we retrospectively enrolled 24 cognitively normal subjects , 45 patients with amnestic mild cognitive impairment ( amci ) , 40 with ad , 38 with parkinson s disease - mild cognitive impairment ( pd - mci ) , 31 with pdd , and 22 with dlb from patients seen in the movement disorders and dementia outpatient clinic at a university hospital .
information on the patients cognitive deficits was obtained from a caregiver - based interview . to determine cognitive subsets in the diagnosis of mci or dementia type
, we used the seoul neuropsychological screening battery ( snsb).17 the snsb covers attention , language , praxis , four elements of gerstmann syndrome , visuoconstructive function , verbal and visual memory , and frontal / executive function .
the quantifiable tests used were the digit span ( forward and backward ) , the korean version of the boston naming test,18 the rey complex figure test ( copying , immediate and 20-minute delayed recall , and recognition ) , the seoul verbal learning test ( three learning - free recall trials of 12 words , 20-minute delayed recall trial for these 12 items , and a recognition test ) , the phonemic and semantic controlled oral word association test , and the stroop test ( word and color reading of 112 items during a 2-minute period ) .
age- , sex- , and education - specific norms for each test based on 447 normal subjects are available.17 the scores of these quantifiable cognitive tests were classified as abnormal when they were below the sixteenth percentiles of the norms for the age- , sex- , and education - matched normal subjects .
a patient was diagnosed with amci when at least one of the five cognitive domains , including the memory domain , was abnormal , and the patient did not meet the criteria for dementia . using the concept of mci suggested by petersen et al.19 the diagnosis of mci in patients with pd was made if at least one of the five cognitive domains was abnormal .
all the amci and pd - mci patients had scores on the korean version of the mmse ( k - mmse ) above the sixteenth percentile for the age- and educational - appropriate norm and showed no evidence of deficits in activities of daily living .
the clinical diagnosis of probable ad followed the national institute of neurological and communicative disorders and stroke / alzheimer s disease and related disorders association guidelines.20 patients were assigned to pdd when dementia occurred in the context of well - established pd ( according to the uk parkinson disease society brain bank criteria ) with a time interval of at least 1 year after the onset of the motor syndrome.21,22 probable dlb was diagnosed according to the consensus guidelines of the third report of the dlb consortium.23 exclusion criteria were evidence of focal brain lesions , diffuse white matter hyperintensities , or multiple lacunae in the basal ganglia on mri .
possible medical comorbidities were excluded by laboratory tests , including thyroid function tests , vitamin b12 and folic acid levels , and the vdrl test .
healthy age- and gender - matched elderly volunteers were used as controls for the mri - based volumetric analysis .
they were recruited by advertisements about the project or were healthy relatives of patients with movement disorders or dementia ( n = 24 , age = 72.0 years ) .
all scans of healthy controls and patients with ad , pdd , and dlb were acquired using a philips 3.0-t scanner ( philips intera ; philips medical system , best , the netherlands ) with a sense head coil ( sense factor = 2 ) .
a high - resolution t1-weighted mri volume dataset was obtained for all subjects using the 3d t1-tfe sequence configured with the following acquisition parameters : axial acquisition with a 224  256 matrix ; 256  256 reconstructed matrix with 182 slices in the coronal plane ; 1-mm - thick sections ; 220-mm field of view ; 0.98  0.98  1.2 mm voxels ; te , 4.6 ms ; tr , 9.6 ms ; flip angle , 8 ; slice gap , 0 mm .
the delineation of the si on mri was based on the method reported by george et al.1 the si volume was measured on three consecutive coronal sections using the following demarcation . for the first section at the level of the crossing of the anterior commissure , the ventral aspect of the globus pallidus demarcated the dorsal border of the si , and the ventral border was the base of the brain containing the anterior perforated space .
the medial border of the si was defined by a vertical line extending from the ventrolateral border of the bed nucleus of the brain .
the second section was between the first and third sections , and the third section was at the level of the emergence of the anterior commissure from the temporal lobe . to correct for individual brain size
, the volumes were normalized by dividing by the total intracranial volume derived from sagittally formatted 10-mm slices .
the normalized si volume was defined by the following formula : total si volume ( mm)/total intracranial volume ( mm )  10,000 . the intra- and inter - rater reliability were 0.82 and 0.80 , respectively .
one - way analysis of variance followed by post hoc comparisons was used to compare group differences in age , duration of education , total intracranial volume , normalized si volume , and the k - mmse and clinical dementia rating scores .
pearson s correlation analysis was used to analyze the relationship between si volume and the k - mmse score .
we retrospectively enrolled 24 cognitively normal subjects , 45 patients with amnestic mild cognitive impairment ( amci ) , 40 with ad , 38 with parkinson s disease - mild cognitive impairment ( pd - mci ) , 31 with pdd , and 22 with dlb from patients seen in the movement disorders and dementia outpatient clinic at a university hospital .
information on the patients cognitive deficits was obtained from a caregiver - based interview . to determine cognitive subsets in the diagnosis of mci or dementia type
, we used the seoul neuropsychological screening battery ( snsb).17 the snsb covers attention , language , praxis , four elements of gerstmann syndrome , visuoconstructive function , verbal and visual memory , and frontal / executive function .
the quantifiable tests used were the digit span ( forward and backward ) , the korean version of the boston naming test,18 the rey complex figure test ( copying , immediate and 20-minute delayed recall , and recognition ) , the seoul verbal learning test ( three learning - free recall trials of 12 words , 20-minute delayed recall trial for these 12 items , and a recognition test ) , the phonemic and semantic controlled oral word association test , and the stroop test ( word and color reading of 112 items during a 2-minute period ) .
age- , sex- , and education - specific norms for each test based on 447 normal subjects are available.17 the scores of these quantifiable cognitive tests were classified as abnormal when they were below the sixteenth percentiles of the norms for the age- , sex- , and education - matched normal subjects .
a patient was diagnosed with amci when at least one of the five cognitive domains , including the memory domain , was abnormal , and the patient did not meet the criteria for dementia . using the concept of mci suggested by petersen et al.19 the diagnosis of mci in patients with pd was made if at least one of the five cognitive domains was abnormal .
all the amci and pd - mci patients had scores on the korean version of the mmse ( k - mmse ) above the sixteenth percentile for the age- and educational - appropriate norm and showed no evidence of deficits in activities of daily living .
the clinical diagnosis of probable ad followed the national institute of neurological and communicative disorders and stroke / alzheimer s disease and related disorders association guidelines.20 patients were assigned to pdd when dementia occurred in the context of well - established pd ( according to the uk parkinson disease society brain bank criteria ) with a time interval of at least 1 year after the onset of the motor syndrome.21,22 probable dlb was diagnosed according to the consensus guidelines of the third report of the dlb consortium.23 exclusion criteria were evidence of focal brain lesions , diffuse white matter hyperintensities , or multiple lacunae in the basal ganglia on mri .
possible medical comorbidities were excluded by laboratory tests , including thyroid function tests , vitamin b12 and folic acid levels , and the vdrl test .
healthy age- and gender - matched elderly volunteers were used as controls for the mri - based volumetric analysis .
they were recruited by advertisements about the project or were healthy relatives of patients with movement disorders or dementia ( n = 24 , age = 72.0 years ) .
all scans of healthy controls and patients with ad , pdd , and dlb were acquired using a philips 3.0-t scanner ( philips intera ; philips medical system , best , the netherlands ) with a sense head coil ( sense factor = 2 ) .
a high - resolution t1-weighted mri volume dataset was obtained for all subjects using the 3d t1-tfe sequence configured with the following acquisition parameters : axial acquisition with a 224  256 matrix ; 256  256 reconstructed matrix with 182 slices in the coronal plane ; 1-mm - thick sections ; 220-mm field of view ; 0.98  0.98  1.2 mm voxels ; te , 4.6 ms ; tr , 9.6 ms ; flip angle , 8 ; slice gap , 0 mm .
the delineation of the si on mri was based on the method reported by george et al.1 the si volume was measured on three consecutive coronal sections using the following demarcation . for the first section at the level of the crossing of the anterior commissure , the ventral aspect of the globus pallidus demarcated the dorsal border of the si , and the ventral border was the base of the brain containing the anterior perforated space .
the medial border of the si was defined by a vertical line extending from the ventrolateral border of the bed nucleus of the brain .
the second section was between the first and third sections , and the third section was at the level of the emergence of the anterior commissure from the temporal lobe . to correct for individual brain size
, the volumes were normalized by dividing by the total intracranial volume derived from sagittally formatted 10-mm slices .
the normalized si volume was defined by the following formula : total si volume ( mm)/total intracranial volume ( mm )  10,000 . the intra- and inter - rater reliability were 0.82 and 0.80 , respectively .
one - way analysis of variance followed by post hoc comparisons was used to compare group differences in age , duration of education , total intracranial volume , normalized si volume , and the k - mmse and clinical dementia rating scores .
pearson s correlation analysis was used to analyze the relationship between si volume and the k - mmse score .
no significant difference in age , gender , education level , or total intracranial volume was found among the control , amci , pd - mci , ad , pdd , and dlb groups . compared with the control subjects ( 2.05  0.52 ) ,
the mean normalized si volume was significantly smaller in the patients with amci ( 1.70  0.39 , p = 0.006 ) , pd - mci ( 1.70  0.35 , p = 0.008 ) , ad ( 1.65  0.41 , p < 0.001 ) , pdd ( 1.36  0.32 , p < 0.001 ) , and dlb ( 1.30  0.33 , p < 0.001 ) . compared with the patients with amci , the normalized si volume was significantly smaller in the patients with pdd ( p = 0.003 ) and dlb ( p = 0.001 ) ; however , the volume did not differ significantly from those with ad .
compared with the patients with pd - mci , the normalized si volume was significantly smaller in the patients with pdd ( p = 0.003 ) and dlb ( p = 0.001 ) . on comparison among dementia subjects , the normalized si volume did not differ between patients with pdd and dlb .
however , the normalized si volume was significantly decreased in subjects with pdd ( p = 0.029 ) and dlb ( p = 0.011 ) compared with ad subjects ( figure 1 ) . in patients with ad - related cognitive impairment ( amci or ad )
, there was no significant correlation between the si volume and general cognitive function , as measured using the k - mmse score ( r = 0.045 , p = 0.685 ) ( figure 2b ) .
in contrast , the si volume in subjects with pd - related cognitive impairment ( pd - mci , pdd , or dlb ) showed a significant positive correlation with general cognitive function ( r = 0.366 , p < 0.001 ) ( figure 2a ) .
no significant difference in age , gender , education level , or total intracranial volume was found among the control , amci , pd - mci , ad , pdd , and dlb groups .
compared with the control subjects ( 2.05  0.52 ) , the mean normalized si volume was significantly smaller in the patients with amci ( 1.70  0.39 , p = 0.006 ) , pd - mci ( 1.70  0.35 , p = 0.008 ) , ad ( 1.65  0.41 , p < 0.001 ) , pdd ( 1.36  0.32 , p < 0.001 ) , and dlb ( 1.30  0.33 , p < 0.001 ) . compared with the patients with amci , the normalized si volume was significantly smaller in the patients with pdd ( p = 0.003 ) and dlb ( p = 0.001 ) ; however , the volume did not differ significantly from those with ad . compared with the patients with pd - mci , the normalized si volume was significantly smaller in the patients with pdd ( p = 0.003 ) and dlb ( p = 0.001 ) . on comparison among dementia subjects ,
however , the normalized si volume was significantly decreased in subjects with pdd ( p = 0.029 ) and dlb ( p = 0.011 ) compared with ad subjects ( figure 1 ) .
in patients with ad - related cognitive impairment ( amci or ad ) , there was no significant correlation between the si volume and general cognitive function , as measured using the k - mmse score ( r = 0.045 , p = 0.685 ) ( figure 2b ) .
in contrast , the si volume in subjects with pd - related cognitive impairment ( pd - mci , pdd , or dlb ) showed a significant positive correlation with general cognitive function ( r = 0.366 , p < 0.001 ) ( figure 2a ) .
this study evaluated whether degeneration of the si and its relationship to general cognitive performance differ in ad- and pd - related cognitive impairments .
the major findings of this study were 1 ) the mean normalized si volume was significantly smaller in patients with either amci or pd - mci , 2 ) the loss of si volume was greater in pd - related dementia ( pdd or dlb ) than in ad , and 3 ) si volume was significantly correlated with general cognitive decline only in patients with pdd or dlb .
a few studies have examined si volume using mri in patients with mci ; however , the results are conflicting .
muth et al.24 and grothe et al.25 reported that the si volume was significantly decreased in mci compared with normal elderly controls , whereas george et al.1 showed that the si volume in mci did not differ from that in controls .
in patients with pd , we previously reported that the si volume was significantly decreased in pd - mci compared with the controls.26 in the present study , we found that the si volume was significantly decreased in amci and pd - mci , suggesting that cholinergic degeneration occurs with mci status regardless of the ad or pd prototypes .
studies that compared the si atrophy in ad and dlb by measuring the si length12,13 have shown that the thickness of the si was significantly greater in ad than in dlb , which concurs with our si volume analysis .
our data showed that the normalized si volume was significantly smaller not only in subjects with dlb but also in subjects with pdd compared with ad . because a study showed that cortical cholinergic activity is more severely affected in parkinsonian dementia than in alzheimer disease,14 our result suggests that the degeneration of the cholinergic system arising from the nucleus basalis of meynert is more closely coupled with pd - related dementia than with ad - related dementia . on comparing subjects with alpha - synuclein - related dementia , the normalized si volume did not differ between patients with pdd and dlb .
this result is in line with a functional pet imaging study that showed that the cholinergic activity did not differ between pdd and dlb.8 accordingly , previous data and ours support the concept that pdd and dlb lie on a common disease spectrum with respect to cholinergic pathophysiology .
contrary to previous reports,1 in the subjects with ad - related cognitive impairment ( amci or ad ) , there was no significant correlation between the si volume and general cognitive function .
in contrast , there was a significant positive correlation between the si volume and general cognitive function in the subjects with pd - related cognitive impairment ( pd - mci , pdd , or dlb ) .
this suggests that cognitive performance is closely dependent on the cholinergic system in pd - related cognitive impairment , whereas this relationship is weak in ad - related cognitive impairment .
furthermore , this finding in our study is supported by a previous clinical study indicating that the response to cholinesterase inhibitors is greater in dlb than in ad.2729 in summary , our data suggest that the si volume loss is greater in alpha - synucleinopathy - related dementia ( pdd or dlb ) than in ad , and the contribution of the si to cognitive performance is greater in alpha - synucleinopathy - related cognitive impairments than in ad .
 background and purposethe substantia innominata ( si ) contains the nucleus basalis of meynert , which is the major source of cholinergic input to the cerebral cortex . 
 we hypothesized that degeneration of the si and its relationship to general cognitive performance differs in amyloidopathy and synucleinopathy.methodswe used magnetic resonance imaging ( mri)-based volumetric analysis to evaluate the si volume in patients with amnestic mild cognitive impairment ( amci ) , alzheimer s disease ( ad ) , parkinson s disease - mild cognitive impairment ( pd - mci ) , pd with dementia ( pdd ) , dementia with lewy bodies ( dlb ) , and healthy elderly controls . the correlation between si volume and general cognitive performance , measured using the korean version of the mini - mental state examination ( k - mmse ) , was examined.resultscompared to control subjects , the mean normalized si volume was significantly decreased in all of the other groups . 
 the normalized si volume did not differ between the subjects with pdd and dlb , whereas it was significantly smaller in subjects with pdd ( p = 0.029 ) and dlb ( p = 0.011 ) compared with ad . in subjects with pd - related cognitive impairment ( pd - mci , pdd , or dlb ) 
 , there was a significant positive correlation between the si volume and k - mmse score ( r = 0.366 , p < 0.001 ) , whereas no correlation was seen in subjects with ad - related cognitive impairment ( amci or ad).conclusionsour data suggest that the si loss is greater in synucleinopathy - related dementia ( pdd or dlb ) than in ad and that the contribution of the si to cognitive performance is greater in synucleinopathy than in amyloidopathy . 
Methods
Subjects
MRI acquisition
Volumetric determination of SI
Statistical analysis
Results
Demographic characteristics
Comparison of SI volume among groups
Correlation analysis of SI volume and general cognition
Discussion