Neuroinflammation predicts disease progression in progressive supranuclear palsy

Malpetti, Maura; Passamonti, Luca; Jones, P. Simon; Street, Duncan; Rittman, Timothy; Fryer, Timothy D; Hong, Young T.; Rodriguez, Patricia Vàsquez; Bevan-Jones, William Richard; Aigbirhio, Franklin I.; O’Brien, John; Rowe, James B.

doi:10.1136/jnnp-2020-325549

Cited by 43 publications

(44 citation statements)

References 45 publications

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“…In other words, in areas with relatively low tau accumulation synaptic density is minimally affected, whereas in areas with higher tau accumulation there is reduction of synaptic density as the disease progresses and this preferentially occurs in synapse rich areas. As the disease progresses, other pathological processes may contribute to synaptic loss, such as inflammation, another predictor of prognosis and mediator of synaptic loss 46 . There is therefore not a simple linear relationship between tau accumulation and synaptic density in moderate and advanced disease.…”

Section: Discussionmentioning

confidence: 99%

Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study

Holland

Malpetti

Rittman

et al. 2021

Preprint

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The relationship between in vivo synaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity. Twenty three patients with PSP, and twelve patients with Corticobasal Syndrome (CBS) were recruited from a tertiary referral centre. Nineteen education, sex and gender–matched control participants were recruited from the National Institute for Health Research Join Dementia Research platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands [11C]UCB–J and [18F]AV–1451, respectively. Patients with CBS also underwent amyloid PET imaging with [11C]PiB to exclude those with likely Alzheimer's pathology – we refer to the amyloid negative cohort as having CBD although acknowledge other pathologies exist. Disease severity was assessed with the PSP rating scale; regional non-displaceable binding potentials (BPND) of [11C]UCB–J and [18F]AV–1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for [18F]AV–1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions, and synaptic density in connected subcortical areas. Across brain regions, there was a positive correlation between [11C]UCB–J and [18F]AV–1451 BPND (β=0.4, t=4.7, p<0.0001). However, the direction of this correlation became less positive as a function of disease severity in patients (β = -0.03, T = -4.0, p = 0.002). Between brain regions, cortical [18F]AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen, and substantia nigra). Brain regions with higher synaptic density are associated with a higher [18F]AV–1451 binding in PSP/CBD, but this association diminishes with disease severity. Moreover, higher cortical [18F]AV–1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and tauopathy, with synapse rich regions vulnerable to accrual of pathology, followed by a loss of synapses in response to pathology. Given the importance of synaptic function for cognition, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study

Holland

Malpetti

Rittman

et al. 2021

Preprint

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Section: Translocator Proteinmentioning

confidence: 99%

“…In preclinical TSPO imaging studies, no evidence with respect to rs6971 polymorphisms has been reported. Microglia activation assessed by using [ 11 C]PK11195 PET was reported to co-localize with tau and can predict disease progression and tau accumulation assessed by [ 18 F]flortaucipir in patients with PSP ( Malpetti et al, 2020 , 2021 ). Takuwa et al (2020) demonstrated higher [ 11 C]PBB3 uptake (tau accumulation) and [ 18 F]AC-5216 (microglia activation) in rTg4510 mice at 6 month-of-age compared to wild-type littermates.…”

Section: Neuroinflammation Imagingmentioning

confidence: 99%

Positron Emission Tomography in Animal Models of Tauopathies

Cao

Kong

et al. 2022

Front. Aging Neurosci.

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The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer’s disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer’s disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer’s disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.

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“…Interestingly, a hypothetical connection between COVID-19 and atypical parkinsonism can be established as well, although data on this topic are rare so far. It was demonstrated that atypical Parkinson syndromes such as multisystem atrophy and progressive supranuclear palsy are associated with microglial activation as a sign of neuroinflammation and that the microglial activation contributes to the progression of neurodegeneration [ 110 , 111 , 112 ]. Recently, it was shown that microglial activation can be visualized by PET imaging, which might function as a biomarker for tauopathies [ 113 , 114 ].…”

Section: Chaptermentioning

confidence: 99%

Can SARS-CoV-2 Infection Lead to Neurodegeneration and Parkinson’s Disease?

et al. 2021

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The SARS-CoV-2 pandemic has affected the daily life of the worldwide population since 2020. Links between the newly discovered viral infection and the pathogenesis of neurodegenerative diseases have been investigated in different studies. This review aims to summarize the literature concerning COVID-19 and Parkinson’s disease (PD) to give an overview on the interface between viral infection and neurodegeneration with regard to this current topic. We will highlight SARS-CoV-2 neurotropism, neuropathology and the suspected pathophysiological links between the infection and neurodegeneration as well as the psychosocial impact of the pandemic on patients with PD. Some evidence discussed in this review suggests that the SARS-CoV-2 pandemic might be followed by a higher incidence of neurodegenerative diseases in the future. However, the data generated so far are not sufficient to confirm that COVID-19 can trigger or accelerate neurodegenerative diseases.

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Neuroinflammation predicts disease progression in progressive supranuclear palsy

Cited by 43 publications

References 45 publications

Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study

Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study

Positron Emission Tomography in Animal Models of Tauopathies

Can SARS-CoV-2 Infection Lead to Neurodegeneration and Parkinson’s Disease?

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Neuroinflammation predicts disease progression in progressive supranuclear palsy

Cited by 43 publications

References 45 publications

Molecular pathology and synaptic loss in primary tauopathies: [18F]AV-1451 and [11C]UCB-J PET study

Molecular pathology and synaptic loss in primary tauopathies: [18F]AV-1451 and [11C]UCB-J PET study

Positron Emission Tomography in Animal Models of Tauopathies

Can SARS-CoV-2 Infection Lead to Neurodegeneration and Parkinson’s Disease?

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Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study

Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study