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Basal forebrain volumes predict circuit specific functional sensitivity to the muscarinic M1 receptor antagonist biperiden on cognition

By Geor Bakker, PhD, Pradeep Nathan PhD, Alex Godwood MSc. | Apr 3, 2019

Conference

14th International Conference on Alzheimer’s and Parkinsons’s Diseases (ADPD 2019)
26-31 March, 2019
Lisbon, Portugal

Conference Website

Summary

In a Sosei Heptares led collaboration with the Amsterdam University Medical Centres and Maastricht University, we presented our findings in a poster presentation showing that the basal forebrain nuclei volumes can sensitively predict circuitry specific effects of M1 receptor antagonist biperiden on cognition.

The basal forebrain nuclei produce the majority of brain cholinergic innervation. These findings help validate basal forebrain volumes as potential biomarker to define optimal treatment response as well as stratify patients that are sensitive to drugs targeting the cholinergic system, including M1 and M4 agonists and positive allosteric modulators and acetylcholinesterase inhibitors. This work forms an important part of the goals of Neuroscience Experimental Medicine group to develop novel biomarkers that could support clinical development of drugs targeting the central nervous system at Sosei Heptares.


Poster Abstract

BASAL FOREBRAIN NUCLEI VOLUMES PREDICT FUNCTIONAL SENSITIVITY TO THE MUSCARINIC M1 RECEPTOR ANTAGONIST BIPERIDEN ON VERBAL EPISODIC MEMORY

Geor Bakker1,2,3 , Pradeep Nathan1,5,6 , Alex Godwood1, Claudia Vingerhoets 2,3, Jan Booij 3, Matthan Caan3, Oswald Bloemen2,4, and Thérèse van Amelsvoort2.

1.       Sosei Heptares, Cambridge, United Kingdom
2.       Department of Psychiatry and Psychology, Maastricht University, the Netherlands
3.       Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, the Netherlands
4.       GGZ Centraal, Center for Mental Health Care Innova, Amersfoort, The Netherlands
5.       Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
6.       The Monash School of Psychological Sciences, Monash University, Melbourne, Australia.

Objectives: The basal forebrain cholinergic neurons provide a major source of cholinergic innervation to the cortex and hippocampus and play a critical role in modulating learning and memory, in part through activation of M1 receptors. Smaller basal forebrain nuclei (BFN) volumes have been shown to be associated with faster rates of cognitive deterioration in Alzheimer’s disease (AD). The relationship between BFN volume and M1 receptor sensitivity is unknown and may underlie greater memory impairments. The objective of this study was to assess whether BFN volumes can predict greater cognitive sensitivity to muscarinic M1 receptor antagonism by biperiden. 

Methods: BFN volumes were quantified from T1 weighted 3TMRI scans. A total of 59 subjects (aged 18-40) were scanned. Cognition was assessed twice for all subjects using the Cambridge neuropsychological test automated battery, once under placebo, and once after the administration of 4mg of the M1 selective antagonist biperiden.

Results: Regression analysis showed no significant predictive relationship between the nucleus basalis volumes (CH4) and biperiden induced cognitive impairments. Medial-septal nuclei and the vertical and diagonal band of Broca nuclei (CH1,2,3) that innervate the hippocampal formation, however, did significantly predict biperiden induced impairment on delayed recall of verbal memory, with smaller CH1,2,3 volumes predicting greater impairment on delayed word recall (F=4.81, p=0.032).

Conclusion: M1 receptor modulation of memory may depend on the integrity of basal forebrain cholinergic neurons, The CH1,2,3 BFN volume may be a potential biomarker predictive of superior cognitive efficacy of drugs targeting the cholinergic system including M1 receptor agonists.

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