Nicola Spotorno1, Markus Nilsson2, Boel Hansson2, Felix Andersson3, Antonie Leuzy3, Danielle van Westen2, Oskar Hansson3, and Itamar Ronen4
1Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States, 2Department of Diagnostic Radiology, Lund University, Lund, Sweden, 3Department of clinical sciences Malmö, Lund University, Lund, Sweden, 4Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
Synopsis
Intraneuronal tau accumulation is a hallmark of Alzheimer's disease. Currently, positron emission tomography with tau specific ligands (Tau-PET) is the only neuroimaging method for measuring tau in AD. In this study that combines Tau-PET with diffusion weighted MRS we show that the apparent diffusion coefficient of NAA, a neuronal metabolite, is significantly lower in AD patients compared to healthy controls in a brain region that shows elevated levels of uptake of the tau-PET ligand. Standard MRS data shows elevated level of glial metabolites, suggesting concomitant gliosis of neuroinflamation. We propose ADC(tNAA) as a putative marker for tau aggregation in AD.
Introduction
Alzheimer’s disease (AD) is
characterized by aggregation of the proteins amyloid beta (Aβ) and hyperphosphorylated
tau, a protein crucial to the structural stabilization of microtubules.
Although cerebral accumulation of Aβ occurs earlier in the disease time course
of AD, tau pathology is more closely linked to disease outcome1
and the distribution of cortical tau appears to recapitulate disease spreading
in AD2.
Importantly, the onset of tau pathology precedes atrophy and neuronal death3.
So far no MR based modality has provided evidence that can be directly linked
to intracellular tau aggregation and positron emission tomography (PET) is the
only neuroimaging tool for in vivo detection and quantification of cortical tau
pathology.
Diffusion weighted magnetic
resonance spectroscopy (DW-MRS) is a unique tool for probing cytomorphological
properties in a cell-specific manner4.
DW-MRS measures, such as metabolite apparent diffusion coefficients (ADC) are
thus independent from metabolite concentrations measured by standard MRS. We
hypothesized that tau aggregation in neurons will selectively affect the
diffusion of N-acetylaspartate (NAA), a metabolite specific to neurons in the
CNS5, and that changes in the ADC of NAA are independent form changes
in NAA concentration, which are
related to neuronal death. In this study we measured DW-MRS and conventional
MRS in a cohort of AD patients and healthy controls, who were also scanned with
tau-PET. materials and methods
Study population: 5 AD patients (participants
with dementia due to AD, accordingly to published criteria6; patient characteristics in
table 1) and 4 healthy controls with no evidence of cerebral amyloidosis
accordingly to CSF Aβ42/40 ratio (HC) were included so far.
MRI and MRS scans were performed
on a 7T whole-body MRI scanner (Philips medical, Best, The Netherlands)
equipped with a dual transmit 32-channel receive RF coil (Nova, Wilmington MA, USA).
Following a localizer and a T1-weighted image, a 2x2x2 cm3
volume of interest (VOI) was positioned on the posterior cingulate cortex (PCC,
figure 1), a region in which tau accumulates early in the disease time course7-9.
MRS (sLASER, TR/TE=4000/30ms) and DW-MRS (bipolar DW-MRS sequence based on
sLASER, TR/TE=4 heart beats/110ms, 3 orthogonal diffusion weighting directions
at b=100/4000 s/mm2) were acquired, followed by a short acquisition
of the water signal with similar DW conditions for eddy current correction. The
same scans were repeated on a VOI in the anterior cingulate cortex (ACC), a
region in which tau accumulation becomes significant much later in the disease
time course7-9.
PET
protocol: The second-generation tau-PET tracer [18F]-RO-948
(previously referred to as [18F]-RO6958948) was synthesized in
situ,
and PET scans were performed on a GE Discovery 690 PET scanner (General
Electric Medical Systems). FreeSurfer parcellation (v6; http://surfer.nmr.mgh.harvard.edu/), carried out in anatomical MRI space,
was applied to processed, co-registered, and time-averaged PET emission images
in order to extract regional uptake values. [18F]-RO-948 standardized uptake
value ratio (SUVR) images were obtained from the mean uptake over a 70-90 min
post-injection interval10, globally
normalized to the mean uptake in an inferior cerebellar gray matter (reference)
region11. results
Figure 2 shows averaged standardized
uptake value ratio (SUVR) maps of [18F]-RO-948 in the AD patients and in HC. The difference in uptake between
AD and HC is clearly seen, as well as the difference in uptake in AD between
the PCC and ACC. Figure 3 shows the apparent diffusion coefficients (ADC) of
NAA, choline compounds (tCho) and total creatine (tCr) in both VOIs in AD and
HC. The ADC(tNAA) in the PCC of AD was significantly lower than in the PCC of
HC (p=0.0089). The difference in ADC(tNAA) between AD and AC in the ACC VOI was
not significant. Metabolites levels (normalized to tCr) in the PCC also showed
significant differences, particularly a significantly higher level of glial
metabolites (Glutamine, myo-inositol and tCho) in AD than in HC (figure 4).
Differences in NAA levels in neither VOI have reached statistical significance.Discussion and conclusions
Results at this stage
of this project show strong evidence to support the notion that ADC(tNAA) is a
putative biomarker for intraneuronal tau aggregation in AD. Intracellular
diffusion has already been shown to be sensitive to cytomorphological changes
in disease, and previous studies in multiple sclerosis already indicated the
potential of ADC(tNAA) as a marker for intraneuronal pathology12 13.
While tNAA concentration differences in the PCC between AD and HC were not
significant, concentration of glial markers associated with inflammatory
processes and gliosis showed significant differences in the PCC between AD and
HC, contributing to the overall picture of pathology in the PCC in this cohort.
As additional analyses when more subjects are included, we intend to correlate
individual ADC(tNAA) and [tNAA] with average SUVR [18F]-RO-948 values within the
spectroscopic VOIs in the PCC and ACC to provide converging evidence that
differences in ADC(tNAA) are related to tau aggregation.We will
also include early stage AD patients (MCI) to examine whether DW-MRS detects
changes in ADC(tNAA) that precede atrophy and drop in tNAA concentrations. We
will also analyze DTI data acquired from the same cohort (not shown) for
correlation with water diffusion values. In conclusion, ADC(tNAA) as measured
by DW-MRS is a promising specific putative marker for intracellular tau
aggregation in AD, and uniquely enriches the pathological picture of AD
provided by MR.Acknowledgements
No acknowledgement found.References
- Jack CR, Jr., Bennett
DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition
of Alzheimer's disease. Alzheimers Dement
2018;14(4):535-62. doi: 10.1016/j.jalz.2018.02.018 [published Online First:
2018/04/15]
- Vogel JW,
Mattsson N, Iturria-Medina Y, et al. Data-driven approaches for tau-PET imaging
biomarkers in Alzheimer's disease. Hum
Brain Mapp 2019;40(2):638-51. doi: 10.1002/hbm.24401 [published Online
First: 2018/10/29]
- Cavedo E,
Lista S, Khachaturian Z, et al. The Road Ahead to Cure Alzheimer's Disease:
Development of Biological Markers and Neuroimaging Methods for Prevention
Trials Across all Stages and Target Populations. The journal of prevention of Alzheimer's disease 2014;1(3):181-202.
doi: 10.14283/jpad.2014.32 [published Online First: 2015/10/20]
- Palombo M,
Shemesh N, Ronen I, et al. Insights into brain microstructure from in vivo
DW-MRS. Neuroimage 2017 doi:
10.1016/j.neuroimage.2017.11.028
- Choi JK,
Dedeoglu A, Jenkins BG. Application of MRS to mouse models of neurodegenerative
illness. NMR Biomed
2007;20(3):216-37. doi: 10.1002/nbm.1145
- Diagnostic and
Statistical Manual of Mental Disorders. fifth ed: American Psychiatric
Association 2013.
- Palmqvist S, Scholl M, Strandberg O, et al. Earliest
accumulation of beta-amyloid occurs within the default-mode network and
concurrently affects brain connectivity. Nat
Commun 2017;8(1):1214. doi: 10.1038/s41467-017-01150-x [published Online
First: 2017/11/02]
- Hoenig MC,
Bischof GN, Seemiller J, et al. Networks of tau distribution in Alzheimer's
disease. Brain 2018;141(2):568-81.
doi: 10.1093/brain/awx353 [published Online First: 2018/01/10]
- Jacobs HIL,
Hedden T, Schultz AP, et al. Structural tract alterations predict downstream
tau accumulation in amyloid-positive older individuals. Nat Neurosci 2018;21(3):424-31. doi: 10.1038/s41593-018-0070-z
[published Online First: 2018/02/07]
- Kuwabara H,
Comley RA, Borroni E, et al. Evaluation of (18)F-RO-948 PET for Quantitative
Assessment of Tau Accumulation in the Human Brain. J Nucl Med 2018;59(12):1877-84. doi: 10.2967/jnumed.118.214437
[published Online First: 2018/08/12]
- Maass A,
Landau S, Baker SL, et al. Comparison of multiple tau-PET measures as
biomarkers in aging and Alzheimer's disease. Neuroimage 2017;157:448-63. doi: 10.1016/j.neuroimage.2017.05.058
[published Online First: 2017/06/08]
- Wood ET,
Ercan E, Sati P, et al. Longitudinal MR spectroscopy of neurodegeneration in
multiple sclerosis with diffusion of the intra-axonal constituent
N-acetylaspartate. Neuroimage Clin
2017;15:780-88. doi: 10.1016/j.nicl.2017.06.028
- Wood ET, Ronen I, Techawiboonwong A, et al. Investigating axonal damage in
multiple sclerosis by diffusion tensor spectroscopy. J Neurosci 2012;32(19):6665-9. doi: 10.1523/JNEUROSCI.0044-12.201232/19/6665
[pii] [published Online First: 2012/05/11]