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 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 < 0.05), and more (N)+ were observed using fluid biomarkers (p < 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 Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer's disease

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011226
Author(s):  
Ignacio Illán-Gala ◽  
Alberto Lleo ◽  
Anna Karydas ◽  
Adam M. Staffaroni ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Severity ◽  
Cortical Thickness ◽  
Frontotemporal Lobar Degeneration ◽  
Amyloid Pet ◽  
Class Iii ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
T Tau

ObjectiveTo test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically-diagnosed Alzheimer's disease (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses.MethodsWe measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-Tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression and survival and cortical thickness.ResultsPlasma NfL, but not plasma t-tau discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-Tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone.ConclusionsPlasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S.Classification of evidenceThis study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance than plasma t-tau in FTLD and AD.

scholarly journals Mass spectrometry measures of plasma Aβ, tau and P‐tau isoforms’ relationship to amyloid PET, tau PET, and clinical stage of Alzheimer’s disease

2020 ◽  
Vol 16 (S5) ◽  
Author(s):  
Randall J. Bateman ◽  
Nicolas R. Barthelemy ◽  
Tammie L.S. Benzinger ◽  
James G. Bollinger ◽  
Anne M. Fagan ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Stage ◽  
Amyloid Pet ◽  
Tau Isoforms ◽  
Tau Pet

scholarly journals Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau

2021 ◽  
Author(s):  
Niklas Mattsson-Carlgren ◽  
Shorena Janelidze ◽  
Randall Bateman ◽  
Ruben Smith ◽  
Erik Stomrud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medial Temporal Lobe ◽  
Amyloid Plaques ◽  
Amyloid Plaque ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Β Amyloid ◽  
Tau Pet ◽  
Disease Stages

Abstract Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N=88), both plaque and tangle density contributed independently to higher P-tau217. Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N=426), where β-amyloid and tau PET were independently associated to P-tau217. P-tau217 correlated with β-amyloid PET (but not tau PET) in early disease stages, and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.

scholarly journals Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

2020 ◽  
Vol 6 (16) ◽  
pp. eaaz2387 ◽  
Author(s):  
Niklas Mattsson-Carlgren ◽  
Emelie Andersson ◽  
Shorena Janelidze ◽  
Rik Ossenkoppele ◽  
Philip Insel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Pet ◽  
Phosphorylated Tau ◽  
Positron Emission ◽  
Aβ Aggregation ◽  
Tau Pet ◽  
5Xfad Mice ◽  
Tau Aggregation ◽  
T Tau

The links between β-amyloid (Aβ) and tau in Alzheimer’s disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

scholarly journals Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET

2020 ◽  
Vol 12 (524) ◽  
pp. eaau5732 ◽  
Author(s):  
Renaud La Joie ◽  
Adrienne V. Visani ◽  
Suzanne L. Baker ◽  
Jesse A. Brown ◽  
Viktoriya Bourakova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Pet ◽  
Specific Distribution ◽  
Positron Emission ◽  
Pet Radiotracers ◽  
Β Amyloid ◽  
Tau Pet ◽  
Prospective Longitudinal

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients’ diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid–PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient’s progression and design future clinical trials.

scholarly journals Efficacy and Limitations of rCBF-SPECT in the Diagnosis of Alzheimer’s Disease With Amyloid-PET

2019 ◽  
Vol 34 (5) ◽  
pp. 314-321
Author(s):  
Miwako Takahashi ◽  
Tomoko Tada ◽  
Tomomi Nakamura ◽  
Keitaro Koyama ◽  
Toshimitsu Momose
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rating Scale ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Amyloid Pet ◽  
Clinical Dementia Rating ◽  
Positron Emission ◽  
Rcbf Spect

This study aimed to assess efficacy and limitations of regional cerebral blood flow imaging using single-photon emission computed tomography (rCBF-SPECT) in the diagnosis of Alzheimer’s disease (AD) with amyloid-positron emission tomography (amyloid-PET). Thirteen patients, who underwent both rCBF-SPECT and amyloid-PET after clinical diagnosis of AD or mild cognitive impairment, were retrospectively identified. The rCBF-SPECTs were classified into 4 grades, from typical AD pattern to no AD pattern of hypoperfusion; amyloid-beta (Aβ) positivity was assessed by amyloid-PET. Four patients were categorized into a typical AD pattern on rCBF-SPECT, and all were Aβ+. The other 9 patients did not exhibit a typical AD pattern; however, 4 were Aβ+. The Mini-Mental State Examination score and Clinical Dementia Rating scale were not significantly different between Aβ+ and Aβ– patients. A typical AD pattern on rCBF-SPECT can reflect Aβ+; however, if not, rCBF-SPECT has a limitation to predict amyloid pathology.

IC-P-156: Baseline amyloid PET imaging, longitudinal amyloid accumulation, and Tau PET imaging in preclinical Alzheimer's disease

2015 ◽  
Vol 11 (7S_Part_2) ◽  
pp. P105-P105
Author(s):  
Aaron P. Schultz ◽  
Elizabeth C. Mormino ◽  
Jasmeer P. Chhatwal ◽  
Molly LaPoint ◽  
Alex S. Dagley ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pet Imaging ◽  
Amyloid Pet ◽  
Preclinical Alzheimer’S Disease ◽  
Amyloid Accumulation ◽  
Tau Pet ◽  
Tau Pet Imaging ◽  
Amyloid Pet Imaging

Associations of Blood Pressure with Functional and Cognitive Changes in Patients with Alzheimer's Disease

2016 ◽  
Vol 41 (5-6) ◽  
pp. 314-323 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Blood Pressure ◽  
Alzheimer's Disease ◽  
Rating Scale ◽  
Late Onset ◽  
Angiotensin Receptor Blockers ◽  
Channel Blockers ◽  
Clinical Dementia Rating ◽  
Cognitive Changes ◽  
Converting Enzyme Inhibitors

Background: Midlife hypertension followed by late life hypotension resulting from neurodegeneration increases amyloidogenesis and tauopathy. Methods: Consecutive outpatients with late-onset Alzheimer's disease (AD) at various stages and their respective caregivers were assessed for score variations in 1 year of tests assessing caregiver burden, functionality and cognition according to blood pressure (BP) variations and APOE haplotypes, while also taking into account differential effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, diuretics, or no antihypertensive medication on score changes. The diagnosis and treatment of arterial hypertension followed the JNC 7 report. Results: Variations in systolic BP (-11.76 ± 17.1 mm Hg), diastolic BP (-4.92 ± 10.3 mm Hg) and pulse pressure (-6.84 ± 12.6 mm Hg) were significant after 1 year (n = 191; ρ < 0.01). For APOE4+ carriers, rises in systolic or diastolic BP improved Clinical Dementia Rating Scale Sum of Boxes scores (ρ < 0.04), with marginally significant improvements in Mini-Mental State Examination scores resulting from risen systolic (ρ = 0.069) or diastolic BP (ρ = 0.079), and in basic independence only regarding risen diastolic BP (ρ = 0.055). APOE4- carriers resisted any functional or cognitive effects of BP variations. No differences were found regarding any antihypertensive class for variations in BP or any test scores, regardless of APOE haplotypes. Conclusions: Targeting mild BP elevations brings better functional and cognitive results for APOE4+ carriers with AD.

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.

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