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

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.

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

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.

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

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3477-3494 ◽  
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.

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

2021 ◽  
Author(s):  
Christina M. Moloney ◽  
Sydney A. Labuzan ◽  
Julia E. Crook ◽  
Habeeba Siddiqui ◽  
Monica Castanedes-Casey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangle ◽  
Global Scale ◽  
Postmortem Brain ◽  
Braak Stage ◽  
Phosphorylated Tau ◽  
Regional Vulnerability ◽  
Early Fluid ◽  
Fluid Biomarker

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.

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

2019 ◽  
Vol 138 (4) ◽  
pp. 597-612 ◽  
Author(s):  
Cathrine Petersen ◽  
Amber L. Nolan ◽  
Elisa de Paula França Resende ◽  
Zachary Miller ◽  
Alexander J. Ehrenberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangle ◽  
Regional Patterns ◽  
Clinical Variants

scholarly journals Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer’s disease

2020 ◽  
Vol 6 (48) ◽  
pp. eabd1327
Author(s):  
Nicolai Franzmeier ◽  
Anna Dewenter ◽  
Lukas Frontzkowski ◽  
Martin Dichgans ◽  
Anna Rubinski ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Patient Specific ◽  
Braak Stage ◽  
Accumulation Rates ◽  
Patient Centered ◽  
Braak Staging ◽  
Two Samples ◽  
Tau Pet

In Alzheimer’s disease (AD), the Braak staging scheme suggests a stereotypical tau spreading pattern that does, however, not capture interindividual variability in tau deposition. This complicates the prediction of tau spreading, which may become critical for defining individualized tau-PET readouts in clinical trials. Since tau is assumed to spread throughout connected regions, we used functional connectivity to improve tau spreading predictions over Braak staging methods. We included two samples with longitudinal tau-PET from controls and AD patients. Cross-sectionally, we found connectivity of tau epicenters (i.e., regions with earliest tau) to predict estimated tau spreading sequences. Longitudinally, we found tau accumulation rates to correlate with connectivity strength to patient-specific tau epicenters. A connectivity-based, patient-centered tau spreading model improved the assessment of tau accumulation rates compared to Braak stage–specific readouts and reduced sample sizes by ~40% in simulated tau-targeting interventions. Thus, connectivity-based tau spreading models may show utility in clinical trials.

scholarly journals Tau-PET and in vivo Braak-staging as a prognostic marker in Alzheimer’s disease

2021 ◽  
Author(s):  
Davina Biel ◽  
Matthias Brendel ◽  
Anna Rubinski ◽  
Katharina Buerger ◽  
Daniel Janowitz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Prognostic Marker ◽  
Cognitive Change ◽  
Patient Specific ◽  
Amyloid Pet ◽  
Braak Stage ◽  
Braak Staging ◽  
Tau Pet

ABSTRACTINTRODUCTIONTau pathology in Alzheimer’s disease tracks clinical status more closely than beta-amyloid. Thus, tau-PET may be a promising prognostic marker for cognitive decline. Here, we systematically compared tau-PET and Braak-staging vs. amyloid-PET as predictors of cognitive decline.METHODSWe included 396 cognitively normal to dementia subjects with 18F-Flutemetamol/18F-Florbetapir-amyloid-PET, 18F-Flortaucipir-tau-PET and ~2-year cognitive assessments. Annual cognitive change rates were calculated via linear-mixed models. We determined global amyloid-PET, global tau-PET, and tau-PET-based Braak-stage (Braak0/BraakI+/BraakI-IV+/BraakI-VI+/Braakatypical+). In bootstrapped linear regression, we assessed whether tau-PET outperformed amyloid-PET in predicting cognitive decline. Using ANCOVAs, we tested whether later Braak-stage predicted accelerated cognitive decline and determined Braak-stage-specific conversion risk to MCI or dementia.RESULTSGlobal tau-PET was a better predictor of cognitive decline than global amyloid-PET (p<0.001). Advanced Braak-stage was associated with faster cognitive decline (p<0.001) and elevated clinical conversion risk.DISCUSSIONTau-PET and Braak-staging show promise for predicting patient-specific risk of clinical AD progression.

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

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.

scholarly journals Donor specific transcriptomic analysis of Alzheimer’s disease associated hypometabolism highlights a unique donor, microglia, and ribosomal proteins

2019 ◽  
Author(s):  
Sejal Patel ◽  
Derek Howard ◽  
Alana Man ◽  
Deborah Schwartz ◽  
Joelle Jee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
Glucose Utilization ◽  
Meta Analysis ◽  
Expression Patterns ◽  
Neurofibrillary Tangle ◽  
Brain Atlas ◽  
Angular Gyrus ◽  
Healthy Controls

AbstractAlzheimer’s disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD and is clinically useful. To identify these regions, we conducted a voxel-wise meta-analysis of positron emission tomography studies that compared AD patients with healthy controls. This meta-analysis included 27 studies that assayed glucose utilization in 915 AD patients and 715 healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes with expression patterns associated with this hypometabolism pattern in the cerebral cortex. Of the six brains in the Atlas, one demonstrated a strong spatial association with the hypometabolism pattern. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when compared with the other five brains. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which primarily encode cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes progressively increases across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization of cortical hypometabolism reveals a molecular link to AD associated hypometabolism that may be relevant to preclinical stages.

scholarly journals Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

2021 ◽  
Author(s):  
Nicholas J. Ashton ◽  
Tharick A. Pascoal ◽  
Thomas K. Karikari ◽  
Andréa L. Benedet ◽  
Juan Lantero-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Great Promise ◽  
Braak Stage ◽  
Braak Staging ◽  
Positron Emission

AbstractThe quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.

scholarly journals Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tatsuhiro Terada ◽  
Joseph Therriault ◽  
Min Su Peter Kang ◽  
Melissa Savard ◽  
Tharick Ali Pascoal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Clinical Symptoms ◽  
Mitochondrial Complex I ◽  
Braak Stage ◽  
Mitochondrial Complex ◽  
Temporal Area

Abstract Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

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