. The objective of the present study was to elucidate the role of Aβ on brain structure in the aged rabbit brain. Among 20 aged rabbits, one batch (n = 10) rabbits was injected chronically with Aβ(1-42) and another batch (n = 10) with saline. The MRI was conducted before Aβ(1-42)/saline injection and after 45 days of Aβ(1-42)/saline injection. All the aged rabbits underwent MRI analysis and were euthanized after 45 days. The MRI results showed a significant reduction in thickness of frontal lobe, hippocampus, midbrain, temporal lobe and increases in the lateral ventricle volume. We also conducted an MRI study on AD (n = 10) and normal (n = 10) cases and analyzed for the thicknesses of frontal lobe, hippocampus, midbrain, temporal lobe and lateral ventricle lobe. We found significant reductions in thickness of the frontal lobe and the hippocampus. However, no significant reduction in the thickness of midbrain, temporal lobe or increase in the lateral ventricle volume was observed compared to normal. Correlations in brain atrophy changes between rabbit brain and human AD brain were found for frontal lobe and hippocampal regions. In contrast, other regions such as midbrain, temporal lobe, and lateral ventricles were not correlated with rabbit brain atrophy changes in the corresponding regions. The relevance of these changes in AD is discussed.     

Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics

Context

Insulin resistance is not fully explained on a molecular level, though several genes and proteins have been tied to this defect. Knockdowns of the SEPP1 gene, which encodes the selenoprotein P (SeP) protein, have been shown to increase insulin sensitivity in mice. SeP is a liver-derived plasma protein and a major supplier of selenium, which is a proposed insulin mimetic and antidiabetic agent.

Objective

SEPP1 single nucleotide polymorphisms (SNPs) were selected for analysis with glucometabolic measures.

Participants and measures

The study included1424 Hispanics from families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). Additionally, the multi-ethnic Insulin Resistance Atherosclerosis Study was used. A frequently sampled intravenous glucose tolerance test was used to obtain precise measures of acute insulin response (AIR) and the insulin sensitivity index (S_I).

Design

21 SEPP1 SNPs (tagging SNPs (n = 12) from HapMap, 4 coding variants and 6 SNPs in the promoter region) were genotyped and analyzed for association.

Results

Two highly correlated (r² = 1) SNPs showed association with AIR (rs28919926; Cys368Arg; p = 0.0028 and rs146125471; Ile293Met; p = 0.0026) while rs16872779 (intronic) was associated with fasting insulin levels (p = 0.0097). In the smaller IRAS Hispanic cohort, few of the associations seen in the IRASFS were replicated, but meta-analysis of IRASFS and all 3 IRAS cohorts (N = 2446) supported association of rs28919926 and rs146125471 with AIR (p = 0.013 and 0.0047, respectively) as well as rs7579 with S_I (p = 0.047).

Conclusions

Overall, these results in a human sample are consistent with the literature suggesting a role for SEPP1 in insulin resistance.     

Diffusion tensor imaging and cognition in cerebral small vessel disease : The RUN DMC study

Background

Cerebral small vessel disease (SVD) is very common in elderly and related to cognition, although this relation is weak. This might be because the underlying pathology of white matter lesions (WML) is diverse and cannot be properly appreciated with conventional FLAIR MRI. In addition, conventional MRI is not sensitive to early loss of microstructural integrity of the normal appearing white matter (NAWM), which might be an important factor. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity and we have used this to investigate the relation between white matter integrity, in both WML and NAWM, and cognition among elderly with cerebral SVD.

Methods

The RUN DMC study is a prospective cohort study among 503 independently living, non-demented elderly with cerebral SVD aged between 50 and 85 years. All subjects underwent MRI and DTI scanning. WML were segmented manually. We measured mean diffusivity (MD) and fractional anisotropy (FA), as assessed by DTI in both WML and NAWM.

Results

Inverse relations were found between MD in the WML and NAWM and global cognitive function (β = −.11, p < 0.05; β = −.18, p < 0.001), psychomotor speed (β = −.15, p < 0.01; β = −.18, p < 0.001), concept shifting (β = −.11, p < 0.05; β = −.10, p < 0.05) and attention (β = −.12, p < 0.05; β = −.15, p < 0.001). The relation between DTI parameters in both WML and NAWM and cognitive performance was most pronounced in subjects with severe WML.

Conclusion

DTI parameters in both WML and NAWM correlate with cognitive performance, independent of SVD. DTI may be a promising tool in exploring the mechanisms of cognitive decline and could function as a surrogate marker for disease progression in therapeutic trials.This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Rates of Decline in Alzheimer Disease Decrease with Age

Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ_1–42, tau, and phospho-tau_181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.     

Faster Cognitive and Functional Decline in Dysexecutive versus Amnestic Alzheimer's Subgroups: A Longitudinal Analysis of the National Alzheimer's Coordinating Center (NACC) Database

Objective

To compare the rate of cognitive and functional decline in dysexecutive, typical and amnestic subgroups of Alzheimer’s disease.

Methods

943 participants from the National Alzheimer’s Coordinating Center (NACC) database who had a diagnosis of probable AD were followed for a mean of 2.3 years. A dysexecutive subgroup (n = 165) was defined as having executive performance >1.5 SD worse than memory performance, an amnestic subgroup (n = 157) was defined as having memory performance >1.5 SD worse than executive performance and a typical subgroup (n = 621) was defined as having a difference in executive and memory performance of <1.5 SD. Generalized estimating equations (GEE) were used to model decline on the Folstein Mini Mental Status Exam (MMSE), rise on the Clinical Dementia Rating (CDR) sum of boxes and rise on the total Functional Assessment Questionnaire (FAQ).

Results

Compared with the amnestic subgroup, the dysexecutive subgroup declined 2.2X faster on the Folstein MMSE (p<.001), rose 42% faster on the CDR sum of boxes (p = .03) and rose 33% faster on the total FAQ (p = .01). Rate of change for the typical subgroup fell between that of the amnestic and dysexecutive subgroups for the MMSE, CDR sum of boxes and total FAQ. Among a subset of participants (n = 129) who underwent autopsy, the dysexecutive, amnestic and typical subgroups did not differ in odds of having an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences.

Conclusions

A dysexecutive subgroup of AD has a unique disease course in addition to cognitive phenotype.     

Changes in White Matter Integrity before Conversion from Mild Cognitive Impairment to Alzheimer’s Disease

Background

Mild cognitive impairment (MCI) may represent an early stage of dementia conferring a particularly high annual risk of 15–20% of conversion to Alzheimer’s disease (AD). Recent findings suggest that not only gray matter (GM) loss but also a decline in white matter (WM) integrity may be associated with imminent conversion from MCI to AD.

Objective

In this study we used Voxel-based morphometry (VBM) to examine if gray matter loss and/or an increase of the apparent diffusion coefficient (ADC) reflecting mean diffusivity (MD) are an early marker of conversion from MCI to AD in a high risk population.

Method

Retrospective neuropsychological and clinical data were collected for fifty-five subjects (MCI converters n = 13, MCI non-converters n = 14, healthy controls n = 28) at baseline and one follow-up visit. All participants underwent diffusion weighted imaging (DWI) and T1-weighted structural magnetic resonance imaging scans at baseline to analyse changes in GM density and WM integrity using VBM.

Results

At baseline MCI converters showed impaired performance in verbal memory and naming compared to MCI non-converters. Further, MCI converters showed decreased WM integrity in the frontal, parietal, occipital, as well as the temporal lobe prior to conversion to AD. Multiple regression analysis showed a positive correlation of gray matter atrophy with specific neuropsychological test results.

Conclusion

Our results suggest that additionally to morphological changes of GM a reduced integrity of WM indicates an imminent progression from MCI stage to AD. Therefore, we suggest that DWI is useful in the early diagnosis of AD.     

Atrophy Rates in Asymptomatic Amyloidosis: Implications for Alzheimer Prevention Trials

There is considerable interest in designing therapeutic studies of individuals at risk of Alzheimer disease (AD) to prevent the onset of symptoms. Cortical β-amyloid plaques, the first stage of AD pathology, can be detected in vivo using positron emission tomography (PET), and several studies have shown that ∼1/3 of healthy elderly have significant β-amyloid deposition. Here we assessed whether asymptomatic amyloid-PET-positive controls have increased rates of brain atrophy, which could be harnessed as an outcome measure for AD prevention trials. We assessed 66 control subjects (age = 73.5±7.3 yrs; MMSE = 29±1.3) from the Australian Imaging Biomarkers & Lifestyle study who had a baseline Pittsburgh Compound B (PiB) PET scan and two 3T MRI scans ∼18-months apart. We calculated PET standard uptake value ratios (SUVR), and classified individuals as amyloid-positive/negative. Baseline and 18-month MRI scans were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes calculated. Increasing baseline PiB-PET measures of β-amyloid load correlated with hippocampal atrophy rate independent of age (p = 0.014). Twenty-two (1/3) were PiB-positive (SUVR>1.40), the remaining 44 PiB-negative (SUVR≤1.31). Compared to PiB-negatives, PiB-positive individuals were older (76.8±7.5 vs. 71.7±7.5, p<0.05) and more were APOE4 positive (63.6% vs. 19.2%, p<0.01) but there were no differences in baseline brain, ventricle or hippocampal volumes, either with or without correction for total intracranial volume, once age and gender were accounted for. The PiB-positive group had greater total hippocampal loss (0.06±0.08 vs. 0.02±0.05 ml/yr, p = 0.02), independent of age and gender, with non-significantly higher rates of whole brain (7.1±9.4 vs. 4.7±5.5 ml/yr) and ventricular (2.0±3.0 vs. 1.1±1.0 ml/yr) change. Based on the observed effect size, recruiting 384 (95%CI 195–1080) amyloid-positive subjects/arm will provide 80% power to detect 25% absolute slowing of hippocampal atrophy rate in an 18-month treatment trial. We conclude that hippocampal atrophy may be a feasible outcome measure for secondary prevention studies in asymptomatic amyloidosis.     

Cerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor and Cognitive Function in Non-Demented Subjects

Background

Brain-derived neurotrophic factor (BDNF) is an activity-dependent secreted protein that is critical to organization of neuronal networks and synaptic plasticity, especially in the hippocampus. We tested hypothesis that reduced CSF BDNF is associated with age-related cognitive decline.

Methodology/Principal Findings, and Conclusions/Significance

CSF concentration of BDNF, Aβ₄₂ and total tau were measured in 128 cognitively normal adults (Normals), 21 patients with Alzheimer''s disease (AD), and nine patients with Mild Cognitive Impairment. Apolipoprotein E and BDNF SNP rs6265 genotype were determined. Neuropsychological tests were performed at baseline for all subjects and at follow-up visits in 50 Normals. CSF BDNF level was lower in AD patients compared to age-matched Normals (p = 0.02). CSF BDNF concentration decreased with age among Normals and was higher in women than men (both p<0.001). After adjusting for age, gender, education, CSF Aβ₄₂ and total tau, and APOE and BDNF genotypes, lower CSF BDNF concentration was associated poorer immediate and delayed recall at baseline (both p<0.05) and in follow up of approximately 3 years duration (both p<0.01).

Conclusions/Significance

Reduced CSF BDNF was associated with age-related cognitive decline, suggesting a potential mechanism that may contribute in part to cognitive decline in older individuals.     

Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population

Few studies have measured the effect of genetic factors on dementia and cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of dementia and cognitive decline, stratified by APOE genotypes and polygenic risk score (PRS) tertiles, in 12,978 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed dementia, cardiovascular disease, physical disability or cognitive impairment. Dementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence for all‐cause dementia and cognitive decline was calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non‐APOE variants. During a median 4.5 years of follow‐up, 324 participants developed dementia, 503 died. Cumulative incidence of dementia to age 85 years was 7.4% in all participants, 12.6% in APOE ε3/ε4 and 26.6% in ε4/ε4. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3‐fold increased dementia risk and 1.4/1.8‐fold cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4‐fold dementia risk versus low (CI 1.04–1.76, p = 0.02), but was not associated with cognitive decline (CI 0.96–1.22, p = 0.18). Incidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.     

Association between genes encoding components of the IL-4/IL-4 receptor pathway and dermatitis in children

Objective

To determine whether IL-4, IL-4Rα and STAT6 polymorphisms are associated with susceptibility to dermatitis in Egyptian children.

Methods

We genotyped three groups of children, consisting of 106 atopic dermatitis (AD) children, 95 non-AD children, and 100 of healthy controls, for IL-4 (− 590 C/T), (− 33 C/T), IL-4Rα (I50V), (Q576R) and STAT6 (2964 G/A), (2892 C/T) gene polymorphisms using PCR-RFLP assay. Total serum IgE and serum IL-4 levels were detected by ELISA.

Results

There was a non-significant association of IL-4 − 590 C/T, − 33 C/T polymorphisms in the children with non-AD or those with AD when compared with the controls. We identified a significant association between IL-4Rα I50V, Q576R polymorphisms and dermatitis susceptibility in AD (p = 0.002, < 0.001 respectively), whereas no such association was observed in non-AD group (p = 0.52, 0.99 respectively). A significant association between STAT6 polymorphisms and both types of dermatitis was found. Patients who were carriers of IL4 − 590C, IL-4Rα I50V G, STAT6 2964 A and STAT6 2892 T had an increased risk of AD [OR and 95% CI: 3.2 (2.5–4.2), p = 0.005]. Furthermore, there was no relation between each polymorphism and serum IL-4 level (p > 0.05 for each) while homozygosity for the risk alleles of IL-4, IL-4Rα and STAT6 SNPs were significantly associated with increased total IgE levels in all subjects.

Conclusion

In Egyptian children, the IL-4Rα and the STAT6 polymorphism may play a role in susceptibility to AD. In addition, gene–gene interaction between the IL-4, the IL-4Rα and the STAT6 significantly increases an individual's susceptibility to AD.     

BDNF VAL66MET polymorphism and memory decline across the spectrum of Alzheimer's disease

The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism has been shown to moderate the extent to which memory decline manifests in preclinical Alzheimer's disease (AD). To date, no study has examined the relationship between BDNF and memory in individuals across biologically confirmed AD clinical stages (i.e., Aβ+). We aimed to understand the effect of BDNF on episodic memory decline and clinical disease progression over 126 months in individuals with preclinical, prodromal and clinical AD. Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who were Aβ + (according to positron emission tomography), and cognitively normal (CN; n = 238), classified as having mild cognitive impairment (MCI; n = 80), or AD (n = 66) were included in this study. Cognition was evaluated at 18 month intervals using an established episodic memory composite score over 126 months. We observed that in Aβ + CNs, Met66 was associated with greater memory decline with increasing age and were 1.5 times more likely to progress to MCI/AD over 126 months. In Aβ + MCIs, there was no effect of Met66 on memory decline or on disease progression to AD over 126 months. In Aβ + AD, Val66 homozygotes showed greater memory decline, while Met66 carriers performed at a constant and very impaired level. Our current results illustrate the importance of time and disease severity to clinicopathological models of the role of BDNF Val66Met in memory decline and AD clinical progression. Specifically, the effect of BDNF on memory decline is greatest in preclinical AD and reduces as AD clinical disease severity increases.     

Inflammatory Proteins in Plasma Are Associated with Severity of Alzheimer’s Disease

Markers of Alzheimer’s disease (AD) are being widely sought with a number of studies suggesting blood measures of inflammatory proteins as putative biomarkers. Here we report findings from a panel of 27 cytokines and related proteins in over 350 subjects with AD, subjects with Mild Cognitive Impairment (MCI) and elderly normal controls where we also have measures of longitudinal change in cognition and baseline neuroimaging measures of atrophy. In this study, we identify five inflammatory proteins associated with evidence of atrophy on MR imaging data particularly in whole brain, ventricular and entorhinal cortex measures. In addition, we observed six analytes that showed significant change (over a period of one year) in people with fast cognitive decline compared to those with intermediate and slow decline. One of these (IL-10) was also associated with brain atrophy in AD. In conclusion, IL-10 was associated with both clinical and imaging evidence of severity of disease and might therefore have potential to act as biomarker of disease progression.     

Leisure activities, cognition and dementia

Accumulated evidence shows that leisure activities have a positive impact on cognitive function and dementia. This review aimed to systematically summarize the current evidence on this topic taking into account the limitations of the studies and biological plausibility for the underlying mechanisms linking cognition, dementia and leisure activities, with special attention on mental, physical and social activities. We included only longitudinal studies, with a follow-up time of at least 2 years, published in English from 1991 to March 2011 on leisure activities and cognition (n = 29) or dementia (n = 23) and provided some evidence from intervention studies on the topic. A protective effect of mental activity on cognitive function has been consistently reported in both observational and interventional studies. The association of mental activity with the risk of dementia was robust in observational studies but inconsistent in clinical trials. The protective effect of physical activity on the risk of cognitive decline and dementia has been reported in most observational studies, but has been less evident in interventional studies. Current evidence concerning the beneficial effect of other types of leisure activities on the risk of dementia is still limited and results are inconsistent. For future studies it is imperative that the assessment of leisure activities is standardized, for example, the frequency, intensity, duration and the type of activity; and also that the cognitive test batteries and the definition of cognitive decline are harmonized/standardized. Further, well designed studies with long follow-up times are necessary. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.