Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer’s disease

Brain, Journal Year: 2024, Volume and Issue: 147(6), P. 2144 - 2157

Published: April 26, 2024

Abstract Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal level of individual. Here we recontextualized levels into temporal domain better understand downstream Alzheimer’s disease processes tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total 601 individuals from Wisconsin Registry for Prevention Disease Research Center that underwent PET, neuropsychological assessments met clinical criteria three diagnosis groups: cognitively unimpaired (n = 537); mild impairment 48); or dementia 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) sampled iterative local approximation were used positive (A+; global PiB DVR > 1.16 equivalent 17.1 centiloids) onset years A+ duration (i.e. chronicity). Tau burden was quantified using 18F-MK-6240 standardized uptake value ratios (70–90 min, inferior cerebellar grey matter reference region). Whole-brain region-specific approaches examine binding along timeline across continuum. Voxel-wise analyses revealed with each decade A+, spatial extent measurable spread progressed) regions associated early late NFT stages. Regional indicated in entorhinal cortex detectable, on average, within 10 onset. Additionally, region most sensitive pathology this predominantly preclinical sample. Among initially 472) follow-up, mixed effects models showed significant linear non-linear interactions decline, suggesting synergistic effect whereby greater duration, together higher burden, increases likelihood decline beyond their separable effects. Overall, time framework enabled spatiotemporal characterization deposition patterns approach, examined cross-sectional data make course inferences, demonstrated explains considerable amount variability magnitude topography spread, largely recapitulated staging observed human neuropathological studies. By anchoring progression amyloid, provides context, may help inform prognosis timing windows anti-amyloid therapies.

Language: Английский

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Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 7, 2024

Abstract Background Antibody-based immunoassays have enabled quantification of very low concentrations phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding the diagnosis AD. Mass spectrometry enables absolute multiple p-tau variants within a single run. The goal this study was to compare performance mass assessments 181 , 217 and 231 with established immunoassay techniques. Methods We measured CSF from 173 participants TRIAD cohort 394 BioFINDER-2 using both methods. All subjects were clinically evaluated by dementia specialists had amyloid-PET tau-PET assessments. Bland–Altman analyses agreement between . P-tau associations uptake also compared. Receiver Operating Characteristic (ROC) compared identify positivity. Results highly comparable terms diagnostic performance, between-group effect sizes PET biomarkers. In contrast, antibody-free lower immunoassays. Conclusions Our results suggest that while similar overall, immunoassay-based biomarkers are slightly superior spectrometry-based Future work is needed determine whether potential evaluate run offsets quantification.

Language: Английский

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Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Patients with Alzheimer's disease (AD) little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those advanced NFTs. The formation NFTs can be prevented by targeting the intermediate soluble assemblies (STAs). However, biochemical understanding and biomarkers STAs are lacking. We show that Tris-buffered saline-soluble aggregates from autopsy-verified AD tissues include core sequence ~tau258-368. In neuropathological assessments, antibodies against phosphorylation sites serine-262 serine-356 within STA almost exclusively stained granular (that is, prefibrillar) in pre-NFTs while at serine-202 threonine-205 threonine-231, outside core, entire spectrum mature NFTs, dystrophic neurites neuropil threads hippocampus. Functionally, a recombinantly produced peptide robustly altered neuronal excitability synaptic transmission mouse hippocampal slices. Furthermore, we developed cerebrospinal fluid assay differentiated non-AD tauopathies, correlated severity NFT burden cognitive decline independently amyloid beta deposition, positron emission tomography uptake across Braak stages. Together, our findings inform about status early-stage aggregation, reveal aggregation-relevant epitopes offer diagnostic biomarker targeted therapeutic opportunities for AD.

Language: Английский

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Staging of Alzheimer’s disease: past, present, and future perspectives

Trends in Molecular Medicine, Journal Year: 2022, Volume and Issue: 28(9), P. 726 - 741

Published: June 15, 2022

Language: Английский

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The central role of tau in Alzheimer’s disease: From neurofibrillary tangle maturation to the induction of cell death

Brain Research Bulletin, Journal Year: 2022, Volume and Issue: 190, P. 204 - 217

Published: Oct. 13, 2022

Language: Английский

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Discriminative binding of tau PET tracers PI2620, MK6240 and RO948 in Alzheimer’s disease, corticobasal degeneration and progressive supranuclear palsy brains

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(3), P. 1272 - 1283

Published: Nov. 29, 2022

Abstract Recent mechanistic and structural studies have challenged the classical tauopathy classification approach revealed complexity heterogeneity of tau pathology in Alzheimer’s disease (AD) primary tauopathies such as corticobasal degeneration (CBD) progressive supranuclear palsy (PSP), progressing beyond distinct isoforms. In this multi-tau tracer study, we focused on new second-generation PET tracers PI2620, MK6240 RO948 to investigate AD, CBD, PSP brains using post-mortem radioligand binding autoradiography large small frozen brain sections. Saturation indicated multiple sites for 3 H-PI2620 CBD with different affinities ( K d ranging from 0.2 0.7 nM) site densities (following order: B max AD > PSP). Competitive complemented these findings, demonstrating presence two [super-high affinity (SHA): IC 50(1) = 8.1 pM; high (HA): 50(2) 4.9 nM] brains. Regional distribution showed that could discriminate between n 6) control cases 9), especially frontal cortex temporal tissue p < 0.001) well hippocampal region 0.02). H-PI2620, H-MK6240 H-RO948 displayed similar behaviour (in both homogenate competitive one hemispherical section studies) terms affinities, number regional patterns. Our 3) 2) specificity but not or H-RO948. findings clearly demonstrate properties among tracers, which may assist further understanding versus non-AD suggests potential development pure selective 4R tracers.

Language: Английский

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The Use of Tau PET to Stage Alzheimer Disease According to the Braak Staging Framework

Journal of Nuclear Medicine, Journal Year: 2023, Volume and Issue: 64(8), P. 1171 - 1178

Published: June 15, 2023

Amyloid-β plaques and neurofibrillary tangles (NFTs) are the 2 histopathologic hallmarks of Alzheimer disease (AD). On basis pattern NFT distribution in brain, Braak proposed a staging system for AD. provides compelling framework monitoring progression in vivo using PET imaging. Because AD remains based on clinical features, there is an unmet need to translate neuropathologic biologic system. Such biomarker might play role preclinical or improving recruitment strategies trials. Here, we review literature regarding with tau imaging, here called PET-based staging. Our aim summarize efforts implementing assess correspondence descriptions biomarkers. Methods: We conducted systematic search May 2022 PubMed Scopus combining terms "Alzheimer" AND "Braak" ("positron emission tomography" OR "PET"). Results: The database returned 262 results, after assessment eligibility, 21 studies were selected. Overall, most indicate that may be efficient method stage since it presents adequate ability discriminate between phases continuum correlates clinical, fluid, imaging biomarkers However, translation original was done taking into account limitations this technique. This led important interstudy variability anatomic definitions regions interest. Conclusion: Refinements necessary incorporate atypical variants Braak-nonconformant cases. Further needed understand possible applications practice research. Furthermore, standardization topographic interest guarantee reproducibility methodologic homogeneity across studies.

Language: Английский

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Retina pathology as a target for biomarkers for Alzheimer's disease: Current status, ophthalmopathological background, challenges, and future directions

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(1), P. 728 - 740

Published: Nov. 2, 2023

Abstract There is emerging evidence that amyloid beta protein (Aβ) and tau‐related lesions in the retina are associated with Alzheimer's disease (AD). Aβ hyperphosphorylated (p)‐tau deposits have been described were small spots visualized by vivo imaging techniques as well degeneration of retina. These changes correlate brain deposition determined histological quantification, positron emission tomography (PET) or clinical diagnosis AD. However, literature not coherent on these histopathological findings. One important reason for this variability methods interpretation findings across different studies. In perspective, we indicate critical methodological deviations among groups suggest a roadmap moving forward how to harmonize (i) histopathologic examination retinal tissue; (ii) methods, devices, algorithms; (iii) inclusion/exclusion criteria studies aiming at biomarker validation.

Language: Английский

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Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 1, 2024

Language: Английский

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Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1689 - 1689

Published: Jan. 30, 2024

Neurodegenerative diseases are an increasingly common group of that occur late in life with a significant impact on personal, family, and economic life. Among these, Alzheimer’s disease (AD) Parkinson’s (PD) the major disorders lead to mild severe cognitive physical impairment dementia. Interestingly, those may show onset prodromal symptoms early after middle age. Commonly, evaluation these neurodegenerative is based detection biomarkers, where functional structural magnetic resonance imaging (MRI) have shown central role revealing or phases, although it can be expensive, time-consuming, not always available. The aforementioned visual system due pathophysiological mechanisms shared between eye brain. In disease, α-synuclein deposition retinal cells, as well dopaminergic neurons substantia nigra, alters cortex function, resulting modifications field. Similarly, modified by neurofibrillary tangles neuritic amyloid β plaques typically seen brain, this reflect accumulation biomarkers retina during stages postmortem retinas AD patients. light, ophthalmic neurodegeneration could become cost-effective method for diagnosis diseases, overcoming limitations deep This analysis commonly used practice, interest has risen recent years. review will discuss relationship degeneration, highlighting how represent noninvasive straightforward diseases.

Language: Английский

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