scholarly journals Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer’s Disease

2019 ◽  
Author(s):  
Sanka Amadoru ◽  
Vincent Doré ◽  
Catriona A McLean ◽  
Fairlie Hinton ◽  
Claire E Shepherd ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Roc Curves ◽  
Neuritic Plaque ◽  
Youden Index ◽  
Amyloid Pet ◽  
Receiver Operator Characteristic ◽  
Post Mortem ◽  
Neuritic Plaques ◽  
Moderate Density

Abstract Background: We aimed to determine the Centiloid unit (CL) thresholds for sparse and moderate density neuritic plaques. Methods: Amyloid PET results in CL for 49 subjects were compared with post-mortem neuritic plaque density, visual read, and final clinicopathological diagnosis. A Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. Results: A threshold of 20.1 CL yielded highest accuracy in detecting moderate or frequent plaque density (ROC AUC 0.97). A threshold of 9.5 CL was optimal for detecting sparse, moderate or frequent plaques (ROC AUC 0.96). Those cases with a final clinicopathological diagnosis of Alzheimer’s disease yielded a median CL result of 87.7 (IQR ±42.2) with 94% > 45 CL. Positive visual read agreed highly with results >26 CL. Conclusions: In this cohort, values <9.5 CL accurately reflected the absence of any neuritic plaques, and >20.1 CL indicated the presence of at least moderate plaque density. Clinicopathological diagnosis of AD was rare with CL <45.

scholarly journals Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer’s Disease

2020 ◽  
Author(s):  
Sanka Amadoru ◽  
Vincent Doré ◽  
Catriona A McLean ◽  
Fairlie Hinton ◽  
Claire E Shepherd ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Roc Curves ◽  
Neuritic Plaque ◽  
Youden Index ◽  
Amyloid Pet ◽  
Neuritic Plaques ◽  
Time To Death ◽  
Post Mortem Findings ◽  
Amyloid Aβ

Abstract Background: The Centiloid scale was developed to standardise the results of beta-amyloid (Aβ) PET. We aimed to determine the Centiloid unit (CL) thresholds for CERAD sparse and moderate density neuritic plaques, Alzheimer’s disease neuropathologic change (ADNC) score of intermediate or high probability of Alzheimer’s Disease (AD), final clinicopathological diagnosis of AD and expert visual read of a positive Aβ PET scan. Methods: Aβ PET results in CL for 49 subjects were compared with post-mortem findings, visual read, and final clinicopathological diagnosis. The Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. Results: A threshold of 20.1 CL (21.3 CL when corrected for time to death, AUC 0.97) yielded highest accuracy in detecting moderate or frequent plaque density while <10 CL was optimal for excluding neuritic plaque. The threshold for ADNC intermediate or high likelihood AD was 49.4 CL (AUC 0.98). Those cases with a final clinicopathological diagnosis of AD yielded a median CL result of 87.7 (IQR ±42.2) with 94% > 45 CL. Positive visual read agreed highly with results >26 CL. Conclusions: Centiloid values <10 accurately reflected the absence of any neuritic plaque, >20 CL indicated the presence of at least moderate plaque density but approximately 50 CL or more best confirmed both neuropathological and clinicopathological diagnosis of Alzheimer’s disease.

scholarly journals Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012513
Author(s):  
Michel J. Grothe ◽  
Alexis Moscoso ◽  
Nicholas J. Ashton ◽  
Thomas K. Karikari ◽  
Juan Lantero-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Braak Stage ◽  
Neuritic Plaques ◽  
Neurofilament Light ◽  
T Tau

Objective:To study cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.Methods:We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).Results:All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.Conclusions:Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.Classification of Evidence:This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.

scholarly journals Identification of retinoblastoma binding protein 7 (Rbbp7) as a mediator against tau acetylation and subsequent neuronal loss in Alzheimer’s disease and related tauopathies

2021 ◽  
Author(s):  
Nikhil Dave ◽  
Austin S. Vural ◽  
Ignazio S. Piras ◽  
Wendy Winslow ◽  
Likith Surendra ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Death ◽  
Binding Protein ◽  
Tau Phosphorylation ◽  
Neuritic Plaque ◽  
Post Mortem ◽  
Post Mortem Brain ◽  
Tau Acetylation

AbstractEvidence indicates that tau hyper-phosphorylation and subsequent neurofibrillary tangle formation contribute to the extensive neuronal death in Alzheimer’s disease (AD) and related tauopathies. Recent work has identified that increased tau acetylation can promote tau phosphorylation. Tau acetylation occurs at lysine 280 resulting from increased expression of the lysine acetyltransferase p300. The exact upstream mechanisms mediating p300 expression remain elusive. Additional work highlights the role of the epigenome in tau pathogenesis, suggesting that dysregulation of epigenetic proteins may contribute to acetylation and hyper-phosphorylation of tau. Here, we identify and focus on the histone-binding subunit of the Nucleosome Remodeling and Deacetylase (NuRD) complex: Retinoblastoma-Binding Protein 7 (Rbbp7). Rbbp7 chaperones chromatin remodeling proteins to their nuclear histone substrates, including histone acetylases and deacetylases. Notably, Rbbp7 binds to p300, suggesting that it may play a role in modulating tau acetylation. We interrogated Rbbp7 in post-mortem brain tissue, cell lines and mouse models of AD. We found reduced Rbbp7 mRNA expression in AD cases, a significant negative correlation with CERAD (neuritic plaque density) and Braak Staging (pathogenic tau inclusions) and a significant positive correlation with post-mortem brain weight. We also found a neuron-specific downregulation of Rbbp7 mRNA in AD patients. Rbbp7 protein levels were significantly decreased in 3xTg-AD and PS19 mice compared to NonTg, but no decreases were found in APP/PS1 mice that lack tau pathology. In vitro, Rbbp7 overexpression rescued TauP301L-induced cytotoxicity in immortalized hippocampal cells and primary cortical neurons. In vivo, hippocampal Rbbp7 overexpression rescued neuronal death in the CA1 of PS19 mice. Mechanistically, we found that increased Rbbp7 reduced p300 levels, tau acetylation at lysine 280 and tau phosphorylation at AT8 and AT100 sites. Collectively, these data identify a novel role of Rbbp7, protecting against tau-related pathologies, and highlight its potential as a therapeutic target in AD and related tauopathies.

scholarly journals A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tim West ◽  
Kristopher M. Kirmess ◽  
Matthew R. Meyer ◽  
Mary S. Holubasch ◽  
Stephanie S. Knapik ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Resolution Mass Spectrometry ◽  
Clinical Performance ◽  
Characteristic Curve ◽  
Youden Index ◽  
Amyloid Pet ◽  
Drug Trials ◽  
Site Specific

Abstract Background The development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. Methods We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. Results Plasma Aβ42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77–0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82–0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87–0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. Conclusions This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer’s disease; and may enhance the efficiency of enrolling participants into Alzheimer’s disease drug trials.

scholarly journals Amyloid β 1-42 deposits do not lead to Alzheimer's neuritic plaques in aged dogs

1996 ◽  
Vol 313 (2) ◽  
pp. 575-580 ◽  
Author(s):  
Thomas WISNIEWSKI ◽  
Maciej LALOWSKI ◽  
Marketta BOBIK ◽  
Michael RUSSELL ◽  
Joanna STROSZNAJDER ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Plaque Formation ◽  
Neuritic Plaque ◽  
Amyloid Angiopathy ◽  
Neuritic Plaques ◽  
Cerebral Vessel ◽  
Aβ Peptides

In Alzheimer's disease, amyloid β (Aβ) is deposited in senile plaques and amyloid angiopathy. Longer Aβ peptides, which extend to residue 42 (Aβ42), have been suggested to be critical for the seeding of amyloid. Aged dogs develop cerebral vessel amyloid and parenchymal preamyloid lesions. Preamyloid in humans is related to senile plaques, whereas in dogs such progression is rare. We evaluated the composition of aged canine vessel amyloid and preamyloid both biochemically and immunohistochemically. The vessel amyloid extended mainly to residue 40 (Aβ40), while preamyloid contained a mixture of Aβ17-42 and Aβ42, with minimal Aβ40. Our results suggest other factors besides Aβ42 are important for neuritic plaque formation.

scholarly journals Optimal Combinations of AT(N) Biomarkers to Determine Longitudinal Cognition in the Alzheimer's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Rong-Rong Lin ◽  
Yan-Yan Xue ◽  
Xiao-Yan Li ◽  
Yi-He Chen ◽  
Qing-Qing Tao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Clinical Manifestations ◽  
Cognitive Status ◽  
Youden Index ◽  
Amyloid Pet ◽  
Cognitive Changes ◽  
Neurofilament Light ◽  
Tau Pet

Background: National Institute on Aging—Alzheimer's Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer's disease (AD) as a biological construct. However, the associations between different AT(N) combinations and cognitive progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants were classified into cognitively unimpaired (CU; n = 200) and cognitively impaired (CI; n = 141) groups according to the clinical manifestations and neuropsychological tests. Cerebrospinal fluid (CSF) Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), hippocampal volume, temporal cortical thickness, [18F]fluorodeoxyglucose (FDG) PET, and plasma neurofilament light (NfL) were used as biomarkers for (N). Binary biomarkers were obtained from the Youden index and publicly available cutoffs. Prevalence of AT(N) categories was compared between different biomarkers within the group using related independent sample non-parametric test. The relationship between AT(N) combinations and 12-year longitudinal cognition was assessed using linear mixed-effects modeling.Results: Among the CU participants, A–T–(N)– was most common. More T+ were detected using p-tau than tau PET (p &lt; 0.05), and more (N)+ were observed using fluid biomarkers (p &lt; 0.001). A+T+(N)+ was more common in the CI group. Tau PET combined with cortical thickness best predicted cognitive changes in the CI group and MRI predicted changes in the CU group.Conclusions: These findings suggest that optimal AT(N) combinations to determine longitudinal cognition differ by cognitive status. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for future studies.

scholarly journals Optimal Combinations of Biomarkers to Determine AT(N) in the Alzheimer’s Disease 

2020 ◽  
Author(s):  
Rong-Rong Lin ◽  
Yan-Yan Xue ◽  
Xiao-Yan Li ◽  
Yi-He Chen ◽  
Qing-Qing Tao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Clinical Stage ◽  
Youden Index ◽  
Amyloid Pet ◽  
Clinical Dementia Rating ◽  
Cognitive Changes ◽  
Neurofilament Light ◽  
Tau Pet

Abstract Background: National Institute on Aging—Alzheimer’s Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer’s disease (AD) as a biological construct. However, the associations between different AT(N) combinations and clinical stage and progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants from ADNI cohort were classified into AT(N) groups, including 200 cognitively unimpaired (CU) participants and 141 cognitively impaired (CI) participants (101 mild cognitive impairment [MCI] and 40 Alzheimer’s disease [AD]). CSF Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), FDG-PET, hippocampal volume, temporal cortical thickness and plasma neurofilament light (NfL) were used as biomarkers for (N). Binarization of biomarkers was acquired from Youden index and public cutoffs. The relationship between different AT(N) biomarkers combinations and cognitive changes (longitudinal Mini-Mental State Examination scores and Clinical Dementia Rating Sum of Boxes) was examined using linear mixed modeling and coefficient of variation.Results: Among CU participants, A−T−(N)− variants were most common. More T+ cases were shown using p-tau than tau PET, and more N+ cases were shown using fluid biomarkers than neuroimaging. Among CI participants, A+T+(N)+ was more common. Tau PET combined with cortical thickness best predicted longitudinal cognitive decline in CI and MRI measurements in CU participants. Conclusion: These findings suggest that optimal combinations of biomarkers to determine AT(N) are differed by clinical stage. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for the future studies.

scholarly journals Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models

2008 ◽  
Vol 205 (12) ◽  
pp. 2781-2789 ◽  
Author(s):  
Hong Qing ◽  
Guiqiong He ◽  
Philip T. T. Ly ◽  
Christopher J. Fox ◽  
Matthias Staufenbiel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Valproic Acid ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Plaque Formation ◽  
Neuritic Plaque ◽  
Amyloid Β Protein ◽  
Neuritic Plaques ◽  
Aβ Production

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Aβ production by inhibiting GSK-3β–mediated γ-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

Computer-aided methods for 3-D visualization of serial sections and thick biological specimens

1992 ◽  
Vol 50 (2) ◽  
pp. 1060-1061
Author(s):  
Mark Ellisman ◽  
Maryann Martone ◽  
Gabriel Soto ◽  
Eleizer Masliah ◽  
David Hessler ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Three Dimensional ◽  
Neuritic Plaque ◽  
Dimensional Structure ◽  
Data Sets ◽  
Molecular Physiology ◽  
Research Activities ◽  
Computer Aided ◽  
Dimensional Reconstruction

Structurally-oriented biologists examine cells, tissues, organelles and macromolecules in order to gain insight into cellular and molecular physiology by relating structure to function. The understanding of these structures can be greatly enhanced by the use of techniques for the visualization and quantitative analysis of three-dimensional structure. Three projects from current research activities will be presented in order to illustrate both the present capabilities of computer aided techniques as well as their limitations and future possibilities.The first project concerns the three-dimensional reconstruction of the neuritic plaques found in the brains of patients with Alzheimer's disease. We have developed a software package “Synu” for investigation of 3D data sets which has been used in conjunction with laser confocal light microscopy to study the structure of the neuritic plaque. Tissue sections of autopsy samples from patients with Alzheimer's disease were double-labeled for tau, a cytoskeletal marker for abnormal neurites, and synaptophysin, a marker of presynaptic terminals.

Elucidating the risk factors for progression from amyloid-negative amnestic mild cognitive impairment to dementia

2020 ◽  
Vol 17 ◽  
Author(s):  
Hyung-Ji Kim ◽  
Jae-Hong Lee ◽  
E-nae Cheong ◽  
Sung-Eun Chung ◽  
Sungyang Jo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amnestic Mild Cognitive Impairment ◽  
Amyloid Pet ◽  
Clinical Progression ◽  
Amnestic Mci

Background: Amyloid PET allows for the assessment of amyloid β status in the brain, distinguishing true Alzheimer’s disease from Alzheimer’s disease-mimicking conditions. Around 15–20% of patients with clinically probable Alzheimer’s disease have been found to have no significant Alzheimer’s pathology on amyloid PET. However, a limited number of studies had been conducted this subpopulation in terms of clinical progression. Objective: We investigated the risk factors that could affect the progression to dementia in patients with amyloid-negative amnestic mild cognitive impairment (MCI). Methods: This study was a single-institutional, retrospective cohort study of patients over the age of 50 with amyloidnegative amnestic MCI who visited the memory clinic of Asan Medical Center with a follow-up period of more than 36 months. All participants underwent brain magnetic resonance imaging (MRI), detailed neuropsychological testing, and fluorine-18[F18]-florbetaben amyloid PET. Results: During the follow-up period, 39 of 107 patients progressed to dementia from amnestic MCI. In comparison with the stationary group, the progressed group had a more severe impairment in verbal and visual episodic memory function and hippocampal atrophy, which showed an Alzheimer’s disease-like pattern despite the lack of evidence for significant Alzheimer’s disease pathology. Voxel-based morphometric MRI analysis revealed that the progressed group had a reduced gray matter volume in the bilateral cerebellar cortices, right temporal cortex, and bilateral insular cortices. Conclusion: Considering the lack of evidence of amyloid pathology, clinical progression of these subpopulation may be caused by other neuropathologies such as TDP-43, abnormal tau or alpha synuclein that lead to neurodegeneration independent of amyloid-driven pathway. Further prospective studies incorporating biomarkers of Alzheimer’s diseasemimicking dementia are warranted.

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