scholarly journals Frontotemporal dementia with the V337M MAPT mutation

Neurology ◽  
2017 ◽  
Vol 88 (8) ◽  
pp. 758-766 ◽  
Author(s):  
Salvatore Spina ◽  
Daniel R. Schonhaut ◽  
Bradley F. Boeve ◽  
William W. Seeley ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Mutation Carrier ◽  
Brain Atrophy ◽  
Brain Mri ◽  
Strong Association ◽  
Paired Helical Filaments ◽  
Structural Mri ◽  
Tau Pathology ◽  
Pet Tracer

Objective:To assess the efficacy of [18F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau (MAPT) mutation.Methods:MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [18F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [18F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [18F]AV1451 imaging.Results:We found a strong association between topography and degree of [18F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the proband's mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [18F]AV1451 binding in the proband and a strong association between the proband's clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [18F]AV1451PET.Conclusion:Our study supports the usefulness of [18F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations.

scholarly journals de novo MAPT mutation G335A causes severe brain atrophy, 3R and 4R PHF-tau pathology and early onset frontotemporal dementia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Kunie Ando ◽  
Lorenzo Ferlini ◽  
Valérie Suain ◽  
Zehra Yilmaz ◽  
Salwa Mansour ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Brain Atrophy ◽  
Early Onset ◽  
De Novo ◽  
Tau Pathology ◽  
Mapt Mutation

scholarly journals Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer's disease

2020 ◽  
Author(s):  
Julia Klein ◽  
Xinyu Yan ◽  
Aubrey Johnson ◽  
Zeljko Tomljanovic ◽  
James Zou ◽  
...  
Keyword(s):  
Brain Mri ◽  
Temporal Cortex ◽  
Posterior Cingulate Cortex ◽  
Cognitive Status ◽  
Odor Identification ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Olfactory Impairment ◽  
T Tau

Background: Olfactory impairment is evident in Alzheimers disease (AD), however, its precise relationships with in vivo measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET and fifty-three underwent 11C-PBR28 PET to measure tau pathology and neuroinflammation, respectively. Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau) and beta;-amyloid (AB42). Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01). Conclusions: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. That amyloid-positivity and cognitive impairment are independently associated with odor identification suggests that low UPSIT performance may signify risk of AD pathophysiology in cognitively normal individuals and that impaired odor identification is associated with AD and non-AD-related neurodegeneration.

scholarly journals Neuroinflammation predicts disease progression in progressive supranuclear palsy

2020 ◽  
Author(s):  
Maura Malpetti ◽  
Luca Passamonti ◽  
P. Simon Jones ◽  
Duncan Street ◽  
Timothy Rittman ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Disease Progression ◽  
Brain Atrophy ◽  
Rating Scale ◽  
Neuronal Loss ◽  
Principal Component ◽  
Rate Of Change ◽  
Tau Pathology ◽  
Clinical Progression

Objective: In addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). We test the hypotheses that baseline in vivo assessments of regional neuroinflammation ([11C]PK11195 PET), tau pathology ([18F]AV-1451 PET), and atrophy (structural MRI) predict disease progression. Methods: Seventeen patients with PSP-Richardson′s syndrome underwent a baseline multi-modal imaging assessment. Disease severity was measured at baseline and serially up to 4 years with the PSP-rating-scale (average interval 5 months). Regional grey-matter volumes and PET ligand binding potentials were summarised by three Principal Component Analyses (PCAs). A linear mixed effects model was applied to the longitudinal PSP-rating-scale scores. Single-modality imaging predictors were regressed against the individuals′ estimated rate of progression to identify the prognostic value of baseline imaging markers. Results: The PCA factors reflecting neuroinflammation and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of change in the PSP-rating-scale. PCA-derived PET markers of neuroinflammation and tau pathology correlated with brain atrophy in the same regions. However, MRI markers of brain atrophy alone did not predict clinical progression. Conclusions: Molecular imaging with PET can predict clinical progression in PSP. These data encourage the evaluation of immunomodulatory approaches to disease-modifying therapies in PSP, and the potential for PET to stratify patients for early phase clinical trials.

scholarly journals High–Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo

2016 ◽  
Vol 186 (10) ◽  
pp. 2709-2722 ◽  
Author(s):  
Emilie Audouard ◽  
Sarah Houben ◽  
Caterina Masaracchia ◽  
Zehra Yilmaz ◽  
Valérie Suain ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Wild Type Mouse ◽  
Paired Helical Filaments ◽  
Wild Type ◽  
Tau Pathology ◽  
Alzheimer Brain

scholarly journals Microglial activation and tau burden predict cognitive decline in Alzheimer’s Disease

2019 ◽  
Author(s):  
Maura Malpetti ◽  
Rogier A. Kievit ◽  
Luca Passamonti ◽  
P. Simon Jones ◽  
Kamen A. Tsvetanov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Predictive Model ◽  
Brain Atrophy ◽  
Grey Matter ◽  
Imaging Modality ◽  
Structural Mri ◽  
Tau Pathology ◽  
Single Modality

AbstractTau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer’s disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, we studied how baseline assessments of in vivo tau pathology (measured by [18F]AV-1451 PET), neuroinflammation (indexed via [11C]PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer’s disease pathology. Twenty-six patients (n=12 with clinically probable Alzheimer’s dementia and n=14 with amyloid positive Mild Cognitive Impairment) and 29 healthy controls underwent baseline assessment with [18F]AV-1451 PET, [11C]PK11195 PET, and structural MRI. Cognition was examined annually over the subsequent 3 years using the revised Addenbrooke’s Cognitive Examination. Regional grey-matter volumes, [18F]AV-1451 and [11C]PK11195 binding were derived from fifteen temporo-parietal regions characteristically affected by Alzheimer’s disease pathology. A Principal Component Analysis (PCA) was used on each imaging modality separately, to identify the main spatial distributions of pathology. A Latent Growth Curve model was applied across the whole sample on longitudinal cognitive scores to estimate the rate of annual decline in each participant. We regressed the individuals’ estimated slope of cognitive decline on the neuroimaging components and examined univariable models with single-modality predictors, and a multi-modality model of prediction, to identify the independent and combined prognostic value of the different neuroimaging markers.PCA identified a single component for the grey-matter atrophy, while two components were found for each PET ligand: one weighted to the anterior temporal lobe, and another weighted to posterior temporo-parietal regions. Across the whole-sample, the single-modality models indicated significant correlations between the slope of cognitive decline and the first component of each imaging modality. In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of [18F]AV-1451 and the first (i.e., anterior temporal) component for [11C]PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline. We conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer’s disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer’s disease, over and above MRI measures of brain atrophy and demographic data. Our findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer’s Disease.

scholarly journals Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum

Neurology ◽  
2018 ◽  
Vol 90 (14) ◽  
pp. e1231-e1239 ◽  
Author(s):  
Lieke H.H. Meeter ◽  
Everard G. Vijverberg ◽  
Marta Del Campo ◽  
Annemieke J.M. Rozemuller ◽  
Laura Donker Kaat ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Corticobasal Syndrome ◽  
Class Iii ◽  
Tau Pathology ◽  
Clinical Value ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Semantic Variant ◽  
T Tau

ObjectiveTo examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort.MethodsCSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS).ResultsNfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau).ConclusionNfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo.Classification of evidenceThis study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders.

scholarly journals Integrated 18F-T807 Tau PET, Structural MRI, and Plasma Tau in Tauopathy Neurodegenerative Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Cheng-Hsuan Li ◽  
Ta-Fu Chen ◽  
Ming-Jang Chiu ◽  
Ruoh-Fang Yen ◽  
Ming-Chieh Shih ◽  
...  
Keyword(s):  
Brain Mri ◽  
Standard Uptake Value ◽  
Structural Mri ◽  
Tracer Uptake ◽  
Cortical Atrophy ◽  
Clinical Assessments ◽  
Positron Emission ◽  
Tau Pet ◽  
And Control

Background and Objective: Tau-specific positron emission topography (PET) imaging enables in vivo assessment of Alzheimer's disease (AD). We aimed to investigate its performance in combination with plasma tau levels in patients with non-AD tauopathy.Methods: A total of 47 participants were enrolled, including 10 healthy controls, 16 with tauopathy parkinsonism syndromes (9 with corticobasal syndrome [CBS], 7 with progressive supranuclear palsy [PSP]), 9 with frontotemporal dementia (FTD), 4 with AD, and 8 with Parkinson's disease (PD). All participants underwent clinical assessments, 18F-T807 tau PET, brain MRI, and plasma tau assay.Results: The global cortical standard uptake value ratio (SUVR) of 18F-T807 PET was comparable between PD and control (p = 0.088). The cortical SUVR was significantly higher in AD group (p = 0.002) but was modestly increased in PSP group compared to the PD group (p = 0.044), especially in parietal and pallidal regions. Asymmetric 18F-T807 uptake at the pallidum was noted in patients with CBS and FTD. Cortical tau tracer uptake was associated with increased plasma total tau level (p = 0.016), especially in frontal and parietal regions. Regional tracer uptake was correlated with cortical thinning in patients with CBS and PSP (CBS: r = −0.092, p = 0.025; PSP: r = −0.114, p = 0.015).Conclusions: The 18F-T807 tau tracer uptake was only modestly increased in patients with PSP. Although the cortical tau tracer uptake correlated with regional cortical atrophy and plasma tau levels, a four-repeated tau-specific tracer is needed for future classifying tauopathy parkinsonism syndromes.

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Glycogen Synthase ◽  
Paired Helical Filaments ◽  
Tau Hyperphosphorylation ◽  
Microtubule Stabilization ◽  
Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 &#946; (GSK3&#946;), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer&#039;s disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

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