Manoj K. Sammi1, Katherine Powers1, Chloe Robinson1, Selda Yildiz1,2, Miranda Lim2,3,4,5,6, Jeffrey J Iliff7,8,9,10,11, and William D Rooney1,2,5,9
1Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, United States, 2Department of Neurology, Oregon Health & Science University, Portland, OR, United States, 3VA Portland Health Care System, Portland, OR, United States, 4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR, United States, 5Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United States, 6Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, United States, 7Department of Neurology, University of Washington, Seattle, WA, United States, 8Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, United States, 9Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, United States, 10VISN 20 Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA, United States, 11Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
Synopsis
Lactate dynamics during sleep-awake cycle in human brain are studied
non-invasively using single voxel diffusion weighted magnetic resonance
spectroscopy (MRS) technique with simultaneous polysomnography (PSG) recordings
to characterize sleep stages. Awake lactate apparent diffusion coefficients (ADC)
values are large compared to other brain metabolites and may support active
transport - Astrocyte-Neuron Lactate Shuttle (ANLS) mechanism. Lactate ADC are
reduced in deep sleep stage in young subjects but are unchanged in older
subjects. These results may reflect
different interstitial fluid exchange activity or changed metabolic state with
aging and require further research.
Introduction
Lactate is an important metabolic
substrate in human brain and can be monitored using magnetic resonance
spectgroscopy.1-3 Lactate
concentration is also modulated by Astrocyte-Neuron Lactate Shuttle (ANLS). Recent work suggests that brain lactate may be
cleared by increased interstitial fluid exchange activity4 during
slow wave sleep stages.5 These
functions may change with age and impact brain metabolism. Here, we investigate lactate dynamics during sleep-wake cycle in aging human
brain using single voxel diffusion weighted spectroscopy.Methods
Subject Recruitment: Three young (YS, 25±2 years, 2 female and 1 male) and
three old human subjects (OS, 57±3 years, 1 female and 2 males) were recruited
and participated under IRB guidelines to study cerebral lactate dynamics under
different sleep stage cycles. Subjects were sleep deprived the night before the
study and avoided any daytime napping, caffeine and alcohol 24 hours prior to
the study.
MRS Pulse Sequence and Parameters: A PRESS pulse sequence was modified
to turn on and off diffusion sensitizing gradients in all three directions (x,
y and z) on alternative scans (Figure 1). A b‑value of 500 s/mm2 (d=25 ms and D=36.6 ms) was used for a voxel placed near
parieto-occipital fissure for diffusion weighting. Rest of the sequence
parameters were kept the same (TE/TR/np/SW/vol = 270/1875 ms/2048/2600Hz/17.1±2.2
mL).
MRS and polysomnography measurements: Subject were scanned early in the
morning at a 3T MR system (Prisma, Siemens Healthcare, Erlangen, Germany) using
a 64-channel head/neck receive RF coil with simultaneously PSG (PSG, electroencephalogram
(EEG), electrooculography(EOG), electrocardiogram (ECG), respiration and 3D
acceleration) recordings using an MR compatible system (Brain Products Inc.,
GmbH, Munich, Germany). After PSG calibration tests, baseline MRS scan and T1‑weighted MPRAGE anatomic scan, MR suite lights were turned off
and subject was asked to sleep. A MRS time series data, with alternating on and
off diffusion gradients during alternative TR durations, were acquired during
different sleep stages for 136±36 minutes.
Data Analysis: Temporally registered PSG data was scored for
each 30 s epoch and classified into 4 sleep stages6: Wake (W) and
non-REM stages (N1, N2, N3) as shown in Figure 2.
Spectra corresponding to Awake (W) and Sleep (N1+N2+N3) sleep stages were binned
and averaged separately into diffusion weighted (S1) and
non-diffusion weighted scans (S0). Individual spectral scans were
phase corrected, zero-filled to 3072 points, Lorentzian line-broadened (2 Hz)
and registered to NAA peak (python, jMRUI-5.17 and Matlab R2017b (The Mathworks, Natick, MA) softwares).
Water peak was digitally suppressed using HLSVD Propack filter8 (jMRUI-5.1). Water suppressed spectra were fit using
LCModel software9 (Figure 3). Apparent diffusion
coefficient (ADC) was calculated for different metabolites NAA, creatine (Cr),
choline (Ch) and lactate (Lac)) using the fitted metabolite signal amplitudes:
ADC = 1/b * ln(S0/S1)
Water signal was fitted as a single peak using AMARES routine in jMRUI-5.1 and
ADC value was calculated using the above equation. Metabolite and water ADC
values were compared in the two sleep stages using Student’s t-test (paired or
unpaired) for reduction in metabolites.Results
Spectra were fit adequately with signal to noise ratio (65±7 for
spectra as determined from LCModel, mean± standard deviation) and discernible lactate peak at 1.33 ppm
(Figure 3). Voxel volume was 20.0 ± 4 and 27.0 ± 0.0 mL for YS and OS, respectively. YS spend 40±19 and 96 ± 39 min in Awake and Sleep stages whereas OS spend 28 ± 4 and 80 ± 29 min, respectively (P ~= 0.4). OS spend marginally less time in N3 sleep stage (11.9 ± 6.8 min) compared to YS (23.3 ± 4.2 min, P = 0.09). Lac ADC values were reduced in deep sleep in YS by 62% (P<0.002)
whereas there was no significant change in ADC values in OS (P=0.96). NAA, Cr,
Ch and water had no significant change in their ADC values (2.9x10-4,
2.4x10-4, 1.7x10-4 and 1.8x10-3 mm2/s, respectively, in Awake stage in YS, Figure 4). Lac ADC values are
marginally smaller in OS compared to YS (P=0.08). Discussion and Conclusions
Lactate ADC value are higher compared to other brain metabolites
indicating an active transport mechanism (ANLS). Its decrease in deep sleep YS may
be explained by increased clearance of Lac with increased interstitial fluid
exchange activity or decreased astroglial activity or active transport (ANLS). This correlates well with our earlier study
looking into decreased lactate concentration changes with sleep. In OS, there is almost no change in ADC
values suggesting an altered metabolism or decreased increased interstitial
fluid exchange component. Further
studies are needed to distinguish influence of these possible mechanisms and bolster
these results.Acknowledgements
Prof. Chris Kroenke’s feed-back on diffusion pulse sequence design is
gratefully acknowledged.
Grants: Paul G. Allen Family Foundation
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