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Neurological soft signs in persons with amnestic mild cognitive impairment and the relationships to neuropsychological functions

Neurological soft signs in persons with amnestic mild cognitive impairment and the relationships... Background: Neurological abnormalities have been reported in people with amnestic mild cognitive impairment (aMCI). The current study aimed to examine the prevalence of neurological soft signs (NSS) in this clinical group and to examine the relationship of NSS to other neuropsychological performances. Methods: Twenty-nine people with aMCI and 28 cognitively healthy elderly people were recruited for the present study. The NSS subscales (motor coordination, sensory integration, and disinhibition) of the Cambridge Neurological Inventory and a set of neuropsychological tests were administered to all the participants. Results: People with aMCI exhibited significantly more motor coordination signs, disinhibition signs, and total NSS than normal controls. Correlation analysis showed that the motor coordination subscale score and total score of NSS were significantly inversely correlated with the combined Z-score of neuropsychological tests in aMCI group. Conclusions: These preliminary findings suggested that people with aMCI demonstrated a higher prevalence of NSS compared to healthy elderly people. Moreover, NSS was found to be inversely correlated with the neuropsychological performances in persons with aMCI. When taken together, these findings suggested that NSS may play a potential important role and serve as a tool to assist in the early detection of aMCI. Keywords: Mild cognitive impairment, Neurological soft signs, Neuropsychological tests Introduction neurological soft signs (NSS) might be associated with Alzheimer’s disease (AD) is the most commonly specific brain regions or even brain connections [5-8]. acquired neurodegenerative disease in elderly people [1]. For example, researchers found that higher rates of Mild cognitive impairment (MCI) is considered as a motor coordination and sensory integration signs were transitional state of normal aging and AD [2], and was associated with a reduction of grey matter volume of also thought to be the earliest clinical manifestation of subcortical structures, including putamen, globus palli- common age-related neurological abnormalities, includ- dus and thalamus in both patients with first-onset ing AD [3]. schizophrenia and healthy volunteers [5,6]. Chan et al. Neurological abnormalities have traditionally been (2006) also showed that brain areas such as bilateral sen- divided into “hard signs” and “soft signs” [4]. “Hard sorimotor, supplementary motor area, left parietal, and signs” usually indicate focal neurological deficits localized right cerebellum were activated during the fist-edge- within specific brain regions, whereas “soft signs” are palm task [7]. Furthermore, the fist-edge-palm task as a conventionally defined as subtle signs without an identifi- soft sign for motor coordinaiton has been shown to be able or localized brain region [4]. However, most recent linked to connectivity between the right inferior and studies using brain imaging technologies suggested that middle prefrontal cortices in healthy control subjects [8]. Patients with AD have also been found to demonstrate significantly higher prevalence of sensory integration * Correspondence: lijuan@psych.ac.cn 1 and motor coordination signs than healthy controls [9]. Center on Aging Psychology, Key Laboratory of Mental Health, Institute of Other studies also found NSS abnormalities in patients Psychology, Chinese Academy of Sciences, Beijing, China Full list of author information is available at the end of the article © 2012 Li et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Li et al. Behavioral and Brain Functions 2012, 8:29 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 with AD [10,11]. Kumamoto et al. (2000) found elderly aMCI was associated with a higher prevalence of NSS as people that were cognitively impaired but not demented, compared to healthy older adults. Moreover, NSS was had exhibited higher frequency of neurological signs expected to show negative association with neuro- than healthy controls, but lower rate of signs than psychological performances in this clinical group. patients with dementia [12]. Gualtieri et al. (2005) also found that individuals with MCI showed poorer per- Methods formance in a finger tapping task in which participants Subjects were required to tap on the mouse button [13]. A previ- Patients with aMCI in this study were recruited from ous study implied that NSS might be a predictor for pro- the communities around the Institute of Psychology, gression to clinical AD [14]. Yet so far there is no Chinese Academy of Sciences and memory clinic of In- empirical study to systematically explore the NSS in stitute of Mental Health, Peking University. One hun- individuals with aMCI. In the present study, we hypothe- dred and sixty-seven participants aged between 60– sized that individuals with aMCI would demonstrate 87 years were screened from the residential communi- more NSS than normal elderly individuals, and that NSS ties. Among them, 18 were screened as patients with might be taken as an easy-identified neurological marker aMCI. Moreover, 11 individuals with aMCI were referred for early detection of AD. by the psychiatrists of the memory clinic. The diagnoses Neuropsychological performance is considered to be of aMCI were made according to published criteria one of the most sensitive and specific markers of pro- [2,26]. Participants were interviewed to determine dromal AD [15]. Previous studies indicated that cogni- whether they had memory complaint, normal general tive decline in patients with MCI was associated with cognitive function (measured by Mini-Mental State widespread structural brain damage [16]. As we know, Examination, MMSE) [27], and normal activities of daily the executive function aging is the main cause of the living [28]. Objective memory impairment was verified cognitive decline in older adults. The so called “frontal with paired-association learning and portrait characteris- hypothesis of cognitive aging” suggests that the pre- tics recall tests, which were two subtests of the standar- frontal cortex deteriorated earlier and disproportionately dized Clinical Memory Scale [29,30]. For the cut-off compared to other cortices [17]. In addition, the patho- scores of these two memory tests, we used a more liberal logical aging causes declines in volume and microstruc- criterion of 1SD below the norms, as previous studies tural pathology in prefrontal cortex, medial temporal suggested that the traditional 1.5 SD cut-off would re- regions, and other regions in grey and white matter duce the possibility of detecting early stage memory im- density [18-21]. Thus, the motor coordination, sensory pairment [31]. An expert team, consisting of psychiatrists integration, and disinhibition subscales of the Cambridge and neuropsychologists, made consensus diagnoses on Neurological Inventory (CNI) have been devised to in- the basis of all available clinical and neuropsychological vestigate the putative regions of prefrontal lobe, parital results. lobe, and frontal lobe, respectivelly [22,23]. Studies using Healthy controls were also recruited from the same sturcutral equaiton modelling showed that there were geographic region where people with aMCI were modest and moderate associations among NSS, execu- recruited. They were matched for age, gender, and edu- tive function, verbal memory, and visual memory in both cation level with aMCI participants. They were also patients with schizophrenia and healthy controls. More- defined by having normal scores on the paired- over, NSS has been associated with poorer performances association learning and portraits characteristics recall in executive function and memory functions in both [29,30], activities of daily living [28], MMSE [27], and groups [24]. Recently, Chan et al. (2011) also observed a had no complaints of memory problems. similar pattern for relationship in healthy older adults Participants were excluded for both groups if they: (1) [25]. When taken together, these findings suggest that had a history of head trauma; (2) had either a disease of neurolgoical soft signs are capable to capture the similar the central nervous system or a psychotic disorder; (3) information measured by conventional neurocognitive abused alcohol or other substance; or (4) were diagnosed tests. with any form of dementia. To date, it is still largely unknown about the preva- The present study was approved by the ethics commit- lence rate of NSS in people with MCI and how these tees of the Institute of Psychology, Chinese Academy of signs are related to conventional neuropsychological per- Sciences. Written informed consent was obtained from formances in this clinical group. The purpose of the all participants. current study was to explore the prevalence of NSS in aMCI and to examine the relationships of NSS to neuro- Neurological soft signs psychological performances in this clinical group. Given The motor coordination, sensory integration, and disinhib- the aforementioned studies, it was hypothesized that ition subscales of the Cambridge Neurological Inventory Li et al. Behavioral and Brain Functions 2012, 8:29 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 (CNI) was used to assess NSS [22]. The CNI is one of the function, processing speed, abstract reasoning ability, most commonly used tools to explore the NSS and it has and memory. been validated among the Chinese population [32]. The Fluency and Trail-making test (TMT) B were used to motor coordination subscale includes items assessing rapid assess the executive function. The fluency test includes motor movements such as finger tapping, finger-thumb verbal fluency [33] and writing fluency testing. For ver- opposition, diadockinesia, fist-edge-palm test, and oser- bal fluency, participants were told to speak as many ani- etsky test. The sensory integration subscale consists of mal names or food names as they could in one minute, items evaluating tactile sensation such as extinction test, respectively. The mean score was considered to be the finger-agnosia, stereognosis, graphesthesia, and left-right performance of verbal fluency. For writing fluency, parti- orientation. The disinhibition subscale includes items for cipants were told to write as many Chinese characters as withholding or inhibiting associated movements. These they could for radicals of “扌” and “亻” in a minute, re- items include saccade blink and saccade head, wink, spectively, and the average score was considered to be go/no-go test, and mirror movements of finger-thumb the performance of writing fluency. For TMT B, 25 cir- opposition (left and right hands) and diadocokinesia cles were printed in black on paper, including the first (leftand righthands) [22,23].The CNIhas full instruc- 13 Arabic numerals and the first 12 Chinese numbers. tion for training guidelines, and it also has been shown Participants were asked to connect Arabic numbers and with good construct and external validity, and inter- Chinese numbers alternately (for example, 1-一,2-二,3-三, rater reliability [23]. etc.), the last link is from the 十二 (12inChinese number) The CNI was administered in a standardized manner to the 13 [34]. according to a fixed order. In the original scale, scoring Digit span subtest of Wechsler Memory Scale-Revised was made according to standardized anchor points to in- Chinese version (WMS-RC) was used to assess working dicate “normal” response (scored as 0), “equivocal re- memory, and both forward and backward tests were sponse” (0.5), “abnormal” response (1) or “grossly included [35]. Processing speed was evaluated by the digit abnormal” response (2). In the present study, item scores symbol subtest of Wechsler Adult Intelligence Scale- were dichotomized into either “absent” (covering normal Chinese version (WAIS-C) [36] and TMT A [34]. Similar- or equivocal) or “present” (covering abnormal or grossly ity subtest of WAIS-C [36] was considered to investigate abnormal) [24]. the verbal abstract reasoning ability, and it was considered to reflect the function of the frontal lobe [37]. Episodic Neuropsychological tests memory was measured by the logic memory, which was Participants also received a battery of neuropsycho- selected from WMS-RC [35]. Participants were required logical tests capturing their capabilities in executive to listen to two short stories and then to recall them Table 1 Demographic variables and neuropsychological tests for aMCI patients and normal older adults aMCI Normal Older Adults tp N M SD N M SD Age (years) 29 73.76 6.42 28 71.25 6.43 1.47 .15 Education (years) 29 10.97 4.82 28 13.89 3.12 −2.71 .009 Activities of daily living 29 14.93 1.36 28 14.54 1.37 1.09 .28 MMSE 29 26.07 2.33 28 27.61 1.95 −2.70 .009 Paired-association learning 29 4.45 3.06 28 11.14 3.29 −7.95 <.001 Portraits characteristics recall 29 4.00 3.76 28 9.39 5.09 −4.56 <.001 Neuropsychological tests Verbal fluency 29 18.81 4.35 28 22.64 4.26 −3.36 .001 Writing fluency 27 4.61 1.95 26 5.23 1.93 −1.16 .25 Digit symbol 27 30.30 10.50 27 35.81 7.53 −2.22 .031 TMT A (seconds) 29 51.07 23.59 24 44.21 16.20 1.21 .23 TMT B (seconds) 28 113.11 75.05 24 78.58 35.94 2.06 .045 Digit span-forward 26 7.31 1.64 27 7.85 1.32 −1.33 .19 Digit span-backward 26 4.15 1.32 27 4.59 1.72 −1.04 .30 Logic memory 27 5.06 2.51 27 8.44 2.89 −4.60 <.001 Similarity 29 15.41 4.20 28 18.36 3.28 −2.94 .005 Li et al. Behavioral and Brain Functions 2012, 8:29 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 immediately; the memory performance was evaluated with showed that people with aMCI exhibited higher preva- the average score of the two stories. lence rate of NSS in most of the items, especially in fist- edge-palm in left hand, oseretsky test in motor coordin- Statistical analysis ation subscale, and go/no-go in disinhibition subscale. Statistical analyses were carried out with the Statistical The MANCOVA results indicated that patients with Package for Social Sciences (SPSS) version 13.0. First, aMCI demonstrated significantly more dysfunctions in Chi-square test was performed to compare the preva- motor coordination (F (1, 54) = 6.95, p = .011), disinhib- lence rate of NSS in patients with aMCI and healthy eld- ition (F (1, 54) = 6.78, p = .012), and the total NSS (F (1, erly people. Second, since years of education was 54) = 8.25, p = .006). For the sensory integration, there significant between two groups, it was controlled as a was no significant differences between the two groups (F covariate in analyses. A MANCOVA was used to analyze (1, 54) = .06, p = .82). Figure 1 shows the NSS profiles of the group differences in NSS with Bonferroni correction. patients with aMCI and healthy controls. The effect sizes The effect sizes of the group comparisons were calcu- lated in terms of Cohen’s d [38]. Finally, Pearson correl- ation analysis was used to test the relationships between Table 2 Prevalence rate of individual items of NSS and neuropsychological performance in patients neurological signs in persons with aMCI (n = 29) and normal control (n = 28) with aMCI. NSS items aMCI Normal χ p control Results Motor coordination Demographics Twenty-nine patients with aMCI (11 males) and 28 nor- Left Finger-thumb tapping 20.7% 0% 6.48 .023 mal control participants (15 males) were included in the Right Finger-thumb tapping 13.8% 3.6% 1.86 .35 present study. The Chi square test indicated that there Left Finger-thumb opposition 27.6% 21.4% .29 .76 was no significant group differences in gender ratio Right Finger-thumb opposition 17.2% 10.7% .50 .71 (χ = 1.41, p = .29). As demonstrated in Table 1, there Left Diadocokinesia 17.2% 10.7% .50 .71 were no significant group differences in age and activ- Right Diadocokinesia 13.8% 7.1% .67 .67 ities of daily living. Patients with aMCI received signifi- cant lower years of education. They also showed Left Fist-edge-palm 51.7% 10.7% 11.01 .001 significant lower performance in MMSE, the paired- Right Fist-edge-palm 27.6% 7.1% 4.12 .079 association learning and portrait characteristics recall Oseretsky test 58.6% 28.6% 5.22 .033 tests. We also examined the medical histories in the two Sensory integration groups. For aMCI group, 21 out of 29 older adults Extinction 10.3% 3.6% 1.00 .61 reported medical histories, among them 14 suffered Left Finger Agnosia 69.0% 42.9% 3.94 .064 from hypertension and/or diabetes mellitus and/or cor- onary heart disease, 3 had cataract or other strabismus, Right Finger Agnosia 34.5% 39.3% .14 .79 2 had cavity infarction, and 2 had benign prostate hyper- Left Stereognosia 0% 0% NA NA trophy or mammary gland hyperplasia. Nineteen of the Right Stereognosia 0% 0% NA NA 28 healthy older adults reported medial histories. Spe- Left Graphesthesia 13.8% 25.0% 1.15 .33 cially, 14 had hypertension and/or diabetes mellitus and/ Right Graphesthesia 6.9% 10.7% .26 .67 or coronary heart disease, 2 had ocular fundus disease or Left-Right Orientation 13.8% 14.3% .003 .99 astigmatism, 2 had cervical vertebral disease or stomach disease, and 1 had sleep disorder. The Chi square test Disinhibition indicated that there was no significant group differences Left Mirror Movement of Finger 6.9% 0% 2.00 .49 Opposition in the ratio of suffering from chronic diseases (χ = .14, p = .78). For the neurocognitive tests, significant group Right Mirror Movement of Finger 10.3% 3.6% 1.00 .61 Oppostion differences were found in verbal fluency, digit symbol, TMT B, logic memory, and similarity, while no signifi- Left Mirror Movement of Diadocokinesia 3.4% 3.6% .001 .99 cant differences were found in writing fluency, TMT A, Right Mirror Movement of Diadocokinesia 24.1% 7.1% 3.10 .14 forward and backward of digit span. Saccade Blink 17.2% 7.1% 1.35 .42 Saccade Head 27.6% 10.7% 2.60 .18 Comparison of NSS between older adults with aMCI and Wink 10.3% 21.4% 1.32 .30 normal controls Go No-Go Stimulus 44.8% 10.7% 8.21 .007 The prevalence rate of “present” NSS in aMCI and nor- mal controls are shown in Table 2. The Chi-square test p-values: two sided, Fisher’s Exact Test. Li et al. Behavioral and Brain Functions 2012, 8:29 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 aMCI Normal elderly Motor coordination Sensory integration Disinhibition total NSS Figure 1 Comparisons of neurological soft signs in persons with aMCI and normal elderly. Error bars represent 95% confidence intervals. for motor coordination (Cohen’s d = 0.93) and total NSS motor coordination and total score and moderate for score (Cohen’s d = 0.96) reached large, while the effect disinhibition. The findings were similar to previous stud- sizes were moderate for disinhibition (Cohen’s d = 0.76) ies focused on normal elderly people and people with and negligible for the sensory integration (Cohen’s pathological aging disease. With the same scale, Chan d = 0.12). et al. (2011) found that NSS was common among elderly people, and the prevalence rate of soft signs increased with advancing age [25]. In a neurological examination Correlations between NSS and neuropsychological tests including few soft signs (etc., saccadic eye movement), in patients with aMCI The neuropsychological performance was indexed by the the older adults who were with cognitively impaired but without dementia were found to produce a higher preva- combined Z-score of the verbal fluency and writing flu- lence of signs than the normal controls [12]. Patients ency, digit symbol, forward and backward of digit span, TMT A and B, similarities, and logic memory. with AD and other several forms of dementia were also found to have higher prevalence of NSS than those with- Pearson correlation analysis showed that the total NSS out dementia [9]. score and motor coordination subscale were significantly negatively correlated with combined Z-score of neuro- The current study indicated that older adults with aMCI showed more motor dysfunctions than cognitively psychological tests (r = −.53, p < .01; r = −.42, p < .05), the normal older people. Previous findings indicated that sensory integration and disinhibition subscales were not found to be significantly correlated with combined Z- people with MCI and mild AD demonstrated dysfunc- tions in equilibrium and limb coordination [39]. Other score of neuropsychological tests (r = −.19, p > .05; studies confirmed that people with aMCI performed r = −.33, p > .05). worse on tasks involving fine and complex motor func- tions than normal older adults [40,41]. Lam et al. (2005) Discussion also found motor coordination signs were very sensitive Our results revealed that patients with aMCI exhibited a in discriminating patients with or without dementia [9]. higher prevalence rate of neurological abnormalities Signs such as primitive reflexes and mirror movements than normal control participants. The preliminary were classified as disinhibition, which included the signs results also suggested NSS and neuropsychological tests of spurious movements in a time and place where it was might reflect somewhat similar information for the brain not expected to occur [22]. In the present study, patients functioning. The present study indicated that NSS may with aMCI demonstrated significantly more signs than play an important role and serve as a tool to assist in the normal controls in the disinhibition subscale. Similar early detection of aMCI. findings were also reported in previous studies. Franssen To our knowledge, this is the first study to investigate et al. (1991) found participants in an early stage of AD the NSS in older adults with aMCI. Our results demon- showed higher mean score of deep tendon reflexes than strated that aMCI individuals displayed significantly normal elderly people, while patients with a later stage more neurological abnormalities than normal controls of AD demonstrated significantly increased prevalence on motor coordination, disinhibition, and the total NSS. of sucking reflexes compared with normal older adults The effect sizes of group comparisons were large for Scores Li et al. Behavioral and Brain Functions 2012, 8:29 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 and patients with the early stage of AD [10]. Further- and dose of medicines they have been taking during the more, more primitive reflexes were found in the more assessment and we did not further follow up with these; terminal stages of AD [11]. Previous studies also found therefore, we are uncertain whether their medication will that MCI patients showed inhibition impairments in influence their neuropsychological or NSS performances. some neuropsychological tasks, such as go/no-go task Moreover, the present study adopted the traditional [42], Stroop task [43,44], Hayling test [45], and Flanker diagnosis criteria of aMCI proposed by Petersen and col- test [46]. leagues [2,26], which was called core clinical criteria by The correlations between NSS and neuropsychological the National Institute on Aging and Alzheimer’s Associ- functions have significant implications. Our results indi- ation workgroup [47]. The workgroup also recom- cated that the total NSS score was negatively correlated mended new diagnosis criteria: research criteria, which with the combined Z-score of neuropsychological tests incorporated the biomarker based on imaging or cere- in aMCI group. The current results were consistent with brospinal fluid measures into the core clinical criteria our recent findings in normal older adults that NSS had [47]. Studies adopting more stringent research criteria moderate associations with neurocognition function for screening aMCI are needed to confirm the current [25]. The present study provided further evidence that findings. the two measures were more or less statistically equiva- Our current findings have shown that aMCI patients lent to capture the similar brain functions. These results demonstrated significantly higher prevalence of NSS support in part the assumption that motor coordination than healthy older adults. The total scores of NSS were might be an indicator of the prefrontal lobe function significantly correlated with the combined Z-score of [7,8]. However, the correlation analysis also indicated neuropsychological tests in aMCI group. NSS has been that sensory integration and disinhibition did not have found to be indicative of the cognitive decline and brain significant correlations with the neuropsychological dysfunction [4,23]. The observed impairment of NSS in tests. The reason might be as mentioned previously, sen- aMCI contributes further evidence to the literature on sory integration and disinhibition subscales were consid- neurological deficits in pathological aging diseases. ered to reflect parietal and frontal lobe functions Given the assessment is simple, non-invasive and time- respectively [22,23], and aMCI patients showed relatively saving, neurological soft sign test may be used as an as- less impairment in these two subscales. Whereas, there sistant tool for the bedside clinical examination of mild were no sensitive neuropsychological tasks to reflect cognitive impairment. frontal lobe function and no tasks specialized to measure Abbreviations the parietal lobe function in current study. To better AD: Alzheimer’s disease; aMCI: Amnestic mild cognitive impairment; understand whether there are same neural substrates be- CNI: Cambridge Neurological Inventory; MCI: Mild cognitive impairment; MMSE: Mini Mental State Examination; NSS: Neurological soft signs; tween NSS and neuropsychological functions, future TMT: Trail-making test; WMS-RC: Wechsler Memory Scale-Revised Chinese studies with larger samples and more comprehensive version; WAIS-C: Wechsler Adult Intelligence Scale-Chinese version. neuropsychological tasks are needed. The present study has several limitations. First, the Competing interests The authors declare that they have no competing interest. sample size of the study is relatively small. More studies with larger sample sizes are needed in order to confirm Authors’ contributions the neurological dysfunctions in persons with aMCI, HJL designed the study, analyzed the data, and wrote up the first draft of the paper. JL conceived the idea and participated in the design of the study which could help to further clarify the early neurological and the writing up of the paper. PYW collected the data and assisted data abnormalities of aMCI. Second, some of the aMCI parti- analysis. RCKC and YJ contributed to the writing up of the manuscript, and cipants were from a memory clinic, and these partici- HLW helped aMCI participants’ recruitment and diagnosis. All authors read and approved the final manuscript. pants were not scored by blinded raters, which might bring some bias during assessment. Future studies Acknowledgements should overcome the difficulties and assess the NSS with We thank Ting Zhou, Bing Li, and Xin Li for their contribution of data blind raters. Third, aMCI participants were recruited collection and McKinley Heflin’s assistance for English editing. This study was supported by National Natural Science Foundation of China (30770725, from both community and the memory disorder clinic, 31000465, 30911120494), National Science & Technology Pillar Program of while the health elderly were only selected from the China (2009BAI77B03), and Knowledge Innovation Project of the Chinese community residents. This may lead to differential selec- Academy of Sciences (KSCX2-YW-R-256 & KSCX2-EW-J-8), and a grant from the National Outstanding Young Investigator Award from National Science tion bias. Fourth, due to the mean age of participants in Foundation of China (81088001). both groups were older than 70 years, 40 out of the 57 participants suffered from one or more chronic diseases Author details Center on Aging Psychology, Key Laboratory of Mental Health, Institute of such as hypertension, diabetes mellitus, coronary heart Psychology, Chinese Academy of Sciences, Beijing, China. Graduate School, disease and other diseases. Also, unfortunately quite a Chinese Academy of Sciences, Beijing, China. Department of Behavioral number of the elderly could not recall the exact type Science, College of Medicine, University of Kentucky, Kentucky, USA. Li et al. Behavioral and Brain Functions 2012, 8:29 Page 7 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 Neuropsychology and Applied Cognitive Neuroscience Laboratory, Key 20. 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Neurological soft signs in persons with amnestic mild cognitive impairment and the relationships to neuropsychological functions

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Copyright © 2012 by Li et al.; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: Neurological abnormalities have been reported in people with amnestic mild cognitive impairment (aMCI). The current study aimed to examine the prevalence of neurological soft signs (NSS) in this clinical group and to examine the relationship of NSS to other neuropsychological performances. Methods: Twenty-nine people with aMCI and 28 cognitively healthy elderly people were recruited for the present study. The NSS subscales (motor coordination, sensory integration, and disinhibition) of the Cambridge Neurological Inventory and a set of neuropsychological tests were administered to all the participants. Results: People with aMCI exhibited significantly more motor coordination signs, disinhibition signs, and total NSS than normal controls. Correlation analysis showed that the motor coordination subscale score and total score of NSS were significantly inversely correlated with the combined Z-score of neuropsychological tests in aMCI group. Conclusions: These preliminary findings suggested that people with aMCI demonstrated a higher prevalence of NSS compared to healthy elderly people. Moreover, NSS was found to be inversely correlated with the neuropsychological performances in persons with aMCI. When taken together, these findings suggested that NSS may play a potential important role and serve as a tool to assist in the early detection of aMCI. Keywords: Mild cognitive impairment, Neurological soft signs, Neuropsychological tests Introduction neurological soft signs (NSS) might be associated with Alzheimer’s disease (AD) is the most commonly specific brain regions or even brain connections [5-8]. acquired neurodegenerative disease in elderly people [1]. For example, researchers found that higher rates of Mild cognitive impairment (MCI) is considered as a motor coordination and sensory integration signs were transitional state of normal aging and AD [2], and was associated with a reduction of grey matter volume of also thought to be the earliest clinical manifestation of subcortical structures, including putamen, globus palli- common age-related neurological abnormalities, includ- dus and thalamus in both patients with first-onset ing AD [3]. schizophrenia and healthy volunteers [5,6]. Chan et al. Neurological abnormalities have traditionally been (2006) also showed that brain areas such as bilateral sen- divided into “hard signs” and “soft signs” [4]. “Hard sorimotor, supplementary motor area, left parietal, and signs” usually indicate focal neurological deficits localized right cerebellum were activated during the fist-edge- within specific brain regions, whereas “soft signs” are palm task [7]. Furthermore, the fist-edge-palm task as a conventionally defined as subtle signs without an identifi- soft sign for motor coordinaiton has been shown to be able or localized brain region [4]. However, most recent linked to connectivity between the right inferior and studies using brain imaging technologies suggested that middle prefrontal cortices in healthy control subjects [8]. Patients with AD have also been found to demonstrate significantly higher prevalence of sensory integration * Correspondence: lijuan@psych.ac.cn 1 and motor coordination signs than healthy controls [9]. Center on Aging Psychology, Key Laboratory of Mental Health, Institute of Other studies also found NSS abnormalities in patients Psychology, Chinese Academy of Sciences, Beijing, China Full list of author information is available at the end of the article © 2012 Li et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Li et al. Behavioral and Brain Functions 2012, 8:29 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 with AD [10,11]. Kumamoto et al. (2000) found elderly aMCI was associated with a higher prevalence of NSS as people that were cognitively impaired but not demented, compared to healthy older adults. Moreover, NSS was had exhibited higher frequency of neurological signs expected to show negative association with neuro- than healthy controls, but lower rate of signs than psychological performances in this clinical group. patients with dementia [12]. Gualtieri et al. (2005) also found that individuals with MCI showed poorer per- Methods formance in a finger tapping task in which participants Subjects were required to tap on the mouse button [13]. A previ- Patients with aMCI in this study were recruited from ous study implied that NSS might be a predictor for pro- the communities around the Institute of Psychology, gression to clinical AD [14]. Yet so far there is no Chinese Academy of Sciences and memory clinic of In- empirical study to systematically explore the NSS in stitute of Mental Health, Peking University. One hun- individuals with aMCI. In the present study, we hypothe- dred and sixty-seven participants aged between 60– sized that individuals with aMCI would demonstrate 87 years were screened from the residential communi- more NSS than normal elderly individuals, and that NSS ties. Among them, 18 were screened as patients with might be taken as an easy-identified neurological marker aMCI. Moreover, 11 individuals with aMCI were referred for early detection of AD. by the psychiatrists of the memory clinic. The diagnoses Neuropsychological performance is considered to be of aMCI were made according to published criteria one of the most sensitive and specific markers of pro- [2,26]. Participants were interviewed to determine dromal AD [15]. Previous studies indicated that cogni- whether they had memory complaint, normal general tive decline in patients with MCI was associated with cognitive function (measured by Mini-Mental State widespread structural brain damage [16]. As we know, Examination, MMSE) [27], and normal activities of daily the executive function aging is the main cause of the living [28]. Objective memory impairment was verified cognitive decline in older adults. The so called “frontal with paired-association learning and portrait characteris- hypothesis of cognitive aging” suggests that the pre- tics recall tests, which were two subtests of the standar- frontal cortex deteriorated earlier and disproportionately dized Clinical Memory Scale [29,30]. For the cut-off compared to other cortices [17]. In addition, the patho- scores of these two memory tests, we used a more liberal logical aging causes declines in volume and microstruc- criterion of 1SD below the norms, as previous studies tural pathology in prefrontal cortex, medial temporal suggested that the traditional 1.5 SD cut-off would re- regions, and other regions in grey and white matter duce the possibility of detecting early stage memory im- density [18-21]. Thus, the motor coordination, sensory pairment [31]. An expert team, consisting of psychiatrists integration, and disinhibition subscales of the Cambridge and neuropsychologists, made consensus diagnoses on Neurological Inventory (CNI) have been devised to in- the basis of all available clinical and neuropsychological vestigate the putative regions of prefrontal lobe, parital results. lobe, and frontal lobe, respectivelly [22,23]. Studies using Healthy controls were also recruited from the same sturcutral equaiton modelling showed that there were geographic region where people with aMCI were modest and moderate associations among NSS, execu- recruited. They were matched for age, gender, and edu- tive function, verbal memory, and visual memory in both cation level with aMCI participants. They were also patients with schizophrenia and healthy controls. More- defined by having normal scores on the paired- over, NSS has been associated with poorer performances association learning and portraits characteristics recall in executive function and memory functions in both [29,30], activities of daily living [28], MMSE [27], and groups [24]. Recently, Chan et al. (2011) also observed a had no complaints of memory problems. similar pattern for relationship in healthy older adults Participants were excluded for both groups if they: (1) [25]. When taken together, these findings suggest that had a history of head trauma; (2) had either a disease of neurolgoical soft signs are capable to capture the similar the central nervous system or a psychotic disorder; (3) information measured by conventional neurocognitive abused alcohol or other substance; or (4) were diagnosed tests. with any form of dementia. To date, it is still largely unknown about the preva- The present study was approved by the ethics commit- lence rate of NSS in people with MCI and how these tees of the Institute of Psychology, Chinese Academy of signs are related to conventional neuropsychological per- Sciences. Written informed consent was obtained from formances in this clinical group. The purpose of the all participants. current study was to explore the prevalence of NSS in aMCI and to examine the relationships of NSS to neuro- Neurological soft signs psychological performances in this clinical group. Given The motor coordination, sensory integration, and disinhib- the aforementioned studies, it was hypothesized that ition subscales of the Cambridge Neurological Inventory Li et al. Behavioral and Brain Functions 2012, 8:29 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 (CNI) was used to assess NSS [22]. The CNI is one of the function, processing speed, abstract reasoning ability, most commonly used tools to explore the NSS and it has and memory. been validated among the Chinese population [32]. The Fluency and Trail-making test (TMT) B were used to motor coordination subscale includes items assessing rapid assess the executive function. The fluency test includes motor movements such as finger tapping, finger-thumb verbal fluency [33] and writing fluency testing. For ver- opposition, diadockinesia, fist-edge-palm test, and oser- bal fluency, participants were told to speak as many ani- etsky test. The sensory integration subscale consists of mal names or food names as they could in one minute, items evaluating tactile sensation such as extinction test, respectively. The mean score was considered to be the finger-agnosia, stereognosis, graphesthesia, and left-right performance of verbal fluency. For writing fluency, parti- orientation. The disinhibition subscale includes items for cipants were told to write as many Chinese characters as withholding or inhibiting associated movements. These they could for radicals of “扌” and “亻” in a minute, re- items include saccade blink and saccade head, wink, spectively, and the average score was considered to be go/no-go test, and mirror movements of finger-thumb the performance of writing fluency. For TMT B, 25 cir- opposition (left and right hands) and diadocokinesia cles were printed in black on paper, including the first (leftand righthands) [22,23].The CNIhas full instruc- 13 Arabic numerals and the first 12 Chinese numbers. tion for training guidelines, and it also has been shown Participants were asked to connect Arabic numbers and with good construct and external validity, and inter- Chinese numbers alternately (for example, 1-一,2-二,3-三, rater reliability [23]. etc.), the last link is from the 十二 (12inChinese number) The CNI was administered in a standardized manner to the 13 [34]. according to a fixed order. In the original scale, scoring Digit span subtest of Wechsler Memory Scale-Revised was made according to standardized anchor points to in- Chinese version (WMS-RC) was used to assess working dicate “normal” response (scored as 0), “equivocal re- memory, and both forward and backward tests were sponse” (0.5), “abnormal” response (1) or “grossly included [35]. Processing speed was evaluated by the digit abnormal” response (2). In the present study, item scores symbol subtest of Wechsler Adult Intelligence Scale- were dichotomized into either “absent” (covering normal Chinese version (WAIS-C) [36] and TMT A [34]. Similar- or equivocal) or “present” (covering abnormal or grossly ity subtest of WAIS-C [36] was considered to investigate abnormal) [24]. the verbal abstract reasoning ability, and it was considered to reflect the function of the frontal lobe [37]. Episodic Neuropsychological tests memory was measured by the logic memory, which was Participants also received a battery of neuropsycho- selected from WMS-RC [35]. Participants were required logical tests capturing their capabilities in executive to listen to two short stories and then to recall them Table 1 Demographic variables and neuropsychological tests for aMCI patients and normal older adults aMCI Normal Older Adults tp N M SD N M SD Age (years) 29 73.76 6.42 28 71.25 6.43 1.47 .15 Education (years) 29 10.97 4.82 28 13.89 3.12 −2.71 .009 Activities of daily living 29 14.93 1.36 28 14.54 1.37 1.09 .28 MMSE 29 26.07 2.33 28 27.61 1.95 −2.70 .009 Paired-association learning 29 4.45 3.06 28 11.14 3.29 −7.95 <.001 Portraits characteristics recall 29 4.00 3.76 28 9.39 5.09 −4.56 <.001 Neuropsychological tests Verbal fluency 29 18.81 4.35 28 22.64 4.26 −3.36 .001 Writing fluency 27 4.61 1.95 26 5.23 1.93 −1.16 .25 Digit symbol 27 30.30 10.50 27 35.81 7.53 −2.22 .031 TMT A (seconds) 29 51.07 23.59 24 44.21 16.20 1.21 .23 TMT B (seconds) 28 113.11 75.05 24 78.58 35.94 2.06 .045 Digit span-forward 26 7.31 1.64 27 7.85 1.32 −1.33 .19 Digit span-backward 26 4.15 1.32 27 4.59 1.72 −1.04 .30 Logic memory 27 5.06 2.51 27 8.44 2.89 −4.60 <.001 Similarity 29 15.41 4.20 28 18.36 3.28 −2.94 .005 Li et al. Behavioral and Brain Functions 2012, 8:29 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 immediately; the memory performance was evaluated with showed that people with aMCI exhibited higher preva- the average score of the two stories. lence rate of NSS in most of the items, especially in fist- edge-palm in left hand, oseretsky test in motor coordin- Statistical analysis ation subscale, and go/no-go in disinhibition subscale. Statistical analyses were carried out with the Statistical The MANCOVA results indicated that patients with Package for Social Sciences (SPSS) version 13.0. First, aMCI demonstrated significantly more dysfunctions in Chi-square test was performed to compare the preva- motor coordination (F (1, 54) = 6.95, p = .011), disinhib- lence rate of NSS in patients with aMCI and healthy eld- ition (F (1, 54) = 6.78, p = .012), and the total NSS (F (1, erly people. Second, since years of education was 54) = 8.25, p = .006). For the sensory integration, there significant between two groups, it was controlled as a was no significant differences between the two groups (F covariate in analyses. A MANCOVA was used to analyze (1, 54) = .06, p = .82). Figure 1 shows the NSS profiles of the group differences in NSS with Bonferroni correction. patients with aMCI and healthy controls. The effect sizes The effect sizes of the group comparisons were calcu- lated in terms of Cohen’s d [38]. Finally, Pearson correl- ation analysis was used to test the relationships between Table 2 Prevalence rate of individual items of NSS and neuropsychological performance in patients neurological signs in persons with aMCI (n = 29) and normal control (n = 28) with aMCI. NSS items aMCI Normal χ p control Results Motor coordination Demographics Twenty-nine patients with aMCI (11 males) and 28 nor- Left Finger-thumb tapping 20.7% 0% 6.48 .023 mal control participants (15 males) were included in the Right Finger-thumb tapping 13.8% 3.6% 1.86 .35 present study. The Chi square test indicated that there Left Finger-thumb opposition 27.6% 21.4% .29 .76 was no significant group differences in gender ratio Right Finger-thumb opposition 17.2% 10.7% .50 .71 (χ = 1.41, p = .29). As demonstrated in Table 1, there Left Diadocokinesia 17.2% 10.7% .50 .71 were no significant group differences in age and activ- Right Diadocokinesia 13.8% 7.1% .67 .67 ities of daily living. Patients with aMCI received signifi- cant lower years of education. They also showed Left Fist-edge-palm 51.7% 10.7% 11.01 .001 significant lower performance in MMSE, the paired- Right Fist-edge-palm 27.6% 7.1% 4.12 .079 association learning and portrait characteristics recall Oseretsky test 58.6% 28.6% 5.22 .033 tests. We also examined the medical histories in the two Sensory integration groups. For aMCI group, 21 out of 29 older adults Extinction 10.3% 3.6% 1.00 .61 reported medical histories, among them 14 suffered Left Finger Agnosia 69.0% 42.9% 3.94 .064 from hypertension and/or diabetes mellitus and/or cor- onary heart disease, 3 had cataract or other strabismus, Right Finger Agnosia 34.5% 39.3% .14 .79 2 had cavity infarction, and 2 had benign prostate hyper- Left Stereognosia 0% 0% NA NA trophy or mammary gland hyperplasia. Nineteen of the Right Stereognosia 0% 0% NA NA 28 healthy older adults reported medial histories. Spe- Left Graphesthesia 13.8% 25.0% 1.15 .33 cially, 14 had hypertension and/or diabetes mellitus and/ Right Graphesthesia 6.9% 10.7% .26 .67 or coronary heart disease, 2 had ocular fundus disease or Left-Right Orientation 13.8% 14.3% .003 .99 astigmatism, 2 had cervical vertebral disease or stomach disease, and 1 had sleep disorder. The Chi square test Disinhibition indicated that there was no significant group differences Left Mirror Movement of Finger 6.9% 0% 2.00 .49 Opposition in the ratio of suffering from chronic diseases (χ = .14, p = .78). For the neurocognitive tests, significant group Right Mirror Movement of Finger 10.3% 3.6% 1.00 .61 Oppostion differences were found in verbal fluency, digit symbol, TMT B, logic memory, and similarity, while no signifi- Left Mirror Movement of Diadocokinesia 3.4% 3.6% .001 .99 cant differences were found in writing fluency, TMT A, Right Mirror Movement of Diadocokinesia 24.1% 7.1% 3.10 .14 forward and backward of digit span. Saccade Blink 17.2% 7.1% 1.35 .42 Saccade Head 27.6% 10.7% 2.60 .18 Comparison of NSS between older adults with aMCI and Wink 10.3% 21.4% 1.32 .30 normal controls Go No-Go Stimulus 44.8% 10.7% 8.21 .007 The prevalence rate of “present” NSS in aMCI and nor- mal controls are shown in Table 2. The Chi-square test p-values: two sided, Fisher’s Exact Test. Li et al. Behavioral and Brain Functions 2012, 8:29 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 aMCI Normal elderly Motor coordination Sensory integration Disinhibition total NSS Figure 1 Comparisons of neurological soft signs in persons with aMCI and normal elderly. Error bars represent 95% confidence intervals. for motor coordination (Cohen’s d = 0.93) and total NSS motor coordination and total score and moderate for score (Cohen’s d = 0.96) reached large, while the effect disinhibition. The findings were similar to previous stud- sizes were moderate for disinhibition (Cohen’s d = 0.76) ies focused on normal elderly people and people with and negligible for the sensory integration (Cohen’s pathological aging disease. With the same scale, Chan d = 0.12). et al. (2011) found that NSS was common among elderly people, and the prevalence rate of soft signs increased with advancing age [25]. In a neurological examination Correlations between NSS and neuropsychological tests including few soft signs (etc., saccadic eye movement), in patients with aMCI The neuropsychological performance was indexed by the the older adults who were with cognitively impaired but without dementia were found to produce a higher preva- combined Z-score of the verbal fluency and writing flu- lence of signs than the normal controls [12]. Patients ency, digit symbol, forward and backward of digit span, TMT A and B, similarities, and logic memory. with AD and other several forms of dementia were also found to have higher prevalence of NSS than those with- Pearson correlation analysis showed that the total NSS out dementia [9]. score and motor coordination subscale were significantly negatively correlated with combined Z-score of neuro- The current study indicated that older adults with aMCI showed more motor dysfunctions than cognitively psychological tests (r = −.53, p < .01; r = −.42, p < .05), the normal older people. Previous findings indicated that sensory integration and disinhibition subscales were not found to be significantly correlated with combined Z- people with MCI and mild AD demonstrated dysfunc- tions in equilibrium and limb coordination [39]. Other score of neuropsychological tests (r = −.19, p > .05; studies confirmed that people with aMCI performed r = −.33, p > .05). worse on tasks involving fine and complex motor func- tions than normal older adults [40,41]. Lam et al. (2005) Discussion also found motor coordination signs were very sensitive Our results revealed that patients with aMCI exhibited a in discriminating patients with or without dementia [9]. higher prevalence rate of neurological abnormalities Signs such as primitive reflexes and mirror movements than normal control participants. The preliminary were classified as disinhibition, which included the signs results also suggested NSS and neuropsychological tests of spurious movements in a time and place where it was might reflect somewhat similar information for the brain not expected to occur [22]. In the present study, patients functioning. The present study indicated that NSS may with aMCI demonstrated significantly more signs than play an important role and serve as a tool to assist in the normal controls in the disinhibition subscale. Similar early detection of aMCI. findings were also reported in previous studies. Franssen To our knowledge, this is the first study to investigate et al. (1991) found participants in an early stage of AD the NSS in older adults with aMCI. Our results demon- showed higher mean score of deep tendon reflexes than strated that aMCI individuals displayed significantly normal elderly people, while patients with a later stage more neurological abnormalities than normal controls of AD demonstrated significantly increased prevalence on motor coordination, disinhibition, and the total NSS. of sucking reflexes compared with normal older adults The effect sizes of group comparisons were large for Scores Li et al. Behavioral and Brain Functions 2012, 8:29 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 and patients with the early stage of AD [10]. Further- and dose of medicines they have been taking during the more, more primitive reflexes were found in the more assessment and we did not further follow up with these; terminal stages of AD [11]. Previous studies also found therefore, we are uncertain whether their medication will that MCI patients showed inhibition impairments in influence their neuropsychological or NSS performances. some neuropsychological tasks, such as go/no-go task Moreover, the present study adopted the traditional [42], Stroop task [43,44], Hayling test [45], and Flanker diagnosis criteria of aMCI proposed by Petersen and col- test [46]. leagues [2,26], which was called core clinical criteria by The correlations between NSS and neuropsychological the National Institute on Aging and Alzheimer’s Associ- functions have significant implications. Our results indi- ation workgroup [47]. The workgroup also recom- cated that the total NSS score was negatively correlated mended new diagnosis criteria: research criteria, which with the combined Z-score of neuropsychological tests incorporated the biomarker based on imaging or cere- in aMCI group. The current results were consistent with brospinal fluid measures into the core clinical criteria our recent findings in normal older adults that NSS had [47]. Studies adopting more stringent research criteria moderate associations with neurocognition function for screening aMCI are needed to confirm the current [25]. The present study provided further evidence that findings. the two measures were more or less statistically equiva- Our current findings have shown that aMCI patients lent to capture the similar brain functions. These results demonstrated significantly higher prevalence of NSS support in part the assumption that motor coordination than healthy older adults. The total scores of NSS were might be an indicator of the prefrontal lobe function significantly correlated with the combined Z-score of [7,8]. However, the correlation analysis also indicated neuropsychological tests in aMCI group. NSS has been that sensory integration and disinhibition did not have found to be indicative of the cognitive decline and brain significant correlations with the neuropsychological dysfunction [4,23]. The observed impairment of NSS in tests. The reason might be as mentioned previously, sen- aMCI contributes further evidence to the literature on sory integration and disinhibition subscales were consid- neurological deficits in pathological aging diseases. ered to reflect parietal and frontal lobe functions Given the assessment is simple, non-invasive and time- respectively [22,23], and aMCI patients showed relatively saving, neurological soft sign test may be used as an as- less impairment in these two subscales. Whereas, there sistant tool for the bedside clinical examination of mild were no sensitive neuropsychological tasks to reflect cognitive impairment. frontal lobe function and no tasks specialized to measure Abbreviations the parietal lobe function in current study. To better AD: Alzheimer’s disease; aMCI: Amnestic mild cognitive impairment; understand whether there are same neural substrates be- CNI: Cambridge Neurological Inventory; MCI: Mild cognitive impairment; MMSE: Mini Mental State Examination; NSS: Neurological soft signs; tween NSS and neuropsychological functions, future TMT: Trail-making test; WMS-RC: Wechsler Memory Scale-Revised Chinese studies with larger samples and more comprehensive version; WAIS-C: Wechsler Adult Intelligence Scale-Chinese version. neuropsychological tasks are needed. The present study has several limitations. First, the Competing interests The authors declare that they have no competing interest. sample size of the study is relatively small. More studies with larger sample sizes are needed in order to confirm Authors’ contributions the neurological dysfunctions in persons with aMCI, HJL designed the study, analyzed the data, and wrote up the first draft of the paper. JL conceived the idea and participated in the design of the study which could help to further clarify the early neurological and the writing up of the paper. PYW collected the data and assisted data abnormalities of aMCI. Second, some of the aMCI parti- analysis. RCKC and YJ contributed to the writing up of the manuscript, and cipants were from a memory clinic, and these partici- HLW helped aMCI participants’ recruitment and diagnosis. All authors read and approved the final manuscript. pants were not scored by blinded raters, which might bring some bias during assessment. Future studies Acknowledgements should overcome the difficulties and assess the NSS with We thank Ting Zhou, Bing Li, and Xin Li for their contribution of data blind raters. Third, aMCI participants were recruited collection and McKinley Heflin’s assistance for English editing. This study was supported by National Natural Science Foundation of China (30770725, from both community and the memory disorder clinic, 31000465, 30911120494), National Science & Technology Pillar Program of while the health elderly were only selected from the China (2009BAI77B03), and Knowledge Innovation Project of the Chinese community residents. This may lead to differential selec- Academy of Sciences (KSCX2-YW-R-256 & KSCX2-EW-J-8), and a grant from the National Outstanding Young Investigator Award from National Science tion bias. Fourth, due to the mean age of participants in Foundation of China (81088001). both groups were older than 70 years, 40 out of the 57 participants suffered from one or more chronic diseases Author details Center on Aging Psychology, Key Laboratory of Mental Health, Institute of such as hypertension, diabetes mellitus, coronary heart Psychology, Chinese Academy of Sciences, Beijing, China. Graduate School, disease and other diseases. Also, unfortunately quite a Chinese Academy of Sciences, Beijing, China. Department of Behavioral number of the elderly could not recall the exact type Science, College of Medicine, University of Kentucky, Kentucky, USA. Li et al. Behavioral and Brain Functions 2012, 8:29 Page 7 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/29 Neuropsychology and Applied Cognitive Neuroscience Laboratory, Key 20. 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