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Considering total intracranial volume and other nuisance variables in brain voxel based morphometry in idiopathic PD

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Samuel Crowley
Samuel Crowley
Samuel Crowley
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Haiqing Huang at University of Pittsburgh
Haiqing Huang
Jared J. Tanner at University of Florida
Jared J. Tanner
Qing Zho
Qing Zho
Qing Zho
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Abstract and Figures

Voxel-based morphometry (VBM) studies of Parkinson’s disease (PD), have yielded mixed results, possibly due to several studies not accounting for common nuisance variables (age, sex, and total intracranial volume [TICV]). TICV is particularly important because there is evidence for larger TICV in PD. We explored the influence of these covariates on VBM by 1) comparing PD patients and controls before adding covariates, after adding age and sex, and after adding age, sex and TICV, and 2) by comparing controls split into large and small TICV before and after controlling for TICV, with age and sex accounted for in both analyses. Experiment 1 consisted of 40 PD participants and 40 controls. Experiment 2 consisted of 88 controls median split by TICV. All participants completed an MRI on a 3 T scanner. TICV was calculated as gray + white + CSF from Freesurfer. VBM was performed on T1 images using an optimized VBM protocol. Volume differences were assessed using a voxel-wise GLM analysis. Clusters were considered significant at >10 voxels and p < .05 corrected for familywise error. Before controlling for covariates, PD showed reduced GM in temporal, occipital, and cerebellar regions. Controlling for age and sex did not affect the pattern of significance. Controlling for TICV reduced the size of the significant region although it still contained portions of bilateral temporal lobes, occipital lobes and cerebellum. The large TICV group showed reduced volume in temporal, parietal, and cerebellar areas. None of these differences survived controlling for TICV. This demonstrates that TICV influences VBM results independently from other factors. Controlling for TICV in VBM studies is recommended.
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ORIGINAL RESEARCH
Considering total intracranial volume and other nuisance
variables in brain voxel based morphometry in idiopathic PD
Samuel Crowley
1
&Haiqing Huang
2
&Jared Tanner
1
&Qing Zhao
2
&Nadine A. Schwab
1
&
Loren Hizel
1
&Daniel Ramon
1
&Babette Brumback
3
&Mingzhou Ding
2
&
Catherine C. Price
1,4
#Springer Science+Business Media New York 2017
Abstract Voxel-based morphometry (VBM) studies of
Parkinson’s disease (PD), have yielded mixed results, possibly
due to several studies not accounting for common nuisance
variables (age, sex, and total intracranial volume [TICV]).
TICV is particularly important because there is evidence for
larger TICV in PD. We explored the influence of these covari-
ates on VBM by 1) comparing PD patients and controls before
adding covariates, after adding age and sex, and after adding
age, sex and TICV, and 2) by comparing controls split into large
and small TICV before and after controlling for TICV, with age
and sex accounted for in both analyses. Experiment 1 consisted
of 40 PD participants and 40 controls. Experiment 2 consisted of
88 controls median split by TICV. All participants completed an
MRIona3Tscanner.TICVwascalculatedasgray+white+
CSF from Freesurfer. VBM was performed on T1 images using
an optimized VBM protocol. Volume differences were assessed
using a voxel-wise GLM analysis. Clusters were considered
significant at >10 voxels and p< .05 corrected for familywise
error. Before controlling for covariates, PD showed reduced GM
in temporal, occipital, and cerebellar regions. Controlling for age
and sex did not affect the pattern of significance. Controlling for
TICV reduced the size of the significant region although it still
contained portions of bilateral temporal lobes, occipital lobes
and cerebellum. The large TICV group showed reduced volume
in temporal, parietal, and cerebellar areas. None of these differ-
ences survived controlling for TICV. This demonstrates that
TICV influences VBM results independently from other factors.
Controlling for TICV in VBM studies is recommended.
Keywords Voxel-based morphometry .VBM .Parkinson’s
disease .Structural MRI .Total intracranial volume .TICV .
TIV
Introduction
Structural MRI is a powerful tool for assessing brain volume
differences, particularly in the context of neurodegenerative
disease such as Parkinson’s disease (PD). It offers insight into
neuroanatomical differences in PD and informs how different
presentations of PD (for example, PD with and without de-
mentia) may differ in terms of whole brain or regional vol-
umes. There are several methods for determining structural or
volumetric brain differences. One popular method is voxel-
based morphomety (VBM), commonly used because it does
not rely on pre-determined brain structures.
VBM has been employed in several studies of PD with
mixed results ranging from widespread volumetric declines
in PD to no differences between individuals with PD and
demographically matched peers (Table 1). Several researchers
have reported regional volumetric decreases in temporal, pa-
rietal, and occipital areas in idiopathic PD relative to peers. In
The original version of this article was revised: QingZhao was incorrectly
spelled as Qing Zho.
Electronic supplementary material The online version of this article
(doi:10.1007/s11682-016-9656-9) contains supplementary material,
which is available to authorized users.
*Catherine C. Price
cep23@phhp.ufl.edu
1
Department of Clinical andHealth Psychology, University of Florida,
1225 Center Drive, Gainesville, FL 32611, USA
2
Department of Biomedical Engineering, University of Florida, 1275
Center Drive, Gainesville, FL 32611, USA
3
Department of Biostatistics, University of Florida, 2004 Mowry
Road, 5th Floor CTRB, Gainesville, FL 32611, USA
4
Clinical and Health Psychology, University of Florida, 101 S. Newell
Drive, PO Box 100165, Gainesville, FL 32610, USA
DOI 10.1007/s11682-016-9656-9
Published online: 9 January 2017
Brain Imaging and Behavior (2018) 12:1–12
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... As a sensitivity analysis, we performed GWAS in the UK Biobank cohort for subcortical brain volumes without adjusting for ICV (Methods and Supplementary Figs. [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78]. The direction and magnitude of SNP effect sizes were largely consistent as suggested by Pearson's correlations using the SNP effect sizes for the same phenotype with and without the adjusting for ICV (correlations range = 0.81-0.92). ...
... All participants included in the present study provided written informed consent, and the investigators in the participating studies obtained approval from their institutional review board or equivalent organization. Individual GWAS for subcortical brain volumes were adjusted for ICV, as this reduces interindividual variation in subcortical brain volume simply due to head size differences 68 . The meta-analyses were performed using MTAG (v1.0.8) 69 . ...
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... All participants included in the present study provided written informed consent and the investigators on the participating studies obtained approval from their institutional review board or equivalent organisation. Individual GWAS for subcortical brain volumes were adjusted for ICV, as this reduces inter-individual variation in subcortical brain volume simply due to head size differences 68 . The meta-analyses were performed using MTAG v1.0.8 69 . ...
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... We labelled significant clusters using the Dartel space Neuromorphometrics atlas. We used the covariates age, sex, and TIV in all analyses (Crowley et al., 2018;Hyatt et al., 2020). Effect sizes were obtained from the tand F-values and degrees of freedom as provided by SPM12 (Lakens, 2013). ...
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... Similarly, as a sensitivity analysis, we conducted Mendelian randomisation analyses. Our results support previous observations of individuals with PD having a larger ICV 18,60 . Nonetheless, until now, the directionality and investigation of potential causal effects of intracranial and subcortical brain volumes and PD were unclear. ...
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... Beside age, one might discuss sex as a potential bias. Of note, a recent study has investigated the impact of the covariates total intracranial volume, age and sex on voxel based morphometry results in another neurodegenerative disease, Parkinson's disease (Crowley et al., 2018). Remarkably, total intracranial volume had an impact on results, whereas the covariates age and sex were negligible. ...
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Article
  • Aug 2013
Whereas the motor dysfunction in Parkinson's disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss. High-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences. PD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients. Non-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized "frontal lobe" function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure-function relationships is needed to understand the neural bases of symptom progression in PD.
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