the role of m1 signalling in cognitive and behavioural

The Role of M1 Signalling in Cognitive and Behavioural Symptoms of Psychosis

Dr. Geor Bakker

Department of Psychiatry and Psychology, University of Maastricht, NetherlandsDepartment of Radiology and Nuclear Medicine, Amsterdam UMC, Netherlands

Conflicts of interest

Currently employed at Sosei Heptares, Cambridge, UK

Indications for Loss of M1 signalling in Psychotic disorders

• Lower M1 receptor expression post-mortem in DLPFC in schizophrenia patients1

• Reduced M1 and M4 receptor availability in schizophrenia patients compared to controls2

• Dual M1 and M4 agonist xanomeline improved learning and memory scores and BPRS scores 3

• xanomeline + trospium (KARX-T) shows efficacy in Phase 2 studies on psychotic symptom severity 4

1Scarr E, Hopper S, Vos V, et al. Low levels of muscarinic M1 receptor-positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia. J Psychiatry Neurosci. 2018;43(5):338-346. 2Raedler TJ, Knable MB, Jones DW, Urbina RA, Egan MF, Weinberger DR. Central muscarinic acetylcholine receptor availability in patients treated with clozapine. Neuropsychopharmacology. 2003 Aug;28(8):1531-7. 3Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-9. 4https://clinicaltrials.gov/ct2/show/NCT03697252

Proposed mechanisms

• M1 highly expressed in PFC and hippocampus and modulates glutamate signalling involved in neuroplasticity (long term potentiation)

• M4 subtype heteroreceptor on glutamatergic and dopaminergic neurons and thereby modulates these neurotransmitters in the hippocampus and striatum.

Grace, A. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 17, 524–532 (2016). https://doi.org/10.1038/nrn.2016.57

Randomised Placebo Controlled Cross over Design with SPECT + PhMRI

• M1 receptor binding measured with M1 preferring radiotracer 123I-IDEX. (see Bakker et al 20151)

• Difference in fMRI response to selective M1/4 antagonism by biperiden

1. Bakker G, Vingerhoets WA, van Wieringen JP, de Bruin K, Eersels J, de Jong J, Chahid Y, Rutten BP, DuBois S, Watson M, Mogg AJ, Xiao H, Crabtree M, Collier DA, Felder CC, Barth VN, Broad LM, Bloemen OJ, van Amelsvoort TA, Booij J. 123I-iododexetimide preferentially binds to the muscarinic receptor subtype M1 in vivo. J Nucl Med. 2015 Feb;56(2):317-22. doi: 10.2967/jnumed.114.147488. Epub 2015 Jan 15. PMID: 25593117.

fMRI - scan 3T

cognitive assessment

CANTAB

123I-IDEXSPECT scanInSPira HD

Visit 1 Visit 2

fMRI –scan 3T

cognitive assessment

CANTAB

Clinical assessments

Counterbalanced

Clinical assessments

Min. 7 days

Psychotic disorder +matched controlsPsychotic disorder +matched controls

Psychotic disorder only

Placebo Biperiden (4mg)

123I-IDEX SPECT M1 receptor binding in psychotic disorders in-vivo

All Medication free; N=5 antipsychotics naïveEarly phase of the disorderN=30 (20 male/ 10 female)

Mean SD

Age (yrs) 28.47 5.39Age of onset (yrs) 20.90 6.49IQ 99.97 15.14

Psychotic symptoms at time of scanningPANSS positive scores 12.13 4.9PANSS negative scores 12.00 5.14PANSS general psychiatry 23.67 6.60

Psychotic disorder subtype (DSM IV and CASH confirmed)Schizophrenia 12Schizophreniform Disorder 2Schizo-affective 3Psychosis NOS 13Number of psychotic episodes : 1/2/3/4 20/6/3/1

Bakker, G., Vingerhoets, C., Boucherie, D., Caan, M., Bloemen, O., Eersels, J., Booij, J., and van Amelsvoort, T. (2018). Relationship between muscarinic M1receptor binding and cognition in medication-free subjects with psychosis. NeuroImage Clin. 18, 713–719.

Measuring M1 binding potential with 123I-IDEX SPECT and Cognition

- M1 Specific binding potential (BPs) assessed in DLPFC, hippocampus and striatum

- Cerebellar grey matter used to measure non-specific BPns

M1 BPnon-displaced (nd) = (BPs- BPns)/ BPns

Where, BP= Bmax/Kd

Subtest Cognitive Domain DeficitPaired Associate Learning (PAL)

Associative learning and memory

Verbal Recognition Memory (VRM)

verbal learning and memory

Spatial Working Memory (SWM) working memoryRapid Visual Processing (RVP)

Sustained attention and vigilance

Reaction Time (RTI) processing speedOne Touch Stockings of Cambridge (OTS)

problem solving and reasoning

Emotion Recognition Test (ERT) social cognition

DLPFC Hippocampus& Striatum

CANTAB- schizophrenia battery


Vingerhoets C, Bakker G, van Dijk J, Bloemen OJN, Wang Y, Chan RCK, Booij J, van Amelsvoort TAMJ. The effect of the muscarinic M1 receptor antagonist biperiden on cognition in medication free subjects with psychosis. Eur Neuropsychopharmacol. 2017 Sep;27(9):854-864. doi: 10.1016/j.euroneuro.2017.06.014. Epub 2017 Jul 6. PMID: 28689687.

M1 BPnd associated with verbal learning and memory on VRM


Lower M1 BPnd in the DLPFC associated with Greater Negative Symptoms


No mediation effect for M1 binding on symptoms


M1 BPndDPFC

Negative symptom severity

Verbal learning and

memory

Conclusions

1. Lower M1 binding in the DLPFC seems to be related to negative symptom severity.

1. Follow-up studies are needed with more variance in severity of psychotic symptoms

2. Lower M1 binding in the DLPFC associated with worse verbal learning and memory

1. M1 binding in de hippocampus specifically related to memory.


Functional MRI with 4mg of Biperiden: PAL task

Greater hippocampal hyperactivity in response to M1/4 antagonist Biperiden: Loss of M1 receptor reserve

Bakker G, Vingerhoets C, Bloemen OJN, et al. The muscarinic M1 receptor modulates associative learning and memory in psychotic disorders. Neuroimage Clin. 2020;27:102278.

Greater Functional Hyperactivity to Biperiden loss of reserve of M1

Greater abnormal hyperactivity after biperiden

Lower abnormal hyperactivity after biperiden

Bakker G, Vingerhoets C, Bloemen OJN, et al. The muscarinic M1 receptor modulates associative learning and memory in psychotic disorders. Neuroimage Clin. 2020;27:102278. doi:10.1016/j.nicl.2020.102278

Conclusions + Future Directions

Preliminary data suggests a loss of M1 receptor reserve underlying associative learning and memory processes in early phase of psychotic disorders.

Lower M1 binding involved learning and memory in psychotic disorders – with no associations found with other cognitive domains.

Lower DLPFC M1 receptor signalling may play a role in the development of negative symptoms.

Cannot rule out that some effects- particularly in the limbic areas may in part be driven by M4.

Selective tracers needed to dis-entangle relative contributions of M1 and M4 signalling on cognitive and behavioural symptoms

Selective and safe M1 agonist compounds have been developed with pharmacodynamic effects on cognition1 and selective M4 compounds hold promise for treatment of cognitive and behavioural symptoms in psychotic disorders.

Brown AJH, Bradley SJ, Brown GA, Bennett KA, Brown J, Cansfield JE, et al. From Structure to Clinic: Discovery of A M1 Muscarinic Acetylcholine Receptor Agonist for the Treatment of Memory Loss in Alzheimer's Disease.

Funding

• Dutch Organization for Health Research and Development (ZonMW)

• Netherlands Brain Foundation

Acknowledgements

Maastricht University

• Dr. Claudia Vingerhoets • MSc Daphne Boucherie• Prof Dr.Therese van Amelsvoort

Amsterdam UMC

• Prof. Dr. Jan Booij• Dr. Eng. Matthan Caan

GGZ-Centraal • Dr. Oswald Bloemen

University of Cambridge• Prof. Dr. Barbara Sahakian• Prof Dr. Pradeep Nathan

Sosei Heptares• Dr. Alastair Brown• Dr. Tim Tasker

the role of m1 signalling in cognitive and behavioural

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