Current Alzheimer Research (v.13, #3)
Meet Our Editorial Board Member: by Kumar Sambamurti (213-213).
Editorial (Thematic Issue: Translational Alzheimer's Disease Research) by Yue Huang, Debomoy K. Lahiri (214-214).
Testosterone, Estradiol, and Sex Hormone-Binding Globulin in Alzheimer's Disease: A Meta-Analysis by Jing Xu, Lei-Lei Xia, Ning Song, Sheng-Di Chen, Gang Wang (215-222).
Background: Previous studies suggested that plasma sex hormones may be implicated in the pathogenesis of Alzheimer's disease (AD). However, the relationship between sex hormones and AD remains unclear. Objective: To systematically review and quantitatively analyze studies observing plasma total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels among AD patients. Methods: Medline, EMBASE, the Cochrane Library, and PsycINFO® were searched for studies published prior to March 28th, 2014. Published studies that reported plasma levels of TT, E2, and SHBG in AD and matched controls were included in the present meta-analysis. Results: Meta-analysis was performed using the random effects model, expressing continuous outcomes as the mean difference (MD) between AD and control populations. The 95% confidence intervals (CI) were also calculated. No differences were found in plasma levels of TT and E2 between AD and matched controls (TT MD -0.17 nmol/l, 95%CI -0.54, 0.20; E2 MD -1.16 pmol/l, 95%CI -9.85, 6.83). Plasma levels of SHBG were significantly increased in AD patients compared to healthy controls (SHBG MD 12.94 nmol/l, 95%CI 2.68, 23.20). Conclusion: Patients with AD had higher plasma levels of SHBG. The up-regulated levels of plasma SHBG show preliminary supportive evidence that SHBG and the bioavailability of functional sex hormones in plasma may be linked to the pathogenesis of AD.
Peripheral Blood Adipokines and Insulin Levels in Patients with Alzheimer';s Disease: A Replication Study and Meta-Analysis by Jing Ma, Wei Zhang, Hui-Fu Wang, Zi-Xuan Wang, Teng Jiang, Meng-Shan Tan, Jin-Tai Yu, Lan Tan (223-233).
Background: Although peripheral blood adipokines and insulin levels have been considered to be biomarkers of Alzheimer's disease (AD), previous researches about levels of adipokines and insulin in blood are no conclusive. We designed this meta-analysis to validate whether peripheral adipokines and insulin can be used as a candidate biomarker in AD diagnosis. Methods: We carried out a replication study in serum by ourselves and further conducted a meta-analysis to estimate the different levels of peripheral blood adipokines and insulin between AD patients and controls. In the section of meta-analysis, the pooled weighted mean difference (WMD) and 95% confidence interval (CI) was used to compare the levels of adipokines and insulin in different groups. Results: According to our replication study, there is statistically significant lower in the levels of leptin, but conspicuous higher in the levels of adiponectin and insulin in the blood of AD patients than controls. We finally identified four studies for leptin, four studies for adiponectin and eleven studies for insulin. From the random-effect model, the pooled WMD of the levels of leptin, adiponectin and insulin of AD subjects compared with the controls was -3.90 ng/ml (95% CI: [-5.68, -2.13]), 9.42 µ;g/mL (95% CI: [4.21, 14.62]), and 2.86 µ;IU/ml (95% CI: [1.21, 4.50]), respectively. Conclusion: Our replication study and meta-analysis support lower levels of leptin and higher levels of adiponectin and insulin in AD patients with respect to controls, and indicate their potential values as important risk factors for AD. Further researches that using standardized assay for leptin, adiponectin, and insulin measurement are still needed to reveal the potential change of peripheral blood leptin, adiponectin, and insulin levels in AD participants.
Functional Activity and Connectivity Differences of Five Resting-State Networks in Patients with Alzheimer's Disease or Mild Cognitive Impairment by Yu Chen, Hao Yan, Zaizhu Han, Yanchao Bi, Hongyan Chen, Jia Liu, Meiru Wu, Yongjun Wang, Yumei Zhang (234-242).
We aimed to investigate the activity within and the connectivity between resting state networks (RSNs) in healthy subjects and patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). Magnetic resonance imaging (MRI) and resting-state MRI were performed on patients diagnosed with AD (n=18) or MCI (n=16) and on healthy subjects (n=18) with matching demographic characteristics (age, sex, and education level). Independent component analysis and Granger causality analysis (GCA) were used during image postprocessing. We calculated 'In + Out degree' for each RSN. Then, we investigated the relationships between “In + Out degree” of each brain network and the cognitive behavioural data. RSNs were obtained using the optimal matching method. The core areas of the five RSNs were similar between the AD, MCI, and healthy control groups, but the activity within these five RSNs was significantly lower in the AD and MCI groups than in the healthy control group (P<0.01, false discovery rate corrected). The GCA results showed that the connectivity between the five RSNs, particularly the connectivity from the default mode network (DMN) to the other RSNs, was slightly lower in MCI patients and was significantly lower in AD patients than in healthy subjects. In contrast, increased connectivity was evident between the memory network and the executive control network in the AD and MCI patients. The “In + Out degree” of the DMN negatively correlated with the Montreal Cognitive Assessment score in AD patients (R=-0.43, P<0.05). In conclusion, the activity within RSNs and the connectivity between RSNs differed between AD patients, MCI patients, and normal individuals; these results provide an imaging reference for the diagnosis of AD and the measurement of disease progression and reveal insight into the pathogenesis of AD.
The Relationship Between Plasma Aβ; Levels, Cognitive Function and Brain Volumetrics: Sydney Memory and Ageing Study by Anne Poljak, John D. Crawford, George A. Smythe, Henry Brodaty, Melissa J. Slavin, Nicole A. Kochan, Julian N. Trollor, Wei Wen, Karen A. Mather, Amelia A. Assareh, Pek C. Ng, Perminder S. Sachdev (243-255).
Objectives: Determine whether (1) a relationship exists between plasma amyloid-β; (Aβ;)1- 40 and 1-42 peptide levels, brain volumetrics and cognitive performance in elderly individuals with and without amnestic mild cognitive impairment (aMCI), (2) plasma Aβ; peptide levels differ between apolipoprotein E (APOE) ε4 carriers and non-carriers and (3) longitudinal changes in cognition and brain volume relate to Aβ; levels. Methods: Subjects with aMCI (n = 89) and normal cognition (n = 126) were drawn from the Sydney Memory and Aging Study (Sydney MAS), a population based study of non-demented 70-90 year old individuals; 39 Alzheimer's disease (AD) patients were recruited from a specialty clinic. Sydney MAS participants underwent brain MRI scans and were assessed on 19 cognitive measures and were APOE ε4 genotyped. Plasma levels of Aβ;1-40 and 1-42 were quantified using ELISA. Results: Wave1 plasma levels of Aβ; peptides and Aβ;1?42/1-40 ratio were lower in aMCI and AD, and Aβ;1?42 was positively associated with global cognition and hippocampal volume and negatively with white matter hyperintensities. The relationships of Aβ;1-40 and Aβ;1-42 were predominantly observed in ε4 allele carriers and non-carriers respectively. Longitudinal analysis revealed greater decline in global cognition and memory for the highest quintiles of Aβ;1?42 and the ratio measure. Conclusion: Plasma Aβ; levels and the Aβ;1?42/1-40 ratio are related to cognition and hippocampal volumes, with differential associations of Aβ;1-40 and Aβ;1-42 in ε4 carriers and non-carriers. These data support the Aβ; sink model of AD pathology, and suggest that plasma Aβ; measures may serve as biomarkers of AD.
Structural MRI Biomarkers of Mild Cognitive Impairment from Young Elders to Centenarians by Zixuan Yang, Wei Wen, Jiyang Jiang, John D. Crawford, Simone Reppermund, Charlene Levitan, Melissa J. Slavin, Nicole A. Kochan, Robyn L. Richmond, Henry Brodaty, Julian N. Trollor, Perminder S. Sachdev (256-267).
Underpinnings of mild cognitive impairment (MCI) change with increasing age. We hypothesize that MRI signatures of mild cognitive impairment (MCI) would be different at a higher age compared to younger elders. Methods - 244 participants (71-103 years) from the Sydney Memory and Ageing Study and the Sydney Centenarian Study were categorized as amnestic MCI (aMCI), non-amnestic MCI (naMCI) or cognitively normal (CN). Brain “atrophy” and white matter hyper-intensities (WMHs) associated with MCI subtypes and age effects were examined by general linear models, controlling for confounding factors. Reduced logistic regressions were performed to determine structures that best discriminated aMCI from CN in individuals <85 and those ≥85 years. Results - aMCI was associated with smaller volumes of overall cortex, medial temporal structures, anterior corpus callosum, and select frontal and parietal regions compared to CN; such associations did not significantly change with age. Structures that best discriminated aMCI from CN differed however in the <85 and ≥85 age groups: cortex, putamen, parahippocampal, precuneus and superior frontal cortices in <85 years, and the hippocampus, pars triangularis and temporal pole in ≥85 years. Differences between naMCI and CN were small and non-significant in the sample. WMHs were not significantly associated with MCI subtypes. Conclusions - Structural MRI distinguishes aMCI, but not naMCI, from CN in elderly individuals. The structures that best distinguish aMCI from CN differ in those <85 from those ≥85, suggesting different neuropathological underpinnings of cognitive impairment in the very old.
Cytoskeletal Pathologies of Age-Related Diseases between Elderly Sri Lankan (Colombo) and Indian (Bangalore) Brain Samples by Printha Wijesinghe, S. K. Shankar, Yasha T. Chickabasaviah, Catherine Gorrie, Dhammika Amaratunga, Sanjayah Hulathduwa, K. Sunil Kumara, Kamani Samarasinghe, Yoo Hun Suh, H. W. Steinbusch, K. Ranil D. De Silva (268-280).
Within South Asia, Sri Lanka represents fastest aging with 13% of the population was aged over 60's in 2011, whereas in India it was 8%. Majority of the Sri Lankan population based genetic studies have confirmed their origin on Indian mainland. As there were inadequate data on aging cytoskeletal pathologies of these two nations with their close genetic affiliations, we performed a comparison on their elderly. Autopsy brain samples of 50 individuals from Colombo, Sri Lanka (mean age 72.1yrs ± 7.8, mean ± S.D.) and 42 individuals from Bangalore, India (mean age 65.9yrs ± 9.3) were screened for neurodegenerative pathologies using immunohistochemical techniques. A total of 79 cases with incomplete clinical history (Colombo- 47 and Bangalore- 32) were subjected to statistical analysis and 13 cases, clinically diagnosed with dementia and/or Parkinsonism disorders were excluded. As per National Institute on Aging- Alzheimer's Association guidelines, between Colombo and Bangalore samples, Alzheimer's disease neuropathologic change for intermediate/ high level was 4.25% vs. 3.12% and low level was 19.15% vs. 15.62% respectively. Pathologies associated with Parkinsonism including brainstem predominant Lewy bodies- 6.4% and probable progressive supra nuclear palsy- 2.13% were found solely in Colombo samples. Alzheimer related pathologies were not different among elders, however, in Colombo males, neurofibrillary tangle grade was significantly higher in the region of hippocampus (odds ratio = 1.46, 95% confidence interval = 0.07-0.7) and at risk in midbrain substantia nigra (p = 0.075). Other age-related pathologies including spongiform changes (p < 0.05) and hippocampus cell loss in dentate gyrus region (p < 0.05) were also identified prominently in Colombo samples. Taken together, aging cytoskeletal pathologies are comparatively higher in elderly Sri Lankans and this might be due to their genetic, dietary and/ or environmental variations.
Defining the earliest pathological changes of Alzheimer's disease by James C. Vickers, Stan Mitew, Adele Woodhouse, Carmen M. Fernandez-Martos, Mathew T. Kirkcaldie, Alison J. Canty, Graeme H. McCormack, Anna E. King (281-287).
The prospects for effectively treating well-established dementia, such as Alzheimer's disease (AD), are slim, due to the destruction of key brain pathways that underlie higher cognitive function. There has been a substantial shift in the field towards detecting conditions such as AD in their earliest stages, which would allow preventative or therapeutic approaches to substantially reduce risk and/or slow the progression of disease. AD is characterized by hallmark pathological changes such as extracellular A? plaques and intracellular neurofibrillary pathology, which selectively affect specific subclasses of neurons and brain circuits. Current evidence indicates that A? plaques begin to form many years before overt dementia, a gradual and progressive pathology which offers a potential target for early intervention. Early A? changes in the brain result in localized damage to dendrites, axonal processes and synapses, to which excitatory synapses and the processes of projection neurons are highly vulnerable. A? pathology is replicated in a range of transgenic models overexpressing mutant human familial AD genes (eg APP and presenilin 1). Studying the development of aberrant regenerative and degenerative changes in neuritic processes associated with A? plaques may represent the best opportunity to understand the relationship between the pathological hallmarks of AD and neuronal damage, and to develop early interventions to prevent, slow down or mitigate against A? pathology and/or the neuronal alterations that leads to cognitive impairment.
Triptolide Rescues Spatial Memory Deficits and Amyloid-? Aggregation Accompanied by Inhibition of Inflammatory Responses and MAPKs Activity in APP/PS1 Transgenic Mice by Yan-Qiu Cui, Qi Wang, Dong-Mei Zhang, Jun-Ya Wang, Bing Xiao, Yan Zheng, Xiao-Min Wang (288-296).
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by aggregation of amyloid-? (A?) peptide in the hippocampus and cortex of brain. Neuroinflammation is considered a driving force of the progression of cognitive decline in AD. During the neuroinflammatory process, activated astrocytes and microglia induced by A? peptide produce pro-inflammatory factors and neurotoxins, which promote neurodegeneration in AD brain, eventually dementia. Thus, the suppression of glial over-activation in AD brain might result in therapeutic effect. Triptolide, a natural compound extracted from the Chinese medicinal herb Tripterygium wilfordii Hook F., has shown anti-inflammatory effects. Whether triptolide exhibits preventive effects on AD-like pathology via anti-inflammatory action is unclear. The present study showed that intraperitoneal injection of triptolide (20 ?g/kg) for 15 weeks markedly alleviated deficits in learning and memory, and prevented A? accumulation in the brain of AD transgenic mice (APP/PS1 mice). These results were accompanied by reduction in glial activation and contents of pro-inflammatory factors in the brain of APP/PS1 mice treated by triptolide compared to saline-treated APP/PS1 mice. In addition, we observed that the Mitogen-activated protein kinases (MAPKs, including p38, ERK and JNK) phosphorylation was also suppressed by treatment of triptolide in the brain of APP/PS1 mice. Taken together, our study suggests that molecular mechanisms underlying the therapeutic effects of triptolide on the AD model might involve inhibition of the neuroinflammation by suppressing MAPKs activity.
SS31, a Small Molecule Antioxidant Peptide, Attenuates β;-Amyloid Elevation, Mitochondrial/Synaptic Deterioration and Cognitive Deficit in SAMP8 Mice by Yan-Li Jia, Su-Juan Sun, Jing-Hong Chen, Qian Jia, Tian-Tian Huo, Li-Fang Chu, Jiang-Tao Bai, Ye-Jing Yu, Xiao-Xin Yan, Jian-Hua Wang (297-306).
Mitochondrial dysfunction, oxidative stress and β; -amyloid (Aβ;) formation are thought to cause neuronal and synaptic degeneration underlying cognitive decline in Alzheimer's disease (AD). The senescence-accelerated mouse-prone 8 (SAMP8) mice have been used as an animal model for mechanistic and translational research for AD. In the present study we characterized mitochondrial and synaptic alterations in SAMP8 mice relative to SAMR1control mice and explored a protective effect of the small molecule peptide SS31, a cell membrane penetrant antioxidant, on mitochondrial and synaptic protein integrity as well as cognitive performance. Electron microscopic analysis revealed mitochondrial/synaptic deterioration in 10 months-old SAMP8 relative to SAMR1 mice, with the changes in the former rescued following 8 weeks treatment with SS31 (5 mg/kg/day, i.p.). Elevation of Aβ;42, mitochondrial fission protein (DLP1, Fis1) and matrix protein cyclophilin D (CypD), and reductions of mitochondrial fusion protein (Mfn2) and synaptic (i.e. synaptophysin, postsynaptic density protein 95 and growth associated protein 43) proteins, were detected in hippocampal lysates in SAMP8 mice relative to SAMR1. The above altered protein expressions in the SAMP8 mouse brain were restored with the SS31 treatment. Moreover, the SS31 treatment rescued learning and memory deficits detected in 10 month-old SAMP8 mice. Together, the findings suggest that this mitochondria-targeting antioxidant peptide may be of potential utility for AD therapy, with its pharmacological efficacy involves lowering of central Aβ; levels and protection of mitochondrial homeostasis and synaptic integrity, which may help slow down cognitive decline.
Perspectives on the Tertiary Prevention Strategy for Alzheimer's Disease by Xian-Le Bu, Shu-Sheng Jiao, Yan Lian, Yan-Jiang Wang (307-316).
Amyloid-beta (Aβ;) plays a pivotal role in Alzheimer's disease (AD) pathogenesis, and is the most promising disease-modifying target for AD. A succession of failures in Aβ;-targeting clinical trials, however, has prompted questions on whether Aβ; is the true cause of AD and a valid therapeutic target. Therefore, current therapeutic targets and intervention strategies must be reconsidered. In addition to Aβ;, multiple pathological events such as tau hyperphosphorylation, oxidative stress and neuroinflammation are involved in the disease pathogenesis and cause cross-talk between these pathological pathways, which synergistically drive disease progression. Increasing evidence also reveals that the pathogenesis varies at different stages of the disease. Therefore, targeting Aβ; alone at all stages of the disease would not be sufficient to halt or reverse disease progression. In the light of the pathophysiologic similarities between the development of ischemic stroke and AD, we can formulate management strategies for AD from the successful practice of ischemic stroke management, namely the tertiary prevention strategy. These new perspectives of tertiary prevention target both Aβ; and different pathological pathways of AD pathogenesis at different stages of the disease, and may represent a promising avenue for the effective prevention and treatment of AD.