Impact of the biological definition of Alzheimer’s disease using amyloid, tau and neurodegeneration (ATN): what about the role of vascular changes, inflammation, Lewy body pathology?

Gauthier, Serge; Zhang, Hao; Ng, Kok Pin; Pascoal, Tharick A.; Rosa‐Neto, Pedro

doi:10.1186/s40035-018-0117-9

Cited by 35 publications

(33 citation statements)

References 96 publications

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“…The differential equations that describeThe differential equations that describeOf course the pathophysiological model presented in this study can only cover a small subspace of possible AD mechanisms. Even Abeta itself is probably only one player in the multifactorial pathogenesis (Selkoe and Hardy, 2016; Gauthier et al, 2018), and synaptic disinhibition is only one of its effects (Furukawa et al, 1996; Good et al, 1996; Hardy and Selkoe, 2002; Chen, 2005; Busche et al, 2012; Prasansuklab and Tencomnao, 2013; Bloom, 2014; Sadigh-Eteghad et al, 2015; Song et al, 2015; Ulrich, 2015; Celebi et al, 2016; Gauthier et al, 2018; Ren et al, 2018). We are fully aware that other major hallmarks as Tau (Bloom, 2014; Guo et al, 2017; Tapia-Rojas et al, 2019) and cardiovascular risk factors (Love and Miners, 2016; Storck and Pietrzik Claus, 2018; Bannai et al, 2019) cannot be excluded in the discussion of AD etiology, as well as alternative concepts such as microglia and neuroinflammation (Heneka et al, 2015a,b; Wang and Colonna, 2019; Zhou et al, 2019), polygenetic risk factors (Mahley, 2016; Hudry et al, 2019; Jansen et al, 2019; Takatori et al, 2019), environmental factors as neurotoxic or infectious agents (Alonso et al, 2018; McLachlan et al, 2019), and concomitant proteinopathies (Robinson et al, 2018a,b).…”

Section: Discussionmentioning

confidence: 99%

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease

Stefanovski

Triebkorn

Spiegler

et al. 2019

Front. Comput. Neurosci.

112

148

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Introduction: While the prevalence of neurodegenerative diseases associated with dementia such as Alzheimer's disease (AD) increases, our knowledge on the underlying mechanisms, outcome predictors, or therapeutic targets is limited. In this work, we demonstrate how computational multi-scale brain modeling links phenomena of different scales and therefore identifies potential disease mechanisms leading the way to improved diagnostics and treatment. Methods: The Virtual Brain (TVB; thevirtualbrain.org ) neuroinformatics platform allows standardized large-scale structural connectivity-based simulations of whole brain dynamics. We provide proof of concept for a novel approach that quantitatively links the effects of altered molecular pathways onto neuronal population dynamics. As a novelty, we connect chemical compounds measured with positron emission tomography (PET) with neural function in TVB addressing the phenomenon of hyperexcitability in AD related to the protein amyloid beta (Abeta). We construct personalized virtual brains based on an averaged healthy connectome and individual PET derived distributions of Abeta in patients with mild cognitive impairment (MCI, N = 8) and Alzheimer's Disease (AD, N = 10) and in age-matched healthy controls (HC, N = 15) using data from ADNI-3 data base ( http://adni.loni.usc.edu ). In the personalized virtual brains, individual Abeta burden modulates regional Excitation-Inhibition balance, leading to local hyperexcitation with high Abeta loads. We analyze simulated regional neural activity and electroencephalograms (EEG). Results: Known empirical alterations of EEG in patients with AD compared to HCs were reproduced by simulations. The virtual AD group showed slower frequencies in simulated local field potentials and EEG compared to MCI and HC groups. The heterogeneity of the Abeta load is crucial for the virtual EEG slowing which is absent for control models with homogeneous Abeta distributions. Slowing phenomena primarily affect the network hubs, independent of the spatial distribution of Abeta. Modeling the N-methyl-D-aspartate (NMDA) receptor antagonism of memantine in local population models, reveals potential functional reversibility of the observed large-scale alterations (reflected by EEG slowing) in virtual AD brains. Discussion: We demonstrate how TVB enables the simulation of systems effects caused by pathogenetic molecular candidate mechanisms in human virtual brains.

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Section: Discussionmentioning

confidence: 99%

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease

Stefanovski

Triebkorn

Spiegler

et al. 2019

Front. Comput. Neurosci.

112

148

View full text Add to dashboard Cite

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“…A second limitation of our study is the limited number of subjects as well as mixed pathologies, namely amyloid positivity in some of the older subjects (Jansen et al., 2015). While comorbidity of pathologies is common in neurodegenerative diseases (Gauthier et al., 2018; Schneider et al., 2007), a clinical misdiagnosis of PSP could result in a clinical-radiological mismatch where an image does not display a typical PSP pattern of uptake in a patient clinically misdiagnosed with PSP. A third limitation is that the in vivo affinity of [ 18 F]THK5351 to MAO-B is unknown, but likely high, suggesting that the rasagiline challenge could potentially affect binding to both high and low affinity targets of [ 18 F]THK5351.…”

Section: Discussionmentioning

confidence: 99%

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [18F]THK5351 uptake in progressive supranuclear palsy

Ng¹,

Therriault²,

Kang³

et al. 2019

NeuroImage: Clinical

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Background[18F]THK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). However, the interpretation of [18F]THK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD.ObjectivesTo test the hypothesis that the MAO-B inhibitor, rasagiline reduces [18F]THK5351 uptake in PSP.MethodsSix individuals (4: PSP; 2: cognitively unimpaired, CU) underwent [18F]THK5351 and [18F]AZD4694 to quantify baseline tau and amyloid deposition, respectively. Following a 10-day course of 1 mg rasagiline, all participants received a post-challenge [18F]THK5351 scan. The baseline and post-rasagiline challenge standardized uptake value (SUV) were generated normalized for patient weight and injected radioactivity.ResultsThe post-rasagiline regional SUV was reduced on average by 69–89% in PSP, and 53–81% in CU. The distributions of post-rasagiline [18F]THK5351 SUV among PSP individuals were not consistent with the typical pattern of tau aggregates in PSP.ConclusionsSimilar to AD, the interpretation of [18F]THK5351 uptake in PSP is likely confounded by off-target binding to MAO-B binding sites. [18F]THK5351 is not sufficient in quantifying tau aggregates in PSP using the proposed rasagiline dosing regimen.

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“…There are no older adults who do not exhibit the presence of plaques and tangles in their brains" [80]. The fact that even the combined association of amyloid and tau pathology does not necessarily lead to dementia, in addition to the fact that other factors might be playing a leading or accelerating role in the age-associated cognitive decline, brings a few researchers to the conviction that research should be aimed at understanding the interactions among these factors during the progress of brain aging, and that the biological, genetic, and cognitive profiles of individuals must be analyzed on an individual basis [81].…”

Section: Further Factors Potentially Harmful For Brain Histological Dmentioning

confidence: 99%

Parting with the Concept of Alzheimer’s Disease in Senium

Kalvach¹,

Vogner²

2019

obm geriatr

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The understanding of mental deterioration associated with old age has undergone several changes over the past two centuries, and has spurred major scientific debates. In the 19 th century, this disorder was still considered an inevitable part of aging. The beginning of the 20 th century offered a histological explanation for presenile dementia, and Alois Alzheimer was credited as the discoverer of a new disease that bears his name to date. In the last quarter of the 20 th century, findings of Alois Alzheimer were applied massively to late-onset dementia as well, thereby virtually excluding natural intellectual impairment as an explanation to dementia. In contradiction to the original concept provided by Alzheimer, amyloid plaques and neurofibrillary tangles are now being considered as the cause of psychological depreciation at all ages, and the presence of these is interpreted as a disease. The present review is aimed at disputing these common views and suggests that continuing with this approach may prove to be increasingly counterproductive. Instead, the present review offers an unbiased view without any preconceived ideas, which considers a long list of natural biological failures that inevitably accompany every human life, such as micro-injuries, microinfarcts, leukoaraiosis, as a consequence of partial failing of the cerebral blood flow, microbleeds, glycemic fluctuations in diabetics, influences of alcohol and toxins, decreasing anisotropy, increasing mean diffusivity on MRIs, and others.

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Impact of the biological definition of Alzheimer’s disease using amyloid, tau and neurodegeneration (ATN): what about the role of vascular changes, inflammation, Lewy body pathology?

Cited by 35 publications

References 96 publications

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [18F]THK5351 uptake in progressive supranuclear palsy

Parting with the Concept of Alzheimer’s Disease in Senium

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