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ABSTRACT: Degeneration of the corpus callosum (CC) is evident in the pathogenesis of Alzheimer's disease (AD). However, the correlation of microstructural damage in the CC on the cognitive performance of patients with amnestic mild cognitive impairment (aMCI) and AD dementia is undetermined. We enrolled 26 normal controls, 24 patients with AD dementia, and 40 single-domain aMCI patients with at least grade 1 hippocampal atrophy and isolated memory impairment. Diffusion tensor imaging (DTI) with fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA), and radial diffusivity (DR) were measured. The entire CC was parcellated based on fiber trajectories to specific cortical Brodmann areas using a probabilistic tractography method. The relationship between the DTI measures in the subregions of the CC and cognitive performance was examined. Although the callosal degeneration in the patients with aMCI was less extended than in the patients with AD dementia, degeneration was already exhibited in several subregions of the CC at the aMCI stage. Scores of various neuropsychological tests were correlated to the severity of microstructural changes in the subregional CC connecting to functionally corresponding cortical regions. Our results confirm that CC degeneration is noticeable as early as the aMCI stage of AD and the disconnection of the CC subregional fibers to the corresponding Brodmann areas has an apparent impact on the related cognitive performance. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
Human Brain Mapping 05/2013; · 5.88 Impact Factor
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ABSTRACT: ABSTRACT Background: Executive dysfunction is not uncommon in patients with amnestic mild cognitive impairment (aMCI). This study aimed to investigate the applicability of executive function tests (EFTs) in aMCI as an aid in establishing the diagnosis of multi-domain MCI. Methods: One hundred and twenty (120) aMCI patients, 126 Alzheimer's disease (AD) patients, and 100 normal controls were enrolled. The EFTs evaluated included the trail making test, digit backward span, Stroop color-word test, and design fluency and category fluency tests. Results: Of the aMCI participants, 66% exhibited impairment in at least one EFT. Among the five selected EFTs, the category fluency test was the most discriminative in detecting executive dysfunction between patients with aMCI (standardized β = 0.264) or AD (standardized β = 0.361) with the controls, followed by the Stroop test. The performance of aMCI patients with two or more impaired EFTs was significantly different from those of controls but not from those of AD patients. Conclusion: In the clinical setting, aMCI patients who fail in two or more EFTs may represent a unique population with multi-domain MCI that require close follow-up.
International Psychogeriatrics 04/2013; · 2.24 Impact Factor
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ABSTRACT: Abstract- The Cognitive Abilities Screening Instrument (CASI) has been commonly used in dementia research and clinical practice to evaluate a subject's cognitive abilities and to follow-up possible progression of dementia. It has a detailed manual for test administration and scoring in order to minimize testing errors. The Chinese version of CASI (CASI C-2.0) has been used in many clinical and epidemiological studies in Taiwan. Since cognitive abilities are influenced by education, and there are high rates of illiterate or loweducation individuals among the elderly in Taiwan, the normative data of CASI, including its total score and its cognitive domain scores, should be divided into different education ranges. In clinical practice, the cut-off scores in differentiating between dementia and normal are suggested to be: 49/50 for Education year = 0; 67/68 for Education years = 1-5; and 79/80 for Education years more than 6.
Acta neurologica Taiwanica 12/2012; 21(4):180-189.
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ABSTRACT: Different diffusivity measurements in diffusion-tensor imaging (DTI) could be helpful for detecting the distinct mechanisms of white matter degeneration in Alzheimer's disease (AD). However, few studies have explored the changes of white matter in amnestic mild cognitive impairment (aMCI) and AD by whole-brain voxel-wise analyses of all diffusivity indices. The association between grey matter atrophy and white matter damage measured by distinct diffusivities is still uncertain. Structural magnetic resonance imaging and DTI with four diffusivity indices, comprising fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, were performed in 30 normal controls, 26 mild AD patients, and 40 aMCI patients with isolated memory impairment. T1 voxel-based morphometry and DTI tract-based spatial statistics were applied to compare the grey and white matter changes in the 3 groups. In contrast to the lack of significant white matter change presenting in aMCI patients, extended white matter degeneration over entire cerebral networks was exhibited in mild AD patients. Both axonal degradation and demyelination contributed to the white matter degeneration in AD; nevertheless, demyelination essentially involved the frontal portion of cerebral networks. Axonal degradation and demyelination over the temporal region were associated with the contiguous grey matter atrophy. However, only the severity of demyelination over the frontal region was correlated with the degree of atrophy over adjacent frontal grey matter. Our results suggest that different mechanisms of white matter damage demonstrate discrete regional distribution in AD. Demyelination may independently correlate with contiguous grey matter over the frontal region.
Journal of Alzheimer's disease: JAD 03/2012; 30(2):423-37. · 3.74 Impact Factor
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ABSTRACT: Increasing evidence has shown that the immunological reaction of leukocytes plays a crucial role in the development of neurodegenerative disorders. We conducted transcriptome analysis of leukocytes from patients of mild cognitive impairment (MCI), Alzheimer's disease (AD), as well as normal controls (NC) by oligonucleotide microarray. The differentially expressed genes of interest were selected by pathway-based functional enrichment and were then validated in 60 subjects (17 NC, 20 MCI and 23 AD) by quantitative PCR (QRT-PCR). Thirty-four differentially expressed genes between NC and AD were enriched in ATP-binding cassette (ABC) transporters, ascorbate and aldarate metabolism, Gly/Ser/Thr metabolism, transforming growth factor-β signaling, and extracellular matrix (ECM)-receptor interaction pathways (Welch t-test; p < 0.05). Comparison of NC, MCI and AD transcriptomes identified 8 genes significantly associated with purine metabolism and the ABC transporters. Furthermore, 13 out of 18 genes selected from the above lists were successfully validated by QRT-PCR (Mann-Whitney U-test), and only ABCB1 gene exhibited significantly positive correlation with MMSE scores among NC, MCI, and AD subjects (r = 0.3858, p = 0.0011). With a limited number of study population, our study may provide a novel direction for evaluating diagnostic biomarkers in monitoring AD progression.
Neurobiology of Disease 06/2011; 43(3):698-705. · 5.40 Impact Factor
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ABSTRACT: The discrimination between normal elderly (NC) and those with mild cognitive impairment (MCI) is of clinical relevance since the conversion from MCI to Alzheimer dementia (AD) is high.
This study enrolled 216 amnestic MCI patients and 103 NC from our memory clinics and assessed whether the learning curve, recall and cued scores, as well as error patterns from the Chinese Version Verbal Learning Test (CVVLT) helped to distinguish between these two groups. Results: Our results revealed that subjects with MCI had a lower rate of acquisition and deceleration of learning in the learning curve. The MCI group also showed a lower retention rate and recall scores as compared with the NC group. Further, the error patterns offered discrimination values between the two groups in total number of perseverations, intrusion in the cued recall, as well as prototypic and unrelated errors in recognition. An inverse correlation was seen between memory scores and error patterns.
This study suggests that by combining the learning and error patterns from the verbal memory test, patients with MCI can be better differentiated from normal elderly.
Acta neurologica Taiwanica 06/2011; 20(2):114-24.
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ABSTRACT: To evaluate the effect of the apolipoprotein E (APOE) ε4 in the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) in ethnic Chinese people in Taiwan.
Subjects older than 60 years with normal cognition, MCI or AD were enrolled from the memory clinic from 2000 to 2008. Normal ageing and MCI subjects were evaluated with clinical and neuropsychological examinations annually, and their APOE genotypes were determined.
A total of 326 normal ageing subjects, 304 amnestic MCI and 537 AD patients were recruited at baseline. The frequencies of APOE ε4 were 22.1% in normal ageing, 26.6% in MCI and 40.8% in AD patients. During the follow-up period (42.5±18.5 months), there were 227 MCI patients, and 248 normal ageing subjects received one or more annual follow-up evaluation. The ε4+carriers had a higher annual conversion rate than did the ε4-negative subjects either in the MCI (15.9% vs 9.0%) or in the normal ageing subjects (2.2% vs 0.7%). The mean survival time before progression to AD was 57.0 months for the MCI ε4+carriers, 85.9 months for MCI ε4-negative patients, 86.2 months for normal ageing e4+carriers and 120.8 months for normal ageing ε4-negative subjects. The adjusted hazard ratio of APOE ε4 for developing AD was 2.0 (95% CI 1.2 to 3.2) in MCI and 5.3 (95% CI 1.2 to 24.1) in normal ageing.
APOE ε4 increased the risk of developing AD both in amnestic MCI and in normal ageing in a clinic-recruited ethnic Chinese population.
Journal of neurology, neurosurgery, and psychiatry 02/2011; 82(2):165-9. · 4.87 Impact Factor
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ABSTRACT: Instrumental activities of daily living (IADL) can be impaired in mild cognitive impairment (MCI), and the severity of functional disability predicts Alzheimer's disease (AD) in amnestic MCI (aMCI). This study investigated the functional profiles of aMCI in a Chinese population.
The Disability Assessment for Dementia scores of 56 subjects with single-domain aMCI (sd-aMCI) and 94 with multiple-domain aMCI (md-aMCI) were compared with normal controls (n = 64) and mild AD patients (n = 102).
Both the sd-aMCI (2.5 ± 2.5) and md-aMCI (3.7 ± 3.5) groups had more impaired IADL items than the controls (0.7 ± 1.7). Their IADL scores were intermediate, between the control and AD groups. sd-aMCI subjects presented deficits in 7 IADL items involving the 'meal preparation', 'telephoning', 'finance', 'medications', 'housework', and 'leisure' subscales. md-aMCI subjects presented deficits in 14 IADL items involving all subscales of daily activities. The Mini-Mental State Examination and Modified Trail-Making Test Part B scores were the major neuropsychological correlates of IADL performance in aMCI.
IADL can be impaired in both sd-aMCI and md-aMCI. Including the functional ability assessment in the evaluation of aMCI may help clinicians to provide appropriate suggestions to maintain daily functioning.
Dementia and Geriatric Cognitive Disorders 01/2011; 31(3):225-32. · 2.14 Impact Factor
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ABSTRACT: Recent research on Alzheimer's disease (AD) has shown that the decline of cognitive and memory functions is accompanied by a disrupted neuronal connectivity characterized by white matter (WM) degeneration. However, changes in the topological organization of WM structural network in AD remain largely unknown. Here, we used diffusion tensor image tractography to construct the human brain WM networks of 25 AD patients and 30 age- and sex-matched healthy controls, followed by a graph theoretical analysis. We found that both AD patients and controls had a small-world topology in WM network, suggesting an optimal balance between structurally segregated and integrative organization. More important, the AD patients exhibited increased shortest path length and decreased global efficiency in WM network compared with controls, implying abnormal topological organization. Furthermore, we showed that the WM network contained highly connected hub regions that were predominately located in the precuneus, cingulate cortex, and dorsolateral prefrontal cortex, which was consistent with the previous diffusion-MRI studies. Specifically, AD patients were found to have reduced nodal efficiency predominantly located in the frontal regions. Finally, we showed that the alterations of various network properties were significantly correlated with the behavior performances. Together, the present study demonstrated for the first time that the Alzheimer's brain was associated with disrupted topological organization in the large-scale WM structural networks, thus providing the structural evidence for abnormalities of systematic integrity in this disease. This work could also have implications for understanding how the abnormalities of structural connectivity in AD underlie behavioral deficits in the patients.
Journal of Neuroscience 12/2010; 30(50):16876-85. · 7.11 Impact Factor
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ABSTRACT: The etiology of age-related white matter changes is unclear. Cerebral white matter changes on magnetic resonance imaging (MRI) and progressive dementia have been reported in patients with dural arteriovenous fistulas of the sigmoid sinus. The frequency of jugular venous reflux, which mimics a dural arteriovenous fistula, significantly increases with age. We investigated whether jugular venous reflux was associated with the severity of age-related white matter changes in 97 persons (aged 55-90 years, mean [standard deviation]: 75.77 [8.19] years; 55 men) from a medical center memory clinic.
MRI (1.5T) and the semiquantitative Scheltens scale were used to investigate the severity of white matter changes. Subjects were classified into 3 groups (no, mild, and severe jugular venous reflux) by duplex ultrasonography.
Subjects with severe jugular venous reflux had more severe age-related white matter changes in occipital subcortical, thalamus, pontine, and summed infratentorial regions compared with subjects with no jugular venous reflux (all corrected p < 0.0166), especially subjects aged ≥75 years (corrected p < 0.0166 in occipital subcortical; corrected p < 0.0001 in pontine and summed infratentorial regions). In subjects ≥75 years, we further noted that the whole brain age-related white matter changes rating scores were higher in the severe jugular venous reflux group than the no and mild jugular venous reflux groups (corrected p < 0.0166).
People with severe jugular venous reflux exhibit more severe age-related white matter changes, especially in caudal brain regions. We also demonstrate age-dependent jugular venous reflux effects on the severity of age-related white matter changes. These findings may provide new clues into the pathophysiology of age-related white matter changes.
Annals of Neurology 10/2010; 69(3):553-9. · 11.09 Impact Factor
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ABSTRACT: Episodic memory tasks are one of the most sensitive tools to discriminate Alzheimer's disease (AD). This study aimed to validate a shorter version verbal memory test that will efficiently assess Chinese elderly with memory complaints. One hundred and eighty-five elderly with normal cognition (NC) and 217 AD patients were evaluated. Each participant received the Chinese Version Verbal Learning Test (CVVLT) consisting of 9 two-character nouns with 4 learning trials, 2 delayed recalls in 30 seconds and 10 minutes, and a word recognition test. In the NC elderly, age and sex had significant effects on recall scores in CVVLT, while education level showed an inverse correlation with 3 different patterns of errors made during the learning, recall, and recognition trials. AD patients had lower scores across all recall tests. In those with lower educational level, NC elderly had higher perseveration errors than AD patients. The cutoff value between the AD and NC groups in the 10-minute recall was 4/5 for those aged >75 years and 5/6 for those aged <75 years. This study has good validity in discriminating AD participants and the data here can help in diagnosing AD and mild cognitive impairment using the CVVLT.
Journal of the International Neuropsychological Society 12/2009; 16(2):244-51. · 2.76 Impact Factor
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ABSTRACT: There is increasing evidence of oxidative stress in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Because mitochondrial DNA (mtDNA) is susceptible to oxidative damage, somatic mtDNA mutations may be induced by oxidative stress. Most of the studies examining mitochondrial mutations have been performed on postmortem brain tissues of AD patients. This study examined peripheral blood samples of AD and MCI patients to determine if peripheral mtDNA mutations are associated with these two conditions. A total of 236 subjects, including 71 AD patients, 84 amnestic MCI patients, 41 cognitively normal aging controls, and 40 young controls, were recruited. There was heteroplasmy of the mtDNA D310 polycytosine repeat region in 37 of 71 (52.1%) AD patients and this was significantly more frequent than in MCI patients (31.0%), normal aging (31.7%), and young controls (27.5%). However, subjects with amnestic MCI did not have a significantly higher rate of heteroplasmy in D310 than cognitively normal elderly subjects. The heteroplasmic alterations of D310 were more frequently in subjects with a larger number of polycytosine repetitions. Insertion of cytosine was the most common mutation type. The results suggest that mutations of mtDNA 310 region are frequently present in the peripheral blood of AD patients. Further prospective investigations to determine if MCI subjects with D310 mutations develop AD is warranted.
Journal of Alzheimer's disease: JAD 08/2009; 18(2):345-53. · 3.74 Impact Factor
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ABSTRACT: Studies suggest that smaller hippocampal volume predicts Alzheimer's disease (AD) in mild cognitive impairment (MCI). However, few studies have demonstrated decline rates in cognition and hippocampal volume in MCI subjects with stable clinical presentation. Furthermore, the effects of apolipoprotein E (ApoE) on the change rates of medial temporal structures and cognition in MCI are rarely investigated. Fifty-eight subjects with amnestic MCI and 20 normal aging elderly controls received annual neuropsychological and magnetic resonance imaging (MRI) assessments. Annual decline rates in neuropsychological test scores, hippocampal and amygdalar volumes were calculated. ApoE genotypes were examined. Nineteen (32.7%) MCI subjects converted to AD during an average 22.5-month follow-up period. The annual hippocampal atrophy rate was correlated with a decline in memory test scores. The presence of the ApoE varepsilon4 allele did not affect the change rates in neuropsychological test scores and medial temporal structures volume. Compared to subjects with stable MCI (MCI-S) and normal aging, progressive MCI (MCI-P) had the highest annual decline rates in cognition and hippocampal volume. Logistic regression analysis showed that higher annual decline rates in hippocampal volume and global cognitive test scores were associated with conversion to AD. Furthermore, although MCI-S subjects had little cognitive decline, their hippocampal atrophy rates were higher than those of normal aging controls. Therefore, accelerated hippocampal atrophy rates may be an early and important presentation in MCI subjects.
Psychiatry Research 03/2009; 171(3):221-31. · 2.52 Impact Factor
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Movement Disorders 03/2009; 24(7):1094-5. · 4.51 Impact Factor
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ABSTRACT: Brain abnormalities, as determined by structural magnetic resonance imaging (MRI), have been reported in patients with attention-deficit hyperactivity disorder (ADHD); however, female subjects have been underrepresented in previous reports. In this study, we used optimized voxel-based morphometry to compare the total and regional gray matter volumes between groups of 7- to 17-year-old ADHD and healthy children (total 114 subjects). Fifty-seven children with ADHD (n=57, 35 males and 22 females) and healthy children (n=57) received MRI scans. Segmented brain MRI images were normalized into standardized stereotactic space, modulated to allow volumetric analysis, smoothed and compared at the voxel level with statistical parametric mapping. Global volumetric comparisons between groups revealed that the total brain volumes of ADHD children were smaller than those of the control children. As for the regional brain analysis, the brain volumes of ADHD children were found to be bilaterally smaller in the following regions as compared with normal control values: the caudate nucleus and the cerebellum. There were two clusters of regional decrease in the female brain, left posterior cingulum and right precuneus, as compared with the male brain. Brain regions showing the interaction effect of diagnosis and gender were negligible. These results were consistent with the hypothesized dysfunctional systems in ADHD, and they also suggested that neuroanatomical abnormalities in ADHD were not influenced by gender.
Psychiatry Research 01/2009; 164(3):245-53. · 2.52 Impact Factor
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ABSTRACT: Survival time and mortality risk factors in patients with Alzheimer's disease (AD) have been documented in Western countries, but comparable information on the ethnic Chinese is scarce. We consecutively recruited 159 AD patients and 145 control subjects from the Memory Clinic of Taipei Veterans General Hospital. After admission to the study, each subject received clinical, neuropsychological, and psychiatric evaluation and apolipoprotein E genotyping. Survival status was followed for 5 years. Forty-six AD patients (28.9%) and 3 control subjects (2.1%) died during the 5-year follow-up period. The mean survival time for AD patients was 4.48 years (SD = 0.1 years) after the time of enrollment. Among individuals with AD, those with severe disease, older patients, and those experiencing hallucinations were at greater risk for increased mortality. As expected, AD shortened life expectancy in these patients. The factors found to correlate with a shorter life span may suggest effective health care strategies for AD patients.
Journal of Geriatric Psychiatry and Neurology 10/2007; 20(3):172-7. · 3.07 Impact Factor
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ABSTRACT: We investigated the conversion rate and the risk factors for conversion to dementia from questionable dementia in 124 ethnic Chinese subjects with questionable dementia at a memory clinic of a university hospital. They were evaluated annually based on cognitive testing, the clinical dementia rating scale, and a psychiatrist's interview for depression and anxiety. Apolipoprotein E genotyping was performed on 111 of these questionable dementia subjects. All subjects were evaluated at least twice during the follow-up period of 20.4 +/- 12.4 months. During that period, 42 questionable dementia subjects were diagnosed as having Alzheimer's disease, with an annual conversion rate to dementia of 19.9%. Compared with the 82 nonconverters, the 42 converters were significantly older, had lower cognitive, depression, and anxiety scores, and a higher frequency of the apolipoprotein E epsilon4 allele. Cox regression analysis revealed that the Alzheimer's disease converters had lower scores for orientation, short-term memory, and anxiety, and a higher frequency of the apolipoprotein E epsilon4 allele than the nonconverters.
Journal of Geriatric Psychiatry and Neurology 07/2007; 20(2):76-83. · 3.07 Impact Factor
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ABSTRACT: To investigate the prevalence of and risk factors for behavioral and psychological symptoms in Taiwanese Alzheimer's disease (AD) patients.
Consecutive AD patients from the Memory Clinic of the Taipei Veterans General Hospital were studied. Cognitive function was evaluated using the Chinese version of the Cognitive Abilities Screening Instrument. Primary caregivers were interviewed for the Clinical Dementia Rating scale, the Barthel Index, and the Alzheimer's Deficit Scale. Behavioral and psychological symptoms were assessed using the Behavioral Pathology in Alzheimer's Disease Rating Scale.
Of the 142 participants, 73 (50.7%) had at least one delusion. The most frequent delusion was delusion of theft (N=43, 30.3%). Thirty-five patients (24.6%) experienced hallucination. Fifty-seven patients (40.1%) had activity disturbances and 39 (27.5%) had aggression. Patients were divided into two subgroups according to the presence or absence of each cluster of symptoms, namely, delusions, hallucinations, activity disturbance, aggression, diurnal rhythm change, affective symptoms, and anxiety. There was no significant correlation between age, age at onset of dementia, number of years of education, and duration of illness and each cluster of symptoms. Correlation between severity of behavioral and psychological symptoms of dementia and cognitive decline was noted.
This study revealed a high prevalence of behavioral and psychological symptoms of dementia in Taiwanese patients with AD and suggests that these symptoms are associated with cognitive deficit.
International Psychogeriatrics 07/2007; 19(3):605-13. · 2.24 Impact Factor
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ABSTRACT: This study analyzed whether platelet amyloid beta-protein precursor (AbetaPP) isoform ratio correlates with cognition or cognitive decline in patients with Alzheimer's disease (AD). Platelet AbetaPP isoform ratio was measured, and cognitive assessment was performed using the Mini-Mental State Examination (MMSE) in 66 AD patients at baseline (T0) and in 29 of these patients in a one-year follow-up (T1). There was a significant correlation between the AbetaPP isoform ratios and MMSE scores in the 66 AD patients at T0. The T1 subjects were divided into two groups: 12 "no decliners" (MMSE score, T1-T0 > or = 0) and 17 "decliners" (MMSE score, T1-T0 < 0). The decliners group showed a significantly greater reduction of AbetaPP isoform ratio from T0 to T1 than the no decliners group. However, the decline of the ratio did not correlate with the decline of MMSE score. These findings indicate that AbetaPP isoform ratio correlates with cognition, and reduction in this ratio may be a marker for cognitive decline in AD patients.
Journal of Alzheimer's disease: JAD 03/2007; 11(1):77-84. · 3.74 Impact Factor
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ABSTRACT: Veterans General Hospital started study for mild cognitive impairment (MCI) since 1996. We used clinical dementia rating (CDR) of 0.5 to define our questionable dementia (QD) subjects. These QD subjects received annual neuropsychological assessment in 5-year follow-up period. Annual conversion rate, apolipoprotein E (ApoE) genotype and neuropsychological risk factors for QD were investigated. We found a 19.9% person-year conversion rate for these QD subjects. Both of the poor cognitive performance and ApoE epsilon4 allele were risk factors for progressing to dementia. Based on the results of this study and the progress in the concept of MCI, we added more complex verbal and visual memory tests as well as MRI-based volumetry measurement in our subsequent research. Peterson's amnestic MCI criteria were used to diagnose our MCI subjects. In the 3-year follow-up period, the conversional rate was 18.2% person-year for MCI subjects, similar to our previous finding in QD. We found hippocampal volume was positively associated with cognitive performance. ApoE genotype had effect on hippocampal volume. Subjects with lower cognitive performance and smaller hippocampi had higher risk converting to AD. With rapidly expanding research on dementia and MCI worldwide, we are looking forward to seeing the integration in neurobiology, neuroimaging, and neurobehavior fields to establish a multidisciplinary approach to MCI and dementia.
Acta neurologica Taiwanica 04/2006; 15(1):66-8.
