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 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 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 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 [11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy

Neurology ◽  
2018 ◽  
Vol 90 (22) ◽  
pp. e1989-e1996 ◽  
Author(s):  
Luca Passamonti ◽  
Patricia Vázquez Rodríguez ◽  
Young T. Hong ◽  
Kieren S.J. Allinson ◽  
W. Richard Bevan-Jones ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Progressive Supranuclear Palsy ◽  
Medial Temporal Lobe ◽  
Microglial Activation ◽  
Case Control Study ◽  
Pet Scanning ◽  
Study Participants ◽  
Parietal Cortices ◽  
Control Study

ObjectiveWe tested whether in vivo neuroinflammation relates to the distinctive distributions of pathology in Alzheimer disease (AD) and progressive supranuclear palsy (PSP).MethodsSixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-positive PET scan), 16 patients with PSP–Richardson syndrome, and 13 age-, sex-, and education-matched healthy controls were included in this case-control study. Participants underwent [11C]PK11195 PET scanning, which was used as an in vivo index of neuroinflammation.Results[11C]PK11195 binding in the medial temporal lobe and occipital, temporal, and parietal cortices was increased in patients with AD, relative both to patients with PSP and to controls. Compared to controls, patients with PSP showed elevated [11C]PK11195 binding in the thalamus, putamen, and pallidum. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory impairment in AD, while [11C]PK11195 binding in the pallidum, midbrain, and pons correlated with disease severity in PSP.ConclusionsTogether, our results suggest that neuroinflammation has an important pathogenic role in the 2 very different human neurodegenerative disorders of AD and PSP. The increase and distribution of microglial activation suggest that immunotherapeutic strategies may be useful in slowing the progression of both diseases.

In vivo comparison of Richardson’s syndrome and progressive supranuclear palsy-parkinsonism

2011 ◽  
Vol 118 (8) ◽  
pp. 1191-1197 ◽  
Author(s):  
Karin Srulijes ◽  
Grit Mallien ◽  
Sarah Bauer ◽  
Elisabeth Dietzel ◽  
Adriane Gröger ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Richardson’S Syndrome

scholarly journals In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease

2010 ◽  
Vol 38 (2) ◽  
pp. 343-351 ◽  
Author(s):  
Masamichi Yokokura ◽  
Norio Mori ◽  
Shunsuke Yagi ◽  
Etsuji Yoshikawa ◽  
Mitsuru Kikuchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Brain Regions ◽  
Amyloid Deposits

scholarly journals Tau seeding activity anticipates phospho-tau pathology in Alzheimer’s disease

2018 ◽  
Author(s):  
Sarah K. Kaufman ◽  
Kelly Del Tredici ◽  
Talitha L. Thomas ◽  
Heiko Braak ◽  
Marc I. Diamond
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Brain Regions ◽  
Tau Pathology ◽  
Age Related ◽  
Important Addition ◽  
Disease Stages ◽  
Relationship Of ◽  
The Relationship

AbstractAlzheimer’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n=247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the first temporal gyrus and visual cortex at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC, and may offer an important addition to classical histopathology.

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.

Falling All the Time

2016 ◽  
Author(s):  
Richard A. Walsh
Keyword(s):  
Cognitive Impairment ◽  
Progressive Supranuclear Palsy ◽  
Postmortem Examination ◽  
Tau Pathology ◽  
Disease Modifying Therapies ◽  
Clinical Syndromes ◽  
Advanced Stages ◽  
Disease Modifying ◽  
Richardson’S Syndrome ◽  
Gaze Palsy

Progressive supranuclear palsy is a four-repeat tauopathy that is confirmed, like all neurodegenerative disease, at postmortem examination. An expanding group of clinical syndromes are now linked with this pathology in its early stages, although with disease progression there tends to be greater clinical similarity with the classical Richardson’s syndrome, an akinetic rigid form of parkinsonism with a progressive supranuclear gaze palsy and prominent frontal cognitive impairment. Currently, there are no disease-modifying therapies for progressive supranuclear palsy; however, there continues to be interest in immunotherapies targeted at tau pathology. Liaison with colleagues with an interest in palliative neurology is appropriate for patients in the advanced stages of the disease.

scholarly journals Prognostic importance of apathy in syndromes associated with frontotemporal lobar degeneration

Neurology ◽  
2019 ◽  
Vol 92 (14) ◽  
pp. e1547-e1557 ◽  
Author(s):  
Claire J. Lansdall ◽  
Ian T.S. Coyle-Gilchrist ◽  
Patricia Vázquez Rodríguez ◽  
Alicia Wilcox ◽  
Eileen Wehmann ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Behavioral Change ◽  
Behavioral Assessment ◽  
Principal Component ◽  
Neuropsychiatric Inventory ◽  
Behavioral Measures ◽  
Measurement Tools ◽  
Patient Groups ◽  
Prognostic Importance ◽  
The Relationship

ObjectiveTo determine the influence of apathy, impulsivity, and behavioral change on survival in patients with frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome.MethodsWe assessed 124 patients from the epidemiologic PiPPIN (Pick's Disease and Progressive Supranuclear Palsy, Prevalence and Incidence) study. Patients underwent detailed baseline cognitive and behavioral assessment focusing on apathy, impulsivity, and behavioral change. Logistic regression identified predictors of death within 2.5 years from assessment, including age, sex, diagnosis, cognition, and 8 neurobehavioral profiles derived from a principal component analysis of neuropsychological and behavioral measures.ResultsAn apathetic neurobehavioral profile predicted death (Wald statistic = 8.119,p= 0.004, Exp(B) = 2.912, confidence interval = >1 [1.396–6.075]) and was elevated in all patient groups. This profile represented apathy, weighted strongly to carer reports from the Apathy Evaluation Scale, Neuropsychiatric Inventory, and Cambridge Behavioral Inventory. Age at assessment, sex, and global cognitive impairment were not significant predictors. Differences in mortality risk across diagnostic groups were accounted for by their neuropsychiatric and behavioral features.ConclusionsThe relationship between apathy and survival highlights the need to develop more effective and targeted measurement tools to improve its recognition and facilitate treatment. The prognostic importance of apathy suggests that neurobehavioral features might be useful to predict survival and stratify patients for interventional trials. Effective symptomatic interventions targeting the neurobiology of apathy might ultimately also improve prognosis.

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