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 Neuroinflammation predicts disease progression in progressive supranuclear palsy

2021 ◽  
pp. jnnp-2020-325549
Author(s):  
Maura Malpetti ◽  
Luca Passamonti ◽  
Peter Simon Jones ◽  
Duncan Street ◽  
Timothy Rittman ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
In Vivo Imaging ◽  
Prognostic Value ◽  
Microglial Activation ◽  
Rating Scale ◽  
Rate Of Change ◽  
Tau Pathology ◽  
Clinical Progression ◽  
Imaging Markers

IntroductionIn addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). However, the prognostic value of the in vivo imaging markers for these processes in PSP remains unclear. We test the primary hypothesis that baseline in vivo imaging assessment of neuroinflammation in subcortical regions predicts clinical progression in patients with PSP.MethodsSeventeen patients with PSP–Richardson’s syndrome underwent a baseline multimodal imaging assessment, including [11C]PK11195 positron emission tomography (PET) to index microglial activation, [18F]AV-1451 PET for tau pathology and structural MRI. Disease severity was measured at baseline and serially up to 4 years with the Progressive Supranuclear Palsy Rating Scale (PSPRS) (average interval of 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 PSPRS scores. Single-modality imaging predictors were regressed against the individuals’ estimated rate of progression to identify the prognostic value of baseline imaging markers.ResultsPCA components reflecting neuroinflammation and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of change in the PSPRS. PCA-derived PET markers of neuroinflammation and tau pathology correlated with regional brain volume in the same regions. However, MRI volumes alone did not predict the rate of clinical progression.ConclusionsMolecular imaging with PET for microglial activation and tau pathology 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 in early phase clinical trials.

scholarly journals PET markers of tau and neuroinflammation are co-localized in progressive supranuclear palsy

2019 ◽  
Author(s):  
Maura Malpetti ◽  
Luca Passamonti ◽  
Timothy Rittman ◽  
P. Simon Jones ◽  
Patricia Vázquez Rodríguez ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Microglial Activation ◽  
Principal Component ◽  
Brain Regions ◽  
Clinical Severity ◽  
Binding Potential ◽  
Tau Pathology ◽  
Richardson’S Syndrome ◽  
The Relationship

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is associated with tau-protein aggregation and neuroinflammation, but it remains unclear whether these pathogenic processes are related in vivo.ObjectivesWe examined the relationship between tau pathology and microglial activation using [18F]AV-1451 (indexing tau burden) and [11C]PK11195 (microglial activation) PET in n=17 patients with PSP-Richardson’s syndrome.MethodsNon-displaceable binding potential (BPND) for each ligand was quantified in 83 regions of interest (ROIs). [18F]AV-1451 and [11C]PK11195 BPND values were correlated across all ROIs. The anatomical patterns of [18F]AV-1451 and [11C]PK11195 binding co-localization was determined across sets of regions derived from principal component analyses (PCAs). Finally, PCA-derived brain patterns of tau pathology and neuroinflammation were linked to clinical severity.Results[18F]AV-1451 and [11C]PK11195 binding were positively related across all ROIs (r=0.577, p<0.0001). PCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [18F]AV-1451 and [11C]PK11195 components were found in sub-cortical (r=0.769, p<0.0001) and cortical components(r=0.836, p<0.0001). PCA-derived components reflecting tau burden (r=0.599, p=0.011) and neuroinflammation (r=0.713, p=0.001) in sub-cortical areas related to disease severity.ConclusionsWe show that tau pathology and neuroinflammation co-localize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine how these molecular pathologies are causally linked, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP.

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 P62 accumulates through neuroanatomical circuits in response to tauopathy propagation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
François-Xavier Blaudin de Thé ◽  
Benjamin Lassus ◽  
Ari W. Schaler ◽  
Stephanie L. Fowler ◽  
Chris N. Goulbourne ◽  
...  
Keyword(s):  
Disease Progression ◽  
Brain Regions ◽  
In Vitro Models ◽  
Tau Pathology ◽  
Neuron Models ◽  
Protein Clearance ◽  
Underlying Mechanisms ◽  
Tau Aggregation

AbstractIn Alzheimer’s disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models, we examined the relationship between these two processes and neuronal clearance. Accumulation of p62 (a marker of defective protein clearance) correlated with pathological tau accumulation in two mouse models of tauopathy spread; Entorhinal Cortex-tau (EC-Tau) mice where tau pathology progresses in time from EC to other brain regions, and PS19 mice injected with tau seeds. In both models and in several brain regions, p62 colocalized with human tau in a pathological conformation (MC1 antibody). In EC-Tau mice, p62 accumulated before overt tau pathology had developed and was associated with the presence of aggregation-competent tau seeds identified using a FRET-based assay. Furthermore, p62 accumulated in the cytoplasm of neurons in the dentate gyrus of EC-Tau mice prior to the appearance of MC1 positive tauopathy. However, MC1 positive tau was shown to be present at the synapse and to colocalize with p62 as shown by immuno electron microscopy. In vitro, p62 colocalized with tau inclusions in two primary cortical neuron models of tau pathology. In a three-chamber microfluidic device containing neurons overexpressing fluorescent tau, seeding of tau in the donor chamber led to tau pathology spread and p62 accumulation in both the donor and the recipient chamber. Overall, these data are in accordance with the hypothesis that the accumulation and trans-synaptic spread of pathological tau disrupts clearance mechanisms, preceding the appearance of obvious tau aggregation. A vicious cycle of tau accumulation and clearance deficit would be expected to feed-forward and exacerbate disease progression across neuronal circuits in human tauopathies.

scholarly journals Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies

2021 ◽  
Vol 3 (4) ◽  
Author(s):  
Toshiki Tezuka ◽  
Keisuke Takahata ◽  
Morinobu Seki ◽  
Hajime Tabuchi ◽  
Yuki Momota ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Progressive Supranuclear Palsy ◽  
Standardized Uptake Value ◽  
Corticobasal Degeneration ◽  
Post Injection ◽  
Healthy Controls ◽  
Tau Pathology ◽  
Tau Pet

Abstract Tau aggregates represent a key pathologic feature of Alzheimer’s disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer’s disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer’s disease and non-Alzheimer’s disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer’s disease tauopathies compared with Alzheimer’s disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer’s disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment and [18F]PI-2620 PET (Image acquisition at 60–90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer’s disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer’s disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer’s disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer’s disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60–90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer’s disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer’s disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer’s disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer’s disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline

2021 ◽  
pp. 1-13
Author(s):  
Luwen Wang ◽  
Mengyu Liu ◽  
Ju Gao ◽  
Amber M. Smith ◽  
Hisashi Fujioka ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Loss ◽  
Mitochondrial Fusion ◽  
Barnes Maze ◽  
Mitochondrial Fragmentation ◽  
Tau Pathology ◽  
Marked Suppression

Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer’s disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.

scholarly journals A COMBINED MEASURE OF COGNITION AND FUNCTION FOR CLINICAL TRIALS: THE INTEGRATED ALZHEIMER’S DISEASE RATING SCALE (IADRS)

2015 ◽  
pp. 1-15
Author(s):  
A.M. Wessels ◽  
E.R. Siemers ◽  
P. Yu ◽  
S.W. Andersen ◽  
K.C. Holdridge ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Psychometric Properties ◽  
Disease Progression ◽  
Treatment Effects ◽  
Rating Scale ◽  
Principal Component ◽  
Disease Assessment ◽  
Disease Rating ◽  
Better Than

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer’s disease (AD) are needed. The integrated Alzheimer’s Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS – mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents.

scholarly journals Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity

2020 ◽  
Author(s):  
Sanne Simone Kaalund ◽  
Luca Passamonti ◽  
Kieren SJ Allinson ◽  
Alexander G Murley ◽  
Trevor W Robbins ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Progressive Supranuclear Palsy ◽  
Disease Severity ◽  
Neuronal Loss ◽  
Clinical Severity ◽  
Adaptive Behaviour ◽  
Clinical Heterogeneity ◽  
Tau Pathology ◽  
Wide Range ◽  
Richardson’S Syndrome

AbstractThe locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

scholarly journals Neuroprotective effect of mitochondrial translocator protein ligand in a mouse model of tauopathy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lauren H. Fairley ◽  
Naruhiko Sahara ◽  
Ichio Aoki ◽  
Bin Ji ◽  
Tetsuya Suhara ◽  
...  
Keyword(s):  
Brain Atrophy ◽  
Calcium Binding ◽  
Neuroprotective Effect ◽  
Neuronal Loss ◽  
Protective Role ◽  
Translocator Protein ◽  
Amyloid Peptide ◽  
Positron Emission

Abstract Background The translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer’s disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer’s beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg). Methods Brain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice. Results TSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy. Conclusions These findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy.

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