scholarly journals Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease

2020 ◽  
Vol 6 (6) ◽  
pp. e517
Author(s):  
Young Ho Park ◽  
Angela Hodges ◽  
Andrew Simmons ◽  
Simon Lovestone ◽  
Michael W. Weiner ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cortical Thickness ◽  
Hippocampal Volume ◽  
Risk Scores ◽  
Functional Genes ◽  
Class Iii ◽  
Herpes Simplex Virus 1 ◽  
Neuroimaging Biomarkers ◽  
Simplex Virus

ObjectiveTo determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD).MethodsBlood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed (n = 674) cohorts. To calculate TRSs, we selected functional genes that were expressed under the control of the AD risk loci and were identified as being responsible for AD by using Bayesian colocalization and mendelian randomization methods. Regression was used to investigate the association of the TRS with diagnosis (AD vs CN) and MRI biomarkers (entorhinal thickness and hippocampal volume). Regression was also used to evaluate whether expression of each functional gene was associated with AD diagnosis.ResultsThe TRS was significantly associated with AD diagnosis, hippocampal volume, and entorhinal cortical thickness in the ADNI. The association of the TRS with AD diagnosis and entorhinal cortical thickness was also replicated in AddNeuroMed. Among functional genes identified to calculate the TRS, CD33 and PILRA were significantly upregulated, and TRAPPC6A was significantly downregulated in patients with AD compared with CN, all of which were identified in the ADNI and replicated in AddNeuroMed.ConclusionsThe blood-based TRS is significantly associated with AD diagnosis and neuroimaging biomarkers. In blood, CD33 and PILRA were known to be associated with uptake of β-amyloid and herpes simplex virus 1 infection, respectively, both of which may play a role in the pathogenesis of AD.Classification of evidenceThe study is rated Class III because of the case control design and the risk of spectrum bias.

scholarly journals Online Learning for Classification of Alzheimer Disease based on Cortical Thickness and Hippocampal Shape Analysis

2014 ◽  
Vol 20 (1) ◽  
pp. 61 ◽  
Author(s):  
Ga-Young Lee ◽  
Jeonghun Kim ◽  
Ju Han Kim ◽  
Kiwoong Kim ◽  
Joon-Kyung Seong
Keyword(s):  
Online Learning ◽  
Alzheimer Disease ◽  
Cortical Thickness ◽  
Shape Analysis

scholarly journals Evaluation of a novel immunoassay to detect p-tau Thr217 in the CSF to distinguish Alzheimer disease from other dementias

Neurology ◽  
2020 ◽  
Vol 95 (22) ◽  
pp. e3026-e3035
Author(s):  
Jozef Hanes ◽  
Andrej Kovac ◽  
Hlin Kvartsberg ◽  
Eva Kontsekova ◽  
Lubica Fialova ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Positive Predictive Value ◽  
Diagnostic Accuracy ◽  
Predictive Value ◽  
Healthy Controls ◽  
Class Iii ◽  
Total Tau ◽  
Β Amyloid ◽  
Healthy Participants

ObjectiveTo investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls.MethodsWe developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44).ResultsThe p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and β-amyloid 40, but not β-amyloid 42.ConclusionsThis study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation.Classification of evidenceThis study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.

scholarly journals Comparing 18F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 90 (5) ◽  
pp. e388-e395 ◽  
Author(s):  
Niklas Mattsson ◽  
Ruben Smith ◽  
Olof Strandberg ◽  
Sebastian Palmqvist ◽  
Michael Schöll ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Diagnostic Performance ◽  
Characteristic Curve ◽  
A Priori ◽  
Hippocampal Volume ◽  
Class Iii ◽  
Tau Pathology ◽  
Alzheimer Dementia ◽  
Prodromal Ad ◽  
T Tau

ObjectiveTo compare PET imaging of tau pathology with CSF measurements (total tau [t-tau] and phosphorylated tau [p-tau]) in terms of diagnostic performance for Alzheimer disease (AD).MethodsWe compared t-tau and p-tau and 18F-AV-1451 in 30 controls, 14 patients with prodromal AD, and 39 patients with Alzheimer dementia, recruited from the Swedish BioFINDER study. All patients with AD (prodromal and dementia) were screened for amyloid positivity using CSF β-amyloid 42. Retention of 18F-AV-1451 was measured in a priori specified regions, selected for known associations with tau pathology in AD.ResultsRetention of 18F-AV-1451 was markedly elevated in Alzheimer dementia and moderately elevated in prodromal AD. CSF t-tau and p-tau was increased to similar levels in both AD dementia and prodromal AD. 18F-AV-1451 had very good diagnostic performance for Alzheimer dementia (area under the receiver operating characteristic curve [AUROC] ∼1.000), and was significantly better than t-tau (0.876), p-tau (0.890), hippocampal volume (0.824), and temporal cortical thickness (0.860). For prodromal AD, there were no significant AUROC differences between CSF tau and 18F-AV-1451 measures (0.836–0.939), but MRI measures had lower AUROCs (0.652–0.769).ConclusionsCSF tau and 18F-AV-1451 have equal performance in early clinical stages of AD, but 18F-AV-1451 is superior in the dementia stage, and exhibits close to perfect diagnostic performance for mild to moderate AD.Classification of evidenceThis study provides Class III evidence that CSF tau and 18F-AV-1451 PET have similar performance in identifying early AD, and that 18F-AV-1451 PET is superior to CSF tau in identifying mild to moderate AD.

Pathophysiology of Alzheimer Disease

2017 ◽  
Author(s):  
David Knopman
Keyword(s):  
Cerebrospinal Fluid ◽  
Alzheimer Disease ◽  
Cortical Thickness ◽  
Hippocampal Volume ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Symptomatic Disease ◽  
18F Fluorodeoxyglucose ◽  
Β Amyloid ◽  
Cortical Association Areas

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations.  Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein 

Pathophysiology of Alzheimer Disease

2017 ◽  
Author(s):  
David Knopman
Keyword(s):  
Cerebrospinal Fluid ◽  
Alzheimer Disease ◽  
Cortical Thickness ◽  
Hippocampal Volume ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Symptomatic Disease ◽  
18F Fluorodeoxyglucose ◽  
Β Amyloid ◽  
Cortical Association Areas

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations.  Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein 

scholarly journals Serum triglycerides in Alzheimer disease

Neurology ◽  
2020 ◽  
Vol 94 (20) ◽  
pp. e2088-e2098 ◽  
Author(s):  
Megan M. Bernath ◽  
Sudeepa Bhattacharyya ◽  
Kwangsik Nho ◽  
Dinesh Kumar Barupal ◽  
Oliver Fiehn ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cortical Thickness ◽  
Principal Components ◽  
Principal Component ◽  
Serum Levels ◽  
Hippocampal Volume ◽  
Chain Polyunsaturated Fatty Acid ◽  
Lipid Profiling ◽  
Serum Triglycerides ◽  
Component Scores

ObjectiveTo investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD.MethodsSerum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons.ResultsThe 84 TGs yielded 9 principal components, 2 of which, consisting of long-chain, polyunsaturated fatty acid–containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying the APOE ε4 allele, these principal components were significantly associated with CSF β-amyloid1–42 values and entorhinal cortical thickness.ConclusionThis study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE ε4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.

scholarly journals Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jason Hassenstab ◽  
Jessica Nicosia ◽  
Megan LaRose ◽  
Andrew J. Aschenbrenner ◽  
Brian A. Gordon ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Multiple Regression ◽  
Cortical Thickness ◽  
Symptom Onset ◽  
Alternative Assessment ◽  
Amyloid Pet ◽  
Cognitively Normal ◽  
Long Form ◽  
Neuroimaging Biomarkers ◽  
Tau Pet

Abstract Background Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a “sampling” of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers. Methods Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer’s Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness. Results Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong’s test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = − 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15–0.16, ps < 0.007). Conclusions Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset.

Golgin A4 in CSF and granulovacuolar degenerations of patients with Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 91 (19) ◽  
pp. e1799-e1808 ◽  
Author(s):  
Felix Kork ◽  
Joachim Jankowski ◽  
Anand Goswami ◽  
Joachim Weis ◽  
Gary Brook ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Diagnostic Marker ◽  
Characteristic Curve ◽  
Treatment Strategies ◽  
Postmortem Brain ◽  
Class Iii ◽  
Granulovacuolar Degeneration ◽  
Direct Role ◽  
Postmortem Brain Tissue

ObjectiveTo isolate and identify a new, as yet unknown molecule in CSF that could serve as marker for Alzheimer disease.MethodsWe immunized mice with human CSF and fused hybridomas for monoclonal antibodies and screened these antibodies for their capacity to discriminate CSF of patients with Alzheimer disease from CSF of controls. We then chromatographically isolated the antigen to the best discriminating antibody and identified the antigen using mass spectrometric methods. Thereafter, we quantified the CSF concentration of the antigen in a new cohort of patients with Alzheimer disease and controls and performed immunohistochemistry of postmortem brain tissue derived from patients with Alzheimer disease and controls.ResultsWe generated >200 hybridomas and selected 1 antibody that discriminated CSF from patients with Alzheimer disease from that of controls. We identified golgin A4 as the antigen detected by this antibody. Golgin A4 concentration was significantly higher in CSF from patients with Alzheimer disease than in CSF of controls (145 [interquartile range 125–155] vs 115 [ 99–128] pg/mL, p < 0.001) and demonstrated a substantial discriminative power (area under the receiver operating characteristic curve 0.80, 95% confidence interval 0.67–0.94). Immunohistochemistry of postmortem brain sections from patients with Alzheimer disease revealed a significant accumulation of golgin A4 in granulovacuolar degeneration bodies (GVBs).ConclusionsThese results support the notion that golgin A4 could serve as a diagnostic marker in Alzheimer disease. For validation of this notion, prospective multicenter diagnostic studies will evaluate golgin A4 as diagnostic marker for Alzheimer disease. Furthermore, it has to be determined whether the association of golgin A4 with GVBs is an epiphenomenon or whether golgin A4 plays a more direct role in Alzheimer disease, allowing it to serve as a target in therapeutic treatment strategies.Classification of evidenceThis study provides Class III evidence that elevated CSF golgin A4 levels identify patients with Alzheimer disease.

Assembly of VP26 in herpes simplex virus-1 capsid implicated by 3-D structure of recombinant capsid

1995 ◽  
Vol 53 ◽  
pp. 840-841
Author(s):  
Z. Hong Zhou ◽  
Jing He ◽  
Joanita Jakana ◽  
J. D. Tatman ◽  
Frazer J. Rixon ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
3D Structure ◽  
Structure Study ◽  
Herpes Simplex Virus 1 ◽  
Shell Proteins ◽  
Life Threatening ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus which is implicated in diseases ranging from self-curing cold sores to life-threatening infections. The 2500 Å diameter herpes virion is composed of a glycoprotein spike containing, lipid envelope, enclosing a protein layer (the tegument) in which is embedded the capsid (which contains the dsDNA genome). The B-, and A- and C-capsids, representing different morphogenetic stages in HSV-1 infected cells, are composed of 7, and 5 structural proteins respectively. The three capsid types are organized in similar T=16 icosahedral shells with 12 pentons, 150 hexons, and 320 connecting triplexes. Our previous 3D structure study at 26 Å revealed domain features of all these structural components and suggested probable locations for the outer shell proteins, VP5, VP26, VP19c and VP23. VP5 makes up most of both pentons and hexons. VP26 appeared to bind to the VP5 subunit in hexon but not to that in penton.

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