scholarly journals Comparison of Amyloid β and Tau Spread Models in Alzheimer’s Disease

2018 ◽  
Vol 29 (10) ◽  
pp. 4291-4302 ◽  
Author(s):  
Hang-Rai Kim ◽  
Peter Lee ◽  
Sang Won Seo ◽  
Jee Hoon Roh ◽  
Minyoung Oh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Amyloid Β ◽  
Brain Network ◽  
Amyloid Positron Emission Tomography ◽  
Local Spread ◽  
Positron Emission ◽  
Spread Model ◽  
Graph Theoretical Approach

Abstract Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer’s disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models’ performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.

The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer’s Disease Continuum: A Longitudinal Study

2021 ◽  
pp. 1-12
Author(s):  
Heng Zhang ◽  
Diyang Lyu ◽  
Jianping Jia ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Dementia Patients ◽  
Positron Emission ◽  
Potential Biomarker ◽  
Synaptic Degeneration ◽  
Over Time

Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

scholarly journals Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

2020 ◽  
Vol 12 (534) ◽  
pp. eaaz4069 ◽  
Author(s):  
Kamalini G. Ranasinghe ◽  
Jungho Cha ◽  
Leonardo Iaccarino ◽  
Leighton B. Hinkley ◽  
Alexander J. Beagle ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Tracer Uptake ◽  
Therapeutic Approaches ◽  
Regional Patterns ◽  
Positron Emission ◽  
Network Synchrony ◽  
Network Disruptions

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer’s disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

Associations of Neprilysin Activity in CSF with Biomarkers for Alzheimer’s Disease

2019 ◽  
Vol 19 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Timo Grimmer ◽  
Oliver Goldhardt ◽  
Igor Yakushev ◽  
Marion Ortner ◽  
Christian Sorg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fdg Pet ◽  
Amyloid Β ◽  
Neuronal Injury ◽  
Pittsburgh Compound B ◽  
Positron Emission ◽  
Amyloid Load ◽  
Alzheimer’S Pathology

Background: Neprilysin (NEP) cleaves amyloid-β 1–42 (Aβ42) in the brain. Hence, we aimed to elucidate the effect of NEP on Aβ42 in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [11C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. Methods: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer’s disease patients. Results: CSF-NEP was significantly inversely associated with CSF-Aβ42 and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. Conclusions: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer’s pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

scholarly journals PLASMA BIOMARKER FOR ALZHEIMER’S DISEASE: ARE WE READY NOW FOR CLINICAL PRACTICE AND DRUG TRIALS?

2018 ◽  
pp. 1-2
Author(s):  
A. Nakamura
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Utility ◽  
Large Scale ◽  
Amyloid Β ◽  
Imaging Biomarker ◽  
Validation Dataset ◽  
Data Sets ◽  
Detailed Kinetics

To facilitate disease-modifying clinical trials for Alzheimer’s Disease (AD), a blood-based amyloid-β (Aβ) biomarker, which can accurately detect an early pathological signature of AD at prodromal or preclinical stages, has been strongly desired, because it is simpler, less invasive and less costly compared to PET or lumbar puncture. Despite plasma Aβ biomarkers having been extensively investigated, most studies failed to demonstrate clinical utility (1, 2), and at the end of 2016, there was a rather pessimistic mood that this objective might be impossible to realize (3). However, since the latter half of 2017, the situation appears to have changed dramatically, in that several groups have reported potential clinical utility of plasma Aβ biomarkers using different methodologies (4-7). Especially, immunoprecipitation followed by mass spectrometry (IP-MS) assays have shown promising converging evidence. In 2014, we, the National Center for Geriatrics and Gerontology (NCGG) and Koichi Tanaka Mass Spectrometry Research Laboratory at Shimadzu Corporation (Shimadzu), reported that the plasma ratio of Aβ1-42 to a novel APP669-711 fragment (APP669–711/Aβ 1–42) as determined by IP-MS could discriminate high Aβ (Aβ+) individuals from low Aβ (Aβ-) individuals (classified using PiB-PET) with more than 90% accuracy (n=62) (8). In 2017, the Washington University group analyzed detailed kinetics of plasma Aβs, and reported that Aβ42/Aβ40 as measured by IP-MS could distinguish Aβ+ and Aβ- individuals with 88.7% areas under the curve value (n=41) (5). Then very recently, we, in collaboration with the Australian Imaging, Biomarker and Lifestyle Study of Aging (AIBL), have demonstrated that plasma biomarkers, APP669-711/Aβ1-42, Aβ1-40/Aβ1-42, and their composites (composite biomarker), as generated by improved IP-MS methodology performs very well in larger independent datasets: a discovery dataset (NCGG, n=121) and a validation dataset (AIBL, n=252 which includes n=111 PiB-PET and 141 with other ligands) both of which included individuals with normal cognition, MCI and AD. Particularly, the composite biomarker showed very high AUCs in both datasets (discovery 96.7%, n=121, and validation 94.1%, n=111) with accuracy c.a. 90% when using PiB-PET as standard of truth. The findings of the study were considered to be robust, reproducible and reliable because biomarker performance was validated in a blinded manner using independent data sets (Japan and Australia) and involved an established large-scale multicenter cohort (AIBL).

scholarly journals Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shorena Janelidze ◽  
Erik Stomrud ◽  
Ruben Smith ◽  
Sebastian Palmqvist ◽  
Niklas Mattsson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Pet Tracer ◽  
Positron Emission ◽  
Diagnostic Work ◽  
Work Up ◽  
The Brain ◽  
Better Than

AbstractCerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

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