scholarly journals Lipid Peroxidation Assessment in Preclinical Alzheimer Disease Diagnosis

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1043
Author(s):  
Carmen Peña-Bautista ◽  
Lourdes Álvarez-Sánchez ◽  
Inés Ferrer ◽  
Marina López-Nogueroles ◽  
Antonio José Cañada-Martínez ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Area Under Curve ◽  
Disease Diagnosis ◽  
Csf Biomarkers ◽  
Preclinical Ad ◽  
Aging Populations ◽  
Advanced Stages ◽  
Preclinical Diagnosis ◽  
T Tau ◽  
And Oxidative Stress

Background: Alzheimer disease (AD) is an increasingly common neurodegenerative disease, especially in countries with aging populations. Its diagnosis is complex and is usually carried out in advanced stages of the disease. In addition, lipids and oxidative stress have been related to AD since the earliest stages. A diagnosis in the initial or preclinical stages of the disease could help in a more effective action of the treatments. Methods: Isoprostanoid biomarkers were determined in plasma samples from preclinical AD participants (n = 12) and healthy controls (n = 31) by chromatography and mass spectrometry (UPLC-MS/MS). Participants were accurately classified according to cerebrospinal fluid (CSF) biomarkers and neuropsychological examination. Results: Isoprostanoid levels did not show differences between groups. However, some of them correlated with CSF biomarkers (t-tau, p-tau) and with cognitive decline. In addition, a panel including 10 biomarkers showed an area under curve (AUC) of 0.96 (0.903–1) and a validation AUC of 0.90 in preclinical AD prediction. Conclusions: Plasma isoprostanoids could be useful biomarkers in preclinical diagnosis for AD. However, these results would require a further validation with an external cohort.

Sex differences in CSF biomarkers vary by Alzheimer disease stage and APOE ε4 genotype

Neurology ◽  
2020 ◽  
Vol 95 (17) ◽  
pp. e2378-e2388 ◽  
Author(s):  
Rosha Babapour Mofrad ◽  
Betty M. Tijms ◽  
Philip Scheltens ◽  
Frederik Barkhof ◽  
Wiesje M. van der Flier ◽  
...  
Keyword(s):  
Sex Differences ◽  
Alzheimer Disease ◽  
Clinical Disease ◽  
Disease Stage ◽  
Subjective Cognitive Decline ◽  
Csf Biomarkers ◽  
Β Amyloid ◽  
Disease Stages ◽  
T Tau

ObjectiveTo evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account.MethodWe included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF β-amyloid1–42 (Aβ42), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (p < 0.05), sex differences were further evaluated by stratifying analyses for clinical disease stage and APOE ε4 genotype, including age as a covariate.ResultsThree-way interactions were significant for t-Tau (p < 0.001) and p-Tau (p < 0.01) but not Aβ42. In APOE ε4 carriers, women showed higher p-Tau concentrations than men in SCD (Cohen d [95% confidence interval]: t-Tau = 0.52 [0.19–0.84], p < 0.001; p-Tau = 0.44 [0.11–0.77] p = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28–0.80], p < 0.001; p-Tau = 0.52 [0.26–0.77], p < 0.001) but not in AD dementia. In APOE ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17–0.80], p = 0.002; p-Tau = 0.47 [0.16–0.78], p = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19–0.65], p < 0.001; p-Tau = 0.38 [0.15–0.61] p = 0.002) but not in SCD.ConclusionsWithin APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD.

scholarly journals White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease

Neurology ◽  
2019 ◽  
Vol 94 (9) ◽  
pp. e950-e960 ◽  
Author(s):  
Anja Soldan ◽  
Corinne Pettigrew ◽  
Yuxin Zhu ◽  
Mei-Cheng Wang ◽  
Abhay Moghekar ◽  
...  
Keyword(s):  
White Matter ◽  
Alzheimer Disease ◽  
Symptom Onset ◽  
White Matter Hyperintensities ◽  
Cox Regression ◽  
Rate Of Change ◽  
Csf Biomarkers ◽  
Risk Of Progression ◽  
Fluid Attenuated Inversion Recovery ◽  
T Tau

ObjectiveRecent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).MethodsTwo sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.ResultsBaseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1–42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06–1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56–1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.ConclusionThese results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

scholarly journals Cognitive Profile and Markers of Alzheimer Disease–Type Pathology in Patients With Lewy Body Dementias

Neurology ◽  
2021 ◽  
Vol 96 (14) ◽  
pp. e1855-e1864
Author(s):  
Erica Howard ◽  
David J. Irwin ◽  
Katya Rascovsky ◽  
Naomi Nevler ◽  
Sanjana Shellikeri ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Lewy Body ◽  
Digit Span ◽  
Onset Time ◽  
Analysis Of Covariance ◽  
Csf Biomarkers ◽  
Available N ◽  
Confrontation Naming ◽  
T Tau ◽  
Dementia Onset

ObjectiveTo determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)–type copathology are more impaired on confrontation naming than those without likely AD-type copathology.MethodsWe selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid1-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD − AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD − AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.ResultsPatients with LBD + AD performed worse on BNT than patients with LBD − AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = −0.28, p < 0.05) and p-tau (ρ = −0.26, p = 0.05) but not Aβ42 (p > 0.1).ConclusionMarkers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

scholarly journals Cerebrospinal Fluid Biomarkers for Diagnosis of Alzheimer’s Disease

2015 ◽  
Vol 31 (1) ◽  
pp. 34-41
Author(s):  
Imran Sarker ◽  
Md Rezaul Karim Khan ◽  
Anisul Haque ◽  
Md Rafiqul Islam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Senile Plaques ◽  
Disease Diagnosis ◽  
Diagnostic Tools ◽  
Csf Biomarkers ◽  
Diagnostic Potential ◽  
Cerebrospinal Fluid Biomarkers ◽  
T Tau

Alzheimer’s disease is the most common cause of dementia among elderly people. The major pathological hallmarks of AD are the loss of neurons, occurrence of extracellular senile plaques as well as intracellular neurofibrillary tangles (NFT). Biochemical changes in the brain are reflected in the cerebrospinal fluid (CSF), and intense research efforts have been made to develop biomarkers for the central pathogenic processes in AD that can be used as diagnostic tools. Biomarkers are essential part of disease management as they are essential for diagnosis, monitoring the disease progression, detecting early onset of the disease, monitoring the effect of therapeutic intervention, and also avoiding false diagnosis of the disease. Unfortunately, none of the biomarkers presently available are able to accomplish the disease diagnosis single-handedly. Three CSF biomarkers, Aâ42, Total-tau (t-tau), and phosphorylated-tau (p-tau), have been found to have the highest diagnostic potential. Bangladesh Journal of Neuroscience 2015; Vol. 31 (1): 34-41

Identification of a Pathogenic PSEN1 Ala285Val Mutation Associated with Early-Onset Alzheimer’s Disease

2020 ◽  
Vol 17 (5) ◽  
pp. 438-445
Author(s):  
Van Giau Vo ◽  
Jung-Min Pyun ◽  
Eva Bagyinszky ◽  
Seong S.A. An ◽  
Sang Y. Kim
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe ◽  
Early Onset ◽  
Parietal Lobe ◽  
Disease Diagnosis ◽  
Random Coil ◽  
Magnetic Resonance Imaging Scan ◽  
Preclinical Ad ◽  
Early Onset Alzheimer’S Disease

Background: Presenilin 1 (PSEN1) was suggested as the most common causative gene of early onset Alzheimer’s Disease (AD). Methods: Patient who presented progressive memory decline in her 40s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using whole exome sequencing. The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs. Results: A pathogenic mutation in PSEN1 (NM_000021.3: c.1027T>C p.Ala285Val), which was found in a Korean EOAD patient. Magnetic resonance imaging scan showed mild left temporal lobe atrophy. Hypometabolism appeared through 18F-fludeoxyglucose Positron Emission Tomography (FDG-PET) scanning in bilateral temporal and parietal lobe, and 18F-Florbetaben-PET (FBB-PET) showed increased amyloid deposition in bilateral frontal, parietal, temporal lobe and hence presumed preclinical AD. Protein modeling showed that the p.Ala285Val is located in the random coil region and could result in extra stress in this region, resulting in the replacement of an alanine residue with a valine. This prediction was confirmed previous in vitro studies that the p.Trp165Cys resulted in an elevated Aβ42/Aβ40 ratio in both COS-1 and HEK293 cell lines compared that of wild-type control. Conclusion: Together, the clinical characteristics and the effect of the mutation would facilitate our understanding of PSEN1 in AD pathogenesis for the disease diagnosis and treatment. Future in vivo study is needed to evaluate the role of PSEN1 p.Ala285Val mutation in AD progression.

scholarly journals Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao Hu ◽  
Lan Tan ◽  
Yan-Lin Bi ◽  
Wei Xu ◽  
Lin Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peripheral Blood ◽  
Late Onset ◽  
Early Stage ◽  
Susceptibility Gene ◽  
Subjective Cognitive Decline ◽  
Preclinical Ad ◽  
T Tau ◽  
New Evidence

AbstractThe bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer’s disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

scholarly journals Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Oriol Grau-Rivera ◽  
◽  
Irene Navalpotro-Gomez ◽  
Gonzalo Sánchez-Benavides ◽  
Marc Suárez-Calvet ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Weight Loss ◽  
Cerebrospinal Fluid ◽  
Weight Change ◽  
Emission Tomography ◽  
Link Type ◽  
Preclinical Ad ◽  
Positron Emission ◽  
T Tau

Abstract Background Recognizing clinical manifestations heralding the development of Alzheimer’s disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults. Methods This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change. Results Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00–1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19–1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25–2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = − 0.141, p = 0.005), t-tau (β = − 0.147 p = 0.004) and neurogranin levels (β = − 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only. Conclusions Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment. Trial registration NCT01835717, NCT02485730, NCT02685969.

scholarly journals Unraveling Pathophysiological Mechanisms of Parkinson’s Disease: Contribution of CSF Biomarkers

2020 ◽  
Vol 15 ◽  
pp. 117727192096407
Author(s):  
Lucia Farotti ◽  
Federico Paolini Paoletti ◽  
Simone Simoni ◽  
Lucilla Parnetti
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical History ◽  
Substantial Contribution ◽  
Csf Biomarkers ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Disease Modifying Drugs ◽  
Precise Diagnosis ◽  
And Oxidative Stress

Diagnosis of Parkinson’s disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer’s disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.

scholarly journals Biological Markers and Alzheimer Disease: A Canadian Perspective

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Hyman M. Schipper
Keyword(s):  
Alzheimer Disease ◽  
Biological Markers ◽  
Primary Care Physicians ◽  
Biomarker Discovery ◽  
Consensus Conference ◽  
Csf Biomarkers ◽  
Protein Levels ◽  
Canadian Perspective ◽  
Diagnostic Confusion ◽  
With Memory

Decreased -amyloid1-42and increased phospho-tau protein levels in the cerebrospinal fluid (CSF) are currently the most accurate chemical neurodiagnostics of sporadic Alzheimer disease (AD). A report (2007) of the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (2006) recommended that biological markers shouldnotbe currently requisitioned by primary care physicians in the routine investigation of subjects with memory complaints. Consideration for such testing should prompt patient referral to a specialist engaged in dementia evaluations or a Memory Clinic. The specialist should consider having CSF biomarkers (-amyloid1-42and phospho-tau) measured at a reputable facility in restricted cases presenting with atypical features and diagnostic confusion, but not as a routine procedure in all individuals with typical sporadic AD phenotypes. We submit that developments in the field of AD biomarker discovery since publication of the 3rd CCCDTD consensus data do not warrant revision of the 2007 recommendations.

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