Parity and the risk of incident dementia: a COSMIC study.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

Functional neuroanatomical correlates of the executive clock drawing task (CLOX) performance in Alzheimer's disease: a FDG-PET study.

The executive clock drawing task (CLOX) is one of the widely used clock drawing tests (CDTs) and is composed of CLOX1, an unprompted CDT, and CLOX2, a simple copying CDT. Although it is conceptually believed that CLOX1 is sensitive to both executive function and constructional ability while CLOX2 reflects only constructional ability, there are still lack of studies on the functional neuroanatomical substrates of CLOX1 and 2 performances. This study aimed to identify the functional brain correlates of CLOX1 and 2 performances in patients with Alzheimer's disease (AD). CLOX was administered to 139 AD patients and 50 normal controls, and regional cerebral glucose metabolism (rCMglc) was measured by (18)F-fluoro-2-deoxy-glucose positron emission tomography. Correlations between CLOX scores and rCMglc were examined on a voxel-by-voxel basis in AD patients. For the overall AD group, significant positive correlations between CLOX1 and rCMglc were found in the bilateral temporo-parietal and left middle frontal regions, while CLOX2 was correlated with rCMglc of the bilateral temporo-parietal regions. Additional subgroup analysis showed that CLOX1 was associated with the left temporal metabolism in less severe AD, and with the right temporo-parietal metabolism in more severe AD. In contrast, CLOX2 was correlated with rCMglc of the diffuse right fronto-temporo-parietal regions in more severe AD, but not with any rCMglc in less severe AD. This is the first neuroimaging study on the functional neuroanatomical correlates of CLOX performances in AD. Given the relationships between specific cognitive performances and regional brain functions, the findings probably support the notion that CLOX1 demands not merely visuospatial functions but also executive control, while CLOX2 depends mainly on visuospatial ability. Our results also indicate that each CLOX performance depends on very different functional brain regions according to AD clinical stages.

Increased striatal dopamine transporter density in moderately severe old restless legs syndrome patients.

BACKGROUND AND PURPOSE: Dopamine dysregulation in restless legs syndrome (RLS) may be varied by the severity of RLS, which could contribute to the conflicting results from previous functional neuroimaging studies on the central dopaminergic neurotransmission of RLS. The aim of this study was to observe whether reduced striatal dopaminergic neurotransmission is associated with moderate to moderately severe RLS. METHODS: Thirteen elderly patients with RLS and 12 normal elderly controls were enrolled in the study. All the subjects were dopaminergic-drug naïve and twelve patients with RLS had the severity of moderate to moderately severe degree based on the International Restless Legs Syndrome Study Group (IRLSSG) Severity Scale. We compared dopamine transporter density (DAT) availability and D2 receptor density in the striatum between patients with RLS and controls using [(123)I]2ß-carbomethoxy-3ß-(4-iodophenyl)tropane single-photon emission computed tomography (SPECT) and [(123)I]iodobenzamide SPECT. RESULTS: Dopamine transporter density of patients with RLS was increased in the caudate (P = 0.037), posterior putamen (P = 0.041), and entire striatum (P = 0.046) compared with that of normal controls. DAT density was higher in the anterior putamen of patients with RLS than controls, although statistically not significant (P = 0.079). There was no difference in the D2 receptor density between patients with RLS and normal controls in the whole striatum or any of subregions. CONCLUSIONS: Dysregulation rather than simple upregulation or downregulation of central dopaminergic neurotransmission may underlie the pathogenesis of RLS, and decreased dopaminergic neurotransmission may cause moderate to moderately severe RLS in the elderly.

Availability of brain serotonin transporters in patients with restless legs syndrome.

BACKGROUND: Selective serotonin reuptake inhibitors have been associated with the risk of restless legs syndrome (RLS), suggesting that dysregulation of serotonergic neurotransmission may provoke or exacerbate RLS. METHODS: We compared the availability of serotonin transporter (SERT) between 16 drug-naïve patients with RLS and 16 healthy controls. SERT was measured in the pons and medulla via [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane (beta-CIT) SPECT. A ratio of specific to nonspecific brain uptake (V(3)'') was used for all comparisons. RLS was diagnosed according to the criteria proposed by the National Institute of Health, and its severity was measured using the International RLS Study Group (IRLSSG) Severity Scale. RESULTS: The availability of SERT was similar in the RLS group and the control group with regards to the pons (1.24 +/- 0.31 vs 1.24 +/- 0.25, p > 0.1) and the medulla (0.99 +/- 0.25 vs 1.00 +/- 0.23, p > 0.1). However, IRLSSG Severity Scale scores increased with decrease of SERT availability in both the pons (beta = -0.50, t = -3.19, p = 0.009) and the medulla (beta = -0.42, t = -2.44, p = 0.03). CONCLUSIONS: Although serotonin transporter (SERT) availability in pons and medulla was similar in the restless legs syndrome (RLS) group and the control group, the severity of RLS symptoms increased as the availability of SERT decreased. These data partially support the hypothesis that an increase of serotonergic neurotransmission in the brainstem may exacerbate RLS, possibly via dual modulations on striatal dopaminergic neurotransmission and on the activities of spinal motor and sensory neurons.

The Severe Cognitive Impairment Rating Scale--an instrument for the assessment of cognition in moderate to severe dementia patients.

BACKGROUND/AIMS: This study aimed to develop a brief, reliable and valid test for cognitive function of severely demented patients. METHODS: We constructed the Severe Cognitive Impairment Rating Scale, which consisted of 11 items covering memory, language, visuospatial function, frontal function and orientation, and investigated its reliability and validity on 267 subjects [normal: 65, very mild Alzheimer's disease (AD): 42, mild AD: 58, moderate AD: 36, severe AD: 44, profound AD: 22]. RESULTS: The internal consistency obtained by Cronbach's coefficient alpha was 0.93. The interrater reliability and test-retest reliability in the moderately to severely impaired subjects with an MMSE score of

Depression in vascular dementia is quantitatively and qualitatively different from depression in Alzheimer's disease.

BACKGROUND/AIMS: To compare the prevalence and characteristics of depression in vascular dementia (VaD) and Alzheimer's disease (AD) after adjusting for dementia severity and gender. METHODS: One hundred and eight pairs of VaD and AD patients matched for dementia severity and gender were assessed. RESULTS: Major depressive disorder (MDD) was more prevalent in the VaD group than in the AD group (20.4% in VaD, 10.2% in AD, p = 0.04, Cochran-Mantel-Haenszel, CMH, test) regardless of the dementia severity and gender. The odds ratio for developing MDD in the VaD group versus the AD group was estimated to be 2.20 (95% confidence interval = 1.02-4.74). Neurovegetative symptoms such as 'felt tired and weak all the time' (30.6% in VaD, 13.9% in AD, p = 0.003, CMH test) and 'changed weight without trying' (16.7% in VaD, 6.5% in AD, p = 0.02, CMH test) were more prevalent in the VaD group than in the AD group. CONCLUSION: Depression in VaD was quantitatively and qualitatively different from that in AD regardless of the severity of dementia and gender; depression was more prevalent, severer and more retarded and vegetative in VaD than in AD.

Diagnostic accuracy of mini-mental status examination and revised hasegawa dementia scale for Alzheimer's disease.

To compare the diagnostic accuracies of the Revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental Status Examination (MMSE) for Alzheimer's diseases (AD), we administered them simultaneously to 82 AD patients and 82 age- and sex-matched nondemented control subjects. The area under the receiver operator curve (AUC) for AD of the HDS-R (AUC(HDS-R)) and MMSE (AUC(MMSE)) were bigger than 0.90 indicating that both tests are useful for detecting AD. However, AUC(HDS-R) (0.952) was significantly larger than that of the AUC(MMSE )(0.902) regardless of the educational level of the subjects, indicating that the HDS-R is more accurate than MMSE in diagnosing AD. Moreover, the superiority of the HDS-R (AUC(HDS-R) = 0.894) to the MMSE (AUC(MMSE) = 0.704) remained significant in mild AD patients alone, who are the focus of screening. In conclusion, the HDS-R is better than the MMSE as a screening instrument for AD.

Selegiline potentiates the effects of EGb 761 in response to ischemic brain injury.

We evaluated whether combined treatment with selegiline, a selective MAO-B inhibitor, and EGb 761, a standard extract of Ginkgo biloba, has synergistic effects against ischemic reperfusion injury (IRI) in gerbils. Interestingly, we observed that pretreatment with EGb 761 significantly attenuated selegiline-induced hyperactivity. This finding paralleled striatal fos-related antigen immunoreactivity (FRA-IR) in mice. Four minutes of bilateral carotid artery occlusion caused substantial cell loss in the CA1 of the hippocampus 5 days post-ischemic insult. Pretreatment with EGb 761, with or without selegiline, significantly attenuated this neuronal loss. Combined treatment with EGb 761 plus selegiline was more efficacious in preventing this loss. Synaptosomal formations of protein carbonyl, lipid peroxidation (malondialdehyde (MDA) + 4-hydroxyalkenal (4-HDA)), and reactive oxygen species (ROS) in the hippocampus remained elevated 5 days post-ischemic insult. The antioxidant effects appeared to be most significant in the group treated with EGb 761 plus selegiline. This combined treatment produced more significant attenuation of IRI-induced alterations in intramitochondrial calcium accumulation, the mitochondrial transmembrane potential, and mitochondrial Mn-superoxide dismutase-like immunoreactivity (Mn-SOD-IR) than either treatment alone. Our results suggest that co-administration of EGb 761 and selegiline produces significant neuroprotective effects via suppression of oxidative stress and mitochondrial dysfunction without affecting neurological function.

Development of the Korean version of Alzheimer's Disease Assessment Scale (ADAS-K).

OBJECTIVE: The purpose of this study was the development of the Korean Version of Alzheimer's Disease Assessment Scale (ADAS-K). METHOD: ADAS-K was administrated to 84 AD patients as well as 105 non-demented control subjects. Three aspects of reliability were tested. To evaluate the validity of ADAS-K, discriminant validity and concurrent validity were tested. To evaluate the sensitivity of ADAS-K to disease severity, all subjects, AD patients and control subjects, were grouped by CDR scale and their mean scores on ADAS-K were compared. RESULT: ADAS-K demonstrated high levels of reliability. Mean ADAS-K scores for AD patients were significantly different from the control group (p < 0.01). Furthermore, ADAS-K exhibited significant correlations with other tests and scales (range 0.45-0.85, p < 0.01). In ROC curve analysis, ADAS-K displayed high diagnostic efficacy and the optimal cut-off point was selected between 18/19. ADAS-K was able to discriminate the degree of AD severity according to CDR classification. Our results suggested that ADAS-K-cog was sensitive to very mild AD. CONCLUSION: We demonstrated that ADAS-K is a reliable and valid instrument not only for AD diagnosis but also for evaluation of its severity.

Apolipoprotein E epsilon 4 allele is not associated with the cognitive impairment in community-dwelling normal elderly individuals.

OBJECTIVES: The aim of this study was to examine whether the APOE epsilon 4 allele also confers a risk for the cognitive impairment in normal aging. METHODS: We administered all the eight neuropsychological tests from the CERAD neuropsychological battery to the CVD-free, community-dwelling normal elderly individuals, and compared their performance by the occurrence of the APOE epsilon 4 allele. RESULTS: Either the impact of APOE epsilon 4 allele itself or its interaction terms with age and gender of the subjects did not influence the performance of the eight neuropsychological tests (epsilon p > 0.1 by ANCOVA). CONCLUSIONS: The APOE epsilon 4 allele is not a risk factor for the cognitive decline in normal elderly individuals regardless of age and gender.

The domain-specific, stage-limited impact of the apolipoprotein E epsilon-4 allele on cognitive functions in Alzheimer's disease.

To examine the impact of the APOE epsilon4 allele on the cognitive functions of Alzheimer's disease (AD) patients, we administered the eight neuropsychological tests from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery to 118 Korean AD patients. The impact of the APOE epsilon4 allele was significant in the Word List Recall Test (WLRT) and the Word List Recognition Test (WLRcT) only, and its impact was confined to the very mild AD (VMAD) patients (F = 7.65, d.f. = 2, p < 0.01 for WLRT; F = 3.27, d.f. = 2, p = 0.04 for WLRcT). In the VMAD group, the performance on the two tests of the APOE-epsilon4-positive patients was poorer than that of the APOE-epsilon4-negative patients. Our findings suggest that the impact of the APOE epsilon4 allele on cognitive functions in AD may be domain specific and confined to the early stage of AD.

Neither the butyrylcholinesterase K variant nor transferrin C2 variant confers a risk for Alzheimer's disease in Koreans.

To investigate the possible involvement of the butyrylcholinesterase (BCHE) K variant and transferrin (TF) C2 variant in the manifestation of Alzheimer's disease (AD), we analyzed the BCHE, TF and apolipoprotein E (APOE) genotypes of 164 sporadic AD patients and 239 normal elderly controls. The frequencies of the BCHE K and TF C2 did not differ between the AD patients and controls (P > 0.1). The occurrence of the APOE epsilon4 did not influence the distribution of the BCHE K and TF C2 variants (P > 0.1). No linkage disequilibrium between the BCHE K and TF C2 was observed either in both the AD patients and controls (P > 0.1). In conclusion, neither the BCHE K nor the TF C2 confers a risk for AD.

Transferrin C2 variant does not confer a risk for Alzheimer's disease in Koreans.

We analyzed the transferrin (TF) and apolipoprotein E (APOE) genotypes of 164 probable Alzheimer's disease (AD) patients and 239 cognitively normal elderly controls in Koreans. We failed to detect a significant difference in genotypic frequencies and allelic frequencies of the TF polymorphism between the AD group and control group (P>0.1 by Chi square test). The frequency of the TF C2 variant did not differ by the diagnosis when the APOE epsilon4-positive subjects and APOE epsilon4-negative subjects were analyzed separately (P>0.1 by Chi square test). The TF C2 variant did not influence the age-at-onset of AD independently or synergistically with the occurrence of the APOE epsilon4 allele (P>0.1 by ANOVA). The TF C2 variant did not confer a risk for AD in Koreans.

CYP2D6*4 polymorphism is not associated with Parkinson's disease and has no protective role against Alzheimer's disease in the Korean population.

CYP2D6*4 polymorphism is reported to be associated with Parkinson's disease (PD) and to have protective role against Alzheimer's disease (AD). Such findings are not extensively studied in the Oriental population, especially Koreans. The effects of CYP2D6*4 polymorphism on AD and PD were investigated by polymerase chain reaction-restriction fragment length polymorphism in Korean subjects. Heterozygous mutant allele was found in four of 93 patients with PD, 0 of 32 patients with AD and one of 121 control subjects (59 stroke, 59 normal controls and four other psychiatric disorders), but no homozygous mutant allele was found. There were no statistically significant differences between the AD group and controls, and between the PD group and controls. In conclusion, we suggest that CYP2D6*4 polymorphism does not confer susceptibility to PD in the Korean population. Also, due to such a rare occurrence of the CYP2D6*4 polymorphism, we can not confirm the protective role of the polymorphism against AD in the Korean population.

Association of alpha-2-macroglobulin deletion polymorphism with sporadic Alzheimer's disease in Koreans.

Alpha-2-macroglobulin (A2M) deletion polymorphism was recently reported to be associated with Alzheimer's disease (AD) in a way comparable to apolipoprotein E (APOE) polymorphism in a family-based study. However, the association of A2M deletion polymorphism with AD has not been consistently replicated in successive case-controlled studies. In order to evaluate whether this A2M polymorphism is associated with AD in Koreans, we examined the frequencies of the A2M deletion (D) allele and D-bearing genotypes in a group of Koreans composed of 100 sporadic AD patients and 203 control subjects. The frequency of the deletion (D) allele (P=0.046) was significantly different between the total group of AD patients and the controls, although the frequency of the D-bearing genotypes did not attain significance (P=0.078). When the subjects were stratified according to age at onset, there was significant difference in the frequencies of the D allele (P=0.044) and D-bearing genotypes (P=0.041) between late-onset AD patients (> or =65 years) and the controls. However, no significant difference was observed between early-onset AD patients (<65 years) and the control group. Additionally, when we divided the late-onset AD and control subjects by APOE epsilon4 status, the difference of the A2M D allelic frequency was significant only in the APOE epsilon4 negative subjects (P=0.015). In conclusion, our data suggests that the A2M D allele is a modest risk factor for late-onset sporadic AD in Koreans, and the AD risk conferred by the A2M D allele increases in APOE epsilon4 negative subjects.

No association between presenilin 1 (PS1) intronic polymorphism and sporadic Alzheimer's disease in Koreans.

To investigate the possible involvement of an intronic polymorphism in the presenilin 1 (PS1) gene and its interactions with the aplolipoprotein E (APOE) or alpha-1 antichymotrypsin (ACT) polymorphisms in the manifestation of AD, we analyzed the PS1, APOE and ACT genotypes of 100 sporadic AD patients and 199 normal elderly controls in Koreans. The genotypic (chi2= 0.92, df = 2, P > 0.1) and allelic (chi2 = 0.01, df = 1, P > 0.1) frequencies of the PS1 polymorphism in the late- and early-onset sporadic AD patients did not differ from those in the controls. And the occurrence of the APOE epsilon4 allele and ACT A allele did not influence the distribution of the PS1 intronic polymorphism. The PS1 intronic polymorphism didn't influence the age-at-onset of AD (F = 0.02, df = 2, P > 0.1). In conclusion, the PS1 intronic polymorphism did not modify the risk for sporadic AD, neither independently nor synergistically with the APOE epsilon4 allele or ACT A allele, in Koreans.

A telemedicine system as a care modality for dementia patients in Korea.

Because dementia is a chronic debilitating disease, there are the issues of the difficulty in continuous long-term care and limited accessibility to medical service. We developed the telemedicine system for dementia patients and aimed to examine the acceptance, reliability, and clinical outcome of our telemedicine service. We established the Dementia Telemedicine Center in connection with two recipient sites in 1996. The reliability of the center, which provides telemedicine, tele-education, and telecounseling services, was tested by comparing assessment via our system with in-person assessment, and the clinical outcome was assessed by rating the changes of behavioral symptoms. There have been 140 registered patients for 2 years. The general acceptance of our system by the patients and caregivers was good, and the consistency rates between the assessment via our telemedicine system and in-person assessment ranged from 76% to 89%. A considerable proportion of dementia patients in nursing homes (46%) showed relative clinical improvements through our service. Our telemedicine system seems to be reliable and effective for the assessment and care of dementia patients. Our future direction is to promote our system as a core model of the home-based care system for dementia patients.

No association between alpha-1-antichymotrypsin polymorphism and Alzheimer's disease in Koreans.

To examine the possible involvement of the alpha-1-antichymotrypsin gene (ACT) polymorphism in the manifestation of Alzheimer's disease (AD), we analyzed genotypes of the ACT and apolipoprotein E gene (APOE) among 110 Korean patients with probable AD and 209 nondemented controls. No significant difference was obtained in genotypic (chi(2)=1.98, df=2, P>0.1) and allelic frequencies (chi(2)=1.61, df=1, P>0.1) of ACT between the AD and control groups. No overexpression of the ACT A/A genotype and ACT A allele was found when we analyzed the late-onset AD patients and the early-onset AD patients, separately. Then we stratified the ACT genotypes based on the presence or absence of the APOE epsilon4 allele to evaluate the possible interaction between them. In the APOE epsilon4-negative subjects, although the ACT A allele tended to be overexpressed in the AD group, the differences in the frequencies of the ACT A allele (chi(2)=2.79, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.16, df=1, P>0.1) were not statistically significant. No significant overrepresentations of the ACT A allele (chi(2)=0.02, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.17, df=1, P>0.1) were found in the APOE epsilon4-positive subjects, either. In addition, the status of the ACT genotype did not influence the age-at-onset of AD (F=0.03, df=2, P>0.1). Therefore, the ACT polymorphism does not contribute to the development of AD independently or interactively with the APOE epsilon4 allele in Koreans.

Association between apolipoprotein E polymorphism and Alzheimer's disease in Koreans.

We analyzed the aplolipoprotein E (APOE) genotypes of 110 probable AD patients and 226 cognitively normal controls in Koreans. The APOE epsilon4 allele was more prevalent in both early- and late-onset AD patients (P < 0.01) than in controls. The odds for the APOE epsilon4-heterozygous subjects were 2.7 (95% CI = 1.6-4.5), and those for the APOE epsilon4-homozygous subjects were 17.4 (95% CI = 2.0-147.3). But the odds were not uniform across age groups, and were higher in women than in men. Although the APOE epsilon2 allele frequency did not differ by diagnosis, the patients carrying an APOE epsilon2 allele showed delayed age-at-onset (P = 0.02). In conclusion, the APOE e4 allele increased the risk for AD in dose-dependent manner, and the APOE epsilon4-conferred AD risk was age- and sex-dependent in Koreans.