Biomarkers of dementia: from bench to clinical side

To date Alzheimer's dementia (AD) is defined biologically, by neuropathologic change, and clinically treating cognitive impairment as a symptom of the disease rather than the definition of the disease. This approach underlines the complexity of such a disease and should enhance efforts to identify a sensitive but easy to get biomarker that will play a key role when innovative and efficacious treatment for AD will be found because, then it will be possible to treat this disease before the onset of clinical symptoms. Several biomarkers have been studied in cerebrospinal fluid: amyloid beta 1-42 (Aβ1-42), total tau (t-tau), phospho-tau (ptau), Aβ1-42/t- tau ratio and Aβ1-42/p-tau ratio are currently revealed in clinical practice. In the next future, it would be useful to dose biomarkers in less invasive samples (such as blood or urine) as like as to use OMICs technologies, including proteomics and metabolomics, to find more predictive and diagnostic biomarkers for AD

Vitamin E family: Role in the pathogenesis and treatment of Alzheimer's disease

AbstractIntroductionVitamin E family, composed by tocopherols and tocotrienols, is a group of compounds with neuroprotective properties. The exact role in the pathogenesis and the benefit of vitamin E as treatment for Alzheimer's disease (AD) are still under debate.MethodsA literature search in PubMed, Medline, and Cochrane databases has been carried out. All types of studies, from bench and animal models to clinical, were included.ResultsHigh plasma vitamin E levels are associated with better cognitive performance, even if clear evidence of their ability to prevent or delay cognitive decline in AD is still lacking. Each vitamin E form is functionally unique and shows specific biological functions. Tocotrienols seem to have superior antioxidant and anti-inflammatory properties compared with tocopherols.DiscussionThe benefit of vitamin E as a treatment for AD is still under debate, mainly because of the inconsistent findings from observational studies and the methodological limitations of clinical trials

Cigarette smoking cessation increases plasma levels of several antioxidant micronutrients and improves resistance towards oxidative challenge

Cigarette smoking is associated epidemiologically with increased risk of cardiovascular diseases, but the pathophysiological mechanisms are still not fully understood. There is evidence that smoking is related to increased free radical production and antioxidant depletion, but the effects of smoking cessation on plasma concentrations of antioxidants and susceptibility to oxidative stress are largely unknown. Plasma levels of vitamins A, C, E, uric acid, total thiols, carotenoids (including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) and malondialdehyde (MDA, a biomarker of lipid peroxidation) were measured in fifteen healthy, normolipidaemic subjects (seven males, eight females, 35·2 (sd2·3) years) before and 4 weeks after smoking cessation. To determine plasma resistance towards oxidative challenge, plasma was incubated for up to 5h with the peroxyl radical-generator 2,2′-azobis(2-amidinopropane) (AAPH); MDA and ascorbate levels were measured at various time points. The concentrations of all plasma antioxidants were lower before smoking cessation than afterwards; MDA levels were higher before than after termination of smoking. Upon AAPH exposure, the consumption of plasma ascorbate and the production of MDA occurred at a significantly faster rate before smoking cessation as compared with afterwards. Cigarette smoking cessation is followed by a marked increase in plasma antioxidant concentrations and substantially improves plasma resistance towards oxidative challenge. Given the importance of cigarette smoking as a risk factor for cardiovascular diseases and the pathophysiological role played by oxidative stress in these illnesses, quitting smoking represents an irreplaceable preventive strategy against tobacco-induced oxidative stress and vascular damage

Dementia in the old age: a gloomy wood later in life

Dementia incidence is growing at an impressive rate worldwide, mostly affecting old age subjects. Looking and considering the disease as the same in younger adult does not seem the successful way to find a proper solution regarding prevention and therapy this since there are too many differences between these two forms from biological to clinical aspects. Three question arises from a deep reflection on dementia in the oldest old: i) if it is a continuum with physiological brain aging; ii) what are the linking mechanisms underlining the disease and brain normal aging; iii) if or how it is possible to prevent or manage the disease differently in this population. We strongly believe that dementia is not an inevitable result of ageing, but when it appears in the oldest olds, it assumes distinctive characteristics of a geriatric syndrome where etiology, pathogenesis, clinical manifestations, course of the disease and management require a patient-tailored approach that can not be separated from a careful multidimensional evaluation

Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer's Disease: Focus on APOE Gene

Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies

Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia

We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE epsilon 4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.Peer reviewe

Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer’s disease: a potential early sign of AD

[EN] Background: Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer's disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers. Methods: Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) (N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (A beta 42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers. Results: In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype. Conclusion: We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated.Open access funding provided by Karolinska Institute. This research was supported by the Margaretha af Ugglas Foundation, the Karolinska institutet KID funding, Gun och Bertil Stohnes Stiftelse, Stiftelsen Syskonen Svenssons, the Karolinska Institutet fund for geriatric research Stiftelsen Gamla Tjanarinnor, and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet

P3‐221: Plasma inflammatory markers correlate with severity in Alzheimer's disease

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Linking Genetics of Brain Changes to Alzheimer's Disease:Sparse Whole Genome Association Scan of Regional MRI Volumes in the ADNI and AddNeuroMed Cohorts

Background: Alzheimer's disease (AD) is a highly heritable disease, but until recently few replicated genetic markers have been identified. Markers identified so far are likely to account for only a tiny fraction of the heritability of AD and many more genetic risk alleles are thought to be undiscovered.  Objective: Identifying genetic markers for AD using combined analysis of genetics and brain imaging data.  Methods: Imaging quantitative trait loci (iQTLs) has recently emerged as an interesting research area for linking genetics of brain changes to AD. We consider a genome-wide association scan of 109 brain-wide regional imaging phenotypes to identify genetic susceptibility loci for AD from a combined set of 1,045 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the AddNeuroMed studies. We use one-SNP-at-a-time as well as multi-SNP Hyperlasso based iQTL methods for the analysis.  Results: We identified several novel markers associated with AD, namely HOMER2 (rs1256429; intronic, p = 8.7x10(-10)), EOMES (rs2724509; flanking), JAM2 (rs2829841; intronic), and WEE1 (rs10770042; coding). The SNP rs1256429 (HOMER2) was one of the top hits in Hyperlasso as well as in the single-SNP analysis showing an association with the volume of the right thalamus and AD, a brain region reported to be linked with AD in several studies.  Conclusion: We believe that the markers identified in this study are novel additions to the existing list of genetic variants associated with AD which can be validated in future replicated studies