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Plasma Levels of Amyloid-β Peptides and Tau Protein in Mexican Patients with Alzheimer's Disease.
Castillo-Mendieta, T, Arana-Lechuga, Y, Campos-Peña, V, Sosa, AL, Orozco-Suarez, S, Pinto-Almazán, R, Segura-Uribe, J, Javier Rodríguez-Sánchez de Tagle, A, Ruiz-Sánchez, E, Guerra-Araiza, C
Journal of Alzheimer's disease : JAD. 2021;(s1):S271-S281
Abstract
BACKGROUND Alzheimer's disease (AD) causes memory deficit and alterations in other cognitive functions, mainly in adults over 60 years of age. As the diagnosis confirmation is performed by a postmortem neuropathological examination of the brain, this disease can be confused with other types of dementia at early stages. About 860,000 Mexicans are affected by dementia, most of them with insufficient access to adequate comprehensive health care services. Plasma biomarkers could be a rapid option for early diagnosis of the disease. OBJECTIVE This study aimed to analyze some plasma biomarkers (amyloid-β, tau, and lipids) in Mexican AD patients and control subjects with no associated neurodegenerative diseases. METHODS Plasma amyloid-β peptides (Aβ40 and Aβ42), total and phosphorylated tau protein (T-tau and P-tau), and cholesterol and triglyceride levels were quantified by enzyme-linked immunosorbent assay in AD patients and control subjects. RESULTS In Mexican AD patients, we found significantly lower levels of Aβ42 (p < 0.05) compared to the control group. In contrast, significantly higher levels of P-tau (p < 0.05) and triglycerides (p < 0.05) were observed in AD patients compared to controls. Furthermore, a significant correlation was found between the severity of dementia and plasma P-tau levels, Aβ42/Aβ40 and P-tau/T-tau ratios, and triglycerides concentrations. This correlation increased gradually with cognitive decline. CONCLUSION The detection of these plasma biomarkers is an initial step in searching for a timely, less invasive, and cost-efficient diagnosis in Mexicans.
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Commentary: Fatty acids and Alzheimer's disease: evidence on cognition and cortical β-amyloid from secondary analyses of the Multidomain Alzheimer Preventive Trial.
Hooper, C, Vellas, B
The journal of prevention of Alzheimer's disease. 2018;(3):168-170
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CSF tau and tau/Aβ42 predict cognitive decline in Parkinson's disease.
Liu, C, Cholerton, B, Shi, M, Ginghina, C, Cain, KC, Auinger, P, , , Zhang, J
Parkinsonism & related disorders. 2015;(3):271-6
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INTRODUCTION A substantial proportion of patients with Parkinson's disease (PD) have concomitant cognitive dysfunction. Identification of biomarker profiles that predict which PD patients have a greater likelihood for progression of cognitive symptoms is pressingly needed for future treatment and prevention approaches. METHODS Subjects were drawn from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, a large clinical trial that enrolled initially untreated PD patients. For the current study, Phase One encompassed trial baseline until just prior to levodopa administration (n = 403), and Phase Two spanned the initiation of levodopa treatment until the end of cognitive follow-up (n = 305). Correlations and linear mixed models were performed to determine cross-sectional and longitudinal associations between baseline amyloid β1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) and measures of memory and executive function. Analyses also considered APOE genotype and tremor- vs. rigidity-dominant phenotype. RESULTS No association was found between baseline CSF biomarkers and cognitive test performance during Phase One. However, once levodopa treatment was initiated, higher p-tau and p-tau/Aβ42 predicted subsequent decline on cognitive tasks involving both memory and executive functions. The interactions between biomarkers and cognition decline did not appear to be influenced by levodopa dosage, APOE genotype or motor phenotype. CONCLUSIONS The current study has, for the first time, demonstrated the possible involvement of tau species, whose gene (MAPT) has been consistently linked to the risk of PD by genome-wide association studies, in the progression of cognitive symptoms in PD.
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Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials.
Donohue, MC, Moghadam, SH, Roe, AD, Sun, CK, Edland, SD, Thomas, RG, Petersen, RC, Sano, M, Galasko, D, Aisen, PS, et al
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2015;(9):1069-79
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INTRODUCTION Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD). METHODS We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). RESULTS Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. DISCUSSION We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of antiamyloid drugs.
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Age dependence of brain β-amyloid deposition in Down syndrome: An [18F]florbetaben PET study.
Jennings, D, Seibyl, J, Sabbagh, M, Lai, F, Hopkins, W, Bullich, S, Gimenez, M, Reininger, C, Putz, B, Stephens, A, et al
Neurology. 2015;(5):500-7
Abstract
OBJECTIVE To investigate brain β-amyloid binding in subjects with Down syndrome (DS) using [(18)F]florbetaben PET imaging. METHODS Thirty-nine subjects with DS (46.3 ± 4.7 years) were assessed with [(18)F]florbetaben PET imaging. Three blinded independent readers assessed the scans to provide a visual analysis. The primary quantitative imaging outcome was a standardized uptake value ratio (SUVR) obtained for 6 brain regions. Cognitive status was evaluated using the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). RESULTS [(18)F]Florbetaben uptake was correlated with age (p < 0.0001, R(2) = 0.39); 90% of scans in subjects with DS aged 50 years or older (SUVR = 1.62 ± 0.26), 53% in those aged 45 to 49 years (SUVR = 1.43 ± 0.16), and 7% in those aged 40 to 45 years (SUVR = 1.27 ± 0.11) were visually assessed as positive. Visual and quantitative assessments were highly related (χ(2) = 11.3823, p = 0.0007; Cohen κ = 0.58). Only 2 of 34 participants were considered to have dementia by the DSQIID. CONCLUSIONS Brain β-amyloid binding, as measured by [(18)F]florbetaben, increases with age in DS. Subjects with DS who have no evidence of dementia demonstrate brain β-amyloid binding in vivo, suggesting that [(18)F]florbetaben PET imaging may detect β-amyloid in this at-risk population.
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Cognitive trajectories associated with β-amyloid deposition in the oldest-old without dementia.
Snitz, BE, Weissfeld, LA, Lopez, OL, Kuller, LH, Saxton, J, Singhabahu, DM, Klunk, WE, Mathis, CA, Price, JC, Ives, DG, et al
Neurology. 2013;(15):1378-84
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OBJECTIVE To determine whether a high prevalence (55%) of Aβ deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging. METHODS A total of 194 participants (mean age 85.5 years, range 82-95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B-PET imaging. We examined cross-sectional associations between Aβ status and performance on a broad neuropsychological test battery completed at GEMS entry 7-9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models. RESULTS At GEMS screening (2000-2002), participants who were Aβ-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aβ-positive relative to Aβ-negative participants (ps < 0.05). CONCLUSIONS Highly prevalent Aβ deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7-9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aβ-status groups may be detectable 7-9 years before neuroimaging.
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Prevalence of asymptomatic vasogenic edema in pretreatment Alzheimer's disease study cohorts from phase 3 trials of semagacestat and solanezumab.
Carlson, C, Estergard, W, Oh, J, Suhy, J, Jack, CR, Siemers, E, Barakos, J
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2011;(4):396-401
Abstract
BACKGROUND Cerebral vasogenic edema (VE) has been reported to occur during antiamyloid immunotherapy. VE may be associated with central nervous system pathology with blood-brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimer's disease (AD). METHODS Fluid-attenuated inversion recovery imaging sequences were obtained from four ongoing multicenter, randomized, double-blind, placebo-controlled, phase 3 trials in patients with mild-to-moderate AD. The first set of baseline scans was from patients in volumetric magnetic resonance imaging addenda in the Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of Amyloid PaThologY (IDENTITY) studies examining semagacestat, a γ-secretase inhibitor (cohort 1, n = 621). The second set of baseline scans was from the EXPanding alzhEimer's Disease InvestigaTIONs (EXPEDITION) studies examining solanezumab, an anti-Aβ monoclonal antibody (cohort 2, n = 2141). Readers were blinded to patient-identifying information and future treatment. A third set of baseline scans was from the first 700 patients who underwent protocol-specified magnetic resonance imaging before randomization in the EXPEDITION studies (cohort 3). The analysis used three neuroradiologists: two performed independent primary interpretations and the third was the adjudicator. Readers were blinded to patient information, treatment, protocol, and time point. RESULTS Four cases of asymptomatic VE were detected at baseline/screening. Two VE cases were due to underlying extra-axial mass lesions. The third VE case was associated with numerous microhemorrhages in keeping with cerebral amyloid angiopathy-related inflammation or Aβ-related angiitis. The final VE case demonstrated localized sulcal fluid-attenuated inversion recovery imaging hyperintensity. No VE was detected in cohort 3 by readers blinded to patient baseline status. CONCLUSIONS VE seems to be rare at baseline in patients with AD in clinical trials, 2 of 2,762 associated with AD. Additional cohorts should be evaluated to support these findings.