Alzheimer Disease: Bennett DA

Bennett DA, Whitmer RA. · No affiliation provided · Neurology. · Pubmed #19386996 No free full text.

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Clarke RJ, Bennett DA. · No affiliation provided · JAMA. · Pubmed #18854547 No free full text.

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Bennett DA, Holtzman DM. · No affiliation provided · Neurology. · Pubmed #15642896 No free full text.

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Bennett DA, McDermott MP. · No affiliation provided · Neurology. · Pubmed #12391336 No free full text.

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Carrillo MC, Blackwell A, Hampel H, Lindborg J, Sperling R, Schenk D, Sevigny JJ, Ferris S, Bennett DA, Craft S, Hsu T, Klunk W. · Alzheimer's Association, Chicago, IL, USA. · Alzheimers Dement. · Pubmed #19328456 No free full text.

Abstract: The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

Bennett DA. · Rush Alzheimer's Disease Center, Chicago, Illinois, USA. · Dis Mon. · Pubmed #11078009 No free full text.

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Bennett DA. · Rush Alzheimer's Disease Center, Chicago, Illinois, USA. · Dis Mon. · Pubmed #11078008 No free full text.

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de Toledo-Morrell L, Goncharova I, Dickerson B, Wilson RS, Bennett DA. · Department of Neurological Sciences, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA. · Ann N Y Acad Sci. · Pubmed #10911878 No free full text.

Abstract: Using quantitative structural MRI protocols, we examined the effects of age on alterations in entorhinal cortex (EC) volume. The left EC was found to be smaller than the right in both young and healthy aged subjects. More importantly, the right EC, but not the left, was significantly smaller in elderly participants compared to young controls. In an attempt to determine the earliest sites of involvement in mild and incipient Alzheimer's disease (AD), we compared entorhinal and hippocampal volume in (1) healthy elderly controls, (2) patients with very mild AD, and (3) elderly patients who were evaluated for cognitive complaints, but did not meet criteria for dementia. Both patient groups differed from controls in EC volume, but not from each other. In contrast, the two patient groups differed in hippocampal volume from controls, as well as from each other, with the mild AD cases showing the greatest atrophy. These results suggest that degeneration of the EC and hippocampal formation occurs before the onset of overt dementia. In fact, follow-up clinical evaluations available on 23 of 28 nondemented patients indicated that 12 of 23 had converted to AD. Converters could be best differentiated from nonconverters on the basis of entorhinal volume.

Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS. · Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Neurology. · Pubmed #16801647 No free full text.

Abstract: OBJECTIVE: To examine the relation of National Institute on Aging-Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). METHODS: More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. RESULTS: Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. CONCLUSIONS: Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.

Zhu H, Gopalraj RK, Kelly JF, Bennett DA, Estus S. · Department of Physiology, University of Kentucky, 800 S. Limestone St., Lexington, KY 40536-0230, USA. · Neurosci Lett. · Pubmed #15882786 No free full text.

Abstract: Dysregulation of cholesterol homeostasis may be associated with the pathogenesis of coronary artery disease (CAD) and Alzheimers disease (AD). Recently, several single nucleotide polymorphisms (SNPs) in cholesteryl ester transfer protein (CETP) were associated with altered plasma CETP concentrations, cholesterol concentrations and CAD. Hence, these CETP SNPs represent excellent candidates for evaluating association with AD. To date, one study has evaluated the association between a single CETP SNP and AD. In this study, we examined three CETP SNPs to evaluate the genetic association of CETP with late onset AD on two study cohorts: the Religious Orders Study (ROS) series, including 85 AD and 70 non-AD individuals, and the University of Kentucky (UKY) series, including 78 AD and 84 non-AD individuals. Significant association between CETP genotypes or haplotypes and late onset AD was not detected in these two study cohorts. Moreover, the CETP genotypes and haplotypes were not significantly associated with AD when the populations were stratified for the presence or absence of apolipoprotein E4 (apoE4). In summary, CETP genetic variants were not associated with AD in two series.

Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal LJ, Anonymous00151. · Alzheimer's Disease Cooperative Study, Department of Neurosciences, University of California-San Diego, 8950 Villa La Jolla Drive, Suite 227, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #14732621 links to  free full text

Abstract: BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

Wilson RS, Gilley DW, Bennett DA, Beckett LA, Evans DA. · Department of Neurological Sciences, Rush Alzheimer's Disease Center and Rush Institute for Healthy Aging, 1645 West Jackson Boulevard, Suite 675, Chicago, Illinois 60612, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #10896689 links to  free full text

Abstract: OBJECTIVES: To examine the occurrence of hallucinations and delusions in Alzheimer's disease over a 4 year period and their association with rate of cognitive decline. METHODS: A cohort of 410 persons with clinically diagnosed Alzheimer's disease underwent annual clinical evaluations over a 4 year period. Participation in follow up exceeded 90% in survivors. Evaluations included structured informant interview, from which the presence or absence of hallucinations and delusions was ascertained, and detailed testing of cognitive function. The primary cognitive outcome measure was a composite cognitive score based on 17 individual performance tests. The mini mental state examination (MMSE) and summary measures of memory, visuoconstruction, repetition, and naming were used in secondary analyses. RESULTS: At baseline, hallucinations (present in 41%) and delusions (present in 55%) were common and associated with lower cognitive function. In analyses that controlled for baseline level of cognitive function, demographic variables, parkinsonism, and use of antipsychotic medications, hallucinations, but not delusions, were associated with more rapid cognitive decline on each cognitive measure. In the primary model, there was a 47% increase in the average annual rate of decline on a composite cognitive measure in those with baseline hallucinations compared with those without them. This effect was mainly due to a subgroup with both auditory and visual hallucinations. CONCLUSION: These findings suggest that the presence of hallucinations is selectively associated with more rapid cognitive decline in Alzheimer's disease.

Wilson RS, Bennett DA, Gilley DW, Beckett LA, Schneider JA, Evans DA. · Rush Alzheimer's Disease Center, 1645 W Jackson Blvd, Suite 675, Chicago, IL 60612, USA. · Arch Neurol. · Pubmed #10867783 links to  free full text

Abstract: OBJECTIVE: To assess the relation between parkinsonism and cognitive function in Alzheimer disease from cross-sectional and longitudinal perspectives. DESIGN: Prospective cohort study with annual clinical evaluations during a 4-year period. SETTING: Alzheimer disease clinic in an urban medical center. PARTICIPANTS: Four hundred ten persons with clinically diagnosed Alzheimer disease. MAIN OUTCOME MEASURES: Global and specific measures of cognitive function and parkinsonism. RESULTS: Higher levels of parkinsonism at baseline were reliably associated with lower levels of cognitive function at baseline and with more rapid cognitive decline during the 4-year study period. However, the associations were small, with baseline parkinsonism accounting for less than 10% of the variation either in baseline cognitive function or in the rate of cognitive decline. By contrast, rates of change in parkinsonism and cognitive function were strongly correlated, with 70% or more shared variance in the rates of change in many models. The association was observed with diverse measures of cognition and parkinsonism and was not explained by demographic variables or use of neuroleptic medications. CONCLUSION: In Alzheimer disease, progressive worsening of parkinsonism is more strongly associated with cognitive decline than previously recognized. Arch Neurol. 2000.

de Toledo-Morrell L, Dickerson B, Sullivan MP, Spanovic C, Wilson R, Bennett DA. · Department of Neurological Sciences, Rush University, Chicago, Illinois, USA. · Hippocampus. · Pubmed #10791835 No free full text.

Abstract: Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects.

Gilmor ML, Erickson JD, Varoqui H, Hersh LB, Bennett DA, Cochran EJ, Mufson EJ, Levey AI. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. · J Comp Neurol. · Pubmed #10421878 No free full text.

Abstract: Immunocytochemistry for choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) was used to examine the expression of these linked cholinergic markers in human basal forebrain, including cases with early stages of Alzheimer's disease (AD). Previous neurochemical studies have measured decreased ChAT activity in terminal fields, but little change or even increased levels of VAChT. To determine total cholinergic neuron numbers in the nucleus basalis of Meynert (nbM), stereologic methods were applied to tissue derived from three groups of individuals with varying levels of cognition: no cognitive impairment (NCI), mild cognitive impairment (MCI), and early-stage Alzheimer's disease (AD). Both markers were expressed robustly in nucleus basalis neurons and across all three groups. On average, there was no significant difference between the number of ChAT- (210,000) and VAChT- (174, 000) immunopositive neurons in the nbM per hemisphere in NCI cases for which the biological variation was calculated to be 17%. There was approximately a 15% nonsignificant reduction in the number of cholinergic neurons in the nbM in the AD cases with no decline in MCI cases. The number of ChAT- and VAChT-immunopositive neurons was shown to correlate significantly with the severity of dementia determined by scores on the Mini-Mental State Examination, but showed no relationship to apolipoprotein E allele status, age, gender, education, or postmortem interval when all clinical groups were combined or evaluated separately. These data suggest that cholinergic neurons, and the coexpression of ChAT and VAChT, are relatively preserved in early stages of AD.

Bennett DA, De Jager PL, Leurgans SE, Schneider JA. · Rush Alzheimer's Disease Center, 600 S. Paulina, Suite 1028, Chicago, IL 60062, USA. · Neurology. · Pubmed #19398704 No free full text.

Abstract: OBJECTIVE: The identification of susceptibility alleles to risk of Alzheimer disease (AD) is a major public health priority. Using apolipoprotein E genotype (APOE), we examined whether neuropathologic intermediate phenotypes, the pathology underlying clinical AD that presumably lies intermediate in the causal chain, would increase power for genetic associations. METHODS: More than 700 older persons underwent annual evaluation and organ donation as part of the Religious Orders Study or Rush Memory and Aging Project. A total of 536 autopsied persons with clinical AD or without dementia with APOE genotyping and a quantitative measure of AD pathology were analyzed. Regression analyses were used to examine the relation of APOE to clinical AD, to the level of cognitive function proximate to death, and to measures of AD neuropathology. RESULTS: APOE epsilon4 was associated with increased odds of clinical AD (p = 3 x 10(-7)), and its association with level of cognition was stronger (p = 8 x 10(-12)). However, the use of quantitative measures of AD pathology markedly enhanced the association (p = 9 x 10(-24)). The APOE epsilon2 was not associated with either AD (p = 0.69) or level of cognition (p = 0.82). However, its association with AD pathology (p = 1 x 10(-5)) was sufficiently strong that it would have warranted follow-up if discovered in a genome-wide association study. Power calculations demonstrate that a sample size of 625 subjects with our measure of AD pathology would be required to meet genome-wide significance of p = 5 x 10(-8) for epsilon2. CONCLUSION: Discovery efforts for susceptibility loci for Alzheimer disease could benefit from the use of neuropathologic intermediate phenotypes as a complement to other approaches.

O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, Lichtenthaler SF, Hébert SS, De Strooper B, Haass C, Bennett DA, Vassar R. · Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · Neuron. · Pubmed #19109907 No free full text.

Abstract: beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for beta-amyloid (Abeta) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2alpha (eIF2alpha-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2alpha-P phosphatase PP1c, directly increases BACE1 and elevates Abeta production in primary neurons. Preventing eIF2alpha phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2alpha kinase PERK, or PERK inhibitor P58(IPK) blocks the energy-deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2alpha-P, BACE1, Abeta, and amyloid plaques. Importantly, eIF2alpha-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2alpha-P, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2alpha phosphorylation increases BACE1 levels and causes Abeta overproduction, which could be an early, initiating molecular mechanism in sporadic AD.

Julien C, Tremblay C, Emond V, Lebbadi M, Salem N, Bennett DA, Calon F. · Faculty of Pharmacy, Laval University, Centre Hospitalier de l'Université Laval Research Center, Quebec, Quebec, Canada. · J Neuropathol Exp Neurol. · Pubmed #19104446 No free full text.

Abstract: Aging and metabolism-related disorders are risk factors for Alzheimer disease (AD). Because sirtuins may increase the life span through regulation of cellular metabolism, we compared the concentration of sirtuin 1 (SIRT1) in the brains of AD patients (n = 19) and controls (n = 22) using Western immunoblots and in situ hybridization. We report a significant reduction of SIRT1 (messenger RNA [mRNA], -29%; protein, -45%) in the parietal cortex of AD patients, but not in the cerebellum. Further analyses in a second cohort of 36 subjects confirmed that cortical SIRT1 was decreased in AD but not in individuals with mild cognitive impairment. SIRT1 mRNA and its translated protein correlated negatively with the duration of symptoms (mRNA, r2 = -0.367; protein, r2 = -0.326) and the accumulation of paired helical filament tau (mRNA, r2 = -0.230; protein, r2 = -0.119), but weakly with insoluble amyloid-beta 42 (mRNA, r2= -0.090; protein, r2 = -0.072). A significant relationship between SIRT1 levels and global cognition scores proximate to death was also found (r2= +0.09, p = 0.049). In contrast, cortical SIRT1 levels remained unchanged in a triple-transgenic animal model of AD. Collectively, our results indicate that loss of SIRT1 is closely associated with the accumulation of amyloid-beta and tau in the cerebral cortex of persons with AD.

Louneva N, Cohen JW, Han LY, Talbot K, Wilson RS, Bennett DA, Trojanowski JQ, Arnold SE. · Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA 19104, USA. · Am J Pathol. · Pubmed #18818379 links to  free full text

Abstract: Progressive synaptic degeneration and neuron loss are major structural correlates of cognitive impairment in Alzheimer's disease (AD). The mechanisms by which synaptic degeneration in AD occurs have not been established. The activation of proteins within the caspase family has been implicated in AD-associated neurodegeneration, and synaptically localized caspase activity could play a role in the synaptic degeneration and loss found in AD. We used synaptosomal fractionation with Western blotting and immunohistochemistry to examine the anatomical, subcellular, and subsynaptic expression patterns of caspase 3 in both the anterior cingulate cortex and hippocampus of control and AD patients. In both control and AD cases, there was a selective enrichment of caspase- 3 at synapses, particularly in the postsynaptic density (PSD) fractions. Compared with controls, AD patients exhibited significant increases in synaptic procaspase- 3 and active caspase-3 expression levels that were most evident in the PSD fractions. These data demonstrate for the first time the preferential localization and increase of caspase-3 in the PSD fractions in AD and suggest an important role for caspase 3 in synapse degeneration during disease progression.

Buchman AS, Schneider JA, Leurgans S, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Armour Academic Facility, Suite 1038, 600 S Paulina St, Chicago, IL 60612, USA. · Neurology. · Pubmed #18695161 No free full text.

Abstract: OBJECTIVE: We examined the extent to which physical frailty in older persons is associated with common age-related brain pathology, including cerebral infarcts, Lewy body pathology, and Alzheimer disease (AD) pathology. METHODS: We studied brain autopsies from 165 deceased participants from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study of aging. Physical frailty, based on four components, including grip strength, time to walk 8 feet, body composition, and fatigue, was assessed at annual clinical evaluations. Multiple regression analyses were used to examine the relation of postmortem neuropathologic findings to frailty proximate to death, controlling for age, sex, and education. RESULTS: The mean age at death was 88.1 years (SD = 5.7 years). The level of AD pathology was associated with frailty proximate to death ( = 0.252, SE = 0.077, p = 0.001), accounting for 4% of the variance of physical frailty. Neither cerebral infarcts ( = -0.121, SE = 0.115, p = 0.294) nor Lewy body disease pathology ( = 0.07, SE = 0.156, p = 0.678) was associated with frailty. These associations were unchanged after controlling for the time interval from last clinical evaluation to autopsy. The association of AD pathology with frailty did not differ by the presence of dementia, and this association was unchanged even after considering potential confounders, including physical activity; parkinsonian signs; pulmonary function; or history of chronic diseases, including vascular risk factors, vascular disease burden, falls, joint pain, or use of antipsychotic or antihypertensive medications. CONCLUSION: Physical frailty in old age is associated with Alzheimer disease pathology in older persons with and without dementia.

Arvanitakis Z, Grodstein F, Bienias JL, Schneider JA, Wilson RS, Kelly JF, Evans DA, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA. · Neurology. · Pubmed #18519870 No free full text.

Abstract: OBJECTIVE: To examine the relation of nonsteroidal anti-inflammatory drugs (NSAIDs) to incident Alzheimer disease (AD), change in cognition, and AD pathology. METHODS: Participants were 1,019 older Catholic clergy followed up annually for up to 12 years (mean baseline age = 75.0 years, education = 18.1 years, Mini-Mental State Examination score = 28.5), enrolled in the Religious Orders Study, a longitudinal clinical-pathologic study of aging and AD. Clinical evaluations allowed for AD classification and assessment of global cognition and five cognitive domains. NSAIDs were identified by direct medication inspection at baseline and follow-up evaluations. Neuropathologic data were available on 328 deceased participants. AD pathology was summarized as a global measure and as measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles. We used Cox proportional hazards models and mixed models for incident AD and cognitive decline, respectively, and logistic and linear regression for pathologic outcomes, adjusted for age, sex, and education. RESULTS: Overall, we found no apparent relation of NSAIDs to incident AD (n = 209 cases), change in cognition, or AD pathology. The hazard ratio of incident AD was 1.19 (95% CI 0.87-1.62) comparing those using NSAIDs with those not using NSAIDs at baseline, and 0.84 (95% CI 0.63-1.11) for specific use of aspirin. Findings were similar in analyses in which we considered NSAID use during follow-up. NSAIDs were not related to change in cognition (all p values > 0.14). There was no relation of NSAIDs to global AD pathology or plaques or tangles. CONCLUSION: These data do not support a strong relation between nonsteroidal anti-inflammatory drugs and Alzheimer disease or cognition. Consistent findings across clinical and pathologic outcomes provide additional confidence in these results.

Wilson RS, Arnold SE, Beck TL, Bienias JL, Bennett DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, 600 S Paulina, Ste 1038, Chicago, IL 60612, USA. · Arch Gen Psychiatry. · Pubmed #18391132 links to  free full text

Abstract: CONTEXT: Prospective studies have established an association between depressive symptoms and risk of dementia, but how depressive symptoms change during the evolution of dementia is uncertain. OBJECTIVE: To test the hypothesis that depressive symptoms increase during the prodromal phase of Alzheimer disease (AD). DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: For up to 13 years, 917 older Catholic nuns, priests, and monks without dementia at study onset completed annual clinical evaluations that included administration of the 10-item Center for Epidemiologic Studies Depression Scale and clinical classification of mild cognitive impairment and AD. MAIN OUTCOME MEASURE: Change in depressive symptoms reported on the Center for Epidemiologic Studies Depression Scale. RESULTS: At baseline, participants reported a mean (SD) of 1.0 (1.5) depressive symptoms. Those who developed AD (n = 190) showed no increase in depressive symptoms before the diagnosis was made, and this finding was not modified by age, sex, education, memory complaints, vascular burden, or personality. There was no systematic change in depressive symptoms after the AD diagnosis, although symptoms tended to decrease in women relative to men and in those with a higher premorbid level of openness and a lower premorbid level of agreeableness. Among those without cognitive impairment at baseline, depressive symptoms did not increase in those who subsequently developed mild cognitive impairment. CONCLUSION: We found no evidence of an increase in depressive symptoms during the prodromal phase of AD.

Boyle PA, Wilson RS, Schneider JA, Bienias JL, Bennett DA. · Rush Alzheimer's Disease Center, Department of Behavioral Sciences, Rush University Medical Center, 600 S. Paulina, 1020B, Chicago, IL 60612, USA. · Neurology. · Pubmed #18354077 No free full text.

Abstract: The cognitive abilities of older persons vary greatly, even among those with similar amounts of Alzheimer disease (AD) pathology, suggesting differences in neural reserve. Although its neurobiologic basis is not well understood, reserve may reflect differences in the ability to compensate for the deleterious effects of pathology by recruiting alternative or additional brain networks to perform a specific task. If this is an effective compensatory strategy, then involvement of additional cognitive systems may help maintain function in other cognitive systems despite the accumulation of pathology. OBJECTIVE: We tested the hypothesis that processing resources, specifically perceptual speed and working memory, modify the associations of AD pathology with other cognitive systems. METHOD: A total of 103 older participants of the Rush Memory and Aging Project underwent detailed annual clinical evaluations and brain autopsy. Five cognitive systems including perceptual speed, working memory, semantic memory, visuospatial abilities, and episodic memory were assessed proximate to death, and AD pathology including tau tangles and amyloid load were quantified postmortem. RESULTS: In multiple regression models adjusted for age, sex, and education, processing resources reduced the associations of tangles with other cognitive systems, such that persons with higher levels of perceptual speed and working memory performed better on semantic memory and visuospatial abilities despite the burden of tangles. Perceptual speed also reduced the associations of amyloid with semantic memory, visuospatial abilities, and episodic memory. CONCLUSION: These findings suggest that processing resources may help compensate for the deleterious effects of Alzheimer disease pathology on other cognitive systems in older persons.

Wang DS, Uchikado H, Bennett DA, Schneider JA, Mufson EJ, Wu J, Dickson DW. · Departments of Neuroscience and Pathology, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · J Alzheimers Dis. · Pubmed #18334757 No free full text.

Abstract: BACKGROUND: Protein cross-linking and aggregation are important molecular processes in Alzheimer's disease (AD), and tissue transglutaminase (tTG) catalyzes protein cross-linking. OBJECTIVES: To measure tTG, tTG enzyme activity and isopeptide, which is the product of tTG, in brain and to relate them to cognitive scores. METHODS: tTG and isopeptide levels were measured in frontal gray matter of 10 normal (NCI), 10 mild cognitive impairment (MCI) and 9 AD brains from the Religious Orders Study. tTG enzymatic activity was measured with a fluorescence assay. RESULTS: tTG protein and enzyme activity were highest in AD, but not significantly greater than MCI or NCI. In contrast, isopeptide immunoreactivity in formic acid extracts was significantly greater in AD than NCI and MCI. The level of insoluble formic acid extractable isopeptide correlated with several measures of cognitive function, including word generation and perceptual speed. Multiple linear regression analyses indicated that insoluble isopeptide immunoreactivity could be accounted for by a combination of factors in the formic acid extract, including Abeta, ubiquitin and tau. CONCLUSIONS: Accumulation of insoluble proteins with isopeptide bonds correlates with cognitive impairment. The relationship of isopeptide to other proteins that are also enriched in formic acid extracts suggests that several substrates of tTG may play a role in the pathogenesis of AD.

Loeffler DA, Camp DM, Bennett DA. · Neurology Research Laboratory, William Beaumont Hospital Research Institute, Royal Oak, MI 48073, USA. · J Neuroinflammation. · Pubmed #18334032 links to  free full text

Abstract: BACKGROUND: Complement activation is increased in Alzheimer's disease (AD), but its significance is unclear. The objective of this study was to determine the relationship between complement activation and cognition during the development of AD. METHODS: iC3b, C9, Bielschowsky, and Gallyas staining was performed on aged normal (n = 17), mild cognitively impaired (n = 12), and AD (n = 17-18) inferior temporal gyrus specimens. Plaques were counted in 10x fields with high numbers of Bielschowsky-stained plaques. One-way ANOVA was used to determine between-group differences for plaque counts and measures of cognitive function, and linear regression was used to evaluate global cognition as a function of Bielschowsky-stained plaques. Terms for iC3b- and C9-stained plaques were then added sequentially as additional predictors in a "mediation analysis" model. RESULTS: Complement was detected on plaques in all groups, and on neurofibrillary tangles only in AD specimens. iC3b, C9, and Bielschowsky-stained plaque counts increased 2.5- to 3-fold in AD vs. other groups (all p < or = 0.01). C9 staining was present on some diffuse plaques, as well as on neuritic plaques. Bielschowsky-stained and complement-stained plaque counts were highly correlated, and were negatively correlated with cognitive measures. When the Bielschowsky plaque count was used as a predictor, its correlations with cognitive measures were statistically significant, but when iC3b and C9 plaque counts were added as additional predictors, these correlations were no longer significant. This loss of significance was attributed to multicollinearity, i.e., high correlations between Bielschowsky-stained and complement-stained plaque counts. CONCLUSION: Both early-stage (iC3b) and late-stage (C9) complement activation occurs on neocortical plaques in subjects across the cognitive spectrum; contrary to previous reports, C9 is present on some diffuse plaques. Because of high correlations between complement-stained and Bielschowsky-stained plaque counts, quantitative assessment of the extent to which complement activation may mediate the relationship between plaques and cognitive function could not be performed. Additional studies with animal models of AD (if late-stage complement activation can be demonstrated), or possibly a trial in AD patients with an inhibitor of late-stage complement activation, may be necessary to determine the significance of this process in AD.