In Vivo Tau Pathology is Associated with Synaptic Loss and Altered Synaptic Function

Overview

Journal Alzheimers Res Ther

Date 2021 Feb 6

PMID 33546722

Citations 40

Authors

Emma M Coomans

Deborah N Schoonhoven

Hayel Tuncel

Sander C J Verfaillie

Emma E Wolters

Ronald Boellaard

Rik Ossenkoppele

Anouk den Braber

Wiep Scheper

Patrick Schober

Steven P Sweeney

J Michael Ryan

Robert C Schuit

Albert D Windhorst

Frederik Barkhof

Philip Scheltens

Sandeep S V Golla

Arjan Hillebrand

Alida A Gouw

Bart N M van Berckel

Affiliations

Soon will be listed here.

Abstract

Background: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([F]flortaucipir PET), synaptic density (synaptic vesicle 2A [C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease.

Methods: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [F]flortaucipir PET, dynamic 60-min [C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [F]flortaucipir- and [C]UCB-J-specific binding (binding potential, BP) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [F]flortaucipir BP, [C]UCB-J BP and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models.

Results: Across subjects, higher regional [F]flortaucipir uptake was associated with lower [C]UCB-J uptake. Within subjects, the association between [C]UCB-J and [F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [F]flortaucipir and lower [C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe.

Conclusions: These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

Citing Articles

The relationship between SV2A levels, neural activity, and cognitive function in healthy humans: A [11C]UCB-J PET and fMRI study.

Shatalina E, Onwordi E, Whitehurst T, Whittington A, Mansur A, Arumuham A Imaging Neurosci (Camb). 2025; 2:1-16.

PMID: 39989611 PMC: 11840333. DOI: 10.1162/imag_a_00190.

Resting-State EEG Alpha Rhythms Are Related to CSF Tau Biomarkers in Prodromal Alzheimer's Disease.

Percio C, Lizio R, Lopez S, Noce G, Carpi M, Jakhar D Int J Mol Sci. 2025; 26(1.

PMID: 39796211 PMC: 11720070. DOI: 10.3390/ijms26010356.

Longitudinal synaptic loss versus tau Braak staging in amnestic mild cognitive impairment.

Vanderlinden G, Koole M, Michiels L, Lemmens R, Vandenbulcke M, Van Laere K Alzheimers Dement. 2024; 21(2):e14412.

PMID: 39732507 PMC: 11848342. DOI: 10.1002/alz.14412.

Post mortem validation and mechanistic study of UCB-J in progressive supranuclear palsy patients' brains.

Scarpa M, Vallera E, Auselle-Bosch S, Rocha F, Mercan B, Roy A Alzheimers Dement. 2024; 21(2):e14409.

PMID: 39670533 PMC: 11848344. DOI: 10.1002/alz.14409.

Plasma Glial Fibrillary Acid Protein and Phosphorated Tau 181 Association with Presynaptic Density-Dependent Tau Pathology at F-SynVesT-1 Brain PET Imaging.

Wu J, Li B, Wang J, Huang Q, Chen X, You Z Radiology. 2024; 313(2):e233019.

PMID: 39560478 PMC: 11605102. DOI: 10.1148/radiol.233019.

References

Sperling R . Potential of functional MRI as a biomarker in early Alzheimer's disease. Neurobiol Aging. 2011; 32 Suppl 1:S37-43. PMC: 3233699. DOI: 10.1016/j.neurobiolaging.2011.09.009. View

Finnema S, Nabulsi N, Mercier J, Lin S, Chen M, Matuskey D . Kinetic evaluation and test-retest reproducibility of [C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2017; 38(11):2041-2052. PMC: 6259313. DOI: 10.1177/0271678X17724947. View

Spires-Jones T, Hyman B . The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron. 2014; 82(4):756-71. PMC: 4135182. DOI: 10.1016/j.neuron.2014.05.004. View

Koole M, van Aalst J, Devrome M, Mertens N, Serdons K, Lacroix B . Quantifying SV2A density and drug occupancy in the human brain using [C]UCB-J PET imaging and subcortical white matter as reference tissue. Eur J Nucl Med Mol Imaging. 2018; 46(2):396-406. DOI: 10.1007/s00259-018-4119-8. View

Finnema S, Nabulsi N, Eid T, Detyniecki K, Lin S, Chen M . Imaging synaptic density in the living human brain. Sci Transl Med. 2016; 8(348):348ra96. DOI: 10.1126/scitranslmed.aaf6667. View

Wu J, Hussaini S, Bastille I, Rodriguez G, Mrejeru A, Rilett K . Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016; 19(8):1085-92. PMC: 4961585. DOI: 10.1038/nn.4328. View

Mecca A, Chen M, ODell R, Naganawa M, Toyonaga T, Godek T . In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET. Alzheimers Dement. 2020; 16(7):974-982. PMC: 7383876. DOI: 10.1002/alz.12097. View

Svarer C, Madsen K, Hasselbalch S, Pinborg L, Haugbol S, Frokjaer V . MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage. 2005; 24(4):969-79. DOI: 10.1016/j.neuroimage.2004.10.017. View

Cho H, Choi J, Hwang M, Kim Y, Lee H, Lee H . In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann Neurol. 2016; 80(2):247-58. DOI: 10.1002/ana.24711. View

10.

Scheltens P, Leys D, Barkhof F, Huglo D, Weinstein H, Vermersch P . Atrophy of medial temporal lobes on MRI in "probable" Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry. 1992; 55(10):967-72. PMC: 1015202. DOI: 10.1136/jnnp.55.10.967. View

11.

Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991; 30(4):572-80. DOI: 10.1002/ana.410300410. View

12.

Stancu I, Vasconcelos B, Ris L, Wang P, Villers A, Peeraer E . Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol. 2015; 129(6):875-94. PMC: 4436846. DOI: 10.1007/s00401-015-1413-4. View

13.

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

14.

Hillebrand A, Barnes G, Bosboom J, Berendse H, Stam C . Frequency-dependent functional connectivity within resting-state networks: an atlas-based MEG beamformer solution. Neuroimage. 2011; 59(4):3909-21. PMC: 3382730. DOI: 10.1016/j.neuroimage.2011.11.005. View

15.

Hammers A, Allom R, Koepp M, Free S, Myers R, Lemieux L . Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003; 19(4):224-47. PMC: 6871794. DOI: 10.1002/hbm.10123. View

16.

Vanhaute H, Ceccarini J, Michiels L, Koole M, Sunaert S, Lemmens R . In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment. Neurology. 2020; 95(5):e545-e553. DOI: 10.1212/WNL.0000000000009818. View

17.

Babiloni C, Percio C, Bordet R, Bourriez J, Bentivoglio M, Payoux P . Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer's disease patients. Clin Neurophysiol. 2012; 124(5):837-50. DOI: 10.1016/j.clinph.2012.09.017. View

18.

Callahan L, Vaules W, Coleman P . Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol. 1999; 58(3):275-87. DOI: 10.1097/00005072-199903000-00007. View

19.

Taulu S, Simola J . Spatiotemporal signal space separation method for rejecting nearby interference in MEG measurements. Phys Med Biol. 2006; 51(7):1759-68. DOI: 10.1088/0031-9155/51/7/008. View

20.

Whitford T, Rennie C, Grieve S, Clark C, Gordon E, Williams L . Brain maturation in adolescence: concurrent changes in neuroanatomy and neurophysiology. Hum Brain Mapp. 2006; 28(3):228-37. PMC: 6871488. DOI: 10.1002/hbm.20273. View