Table Info

Table 3.

Regional and global PK11195 BP values for the treatment and placebo group at baseline and FU as well as for healthy controls

	Treatment									Placebo							Healthy control values
Baseline PK-11195 BP	Participant No.	1	3	6	8	9	10			Participant No.	2	4	5	7
	Regions							Mean	SD	Regions					Mean	SD	Mean	SD
	Frontal lobe	0.0985	0.0968	−0.0996	0.1184	0.1046	0.0226	0.0569	0.0837	Frontal lobe	0.0310	0.0064	0.1226	0.0850	0.0613	0.0524	0.0394	0.0487
	Parietal lobe	0.0752	0.0800	−0.1212	0.0792	0.0627	0.0124	0.0314	0.0790	Parietal lobe	−0.0693	−0.0276	0.0732	0.0216	−0.0005	0.0616	0.0192	0.0420
	Temporal lobe	−0.0888	−0.0201	−0.1089	0.0659	0.0579	0.0034	−0.0162	−0.0725	Temporal lobe	−0.0013	−0.0069	0.0235	0.0442	0.0149	0.0236	−0.0602	0.0429
	Occipital lobe	−0.0361	0.0397	−0.0879	0.0668	0.0584	0.0572	0.0164	0.0635	Occipital lobe	0.0262	0.0011	0.0804	0.0522	0.0400	0.0341	−0.0030	0.0589
	Insula	−0.0033	0.1431	−0.1148	0.0960	0.1180	0.0576	0.0302	0.1045	Insula	−0.0924	−0.0263	0.1132	0.1187	0.0283	0.1048	−0.0409	0.0461
	Anterior cingulate	0.1137	0.0753	−0.1054	0.0758	0.1409	0.0167	0.0528	0.0881	Anterior cingulate	0.0400	0.0234	0.1431	0.1476	0.0885	0.0660	0.0086	0.0435
	Posterior cingulate	0.1142	0.1112	−0.1398	0.1435	0.1565	0.0736	0.0765	0.1098	Posterior cingulate	−0.0614	0.0640	0.1786	0.1193	0.0751	0.1023	0.0074	0.0348
	Thalamus	0.0468	0.2685	−0.0055	0.2671	0.1891	0.0879	0.1423	0.1163	Thalamus	0.0715	0.1326	0.2627	0.2468	0.1784	0.0919	0.0814	0.0533
	Cerebellum	−0.0391	0.0397	−0.0964	0.0532	−0.0139	−0.0610	−0.0196	0.0580	Cerebellum	0.0034	−0.0094	0.0438	0.0173	0.0138	0.0228	−0.0308	0.0272
	Brainstem	−0.0174	0.0859	−0.0272	0.1674	0.1482	0.0679	0.0708	0.0812	Brainstem	0.1731	0.1178	0.1750	0.1952	0.1653	0.0332	0.0321	0.0264
	Global mean	0.0234	0.0646	−0.1025	0.0896	0.0722	0.0100	0.0262	0.0699	Global mean	0.0015	−0.0010	0.0858	0.0600	0.0366	0.0433	0.024	0.038
FU PK-11195 BP	Participant No.	1	3	6	8	9	10			Participant No.	2	4	5	7
	Regions							Mean	SD	Regions					Mean	SD
	Frontal lobe	0.0672	0.0990	−0.0548	0.1372	0.1108	−0.0514	0.0513	0.0840	Frontal lobe	0.0588	0.0167	0.0791	−0.0149	0.0349	0.0422
	Parietal lobe	0.0422	0.0760	−0.0979	0.1056	0.0651	−0.0572	0.0223	0.0810	Parietal lobe	0.0618	−0.0186	0.0450	−0.0543	0.0085	0.0543
	Temporal lobe	−0.1016	−0.0157	−0.0538	0.0985	0.0597	−0.0507	−0.0106	0.0757	Temporal lobe	−0.0178	−0.0293	−0.0106	−0.0668	−0.0311	0.0250
	Occipital lobe	−0.0664	0.0348	0.0108	0.1189	0.0845	−0.0108	0.0286	0.0667	Occipital lobe	0.0794	−0.0634	0.0150	−0.0535	−0.0056	0.0665
	Insula	−0.0306	0.0741	−0.0504	0.1137	0.1236	−0.1063	0.0207	0.0958	Insula	0.0652	−0.0445	0.0525	−0.0195	0.0134	0.0537
	Anterior cingulate	0.0920	0.0360	−0.0878	0.0821	0.1500	−0.0702	0.0337	0.0947	Anterior cingulate	0.0279	0.0420	0.1234	0.0285	0.0555	0.0458
	Posterior cingulate	0.0974	0.0712	−0.0684	0.1865	0.1669	−0.0151	0.0731	0.1001	Posterior cingulate	0.1174	0.0263	0.1364	−0.0175	0.0657	0.0734
	Thalamus	0.0216	0.1851	0.1608	0.2551	0.1889	0.0544	0.1443	0.0887	Thalamus	0.2287	0.1225	0.1861	0.1495	0.1717	0.0461
	Cerebellum	−0.0843	−0.0402	−0.0119	0.1223	0.0089	−0.0695	−0.0125	0.0746	Cerebellum	0.0251	−0.0422	0.0588	−0.0525	−0.0027	0.0535
	Brainstem	−0.0178	0.0893	0.1294	0.2731	0.1447	0.0080	0.1045	0.1050	Brainstem	0.0948	0.0697	0.2253	0.0702	0.1150	0.0745
	Global mean	0.0046	0.0517	0.0456	0.1236	0.0810	−0.0489	0.0277	0.0698	Global mean	0.0480	−0.0127	0.0529	−0.0363	0.0130	0.0444

Declarations

Acknowledgments

The authors thank study personnel at the Memory Assessment and Research Centre, Southampton, the Institute of Brain, Behaviour and Mental Health, and the Wolfson Molecular Imaging Centre, University of Manchester who were involved in administration, drug delivery, venesection, sample preparation, and imaging procedures. The authors also thank all patients and carers who took part in the study.

Author contributions

AG, AHJ, KH and CH: Conceptualization, Funding acquisition. AG, CH, RS, TG, KM, EV and IL: Investigation, Data curation, Formal Analysis. CH and FT: Formal Analysis. AG and CH: Writing—original draft. All authors: Writing—review & editing.

Conflicts of interest

The authors report no conflict of interest.

Ethical approval

The protocol and consent forms were approved by a multi-centre research ethics committee (South Central-Hampshire A Research Ethics Committee), reference number 15/SC/0435. The study was performed in accordance with the Declaration of Helsinki and principles of Good Practice. An independent data and safety monitoring board monitored adverse events.

Consent to participate

Informed consent to participate in the study was obtained from all participants.

Consent to publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding

The study was funded by the Alzheimer’s Society UK, Alzheimer’s Drug Discovery Foundation and the European Union Seventh Framework Programme [FP7/2007-13] INMIND. Grant agreement number 278850. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Webers A, Heneka MT, Gleeson PA. The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer’s disease. Immunol Cell Biol. 2020;98:28–41. [DOI] [PubMed]

Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45. [DOI] [PubMed] [PMC]

Song WM, Colonna M. The identity and function of microglia in neurodegeneration. Nat Immunol. 2018;19:1048–58. [DOI] [PubMed]

Taipa R, Brochado P, Robinson A, Reis I, Costa P, Mann DM, et al. Patterns of microglial cell activation in Alzheimer disease and frontotemporal Lobar Degeneration. Neurodegener Dis. 2017;17:145–54. [DOI] [PubMed]

Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–9. [DOI] [PubMed]

Turkheimer FE, Rizzo G, Bloomfield PS, Howes O, Zanotti-Fregonara P, Bertoldo A, et al. The methodology of TSPO imaging with positron emission tomography. Biochem Soc Trans. 2015;43:586–92. [DOI] [PubMed] [PMC]

Perani D, Iaccarino L, Jacobs AH; IMBI Brain Imaging Working Group. Application of advanced brain positron emission tomography-based molecular imaging for a biological framework in neurodegenerative proteinopathies. Alzheimers Dement (Amst). 2019;11:327–32. [DOI] [PubMed] [PMC]

Boche D, Gerhard A, Rodriguez-Vieitez E; MINC Faculty. Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2019;46:2831–47. [DOI] [PubMed] [PMC]

Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology. 2009;72:56–62. [DOI] [PubMed] [PMC]

10.

Parbo P, Ismail R, Hansen KV, Amidi A, Mårup FH, Gottrup H, et al. Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer’s disease. Brain. 2017;140:2002–11. [DOI] [PubMed]

11.

Drake C, Boutin H, Jones MS, Denes A, McColl BW, Selvarajah JR, et al. Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immun. 2011;25:1113–22. [DOI] [PubMed] [PMC]

12.

Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73:768–74. [DOI] [PubMed] [PMC]

13.

Butchart J, Brook L, Hopkins V, Teeling J, Püntener U, Culliford D, et al. Etanercept in Alzheimer disease: a randomised, placebo-controlled, double-blind, phase 2 trial. Neurology. 2015;84:2161–8. [DOI] [PubMed] [PMC]

14.

Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9. [DOI] [PubMed] [PMC]

15.

Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllister VL, Marshall J, et al. Cerebral blood flow in dementia. Arch Neurol. 1975;32:632–7. [DOI] [PubMed]

16.

Kobylecki C, Langheinrich T, Hinz R, Vardy ERLC, Brown G, Martino ME, et al. ¹⁸F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease. J Nucl Med. 2015;56:386–91. [DOI] [PubMed]

17.

Joshi AD, Pontecorvo MJ, Clark CM, Carpenter AP, Jennings DL, Sadowsky CH, et al.; Florbetapir F 18 Study Investigators. Performance characteristics of amyloid PET with florbetapir F 18 in patients with Alzheimer’s disease and cognitively normal subjects. J Nucl Med. 2012;53:378–84. [DOI] [PubMed]

18.

Hammers A, Koepp MJ, Richardson MP, Hurlemann R, Brooks DJ, Duncan JS. Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients. Brain. 2003;126:1300–18. [DOI] [PubMed]

19.

Su Z, Herholz K, Gerhard A, Roncaroli F, Du Plessis D, Jackson A, et al. [¹¹C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur J Nucl Med Mol Imaging. 2013;40:1406–19. [DOI] [PubMed] [PMC]

20.

Robb RA, Hanson DP. A software system for interactive and quantitative visualization of multidimensional biomedical images. Australas Phys Eng Sci Med. 1991;14:9–30. [PubMed]

21.

Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695–9. [DOI] [PubMed]

22.

Grober E, Buschke H, Crystal H, Bang S, Dresner R. Screening for dementia by memory testing. Neurology. 1988;38:900. [DOI] [PubMed]

23.

Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20:310–9. [DOI] [PubMed]

24.

Dodel R, Spottke A, Gerhard A, Reuss A, Reinecker S, Schimke N, et al. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [¹¹C] (R)-PK11195 PET (MEMSA-trial). Mov Disord. 2010;25:97–107. [DOI] [PubMed]

25.

Kübler D, Wächter T, Cabanel N, Su Z, Turkheimer FE, Dodel R, et al. Widespread microglial activation in multiple system atrophy. Mov Disord. 2019;34:564–8. [DOI] [PubMed] [PMC]

26.

Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, et al. Reference and target region modeling of [¹¹C]-(R)-PK11195 brain studies. J Nucl Med. 2007;48:158–67. [PubMed]

27.

Hamelin L, Lagarde J, Dorothée G, Potier MC, Corlier F, Kuhnast B, et al. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer’s disease. Brain. 2018;141:1855–70. [DOI] [PubMed]