vascular dementia ( vd ) is the third most common cause of dementia ( 8 to 10% ) , following alzheimer 's disease ( ad ) ( 60 to 70% ) and dementia with lewy bodies ( dlb ) ( 10 to 25% ) , but these numbers vary considerably according to the different criteria used for vad 1,2 .
subcortical ischemic vascular dementia ( sivd ) is an important subtype of them caused by the cerebral vessels factors ( ischemia , hypoxia , etc . ) which lead to brain tissue damage .
it is characterized by lacunar infarcts and deep white matter changes and affects the inner parts of the brain consisting of deep white matter made up of nerve cell fibers . the term 
the syndromes consist of loss of memory , judgment , reasoning , and changes in mood , behavior and communication abilities 3 .
the proportion of vascular dementia ( vad ) attributed to sivd ranges from 36 to 50% , with higher rates in african americans and asian americans 4 than whites 5,6 . for ad patients , brain 's anatomical structures have been analyzed using the vbm ( voxel - based morphometry ) technique recently , demonstrating that the gray matter volume of the hippocampus , parahippocampal gyrus , insula , superior / middle temporal gyrus , thalamus , cingulate gyrus , and superior / inferior parietal lobule is decreased .
volumetric analysis of the entorhinal cortex can even distinguish subjects who were destined to develop dementia from normal controls with high accuracy 7 .
recently it has been found subcortical vascular dementia ( sivd ) patients has notable cortical thickness and volume alterations in frontal and tempral cortices , and the conversion from mci associated with small - vessel disease ( svmci ) to sivd is associated with cortical atrophy in dorsolateral prefrontal and temporal cortices 8 - 9 . until now
alterations of cortical gray matter density in subjects with cognitive impairment have not been reported .
the aim of the present study was to prove the possibility of gray matter density detection using fsl - vbm ( http://www.fmrib.ox.ac.uk/fsl/fslvbm ) 10 - 11 , to characterize the cerebral morphology and atrophy patterns of the cortex , and to provide a new method and biomarker for the diagnosis of sivd .
nine sivd patients were recruited by physician referral from the department of neurology in southwest hospital , chongqing , china ( table 1 ) .
the clinical diagnosis of sivd was made by a senior neurologist according to the criteria suggested by erkinjuntti 12 and dsm - iv ( diagnostic and statistical manual of mental disorders , iv ) .
ad patients with subcortical ischemia or mixed dementia who can also meet dsm - iv vad criteria and the patients with large territorial infarction involving cortex or single strategic infarction such as anterior nucleus of thalamus were excluded .
all patients have visible white matter hyperintensities ( wmh ) ( grade 3 or more by a reported rating scale 13 ) addressed with t2/flair imaging data in mri scanning .
cognitive performance was evaluated through neuropsychological tasks that included : mini mental state examination ( mmse ) , clinical dementia rating ( cdr ) , neuropsychiatric inventory ( npi ) , activities of daily living scale ( adl ) , hachinski and hamilton test .
nine age- and sex - matched old people with normal - cognition were recruited from surrounding regions by advertisement .
they underwent a comprehensive brain examination to ensure that they had normal brain structure and no neurological lesions .
exclusion criteria included patients with aphasia or who otherwise could not complete psychological testing because of a language disorder ; diagnosed chronic or degenerative disease affecting the central nervous system ; active substance abuse disorders ; intracranial hemorrhage ; difficult to control epilepsy that could present with cognitive impairment ; or temporal lobe epilepsy .
all of those subjects who with brain trauma , brain tumor , psychiatric disorders , systemic disease or other mri contraindication such as claustrophobia were excluded from this study . present or past use of medication to treat cognition and infarction was not an exclusion criterion .
all subjects provided informed consents and the ethics committee at the third military medical university approved the study protocols .
the mri brain scanning was performed on a siemens avanto 1.5 tesla scanner with head matrix coil at the department of radiology in southwest hospital , chongqing , china . during the examination ,
scanner noise was attenuated with earplugs and head motion was restricted with foam padding ( provided by the manufacturer ) around the head and the necessity of head immobility was emphasized to each subject .
anatomical image datasets were acquired with a standard t1-weighted high - resolution anatomic scan of magnetization - prepared rapid gradient echo ( mprage ) sequence : tr=1900ms , te=3.37ms , ti=1100ms , flip angle=15 , fov=256mm192 mm , nex=1 , matrix=256192 , 1.001.00 mm in - plane resolution , horizontal slices with slice thickness of 1.3 mm and no gap .
the mprage acquisition of each study was ensured the same slice orientation ( paralleled to the anterior commissure ( ac ) and commissural posterior ( pc ) line ) .
subsequently , t2-weighted ( t2wi ) images with 36 axial slices , 3 mm thick and 1 mm gap , oriented to ac - pc line were obtained . before further analysis of the 3d brain images
the 3d data were copied from the mri scanner and imported to a personal computer running a linux operating system , on which off - line analysis was carried out by anatomical structure image analysis software fsl - vbm .
first , by using mri_convert command , dicom files were completely converted to nii.gz format and then these structural images were brain - extracted using bet 14 in order to remove skin and skull .
next , tissue - type segmentation was carried out using fast4 15 package , after that gray matter , white matter and csf were produced .
the resulting gray - matter partial volume images were then aligned to mni152 standard space using the affine registration tool flirt 16,17 , followed optionally by nonlinear registration using fnirt , which uses a b - spline representation of the registration warp field 18 .
the resulting images were averaged to create a study - specific template in order to reduce the effect of inter - subject brain variability during the registration procedure , to which the native gray matter images were then non - linearly re - registered .
the registered partial volume images were modulated ( to correct for local expansion or contraction ) by dividing using the jacobian of the warp field .
the modulated segmented images were then smoothed with an isotropic gaussian kernel with a sigma of 3 mm for the tfce - based analysis 19 .
finally , differences in cerebral gray matter density between the patient group and control group were assessed by voxelwise glm applied using permutation - based non - parametric testing ( 5000 permutations ) 20 . cluster - size shareholding at p - values<0.05 , fully correcting for multiple comparisons across space , was used .
nine sivd patients were recruited by physician referral from the department of neurology in southwest hospital , chongqing , china ( table 1 ) .
the clinical diagnosis of sivd was made by a senior neurologist according to the criteria suggested by erkinjuntti 12 and dsm - iv ( diagnostic and statistical manual of mental disorders , iv ) .
ad patients with subcortical ischemia or mixed dementia who can also meet dsm - iv vad criteria and the patients with large territorial infarction involving cortex or single strategic infarction such as anterior nucleus of thalamus were excluded .
all patients have visible white matter hyperintensities ( wmh ) ( grade 3 or more by a reported rating scale 13 ) addressed with t2/flair imaging data in mri scanning .
cognitive performance was evaluated through neuropsychological tasks that included : mini mental state examination ( mmse ) , clinical dementia rating ( cdr ) , neuropsychiatric inventory ( npi ) , activities of daily living scale ( adl ) , hachinski and hamilton test .
nine age- and sex - matched old people with normal - cognition were recruited from surrounding regions by advertisement .
they underwent a comprehensive brain examination to ensure that they had normal brain structure and no neurological lesions .
exclusion criteria included patients with aphasia or who otherwise could not complete psychological testing because of a language disorder ; diagnosed chronic or degenerative disease affecting the central nervous system ; active substance abuse disorders ; intracranial hemorrhage ; difficult to control epilepsy that could present with cognitive impairment ; or temporal lobe epilepsy .
all of those subjects who with brain trauma , brain tumor , psychiatric disorders , systemic disease or other mri contraindication such as claustrophobia were excluded from this study . present or past use of medication to treat cognition and infarction was not an exclusion criterion .
all subjects provided informed consents and the ethics committee at the third military medical university approved the study protocols .
the mri brain scanning was performed on a siemens avanto 1.5 tesla scanner with head matrix coil at the department of radiology in southwest hospital , chongqing , china . during the examination ,
scanner noise was attenuated with earplugs and head motion was restricted with foam padding ( provided by the manufacturer ) around the head and the necessity of head immobility was emphasized to each subject .
anatomical image datasets were acquired with a standard t1-weighted high - resolution anatomic scan of magnetization - prepared rapid gradient echo ( mprage ) sequence : tr=1900ms , te=3.37ms , ti=1100ms , flip angle=15 , fov=256mm192 mm , nex=1 , matrix=256192 , 1.001.00 mm in - plane resolution , horizontal slices with slice thickness of 1.3 mm and no gap .
the mprage acquisition of each study was ensured the same slice orientation ( paralleled to the anterior commissure ( ac ) and commissural posterior ( pc ) line ) .
subsequently , t2-weighted ( t2wi ) images with 36 axial slices , 3 mm thick and 1 mm gap , oriented to ac - pc line were obtained .
before further analysis of the 3d brain images , we confirmed that all images were uncontaminated with major head motion .
the 3d data were copied from the mri scanner and imported to a personal computer running a linux operating system , on which off - line analysis was carried out by anatomical structure image analysis software fsl - vbm .
first , by using mri_convert command , dicom files were completely converted to nii.gz format and then these structural images were brain - extracted using bet 14 in order to remove skin and skull .
next , tissue - type segmentation was carried out using fast4 15 package , after that gray matter , white matter and csf were produced .
the resulting gray - matter partial volume images were then aligned to mni152 standard space using the affine registration tool flirt 16,17 , followed optionally by nonlinear registration using fnirt , which uses a b - spline representation of the registration warp field 18 .
the resulting images were averaged to create a study - specific template in order to reduce the effect of inter - subject brain variability during the registration procedure , to which the native gray matter images were then non - linearly re - registered .
the registered partial volume images were modulated ( to correct for local expansion or contraction ) by dividing using the jacobian of the warp field .
the modulated segmented images were then smoothed with an isotropic gaussian kernel with a sigma of 3 mm for the tfce - based analysis 19 . finally , differences in cerebral gray matter density between the patient group and control group were assessed by voxelwise glm applied using permutation - based non - parametric testing ( 5000 permutations ) 20 . cluster - size shareholding at p - values<0.05 , fully correcting for multiple comparisons across space , was used .
the two groups did not differ significantly in age , sex ratio , or education .
the scores include mmse , npi , cdr and adl , as well as those key excluded measuring scales such as hachinski score and hamilton score were summarized in table 1 .
the cerebral gray matter density in sivd patients were found significant decreasing than that of the normal controls in brain regions of thalamus , parietal lobe , frontal lobe and temporal lobe ( p<0.05 ) .
to date , limited studies of cortical gray matter density have been performed due to the lack of efficient methods . before the methods for automatic calculation of cortical thickness were established , measurement of cortical thickness was performed primarily on the basis of manual contouring , which inevitably incurred significant inter - operator variability .
manual measurement also has the drawback of inability to achieve sub - millimeter precision ; therefore the accuracy of the measurements is quite questionable .
fsl - vbm is more accurate than spm - vbm and can found more significant cluster 10 , because this method depends on the degrees of freedom of the non - rigid registration 21 and non - linear registration the alteration in cortical thickness have been well studied in several neurological diseases , such as multiple sclerosis 11 , schizophrenia 10 and so on , by using the fsl - vbm analysis .
svmci patients have been reported cortical thinning in inferior frontal and orbitofrontal gyri , anterior cingulate , insula , superior temporal gyrus , and lingual gyrus , while cortical thinning in sivd patients involved all these areas plus dorsolateral prefrontal and temporal cortices 22 . to our best knowledge , the present study represents the first attempt to adapt this method to analyze the cerebral gray matter density of vascular cognitive impairment . in this study ,
the mri technique and anaphase analysis method provide a new way to study the structure of the brain .
gray matter density in brain regions of thalamus , parietal lobe , frontal lobe and temporal lobe were found decreasing greatly , which mri can detect .
these findings suggest that these brain regions may be the most affected in sivd , that the alterations in gray matter density are a possible characteristic of this type of dementia , and that the measurement of gray matter density in the above regions might help its detection .
temporal lobe has been found closed correlation with memory and emotion . based on experimental evidence from both monkeys as well as humans , the prefrontal cortex has been proved to be important not only for attention , emotion and execution processing , but also for inhibition of " prepotent " habitual 23 . some human diseases , such as schizophrenia , involving prefrontal abnormalities result in impairments in attention conflict paradigms 24 .
for example , the region of the left inferior parietal has been reported to become active when processing words compared to letter strings .
the lateral left inferior region has been reported to be more active when viewing or naming words compared to pictures 25 .
thalamus lesion was found associate with memory damage in animal 26 and other human studies 27 .
previously , by using tc - hmpao spect method , regional cerebral blood flow in thalamus was found decreased significant in vascular dementia when compared with that in the controls 28 .
there is no cure for vascular dementia until now and the focus is currently on early diagnosis and preventing further brain damage .
diagnostic research criteria for sivd are based on magnetic resonance imaging ( mri ) findings including substantial white matter lesions ( wml ) , multiple lacunar infarcts , and neuropsychological tests .
efforts to relate mri - measured lacunes and white matter changes to cognitive impairment have not been straightforward 26,30 . in this study
we found a new biological marker of sivd patients , which can be detected conveniently by fsl -vbm .
as a new atraumatic technology , we believe fsl -vbm has much potential value and could promote the diagnosis of sivd in future .
 background and purpose : the present study was designed to detect the abnormalities of the cerebral grey - matter density in subcortical ischemic vascular dementia patients by fsl - vbm method to promote the early diagnosis of it.methods : nine subcortical ischemic vascular dementia patients and nine age - matched normal controls underwent mri brain structure scanning that was performed on a siemens avanto 1.5 tesla scanner and standard t1-weighted high - resolution anatomic scans of mprage sequence were obtained . 
 the 3-demensional mprage images were processed with fsl - vbm package and the cerebral gray matter density was compared between the subcortical ischemic vascular dementia patients and normal controls.results : compared with the normal control group , the cerebral gray matter density of subcortical ischemic vascular dementia patients was found significantly decreasing , including brain regions of thalamus , parietal lobe , frontal lobe and temporal lobe ( p<0.05).conclusions : the cerebral gray matter density alterations have closed correlation with cognitive dysfunction in subcortical ischemic vascular dementia patient and can be detected by mri . 
 mri has some potential value in the diagnosis of them . 
Introduction
Materials and methods
Subjects
MRI data acquisition
MRI data analysis
Results
Discussion