Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in dementia and eventual death. It is the leading cause of dementia and the number of cases are projected to rise in the next few decades. Pathological hallmarks of AD include the presence of hyperphosphorylated tau and amyloid protein deposition. Currently, these pathological biomarkers are detected either through cerebrospinal fluid analysis, brain imaging or post-mortem. Though effective, these methods are not widely available due to issues such as the difficulty in acquiring samples, lack of infrastructure or high cost. Given that the eye possesses clear optics and shares many neural and vascular similarities to the brain, it offers a direct window to cerebral pathology. These unique characteristics lend itself to being a relatively inexpensive biomarker for AD which carries the potential for wide implementation. The development of ocular biomarkers can have far implications in the discovery of treatments which can improve the quality of lives of patients. In this review, we consider the current evidence for ocular biomarkers in AD and explore potential future avenues of research in this area.

Our objective was to assess the copper(II) complex of diacetylbis(4-methylthiosemicarbazone) [Cu(II)(atsm)] for its preclinical potential as a novel therapeutic for ALS. Experimental paradigms used were designed to assess Cu(II)(atsm) efficacy relative to treatment with riluzole, as a function of dose administered, and when administered post symptom onset. Mice expressing human Cu/Zn superoxide dismutase harbouring the disease-causing G37R mutation (SOD1-G37R) were used and effects of Cu(II)(atsm) determined by assessing mouse survival and locomotor function (rotarod assay). Cu(II)(atsm) improved SOD1-G37R mouse survival and locomotor function in a dose-dependent manner. The highest dose tested improved survival by 26%. Riluzole had a modest effect on mouse survival (3.3%) but it did not improve locomotor function. Cotreatment with Cu(II)(atsm) did not alter the protective activity of Cu(II)(atsm) administered on its own. Commencing treatment with Cu(II)(atsm) after the onset of symptoms was less effective than treatments that commenced before symptom onset but still significantly improved locomotor function and survival. Improved locomotor function and survival of SOD1-G37R mice supports the potential for Cu(II)(atsm) as a novel treatment option for ALS.

ObjectiveTo examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles.MethodsPooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1–42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years).ResultsUsing different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A−T−N−). Replicating prior findings using the 2011 National Institute on Aging–Alzheimer's Association/suspected non–Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0).ConclusionThe results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.

XPC polymorphisms may alter DNA repair capacity, thus leading to genetic instability and carcinogenesis. Numerous studies have investigated the associations of XPC Lys939Gln (rs2228001) and Ala499Val (rs2228000) polymorphisms with cancer susceptibility; however, the findings are inconclusive. We searched literature from MEDLINE and EMBASE for eligible publications that assessed the associations between these two polymorphisms and cancer risk. We also assessed genotype-mRNA expression correlation data from HapMap for rs2228001 and rs2228000 in normal cell lines derived from 270 subjects with different ethnicities. The final analysis included 62 published studies of 25,708 cases and 30,432 controls for the Lys939Gln and 34 studies with 14,877 cases and 17,888 controls for the Ala499Val. Overall, Lys939Gln was significantly associated with an increased overall cancer risk (Gln/Gln vs. Lys/Lys: OR 5 1.16, 95% CI 5 1.07 2 1.25, p < 0.001; recessive model: OR 5 1.14, 95% CI 5 1.06 2 1.22, p < 0.001; dominant model: OR 5 1.06, 95% CI 5 1.01 2 1.11, p 5 0.015 and Gln vs. Lys: OR 5 1.07, 95% CI 5 1.03 2 1.10, p < 0.001) and further stratifications showed an increased risk for bladder, lung and colorectal cancer, Asian populations and population-based studies. Likewise, Ala499Val was also significantly associated with an increased overall cancer risk (Val/Val vs. Ala/Ala: OR 5 1.21, 95% CI 5 1.07 2 1.36, p 5 0.003 and recessive model: OR 5 1.20, 95% CI 5 1.08 2 1.34, p 5 0.001) and further stratification showed an increased risk for breast and bladder cancer, particularly in Asian populations. Interestingly, significantly correlation between XPC genotypes and mRNA expression was found only for Asian populations as well. Despite some limitations, this meta-analysis established some solid statistical evidence for an association between XPC polymorphisms and cancer risk, which warrants further validation in single large studies.

Background: β-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer's disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology. Methods: Using automated Elecsys® assays (Roche Diagnostics) for Aβ (1-42) (Aβ42), Aβ (1-40) (Aβ40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging. Results: Ratios Aβ42/Aβ40, tTau/Aβ42 and pTau/Aβ42 had higher receiver operator characteristic-area under the curve (all 0.94), and greater concordance with Aβ-PET (overall percentage agreement~90%), compared with individual biomarkers. Conclusion: Strong concordance between CSF biomarkers and Aβ-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is an anti apoptotic and pro-oncogenic signaling molecule involved in the process of immunity, carcinogenesis and tumor progression. Single nucleotide polymorphisms (SNPs) at microRNA-binding sites may change messenger RNA target gene function, thus leading to cancer susceptibility and tumor progression. In this study of 1584 cervical cancer cases and 1394 cancer-free female controls, we investigated associations between three potentially functional SNPs in TNFAIP8 family genes and cervical cancer risk as well as platinum resistance and clinical outcomes in Eastern Chinese women. We found that the TNFAIP8-rs11064 variant GG genotype was associated with an increased risk of cervical cancer compared with AA/AG genotypes (adjusted odds ratio = 2.16, 95% confidence interval = 1.16-4.03, P = 0.015). Further in vitro and ex vivo functional experiments demonstrated that the TNFAIP8-rs11064 variant G allele weakened the binding affinity of miR-22 to the TNFAIP8 3'-untranslated region (UTR) in four cancer cell lines, resulting in increased production of the TNFAIP8 protein in the patients' cervical tissues. In the survival subset, the high TNFAIP8 protein expression was significantly associated with both resistance to cisplatin and nedaplatin, recurrence and death from cervical cancer. Taken together, in the absence of information on human papillomavirus (HPV) infection, the TNFAIP8-rs11064 SNP may function by affecting the affinity of miR-22 binding to the 3'-UTR of TNFAIP8 and regulating TNFAIP8 expression, thus contributing to cervical cancer risk. Additionally, the increased TNFAIP8 protein expression may predict platinum resistance and clinical outcomes in cervical cancer patients. Larger, prospective studies with detailed HPV infection data are warranted to validate our findings.

Redox-active copper is implicated in the pathogenesis of Alzheimer disease (AD), ␤-amyloid peptide (A␤) aggregation, and amyloid formation. A␤⅐copper complexes have been identified in AD and catalytically oxidize cholesterol and lipid to generate H 2 O 2 and lipid peroxides. The site and mechanism of this abnormality is not known. Growing evidence suggests that amyloidogenic processing of the ␤-amyloid precursor protein (APP) occurs in lipid rafts, membrane microdomains enriched in cholesterol. ␤-and ␥-secretases, and A␤ have been identified in lipid rafts in cultured cells, human and rodent brains, but the role of copper in lipid raft amyloidogenic processing is presently unknown. In this study, we found that copper modulates flotillin-2 association with cholesterol-rich lipid raft domains, and consequently A␤ synthesis is attenuated via copper-mediated inhibition of APP endocytosis. We also found that total cellular copper is associated inversely with lipid raft copper levels, so that under intracellular copper deficiency conditions, A␤⅐copper complexes are more likely to form. This explains the paradoxical hypermetallation of A␤ with copper under tissue copper deficiency conditions in AD.Imbalance of metal ions has been recognized as one of the key factors in the pathogenesis of Alzheimer disease (AD).2 Aberrant interactions between copper or zinc with the ␤-amyloid peptide (A␤) released into the glutamatergic synaptic cleft vicinity could result in the formation of toxic A␤ oligomers and aggregation into plaques characteristic of AD brains (reviewed in Ref. 1). Copper, iron, and zinc are highly concentrated in extracellular plaques (2, 3), and yet brain tissues from AD (4 -6) and human ␤-amyloid precursor protein (APP) transgenic mice (7-10) are paradoxically copper deficient compared with agematched controls. Elevation of intracellular copper levels by genetic, dietary, and pharmacological manipulations in both AD transgenic animal and cell culture models is able to attenuate A␤ production (7,9,(11)(12)(13)(14)(15). However, the underlying mechanism is at present unclear.Abnormal cholesterol metabolism is also a contributing factor in the pathogenesis of AD. Hypercholesterolemia increases the risk of developing AD-like pathology in a transgenic mouse model (16). Epidemiological and animal model studies show that a hypercholesterolemic diet is associated with A␤ accumulation and accelerated cognitive decline, both of which are further aggravated by high dietary copper (17, 18). In contrast, biochemical depletion of cholesterol using statins, inhibitors of 3-hydroxy-3-methyglutaryl coenzyme A reductase, and methyl-␤-cyclodextrin, a cholesterol sequestering agent, inhibit A␤ production in animal and cell culture models (19 -25).Cholesterol is enriched in lipid rafts, membrane microdomains implicated in A␤ generation from APP cleavage by ␤-and ␥-secretases. Recruitment of BACE1 (␤-secretase) into lipid rafts increases the production of sAPP ␤ and A␤ (23, 26). The ␤-secretase-cleaved APP C-terminal fragment (␤-C...

Introduction This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. Methods CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results CSF NfL levels as well as NfL/amyloid β (Aβ42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aβ42). CSF NfL and NfL/Aβ42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aβ42 predicted cortical amyloid load, brain atrophy, and cognition. Discussion CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.