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ABSTRACT: The relationship between apolipoprotein E (ApoE) and clinical manifestations of mild cognitive impairment (MCI) has not been investigated in non-Caucasian populations. This prospective study was conducted in an ethnic Chinese population to evaluate the correlations of ApoE genotype, cognitive performance, medial temporal structure volumes, and clinical outcome in amnestic MCI. Twenty normal elders, 58 MCI, and 20 mild Alzheimer's disease (AD) patients received neuropsychological, MRI, and ApoE genotype assessments at baseline. Patients with MCI had intermediate cognitive performance and hippocampal volumes between those in normal and AD groups. In each diagnostic group, epsilon4 carriers (E4+) consistently had smaller hippocampal volume than non-carriers (E4-) did. Nineteen MCI subjects (32.7%) converted to AD during the 3-year study period. Compared with MCI non-converters and E4- MCI converters, E4+ MCI converters had the smallest hippocampal volume. However, epsilon4 was not a predictor for AD. Both cognitive performance and hippocampal volume were predictive for progression to AD. However, stepwise Cox regression model integrating both neuropsychological and radiological variables showed that global cognitive performance was the only significant predictor for AD. A poor global cognitive score may be more crucial than a small hippocampal volume in the prediction of AD.
Neurobiology of aging 01/2007; 27(12):1797-806. · 5.94 Impact Factor
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ABSTRACT: Given the implications with respect to the pathogenesis of dopaminergic dysfunction in schizophrenia and Parkinson's disease (PD), as well as the reciprocal antagonistic interactions between adenosine A2a receptor (A2aAR) and the dopamine D2 receptors, A2aAR may be a candidate gene conferring susceptibility to PD or schizophrenia. In this study, we tested the hypothesis that the A2aAR 1976T > C genetic variant confers susceptibility to or is related to the onset age of schizophrenia or PD using a sample population consisting of 94 PD and 227 schizophrenic patients. We also tested whether the A2aAR 1976T > C relates to antipsychotic-induced tardive dyskinesia in the schizophrenic population. The results demonstrated that in comparing PD patients and controls the distribution of the A2aAR 1976T > C genotypes (P=0.788) and alleles (P=0.702) did not vary significantly. Furthermore, the PD onset age was not significantly different amongst the three A2aAR 1976T > C genotypic groups. In comparing schizophrenic patients and controls, the distribution of the A2aAR genotypes (P=0.330) and alleles (P=0.632) also did not differ significantly. The onset age of schizophrenia and tardive dyskinesia (evaluated with Abnormal Involuntary Movements Scale) were similar within the three A2aAR genotypic groups. Our findings suggest that it is unlikely that the A2aAR 1976T > C polymorphism plays a major role in the pathogenesis of PD, schizophrenia, or antipsychotic-induced tardive dyskinesia in the Chinese population.
Acta Neurovegetativa 11/2005; 112(11):1503-10. · 2.73 Impact Factor
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ABSTRACT: Alzheimer disease (AD) is a polygenic multifactorial disorder. Several studies suggested that the neuroprotective effect of estrogen was based on an APOE-dependent mechanism. The goals of the current study were to determine if the genes involved in estrogen metabolism were linked to the risk of AD and find out if there was an interaction between estrogen-metabolizing gene polymorphisms and the APOE epsilon4 allele in the risk of prevalent AD. We investigated 66 patients with AD and 86 age- and gender-matched normal subjects. The polymorphisms of APOE and estrogen-metabolizing genes CYP17, CYP1A1 and COMT were examined. No association was found between each estrogen-metabolizing gene polymorphism and AD. However, the COMT HH genotype and APOE epsilon4 allele had a synergistic effect on the risk of AD. Taking subjects with epsilon4-epsilon4-/HH- as reference, the risk of developing AD in subjects with one epsilon4 allele (epsilon4+epsilon4-/HH-) was 2.6 (95% confidence interval, CI, 0.7- 9.1); however, the risk in subjects with both HH and one epsilon4 (epsilon4+epsilon4-/HH+) increased to 3.6 (95% CI 1.2-10.6). The subjects with homozygous epsilon4 still had the highest risk in developing AD (odds ratio 6.6, 95% CI 0.6-69.6). The p value of the linear trend test for this regression model was 0.004. It is possible that a high metabolism of estrogen by COMT may have reduced the protective effect of estrogen in AD. Further studies to clarify this interaction may improve our understanding of the generic risks for AD.
Dementia and Geriatric Cognitive Disorders 02/2005; 19(2-3):120-5. · 2.14 Impact Factor
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ABSTRACT: An altered platelet ratio of amyloid precursor protein (APP) isoforms might be a diagnostic, predictive, or therapeutic marker for Alzheimer's disease (AD). Our purpose was to test the hypothesis that this ratio might serve as a therapeutic marker for AD patients treated with the cholinesterase inhibitor, galantamine. Thirty-nine patients (mean age 76.6 +/- 9.4 years) with AD were treated with galantamine for 12 weeks. Patients were evaluated at baseline, 4 and 12 weeks by cognitive testing along with a determination of their platelet APP isoform ratio. Western blotting was performed to calculate the APP isoform ratio. At the end of the treatment, cognitive scores significantly improved, and the ratio of the high-molecular-weight (130 kDa) isoform to the low-molecular-weight (110-106 kDa) isoforms increased. These results suggest that cholinesterase inhibition might be involved in APP processing.
Dementia and Geriatric Cognitive Disorders 02/2005; 19(5-6):345-8. · 2.14 Impact Factor
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ABSTRACT: Of 135 patients with Alzheimer disease (AD), 56 without psychiatric symptoms at the first visit were followed for a mean period of 51.9 +/- 10.3 months to identify incident psychiatric symptoms. The hazard ratios of ApoE epsilon4 allele in developing psychiatric symptoms were calculated by Cox regression hazard analyses. The presence of the ApoE epsilon4 allele carried a 19.0-fold risk for developing hallucinations and a 3.4-fold risk for delusions.
Neurology 10/2004; 63(6):1105-7. · 8.31 Impact Factor
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ABSTRACT: Cataract is the leading cause of visual impairment in older adults in the world. Age-related lens opacities are common and are frequent causes of loss of vision. The incidence of cataract increases significantly with increasing age in women only. The onset coincides with estrogen deficiency that occurs after menopause. Hormone replacement therapy has proven beneficial to selected postmenopausal women. Estrogen effects on biological system are modulated via the estrogen receptors (ER) and/or estrogen metabolites. Although ER have been detected in ocular tissue, whether ER polymorphism is related to cataract is not known at present. The polymorphisms of estrogen metabolizing enzymes are also related to the serum concentration and activity of estrogen. Polymorphism such as cytochrome P450c17 (A2/A2), cytochrome P450c1A (vt/vt) will result in increased formation of catechol estrogen, while people with catechol-O-methyltransferase (COMT) polymorphism COMT (L/L) will have decreased metabolism of catechol estrogen and decreased level of methoxyestradiol. COMT was also involved in tamoxifen metabolism which may further decrease the activity of COMT in breast cancer patients treated with tamoxifen. It is known that a 4-7% increase in cataract was found in tamoxifen-treated breast cancer patients than non-user. The 7.0% COMT (L/L) genotype in general population corresponded well with the 4-7% of cataract formation in tamoxifen-treated breast cancer patients. Our hypothesis is that breast cancer patients with COMT (L/L) genotype may be at increased risk of cataract formation after tamoxifen treatment.
Medical Hypotheses 02/2004; 63(3):494-7. · 1.39 Impact Factor
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ABSTRACT: Recent studies have implicated N-methyl-D-aspartate (NMDA) receptor dysfunction in the pathogenesis and treatment of Parkinson's disease (PD). The NMDA receptor is composed of several subunits, of which, the receptor 2b subunit (GRIN2B) is of particular significance for PD. This subunit is found enriched in the basal ganglia, and PD-monotherapy potential has been determined for GRIN2B antagonists. For this study of a sample population consisting of 101 PD patients and 108 controls, we tested the hypothesis that an ACC --> ACT transversion (2664(th) nucleotide of the coding sequence) affecting codon 888 (tyrosine) of GRIN2B confers susceptibility to PD, or relates to the age of onset. Comparing PD patients and controls, the distribution of the GRIN2B genotypes (p = 0.754) and alleles (p = 0.269) did not differ significantly. The onset age was not significantly different comparing the three genotypic groups (p = 0.189). Our negative findings suggest that it is unlikely that the GRIN2B C2664T polymorphism plays a substantial role in conferring susceptibility to PD in the Chinese population. Further studies with other genetic variations of NMDA subunits, relating either to PD or to the therapeutic response for PD, are suggested.
Acta Neurovegetativa 05/2002; 109(4):483-8. · 2.73 Impact Factor
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ABSTRACT: A significant increase of 267C allele of the 5-HT(6) receptor gene has been reported in patients with Alzheimer's disease (AD). Because a deficit in serotonergic neurotransmission is involved in major depression, we tried to find out whether 267C allele is associated with depressive disorders in AD. A psychiatrist interviewed all AD patients and their caregivers for evidence of depression using a Chinese version of the Standard Clinical Interview for DSM-III-R. The difference in the 5-HT(6) genotype or allele distributions between the AD patients with depressive disorders (n = 25) and those without (n = 120) was not significant.
Psychiatry and Clinical Neurosciences 09/2001; 55(4):427-9. · 2.13 Impact Factor
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ABSTRACT: There exists considerable evidence implicating abnormalities of the alpha (alpha)-adrenergic system in the development of Alzheimer disease (AD). We propose to investigate potential correlations between the presence or otherwise of alpha-adrenoceptor polymorphisms and the presence of AD. We studied the polymorphisms of the alpha1a- and the alpha2a-adrenoceptor genes in 142 AD patients and 98 normal controls. The result demonstrated that none of the alpha2a-adrenoceptor genotypes was associated with increased susceptibility to AD. However, there was a trend that the frequency of the C allele of the alpha1a-adrenoceptor was elevated and an excess of the CC genotype (90.1%) was found in the subjects with AD in comparison with the controls (78.6%). This association was unrelated to the apolipoprotein E genotypes. The hypothesis that the alpha1a-adrenoceptor gene may be implicated in the pathogenesis of AD may deserve further study.
Acta Neurovegetativa 02/2001; 108(4):445-50. · 2.73 Impact Factor
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ABSTRACT: Serotonergic dysfunction is implicated in Alzheimer's disease (AD) on the basis of studies of serotonin and its metabolite in postmortem specimens and CSF. There were also reports on association of a tryptophan hydroxylase (TPH) intron 7 variant and CSF 5-hydroxyindoleacetic acid concentrations. These suggested TPH might be a candidate to study for possible involvement in AD. Using a case-control association approach, we studied the TPH polymorphism in 150 subjects with AD and 100 controls. There were no significant differences in genotype or allele frequencies between controls and AD patients. The negative findings suggested that this TPH polymorphism has no major effect on the development of AD. However, the genetic variation of the TPH gene related to the symptomatology of AD deserves further investigation.
Neuropsychobiology 02/2001; 43(1):1-4. · 2.67 Impact Factor
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ABSTRACT: alpha(1)-Antichymotrypsin (ACT) gene has been suggested as a susceptibility factor for Parkinson's disease (PD) and might be related to the onset of PD. We replicated these findings in a Chinese population. The results demonstrated that the ACT genotypic and allelic distributions showed no significant differences between the PD patient and the control groups. The age at onset was younger in the heterozygotes than in the homozygotes (p = 0.042). We suggest that the ACT polymorphism might play some role in the pathogenesis of PD, especially in the onset.
European Neurology 02/2001; 45(4):254-6. · 1.81 Impact Factor
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ABSTRACT: Two recent studies have demonstrated an association for a deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR), and Alzheimer's disease (AD). According to these studies, subjects with the short variant of the 5-HTTLPR gene are at increased risk for AD; however, this finding has not been confirmed by other workers. To evaluate the role of the 5-HTTLPR gene in susceptibility for AD, we conducted an association study for this polymorphism in a Chinese population. No significant differences were determined for genotype distribution or allele frequencies, comparing AD patients and normal controls. Even dividing the population into subgroups according to the presence of the APOE epsilon4 allele, no differences for genotype or allele frequencies were determined, comparing patients and controls. These results suggest that it is unlikely that the 5-HTTLPR polymorphism plays a substantial role in conferring susceptibility to AD.
Neuropsychobiology 02/2001; 44(1):27-30. · 2.67 Impact Factor
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Neurology 01/2001; 55(11):1758-9. · 8.31 Impact Factor
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ABSTRACT: Problem-based learning (PBL) in small-group tutorials has been a trend in medical education. Chinese students are known to be reserved and passive; thus, they may not be adaptable to PBL. Neuroanatomy, important to clinical neurology, is difficult to learn. We incorporated clinical neurology with PBL, complementary to the traditional neuroanatomy curriculum, to evaluate the feasibility of PBL for Chinese students in Taiwan.
Forty-two second-year medical students and seven tutors participated in the clinical neurology PBL small-group tutorials. Twelve case reports were discussed weekly beginning in February, 1999. Each case was designed to meet the progressive curriculum of the neuroanatomy course. The tutors evaluated the students by the degree of their preparation, participation, key-point comprehension and interaction. All tutors and students filled out questionnaires at the end of each session.
The majority of the students and tutors agreed that the case materials were clearly written. Ninety percent of the students agreed that the case materials matched the traditional content of neuroanatomy. Eighty-five percent of students and 71% of tutors were satisfied and found the class rewarding. Ninety-one percent of students and 74% of tutors were in favor of PBL being continued.
This preliminary PBL, small-group tutorial learning in clinical neurology showed satisfactory results and was, indeed, complementary to a traditional neuroanatomy course. The students, as early as during the second year of their medical school education, were able to learn through the PBL. More integration of basic and clinical sciences by PBL may be considered in future curricula designs.
Zhonghua yi xue za zhi = Chinese medical journal; Free China ed 09/2000; 63(8):598-604.
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ABSTRACT: To examine the effects of estrogen therapy on cognition, mood, and cerebral blood flow in patients with AD.
Some studies have suggested estrogen may be effective in the treatment of AD. However, most of these studies were not controlled adequately.
Fifty female AD patients were recruited in a randomized, double-blind, placebo-controlled 12-week trial. Each member of the estrogen-treated group received conjugated estrogen (Premarin) 1.25 mg/day. The primary outcome measures were the Cognitive Ability Screening Instrument (CASI), Clinical Dementia Rating (CDR), and Clinician Interview-Based Impression of Change (CIBIC-plus). The secondary outcome measures were Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD), Hamilton Anxiety Rating Scale (HARS), Hamilton Depression Rating Scale (HDRS), and 99mTc hexamethylpropylene amine oxime SPECT of the brain.
No meaningful differences were found between the outcome measures (CASI, CDR, CIBIC-plus, BEHAVE-AD, HARS, HDRS, and cerebral blood flow) taken from the estrogen-treated group and those from the control group.
A 1.25-mg/day dose of Premarin administered for 12 consecutive weeks does not produce a meaningful effect on cognitive performance, dementia severity, behavior, mood, and cerebral perfusion in female AD patients. Because estrogen therapy has been suspected of yielding adverse effects, and its therapeutic effectiveness is in doubt, additional evaluation of its role in AD treatment ought to be conducted.
Neurology 07/2000; 54(11):2061-6. · 8.31 Impact Factor
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ABSTRACT: Increased butyrylcholinesterase (BChE) activity has been reported to be associated with the formation of amyloid plaques and neurofibrillary tangles and may consequently be involved in the pathogenesis of Alzheimer disease (AD). Because the catalytic activity of BChE-K variant is reduced by one-third compared with non-variant, we speculated that BChE-K variant has a protective effect on AD. However, Lehmann et al. [1997] reported a synergistic effect between the genes for BChE-K variant and apolipoprotein E (ApoE) ϵ4, which increases the risk for late onset AD. In the present study, we tested 89 Chinese AD patients and 101 Chinese controls and found no evidence of association between BCHE-K and AD of either early or late onset (age > 65 years). No evidence of a synergistic effect was found between the BCHE-K variant and APOE ϵ4 in this study. Our data suggest that BChE-K variant has no modifying effect on the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:167–169, 2000. © 2000 Wiley-Liss, Inc.
American Journal of Medical Genetics 04/2000; 96(2):167 - 169.
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ABSTRACT: Increased butyrylcholinesterase (BChE) activity has been reported to be associated with the formation of amyloid plaques and neurofibrillary tangles and may consequently be involved in the pathogenesis of Alzheimer disease (AD). Because the catalytic activity of BChE-K variant is reduced by one-third compared with non-variant, we speculated that BChE-K variant has a protective effect on AD. However, Lehmann et al. [1997] reported a synergistic effect between the genes for BChE-K variant and apolipoprotein E (ApoE) epsilon 4, which increases the risk for late onset AD. In the present study, we tested 89 Chinese AD patients and 101 Chinese controls and found no evidence of association between BCHE-K and AD of either early or late onset (age > 65 years). No evidence of a synergistic effect was found between the BCHE-K variant and APOE epsilon 4 in this study. Our data suggest that BChE-K variant has no modifying effect on the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:167-169, 2000.
American Journal of Medical Genetics 04/2000; 96(2):167-9.
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ABSTRACT: To examine the associations of subjective memory complaint (SMC) in old age with (a) objective test performance, (b) past and subsequent cognitive decline, and (c) depression.
A group of community residents were examined twice during a 3-year period.
Two townships on a rural Chinese islet.
A total of 543 men and women aged 65 years and older.
During each examination, neurologists interviewed and examined all participants for dementia and asked the question, "Do you have trouble with your memory?" In addition, research assistants administered (a) the Cognitive Abilities Screening Instrument (CASI) to assess cognitive abilities, including long-term memory (LTM) and short-term memory (STM), and (b) the Geriatric Depression Scale-Short Version (GDS-S) to assess symptoms of depression.
At each examination, almost half of the subjects acknowledged having trouble with their memory (the SMC+ group). At both examinations, the SMC+ group scored significantly lower on the CASI and significantly higher on the GDS-S than the SMC- group. However, the presence of SMC was not associated with faster cognitive decline over the past or subsequent 3 years. There were no consistent associations between SMC and the demographic variables of age, gender, and education at the two examinations. Logistic regression analysis showed that SMC was associated with poorer memory test scores after controlling for gender, age, education, and depression.
SMC was associated with poorer objective memory performance even after controlling the effect of depression and demographic data, but SMC did not predict faster cognitive decline or dementia over 3 years.
Journal of the American Geriatrics Society 04/2000; 48(3):295-9. · 3.74 Impact Factor
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ABSTRACT: To investigate the prevalence, risk factors, and prognosis of chronic daily headache (CDH) in a population of elderly Chinese subjects.
A community-based survey of registered residents > or =65 years old (n = 2,003) in two townships of Kinmen Island in 1993. A neurologist used a structured questionnaire and clinical interview to make the diagnosis of headache. Subjects who had headaches > or =15 days/month for > or =6 months in the previous year were considered to have CDH. CDH was further classified into chronic tension-type headache (CTTH), CDH with migrainous features (CDH/MF), and other CDH. Person-to-person biannual follow-up of the subjects with CDH was done in June 1995 and August 1997.
A total of 1,533 people (77%) participated in our prevalence study. Sixty subjects (3.9%) fulfilled the criteria for CDH, with a higher prevalence in women (F/M: 5.6%/1.8%, p < 0.001). Of these subjects, 42 (70%) had CTTH, 15 (25%) had CDH/MF, and 3 (5%) had other CDH. Only 23% of those with CDH had consulted physicians for their headaches in the previous year. Multivariate logistic regression revealed the significant risk factors for CDH to be analgesic overuse (OR = 79), a history of migraine (OR = 6.6), and a Geriatric Depression Scale-Short Form score of > or =8 (OR = 2.6). The follow-up results in 1995 and 1997 showed that about two-thirds of the subjects still had CDH. Analgesic overuse (relative risk = 1.6) in 1993 was a significant predictor of persistent CDH at follow-up.
A total of 3.9% of this elderly population had CDH, with CTTH being the most common subtype. Almost two-thirds of those with CDH had persistent frequent headaches at follow-up. Analgesic overuse was a significant predictor of a poor outcome.
Neurology 02/2000; 54(2):314-9. · 8.31 Impact Factor
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ABSTRACT: The present study was to investigate the prevalence and potential risk factors of depressive disorders in Chinese patients with Alzheimer's disease (AD).
A series of consecutive AD patients from the Memory Disorders Clinic of the Veterans General Hospital, Taipei were studied. Psychiatric diagnosis was made according to DSM-III-R criteria with the use of the Structured Clinical Interview for DSM-III-R (SCID). The Chinese version of the Cognitive Abilities Screening Instrument (CASI) and the Hamilton Depression Rating Scale (HDRS) were also applied. Primary caregivers were interviewed for the Clinical Dementia Rating (CDR) scale, the Barthel Index and the Alzheimer's Deficit Scale (ADS).
Among 141 AD patients, seven (5.0%) were diagnosed with major depression, 11 (7.8%) with dysthymia and five (3.5%) with depressive disorder not otherwise specified. Women were at elevated risk for depressive disorders and had more severe symptoms of depression.
The prevalence of depressive disorders among Chinese AD patients is in the middle of the range of western findings. The risk factor for depression is female gender.
Acta Psychiatrica Scandinavica 01/2000; 100(6):451-5. · 4.22 Impact Factor
