Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Nutma, Erik; Fancy, Nurun; Weinert, Maria; Marzin, Manuel; Tsartsalis, Stergios; Muirhead, Robert C. J.; Falk, Irene; Bruin, Joy de; Hollaus, David; Pieterman, Robin; Anink, Jasper J.; Story, David; Chandran, Siddharthan; Tang, Jiabin; Trolese, Maria Chiara; Saito, Takashi; Saido, Takaomi C.; Wiltshire, Katie; Beltran-Lobo, Paula; Philips, Alexandra; Antel, Jack; Healy, Luke M.; Moore, Craig S.; Bendotti, Caterina; Aronica, Eleonora; Radulescu, Carola I.; Barnes, Samuel J.; Hampton, David W.; Valk, Paul van der; Jacobson, Steven; Matthews, Paul M.; Amor, Sandra; Owen, David R.

doi:10.1101/2022.05.11.491453

Cited by 12 publications

(7 citation statements)

References 89 publications

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“…[79][80][81][82] Recent studies in rodent models suggest that TSPO signal may be related more to microglial number than microglial activation. 83 Although our observations suggest that increased TSPO signal reflects central inflammation and correlates with cognitive measures, the TSPO signal we observed does not reveal which cell types are responsible. Additionally, second generation TSPO ligands, including 18 F-DPA-714, are affected by the SNP rs6971 genotype.…”

Section: Discussioncontrasting

confidence: 70%

Brain and Systemic Inflammation in De Novo Parkinson's Disease

et al. 2023

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A BS TRACT: Objective: To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson's disease (PD). Background: Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation and whether proinflammatory signals are associated with clinical features and/or predict more rapid progression. Methods: We enrolled subjects with de novo PD (n = 58) and age-matched controls (n = 62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson's Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18 F-DPA-714, a translocator protein 18kd ligand, and lumbar puncture if eligible and consented.Results: Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. Positron emission tomography imaging showed increased 18 F-DPA-714 signal in PD subjects. 18 F-DPA-714 signal correlated with several cognitive measures and some chemokines. Conclusions: 18 F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline.

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Section: Discussioncontrasting

confidence: 70%

Brain and Systemic Inflammation in De Novo Parkinson's Disease

et al. 2023

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“…Beyond AD-related protein deposition, our method can also investigate the influence of other critical factors. It has been hypothesized, and to some extent observed 6, 7, 15 , that microglial activation (a probable marker for neuroinflammation 35, 50 ) affects excitability and neuronal activity in AD. Consequently, we performed a set of complimentary experiments where we recreated the obtained results in a model that also considers deviations to neuronal excitability due to microglial activation –measured with 18kDa Translocator Protein PET.…”

Section: Discussionmentioning

confidence: 99%

Revealing the combined roles of Aβ and tau in Alzheimer’s disease via a pathophysiological activity decoder

Sanchez-Rodriguez

Bezgin

Carbonell

et al. 2023

Preprint

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Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we develop and validate a personalized brain activity model that incorporates functional MRI, amyloid-beta (Abeta) and tau-PET from AD-related participants (N=132). By simulating electrophysiological activity mediated by toxic protein deposition, this integrative approach uncovers key patho-mechanistic interactions, including synergistic Abeta and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Abeta-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

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“…Moreover, a recent preprint suggested that -in humans -TSPO-targeted radiotracers reflect microglial density rather than activated microglia. 54 Also, it is well-acknowledged that TSPO is expressed in other cell types than microglia. 23 These methodological issues may limit the conclusions that can be drawn from our results.…”

Section: Discussionmentioning

confidence: 99%

Insulin resistance and body mass index are associated with TSPO PET in cognitively unimpaired elderly

Ekblad

Tuisku

Koivumäki

et al. 2023

J Cereb Blood Flow Metab

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Metabolic risk factors are associated with peripheral low-grade inflammation and an increased risk for dementia. We evaluated if metabolic risk factors i.e. insulin resistance, body mass index (BMI), serum cholesterol values, or high sensitivity C-reactive protein associate with central inflammation or beta-amyloid (Aβ) accumulation in the brain, and if these associations are modulated by APOE4 gene dose. Altogether 60 cognitively unimpaired individuals (mean age 67.7 years (SD 4.7); 63% women; 21 APOE3/3, 20 APOE3/4 and 19 APOE4/ 4) underwent positron emission tomography with [11C]PK11195 targeting TSPO (18 kDa translocator protein) and [11C]PIB targeting fibrillar Aβ. [11C]PK11195 distribution value ratios and [11C]PIB standardized uptake values were calculated in a cortical composite region of interest typical for Aβ accumulation in Alzheimer’s disease. Associations between metabolic risk factors, [11C]PK11195, and [11C]PIB uptake were evaluated with linear models adjusted for age and sex. Higher logarithmic HOMA-IR (standardized beta 0.40, p = 0.002) and BMI (standardized beta 0.27, p = 0.048) were associated with higher TSPO availability. Voxel-wise analyses indicated that this association was mainly seen in the parietal cortex. Higher logarithmic HOMA-IR was associated with higher [11C]PIB (standardized beta 0.44, p = 0.02), but only in APOE4/4 homozygotes. BMI and HOMA-IR seem to influence TSPO availability in the brain.

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Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Cited by 12 publications

References 89 publications

Brain and Systemic Inflammation in De Novo Parkinson's Disease

Brain and Systemic Inflammation in De Novo Parkinson's Disease

Revealing the combined roles of Aβ and tau in Alzheimer’s disease via a pathophysiological activity decoder

Insulin resistance and body mass index are associated with TSPO PET in cognitively unimpaired elderly

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