Phosphorylated tau fluid biomarker sites recognize earlier neurofibrillary tangle maturity levels in the postmortem Alzheimer’s disease brain

AbstractAlzheimer’s disease (AD) biomarkers have become increasingly more reliable in predicting AD pathology. While phosphorylated tau fluid biomarkers have been studied for over 20 years, there is a lack of deep characterization of these sites in the postmortem brain. Neurofibrillary tangle-bearing neurons, one of the major neuropathologic hallmarks of AD, undergo morphologic changes that mature along a continuum as hyperphosphorylated tau aggregates. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, our goal was to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) they recognize. We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases from Braak stages I-VI. We excluded non-AD pathologies and tauopathies. A total of 24 cases, 2 males and 2 females for each Braak stage, were selected. We performed immunohistochemistry on the posterior hippocampus using antibodies directed towards phospho (p) threonine (T) 181, pT205, pT217, and pT231. Slides were digitized to enable quantification of tau burden. To examine differences in regional vulnerability between CA1 and subiculum, we developed a semi-quantitative system to rank the frequency of each neurofibrillary tangle maturity level. We identified all neurofibrillary tangle maturity levels at least once for each phosphorylated tau site. Primarily earlier neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle) were recognized for all phosphorylated tau sites. There was an increase in tau burden in the subiculum compared to CA1; however, this was attenuated compared to thioflavin-S positive tangle counts. On a global scale, tau burden generally increased with each Braak stage. These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during earlier neurofibrillary tangle maturity levels. This may help explain why these phosphorylated tau biomarker sites are observed before symptom onset in fluids.

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Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-210059 ◽

2021 ◽

pp. 1-10

Author(s):

Douglas Barthold ◽

Laura E. Gibbons ◽

Zachary A. Marcum ◽

Shelly L. Gray ◽

C. Dirk Keene ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Education ◽

Descriptive Analysis ◽

Neurofibrillary Tangle ◽

Apoe Genotype ◽

Severity Index ◽

Neuritic Plaque ◽

Braak Stage ◽

Total N

Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

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The Correlations between Postmortem Brain Pathologies and Cognitive Dysfunction in Aging and Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666171106150915 ◽

2018 ◽

Vol 15 (5) ◽

pp. 462-473 ◽

Cited By ~ 10

Author(s):

Wen-Ying Qiu ◽

Qian Yang ◽

Wanying Zhang ◽

Naili Wang ◽

Di Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Brain ◽

Amyloid Β ◽

Cognitive Status ◽

Postmortem Brain ◽

Braak Stage ◽

Brain Bank ◽

General Linear Multivariate Model ◽

Human Brains

Background: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. Objective: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. Method: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the “ABC” score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. Results: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-β (Aβ) deposits (A score) present no significant correlation with any of ECog domains. Conclusion: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank.

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18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases

Brain ◽

10.1093/brain/awaa276 ◽

2020 ◽

Vol 143 (11) ◽

pp. 3477-3494 ◽

Cited By ~ 1

Author(s):

David N Soleimani-Meigooni ◽

Leonardo Iaccarino ◽

Renaud La Joie ◽

Suzanne Baker ◽

Viktoriya Bourakova ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Progressive Supranuclear Palsy ◽

Frontotemporal Lobar Degeneration ◽

Neurofibrillary Tangle ◽

Corticobasal Degeneration ◽

Braak Stage ◽

Tau Pathology ◽

Cognitively Normal ◽

Normal Controls

Abstract Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34–76); eight female; median PET-to-autopsy interval of 30 months (range 4–59 months)]. Eight patients had primary Alzheimer’s disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80–100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer’s disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer’s disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer’s disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer’s (Braak VI) pathology. However, patients with earlier Braak stages (Braak I–IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer’s disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.

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Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation

10.1101/538496 ◽

2019 ◽

Author(s):

Cathrine Petersen ◽

Amber L Nolan ◽

Elisa de Paula França Resende ◽

Alexander Ehrenberg ◽

Salvatore Spina ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hierarchical Clustering ◽

Primary Motor Cortex ◽

Regional Distribution ◽

Neurofibrillary Tangle ◽

Angular Gyrus ◽

Braak Stage ◽

Regional Patterns ◽

Braak Staging

ABSTRACTBackgroundNeurofibrillary tangle (NFT) pathology in Alzheimer’s disease (AD) follows a stereotypic progression well-characterized by Braak staging. However, some AD cases show deviations from the Braak staging scheme. In this study, we tested the hypothesis that these variations in the regional distribution of tau pathology are linked to heterogeneity in the clinical phenotypes of AD.MethodsWe included a clinicopathological cohort of ninety-four AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E (APOE) genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z-score. We assessed NFT density and distribution from thioflavin S fluorescent microscopy throughout four neocortical and two hippocampal regions. A mathematical algorithm classifying AD cases into typical, hippocampal sparing (HpSp), and limbic predominant (LP) subtypes based on regional NFT burden was compared to unbiased hierarchical clustering for cases with Braak stage > IV.ResultsPatients diagnosed with logopenic primary progressive aphasia showed significantly higher NFT density in the superior temporal gyrus relative to patients diagnosed with Alzheimer-type dementia (p = 0.0091), while patients with corticobasal syndrome showed significantly higher NFT density in the primary motor cortex (p = 0.0205). Hierarchical clustering identified three discrete clusters of patients characterized respectively by low overall NFT burden (n = 18), high overall burden (n = 30), and cortical-predominant burden (n = 24). A regionally specific effect was observed for visuospatial ability; higher NFT density in the angular gyrus (β = - 0.0921, p = 0.0099) and in the CA1 sector of the hippocampus (β = −0.0735, p = 0.0380) was significantly associated with more severe visuospatial dysfunction, modulated by age of death.ConclusionsOur results suggest domain-specific functional consequences of regional NFT accumulation. In particular, we observed focal aggregation of NFT density in clinically relevant regions among different clinical AD variants. Continued work to map the regionally specific clinical consequences of tau accumulation presents an opportunity to increase understanding of disease mechanisms underlying atypical clinical manifestations.

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Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease

10.1101/514927 ◽

2019 ◽

Cited By ~ 1

Author(s):

Yi-Chen Hsieh ◽

Caiwei Guo ◽

Hari K. Yalamanchili ◽

Measho Abreha ◽

Rami Al-Ouran ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rna Splicing ◽

Intron Retention ◽

Neurofibrillary Tangle ◽

Neuronal Loss ◽

Mrna Splicing ◽

Postmortem Brain ◽

Loss Of Function ◽

Human Postmortem Brain

SUMMARYIn Alzheimer’s disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal core components. In Drosophila models, pan-neuronal Tau expression triggers reductions in core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss-of-function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA-sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle pathologic burden. Our results implicate spliceosome disruption and perturbations of the neuronal transcriptome in Tau-mediated neurodegeneration in AD.

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Microglia Activation in the Brain as Inflammatory Biomarker of Alzheimer’s Disease Neuropathology and Clinical Dementia

Disease Markers ◽

10.1155/2006/276239 ◽

2006 ◽

Vol 22 (1-2) ◽

pp. 95-102 ◽

Cited By ~ 65

Author(s):

Zhongmin Xiang ◽

Vahram Haroutunian ◽

Lap Ho ◽

Dushant Purohit ◽

Giulio Maria Pasinetti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Layer ◽

Neurofibrillary Tangle ◽

Microglia Activation ◽

Postmortem Brain ◽

Neuritic Plaque ◽

Clinical Dementia Rating ◽

Inflammatory Biomarker ◽

Hla Dr

The role of microglia-mediated inflammation in the progression of Alzheimer’s disease (AD) neuropathology remains unclear. In this study, postmortem brain sections from AD and control cases were subjected to Human Leukocyte Antigen (HLA)-DR immunohistochemistry to examine microglia activation in the progression of AD assessed by pre-mortem clinical dementia rating (CDR) and postmortem pathological manifestations of neuritic plaque (NP) and neurofibrillary tangle (NT) according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). In both gray and white matter of the entorhinal cortex (EC) and HLA-DR immunostaining increased with the progression of CDR or CERAD NP, and to a lesser degree with CERAD NT. Between CDR stages HLA-DR significance was found in moderate (CDR 2) to severe dementia (CDR 5) where as between CERAD NP stages staining increased significantly from NP 0 (no plaque) to NP 1 (sparse plaques), suggesting increased microglia activation begins with amyloid NP deposition. In the hippocampus, a significant increase in microglia immunostaining was found in the pyramidal cell layer of CA1 as early as CDR 1, and in the upper molecular layer of the dentate gyrus in CDR 0.5. This increase continues with the progression of CDR and reaches maximum in CDR 5. When assessed by CERAD NP stages however, a significant increase in microglia immunostaining was found only in mid-to-late stages (NP 3) and reduced staining was seen in NP 5. These results suggest that microglia activation increases with the progression of AD, with the increase varying depending on the involved brain region.

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Stages of Objective Memory Impairment Predict Alzheimer’s Disease Neuropathology: Comparison with the Clinical Dementia Rating Scale–Sum of Boxes

Journal of Alzheimer s Disease ◽

10.3233/jad-200946 ◽

2021 ◽

pp. 1-11

Author(s):

Ellen Grober ◽

Qi Qi ◽

Lynn Kuo ◽

Jason Hassenstab ◽

Richard J. Perrin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Logistic Regression ◽

Memory Impairment ◽

Rating Scale ◽

Neurofibrillary Tangle ◽

Staging System ◽

Braak Stage ◽

Operating Characteristics ◽

Clinical Dementia Rating

Background: The ultimate validation of a clinical marker for Alzheimer’s disease (AD) is its association with AD neuropathology. Objective: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD neuropathologic change and extent of neurofibrillary tangle (NFT) pathology defined by Braak stage, in comparison to the Clinical Dementia Rating (CDR) Scale sum of boxes (CDR-SB). Methods: 251 well-characterized participants from the Knight ADRC clinicopathologic series were classified into SOMI stage at their last assessment prior to death using the free recall and total recall scores from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR). Logistic regression models assessed the predictive validity of SOMI and CDR-SB for intermediate/high AD neuropathologic change. Receiver operating characteristics (ROC) analysis evaluated the discriminative validity of SOMI and CDR-SB for AD pathology. Ordinal logistic regression was used to predict Braak stage using SOMI and CDR-SB in separate and joint models. Results: The diagnostic accuracy of SOMI for AD diagnosis was similar to that of the CDR-SB (AUC: 85%versus 83%). In separate models, both SOMI and CDR-SB predicted Braak stage. In a joint model SOMI remained a significant predictor of Braak stage but CDR-SB did not. Conclusion: SOMI provides a neuropathologically validated staging system for episodic memory impairment in the AD continuum and should be useful in predicting tau positivity based on its association with Braak stage.

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LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease

10.1101/2020.01.14.905661 ◽

2020 ◽

Author(s):

Katelyn Cuttler ◽

Monique J. Bignoux ◽

Tyrone C. Otgaar ◽

Stephanie Chigumba ◽

Eloise Ferreira ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangle ◽

Direct Interaction ◽

Telomerase Activity ◽

Laminin Receptor ◽

Phosphorylated Tau ◽

Hek 293 ◽

293 Cells ◽

Potential Alternative

AbstractAlzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently it has been demonstrated that the 37kDa/67kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Here we show that LRP/LR co-localizes with tau in the perinuclear cell compartment and FRET confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrPc levels, a tauopathy-related protein. Additionally, LRP::FLAG overexpression resulted in increased hTERT levels. These data indicate for the first time a role of LRP/LR in tauopathy of Alzheimer’s Disease and recommend LRP::FLAG as a potential alternative therapeutic tool for Alzheimer’s Disease treatment through rescuing cells from Aβ induced cytotoxicity and, as shown in this report, decreased phosphorylated tau levels.

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