Alzheimer Disease: Tang Y

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #18334827 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate the quality of longitudinal statistical applications in published studies on Alzheimer's disease (AD). METHODS: A 21-item instrument, the Quality of Longitudinal AD Studies (QLADS), was developed by the research team (4 biostatisticians, 1 neuroepidemiologist, and 1 neurologist). All items were extensively discussed within the team for content validity. After pilot testing on 5 publications, the instrument was revised and tested for reliability with a sample of 40 published longitudinal AD studies randomly sampled from MEDLINE. RESULTS: Item-specific test-retest reliability coefficients for QLADS ranged from 0.53 to 1.00 with the associated standard error (SE) ranging from 0.02 to 0.13. The test-retest reliability for the overall score over the 21 items was high (intraclass correlation coefficient (ICC) = 0.94, 95% CI 0.90, 0.97). Item-specific inter-rater reliability coefficients for QLADS ranged from 0.46 to 1.00 with the associated SE ranging from 0.07 to 0.18. The inter-rater reliability for the overall score was also high (ICC = 0.87, 95% CI 0.77, 0.93). CONCLUSIONS: This study indicates that the quality of longitudinal statistical applications in AD publications can be reliably assessed.

Wang R, Tang Y, Feng B, Ye C, Fang L, Zhang L, Li L. · Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China. · Neuroscience. · Pubmed #17935895 No free full text.

Abstract: The aim of the present study is to investigate the changes in hippocampal synapses and their relation with learning-memory abilities at different ages, and evaluate the effects of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside (TSG), which is one of the major components of a traditional Chinese herb Polygonum multiflorum, on brain aging. Sprague-Dawley rats at the age of 1, 3, 6, 18 and 24 months were used. TSG at doses of 30 and 60 mg/kg/day was intragastrically administered to 21-month-old rats for 3 months, respectively. Learning-memory abilities were determined by Morris water maze and passageway water maze tests. The ultrastructure of synapses in the hippocampal CA1 region was observed by electronic microscopy. The expression of synaptophysin (SYP) in whole hippocampus was measured by using immunohistochemistry. Compared with rats at 6 months of age, both the 1-month-old rats and 24-month-old rats showed longer escape latency and swimming distance in the Morris water maze test, while more errors were detected in the passageway water maze test, with a smaller number of synapses and synaptic vesicles and less expression of SYP in the hippocampus. Treatment with high-dose TSG in rats at 24 months of age had significant improvement in the learning-memory abilities in the water maze tests associated with an increase in the number of synapses and synaptic vesicles, and an elevation of expression of SYP in the hippocampus. In conclusion, hippocampal synapses count and synaptophysin expression decreased in aged rats, which may be one of the mechanisms involved in learning-memory deficit. TSG reversed the above changes in aged rats, suggesting that TSG may be beneficial for the treatment of Alzheimer disease or cognitive impairment in old people.

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Bergmann KR, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #17878738 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate statistical applications in publications on Alzheimer's disease (AD). METHODS: Three instruments/checklists were developed: Assessment of Statistical Reporting (ASR; 44 items), Survey of Statistical Designs (SSD; 10 items), and Survey of Statistical Methods (SSM; 7 items). After a pilot testing on 5 AD publications, the instruments/checklists were revised and tested for reliability with a sample of 30 AD articles and for validity with another sample of 10 AD articles from MEDLINE. RESULTS: Item-specific test-retest and interrater reliability for ASR ranged from 0.29 to 1.0 with the associated standard errors (SEs) ranging from 0.01 to 0.31. The test-retest reliability (intraclass correlation coefficient = 0.94, 95% CI: 0.88-0.97) and the interrater reliability (intraclass correlation coefficient = 0.84, 95% CI: 0.69-0.92) for the overall score of ASR were high. The correlational validity of the ASR with a published checklist was also high (r = 0.74, SE = 0.24). The item-specific test-retest reliability in SSD and SSM ranged from 0.58 to 1.00 with the associated SEs ranging from 0.01 to 0.32. The item-specific interrater reliability in SSD and SSM ranged from 0.17 to 1.00 with the associated SEs ranging from 0.01 to 0.22. CONCLUSIONS: This study suggested that it was feasible to assess statistical applications in AD publications.

Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, 600 S Paulina, Ste 1038, Chicago, IL 60612, USA. · Arch Gen Psychiatry. · Pubmed #17606814 links to  free full text

Abstract: CONTEXT: Mild cognitive impairment (MCI) is often a precursor to Alzheimer disease, but knowledge about factors that predict its development is limited. OBJECTIVE: To test the hypothesis that impaired odor identification is related to increased risk of incident MCI. DESIGN: Longitudinal cohort study. SETTING: Academic research. PARTICIPANTS: Subjects were 589 community-dwelling older persons without cognitive impairment at study baseline, at which time odor identification was assessed using the 12-item Brief Smell Identification Test (mean +/- SD score, 9.3 +/- 1.9). MAIN OUTCOME MEASURES: Incidence of MCI and rate of decline in cognitive function. RESULTS: During annual observation of up to 5 years, 177 subjects developed MCI. In a proportional hazards model adjusted for age, sex, and education, odor identification score predicted development of MCI (relative risk, 1.15; 95% confidence interval, 1.07-1.23), with risk increased by 50% in persons with below-average (score of 8 [25th percentile]) compared with above-average (score of 11 [75th percentile]) odor identification scores. Results were not substantially changed in subsequent analyses that controlled for level of cognitive function or disability, presence of stroke, or smoking status at baseline or that required MCI to persist for at least 1 year. Impaired odor identification was also associated with a lower level of global cognition at baseline and with more rapid decline in episodic memory, semantic memory, and perceptual speed. CONCLUSION: Among older persons without manifest cognitive impairment, difficulty in identifying odors predicts subsequent development of MCI.

Wilson RS, Scherr PA, Schneider JA, Tang Y, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, 600 South Paulina, Suite 1038, Chicago, IL 60612, USA. · Neurology. · Pubmed #17596582 No free full text.

Abstract: BACKGROUND: Frequent cognitive activity in old age has been associated with reduced risk of Alzheimer disease (AD), but the basis of the association is uncertain. METHODS: More than 700 old people underwent annual clinical evaluations for up to 5 years. At baseline, they rated current and past frequency of cognitive activity with the current activity measure administered annually thereafter. Those who died underwent a uniform postmortem examination of the brain. Amyloid burden, density of tangles, and presence of Lewy bodies were assessed in eight brain regions and the number of chronic cerebral infarctions was noted. RESULTS: During follow-up, 90 people developed AD. More frequent participation in cognitive activity was associated with reduced incidence of AD (HR = 0.58; 95% CI: 0.44, 0.77); a cognitively inactive person (score = 2.2, 10th percentile) was 2.6 times more likely to develop AD than a cognitively active person (score = 4.0, 90th percentile). The association remained after controlling for past cognitive activity, lifespan socioeconomic status, current social and physical activity, and low baseline cognitive function. Frequent cognitive activity was also associated with reduced incidence of mild cognitive impairment and less rapid decline in cognitive function. Among 102 persons who died and had a brain autopsy, neither global nor regionally specific measures of neuropathology were related to level of cognitive activity before the study, at study onset, or during the course of the study. CONCLUSION: Level of cognitively stimulating activity in old age is related to risk of developing dementia.

Buchman AS, Boyle PA, Wilson RS, Tang Y, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA. · Psychosom Med. · Pubmed #17556640 links to  free full text

Abstract: OBJECTIVE: To assess the association between frailty and incident Alzheimer's disease (AD) and cognitive decline. Frailty is common in older persons and associated with adverse health outcomes. METHODS: Study subjects included 823 older persons without dementia who participated in the Rush Memory and Aging Project, a longitudinal study of aging, and underwent annual assessments of frailty, cognition, and diagnostic evaluation for AD. RESULTS: During a 3-year follow-up, 89 of 823 participants developed AD. In a proportional hazards model, both baseline level of frailty and annual rate of change in frailty were associated with an increased risk of incident AD. Each additional one tenth of a unit increase on the frailty scale at baseline was associated with >9% increased risk of AD (hazard ratio: 2.44; 95% confidence interval (CI): 1.49, 3.37); each one tenth of a unit increase in annual rate of change in frailty was associated with a 12% increased risk of AD (hazard ratio: 3.30; 95% CI: 1.52, 7.13). These results were unchanged in analyses controlling for vascular risk factors and vascular diseases. Results were similar with a categorical measure of frailty instead of a continuous measure. Further, linear mixed-effects models showed that the level of and rate of change in frailty were also associated with the rate of cognitive decline. CONCLUSION: Increasing frailty is associated with incident AD and the rate of cognitive decline in older persons. These findings suggest that frailty and AD may share similar etiologies.

Wilson RS, Krueger KR, Arnold SE, Schneider JA, Kelly JF, Barnes LL, Tang Y, Bennett DA. · Rush Alzheimer's Disease Center, Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL 60612, USA. · Arch Gen Psychiatry. · Pubmed #17283291 links to  free full text

Abstract: CONTEXT: Social isolation in old age has been associated with risk of developing dementia, but the risk associated with perceived isolation, or loneliness, is not well understood. OBJECTIVE: To test the hypothesis that loneliness is associated with increased risk of Alzheimer disease (AD). DESIGN: Longitudinal clinicopathologic cohort study with up to 4 years of annual in-home follow-up. PARTICIPANTS: A total of 823 older persons free of dementia at enrollment were recruited from senior citizen facilities in and around Chicago, Ill. Loneliness was assessed with a 5-item scale at baseline (mean +/- SD, 2.3 +/- 0.6) and annually thereafter. At death, a uniform postmortem examination of the brain was conducted to quantify AD pathology in multiple brain regions and the presence of cerebral infarctions. MAIN OUTCOME MEASURES: Clinical diagnosis of AD and change in previously established composite measures of global cognition and specific cognitive functions. RESULTS: During follow-up, 76 subjects developed clinical AD. Risk of AD was more than doubled in lonely persons (score 3.2, 90th percentile) compared with persons who were not lonely (score 1.4, 10th percentile), and controlling for indicators of social isolation did not affect the finding. Loneliness was associated with lower level of cognition at baseline and with more rapid cognitive decline during follow-up. There was no significant change in loneliness, and mean degree of loneliness during the study was robustly associated with cognitive decline and development of AD. In 90 participants who died and in whom autopsy of the brain was performed, loneliness was unrelated to summary measures of AD pathology or to cerebral infarction. CONCLUSION: Loneliness is associated with an increased risk of late-life dementia but not with its leading causes.

Wang B, Jin F, Xie Y, Tang Y, Kan R, Zheng C, Yang Z, Wang L. · Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. · Neurosci Lett. · Pubmed #17027152 No free full text.

Abstract: Alterations of the NAD(P)H:quinone oxidoreductase (NQO1) activity are associated with Alzheimer's disease (AD). A polymorphism consisting of a single nucleotide (C-->T) change at position 609 of NQO1 influences the NQO1 activity. Therefore the NQO1 C609T polymorphism may confer susceptibility for AD developing. To test the hypothesis, we have performed an association study between the NQO1 gene polymorphism C609T and late-onset Alzheimer's disease (LOAD) in Chinese population. Totally 104 LOAD patients and 128 controls were enrolled in our data set. All subjects were genotyped for NQO1 and Apolipoprotein E (APOE). There were no significant differences in NQO1 genotype or allele frequencies between cases and controls. Likewise, with the stratification of APOE psilon4 status, no statistical difference was observed between cases and controls. Our findings suggested that this polymorphism might not represent additional genetic risk factor for LOAD. However, the present study cannot exclude NQO1 as a possible candidate for LOAD. Further study in a larger population and biological functional analysis of NQO1 gene is required to verify the role of NQO1 in LOAD.

Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, 600 South Paulina, Suite 1038, Chicago, IL 60612, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #17012338 No free full text.

Abstract: BACKGROUND: Olfactory dysfunction is common in old age, but its basis is uncertain. OBJECTIVE: To test the hypothesis that difficulty in identifying odours in old age is related to the accumulation of Alzheimer's disease pathology. METHODS: As part of the Rush Memory and Aging Project, participants completed the 12-item Brief Smell Identification Test, a standard measure of odour identification. During a mean (standard deviation (SD)) of 2.2 (1.2) years of follow-up (range 0.2-4.9), 166 people died, with brain autopsies performed on 129 (77.7%) people and neuropathological examinations completed on 77 (mean (SD) age at death 87.5 (5.9) years; median postmortem interval 6.1 h). From a uniform postmortem examination of multiple brain regions, summary measures of plaque and tangle pathology were derived on the basis of silver staining, and those of amyloid beta burden, tangle density and Lewy bodies on the basis of immunohistochemistry. RESULTS: Odour identification performance ranged from 0 to 12 correct (mean (SD) 8.0 (2.6)). In analyses adjusted for age, sex and education, a composite measure of plaques and tangles accounted for >12% of the variation in odour identification. The association remained after controlling for dementia or semantic memory. Density of tau tangles was inversely related to odour identification. A similar effect for amyloid burden was attenuated after controlling for tangles. The association with odour identification was robust for tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites. Lewy bodies, identified in 12.5%, were not related to odour identification, probably partly due to to their relative infrequency. CONCLUSION: The results suggest that difficulty in identifying familiar odours in old age is partly due to the accumulation of neurofibrillar pathology in central olfactory regions.

Wilson RS, Arnold SE, Schneider JA, Kelly JF, Tang Y, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Ill, USA. · Neuroepidemiology. · Pubmed #16974109 No free full text.

Abstract: Clinical and pathological data from the Rush Memory and Aging Project were used to test the hypothesis that distress proneness is associated with increased risk of Alzheimer's disease (AD). More than 600 older persons without dementia completed a 6-item measure of neuroticism, a stable indicator of proneness to psychological distress. At annual intervals thereafter, they underwent uniform evaluations that included clinical classification of AD and administration of 18 cognitive tests. Those who died underwent brain autopsy from which composite measures of AD pathology were derived. During a mean of about 3 years of follow-up, 55 people were clinically diagnosed with AD. In analyses that controlled for age, sex, and education, persons with a high level of distress proneness (score = 24, 90th percentile) were 2.7 times more likely to develop AD than those not prone to distress (score = 6, 10th percentile). Adjustment for depressive symptomatology or frequency of cognitive, social, and physical activity did not substantially change this effect. Distress proneness was also associated with more rapid cognitive decline. Among 45 participants who died and underwent brain autopsy, distress proneness was unrelated to diverse measures of AD pathology and was inversely related to cognition after controlling for AD pathology. The results support the hypothesis that distress proneness is associated with increased risk of dementia and suggest that neurobiologic mechanisms other than AD pathology may underlie the association.

Boyle PA, Wilson RS, Aggarwal NT, Tang Y, Bennett DA. · Rush Alzheimer's Disease Center, Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Neurology. · Pubmed #16894105 No free full text.

Abstract: OBJECTIVE: To examine the extent to which persons with mild cognitive impairment (MCI) have an increased risk of Alzheimer disease (AD) and a more rapid rate of decline in cognitive function compared to similar persons without cognitive impairment. METHOD: Participants were 786 community-based persons (221 with MCI and 565 without cognitive impairment) from the Rush Memory and Aging Project, an ongoing longitudinal clinical-pathologic study of common chronic conditions of old age. All participants underwent detailed annual clinical and neuropsychological evaluations. The authors examined the risk of incident AD and rate of change in global cognitive function among persons with MCI and those without cognitive impairment; all statistical models controlled for age, sex, and education. RESULTS: Over an average of 2.5 years of follow-up, 57 persons with MCI (25.8%) developed AD, a rate 6.7 times higher than those without cognitive impairment. In addition, persons with MCI declined considerably more rapidly each year on a measure of global cognitive function than those without cognitive impairment. CONCLUSIONS: Mild cognitive impairment is associated with a greatly increased risk of incident Alzheimer disease and a more rapid rate of decline in cognitive function.

Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA. · Lancet Neurol. · Pubmed #16632311 No free full text.

Abstract: BACKGROUND: Few data are available about how social networks reduce the risk of cognitive impairment in old age. We aimed to measure this effect using data from a large, longitudinal, epidemiological clinicopathological study. METHODS: 89 elderly people without known dementia participating in the Rush Memory and Aging Project underwent annual clinical evaluation. Brain autopsy was done at the time of death. Social network data were obtained by structured interview. Cognitive function tests were Z scored and averaged to yield a global and specific measure of cognitive function. Alzheimer's disease pathology was quantified as a global measure based on modified Bielschowsky silver stain. Amyloid load and the density of paired helical filament tau tangles were also quantified with antibody-specific immunostains. We used linear regression to examine the relation of disease pathology scores and social networks to level of cognitive function. FINDINGS: Cognitive function was inversely related to all measures of disease pathology, indicating lower function at more severe levels of pathology. Social network size modified the association between pathology and cognitive function (parameter estimate 0.097, SE 0.039, p=0.016, R(2)=0.295). Even at more severe levels of global disease pathology, cognitive function remained higher for participants with larger network sizes. A similar modifying association was observed with tangles (parameter estimate 0.011, SE 0.003, p=0.001, R(2)=0.454). These modifying effects were most pronounced for semantic memory and working memory. Amyloid load did not modify the relation between pathology and network size. The results were unchanged after controlling for cognitive, physical, and social activities, depressive symptoms, or number of chronic diseases. INTERPRETATION: These findings suggest that social networks modify the relation of some measures of Alzheimer's disease pathology to level of cognitive function.

Glatz DC, Rujescu D, Tang Y, Berendt FJ, Hartmann AM, Faltraco F, Rosenberg C, Hulette C, Jellinger K, Hampel H, Riederer P, Möller HJ, Andreadis A, Henkel K, Stamm S. · Molecular and Clinical Neurobiology, Department of Psychiatry Ludwig-Maximilians-University, Munich, Germany. · J Neurochem. · Pubmed #16371011 No free full text.

Abstract: Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in tauopathies, which include Alzheimer's disease (AD). Tau is a microtubule-associated protein whose transcript undergoes alternative splicing in the brain. Exon 10 encodes one of four microtubule-binding repeats. Exon 10 inclusion gives rise to tau protein isoforms containing four microtubule-binding repeats (4R) whereas exclusion leads to isoforms containing only three repeats (3R). The ratio between 3R and 4R isoforms is tightly controlled via alternative splicing in the human adult nervous system and distortion of this balance results in neurodegeneration. Previous studies showed that several splicing regulators, among them hTRA2-beta1 and CLK2, regulate exon 10 alternative splicing. Like most splicing factors, htra2-beta and clk2 pre-mRNAs are regulated by alternative splicing. Here, we investigated whether human postmortem brain tissue of AD patients reveal differences in alternative splicing patterns of the tau, htra2-beta, presenilin 2 and clk2 genes when compared with age-matched controls. We found that the splicing patterns of all four genes are altered in affected brain areas of sporadic AD patients. In these affected areas, the amount of mRNAs of tau isoforms including exon 10, the htra2-beta1 isoform and an inactive form of clk2 are significantly increased. These findings suggest that a misregulation of alternative splicing seems to contribute to sporadic AD.

Wilson RS, Tang Y, Aggarwal NT, Gilley DW, McCann JJ, Bienias JL, Evans DA. · Rush Alzheimer's Disease Center, Rush Institute for Healthy Aging, and Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Neuroepidemiology. · Pubmed #16352909 No free full text.

Abstract: The relation of psychotic symptoms to cognitive decline and mortality in Alzheimer's disease (AD) was examined during a mean of 2.2 years in 478 persons selected from clinical settings. Psychotic symptoms were ascertained at baseline and cognition was assessed semiannually with nine tests from which a global measure was formed. In analyses that controlled for age, sex, race, and education, hallucinations (29.6%), especially visual ones, were associated with more rapid global cognitive decline and increased mortality, even after controlling for baseline level of cognition and use of antipsychotic medication, and the association with mortality increased with higher level of education. Delusions and misperceptions were not strongly related to cognitive decline or mortality. The results suggest that hallucinations in Alzheimer's disease, particularly visual ones, are associated with more rapid progression.

Wilson RS, Krueger KR, Kamenetsky JM, Tang Y, Gilley DW, Bennett DA, Evans DA. · Rush Alzheimer's Disease Center, Dept. of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Am J Geriatr Psychiatry. · Pubmed #16286442 No free full text.

Abstract: OBJECTIVE: The authors tested the relationship of hallucinations and delusions to mortality in Alzheimer disease (AD). METHODS: A group of 407 persons with clinically diagnosed AD completed a uniform clinical evaluation, after which vital status was monitored for a mean of 3.7 years. At the initial evaluation, a previously established, structured, informant interview was used to ascertain the presence of hallucinations and delusional thinking. The evaluation also included a structured medical history, inspection of all medications, and detailed assessment of cognitive functioning and parkinsonian signs. RESULTS: At study onset, hallucinations were present in 41.0% of participants and delusions in 54.4%. During follow-up, 146 deaths occurred. In a proportional-hazards model adjusted for age, sex, race, and education, hallucinations were associated with a 78% increase in risk of death. The association was not substantially altered in subsequent analyses that controlled for level of cognitive impairment, severity of parkinsonism, use of antipsychotic medications, and the presence of chronic medical conditions. Risk of death was more than doubled in those with both auditory and visual hallucinations. By contrast, we did not find evidence of an association of delusions with mortality. CONCLUSION: Hallucinations are associated with an increased risk of death in AD.

Tang Y, Yin HY, Zeng F, Yu SG. · Institute of Biomedical Engineering, West China Center of Medical Science, Sichuan University, Chengdu, Sichuan Province 610041, China. · Zhong Xi Yi Jie He Xue Bao. · Pubmed #16159565 links to  free full text

Abstract: Analysis of domestic and overseas literature on the relationship between Alzheimer disease (AD) and neural stem cells (NSC) shows that inducing the proliferation and differentiation of hippocampal endogenous NSC in-situ by acupuncture is probably the mechanism of acupuncture therapy in treating AD, and that it may further improve the method for the research on AD.

Tang Y, Yamada K, Kanou Y, Miyazaki T, Xiong X, Kambe F, Murata Y, Seo H, Nabeshima T. · Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, 466-8560, Nagoya, Japan. · Brain Res Mol Brain Res. · Pubmed #11038251 No free full text.

Abstract: The beta-amyloid protein (Abeta) is the major component of senile plaques found in the brain in Alzheimer's disease (AD). Its neurotoxic properties in vivo, however, are not well defined. Since the expression of neurotrophin genes is considered an important component of the intrinsic neuroprotective response to insults, we analyzed the gene expression of neurotrophins in the brains of rats which received a continuous infusion of Abeta-(1-42) into the cerebroventricle. Northern blot analysis revealed a significant increase in brain-derived neurotrophic factor (BDNF) expression in the hippocampus but no change in the cerebral cortices. The alteration peaked on days 3-7 and returned to the basal level on day 14 after the start of Abeta-(1-42) infusion. No significant changes in nerve growth factor or neurotrophin-3 mRNA expression were observed. The infusion of Abeta-(1-40) and (25-35) also triggered the expression of BDNF mRNA, whereas neither Abeta-(40-1) nor (1-16) had any effect. In situ hybridization histochemistry revealed that the expression mainly occurred in the hilus and granular layer of the dentate gyrus and to a lesser extent in the pyramidal neurons of the CA1 region. These results demonstrate that the continuous intracerebroventricular infusion of Abeta induces selective and spatiotemporal expression of BDNF mRNA in the hippocampus.