HAI Book 2025 - Flipbook - Page 278
Lawn, Timothy
Functional submodules in the human locus coeruleus are differentially
susceptible to tau pathology
Timothy Lawn1, Prokopis C. Prokopiou1, Maxime Van Egroo1,2, Nicholas J. Ashton3,4,5,6, Shorena
Janelidze7, Kaj Blennow8,9, Oskar Hansson7,10, Henrik Zetterberg3,11,12,13,14, Heidi I. L. Jacobs1,2
1
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and
Harvard Medical School, 02129, Boston, MA, USA, Boston, MA, US
2
Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre
Limburg, Maastricht University, Maastricht, The Netherlands, Maastricht, NL
3
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy
at the University of Gothenburg, Mölndal, Sweden, Mölndal, SE
4
Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway, Stavanger, NO
5
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical
Neuroscience Institute, London, UK, London, GB
6
NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London
and Maudsley NHS Foundation, London, UK, London, GB
7
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden, Lund, SE
8
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy
at the University of Gothenburg, Mölndal, Sweden, Mölndal, SE
9
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden, Mölndal, SE
10
Memory Clinic, Skåne University Hospital, Malmö, Sweden, Malmö, SE
11
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden, Mölndal, SE
12
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK, London, GB
13
UK Dementia Research Institute at UCL, London, UK, London, GB
14
Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China, Hong Kong, CN
Background: The locus coeruleus(LC) is amongst the earliest brain regions to accrue tau pathology in Alzheimer9s
disease(AD), with its dorso-rostral portion being more vulnerable. This pathology may diminish LC neurons
capacity to deploy their full repertoire of varying tonic and brief phasic activity to meet task demands. Here, we
examine functional vulnerability within the LC, hypothesising dorso-rostral activity shows selectively reduced
task-related variability with increasing tau pathology.
Methods: 87 individuals from a lifespan-cohort(table-1) underwent 7T task-fMRI(high/low arousal images),
provided samples for plasma biomarkers(pTau181, pTau217, and pTau231), and completed the Preclinical
Alzheimer Cognitive Composite(PACC). We utilised Hursts exponent(HE) to quantify the temporal structure of
BOLD fluctuations in each voxel across the entire timeseries, with higher values representing lower variability.
Agglomerative hierarchical clustering was applied to within-LC connectivity matrices to delineate functionally
similar submodules. Robust linear models tested if submodular or caudo-rostral gradients of HE were related
to(or moderated the relationship between) pTau and PACC, controlling for age, sex, education, and framewise
displacement.
Results: Rostral HE was positively associated with pTau231 and pTau181, and this was stronger than
middle/caudal HE for pTau231(fig-1B/C). Rostral HE was negatively associated with PACC(fig-1D), but did not
moderate the relationship between pTau231 or pTau181 and PACC(fig-1E/F). The caudo-rostral HE gradient(fig-2A)
was also associated with both pTau231(fig-2B) and pTau181(fig-2C), with lower caudal-vs-rostral values
corresponding to elevated pTau levels. Whilst HE gradients did not directly relate to PACC, higher gradients were
associated with worse cognitive performance at higher pTau231 and pTau181(fig-2D/E). No relationships were
found for pTau217.
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