This paper by many authors worldwide, including Prof Masters, tells how grey matter networks become disrupted as happens in neurodegenerative diseases. These network disruptions are related to impaired cognition and future cognitive decline, both in sporadic and autosomal dominant AD.

The authors' summary says: "To summarize, loss of synaptic integrity and, in particular, axonal integrity, as evidenced by increased NfL in CSF, appears to be related to disrupted grey matter network organization in ADAD (autosomal dominant AD). These findings suggest that normalization of neuronal injury or synaptic processes might lead to stabilization or improvement of grey matter network integrity". I just hope that PBT2 will just do this normalization. Masters could have a hint of that in the Imagine study he designed if there is some CSF left in the ice box (???).

Nfl (neurofilament light) is also a measure in the ATH434 MSA phase 2 study and IMO it will be used the future AD studies by Masters when he gets started with his new license agreement studies with ATH.

Better to read the free paper than only the abstract below. IMO this paper is a good step forward in understanding what happens when developing impaired cognition.

medRxiv

. 2023 Mar 22;2023.03.21.23287468.

doi: 10.1101/2023.03.21.23287468. Preprint

Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease

L Vermunt, C Sutphen, E Dicks, D M de Leeuw, R Allegri, S B Berman, D M Cash, J P Chhatwal, C Cruchaga, G Day, M Ewers, M Farlow, N C Fox, B Ghetti, N Graff-Radford, J Hassenstab, M Jucker, C M Karch, J Kuhle, C Laske, J Levin, C L Masters, E McDade, H Mori, J C Morris, R J Perrin, O Preische, P R Schofield, M Suárez-Calvet, C Xiong, P Scheltens, C E Teunissen, P J Visser, R J Bateman, T L S Benzinger, A M Fagan, B A Gordon, B M Tijms

• PMID: 37016671

PMCID: PMC10071836 DOI: 10.1101/2023.03.21.23287468Free PMC article

Abstract

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aβ, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.

Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.