Synopsis
Essential
tremor (ET) and Parkinson’s disease (PD) are two most prevalent movement
disorders. It was suggested that tremors in both diseases, though of different
types, may be modulated by neuropathways involving the thalamus. We found a
significant trend of elevated thalamic GABA levels from controls to ET patients
to PD patients, which may be related to the increased risk of ET patients to
develop PD, and thus suggesting thalamic GABA as imaging
marker of preclinical parkinsonism. However, thalamic GABA is not associated
with tremor of either type.Purpose
Essential tremor (ET) and Parkinson’s Disease (PD) are two
distinct, yet common movement disorders
1. One of the
differences lies in the tremor type, which is kinetic tremor for ET and resting
tremor for PD. It was suggested that tremor in both conditions may be modulated by thalamic pathways
1,2,3. A previous study found an increase of thalamic γ-aminobutyric acid (GABA) levels in PD patients
4.
Therefore, this study aims at comparing the levels of thalamic GABA and Glx
(glutamate and glutamine), the main inhibitory and excitatory
neurotransmitters, between PD and ET patients.
Methods
17
PD patients (63±10 yrs), 10 ET patients (73±6 yrs) and 17 healthy controls (58±10yrs)
have been recruited to the study. Tremor levels of PD and ET patients were estimated
using the tremor scores from the Unified Parkinson’s Disease Rating Scale
(UPDRS) III5 and the Washington Heights-Inwood Genetic Study of ET
(WHIGET) tremor rating scale6, respectively. MRI examinations were
performed on a 3T Siemens Tim Trio scanner, equipped with a 32 channel head
coil. Thalamic GABA and Glx levels were measured using MEGA-PRESS7 (TR/TE=2000ms/68ms, 256 averages with editing pulses
at 1.9 and 7.5 ppm, voxel size 25mm×30mm×25mm) and quantified using LCModel8
V6.2-0R. Basis sets were generated from density matrix simulation of the pulse sequence using values for chemical shifts and J-couplings from Kaiser et al9. Water-unsuppressed scans on the same voxels were acquired for eddy current
correction and water scaling. MPRAGE 3D T1-weighted images were acquired for
segmentation. Cerebrospinal fluid (CSF) correction was performed using statistical
parametric mapping (SPM8, Wellcome Department of Imaging Neuroscience, London,
UK) for tissue segmentation and an in-house MATLAB program (MathWorks Inc.,
Natick, MA, USA) for partial volume correction. GABA and Glx levels, corrected
for CSF, were obtained using the method described by Chowdhury et al10.
The voxel placement overlaid on T1-weighted images and segmented gray matter
images, as well as a typical MEGA-edited spectrum are shown in Fig. 1. Group
difference analysis of the GABA and Glx levels across the three groups were performed
using a multiple linear regression model in SAS 9.3. Age and gender were
included in the regression model (Eq.1) as potential confounds11,12.
Separate age-controlled correlations between tremor scores and GABA, as well as
Glx levels, were performed for PD patients (using tremor scores from UPDRS III)
and for ET patients (using tremor scores from WHIGET).
Eq. 1 $$$GABA=a×age+b×group+c×gender+d$$$
Results
Results: Thalamic
GABA levels were found to be highest in PD patients, followed by ET patients
and controls (controls: 1.74±0.30, ET patients: 1.89±0.36, PD patients: 2.06±0.36), as shown in Figure 2. The multiple regression model with GABA as
dependent variable was estimated by setting the group variable to 0 for
controls, 1 for ET cases and 2 for PD patients, according to the distribution
of the mean value of each group. A significant group effect was found in the
regression equation (F(2,42)=3.99,p=0.058,R2=0.16). The estimated
parameters for each variable with the p values are listed in Eq. 2.
Eq. 2 $$$GABA=0.002(p=0.72)×age+0.160(p=0.01)×group-0.050(p=0.61)×gender+1.641$$$
The thalamic Glx levels were highest in ET patients, followed
by similar values in PD patients and controls (controls: 6.54±1.58, ET patients:
7.41±1.63, PD patients: 6.19±1.57). However, by setting the group variable
to be 0 for controls, 1 for PD patients and 2 for ET patients, it was found
that the difference in Glx levels was driven by age, not by group, as shown in
Eq. 3.
Eq. 3 $$$GABA=0.054(p=0.03)×age+0.004(p=0.98)×group-0.049(p=0.91)×gender+3.180$$$
No significant correlation between tremor scores from 1)
UPDRS and GABA levels in PD patients (r=-0.29,p=0.26) or 2) WHIGET scores and
GABA levels in ET patients (r=-0.09,p=0.86) or 3) UPDRS and Glx levels in PD
patients (r=-0.29,p=0.26) or 4) WHIGET scores and GABA levels in ET patients
(r=0.34,p=0.49) was found.
Conclusion
and discussion
The significant positive group effect on GABA
levels shows a trend that thalamic GABA levels of ET patients lies in-between
the significantly increased levels of PD patients
4 and the lower control values. Increased thalamic GABA leads to an over-inhibition of the thalamo-cortical loop and consequently to reduced neuronal excitation of the cortex, explaining the hypokinetic symptoms in PD
13. Yet, as our data shows, there seems to be no association between thalamic GABA and tremor. ET has been identified to significantly increase the risk factor to develop PD
14. Therefore, the trend of increased thalamic GABA levels in ET might possibly be interpreted as imaging marker of preclinical parkinsonism. This would be in line with findings of increased thalamic GABA in non-symptomatic welders and metal workers exposed to Mn
15,16, an exposure that may lead to Mn-induced parkinsonism. A current limitation of our study is the small number of ET patients.
Acknowledgements
This study was supported by NIH/NIEHS R01
ES020529 and NINDS R01 NS085136 from the National Institutes of Health.References
1. Shahed J, and Jankovic J, Exploring the relationship
between essential tremor and Parkinson’s disease. Parkinsonism Rel. Disord.
2007; 13: 67-76.
2. Brooks DJ, Playford ED et al. Isolated tremor and
disruption of the nigrostriatal dopaminergic system: an 18F-dopa PET study.
Neurology 1992; 42:1554–1560.
3. Louis ED. Essential tremor. Lancet Neurol. 2005;4:100-110.
4. Dharmadhikari S. et al. Int. Mag. Res. Med. 2915; 2209.
5. Christopher G. G, Stanley F et al. Movement Disorder
Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale
(MDS-UPDRS): Process, Format, and Clinimetric Testing Plan Movement Disorders.
Mov. Disord. Soc. 2007; 22(1):41-47.
6.
Louis ED. Utility of the hand-drawn spiral as a tool in
clinical-epidemiological research on essential tremor: data from four essential
tremor cohorts: Neuroepidemiology. 2015;44:45-50.
7. Edden RA, Barker PB. Spatial effects in the detection of
gamma-aminobutyric acid: improved sensitivity at high fields using inner volume
saturation. Magn Reson Med. 2007;58:1276-1282.
8. Provencher SW. Estimation of metabolite concentrations
from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30:672-679.
9. Kaiser LG, Young K et al. A detailed analysis of
localized J-difference GABA editing: theoretical and experimental study at 4 T:
NMR Biomed 2008; 21(1):22-32.
10. Chowdhury FA, O'Gorman RL et al. Investigation of
glutamine and GABA levels in patients with idiopathic generalized epilepsy
using MEGAPRESS: J Magn Reson Imaging, 2015; 41(3): 694–699.
11. O'Gorman RL,
Michels L et al. In vivo detection of GABA and glutamate with
MEGA-PRESS: reproducibility and gender effect. J Magn Reson Imaging, 2011; 33(3):
1262-1267.
12. Gao F, Edden RA et al. Edited magnetic resonance
spectroscopy detects an age-related decline in brain GABA levels. Neuroimage,
2013; 78:75-82.
13.
Obeso JA, Rodríguez-Oroz MC, Rodríguez M, Arbizu J, Giménez-Amaya JM. The basal
ganglia and disorders of movement: pathophysiological mechanisms.
Physiology, 2002, 17(2):51-55.
14. Leon JB, Louis ED, Pareja FB. Risk of incicident Parkinson’s disease and parkinsonism in essential tremor: a population based study. J Neurol Neurosurg Psychiatry, 2009; 80: 423-425.
15. Dydak U, Jiang YM, Long LL et al. In vivo measurement of brain GABA concentrations by magnetic resonance spectroscopy in smelters occupationally exposed to manganese. Environ. Health Perspect. 2011; 119(2):219-224.
16. Long Z, Li X-R, Xu J, Edden RAE, Qin W-P, Long L-L, et al. (2014) Thalamic GABA Predicts Fine Motor Performance in Manganese-Exposed Smelter Workers. PLoS ONE 9(2): e88220. doi:10.1371/journal.pone.0088220.