Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy
Open accessPublished version of a preprint
Abstract
Objective: We examined the relationship between tau pathology and neuroinflammation using [ 11 C]PK11195 and [ 18 F]AV‐1451 PET in 17 patients with progressive supranuclear palsy (PSP) Richardson's syndrome. We tested the hypothesis that neuroinflammation and tau protein aggregation colocalize macroscopically, and correlate with clinical severity. Methods: Nondisplaceable binding potential (BP ND ) for each ligand was quantified in 83 regions of interest (ROIs). The [ 11 C]PK11195 and [ 18 F]AV‐1451 BP ND values were correlated across all regions. The spatial distributions of [ 11 C]PK11195 and [ 18 F]AV‐1451 binding were determined by principal component analyses (PCAs), and the loading of each spatial component compared against the patients’ clinical severity (using the PSP rating scale). Results: Regional [ 11 C]PK11195 and [ 18 F]AV‐1451 binding were positively correlated (R = 0.577, p < 0.0001). The PCA identified 4 components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [ 11 C]PK11195 and [ 18 F]AV‐1451 components’ loadings were found in both subcortical (R = 0.769, p < 0.0001) and cortical regions (R = 0.836, p < 0.0001). There were positive correlations between clinical severity and both subcortical tau pathology (R = 0.667, p = 0.003) and neuroinflammation (R = 0.788, p < 0.001). Interpretation: We show that tau pathology and neuroinflammation colocalize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine causal associations between these molecular pathologies, we suggest that the combination of tau‐ and immune‐oriented strategies may be useful for effective disease‐modifying treatments in PSP. ANN NEUROL 2020;88:1194–1204
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- Findingown data
Clinical severity was positively correlated with neuroinflammation.
“There were positive correlations between clinical severity and both sub-cortical tau pathology (R=0.667, p=0.003) and neuroinflammation (R=0.788, p<0.001).”
Quote in the paperSubstantial claim - Findingown data
Similar results were obtained when using the closest raw PSP-RS to the PET scans as the clinical severity measure.
“Similar results were obtained using the closest raw PSP-RS to the PET scans as clinical severity measure.”
Quote in the paperNot a substantial claim - Findingown data
Principal component analysis of [11C]PK11195 BPND yielded four components that together accounted for 81.4% of the variance.
“For [11C]PK11195 BPND, four components were identified which collectively explained 81.4% of the data variance (Figure 3, left panel).”
Quote in the paperNot a substantial claim - Findingown data
Clinical severity was positively correlated with subcortical tau pathology.
“There were positive correlations between clinical severity and both sub-cortical tau pathology (R=0.667, p=0.003) and neuroinflammation (R=0.788, p<0.001).”
Quote in the paperSubstantial claim - Findingown data
The interaction between [11C]PK11195 component #3 and [18F]AV-1451 component #4 did not significantly predict PSP-RS.
“We then applied a linear model to test whether the interaction between [11C]PK11195 component #3 and [18F]AV-1451 component #4 predicts PSP-RS. The interaction term was not significant in the model with the estimated PSP-RS score, adjusted to the time midway between the PET scans (p=0.883).”
- Also stated in: § Discussion · plain
“In our sample, although the two components individually correlate with clinical severity, they did not interact in their association with PSP-RS.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Imputed PSP-RS scores at the time of PET correlated highly with the nearest actual PSP-RS assessment for both [11C]PK11195 and [18F]AV-1451.
“The imputed PSP-RS scores for the time of PET correlated highly with the nearest actual PSP-RS assessment ([11C]PK11195, R=0.948, 95% CI= 0.858 to 0.981, p<0.0001; and [18F]AV-1451, R=0.965, 95% CI= 0.902 to 0.987, p<0.0001).”
Quote in the paperSubstantial claim - Findingown data
The correlations between those components and disease severity remained significant after correcting for age, education and sex.
“These correlations remained significant after correcting for age, education and sex ([11C]PK11195 #3: R=0.773, 95% CI= 0.464 to 0.914, p=0.001; [18F]AV-1451 #4: R=0.671, 95% CI= 0.280 to 0.871, p=0.009).”
Quote in the paperSubstantial claim - Findingown data
Both [11C]PK11195 component #3 and [18F]AV-1451 component #4 positively correlated with disease severity when using imputed PSP-RS at the time of PET.
“Considering the imputed PSP-RS at the time of the PET scans, both [11C]PK11195 component #3 (R=0.788, 95% CI= 0.496 to 0.920, p<0.001) and [18F]AV-1451 component #4 (R=0.667, 95% CI= 0.275 to 0.869, p=0.003) positively correlated with disease severity (Figure 5).”
- Also stated in: § Discussion · plain
“Of note, both tau pathology and microglial activation in the brainstem-cerebellar component correlated with disease severity, using either the imputed PSP-RS scores for time of PET scans (Figure 5) or the score of the closest PSP-RS assessment to PET scans.”
- Also stated in: § Discussion · plain
“The in vivo measures of neuroinflammation and tau burden in the brainstem and cerebellum were both associated with disease severity.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Individual PCA-derived scores for ligand-specific subcortical components separately correlated with disease severity as measured by PSP-RS.
“The individual PCA-derived scores for ligand-specific subcortical components separately correlated with disease severity (PSP-RS) (Figure 5).”
Quote in the paperSubstantial claim - Findingown data
The second component of [11C]PK11195 binding was positively correlated with the second component of [18F]AV-1451 binding.
“[11C]PK11195 component #2 positively correlated with [18F]AV-1451 component #2 (R=0.836, 95% CI= 0.594 to 0.939, p<0.001)”
Quote in the paperSubstantial claim - Findingown data
Principal component analysis of [18F]AV-1451 BPND yielded four components that together accounted for 81.8% of the variance.
“Likewise, four components were found for [18F]AV-1451 BPND which explained together 81.8% of the data variance (Figure 3, right panel).”
Quote in the paperNot a substantial claim - Findingown data
Across the whole brain in PSP, regional [11C]PK11195 binding and [18F]AV-1451 binding are positively associated.
“Regional [11C]PK11195 and [18F]AV-1451 binding were positively correlated (R=0.577, p<0.0001).”
- Also stated in: § Regional [11C]PK11195 and [18F]AV-1451 BPND in PSP · plain
“Regional group mean [11C]PK11195 BPND correlated with the corresponding [18F]AV-1451 BPND across the whole brain (R=0.577, p<0.0001) (Figure 2A).”
- Also stated in: § Regional [11C]PK11195 and [18F]AV-1451 BPND in PSP · plain
“In this model, the effect of [11C]PK11195 on [18F]AV-1451 regional values at group level (fixed effect) was significant (Estimate=0.685, SD=0.053, Std Beta=0.550, 95% CI: 0.47 to 0.63, p = 2.2e-16, perm-p= 0.001) (Figure 2B).”
Quote in the paperSubstantial claim - Also stated in: § Regional [11C]PK11195 and [18F]AV-1451 BPND in PSP · plain
- Findingown data
The third component of [11C]PK11195 binding was positively correlated with the fourth component of [18F]AV-1451 binding.
“[11C]PK11195 component #3 positively correlated with [18F]AV-1451 component #4 (R=0.769, 95% CI= 0.458 to 0.913, p<0.001)”
Quote in the paperSubstantial claim - Findingown data
There is a positive correlation between [11C]PK11195 and [18F]AV-1451 binding in brainstem and cerebellar regions, loaded into anatomically overlapping components of both ligands.
“When assessing the ligand-specific components from principal component analysis, we found a positive correlation between [11C]PK11195 and [18F]AV-1451 binding in brainstem and cerebellar regions, loaded into anatomically overlapping components of both ligands (Figure 4, right panel).”
Quote in the paperSubstantial claim - Findingown data
[11C]PK11195 and [18F]AV-1451 binding were correlated in a cortical component weighted towards the medial temporal lobe, insula, and temporo-parietal junction.
“[11C]PK11195 and [18F]AV-1451 binding were also correlated in a cortical component (Figure 4, left panel), which for both ligands was weighted towards regions of the medial temporal lobe, insula and temporo-parietal junction.”
Quote in the paperSubstantial claim - Findingown data
There is a positive correlation at group level between [11C]PK11195 and [18F]AV-1451 binding across the whole brain, which remained significant after accounting for variability between patients.
“With the first approach, we found a positive correlation at group level between [11C]PK11195 and [18F]AV-1451 binding across the whole brain (Figure 2A), which remained significant also after accounting for the variability between patients (Figure 2B).”
Quote in the paperSubstantial claim - Premisecitation
In PSP-Richardson's syndrome, the correlation between clinical and pathological findings is very strong.
“the clinical-pathological correlation in PSP-Richardson’s syndrome is very high22”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Gazzina S Respondek G Compta Y Neuropathological validation of the MDS-PSP criteria with PSP and other frontotemporal lobar degeneration bioRxiv [online serial] Epub 2019, 520510 10.1101/520510v1.abstract
Not checked in the free run.
- Premisecitation
The co-localization resembles that observed between protein aggregation and microglial activation in Tau- and TDP43-associated forms of frontotemporal lobar degeneration.
“This co-localization resembles that observed between protein aggregation and microglial activation in both Tau- and TDP43-associated forms of frontotemporal lobar degeneration observed by post mortem immunohistochemistry and in vivo with the ligands used in this PET study7.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Bevan-Jones WR Cope TE Jones PS Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum Brain 2020 143 1010 1026 32179883 PMC7089669 source
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- Interpretationown data
In PSP, individual variation in subcortical tau pathology and neuroinflammation is associated with clinical severity.
“individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity”
Quote in the paperSubstantial claim- Rests on an assumption: The ligand [18F]AV-1451 cannot differentiate tau pathology from TDP43 pathology.
- Rests on an assumption: [11C]PK11195 targets the translocator protein on mitochondria of activated microglia.
- Rests on an assumption: Common genetic polymorphisms that influence second-generation TSPO ligands do not substantially affect [11C]PK11195.
- Rests on an assumption: Substantial TDP43 pathology is very uncommon in PSP.
- Premisecitation
[11C]PK11195 is commonly employed as an indicator of microglial activation in neurodegenerative conditions, including PSP.
“[11C]PK11195 is widely used as a marker of microglial activation in neurodegenerative diseases23, including PSP17,18.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [23] Stefaniak J O’Brien J Imaging of neuroinflammation in dementia: a review J Neurol Neurosurg Psychiatry [online serial] 2015 87 jnnp-2015-311336 10.1136/jnnp-2015-311336 26384512
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- cites [17] Gerhard A Trender-Gerhard I Turkheimer F Quinn NP Bhatia KP Brooks DJ In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy Mov Disord 2006 21 89 93 16108021 source
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- cites [18] Passamonti L Rodríguez PV Hong YT [11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy Neurology [online serial] 2018 90 e1989 e1996 10.1212/WNL.0000000000005610 PMC5980519 29703774 source
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- Interpretationown data
Microglial activation and tau protein aggregation are co-localized macroscopically in PSP.
“This study suggests that microglial activation and tau protein aggregation are co-localized in PSP, macroscopically.”
- Also stated in: § Discussion · hedged
“Our findings indicate a macroscopic anatomical relationship between neuroinflammation and tau pathology.”
- Also stated in: § Discussion · boosted
“To conclude, our results confirm the relevance of neuroinflammation to PSP-Richardson’s syndrome and a close association with tau pathology.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Premisecitation
Earlier PET investigations have detected alterations in PSP with ligands for tau and for microglial activation.
“Previous positron emission tomography (PET) has indicated changes in PSP using ligands targeting tau8–16 and microglial activation17,18.”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [8] Passamonti L Vázquez Rodríguez P Hong YT 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy Brain Epub 2017.:aww340 PMC5382948 28122879
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- cites [9] Cho H Choi JY Hwang MS Subcortical 18F-AV-1451 binding patterns in progressive supranuclear palsy Mov Disord 2017 32 134 140 27813160 source
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- cites [10] Hammes J Bischof GN Giehl K Elevated in vivo [18F]-AV-1451 uptake in a patient with progressive supranuclear palsy Mov Disord 2017 32 170 171 27476874 source
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- cites [11] Kepe V Bordelon Y Boxer A PET imaging of neuropathology in tauopathies: progressive supranuclear palsy J Alzheimers Dis 2013 36 145 153 23579330 PMC3674205 source
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- cites [12] Ishiki a Harada R Okamura N Tau imaging with [18F]THK-5351 in progressive supranuclear palsy Eur J Neurol 2017 24 130 136 27797445 source
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- cites [13] Smith R Schain M Nilsson C Increased basal ganglia binding of 18F-AV-1451 in patients with progressive supranuclear palsy Mov Disord 2017 32 108 114 27709757 PMC6204612 source
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- cites [14] Whitwell JL Lowe VJ Tosakulwong N [18F]AV-1451 tau positron emission tomography in progressive supranuclear palsy Mov Disord 2017 32 124 133 27787958 PMC5552410 source
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- cites [15] Brendel M Schönecker S Höglinger G [18F]-THK5351 PET Correlates with Topology and Symptom Severity in Progressive Supranuclear Palsy Front Aging Neurosci 2018 9 1 12 PMC5776329 29387005 source
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- cites [16] Schonhaut DR McMillan CT Spina S 18F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study Ann Neurol 2017 82 622 634 28980714 PMC5665658 source
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- cites [17] Gerhard A Trender-Gerhard I Turkheimer F Quinn NP Bhatia KP Brooks DJ In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy Mov Disord 2006 21 89 93 16108021 source
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- Premisecitation
In PSP, the superior cerebellar cortex grey matter contains little tau pathology.
“This cerebellar region was selected as reference region given post-mortem evidence showing minimal tau pathology in PSP8.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Passamonti L Vázquez Rodríguez P Hong YT 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy Brain Epub 2017.:aww340 PMC5382948 28122879
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- Study design and conductown data
Patients scanned on the two PET scanners did not differ in demographic or clinical features.
“These two groups did not differ in demographic or clinical characteristics (p>0.05).”
Quote in the paperSubstantial claim - Interpretationown data
In PSP, tau pathology and neuroinflammation are co-localized.
“We show that tau pathology and neuroinflammation co-localize in PSP”
Quote in the paperSubstantial claim- Rests on an assumption: The ligand [18F]AV-1451 cannot differentiate tau pathology from TDP43 pathology.
- Rests on an assumption: [11C]PK11195 targets the translocator protein on mitochondria of activated microglia.
- Rests on an assumption: Common genetic polymorphisms that influence second-generation TSPO ligands do not substantially affect [11C]PK11195.
- Rests on an assumption: Substantial TDP43 pathology is very uncommon in PSP.
- Premisecitation
[18F]AV-1451 shows a distinct anatomical binding pattern that separates PSP from Alzheimer's disease.
“[18F]AV-1451 displays a specific anatomical pattern of binding that clearly distinguishes PSP from AD8.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Passamonti L Vázquez Rodríguez P Hong YT 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy Brain Epub 2017.:aww340 PMC5382948 28122879
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- Premisecitation
Microglial activation, indicating neuroinflammation, is present in PSP.
“However, neuroinflammation also occurs in PSP, with microglial activation5,6, with a proposed toxic alliance between tau-mediated neurodegeneration and neuroinflammation.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Ishizawa K Dickson DW Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration J Neuropathol Exp Neurol 2001 60 647 657 11398841 source
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- cites [6] Fernández-Botrán R Ahmed Z Crespo FA Cytokine expression and microglial activation in progressive supranuclear palsy Parkinsonism Relat Disord 2011 17 683 688 21741294 PMC3196843 source
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- Premisecitation
This association occurs in motor-related regions involved in the neuropathology and symptomatology of PSP.
“This association occurs in motor-related regions that are involved in the neuropathology and symptomatology of PSP (i.e. functional deficits, postural instability, and supranuclear gaze palsy) associated with PSP Richardson’s syndrome44.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Williams DR Lees AJ Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges Lancet Neurol [online serial] Elsevier Ltd 2009 8 270 279 10.1016/S1474-4422(09)70042-0 19233037 source
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- Premisecitation
The spatial distribution of the in vivo association between microglial activation and tau pathology in PSP mirrors previous findings that tau pathology affects both subcortical and cortical regions in PSP Richardson's syndrome.
“The spatial distribution of this in vivo association between microglial activation and tau pathology in PSP mirrors previous findings showing that tau pathology affects not only subcortical but also cortical regions in PSP Richardson’s syndrome42,43.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [42] Dickson DW Ahmed Z Algom AA Tsuboi Y Josephs KA Neuropathology of variants of progressive supranuclear palsy Curr Opin Neurol 2010 23 394 400 20610990 source
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- cites [43] Schofield EC Hodges JR Macdonald V Cordato NJ Kril JJ Halliday GM Cortical atrophy differentiates Richardson’s syndrome from the parkinsonian form of progressive supranuclear palsy Mov Disord 2011 26 256 263 21412832 source
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- Premisecitation
[11C]PK11195 has well-established methods of kinetic analysis.
“[11C]PK11195 binding is less affected by this polymorphism, and has well established methods of kinetic analysis39.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Turkheimer FE Edison P Pavese N Reference and target region modeling of [11C]-(R)-PK11195 brain studies J Nucl Med 2007 48 158 167 17204713
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- Premisecitation
Only a few previous studies have explored how [11C]PK11195 and [18F]AV-1451 binding relate to disease severity in PSP.
“This finding adds relevant information to the literature as only a few previous studies have explored how [11C]PK11195 and [18F]AV-1451 binding relate to disease severity in PSP8,9,13,14,16,18.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [8] Passamonti L Vázquez Rodríguez P Hong YT 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy Brain Epub 2017.:aww340 PMC5382948 28122879
Not checked in the free run.
- cites [9] Cho H Choi JY Hwang MS Subcortical 18F-AV-1451 binding patterns in progressive supranuclear palsy Mov Disord 2017 32 134 140 27813160 source
Not checked in the free run.
- cites [13] Smith R Schain M Nilsson C Increased basal ganglia binding of 18F-AV-1451 in patients with progressive supranuclear palsy Mov Disord 2017 32 108 114 27709757 PMC6204612 source
Not checked in the free run.
- cites [14] Whitwell JL Lowe VJ Tosakulwong N [18F]AV-1451 tau positron emission tomography in progressive supranuclear palsy Mov Disord 2017 32 124 133 27787958 PMC5552410 source
Not checked in the free run.
- cites [16] Schonhaut DR McMillan CT Spina S 18F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study Ann Neurol 2017 82 622 634 28980714 PMC5665658 source
Not checked in the free run.
- cites [18] Passamonti L Rodríguez PV Hong YT [11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy Neurology [online serial] 2018 90 e1989 e1996 10.1212/WNL.0000000000005610 PMC5980519 29703774 source
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- Interpretationown data
This indicates a close association between microglial activation and tau pathology in PSP that extensively involves subcortical and cortical regions.
“This indicates a close association between microglial activation and tau pathology in PSP that extensively involves subcortical and cortical regions.”
Quote in the paperSubstantial claim - Premisecitation
The affinity of [18F]AV-1451 for 4-repeat tau in non-AD tauopathies such as PSP is lower than its affinity for 3/4-repeat AD-related tau pathology.
“Nevertheless, we acknowledge that the affinity of [18F]AV-1451 to the 4-repeat tau in non-AD tauopathies as PSP is lower than its affinity to 3/4-repeat AD-related tau pathology29,30.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [29] Marquié M Normandin MD Vanderburg CR Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue Ann Neurol [online serial] 2015 78 787 800 PMC4900162 26344059 source
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- cites [30] Sander K Lashley T Gami P Characterization of tau positron emission tomography tracer [18F]AV-1451 binding to postmortem tissue in Alzheimer’s disease, primary tauopathies, and other dementias Alzheimer’s Dement 2016 12 1116 1124 26892233 source
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- Premisecitation
Multi-tracer PET studies support previous in vitro evidence of an association between microglial activation and tau aggregation in different tauopathies.
“Collectively, these multi-tracer PET studies support previous in vitro evidence of the association between microglial activation and tau aggregation in different tauopathies41.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Vogels T Murgoci AN Hromádka T Intersection of pathological tau and microglia at the synapse Acta Neuropathol Commun 2019 7 109 31277708 PMC6612163 source
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- Interpretationreasoning
This supports the use of [18F]AV-1451 PET to quantify and localize tau pathology in tauopathies with clear and known pathologic substrates, such as PSP.
“This supports the use of [18F]AV-1451 PET to quantify and localize tau pathology in different tauopathies with clear and known pathologic substrates, such as PSP.”
Quote in the paperSubstantial claim - Interpretationown data
Our findings indicate a macroscopic anatomical relationship between neuroinflammation and tau pathology.
“Our findings indicate a macroscopic anatomical relationship between neuroinflammation and tau pathology.”
Quote in the paperSubstantial claim - Interpretationreasoning
The absence of in vivo evidence about supramarginal atrophy may enhance the importance of the demonstrated association between neuroinflammation and tau accumulation in this region as an early biomarker of later-stage neuronal loss.
“The absence of in vivo evidence about supramarginal atrophy in the literature may enhance the importance of the demonstrated association between neuroinflammation and tau accumulation in this region as an early biomarker of later-stage neuronal loss.”
Quote in the paperNot a substantial claim - Study design and conductown data
The study had limited power due to the relatively small sample size.
“First, we acknowledge the limited power of the analyses related to the relatively small size of our sample.”
Quote in the paperNot a substantial claim - Premisecitation
The supramarginal gyrus has been described as the most affected brain region in two independent pathological cohorts of PSP Richardson's syndrome patients.
“Specifically, the supramarginal gyrus has been described as the most affected brain region in two independent pathological cohorts of patients with PSP Richardson’s syndrome43.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] Schofield EC Hodges JR Macdonald V Cordato NJ Kril JJ Halliday GM Cortical atrophy differentiates Richardson’s syndrome from the parkinsonian form of progressive supranuclear palsy Mov Disord 2011 26 256 263 21412832 source
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- Study design and conductown data
All 8 patients with post-mortem confirmation had PSP.
“However, all 8 had PSP, and over 95% of patients with a clinical diagnosis of PSP-Richardson’s syndrome have PSP pathology or related 4R-tuaopathy.”
Quote in the paperSubstantial claim - Interpretationreasoning
The association between microglial activation and tau pathology found in limbic regions may complement biological explanations of emotion-related and social deficits in PSP.
“the association between microglial activation and tau pathology we found in limbic regions may complement biological explanations of emotion-related and social deficits in PSP.”
Quote in the paperSubstantial claim - Premisecitation
The finding of tau and neuroinflammation co-localization in the cortex of PSP Richardson's syndrome patients is in keeping with previous post-mortem evidence showing tau pathology and atrophy in subcortical, limbic, and parietal regions.
“Our finding of tau and neuroinflammation co-localization in the cortex of patients with PSP Richardson’s syndrome is in keeping with previous post-mortem evidence showing tau pathology and atrophy not only in subcortical and limbic regions, but also in the parietal lobe43.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Schofield EC Hodges JR Macdonald V Cordato NJ Kril JJ Halliday GM Cortical atrophy differentiates Richardson’s syndrome from the parkinsonian form of progressive supranuclear palsy Mov Disord 2011 26 256 263 21412832 source
Not checked in the free run.
- May combine two claims. 20
- The quote only partly states this claim. 2
- Classified as probably not a substantial claim. 12
May combine two claims.
Findingown dataThe relationship between neuroinflammation and tau pathology is observed across widespread brain regions, most evidently in the insula, temporo-parietal junction, brainstem, and cerebellum.
“The relationship between neuroinflammation and tau pathology is observed across widespread brain regions, although it is most evident in a subset of cortical regions (i.e. insula and temporo-parietal junction) and subcortical structures (i.e. brainstem and cerebellum).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataWithin the basal ganglia alone, [11C]PK11195 binding showed a significant positive effect on [18F]AV-1451 binding values.
“indicated a significant effect of [11C]PK11195 on [18F]AV-1451 values in these regions (Estimate=0.426, SD=0.133, Std Beta=0.280, 95% CI: 0.11 to 0.46; ∆χ2 (1) = 8.82, p = 0.003, perm-p= 0.007)”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe ligand [18F]AV-1451 binds aggregated tau in Alzheimer's disease and, less avidly, in non-Alzheimer tauopathies.
“The latter binds to aggregated tau in Alzheimer’s disease (AD) and, with lower affinity, to non-AD tauopathies21.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Hall B Mak E Cervenka S Aigbirhio FI Rowe JB O’Brien JT In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings Ageing Res Rev [online serial] Elsevier B.V 2017 36 50 63 10.1016/j.arr.2017.03.002 28315409 source
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The quote only partly states this claim.
Study design and conductown dataThe associations between the [11C]PK11195 and [18F]AV-1451 components remained significant after adjustment for age, education, sex, the interval between PET scans, and scanner type.
“Importantly, these correlations remained significant after correcting for age, education and sex ([11C]PK11195 #2 - [18F]AV-1451 #2: R=0.781, 95% CI= 0.480 to 0.917, p<0.001; [11C]PK11195 #3 - [18F]AV-1451 #4: R=0.742, 95% CI= 0.406 to 0.901, p=0.002), or for the variability in the time interval between PET scans ([11C]PK11195 #2 - [18F]AV-1451 #2: R=0.804, 95% CI= 0.526 to 0.926, p<0.001; [11C]PK”
- Also stated in: § Correlation between [11C]PK11195 and [18F]AV-1451 principal components in PSP · plain
“The correlations also remained significant when PET scanner type (GE Advance/GE Discovery) was included as covariate ([11C]PK11195 #2 - [18F]AV-1451 #2: R=0.796, 95% CI= 0.510 to 0.923, p<0.001; [11C]PK11195 #3 - [18F]AV-1451 #4: R=0.776, 95% CI= 0.471 to 0.915, p<0.001).”
Quote in the paperSubstantial claim- Also stated in: § Correlation between [11C]PK11195 and [18F]AV-1451 principal components in PSP · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationProgressive supranuclear palsy arises from the aggregation of tau protein in neuroglial cells, most prominently in the basal ganglia, diencephalon, and brainstem.
“Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder caused by the neuro-glial aggregation of tau protein, particularly in the basal ganglia, diencephalon, and brainstem1,2.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Dickson DW Rademakers R Hutton ML Progressive supranuclear palsy: Pathology and genetics Brain Pathol 2007 17 74 82 17493041 PMC8095545 source
Not checked in the free run.
- cites [2] Kovacs GG Lukic MJ Irwin DJ Distribution patterns of tau pathology in progressive supranuclear palsy Acta Neuropathol [online serial] Springer Berlin Heidelberg 2020 140 99 119 10.1007/s00401-020-02158-2 PMC7360645 32383020 source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisenone givenPrior research has not examined whether tau pathology and microglial activation are related in vivo in PSP.
“However, previous work has not addressed whether in vivo tau pathology and microglial activation are related in PSP.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningThe two PET scanners yield effectively comparable data, as identical emission acquisition and reconstruction protocols restrict differences to attenuation correction and axial resolution.
“The use of identical emission data acquisition protocols and image reconstruction algorithms on the two scanners meant that the differences were effectively limited to the attenuation correction method (rotating rod 68Ge/68Ga transmission scan vs. a low dose CT scan) and the axial spatial resolution (6.8 mm FWHM vs. 5.1 mm FWHM).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn frontotemporal dementia, the macroscopic distributions of tau burden and microglial activation overlap.
“In the related condition of frontotemporal dementia, tau burden and microglial activation are macroscopically co-localized7.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Bevan-Jones WR Cope TE Jones PS Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum Brain 2020 143 1010 1026 32179883 PMC7089669 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataPSP patients and controls did not differ significantly in age or sex.
“There were no significant group differences in age (t(46)= -0.14, 95% CI= -4.29 to 3.74, p=0.892) or sex (X2(1)=0.230, 95% CI= -0.20 to 0.34, p=0.632).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation[18F]AV-1451 shows strong in vivo and post-mortem binding to tau pathology in Alzheimer's disease, but has variable affinity in healthy aging and non-AD tauopathies.
“Although [18F]AV-1451 shows strong in vivo and post-mortem binding to tau pathology in AD, it displays variable affinity in healthy aging and non-AD tauopathies28–30.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [28] Lowe VJ Curran G Fang P An autoradiographic evaluation of AV-1451 Tau PET in dementia Acta Neuropathol Commun [online serial] Acta Neuropathologica Communications 2016 4 1 19 10.1186/s40478-016-0315-6 27296779 PMC4906968 source
Not checked in the free run.
- cites [29] Marquié M Normandin MD Vanderburg CR Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue Ann Neurol [online serial] 2015 78 787 800 PMC4900162 26344059 source
Not checked in the free run.
- cites [30] Sander K Lashley T Gami P Characterization of tau positron emission tomography tracer [18F]AV-1451 binding to postmortem tissue in Alzheimer’s disease, primary tauopathies, and other dementias Alzheimer’s Dement 2016 12 1116 1124 26892233 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRecognition of happiness is preserved in PSP, while recognition of negative emotions is affected.
“While recognition of happiness was reported to be preserved in patients with PSP, their recognition of negative emotions (i.e. anger, disgust, surprise, fear and sadness) has been reported as affected45.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Ghosh BCP Rowe JB Calder AJ Hodges JR Bak TH Emotion recognition in progressive supranuclear palsy J Neurol Neurosurg Psychiatry 2009 80 1143 1145 19762901 PMC3044450 source
Not checked in the free run.
May combine two claims.
PremisecitationIn PSP, higher [18F]AV-1451 binding is found in subcortical rather than cortical regions, consistent with the known distribution of PSP-Richardson's syndrome.
“In PSP, higher [18F]AV-1451 binding has been found in sub-cortical rather than cortical regions (the reverse for AD), consistent with the well-established cortical versus sub-cortical distribution of PSP-Richardson’s syndrome8–10,13,14,16.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [8] Passamonti L Vázquez Rodríguez P Hong YT 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy Brain Epub 2017.:aww340 PMC5382948 28122879
Not checked in the free run.
- cites [9] Cho H Choi JY Hwang MS Subcortical 18F-AV-1451 binding patterns in progressive supranuclear palsy Mov Disord 2017 32 134 140 27813160 source
Not checked in the free run.
- cites [10] Hammes J Bischof GN Giehl K Elevated in vivo [18F]-AV-1451 uptake in a patient with progressive supranuclear palsy Mov Disord 2017 32 170 171 27476874 source
Not checked in the free run.
- cites [13] Smith R Schain M Nilsson C Increased basal ganglia binding of 18F-AV-1451 in patients with progressive supranuclear palsy Mov Disord 2017 32 108 114 27709757 PMC6204612 source
Not checked in the free run.
- cites [14] Whitwell JL Lowe VJ Tosakulwong N [18F]AV-1451 tau positron emission tomography in progressive supranuclear palsy Mov Disord 2017 32 124 133 27787958 PMC5552410 source
Not checked in the free run.
- cites [16] Schonhaut DR McMillan CT Spina S 18F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study Ann Neurol 2017 82 622 634 28980714 PMC5665658 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe low signal-to-noise ratio and low brain penetration of [11C]PK11195 would reduce effect sizes and increase type II errors, rather than produce false positive findings.
“Nevertheless, this would reduce effect sizes and increase type II errors, rather than leading to false positive findings.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationPrevious studies have implicated the medial temporal lobe and limbic structures in basic emotional recognition, which is impaired in PSP, alongside theory of mind and social cognition.
“Previous studies have implicated the medial temporal lobe and limbic structures in basic emotional recognition, which is in turn found to be impaired in PSP, alongside theory of mind and social cognition45,46.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [45] Ghosh BCP Rowe JB Calder AJ Hodges JR Bak TH Emotion recognition in progressive supranuclear palsy J Neurol Neurosurg Psychiatry 2009 80 1143 1145 19762901 PMC3044450 source
Not checked in the free run.
- cites [46] Ghosh BCP Calder AJ Peers PV Social cognitive deficits and their neural correlates in progressive supranuclear palsy Brain 2012 135 2089 2102 22637582 PMC3381722 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe two components individually correlate with clinical severity but do not interact in their association with PSP-RS, suggesting an additive and partially independent effect rather than a synergistic effect.
“In our sample, although the two components individually correlate with clinical severity, they did not interact in their association with PSP-RS. This suggests an additive and partially independent effect of the two pathological processes on clinical progression rather than a synergistic effect, although larger sample sizes and longitudinal designs will need to explore this relationship further.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation[18F]AV-1451 binds to non-tau proteinopathies and to other targets such as neuromelanin, choroid plexus, and monoamine oxidase.
“The tracer also binds to non-tau proteinopathies (i.e., is positive in TDP43 pathology with C9orf72 mutations and semantic dementia31), and other targets such as neuromelanin29, choroid plexus28 and monoamine oxidase (MAO)32.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [31] Bevan-Jones WR Cope TE Jones PS [18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia J Neurol Neurosurg Psychiatry [online serial] 2018 89 1032 1037 10.1136/jnnp-2017-316402 PMC6166613 28912300 source
Not checked in the free run.
- cites [29] Marquié M Normandin MD Vanderburg CR Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue Ann Neurol [online serial] 2015 78 787 800 PMC4900162 26344059 source
Not checked in the free run.
- cites [28] Lowe VJ Curran G Fang P An autoradiographic evaluation of AV-1451 Tau PET in dementia Acta Neuropathol Commun [online serial] Acta Neuropathologica Communications 2016 4 1 19 10.1186/s40478-016-0315-6 27296779 PMC4906968 source
Not checked in the free run.
May combine two claims.
PremisecitationThe basal ganglia, insula, and amygdala are implicated in recognition of predominantly negative emotions, and these neuropsychological functions are abnormal in PSP.
“Basal ganglia, insula and amygdala have been reported to be implicated in the recognition of predominately negative emotions, and these neuropsychological function is abnormal in PSP43,46.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [43] Schofield EC Hodges JR Macdonald V Cordato NJ Kril JJ Halliday GM Cortical atrophy differentiates Richardson’s syndrome from the parkinsonian form of progressive supranuclear palsy Mov Disord 2011 26 256 263 21412832 source
Not checked in the free run.
- cites [46] Ghosh BCP Calder AJ Peers PV Social cognitive deficits and their neural correlates in progressive supranuclear palsy Brain 2012 135 2089 2102 22637582 PMC3381722 source
Not checked in the free run.
May combine two claims.
PremisecitationOff-target binding cannot fully account for [18F]AV-1451 signal in the striatum or cortex, nor in the choroid plexus.
“However, ‘off-target’ binding can neither fully account for [18F]AV-1451 signal in striatum or cortex – as previous post mortem analyses reveal that no neuromelanin accumulates there8,33 – nor in choroid plexus as histological analysis revealed tangle-like inclusions in its epithelial cells34.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Passamonti L Vázquez Rodríguez P Hong YT 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy Brain Epub 2017.:aww340 PMC5382948 28122879
Not checked in the free run.
- cites [33] Hansen AK Knudsen K Lillethorup TP In vivo imaging of neuromelanin in Parkinson’s disease using 18F-AV-1451 PET Brain 2016 139 2039 2049 27190023 source
Not checked in the free run.
- cites [34] Ikonomovic MD Abrahamson EE Price JC Mathis CA Klunk WE [F-18]AV-1451 positron emission tomography retention in choroid plexus: More than “off-target” binding Ann Neurol 2016 80 307 308 27314820 PMC4982815 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThis finding aligns with in vivo correlations between neuroinflammation and tau aggregation in Alzheimer's disease and frontotemporal dementia.
“This finding aligns with in vivo correlation between neuroinflammation and tau aggregation in AD and frontotemporal dementia7,40.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [7] Bevan-Jones WR Cope TE Jones PS Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum Brain 2020 143 1010 1026 32179883 PMC7089669 source
Not checked in the free run.
- cites [40] Dani M Wood M Mizoguchi R Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’ s disease Epub 2018 1 15 30052812
Not checked in the free run.
May combine two claims.
Premisecitation[11C]PK11195 is selective for activated microglia over quiescent microglia or reactive astrocytes, but has low signal-to-noise ratio and low brain penetration.
“The [11C]PK11195 ligand is selective for activated microglia over quiescent microglia or reactive astrocytes38, but, it has been criticised for its relatively low signal-to-noise ratio and low brain penetration which may affect its sensitivity to activated microglia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Banati RB Visualising microglial activation in vivo Glia 2002 40 206 217 12379908 source
Not checked in the free run.
May combine two claims.
PremisecitationThe affinity of [18F]AV-1451 for monoamine oxidase is weak, and MAO inhibitors do not significantly displace its binding in patients with tauopathies.
“Furthermore, affinity of [18F]AV-1451 for monoamine oxidase is weak and the use of MAO-inhibitors does not significantly displace [18F]AV-1451 binding in patients with tauopathies37.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Hansen AK Brooks DJ Borghammer P MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding Mol Imaging Biol Molecular Imaging and Biology 2018 20 356 360 29127552 source
Not checked in the free run.
May combine two claims.
PremisecitationA previous report of a MAPT mutation carrier described high [11C]PK11195 binding without significant [18F]AV-1451 binding, suggesting the two ligands are not equivalent in their binding.
“However, a previous report of a carrier of a MAPT genetic mutation described high [11C]PK11195 binding in the absence of significant [18F]AV-1451 binding36, which suggests that despite the potential for a common target, the two ligands are not equivalent in their binding.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Bevan-Jones WR Cope TE Jones PS In vivo evidence for pre-symptomatic neuroinflammation in a MAPT mutation carrier Ann Clin Transl Neurol 2019 6 373 378 30847369 PMC6389753 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPre-clinical research suggests that microglial activation may precede tangle formation and promote the spreading of pathological tau.
“Pre-clinical research suggests that microglial activation may precede the formation of tangles47 and then promote the spreading of pathological tau48.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [47] Yoshiyama Y Higuchi M Zhang B Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model Neuron 2007 53 337 351 17270732 source
Not checked in the free run.
- cites [48] Asai H Ikezu S Tsunoda S Depletion of microglia and inhibition of exosome synthesis halt tau propagation Nat Neurosci 2015 18 1584 1593 26436904 PMC4694577 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe co-localization of neuroinflammation and tau pathology is an important pathogenetic mechanism in PSP, and both processes may be involved in defining PSP clinical severity.
“Our findings suggest that the co-localization of neuroinflammation and tau pathology is an important pathogenetic mechanism in PSP, and both processes may be involved in defining PSP clinical severity.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataRecruitment was based on clinical diagnosis confirmed at each follow-up, but post-mortem pathological confirmation was available only in 8 patients.
“Second, the recruitment was based on clinical diagnosis, which was confirmed at each follow-up visit; however, post-mortem pathological confirmation was available only in 8 patients.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataOur results confirm the relevance of neuroinflammation to PSP-Richardson's syndrome and a close association with tau pathology.
“To conclude, our results confirm the relevance of neuroinflammation to PSP-Richardson’s syndrome and a close association with tau pathology.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductreasoningThe cross-sectional design cannot be used to infer a causal relationship between tau and microglial activation.
“Third, our results are based on a cross-sectional design, which cannot be used to infer causal relationship between tau and microglial activation.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The ligand [18F]AV-1451 cannot differentiate tau pathology from TDP43 pathology.
“It also does not distinguish tau- from TDP43-pathololgies.”
The paper relies on this without support.
[11C]PK11195 targets the translocator protein on mitochondria of activated microglia.
“It binds the translocator protein (TSPO) on mitochondrial membranes in activated microglia.”
The paper relies on this without support.
Common genetic polymorphisms that influence second-generation TSPO ligands do not substantially affect [11C]PK11195.
“Although its sensitivity may be affected by its relatively low signal-to-noise ratio and low brain penetration, [11C]PK11195 is not significantly influenced by common genetic polymorphisms that affect second generation TSPO ligands.”
The paper relies on this without support.
Substantial TDP43 pathology is very uncommon in PSP.
“significant TDP43 pathology is exceedingly rare in PSP”
The paper relies on this without support.
The motor syndrome in PSP is essentially symmetric.
“This step reduces the degrees of freedom, increasing power, and is justified in PSP in which the motor syndrome is essentially symmetric.”
The paper relies on this without support.
Second-generation TSPO PET radioligands have a higher signal-to-noise ratio than [11C]PK11195, but their binding is markedly affected by the rs6971 polymorphism, causing heterogeneity and requiring genetic screening.
“Second-generation PET radioligands for TSPO are characterised by higher signal-noise ratio than [11C]PK11195 but their binding is markedly affected by single nucleotide polymorphisms (rs6971) which cause heterogeneity in PET data and require genetic screening.”
The paper relies on this without support.
[11C]PK11195 binding is less affected by the rs6971 polymorphism.
“[11C]PK11195 binding is less affected by this polymorphism, and has well established methods of kinetic analysis39.”
The paper relies on this without support.
The cohort is larger than many previous multi-tracer PET studies on rare neurodegenerative diseases like PSP.
“Although our cohort is larger than many previous multi-tracer PET studies on rare neurodegenerative diseases like PSP, larger and independent replication samples would be helpful.”
The paper relies on this without support.
Over 95% of patients with a clinical diagnosis of PSP-Richardson's syndrome have PSP pathology or related 4R-tauopathy.
“However, all 8 had PSP, and over 95% of patients with a clinical diagnosis of PSP-Richardson’s syndrome have PSP pathology or related 4R-tuaopathy.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Subcortical tau pathology and microglial activation positively correlated with clinical severity and could predict disease progression in PSP.
“Additionally, subcortical tau pathology and microglial activation positively correlated with clinical severity376,378,379 and could predict disease progression in PSP.379”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [378]
Using [11C]PK11195 and [18F]AV-1451, studies found that microglial activation in cortical and subcortical regions was positively correlated with tau pathology.
“studies found that microglial activation in cortical and subcortical regions was positively correlated with tau pathology.378”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [378]
Microglial activation colocalized and correlated with tau pathology in PSP patients and transgenic mice expressing mutant tau P301L.
“Firstly, microglial activation colocalized and correlated with tau pathology in PSP patients374,378 and transgenic mice expressing mutant tau P301L.380”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [378]
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- Consistentχ²(1) = 21.28reported p = .000003972 · recomputed p < .001
“χ2 (1) = 21.28, p = 3.972e-06”
- Consistentχ²(1) = 8.82reported p = .003 · recomputed p = .003
“χ2 (1) = 8.82, p = .003”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
The PET tracers' targets are reversed in the participant description
MinorThe participant description assigns tau pathology to [11C]PK11195 and neuroinflammation to [18F]AV-1451. Elsewhere, the paper assigns microglial activation to [11C]PK11195 and tau burden to [18F]AV-1451.
“Patients underwent PET scanning with both [11C]PK11195 and [18F]AV-1451, to respectively assess tau pathology and neuroinflammation.”
“We used [11C]PK11195 PET to measure of microglial activation and [18F]AV-1451 PET as an index of tau burden”
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“The tracer also binds to nontau proteinopathies (ie, is positive in TDP43 pathology with C9orf72 mutations and semantic dementia(31)), and other targets, such as neuromelanin,(29) choroid plexus,(28) and monoamine oxidase (MAO).(32) However, “off-target” binding can neither fully account for [(18)F]AV-1451 signal in s…”
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Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
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Self-citationSocial cognitive deficits and their neural correlates in progressive supranuclear palsy
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Self-citationSubcortical <sup>18</sup>F‐AV‐1451 binding patterns in progressive supranuclear palsy
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[ <sup>11</sup> C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy
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Self-citationImaging of neuroinflammation in dementia: a review
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Self-citationPET Imaging of Neuropathology in Tauopathies: Progressive Supranuclear Palsy
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Cytokine expression and microglial activation in progressive supranuclear palsy
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Tau imaging with [<sup>18</sup>F]<scp>THK</scp>‐5351 in progressive supranuclear palsy
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Self-citation[18F]‐THK5351 PET correlates with topology and symptom severity in progressive supranuclear palsy
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Emotion recognition in progressive supranuclear palsy
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Positron emission tomography imaging of tau pathology in progressive supranuclear palsy
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MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding
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Elevated in vivo [18F]‐AV‐1451 uptake in a patient with progressive supranuclear palsy
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[<sup>18</sup>F]AV‐1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation
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Self-citationIn vivo evidence for pre‐symptomatic neuroinflammation in a <scp>MAPT</scp> mutation carrier
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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Tauopathies: new perspectives and challenges
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Neuroinflammation predicts disease progression in progressive supranuclear palsy
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“Grey-matter volumes and BP ND values for each ligand were combined across the two hemispheres to derive 43 bilateral ROIs, 7 9 19 which were next included in separate principal component analyses (PCAs) for each imaging modality.”
Self-citationNeuroinflammation is linked to dementia risk in Parkinson’s disease
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Self-citationPrimary Progressive Aphasia: Toward a Pathophysiological Synthesis
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Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences
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Self-citationInflammation in multiple system atrophy
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Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration
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Self-citationMolecular pathology and synaptic loss in primary tauopathies: an 18F-AV-1451 and 11C-UCB-J PET study
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Self-citationType-I Interferons in Alzheimer's Disease and Other Tauopathies
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Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity
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Self-citationPost-mortem validation of in vivo TSPO PET as a microglial biomarker
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Progressive Supranuclear Palsy Syndrome: An Overview
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Candia, R. F., Cohen, L. S., Morozova, V., Corbo, C. P., & Alonso, A. D. C. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.888420 · Cited by 25 · see citing works
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Self-citationGender differences in progressive supranuclear palsy
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Validation of the new pathology staging system for progressive supranuclear palsy
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Self-citationNeuroimaging correlates of gait abnormalities in progressive supranuclear palsy
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Self-citationUpdate on neuroimaging for categorization of Parkinson's disease and atypical parkinsonism
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Targeting tau in Alzheimer’s and beyond: Insights into pathology and therapeutic strategies
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Imaging pathological tau in atypical parkinsonisms: A review
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Midbrain cytotoxic T cells as a distinct neuropathological feature of progressive supranuclear palsy
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Pathomechanisms of cognitive impairment in progressive supranuclear palsy
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Proton magnetic resonance spectroscopy in frontotemporal lobar degeneration-related syndromes
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Self-citationPositron Emission Tomography in Animal Models of Tauopathies
Cao, L., Kong, Y., Ji, B., Ren, Y., Guan, Y., & Ni, R. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.761913 · Cited by 14 · see citing works
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PET Imaging to Measure Neuroinflammation In Vivo
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Self-citationAssociation between hippocampal microglia, AD and LATE‐NC, and cognitive decline in older adults
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Self-citationImmunometabolic Signature and Tauopathy Markers in Blood Cells of Progressive Supranuclear Palsy
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PET/CT in Movement Disorders: Update
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Self-citationTau in Atypical Parkinsonisms: A Meta‐Analysis of in Vivo PET Imaging Findings
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Pathomechanisms of depression in progressive supranuclear palsy
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Imaging of Tauopathies with PET Ligands: State of the Art and Future Outlook
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Brain Networks Route Neurodegeneration Patterns in Patients with Progressive Supranuclear Palsy
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Pathomechanisms of neuropsychiatric disturbances in atypical parkinsonian disorders: a current view
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Comparing and combining TSPO-PET tracers in tauopathies
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Self-citationDiagnostic utility of biomarkers in progressive supranuclear palsy: toward a biotyping framework
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Small tau aggregates exhibit disease-specific molecular profiles across tauopathiesPreprint
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Self-citation
- Authors
- Malpetti, M., Passamonti, L., Rittman, T., Jones, P. S., Vázquez Rodríguez, P., Bevan‐Jones, W. R., Hong, Y. T., Fryer, T. D., Aigbirhio, F. I., O'Brien, J. T., & Rowe, J. B.
- Affiliations
- University of Cambridge (GB)
- Department of Clinical Neurosciences University of Cambridge Cambridge UK
- Department of Psychiatry University of Cambridge Cambridge UK
- Corresponding author
- Rowe, James B.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2020-10-10
- Volume
- 88
- Issue
- 6
- Pages
- 1194-1204
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC7116392
- OpenAlex
- W3087113353
- Semantic Scholar
- 7c54253cee745c25fec7615e1b2a0122d700a212
- Cited by
- 83
- References
- 65
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 21 · 2023: 14 · 2022: 9 · 2021: 10 · 2020: 3
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Gates Cambridge Trust
- Medical Research Council Canada (MR/P01271X/1)
- PSP Association
- Wellcome Trust (103838)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- progressive supranuclear palsy, neuroinflammation, tau pathology, [11C]PK11195, 18F-AV-1451, microglial activation, clinical severity, disease-modifying therapy, neurodegeneration, Richardson's syndrome
- MeSH terms
- Aged, Brain, Carbolines, Carbon Radioisotopes, Female, Humans, Isoquinolines, Magnetic Resonance Imaging, Male, Severity of Illness Index, Supranuclear Palsy, Progressive, tau Proteins, Inflammation Mediators, Positron-Emission Tomography, Neuroimaging
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