In Vivo TSPO Signal and Neuroinflammation in Alzheimer’s Disease
Abstract
:1. Introduction
2. TSPO: An In Vivo Marker of Neuroinflammation
2.1. Evidence of TSPO Upregulation in Alzheimer’s Disease
2.1.1. TSPO Alterations Are Brain Region Specific
2.1.2. Impact of the Method of In Vivo TSPO Quantification
Methods of In Vivo TSPO Quantification
Impact of the Method of In Vivo TSPO Quantification
2.1.3. Other Influencing Factors
2.2. Evidence of a TSPO Upregulation in Preclinical Models of Alzheimer’s Disease
2.2.1. TSPO Is Increased in Tau, APP/PS1 and APP/PS1/Tau Mouse Models
2.2.2. TSPO Binding in Cerebellum and Choroid Plexus
2.3. Is TSPO Altered in Other Pathologies?
3. Cell Origin of TSPO Alterations
3.1. TSPO in Astrocytes and Microglia
3.2. Other Cells Types
3.3. Cells Expressing TSPO in Other Pathologies
4. Possible Biological Roles of TSPO
4.1. Relationship between TSPO and Alzheimer’s Disease
4.1.1. TSPO and Aβ Relationship
4.1.2. TSPO and Tau Relationship
4.1.3. TSPO and Clinical Symptoms of Alzheimer’s Disease
4.1.4. Is TSPO Protector or Aggravator?
4.2. Relationship between TSPO and Schizophrenia
5. Conclusions and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Radiotracer | Population | m/f (%males) | Age Range (mean) | MMSE Score Range (mean) | TSPO Methodology: Scan Acquisition and Analysis | Main Results | Reference |
---|---|---|---|---|---|---|---|
Studies showing no main effect of AD on TSPO | |||||||
11C-PK11195 * 11C-PiB | 6 modAD-A+ 6 MCI (4 AD-A+) 5 HC (2 HC-A+) | 4/2 (67) 4/2 (67) 3/2 (60) | 65–94 (76) 61–81 (72) 65–79 (72) | 13–28 (19.3) 27–30 (28.7) 28–30 (29.4) | 0–90min BPSRTM with RefCE 10–60min images SUR with Refsubcortical white matter | BPSRTM and SUR: AD = MCI = HC A+ = A− | [62] |
11C-PK11195 * No amyloid detection | 20 AD 13 proAD 21 HC | 11/8 (58) 7/3 (70) 13/8 (62) | (69) (72) (68) | (23) (26) (29) | 0–60.5 min. BPSRTM with RefCluster Analysis VWA-SPM | BPSRTM: AD = prodromal = HC VWA-SPM: AD > HC:Occ No correlations between PK11195 and neuropsychological tests. No difference between prodromal AD patients who remained clinically stable and those who progressed clinically to dementia. | [63] |
11C-Vinpocetine No amyloid detection | 6 AD 6 young HC 6 old HC | 3/3 (50) 6/0 (100) 6/0 (100) | 67–82 (73) 54–78 (67) 25–44 (35) | (dnf) | 0–66 min SUVR with RefCE BPLogan with RefCE | SUVR Old HC > Young HC: pF, medT, latT, Occ, Th, St AD = Old HC BPLogan AD = HC: Th AD = Old HC > Young HC: whole-brain, grey matter | [64] |
18F-FEDAA1106 No amyloid detection | 9 AD 7 HC | 6/3 (67) 5/2 (71) | 64–76 (69) 63–73 (68) | 21–30 (25) 28–30 (29) | 0–60 min and 80–140 min. VT BPND VT Logan | AD: 8 AChE inhibitor + 1 AchE inhibitor- VT, BPND, VT Logan AD = HC | [65] |
18F-DAP-714 No amyloid detection | 9 AD 6 HC | 4/4 (50) 1/5 (17) | 60–80 (73.7) 60–73 (64.5) | 20–29 (24.5) 28–30 (28.8) | 0–90 min and 120–150 min VT BPSRTM with RefCE | Age effect: AD > HC VT, BPSRTM AD = HC | [66] |
Studies showing TSPO overexpression in AD | |||||||
123I-PK11195 * No amyloid detection | 10 AD 9 HC | 4/6 (40) 6/3 (67) | 55–87 (77) 53–76 (67) | 9–25 (19) | 60–80 min SUR with RefCE | HC: no age effect. AD > HC: loF, pF, latF, rMT, bG Diverse inverse correlations between regional PK1195 and neuropsychological tests. | [67] |
11C-PK11195 * No amyloid detection | 8 AD 15 HC | 4/4 (50) 7/8 (47) | 58–68 (65) 32–80 (75) | 6–24 (17.25) | 0–60 min. BPSRTM with RefCluster Analysis | HC: age effect in Th AD > HC: iTG, mTG, fG, lPG, lAm, lpCin, iPG, Pu, rPall AD trend to > HC: rCE (p=0.06) | [68] |
11C-PK11195 * No amyloid detection | 13 AD 10 HC | 8/5 (62) 6/4 (60) | 54–73 (65) 54–71 (64) | 15–26 (21) (30) | 0–60 min. BPSRTM with RefCluster Analysis VWA-SPM | BPSRTM AD = HC: Th, Hipp AD > HC: aCin, pCin, St, F, T, P, Occ, WC, Am, PG, mTG, CE (+22%) VWA-SPM: AD > HC: iTG, mTG, mFG, rF, latOcc, loF, lpostCG, rpostT, infF, roF, preCG, supFG. Negative correlations between regional PK11195 and MMSE scores | [69] |
11C-PK11195 * 11C-PiB | 10 AD-A+ 10 MCI (5 MCI-A+) 8 HC | 4/6 (40) 5/5 (50) 4/4 (50) | 51–74 (66) 55–77 (67) 58–71 (65) | (20.5) (28.2) (30) | (dnf) min BPSRTM with RefCluster Analysis VWA-SPM | BPSRTM AD > HC: aCin, F, T, P, Occ, mTG, Am, Hipp MCI > HC: aCin, F, T, P, Occ, mTG, Am, Hipp, pCin VWA-SPM AD > HC: lHipp, rPG, lpostT, lpreCG, lpostCG, lsupTG, liTG, lmTG, latOcc. MCI > HC: liTG, lmTG, rsupFG, rsupPG, lIns, lPu, rmedOG, lmFG, raOG, rStG, rlatOcc In different regions (AD only): Positive correlations between PK1195 and MMSE scores; Positive correlations between PK1195 and PiB | [70] |
11C-PK11195 * 11C-PiB | 8 AD (7 AD-A+) 8 HC out of 14 | 3/5 (37) 7/9 (44) ** | 51–74 (66) 54–75 (65) ** | (21) | 0–60 min BPSRTM with RefCluster Analysis VWA-SPM | BPSRTM and VWA-SPM AD > HC: F, T, P, Occ, Hipp, St Positive correlations between PK1195 and PiB | [71] |
11C-PK11195 * 11C-PiB | 26 MCI-A+ 16 MCI-A− 10 HC out of 15 | 17/9 (65) 7/9 (44) 6/) (40) ** | 62–83 (73) 50–79 (66) 58–80 (68) ** | 23–30 (27) 23–30 (28) 25–30 (29) ** | 0–60min BPSRTM with RefCluster Analysis | MCI-A+ > HC: F, latT, P MCI-A+ > MCI-A−: Hipp MCI-A− = HC In different regions: positive correlations PK1195 and PiB | [72] |
18F-FEMPA No amyloid detection | 5 HAB-AD 3 MAB-AD 2 ?-AD 4 HAB-HC 3 MAB-HC | 2/3 (40) 2/1 (67) 1/1 (50) 1/3 (25) 2/1 (67) | 67–73 (71.2) 55–67 (61) 56–74 (65) 66–71 (69) 55–58 (56) | 23–28 (25.6) 22–28 (25) 23–29 (26) 28–30 (29) 29–30 (29.7) | 0–90 min and 120–150 min. VT VT Logan | VT Logan HAB/MAB-AD > HAB/MAB-HC: medT HAB-AD > HAB-HC: medT, latT, pCin, Cau, Pu, Th, CE (+19%) No correlations between FEMPA and MMSE scores | [73] |
11C-PBR28 No amyloid detection | 9 HAB-AD 10 MAB-AD 4 HAB-MCI 6 MAB-MCI 5 HAB-HC 8 MAB-HC | 11/8 6/4 9/4 | (63.1) (72.6) (62.9) | (20.3) (27.5) (29.8) | 0–90 min VT | Age effect: MCI > AD = HC AD: 15 AchE inhibitor +, 4 AchE inhibitor- MCI: 4 AchE inhibitor +, 6 AchE inhibitor- HAB > MAB (controls and patients combined) in whole brain. AD > HC: pF, iP, supT, iTG, mTG, Prec, pCin, Occ, Hipp, Ent AD > MCI: pF, iP, supT, iTG, mTG, Occ HAB-AD > HAB-HC: iP HAB-AD > HAB-MCI: iP MAB-AD > MAB-HC: iP Correlation between regional PBR28 (AD and MCI) and neuropsychological tests, grey matter volume and age of symptom onset. | [74] |
11C-PBR28 11C-PiB | 11 HAB-AD-A+ 14 MAB-AD-A+ 5 HAB-MCI-A+ 6 MAB-MCI-A+ 7 HAB-HC 14 MAB-HC | AD: 11/14 MCI: 7/4 HC: 15/6 | AD: (63) MCI: (72) HC: (55) | 0–90 min. VT SUVR with RefCE (60–90 min) DVR (VT target/VT CE) | Some subjects were previously included in Reference [74]. VT uncorrected for plasma free fraction of radioligand AD=MCI=HC VT corrected for plasma free fraction of radioligand AD > HC: iP, mTG, iTG, Ent AD > MCI: mTG, iTG, Ent SUVR with genotype correction: AD > HC: mTG, iTG, iP, Ent, PG MAB > HAB: in all diagnostic groups. DVR AD > HC: mTG, iTG, iP, Prec, Hipp, Ent, PG AD > MCI: mTG, iTG, iP, Ent, PG, Occ Positive correlations between PBR28 (combined mTG-iTG) and CDR | [75] | |
11C-PBR28 No amyloid detection | 5 HAB-MCI/AD 9 MAB-MCI/AD 3 HAB-HC 5 MAB-HC | MCI/AD: (65) HC: (62) | MCI/AD: 14–30 (22) HC: >29 (30) | 0–90 min VT (n = 17). DVR (n = 17) SUVR with RefCE (60–90 min) 2nd PBR28 scan sessions: 1.2–5.7 years after. | AD: 10 AchE inhibitor +, 4 AchE inhibitor- at baseline, and 8 AchE inhibitor +, 6 AchE inhibitor- at the 2nd examination. Time to the 2nd PBR28 imaging: AD (2.5 years) < HC (4 years). Follow-up CDR: 5 AD stable and 9 with increased CDR. Magnitude of SUVR increase AD > HC: iTG, mTG, iP, Prec, Occ, Hipp, Ent. Magnitude of DVR increase AD > HC: iTG, mTG, iP, Prec, Occ, Ent. Annual increased in PBR binding: AD with increased CDR > stable AD Correlation between increase in PBR28 (pF, Prec, supP, iP) and increase in CDR score. | [76] | |
18F-DPA-714 11C-PiB | 12 HAB-AD 12 MAB-AD 2 LAB-AD 17 HAB-proAD 17 MAB-proAD 4 LAB-proAD 11 HAB-HC-A− 9 MAB-HC-A− 4 LAB-HC- A− 2 HAB-HC-A+ 4 MAB-HC-A+ 2 LAB-HC-A+ | AD: 8/22 (27) proAD: 16/22 (42) HC-A−: 6/18 (25) HC-A+: 4/4 (50) | AD: (68.3) proAD: (67.8) HC-A−: (68.2) HC- A+: (74.3) | AD: (15.8) proAD: (24) HC-A−: (29.5) HC-A+: (29.1) | 0–90 min. SUVR with RefCE (60–90 min) VWA-SPM Clinical follow up: 2 years | SUVR LAB-AD=LAB-proAD=LAB-HC HAB-AD > HAB-HC: pCin, T, Prec HAB-proAD > HAB-HC: GCI, medCin, pCin, P, T, Prec MAB-AD > MAB-HC: P, T, Prec MAB-proAD > MAB-HC: GCI, P, T, Prec VWA-SPM HAB/MAD AD > HC: P, T HAB/MAD proAD > HC: F, P, T At baseline: Slow decliners (stable CDR) > Fast decliners (≥0.5 CDR) No correlation between age and DPA in the whole population. Positive correlations between DPA (global cortical binding) and MMSE scores, grey matter volume. In different regions: positive correlations between DPA and PiB | [77] |
18F-DPA-714 No amyloid detetion | 33proAD-19AD: 22 HAB-AD 30 MAB-AD 9 HAB-HC 8 MAB-HC | (dnf) | proAD/AD: (67) HC: (69) | proAD/AD: (21) HC: (29) | 0–90 min. SUVR with RefCE (60–90 min) Clinical follow up: 2 years defining slow and fast CDR and MMSE decliners. Slow: stable CDR or ΔMMSE = −1; Fast: increase in CDR or ΔMMSE = −8 | SUVR proAD = AD HAB/MAD AD > HC: GCI, medCin, pCin, F, P, T, Prec, Occ At baseline: proAD slow decliners (CDR, n = 11) > Fast decliners (n = 22) proAD slow decliners (ΔMMSE, n = 15) > Fast decliners (n = 18) AD slow decliners (CDR, n = 6) > Fast decliners (n = 13) AD slow decliners (ΔMMSE, n = 8) > Fast decliners (n = 8) Positive correlations between DPA (global cortical binding) and MMSE scores | [78] |
Radiotracer | Population | m/f (%males) | Age Range (mean) | Main Information | TSPO Methodology: Scan Acquisition and Analysis | Main Results | Reference |
---|---|---|---|---|---|---|---|
11C-PBR28 | 8 HAB-FEP 8 MAB-FEP 9 HAB-HC 7 MAB-HC | FEP: 11/5 HC: 7/9 | FEP: (28) HC: (26) | Nicotine 2 in FEP 0 in HC FEP: 5 with benzodiazepine treatment | 0–91 min VT | FEP < HC: F, T, Hipp | [106] |
11C-DPA-713 | 8 HAB-SCZ 4 MAB-SCZ 2 LAB-SCZ 9 HAB-HC 5 MAB-HC 2 LAB-HC | SCZ: 11/3 (79) HC: 9/7 (56) | SCZ: (24) HC: (25) | Nicotine: 2 in HC 3 in SCZ SCZ: 2 unmedicated (last month) 1 with two antipsychotic 11 with one antipsyxchotic [range: 0–1119 chlorpromazine equivalent] | 0–90 min VT Logan | LAB were excluded. HAB-SCZ = HAB-HC MAB-SCZ = MAB-HC | [107] |
18F-FEPPA | 14 HAB-FEP 5 MAB-FEP 14 HAB-HC 6 MAB-HC | FEP: 12/19 (63) HC: 9/11 (45) | FEP: (28) HC: (28) | FEP: 14 antipsychotic naïve, 5 unmedicated (last 4 weeks) | 0–125 min VT | HAB-FEP = HAB-HC MAB-FEP = MAB-HC | [108] |
18F-FEPPA | 10 HAB-SCZ 6 MAB-SCZ 1 LAB-SCZ 19 HAB-HC 8 MAB-HC 0 LAB-HC | SCZ. 10/6 HC: 10/17 | SCZ: (43) HC: (44) | SCZ: 16 with antipsychotics and others (antidepressants…) | 0–125 min VT | HAB-SCZ = HAB-HC MAB-SCZ = MAB-HC | [110] |
11C-PK11195 | 16 SCZ 16 HC | 11/5 11/5 | (33) (33) | Nicotine 11 in SCZ 0 in HC SCZ: 8 antipsychotic-free | 0–60 min BPSRTM with RefCE | Nicotine status SCZ > HC BPSRTM SCZ antipsychotic-free = HC SCZ > SCZ antipsychotic-free (83% of increase but p = 0.097) | [109] |
11C-PK11195 | 19 SCZ 17 HC | 16/3 14/3 | (24) (47) | Nicotine 13 in SCZ 5 in HC SCZ: 4 antipsychotic-free, 16 with antipsychotic | 60 min BPSRTM with RefCluster Analysis | SCZ = HC | [113] |
11C-PBR28 | 7 HAB-UHR 7 MAB-UHR 10 HAB-HC 4 MAB-HC 13 HAB-SCZ 1 MAB-SCZ 14 HAB-HC | UHR: 7/7 (50) HC: 4/10 SCZ: 3/12 3/12 | UHR: (24) HC: (28) SCZ: (47) (46) | 2 UHR with citalopram by the past | 0–90 min. DVR (VT target/VT whole brain) | UHR > HC: Gm, F, T UHR excluding 2 subjects with citalopram > HC: F HAB-UHR > HAB-HC: Gm MAB-UHR > MAB-HC: Gm SCZ > HC: F, T UHR: Positive correlations between the mean PBR28 DVR and CAARMS | [105] |
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Tournier, B.B.; Tsartsalis, S.; Ceyzériat, K.; Garibotto, V.; Millet, P. In Vivo TSPO Signal and Neuroinflammation in Alzheimer’s Disease. Cells 2020, 9, 1941. https://doi.org/10.3390/cells9091941
Tournier BB, Tsartsalis S, Ceyzériat K, Garibotto V, Millet P. In Vivo TSPO Signal and Neuroinflammation in Alzheimer’s Disease. Cells. 2020; 9(9):1941. https://doi.org/10.3390/cells9091941
Chicago/Turabian StyleTournier, Benjamin B., Stergios Tsartsalis, Kelly Ceyzériat, Valentina Garibotto, and Philippe Millet. 2020. "In Vivo TSPO Signal and Neuroinflammation in Alzheimer’s Disease" Cells 9, no. 9: 1941. https://doi.org/10.3390/cells9091941