Low blood pressure and dementia in elderly people: the Kungsholmen project.

OBJECTIVE--To examine the relation between blood pressure and dementia in elderly people. DESIGN--Cross sectional, population based study. SETTING: Kungsholmen district of Stockholm, Sweden. SUBJECTS-- 1642 subjects aged 75-101 years. MAIN OUTCOME MEASURES--Prevalence and adjusted odds ratio of dementia by blood pressure. RESULTS--People with systolic pressure < or = 140 mm Hg were more often diagnosed as demented than those with systolic pressure >140 mm Hg: odds ratios (95% confidence interval) adjusted for age, sex, and education were 2.98 (2.17 to 4.08) for all dementias, 2.91 (1.93 to 4.38) for Alzheimer''s disease, 2.00 (1.09 to 3.65) for vascular dementia, and 5.07 (2.65 to 9.70) for other dementias. Similar results were seen in subjects with diastolic pressure < or = 75 mm Hg compared with those with higher diastolic pressure. When severity and duration of dementia were taken into account, only moderate and severe dementia were found to be significantly related to relatively low blood pressure, and the association was stronger in subjects with longer disease duration. Use of hypotensive drugs and comorbidity with cardiovascular disease did not modify the results for all dementias, Alzheimer''s disease, and other dementias but slightly reduced the association between vascular dementia and diastolic blood pressure. CONCLUSIONS--Both systolic and diastolic blood pressure were inversely related to prevalence of dementia in elderly people. We think that relatively low blood pressure is probably a complication of the dementia process, particularly Alzheimer''s disease, although it is possible that low blood pressure may predispose a subpopulation to developing dementia.     

Relation between nicotine intake and Alzheimer's disease.

OBJECTIVE--To study the association between Alzheimer''s disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer''s disease, 198 controls matched for age and sex, and families of 17 patients in whom Alzheimer''s disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia, relative risk of Alzheimer''s disease. RESULTS--89 of 193 patients with Alzheimer''s disease had a history of smoking compared with 102 of 195 controls. Among the patients and controls with a family history of dementia, smoking was significantly less common in those with dementia (40/95 with dementia v 55/96 controls; relative risk 0.35; 95% confidence interval 0.16 to 0.78). The risk of Alzheimer''s disease decreased with increasing daily number of cigarettes smoked before onset of disease (relative risk 0.3 in those smoking greater than 21/day v 1 in non-smokers). In six families in which the disease was apparently inherited as an autosomal dominant disorder, the mean age of onset was 4.17 years later in smoking patients than in non-smoking patients from the same family (p = 0.03). CONCLUSIONS--These findings suggest an inverse association between smoking and Alzheimer''s disease, although smoking cannot be advocated for other health reasons. We speculate that nicotine may have a role in the aetiology of both Alzheimer''s disease and Parkinson''s disease.     

Apolipoprotein E genotype and association between smoking and early onset Alzheimer's disease.

OBJECTIVE--To investigate the hypothesis that differential survival between smokers and non-smokers leading to a decrease in the frequency of the e4 allele of the apolipoprotein E gene may explain the inverse relation between smoking history and early onset Alzheimer''s disease. DESIGN--A population based case-control study. SETTING--The four northern provinces of the Netherlands and metropolitan Rotterdam. SUBJECTS--175 patients with early onset Alzheimer''s disease and two independent control groups of 159 and 457 subjects. MAIN OUTCOME MEASURES--Frequencies of the apolipoprotein e4 allele and relative risk of early onset Alzheimer''s disease. RESULTS--The inverse association between smoking history and early onset Alzheimer''s disease could not be explained by a decrease in the frequency of the apolipoprotein e4 allele. Among carriers of this allele with a family history of dementia subjects with a history of smoking had a strongly reduced risk of early onset Alzheimer''s disease (odds ratio 0.10 (95% confidence interval 0.01 to 0.87)). CONCLUSIONS--The results suggest that the inverse relation between smoking history and early onset Alzheimer''s disease cannot be explained by an increased mortality in carriers of the apolipoprotein e4 allele who smoke. The association is strongly modified by the presence of the apolipoprotein e4 allele as well as by a family history of dementia.     

Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study.

OBJECTIVE--To determine the association between the e4 allele of apolipoprotein E and Alzheimer''s disease in a randomly selected population sample. DESIGN--Cross sectional population based study. SUBJECTS--980 people aged 69 to 78 (349 men, 631 women). SETTING--Population of Kuopio, eastern Finland. MAIN OUTCOME MEASURES--Presence of e4 allele and diagnosis of Alzheimer''s disease by detailed neurological and neurophysiological evaluation. RESULTS--46 (4.7%) subjects were classified as having probable or possible Alzheimer''s disease. The frequency of the apolipoprotein E e4 allele was 0.359 in patients with Alzheimer''s disease and 0.165 subjects without dementia (P < 0.0001). The prevalence of Alzheimer''s disease was 2.9% in subjects with no e4 alleles, 7.6% in subjects with one e4 allele, and 21.4% in subjects with two e4 alleles of apolipoprotein E. CONCLUSIONS--Allele e4 of apolipoprotein is associated with Alzheimer''s disease in a dose-response fashion in a randomly selected elderly population.     

Epidemiology of Alzheimer's presenile dementia in Scotland, 1974-88.

OBJECTIVE--To describe the epidemiology of presenile Alzheimer''s disease in Scotland from 1974 to 1988. DESIGN--Retrospective review of hospital records of patients aged less than 73 years admitted to psychiatric hospital with various diagnoses of dementia. Diagnoses were classified by National Institute for Communicative Disorders and Stroke and Alzheimer''s Disease and Related Disorders Association Criteria and the Hachinski score. Completeness of the study sample was evaluated by scrutiny of neurology outpatient and general hospital records. SETTING--All general psychiatric hospitals in Scotland. SUBJECTS--All patients with onset of dementia aged 40-64. MAIN OUTCOME MEASURES--Probable and broad Alzheimer''s disease, sex of patient, age at onset. RESULTS--5874 psychiatric hospital records, 129 neurology outpatient records, and 89 records from non-psychiatric hospitals were examined. 317 patients met criteria for probable Alzheimer''s disease, 569 met criteria for broad Alzheimer''s disease, and 267 met those for multi-infarct dementia. Minimal incidences per 100,000 population aged 40-64 years were 22.6 (95% confidence interval, 20.2 to 25.2) and 40.5 (38.9 to 42.3) per 100,000 for probable and broad Alzheimer''s disease. In the 1981 census year the annual incidence of probable Alzheimer''s disease was 1.6 (1.0 to 2.6). Women were at greater risk with incidence rates for probable Alzheimer''s disease of 28.2 (24.5 to 32.4) per 100,000 compared with 16.5 (13.8 to 19.8) per 100,000 for men. The incidence per 100,000 for multi-infarct dementia was greater in men (25.1, 23.3 to 27.1) than women (13.4, 12.1 to 14.8). CONCLUSION--Female sex seems to be positively associated with development of Alzheimer''s disease before age 65 years.     

Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study.

OBJECTIVE: To determine the association between features of the insulin resistance syndrome and Alzheimer''s disease. DESIGN: Cross sectional population based study. SUBJECTS: 980 people aged 69 to 78 (349 men, 631 women). SETTING: Population of Kuopio, eastern Finland. MAIN OUTCOME MEASURES: Presence of features of the insulin resistance syndrome and diagnosis of Alzheimer''s disease by detailed neurological and neuropsychological evaluation. RESULTS: 46 (4.7%) subjects were classified as having probable or possible Alzheimer''s disease. In univariate analyses, apolipoprotein E4 phenotype (odds ratio; 95% confidence interval 3.24: 1.77 to 5.92), age (1.16; 1.05 to 1.29), low level of education (0.82; 0.72 to 0.93), low total cholesterol concentration (0.77; 0.59 to 1.00), high systolic blood pressure (1.01; 1.00 to 1.03), high fasting and 2 hour plasma glucose concentrations (1.11; 1.01 to 1.23 and 1.08; 1.03 to 1.13, respectively), high fasting and 2 hour insulin concentrations (1.05; 1.02 to 1.08 and 1.003; 1.00 to 1.01, respectively), and abnormal glucose tolerance (1.86; 1.23 to 2.80) were significantly associated with Alzheimer''s disease. In multivariate analysis including apolipoprotein E4 phenotype, age, education, systolic blood pressure, total cholesterol concentration, fasting glucose concentration, and insulin concentration, apolipoprotein E4 phenotype, age, education, total cholesterol, and insulin were significantly associated with Alzheimer''s disease. In 532 non-diabetic subjects without the e4 allele hyperinsulinaemia was associated with an increased risk for Alzheimer''s disease (prevalence of disease 7.5% v 1.4% in normoinsulinaemic subjects, P = 0.0004). In contrast, in the 228 with the e4 allele hyperinsulinaemia had no effect on the risk of disease (7.0% v 7.1%, respectively). CONCLUSION: Features of the insulin resistance syndrome are associated with Alzheimer''s disease independently of apolipoprotein E4 phenotype.     

Neurochemical characteristics of early and late onset types of Alzheimer's disease.

Brains of 49 patients who had died with Alzheimer''s disease and 54 controls were examined. The Alzheimer group exhibited noticeably reduced activity of the cholinergic marker enzyme choline acetyltransferase in the cerebral cortex, but cortical concentrations of noradrenaline, gamma-aminobutyric acid, and somatostatin were also significantly reduced. Analysis of the results according to age at death showed that the older patients, dying in their 9th and 10th decades, had a relatively pure cholinergic deficit confined to temporal lobe and hippocampus, together with a reduced concentration of somatostatin confined to temporal cortex. By contrast, the younger patients, dying in their 7th and 8th decades, had a widespread and severe cholinergic deficit together with the abnormalities of noradrenaline, gamma-aminobutyric acid, and somatostatin, and the younger patients accounted for most of the abnormalities in these systems observed in the overall group. Comparison of the young subjects with Alzheimer''s disease with the older controls did not support the concept of Alzheimer''s disease representing an acceleration of the aging process. These results suggest that Alzheimer''s disease in people aged under 80 may represent a distinct form of presenile dementia which differs in important respects from the dementia of old age.     

Detection of Alzheimer's disease and dementia in the preclinical phase: population based cohort study

ObjectivesTo evaluate a simple three step procedure to identify people in the general population who are in the preclinical phase of Alzheimer''s disease and dementia.DesignThree year population based cohort study.SettingKungsholmen cohort, Stockholm, Sweden.Participants1435 people aged 75-95 years without dementia.AssessmentsSingle question asking about memory complaints, assessment by mini-mental state examination, and neuropsychological testing.ResultsNone of the three instruments was sufficiently predictive of Alzheimer''s disease and dementia when administered separately. After participants had been screened for memory complaints and global cognitive impairment, specific tests of word recall and verbal fluency had positive predictive values for dementia of 85-100% (95% confidence intervals range from 62% to 100%). However, only 18% of future dementia cases were identified in the preclinical phase by this three step procedure. Memory complaints were the most sensitive indicator of Alzheimer''s disease and dementia in the whole population, but only half the future dementia cases reported memory problems three years before diagnosis.ConclusionThis three step procedure, which simulates what might occur in clinical practice, has a high positive predictive value for dementia, although only a small number of future cases can be identified.

What is already known on this topic

Alzheimer''s disease is characterised by a preclinical phase, during which cognitive deficits are seen before diagnosisElderly people with subjective memory complaints and objective global cognitive impairment have a high risk of developing Alzheimer''s disease and dementia

What this study adds

This three step procedure (self report of memory complaints, test of global cognitive functioning, and then domain specific cognitive tests) has a positive predictivity of 85-100% for Alzheimer''s disease and dementia at three yearsHowever, only 18% of people in the preclinical phase can be identified using this procedureAbout half of the people in the preclinical phase of Alzheimer''s disease and dementia do not report problems with their memory three years before diagnosis     

Paget's disease of bone in 14 British towns.

The radiological prevalence of Paget''s disease was studied in 14 towns. Routine radiographs showed that the disease was present in 5.4% of people aged 55 years and over. The disease was more prevalent in men than in women at all ages, and the prevalence increased with age. The three Lancashire towns studied (Preston, Bolton, and Blackburn) had higher rates than elsewhere. This probably reflects a real geographical variation in the prevalence of Paget''s disease in England and Wales.     

Relation between severity of Alzheimer's disease and costs of caring

BACKGROUND: Data from the Canadian Study of Health and Aging (CSHA) were used to examine the relation between severity of Alzheimer''s disease, as measured by the Mini-Mental State Examination (MMSE), and costs of caring. METHODS: The CSHA was a community-based survey of the prevalence of dementia, including subtypes such as Alzheimer''s disease, among elderly Canadians. Survey subjects with a diagnosis of possible or probable Alzheimer''s disease were grouped into disease severity levels of mild (MMSE score 21-26), mild to moderate (MMSE score 15-20), moderate (MMSE score 10-14) and severe (MMSE score below 10). Components of care available from the CSHA were use of nursing home care, use of medications, use of community support services by caregivers and unpaid caregiver time. Costs were calculated from a societal perspective and are expressed in 1996 Canadian dollars. RESULTS: The annual societal cost of care per patient increased significantly with severity of Alzheimer''s disease. The cost per patient was estimated to be $9451 for mild disease, $16,054 for mild to moderate disease, $25,724 for moderate disease and $36,794 for severe disease. Institutionalization was the largest component of cost, accounting for as much as 84% of the cost for people with severe disease. For subjects living in the community, unpaid caregiver time and use of community services were the greatest components of cost and increased with disease severity. INTERPRETATION: The societal cost of care of Alzheimer''s disease increases drastically with increasing disease severity. Institutionalization is responsible for the largest cost component.     

基于BP神经网络和RBF神经网络预测老年痴呆症疾病进展的对比研究

目的:比较反向传播算法(BP)神经网络和径向基函数(RBF)神经网络预测老年痴呆症疾病进展的效果。方法:以老年痴呆症随访数据为研究对象,以性别、年龄、受教育程度、有无高血压、有无高胆固醇、有无心脏病、有无中风史、有无家族史8个指标作为输入变量,以五年随访的MMSE差值为输出变量,构建基于BP神经网络和RBF神经网络的老年痴呆症疾病进展预测模型。结果:与BP神经网络模型相比,RBF神经网络预测的结果更好,能够有效地预测老年痴呆症疾病进展。结论:神经网络模型将老年痴呆症疾病进展预测问题转化为随访数据中相关测量指标与MMSE差值的非线性问题,为复杂的老年痴呆症疾病进展预测提供了新思路。     

Prevalence of Dementia and Subtypes in Valladolid,Northwestern Spain: The DEMINVALL Study

Objective

To describe the prevalence of dementia and subtypes in a general elderly population in northwestern Spain and to analyze the influence of socio-demographic factors.

Methods

Cross-sectional, two-phase, door-to-door, population-based study. A total of 870 individuals from a rural region and 2,119 individuals from an urban region of Valladolid, Spain, were involved. The seven-minute screen neurocognitive battery was used in the screening phase. A control group was included.

Results

A total of 2,170 individuals aged 65 to 104 years (57% women) were assessed. There were 184 subjects diagnosed with dementia. The crude prevalence was 8.5% (95% CI: 7.3-9.7). Age- and sex-adjusted prevalence was 5.5 (95% CI: 4.5-6.5). Main subtypes of dementia were: Alzheimer’s disease (AD) 77.7%, Lewy Body disease, 7.6% and vascular dementia (VD) 5.9%. Crude prevalences were 6.6% (AD), 0.6% (Lewy Body disease), and 0.5% (VD). Dementia was associated with age (OR 1.14 for 1-year increase in age), female sex (OR 1.79) and the absence of formal education (OR 2.53 compared to subjects with primary education or more).

Conclusion

The prevalence of dementia in the study population was lower than the most recent estimates for Western Europe. There was a high proportion of AD among all dementia cases and very low prevalence of VD. Old age, female sex, and low education level were independent risk factors for dementia and AD.     

Smoking and dementia in male British doctors: prospective study

ObjectiveTo assess the possible association between smoking and dementia.DesignProspective study.SettingCohort of British male doctors followed up since 1951.Subjects34 439 male British doctors, with 24 133 deaths recorded.ResultsFor all types of dementia combined the relative risk was 0.96 (95% confidence interval 0.78 to 1.18), based on 473 deaths at a mean age of 81 years. For probable or definite Alzheimer''s disease, the relative risk in continuing smokers was 0.99 (0.78 to 1.25), based on 370 deaths at a mean age of 82 years. In aggregate, however, the other prospective studies indicate a direct, although not clearly significant, association between smoking and the onset of dementia in general and of Alzheimer''s disease in particular. ConclusionsContrary to previous suggestions persistent smoking does not substantially reduce the age specific onset rate of Alzheimer''s disease or of dementia in general. If anything, it might increase rather than decrease the rate, but any net effect on severe dementia cannot be large in either direction.     

Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam Study.

OBJECTIVE--To investigate the distribution of cognitive function in elderly people and to assess the impact of clinical manifestations of atherosclerotic disease on this distribution. DESIGN--Single centre population based cross sectional door to door study. SETTING--Ommoord, a suburb of Rotterdam, the Netherlands. SUBJECTS--4971 subjects aged 55 to 94 years. MAIN OUTCOME MEASURE--Cognitive function as measured by the mini mental state examination. RESULTS--The overall participation rate in the study was 80%. Cognitive test data were available for 90% of the participants. Increasing age and lower educational level were associated with poorer cognitive function. Previous vascular events, presence of plaques in the carotid arteries, and presence of peripheral arterial atherosclerotic disease were associated with worse cognitive performance independent of the effects of age and education. On average the differences were moderate; however, they reflected the net result of a shift of the total population distribution of cognitive function towards lower values. Thereby, they resulted in a considerable increase in the proportion of subjects with scores indicative of dementia. CONCLUSIONS--These findings are compatible with the view that atherosclerotic disease accounts for considerable cognitive impairment in the general population.     

Positron emission tomography in patients with clinically diagnosed Alzheimer's disease.

Fourteen patients who had clinically diagnosed Alzheimer''s disease with mild to severe dementia (mean age 69.1 years) were evaluated by calculation of local cerebral metabolic rate for glucose (LCMR-gl) based on uptake of 18F-2-fluoro-2-deoxyglucose (FDG) detected with positron emission tomography (PET). PET scanning showed that the patients had significantly lower LCMR-gl values than 11 age-matched neurologically normal volunteers (mean age 66.3 years). The differences were most marked in the temporal cortex, followed by the frontal, parietal and occipital cortex. In each case the LCMR-gl value was below the lowest control value in at least one cortical area and usually in several; the reduction in LCMR-gl and the number of regions involved in the patients increased with the severity of the dementia. Deficits noted in neuropsychologic testing generally correlated with those predicted from loss of regional cortical metabolism. The patients with Alzheimer''s disease were also examined with magnetic resonance imaging, computed tomography or both; the degree of atrophy found showed only a poor correlation with the neuropsychologic deficit. Significant atrophy was also noted in some of the controls. A detailed analysis of LCMR-gl values in selected cerebral regions of various sizes refuted the hypothesis that the reduction in cortical glucose metabolism in Alzheimer''s disease is due to the filling by metabolically inert cerebrospinal fluid of space created by tissue atrophy.     

A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease

Background

Mild cognitive impairment is often a precursor to dementia due to Alzheimer''s disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment.

Objective

To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings.

Design and Participants

382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer''s Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study.

Main Predictors Measures

Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales.

Main Outcome Measure

Progression to probable Alzheimer''s disease.

Key Results

Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer''s disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell''s c-statistic was 0.71(95% CI: 0.68–0.75). Fourteen percent of subjects with low risk scores (0–2 points, n = 124) converted to probable Alzheimer''s disease over 3 years, compared to 51% of those with moderate risk scores (3–8 points, n = 223) and 91% of those with high risk scores (9–16 points, n = 35).

Conclusions

An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer''s disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression.     

Diagnosing dementia: do we get it right?

To find out whether the diagnosis of dementia agreed with findings at necropsy a detailed assessment of 27 elderly patients (mean age 82 (range 70-94] presenting with dementia was conducted at a combined department of geriatric medicine and psychiatry for the elderly. On the basis of the results the cause of the dementia was diagnosed clinically. Neuropathological examinations were performed after death. The clinical diagnosis made during life was not supported by the findings at necropsy in 11 cases. Alzheimer''s disease was overdiagnosed in life (13 cases, of which only six were confirmed at necropsy). Although the clinical investigation was limited by availability of resources, neither cranial computed tomography nor the Hachinski score helped to distinguish between multi-infarct dementia and Alzheimer''s disease in this age group. This study confirms the value of neuropathological studies in the precise diagnosis of dementia.     

The decline and resurgence of vascular dementia.

Arteriosclerotic narrowing of cerebral arteries was once viewed as the key to mental decline. As Alzheimer''s disease gained recognition and the concept of multi-infarct dementia achieved acceptance, vascular dementia came to be regarded as uncommon. The changing nature of cerebral vascular disease, the aging of the population and the widespread use of brain imaging techniques have brought new prominence to vascular dementia, chiefly in the form of an epidemic of "Binswanger''s disease". Growing evidence suggests that not only grey matter lesions but also white matter lesions contribute to dementia, that vascular factors commonly coexist and interact with Alzheimer changes and that Alzheimer''s disease has a vascular and potentially treatable component. Vascular dementia needs to be redefined, reappraised and reinvestigated.     

A community survey of Parkinson's disease.

In a rural community of 80,000 people 69 patients were identified as having a diagnosis of Parkinson''s disease. After interview and examination we found that 55 met the generally accepted diagnostic criteria for Parkinson''s disease, 4 had possible Parkinson''s disease, 6 had essential tremor, 2 had dementia and 2 had other conditions. The patients with Parkinson''s disease had clinical and epidemiologic characteristics similar to those of patients in previous, mainly hospital-based, studies. These characteristics included mean age at onset (63 years), frequency rate of dementia (20%) and presence of postural tremor (11%). The pattern of treatment varied, some patients receiving more medication than is usual for the severity of their illness, and some patients receiving less than is usual. Parkinson''s disease can be difficult to diagnose and manage because of the clinical variation between patients in presentation and response to treatment.     

阿尔茨海默病和血管性痴呆与血糖代谢水平的关系及危险因素分析

目的:研究阿尔茨海默病和血管性痴呆与血糖代谢水平的关系及危险因素。方法:选取2013年12月到2014年12月我院收治的阿尔茨海默病80例(A组)和血管性痴呆70例(B组),另选取同时期无痴呆者70例(对照组),测量三组入选者血糖各指标水平,并分析阿尔茨海默病和血管性痴呆的危险因素。结果:A组和B组空腹血糖(FPG)均显著高于对照组,胰岛素降解酶(IDE)显著低于对照组,比较差异具有统计学意义(P0.05);B组糖尿病、冠心病和高血压疾病的发病率显著高于A组和对照组,比较差异具有统计学意义(P0.05),A组和B组高血脂发病率均显著高于对照组,比较差异具有统计学意义(P0.05)。结论:阿尔茨海默病和血管性痴呆均与FPD、IDE以及高血脂有较大关系,高血压、冠心病和糖尿病与血管性痴呆有较大关系。