Abstract Background Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer’s disease (AD). This study investigated whether genetic variants in two ...members of the sirtuin family, SIRT2 and SIRT3 , affected AD susceptibility. Methods A genetic case–control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E ( APOE ) gene, were genotyped by real-time polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously. Results In the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio OR = 1.23, 95% confidence interval CI: 1.02–1.50, P = .02, after correction for sex, age, and APOE ɛ4 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE ɛ4 noncarriers (adjusted OR = 1.29, 95% CI: 1.03–1.61, P = .03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR = 1.17, 95% CI: 1.02–1.35, P = .02), and only APOE ɛ4 noncarriers were at risk (adjusted OR = 1.2, 95% CI: 1.02–1.43, P = .03). Conclusions The SIRT2 rs10410544 T allele deserves further investigation as a novel minor genetic risk factor for AD in the APOE ɛ4-negative Caucasian population.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Alzheimer's disease (AD) is the major cause of dementia in the elderly. The biochemical changes that precede AD may be present up to 20 years before the clinical manifestation of the disease. The ...translational development of AD biomarkers may be theoretically achieved via two different strategies: the first strategy can be defined as 'knowledge-based' (deductive method), while the second one is a hypothesis-generating 'unbiased' approach (inductive strategy). The 'knowledge-based' approach relies on a direct understanding of the neuropathological processes that underlie the development of AD. In contrast, the 'unbiased' approach involves the use of modern techniques including proteomics and bioinformatics that allow unbiased investigations of numerous putative markers that may be informative with regard to AD. Cerebrospinal fluid (CSF) dosage of neuropathological AD-associated proteins has already been incorporated into the neurochemical diagnosis of AD, attesting the relevance of translational research. In the last few years, biomarker discovery research has successfully utilized genomics and proteomics for the identification of several promising molecular markers for AD. In the present article, we discuss the present state of the art and the future challenges in the search of CSF biomarkers for AD.
Mild cognitive impairment (MCI) is a clinical stage indicating a prodromal phase of dementia. This practical concept could be used also for fronto-temporal dementia (FTD). Progranulin (PGRN) has been ...recently recognized as a useful diagnostic biomarker for fronto-temporal lobe degeneration (FTLD) due to GRN null mutations. Electroencephalography (EEG) is a reliable tool in detecting brain networks changes. The working hypothesis of the present study is that EEG oscillations could detect different modifications among FTLD stages (FTD-MCI versus overt FTD) as well as differences between GRN mutation carriers versus non-carriers in patients with overt FTD.
EEG in all patients and PGRN dosage in patients with a clear FTD were detected. The cognitive state has been investigated through mini mental state examination (MMSE).
MCI-FTD showed a significant lower spectral power in both alpha and theta oscillations as compared to overt FTD. GRN mutations carriers affected by FTLD show an increase in high alpha and decrease in theta oscillations as compared to non-carriers.
EEG frequency rhythms are sensible to different stage of FTD and could detect changes in brain oscillatory activity affected by GRN mutations.
Objective
Relationships between the apolipoprotein E ε4 allele and electroencephalographic (EEG) rhythmicity have been demonstrated in Alzheimer's disease (AD) patients but not in the preclinical ...stage prodromic to it, namely, mild cognitive impairment (MCI). The present multicentric EEG study tested the hypothesis that presence of ε4 affects sources of resting EEG rhythms in both MCI and AD subjects.
Methods
We enrolled 89 MCI subjects (34.8% with ε4) and 103 AD patients (50.4% with ε4). Resting eyes‐closed EEG data were recorded for all subjects. EEG rhythms of interest were delta (2—4Hz), theta (4–8Hz), alpha 1 (8–10.5Hz), alpha 2 (10.5–13Hz), beta 1 (13–20Hz), and beta 2 (20–30Hz). EEG cortical sources were estimated by low‐resolution brain electromagnetic tomography.
Results
Results showed that amplitude of alpha 1 and 2 sources in occipital, temporal, and limbic areas was lower in subjects carrying the ε4 allele than in those not carrying the ε4 allele (p < 0.01). This was true for both MCI and AD. For the first time to our knowledge, a relationship was shown between ApoE genotype and global neurophysiological phenotype (ie, cortical alpha rhythmicity) in a preclinical AD condition, MCI, in addition to clinically manifest AD.
Interpretation
Such a demonstration motivates future genotype–EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects. Ann Neurol 2005
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau
(p-Tau
) in a large cohort of patients with frontotemporal lobar degeneration (FTLD).
In this ...retrospective study, performed on 417 participants, we analysed serum NfL and p-Tau
concentrations with an ultrasensitive single molecule array (Simoa) approach. We assessed the diagnostic values of serum biomarkers in the differential diagnosis between FTLD, Alzheimer's disease (AD) and healthy ageing; their role as markers of disease severity assessing the correlation with clinical variables, cross-sectional brain imaging and neurophysiological data; their role as prognostic markers, considering their ability to predict survival probability in FTLD.
We observed significantly higher levels of serum NfL in patients with FTLD syndromes, compared with healthy controls, and lower levels of p-Tau
compared with patients with AD. Serum NfL concentrations showed a high accuracy in discriminating between FTLD and healthy controls (area under the curve (AUC): 0.86, p<0.001), while serum p-Tau
showed high accuracy in differentiating FTLD from patients with AD (AUC: 0.93, p<0.001). In FTLD, serum NfL levels correlated with measures of cognitive function, disease severity and behavioural disturbances and were associated with frontotemporal atrophy and indirect measures of GABAergic deficit. Moreover, serum NfL concentrations were identified as the best predictors of survival probability.
The assessment of serum NfL and p-Tau
may provide a comprehensive view of FTLD, aiding in the differential diagnosis, in staging disease severity and in defining survival probability.
•Metallomics can contribute to the biomarkers identification in NDDs.•Altered Zinc, Copper, Iron, Manganese levels have been detected in NDDs.•Drugs treatment seems to influence Zinc, Copper, Iron, ...Manganese levels in NDDs.•These trace elements appear to be good candidates as biomarkers for NDDs.•Drugs effects on trace elements homeostasis could be used to guide successful future development strategies.
Diagnosis and treatment of complex diseases such as Neurodevelopmental Disorders (NDDs) can be resolved through the identification of biomarkers. Metallomics (research on biometals) and metallomes (metalloproteins/metalloenzymes/chaperones) along with genomics, proteomics and metabolomics, can contribute to accelerate and improve this process.
This review focused on four NDDs pathologies (Schizophrenia, SZ; Attention Deficit Hyperactivity Disorder, ADHD; Autism, ADS; Epilepsy), and we reported, for the first time, different studies on the role played by the principal six essential trace elements (Cobalt, Co; Copper, Cu; Iron, Fe; Manganese, Mn; Selenium, Se; Zinc, Zn) that can influence diagnosis/treatment.
in light of the literature presented, based on meta-analyses, we suggest that Zn (glutamatergic neurotransmission, inflammation, neurodegeneration, autoimmunity alterations), could be a potential diagnostic biomarker associated to SZ. Moreover, considering the single association studies going in the same direction, increased Cu (catecholamine alterations, glucose intolerance, altered lipid metabolism/oxidative stress) and lower Fe (dopaminergic dysfunctions) levels were associated with a specific negative symptomatology. Lower Mn (lipid metabolism/oxidative stress alterations), and lower Se (metabolic syndrome) were linked to SZ. From the meta-analyses in ADHD, it is evidenced that Fe (and ferritin in particular), Mn, and Zn (oxidative stress dysfunctions) could be potential diagnostic biomarkers, mainly associated to severe hyperactive or inattentive symptoms; as well as Cu, Fe, Zn in ADS and Zn in Epilepsy. Fe, Zn and Mn levels seem to be influenced by antipsychotics treatment in SZ; Mn and Zn by methylphenidate treatment in ADHD; Cu and Zn by antiepileptic drugs in Epilepsy.
Although there is controversy and further studies are needed, this work summarizes the state of art of the literature on this topic. We claim to avoid underreporting the impact of essential trace elements in paving the way for biomarkers research for NDDs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The oxidized LDL receptor 1 gene (OLR1) rs1050283 single nucleotide polymorphism (SNP) has been previously shown to be associated with Alzheimer's disease (AD). An association analysis of OLR1 was ...carried out in a population of 443 patients with AD as compared with 393 age-matched controls. In addition, an expression analysis of OLR1 and its regulatory hsa-miR369-3p was performed in peripheral mononuclear blood cells (PBMC) from 20 patients and 15 controls. Logistic regression analysis, adjusted for gender and apolipoprotein E (ApoE) status, showed a statistically significant association of OLR1 rs1050283 under the assumption of a dominant model (CC and CT individuals versus TT: p = 0.014, OR: 1.50, 95%CI: 1.08-2.08) and a genotypic model (TC versus TT: p = 0.002, OR: 1.61, 95%CI: 1.14-2.26). No significant differences in OLR1 expression was observed between patients and controls (p > 0.05). However, stratifying patients according to the rs1050283 status, significantly decreased relative PBMC expression levels of OLR1 were observed in carriers of CC+CT genotypes as compared with TT carriers (0.13 ± 0.013 versus 0.46 ± 0.028, p = 0.022), whereas no differences in relative expression levels of the hsa-miR369-3p were observed (p > 0.05). The effect observed was not due to the presence of the ApoE ε4 allele. The OLR1 rs1050283 SNP likely acts as a risk factor for sporadic AD. The presence of at least one C allele is associated with a decreased expression of OLR1 mRNA in the absence of hsa-miR369-3p de-regulation, suggesting that the presence of the polymorphic allele influences the binding of hsa-miR369-3p to its 3'UTR consensus sequence. Nevertheless, the limited power of the study requires further investigations with a larger sample size.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the ...amyloid/tau/neurodegeneration A/T/(N) framework for Alzheimer’s disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer’s disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources.
We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed ‘big tau’ isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts.
In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer’s disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52–0.67, P = 0.003), but not neurofilament light (rho = −0.14–0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer’s disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer’s disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function.
Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer’s disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.
A blood-based biomarker that tracks neurodegeneration in Alzheimer’s disease and differentiates it from other dementias is lacking. Gonzalez et al. report the discovery and clinical validation of plasma brain-derived tau, an improved total-tau assay that specifically targets CNS tau in blood.
The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42), total-tau ...(t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.
Background and aims:
To describe the clinical and neuropsychological features of a large group of cognitively intact persons subjected to brain high-resolution magnetic resonance (MR), to compare ...them with the general population, and to set norms for medial temporal atrophy and white matter lesions.
Methods:
Participants in the Italian Brain Normative Archive (IBNA) study were 483 consecutive volunteers undergoing MR for reasons unrelated to cognition (migraine or headache, visual and balance or auditory disturbances, paresthesias, and others) and showing no brain damage. Manual tracing of hippocampal and amygdalar volumes and visual rating of white matter lesions were made. The whole study group was stratified by age (≤60 and 60+ yrs) and by the reason for MR prescription.
Results:
In the whole group, mean age and education were 52.4±13.7 and 9.8±4.2 years, respectively, and the prevalence of women was 63%. Clinical, neuropsychological and morphometric features were similar in the stratified subgroups. Neuropsychological features were those expected for age and education based on Italian normative values. Hippocampal and amygdalar volumes were not associated with age, except for the right amygdala (B −0.159, 95% CI −0.28 to −0.03, p=0.016).
Conclusions:
Persons in the IBNA study had clinical and neuropsychological features consistent with that of the general population. Their brain morphometric features may be used as normative references for patients with suspected neurodegenerative disorders.
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