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1.  Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease 
Neurobiology of aging  2008;31(10):1805-1813.
The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimer’s disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P = 0.012), provoked hallucinations or delirium (P = 0.042), or the presence of any of these noncognitive symptoms of DLB (P < 0.0001). Letter fluency (P = 0.007) was significantly lower and Wechsler Logical Memory I (P = 0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD.
PMCID: PMC2891418  PMID: 19026468
Mild cognitive impairment; Alzheimer’s disease; Dementia with Lewy bodies
2.  Cognitive correlates of HVOT performance differ between individuals with mild cognitive impairment and normal controls 
To clinically characterize performance on the Hooper Visual Organization Test (HVOT) among participants with mild cognitive impairment (MCI) and to identify naming and executive functioning correlates associated with HVOT performance among MCI participants and normal controls (NC).
The HVOT is a common neuropsychological instrument that measures visuospatial skills and agnosia. It has, however, been criticized for its multifactorial nature, as several studies have reported executive or language correlates of HVOT performance. To our knowledge, simultaneous comparison of executive functioning and language demands of the HVOT has never been performed among an older cohort.
The HVOT, two tests of executive functioning [Trail Making Test, Part B (TMT-B), Controlled Oral Word Association (COWA)] and two tests of naming [abbreviated Boston Naming Test (BNT), Animal Naming] were administered to 222 NC, 166 MCI, and 68 Alzheimer’s disease (AD) individuals.
HVOT scores were significantly different between all three groups in the expected direction (AD < MCI < NC). Linear regression among NC participants revealed that COWA, age, and BNT were significantly associated with HVOT scores, accounting for 12%, 6%, and 4% of HVOT variance, respectively. Among MCI participants, the BNT accounted for 43% of HVOT variance. Neither TMT-B nor Animal Naming was a significant predictor for either group.
Among NC participants, rapid word generation (i.e., COWA), a measure of executive functioning, is the most salient predictor of HVOT performance. In contrast, lexical retrieval (i.e., BNT) is the most salient language or executive functioning predictor of HVOT performance among MCI participants. These findings extend previous claims that the HVOT is multifactorial by suggesting that reduced HVOT performance in MCI patients may be related to mild lexical retrieval impairments.
PMCID: PMC2746420  PMID: 16893623
Object recognition; Mild cognitive impairment; Hooper Visual Organization Test
3.  Neuropsychological characteristics of mild cognitive impairment subgroups 
To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study.
MCI was classified as MCI‐amnestic type (MCI‐AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI‐multiple cognitive deficits type (MCI‐MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition.
MCI‐AT (n = 10) had worse verbal and non‐verbal memory performance than MCI‐MCDT (n = 28) or normal controls (n = 374). By contrast, MCI‐MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI‐AT or normal controls. MCI‐MCDT subjects had memory deficits, though they were less pronounced than in MCI‐AT. Of the MCI‐MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI‐MCDT with memory disorders had more language deficits than MCI‐MCDT without memory disorders. By contrast, MCI‐MCDT without memory deficits had more fine motor control deficits than MCI‐MCDT with memory deficits.
The most frequent form of MCI was the MCI‐MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI‐MCDT cases did not have memory impairment. Study of idiopathic amnestic and non‐amnestic forms of MCI is essential for an understanding of the aetiology of MCI.
PMCID: PMC2077558  PMID: 16103044
Alzheimer's disease; aging; dementia; mild cognitive impairment; neuropsychology
4.  Cholinergic Enhancement of Brain Activation in Mild Cognitive Impairment during Episodic Memory Encoding 
Objective: To determine the physiological impact of treatment with donepezil (Aricept) on neural circuitry supporting episodic memory encoding in patients with amnestic mild cognitive impairment (MCI) using functional magnetic resonance imaging (fMRI).
Methods: Eighteen patients with MCI and 20 age-matched healthy controls (HC) were scanned twice while performing an event-related verbal episodic encoding task. MCI participants were scanned before treatment and after approximately 3 months on donepezil; HC were untreated but rescanned at the same interval. Voxel-level analyses assessed treatment effects on activation profiles in MCI patients relative to retest changes in non-treated HC. Changes in task-related connectivity in medial temporal circuitry were also evaluated, as were associations between brain activation, task-related functional connectivity, task performance, and clinical measures of cognition.
Results: At baseline, the MCI group showed reduced activation during encoding relative to HC in the right medial temporal lobe (MTL; hippocampal/parahippocampal) and additional regions, as well as attenuated task-related deactivation, relative to rest, in a medial parietal lobe cluster. After treatment, the MCI group showed normalized MTL activation and improved parietal deactivation. These changes were associated with cognitive performance. After treatment, the MCI group also demonstrated increased task-related functional connectivity from the right MTL cluster seed region to a network of other sites including the basal nucleus/caudate and bilateral frontal lobes. Increased functional connectivity was associated with improved task performance.
Conclusion: Pharmacologic enhancement of cholinergic function in amnestic MCI is associated with changes in brain activation and functional connectivity during episodic memory processing which are in turn related to increased cognitive performance. fMRI is a promising biomarker for assessing treatment related changes in brain function.
PMCID: PMC3775540  PMID: 24062699
functional magnetic resonance imaging; mild cognitive impairment; donepezil (Aricept); Alzheimer’s disease; task-related functional connectivity; episodic encoding
5.  Geriatric Performance on an Abbreviated Version of the Boston Naming Test 
Applied neuropsychology  2007;14(3):215-223.
Abbreviated neuropsychological protocols are increasingly utilized secondary to time-constraints within research and healthcare settings, yet normative data for these abbreviated instruments are lacking. We present geriatric performances and normative data for the Boston Naming Test 30-item even verion (BNT-30). Data were utilized from the BU-ADCC registry (n = 441, ages 55-98) and included 219 normal controls (NC), 155 participants with mild cognitive impairment (MCI), and 67 participants with Alzheimer’s disease (AD). The NC group (M = 28.7, SD = 1.8) significantly outperformed both MCI (M = 26.2, SD = 4.4) and AD (M = 22.1, SD = 4.8) groups, and the MCI group outperformed the AD group. Normative data generated for the NC participants revealed a significant between-group difference for sex (males M = 29.1, SD = 1.7; females M = 28.4, SD = 1.8) and race (White M = 28.8, SD = 1.7; African American M = 27.5, SD = 2.1). The racial disparity remained even after adjusting for education level (p = .002) and literacy (p < .001). ANOVAs for the NC group were non-significant for age but significant for education level (p = .001). Geriatric normative data therefore suggest that sex, race, and education are all associated with naming performance, and these variables should be taken into consideration when interpreting geriatric BNT-30 performance.
PMCID: PMC2741691  PMID: 17848132
Alzheimer’s disease; Boston Naming Test; geriatrics; language; lexical retrieval; mild cognitive impairment; neuropsychological measures; normative data
6.  Cut-off Scores of a Brief Neuropsychological Battery (NBACE) for Spanish Individual Adults Older than 44 Years Old 
PLoS ONE  2013;8(10):e76436.
The neuropsychological battery used in Fundació ACE (NBACE) is a relatively brief, and easy to administer, test battery that was designed to detect cognitive impairment in the adulthood. The NBACE includes measures of cognitive information processing speed, orientation, attention, verbal learning and memory, language, visuoperception, praxis and executive functions. The aim of the present study was to establish the cut-off scores for impairment for different levels of age and education that could be useful in the cognitive assessment of Spanish subjects who are at risk for cognitive impairment, especially dementia. Data from 1018 patients with a mild dementia syndrome, and 512 cognitively healthy subjects, older than 44 years, from the Memory Clinic of Fundació ACE (Barcelona, Spain) were analyzed. In the whole sample, cut-off scores and sensitivity/specificity values were calculated for six conditions after combining 3 age ranges (44 to 64; 65 to 74; and older than 74 years old) by 2 educational levels (until Elementary school; and more than Elementary school). Moreover, general cut-offs are reported for Catalan and Spanish speakers. The results showed that most of NBACE tests reached good sensitivity and specificity values, except for Ideomotor praxis, Repetition and Verbal Comprehension tests, which had a ceiling effect. Word List Learning from the Wechsler Memory Scale-III and Semantic Verbal Fluency were the most useful tests to discriminate between cognitively healthy and demented subjects. The NBACE has been shown to be a useful tool able to detect cognitive impairment, especially dementia, in older than 44 years Spanish persons.
PMCID: PMC3797837  PMID: 24146868
7.  Wechsler Memory Scale–III Faces test performance in patients with mild cognitive impairment and mild Alzheimer’s disease 
Little is known about the sensitivity of the Wechsler Memory Scale–Third Edition (WMS-III) Faces subtest to memory impairment associated with mild cognitive impairment (MCI). In this study, Faces performance was examined in 24 MCI patients, 46 mild Alzheimer’s disease (AD) patients, and 98 elderly controls. We hypothesized that participants with diagnoses of MCI or AD would be impaired relative to controls on Faces. Analyses showed that AD participants performed significantly worse than MCI and intact participants, although there were no significant differences between MCI and intact participants. Data suggest that brain areas specialized for face recognition memory may be less affected by MCI and mild AD than regions specialized for verbal memory.
PMCID: PMC2829111  PMID: 19037811
Wechsler Memory Scale–Third Edition; Face recognition; Face memory; Mild cognitive impairment; Alzheimer’s disease
8.  Which part of the Quick mild cognitive impairment screen (Qmci) discriminates between normal cognition, mild cognitive impairment and dementia? 
Age and Ageing  2013;42(3):324-330.
Introduction: the Qmci is a sensitive and specific test to differentiate between normal cognition (NC), mild cognitive impairment (MCI) and dementia. We compared the sensitivity and specificity of the subtests of the Qmci to determine which best discriminated NC, MCI and dementia.
Objective: the objective was to determine the contribution each subtest of the Qmci makes, to its sensitivity and specificity in differentiating MCI from NC and dementia, to refine and shorten the instrument.
Methods: existing data from our previous study of 965 subjects, testing the Qmci, was analysed to compare the sensitivity and specificity of the Qmci subtests.
Results: all the subtests of the Qmci differentiated MCI from NC. Logical memory (LM) performed the best (area under the receiver operating curve of 0.80), registration the worst, (0.56). LM and verbal fluency had the largest median differences (expressed as percentage of total score) between MCI and NC, 20 and 25%, respectively. Other subtests did not have clinically useful differences. LM was best at differentiating MCI from NC, irrespective of age or educational status.
Conclusion: the Qmci incorporates several important cognitive domains making it useful across the spectrum of cognitive impairment. LM is the best performing subtest for differentiating MCI from NC.
PMCID: PMC3633367  PMID: 23612864
Quick mild cognitive impairment screen; mild cognitive impairment; standardised Mini-Mental State Examination; sensitivity and specificity; cognitive domains
9.  Dual-tasking and gait in people with Mild Cognitive Impairment. The effect of working memory 
BMC Geriatrics  2009;9:41.
Cognition and mobility in older adults are closely associated and they decline together with aging. Studies evaluating associations between cognitive factors and gait performance in people with Mild Cognitive Impairment (MCI) are scarce. In this study, our aim was to determine whether specific cognitive factors have a more identifiable effect on gait velocity during dual-tasking in people with MCI.
Fifty-five participants, mean age 77.7 (SD = 5.9), 45% women, with MCI were evaluated for global cognition, working memory, executive function, and attention. Gait Velocity (GV) was measured under a single-task condition (single GV) and under two dual-task conditions: 1) while counting backwards (counting GV), 2) while naming animals (verbal GV). Multivariable linear regression analysis was used to examine associations with an alpha-level of 0.05.
Participants experienced a reduction in GV while engaging in dual-task challenges (p < 0.005). Low executive function and working memory performances were associated with slow single GV (p = 0.038), slow counting GV (p = 0.017), and slow verbal GV (p = 0.031). After adjustments, working memory was the only cognitive factor which remained significantly associated with a slow GV.
In older adults with MCI, low working memory performance was associated with slow GV. Dual-task conditions showed the strongest associations with gait slowing. Our findings suggest that cortical control of gait is associated with decline in working memory in people with MCI.
PMCID: PMC2748075  PMID: 19723315
10.  P300 and Neuropsychological Assessment in Mild Cognitive Impairment and Alzheimer Dementia 
Only a small proportion of individuals with Mild Cognitive Impairment (MCI) will convert to dementia. Methods currently available to identify risk for conversion do not combine enough sensitivity and specificity, which is even more problematic in low-educated populations. Current guidelines suggest the use of combined markers for dementia to enhance the prediction accuracy of assessment methods. The present study adhered to this proposal and investigated the sensitivity and specificity of the electrophysiological component P300 and standard neuropsychological tests to assess patients with Alzheimer’s disease (AD) and MCI recruited from a low-income country. The neuropsychological battery comprised tests of memory, attention, language, praxis, and executive functions. The P300 was recorded using a classical visual odd-ball paradigm. Three variables were found to achieve sensitivity and specificity values above 80% (Immediate and Delayed recall of word list – CERAD – and the latency of P300) for both MCI and AD. When they entered the model together (i.e., combined approach) the sensitivity for MCI increased to 96% and the specificity remained high (80%). Our preliminary findings suggest that the combined use of sensitive neuropsychological tasks and the analysis of the P300 may offer a very useful method for the preclinical assessment of AD, particularly in populations with low socioeconomic and educational levels. Our results provide a platform and justification to employ more resources to convert P300 and related parameters into a biological marker for AD.
PMCID: PMC3514532  PMID: 23227021
Alzheimer’s disease; mild cognitive impairment; event related potentials; P300; neuropsychology; early detection; preclinical markers
11.  Dysexecutive Functioning in Mild Cognitive Impairment: Derailment in Temporal Gradients 
Libon et al. (2010) provided evidence for three statistically determined clusters of patients with mild cognitive impairment (MCI): amnesic (aMCI), dysexecutive (dMCI), and mixed (mxMCI). The current study further examined dysexecutive impairment in MCI using the framework of Fuster's (1997) derailed temporal gradients, that is, declining performance on executive tests over time or test epoch. Temporal gradients were operationally defined by calculating the slope of aggregate letter fluency output across 15-s epochs and accuracy indices for initial, middle, and latter triads from the Wechsler Memory Scale-Mental Control subtest (Boston Revision). For letter fluency, slope was steeper for dMCI compared to aMCI and NC groups. Between-group Mental Control analyses for triad 1 revealed worse dMCI performance than NC participants. On triad 2, dMCI scored lower than aMCI and NCs; on triad 3, mxMCI performed worse versus NCs. Within-group Mental Control analyses yielded equal performance across all triads for aMCI and NC participants. mxMCI scored lower on triad 1 compared to triads 2 and 3. dMCI participants also performed worse on triad 1 compared to triads 2 and 3, but scored higher on triad 3 versus triad 2. These data suggest impaired temporal gradients may provide a useful heuristic for understanding dysexecutive impairment in MCI.
PMCID: PMC3315354  PMID: 22014116
Mild cognitive impairment; Single domain mild cognitive impairment; Multiple domain mild cognitive impairment; Alzheimer's disease; The Titanic Effect; Executive control
12.  Mild cognitive impairment in Parkinson disease 
Neurology  2010;75(12):1062-1069.
In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies.
The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI.
A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data.
A total of 25.8% of subjects (95% confidence interval [CI] 23.5–28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6–15.3), followed by visuospatial (11.0%; 9.4–13.0) and attention/executive ability impairment (10.1%; 8.6–11.9). Regarding cognitive profiles, 11.3% (9.7–13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0–9.9) as amnestic single-domain, 4.8% (3.8–6.1) as amnestic multiple-domain, and 1.3% (0.9–2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage.
MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage.
= amnestic multiple-domain MCI;
= amnestic single-domain MCI;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= mild cognitive impairment;
= Mini-Mental State Examination;
= nonamnestic multiple-domain MCI;
= nonamnestic single-domain MCI;
= Parkinson disease;
= Parkinson's Disease Cognitive Rating Scale;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC2942065  PMID: 20855849
13.  Level of Executive Function Influences Verbal Memory in Amnestic Mild Cognitive Impairment and Predicts Prefrontal and Posterior Cingulate Thickness 
Cerebral Cortex (New York, NY)  2009;20(6):1305-1313.
This study aims to investigate the relationship between executive function and verbal memory and to explore the underlying neuroanatomical correlates in 358 individuals with amnestic mild cognitive impairment (MCI) and 222 healthy controls (HCs). The MCI participants were divided into 2 groups (high vs. low) based on executive function task performance. Results demonstrated that although both MCI groups were impaired on all memory measures relative to HCs, MCI individuals with higher executive function (HEF) demonstrated better verbal memory performance than those with lower executive function (LEF), particularly on measures of learning. The 2 MCI groups did not differ in mesial temporal morphometric measures, but the MCI LEF group showed significant thinning in dorsolateral prefrontal and posterior cingulate cortices bilaterally compared with the MCI HEF and HCs. Further, thickness in numerous regions of frontal cortex, and bilateral posterior cingulate, was significantly associated with memory performance in all MCI participants above and beyond the contribution of the mesial temporal regions known to be associated with episodic memory. Overall, these results demonstrate the importance of evaluating executive function in individuals with MCI to predict involvement of brain areas beyond the mesial temporal lobe.
PMCID: PMC2912652  PMID: 19776343
Alzheimer's disease; clinical subtypes; cognition; longitudinal outcome; morphometry
14.  The Goteborg MCI study: mild cognitive impairment is a heterogeneous condition 
Background: Mild cognitive impairment (MCI) has been considered a transitional state between normal aging and dementia, characterised by memory impairment but normal general cognitive functioning. Recently other cognitive deficits have been reported. This has led to a modification of MCI criteria.
Objective: To examine which neuropsychological tests most clearly distinguish MCI subjects from normal controls.
Methods: 112 consecutive MCI subjects and 35 controls were included in the study. The diagnosis of MCI was based on an objective history of cognitive decline and a neuropsychiatric examination, comprising instruments STEP, I-Flex, MMSE, and CDR. Participants were examined with 21 neuropsychological tests in the cognitive domains speed/attention, memory and learning, visuospatial function, language, and executive function.
Results: Controls were significantly older. No differences were found in education or general intellectual capacity. Controls performed significantly better than MCI on tests within all five cognitive domains. The clearest differences were seen on language tests, followed by executive function, and learning and memory. Only two subjects (1.8%) were purely amnestic; 17% showed no impairment compared with controls, with a cut off of 1.5 SD below age mean. These subjects were better educated and performed significantly better on measures of general cognitive capacity.
Conclusions: The results illustrate the heterogeneity of MCI, with a significant degree of impairment in all five cognitive domains. When examined with a comprehensive neuropsychological battery, very few subjects had an isolated memory impairment.
PMCID: PMC1739388  PMID: 16227535
15.  Cognitive Training Changes Hippocampal Function in Mild Cognitive Impairment: A Pilot Study 
Journal of Alzheimer's Disease  2011;26(Suppl 3):349-357.
A randomized pilot experiment examined the neural substrates of response to cognitive training in participants with mild cognitive impairment (MCI). Participants performed exercises previously demonstrated to improve verbal memory and an active control group performed other computer activities. An auditory-verbal fMRI task was conducted before and after the two-month training program. Verbal memory scores improved significantly and left hippocampal activation increased significantly in the experimental group (gains in 5 of 6 participants) relative to the control group (reductions in all 6 participants). Results suggest that the hippocampus in MCI may retain sufficient neuroplasticity to benefit from cognitive training.
PMCID: PMC3277842  PMID: 21971474
MRI; dementia; cognition; MCI; mild cognitive impairment; fMRI; functional MRI; cognitive training; hippocampus; medial temporal lobe
16.  3D mapping of language networks in clinical and pre-clinical Alzheimer’s disease 
Brain and language  2007;104(1):33-41.
We investigated the associations between Boston Naming and the animal fluency tests and cortical atrophy in 19 probable AD and 5 multiple domain amnestic mild cognitive impairment patients who later converted to AD. We applied a surface-based computational anatomy technique to MRI scans of the brain and then used linear regression models to detect associations between animal fluency and Boston naming test (BNT) performance and cortical atrophy. The global permutation-corrected significance for the maps associating BNT performance with cortical atrophy was p=0.0124 for the left and p=0.0196 for the right hemisphere and for the animal fluency maps p=0.055 for the left and p=0.073 for the right hemisphere. The degree of language impairment correlated with cortical atrophy in the left temporal and parietal lobes (BA 20, 21, 37, 39, 40, 7), bilateral frontal lobes (BA 8, 9, 44) and the right temporal pole (BA 38). Using a novel 3D mapping technique, we demonstrated that in AD language abilities are strongly influenced by the integrity of the perisylvian cortical regions.
PMCID: PMC2211373  PMID: 17485107
17.  Subjective memory beliefs and cognitive performance in normal and mildly impaired older adults 
Aging & mental health  2006;10(4):413-423.
Previous research suggests that subjective perceptions of memory may be related to objective memory performance. In the present study, healthy community-dwelling elders (N = 73, mean age = 75.25 years, education = 16.2 years) completed a neuropsychological assessment, including two questionnaires of subjective memory beliefs. Each participant was identified, via consensus conference, as belonging to either an amnestic mild cognitive impairment (MCI, n = 16) or no mild cognitive impairment (noMCI, n = 57) group. Results indicated that subjective memory capacity beliefs were significantly related to verbal memory performance in the MCI group, but not in the noMCI group. This differential relationship persisted even after controlling for depressive symptoms, and was not reflective of unequal variances in the two groups. Thus, results indicate that subjective memory beliefs may be better indicators of performance in those with possible incipient cognitive impairment than normal older adults, perhaps because persons with MCI have heightened insight into their memory functioning, and that this relationship is not due to group differences in depressive symptoms.
PMCID: PMC2905785  PMID: 16798634
18.  Generalist genes and cognitive abilities in Chinese twins 
Developmental Science  2013;16(2):260-268.
This study considered how far nonverbal cognitive, language and reading abilities are affected by common genetic influences in a sample of 312 typically developing Chinese twin pairs aged from 3 to 11 years. Children were individually given tasks of Chinese word reading, receptive vocabulary, phonological memory, tone awareness, syllable and rhyme awareness, rapid automatized naming, morphological awareness and orthographic skills, and Raven's Colored Progressive Matrices. Factor analyses on the verbal tasks adjusted for age indicated two factors: Language as the first factor and Reading as the second factor. Univariate genetic analyses indicated that genetic influences were substantial for nonverbal cognitive ability and moderate for language and reading. Multivariate genetic analyses showed that nonverbal cognitive ability, language and reading were influenced by shared genetic origins, although there were specific genetic influences on verbal skills that were distinct from those on nonverbal cognitive ability. This study extends the Generalist Genes Hypothesis to Chinese language and reading skills, suggesting that the general effects of genes could be universal across languages.
PMCID: PMC3757317  PMID: 23432835
19.  The Self-Fulfilling Prophecy of Episodic Memory Impairment in Mild Cognitive Impairment: Do Episodic Memory Deficits Identified at Classification Remain Evident When Later Examined with Different Memory Tests? 
Previous studies of mild cognitive impairment (MCI) have been criticised for using the same battery of neuropsychological tests during classification and longitudinal followup. The key concern is that there is a potential circularity when the same tests are used to identify MCI and then subsequently monitor change in function over time. The aim of the present study was to examine the evidence of this potential circularity problem. The present study assessed the memory function of 72 MCI participants and 50 healthy controls using an alternate battery of visual and verbal episodic memory tests 9 months following initial comprehensive screening assessment and MCI classification. Individuals who were classified as multiple-domain amnestic MCI (a-MCI+) at screening show a significantly reduced performance in visual and verbal memory function at followup using a completely different battery of valid and reliable tests. Consistent with their initial classification, those identified as nonamnestic MCI (na-MCI) or control at screening demonstrated the highest performance across the memory tasks. The results of the present study indicate that persistent memory deficits remain evident in amnestic MCI subgroups using alternate memory tests, suggesting that the concerns regarding potential circularity of logic may be overstated in MCI research.
PMCID: PMC3770046  PMID: 24062948
20.  Demyelination in Mild Cognitive Impairment Suggests Progression Path to Alzheimer’s Disease 
PLoS ONE  2013;8(8):e72759.
The preclinical Alzheimer's disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.
PMCID: PMC3758332  PMID: 24023644
21.  The PACE Study: A randomised clinical trial of cognitive activity (CA) for older adults with mild cognitive impairment (MCI) 
Trials  2009;10:114.
Research evidence from observational studies suggests that cognitive activity reduces the risk of cognitive impairment in later life as well as the rate of cognitive decline of people with dementia. The Promoting Healthy Ageing with Cognitive Exercise (PACE) study has been designed to determine whether a cognitive activity intervention decreases the rate of cognitive decline amongst older adults with mild cognitive impairment (MCI).
The study will recruit 160 community-dwelling men and women aged 65 years of age or over with mild cognitive impairment (MCI). Participants will be randomly allocated to two treatment groups: non-specific education and cognitive activity. The intervention will consist of ten 90-minute sessions delivered twice per week over a period of five weeks. The primary outcome measure of the study is the change from baseline in the total score on the Cambridge Cognitive Score (CAMCOG). Secondary outcomes of interest include changes in memory, attention, executive functions, mood and quality of life. Primary endpoints will be collected 12, 52 and 104 weeks after the baseline assessment.
The proposed project will produce the best available evidence on the merits of increased cognitive activity as a strategy to prevent cognitive decline among older adults with MCI. We anticipate that the results of this study will have implications for the development of evidence-based preventive strategies to reduce the rate of cognitive decline amongst older people at risk of dementia.
Trial registration
PMCID: PMC2803454  PMID: 20003398
22.  Plasma Lipid Levels in the Elderly Are Not Associated with the Risk of Mild Cognitive Impairment 
There are conflicting data relating plasma lipids to the risk of Alzheimer's disease (AD). We explored the association of plasma lipids to mild cognitive impairment (MCI), a transitional stage between normal cognition and dementia, in a prospective community-based cohort study among randomly sampled Medicare recipients ≥65 years. Baseline data were collected from 1992 to 1994, follow-up data were collected at 18-month intervals.
Multivariate proportional hazards regression was used to relate plasma lipid levels to incident total MCI, amnestic MCI and nonamnestic MCI in 854 persons without MCI or dementia at baseline.
There were 324 cases of incident MCI, 153 cases of amnestic MCI and 171 cases of nonamnestic MCI during 4,189 person-years of follow-up. Higher levels of total cholesterol and LDL were associated with a decreased risk of total MCI in models adjusting for age and sex. However, these associations were attenuated after adjusting for ethnicity, education, APOEε4 and vascular risk factors. There was no association between lipids and the risk of amnestic or nonamnestic MCI, and there was no effect of lipid-lowering treatment on MCI risk.
Plasma lipid levels or lipid-lowering treatment in the elderly are not associated with the risk of MCI.
PMCID: PMC2725016  PMID: 18264008
Plasma lipid levels; Mild cognitive impairment
23.  Profile of Cognitive Complaints in Vascular Mild Cognitive Impairment and Mild Cognitive Impairment 
ISRN Neurology  2013;2013:865827.
Objective. Vascular mild cognitive impairment (VaMCI) is differentiated from mild cognitive impairment (MCI) by the presence of vascular events such as stroke or small vessel disease. Typically, MCI and VaMCI patients present with subjective complaints regarding cognition; however, little is known about the specific nature of these complaints. We aimed to create a profile of subjective cognitive complaints in MCI and VaMCI patients with similar levels of objective cognitive performance. Methods. Twenty MCI and twenty VaMCI patients were recruited from a Memory Disorders Clinic in Toronto. Subjective cognitive complaints were assessed and categorized using the Neuropsychological Impairment Scale. Results. MCI and VaMCI patients achieved similar scores on measures of objective cognitive function (P > 0.100). However, the VaMCI group had more subjective complaints than the MCI group (P = 0.050), particularly in the critical items, cognitive efficiency, memory, and verbal learning domains of the Neuropsychological Impairment Scale. Conclusions. Our findings support the idea that VaMCI and MCI differ in their clinical profiles, independent of neuroimaging. VaMCI patients have significantly more subjective cognitive complaints and may be exhibiting particular deficits in memory, verbal learning, and cognitive efficiency. Our findings promote the need for further research into VaMCI-specific cognitive deficits.
PMCID: PMC3830842  PMID: 24288623
24.  The Effect of Cognitive Training in Patients with Mild Cognitive Impairment and Early Alzheimer's Disease: A Preliminary Study 
Background and Purpose
The objective of this study was to determine the benefits of cognitive training in patients with amnestic mild cognitive impairment (aMCI) and those with early Alzheimer's disease (AD).
Eleven patients with aMCI and nine with early AD (stage 4 on the Global Deterioration Scale) participated in this study. Six participants with aMCI and six with AD were allocated to the cognitive training group, while five participants with aMCI and three with AD were allocated to a wait-list control group. Multicomponent cognitive training was administered in 18 weekly, individual sessions. Outcome measures were undertaken at baseline, and at 2 weeks and 3 months of follow-up.
In the trained MCI group, there were significant improvements in the delayed-recall scores on the Seoul Verbal Learning Test at both the 2-week and 3-month follow-ups compared with baseline (baseline, 1.6±1.5; 2 weeks, 4.4±1.5, p=0.04; 3 months, 4.6±2.3, p=0.04). The phonemic fluency scores (1.0±0.8 vs. 5.0±1.8, p=0.07) and Korean Mini-Mental State Examination scores (18.8±0.5 vs. 23.8±2.2, p=0.07) also showed a tendency toward improvement at the 2-week follow-up compared to baseline in the trained AD group.
This study provides evidence of the effectiveness of cognitive training in aMCI and early AD. The efficacy of cognitive training programs remains to be verified in studies with larger samples and a randomized design.
PMCID: PMC3469799  PMID: 23091528
Alzheimer's disease; cognitive therapy; memory; mild cognitive impairment; training
25.  Longitudinal change in neuropsychological performance using latent growth models: a study of mild cognitive impairment 
Brain imaging and behavior  2012;6(4):540-550.
The goal of the current study was to examine cognitive change in both healthy controls (n=229) and individuals with mild cognitive impairment (MCI) (n=397) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We applied latent growth modeling to examine baseline and longitudinal change over 36 months in five cognitive factors derived from the ADNI neuropsychological test battery (memory, executive function/processing speed, language, attention and visuospatial). At baseline, MCI patients demonstrated lower performance on all of the five cognitive factors when compared to controls. Both controls and MCI patients declined on memory over 36 months; however, the MCI patients declined at a significantly faster rate than controls. The MCI patients also declined over 36 months on the remaining four cognitive factors. In contrast, the controls did not exhibit significant change over 36 months on the non-memory cognitive factors. Within the MCI group, executive function declined faster than memory, while the other factor scores changed slower than memory over time. These findings suggest different patterns of cognitive change in healthy older adults and MCI patients. The findings also suggest that, when compared with memory, executive function declines faster than other cognitive factors in patients with MCI. Thus, decline in non-memory domains may be an important feature for distinguishing healthy older adults and persons with MCI.
PMCID: PMC3532521  PMID: 22562439
ADNI; Neuropsychology; Cognition; Mild cognitive impairment; Cognitive change; Executive function

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