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We herein report the development of an automation platform for rapid purification and quantification of chemical libraries including reformatting of chemical matter to 10 mM DMSO stock solutions. This fully integrated workflow features tailored conditions for preparative reversed-phase (RP) HPLC-MS on microscale based on analytical data, online fraction QC and CAD-based quantification as well as automated reformatting to enable rapid purification of chemical libraries. This automated workflow is entirely solution-based, eliminating the need to weigh or handle solids. This increases process efficiency and creates a link between high-throughput synthesis and profiling of novel chemical matter with respect to biological and physicochemical properties in relevant assays.

To characterize the driving and mobility status of older adults with dementia, a questionnaire was mailed to 527 informants; 119 were returned. The majority of patients were diagnosed with dementia of the Alzheimer type. Only 28% were actively driving at the time of survey. Informants rated 53% of current or recently retired drivers as potentially unsafe. Few informants reported using community/educational resources. Individuals with progressive dementia retire from driving for differing reasons, many subsequent to family recognition of impaired driving performance. Opportunities for education and supportive assistance exist but are underutilized. [ABSTRACT FROM AUTHOR]

The effects of heat and/or hypoxia have been well-documented in match-play data. However, large match-to-match variation for key physical performance measures makes environmental inferences difficult to ascertain from soccer match-play. Therefore, the present study aims to investigate the hot (HOT), hypoxic (HYP) and hot-hypoxic (HH) mediated-decrements during a non-motorised treadmill based soccer-specific simulation. Twelve male University soccer players completed three familiarisation sessions and four randomised crossover experimental trials of the intermittent Soccer Performance Test (iSPT) in normoxic-temperate (CON: 18oC 50% rH), HOT (30oC; 50% rH), HYP (1,000m; 18oC 50% rH) and HH (1,000m; 30oC; 50% rH). Physical performance and its performance decrements, body temperatures (rectal, skin and estimated muscle temperature), heart rate (HR), arterial blood oxygen saturation (SaO2), perceived exertion, thermal sensation (TS), body mass changes, blood lactate and plasma volume were all measured. Performance decrements were similar in HOT and HYP [Total Distance (-4%), High-speed distance (~-8%) and variable run distance (~-12%) covered] and exacerbated in HH [total distance (-9%), high-speed distance (-15%) and variable run distance (-15%)] compared to CON. Peak sprint speed, was 4% greater in HOT compared with CON and HYP and 7% greater in HH. Sprint distance covered was unchanged (p > 0.05) in HOT and HYP and only decreased in HH (-8%) compared with CON. Body mass (-2%), temperatures (+~5%) and TS (+18%) were altered in HOT. Furthermore, SaO2 (-7%) and HR (+3%) were changed in HYP. Similar changes in body mass and temperatures, HR, TS and SaO2 were evident in HH to HOT and HYP, however, blood lactate (p < 0.001) and plasma volume (p < 0.001) were only significantly altered in HH. Perceived exertion was elevated (p < 0.05) by 7% in all conditions compared with CON. Regression analysis identified that absolute TS and absolute rise in skin and estimated muscle temperature (r = 0.82, r = 0.84 r = 0.82, respectively; p

In 2022, the U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and state partners conducted a sample-initiated investigation of a multistate outbreak of Salmonella Senftenberg illnesses linked to peanut butter. Twenty-one illnesses and four hospitalizations were reported in 17 states, with a significant epidemiological signal for peanut butter from Firm A. Whole genome sequence (WGS) data from a Salmonella -positive environmental swab sample collected at Firm A in 2010 yielded the outbreak strain that was a match to the WGS data from the 2022 clinical isolates. Lot code information collected from patients indicated Firm A's facility in Kentucky as a common manufacturing source, and FDA and state partners initiated an inspection. In 2021, Firm A installed two new roasters with at least one of the cooling air supply vents leaking, allowing unfiltered air and rainwater to enter the cooling section after the roasting process. Investigators noted the limitations of Firm A's finished product testing program to identify contamination. Investigative partners from five states collected and analyzed 14 product samples, and FDA collected 205 environmental swabs, and all were negative. Although the exact source and route of the contamination were not determined, epidemiological and traceback evidence confirmed peanut butter consumed by patients was produced by Firm A. Firm A voluntarily recalled all implicated products and provided a plan for corrective actions and restart to FDA. This was the first major domestic investigation of a multistate-foodborne illness outbreak linked to peanut butter since 2012. This investigation demonstrates the importance of caution with reliance on finished product testing, taking appropriate corrective actions when detection occurs, and potential benefits for industry to incorporate WGS as a tool in their environmental monitoring program.

Previous studies have reported on the health impact of systemic racism among historically oppressed populations. In fact, there is an emerging body of literature, including systematic reviews, which describe the negative health consequences of systemic racism among racial/ethnic minoritized groups in the US. Less is known, however, about effective intervention strategies to address systemic racism and the resulting health inequities. This scoping review was conducted to synthesize the published literature on U.S.-based interventions designed to improve health equity by addressing systemic racism. The Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping review (PRISMA-ScR) checklist was used to report this review. We searched six databases (MEDLINE, CINAHL, PsycINFO, Sociological Abstracts, Web of Science Core Collection, and Scopus) to examine the intervention studies. A total of 172 articles were included in review. These interventions were classified by typology which included healing-centered approaches, community-based interventions targeting health disparities, diversity, equity, inclusion (DEI) efforts, anti-racism training interventions, and policy interventions. The findings from this review have important implications for the development, testing, and scaling of interventions designed to addressed systemic racism., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups., Methods: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations., Results: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aβ42/40, total tau, p-tau181, and neurofilament light. CSF Aβ42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aβ42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aβ42/40, Aβ42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures., Interpretation: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506., (© 2023 American Neurological Association.)

Questionnaires are used to assess instrumental activities of daily living (IADL) among individuals with preclinical Alzheimer disease (AD). They have indicated no functional impairment among this population. We aim to determine among cognitively normal (CN) older adults with and without preclinical AD whether: (a) performance-based IADL assessment measures a wider range of function than an IADL questionnaire and (b) biomarkers of AD are associated with IADL performance. In this cross-sectional analysis of 161 older adults, participants in studies of AD completed an IADL questionnaire, performance-based IADL assessment, cognitive assessments, and had biomarkers of AD (amyloid, hippocampal volume, brain network strength) assessed within 2 to 3 years. Performance-based IADL scores were more widely distributed compared with the IADL questionnaire. Smaller hippocampal volumes and reduced brain network connections were associated with worse IADL performance. A performance-based IADL assessment demonstrates functional impairment associated with neurodegeneration among CN older adults.

Background: Racial, ethnic, and gender disparities in effective pain management have been well-documented across healthcare settings. However, discrepancies in the treatment of patients in prehospital pain management settings have not been well researched. The objective of this study was to determine whether Wyoming emergency medical service (EMS) providers' use of opioids to treat prehospital pain or injury varies by patient race/ethnicity or gender., Methods: This cross-sectional study of EMS records examined 27 448 patient care reports (PCRs) generated during emergency medical responses to pain/injury emergencies in the state of Wyoming between January 2016 and March 2019. We included PCRs in the sample when 1) the primary impression was pain or injury, 2) the type of service was a 911 response, 3) the patient received treatment from and was transported by the EMS unit completing the PCR, and 4) the responding unit included one or more providers authorized to administer opioids., Results: The analysis identified a disparity in opioid administration by EMS providers during emergency transport (N = 27 448). Logistic regression reveals that EMS providers administered opioids to American Indian/Alaska Native patients (AI/AN) [n = 1610; 5.9%; P < .001; OR = 0.44] and those of Hispanic ethnicity (n = 1351; 4.9%; P = .001; OR = 0.74) at statistically significant lower rates (n = 14 769; 53.8%; P = .004; OR = 0.90) than they administer opioids to White patients. The analysis found EMS providers administer opioids to females at significantly lower rates ( P = .004) compared to males., Conclusion: Wyoming EMS providers administer opioids to White and male patients more often than non-White and female patients. Our results do not show a significant difference in the administration of opioids between White and Black patients. However, the data indicate a statistically significant difference between Hispanic, AI/AN, and White patients as well as between male and female patients., Competing Interests: Conflicts of Interest The authors declare they have no conflicts of interest., (© 2022 HCA Physician Services, Inc. d/b/a Emerald Medical Education.)

Importance: Female sex is a major risk factor for late-onset Alzheimer disease (AD), and sex hormones have been implicated as a possible protective factor. Neuroimaging studies that evaluated the effects of sex hormones on brain integrity have primarily emphasized neurodegenerative measures rather than amyloid and tau burden., Objective: We compared cortical amyloid and regional tau positron emission tomography (PET) deposition between cognitively normal males and females. We also compared preclinical AD pathology between females who have and have not used hormone therapy (HT). Finally, we compared the effects of amyloid and tau pathology on cognition, testing for both sex and HT effects., Design, Setting, and Participants: We analyzed amyloid, tau, and cognition in a cognitively normal cross-sectional cohort of older individuals (n=148) followed at the Knight Alzheimer Disease Research Center. Amyloid and tau PET, medication history, and neuropsychological testing were obtained for each participant., Results: Within cognitively normal individuals, there was no difference in amyloid burden by sex. Whether or not we controlled for amyloid burden, female participants had significantly higher tau PET levels than males in multiple regions, including the rostral middle frontal and superior and middle temporal regions. HT accounted for a small reduction in tau PET; however, males still had substantially lower tau PET compared with females. Amyloid PET and tau PET burden were negatively associated with cognitive performance, although increasing amyloid PET did not have a deleterious effect on cognitive performance for women with a history of HT., Conclusions and Relevance: Regional sex-related differences in tau PET burden may contribute to the disparities in AD prevalence between males and females. The observed decreases tau PET burden in HT users has important implications for clinical practice and trials and deserves future consideration in longitudinal studies., Competing Interests: T.L.B. is a site investigator on clinical trials with Biogen, Roche, Jaansen, and Eli Lilly. She receives research support from Eli Lilly and Avid Radiopharmaceuticals. Avid Radiopharmaceuticals provided the 18F-AV45 doses and assisted with scanning expenses, and provided precursor and technology transfer for the 18F-AV1451 doses which were used in this study. The remaining authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Vector-borne diseases (VBDs) are embedded within complex socio-ecological systems. While research has traditionally focused on the direct effects of VBDs on human morbidity and mortality, it is increasingly clear that their impacts are much more pervasive. VBDs are dynamically linked to feedbacks between environmental conditions, vector ecology, disease burden, and societal responses that drive transmission. As a result, VBDs have had profound influence on human history. Mechanisms include: (1) killing or debilitating large numbers of people, with demographic and population-level impacts; (2) differentially affecting populations based on prior history of disease exposure, immunity, and resistance; (3) being weaponised to promote or justify hierarchies of power, colonialism, racism, classism and sexism; (4) catalysing changes in ideas, institutions, infrastructure, technologies and social practices in efforts to control disease outbreaks; and (5) changing human relationships with the land and environment. We use historical and archaeological evidence interpreted through an ecological lens to illustrate how VBDs have shaped society and culture, focusing on case studies from four pertinent VBDs: plague, malaria, yellow fever and trypanosomiasis. By comparing across diseases, time periods and geographies, we highlight the enormous scope and variety of mechanisms by which VBDs have influenced human history., (© 2021 John Wiley & Sons Ltd.)

Background: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework., Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD., Methods: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall., Results: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall., Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-β42, tau, ptau181, tau/amyloid-β42, ptau181/amyloid-β42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test - Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean ± standard deviation = 71.4 ± 9.2) were followed for up to 16.9 years (mean ± standard deviation = 6.2 ± 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE ɛ4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE ɛ2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), ∼70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitudinal data and provide a potential time for changes seen during this transition. These findings support the use of molecular biomarkers for trial inclusion and cognitive/structural biomarkers for evaluating trial outcomes. Finally, results support a potential role for APOE ɛ in modulating amyloid accumulation in CDR > 0 with APOE ɛ4 being deleterious and APOE ɛ2 protective.

Introduction: With 36 million older adult U.S. drivers, safety is a critical concern, particularly among those with dementia. It is unclear at what stage of Alzheimer's disease (AD) older adults stop driving and whether preclinical AD affects driving cessation., Methods: Time to driving cessation was examined based on Clinical Dementia Rating (CDR) and AD cerebrospinal fluid biomarkers. 1795 older adults followed up to 24 years received CDR ratings. A subset (591) had cerebrospinal fluid biomarker measurements and was followed up to 17 years. Differences in CDR and biomarker groups as predictors of time to driving cessation were analyzed using Kaplan-Meier curves and Cox proportional models., Results: Higher CDR scores and more abnormal biomarker measurements predicted a shorter time to driving cessation., Discussion: Higher levels of AD biomarkers, including among individuals with preclinical AD, lead to earlier driving cessation. Negative functional outcomes of preclinical AD show a nonbenign phase of the disease., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: To identify clinical features that reliably differentiate individuals with cognitive impairment due to corticobasal degeneration (CBD) and Alzheimer disease (AD)., Methods: Clinical features were compared between individuals with autopsy-proven CBD (n = 17) and AD (n = 16). All individuals presented with prominent cognitive complaints and were evaluated annually with semistructured interviews, detailed neurologic examinations, and neuropsychological testing., Results: Substantial overlap was observed between individuals with dementia due to CBD and AD concerning presenting complaints, median (range) duration of symptoms before assessment (CBD = 3.0 [0-5.0] years, AD = 2.5 [0-8.0] years; p = 0.96), and median (range) baseline dementia severity (Clinical Dementia Rating Sum of Boxes: CBD = 3.5 [0-12.0], AD = 4.25 [0.5-9.0], p = 0.49). Subsequent emergence of asymmetric motor/sensory signs, hyperreflexia, gait abnormalities, parkinsonism, falls, urinary incontinence, and extraocular movement abnormalities identified individuals with CBD, with ≥3 discriminating features detected in 80% of individuals within 3.1 years (95% confidence interval 2.9-3.3) of the initial assessment. Individuals with CBD exhibited accelerated worsening of illness severity and declines in episodic memory, executive functioning, and letter fluency. Semiquantitative pathologic assessment revealed prominent tau pathology within the frontal and parietal lobes of CBD cases. Comorbid AD neuropathologic change was present in 59% (10 of 17) of CBD cases but did not associate with the clinical phenotype, rate of dementia progression, or dementia duration., Conclusions: CBD may mimic AD dementia early in its disease course. Interval screening for discriminating clinical features may improve antemortem diagnosis in individuals with CBD and prominent cognitive symptoms., (© 2017 American Academy of Neurology.)

Introduction: Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs., Methods: 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits., Results: Higher values of CSF tau/Aβ 42 and ptau 181 /Aβ 42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aβ 42 ; 6.19 (1.75-21.88) and p=.005 for CSF ptau 181 /Aβ 42 ., Discussion: Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials., Competing Interests: Declaration of interest Dr. Roe reports no conflicts of interest. Dr. Babulal reports no conflicts of interest. Dr. Head reports no conflicts of interest. Ms. Stout reports no conflicts of interest. Ms. Vernon reports no conflicts of interest. Dr. Ghoshal reports no conflicts of interest. Mr. Garland reports no conflicts of interest. Dr. Barco reports no conflicts of interest. Dr. Williams reports no conflicts of interest. Ms. Johnson reports no conflicts of interest. Ms. Fierberg reports no conflicts of interest. Mr. Fague reports no conflicts of interest. Dr. Xiong reports no conflicts of interest. Dr. Mormino reports no conflicts of interest. Dr. Grant reports no conflicts of interest. Dr. Holtzman reports no conflicts of interest. Dr. Holtzman reports no conflicts of interest. Dr. Fagan reports no conflicts of interest. Dr. Ott reports no conflicts of interest. Dr. Carr reports no conflicts of interest. Dr. Morris reports no conflicts of interest.

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42). Higher ratios of CSF tau/Aβ42, ptau181/Aβ42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving., Competing Interests: Possible Conflicts of Interest: Dr. Roe has no conflicts of interest. Dr. Barco has no conflicts of interest. Dr. Head has no conflicts of interest. Dr. Ghoshal has no conflicts of interest. Ms. Selsor reports no disclosures and has no conflicts of interest. Dr. Babulal has no conflicts of interest. Ms. Fierberg reports no disclosures and has no conflicts of interest. Ms. Vernon reports no disclosures and has no conflicts of interest. Mr. Shulman reports no disclosures and has no conflicts of interest. Ms. Johnson reports no conflicts of interest. Mr. Fague has no conflicts of interest. Dr. Xiong has no conflicts of interest. Dr. Grant has no conflicts of interest. Ms. Campbell reports no disclosures and has no conflicts of interest. Dr. Ott reports no conflicts of interest. Dr. Holtzman has no conflicts of interest. Dr. Benzinger has no conflicts of interest. Dr. Fagan has no conflicts of interest. Dr. Carr has no conflicts of interest. Dr. Morris has no conficts of interest.

Background: The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood., Objective: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior., Methods: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants., Results: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers., Conclusions: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

Objectives: To test whether CSF Alzheimer disease biomarkers (β-amyloid 42 [Aβ42], tau, phosphorylated tau at threonine 181 [ptau181], tau/Aβ42, and ptau181/Aβ42) predict future decline in noncognitive outcomes among individuals cognitively normal at baseline., Methods: Longitudinal data from participants (N = 430) who donated CSF within 1 year of a clinical assessment indicating normal cognition and were aged 50 years or older were analyzed. Mixed linear models were used to test whether baseline biomarker values predicted future decline in function (instrumental activities of daily living), weight, behavior, and mood. Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination scores were also examined., Results: Abnormal levels of each biomarker were related to greater impairment with time in behavior (p < 0.035) and mood (p < 0.012) symptoms, and more difficulties with independent activities of daily living (p < 0.012). However, biomarker levels were unrelated to weight change with time (p > 0.115). As expected, abnormal biomarker values also predicted more rapidly changing Mini-Mental State Examination (p < 0.041) and Clinical Dementia Rating Sum of Boxes (p < 0.001) scores compared with normal values., Conclusions: CSF biomarkers among cognitively normal individuals are associated with future decline in some, but not all, noncognitive Alzheimer disease symptoms studied. Additional work is needed to determine the extent to which these findings generalize to other samples.

Background: New research criteria for preclinical Alzheimer's disease have been proposed, which include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), or abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3). We aimed to investigate the prevalence and long-term outcome of preclinical Alzheimer's disease according to these criteria., Methods: Participants were cognitively normal (clinical dementia rating [CDR]=0) community-dwelling volunteers aged at least 65 years who were enrolled between 1998 and 2011 at the Washington University School of Medicine (MO, USA). CSF amyloid-β1-42 and tau concentrations and a memory composite score were used to classify participants as normal (both markers normal), preclinical Alzheimer's disease stage 1-3, or suspected non-Alzheimer pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). The primary outcome was the proportion of participants in each preclinical AD stage. Secondary outcomes included progression to CDR at least 0·5, symptomatic Alzheimer's disease (score of at least 0·5 for memory and at least one other domain and cognitive impairments deemed to be due to Alzheimer's disease), and mortality. We undertook survival analyses using subdistribution and standard Cox hazards models and linear mixed models., Findings: Of 311 participants, 129 (41%) were classed as normal, 47 (15%) as stage 1, 36 (12%) as stage 2, 13 (4%) as stage 3, 72 (23%) as SNAP, and 14 (5%) remained unclassified. The 5-year progression rate to CDR at least 0·5, symptomatic Alzheimer's disease was 2% for participants classed as normal, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with individuals classed as normal, participants with preclinical Alzheimer's disease had an increased risk of death after adjusting for covariates (hazard ratio 6·2, 95% CI 1·1-35·0; p=0·040)., Interpretation: Preclinical Alzheimer's disease is common in cognitively normal elderly people and is associated with future cognitive decline and mortality. Thus, preclinical Alzheimer's disease could be an important target for therapeutic intervention., Funding: National Institute of Aging of the National Institutes of Health (P01-AG003991, P50-AG05681, P01-AG02676), Internationale Stichting Alzheimer Onderzoek, the Center for Translational Molecular Medicine project LeARN, the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, and the Charles and Joanne Knight Alzheimer Research Initiative., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau., Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ₄₂ and CSF phosphorylated tau/Aβ₄₂, after adjustment for common fall risk factors., Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall., Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

Objectives: We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years., Methods: Longitudinal data from Knight Alzheimer's Disease Research Center participants (N = 201) followed for a mean of 3.70 years (SD = 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. "Expanded" models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared., Results: Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p > 0.074), nor did we find differences between the expanded biomarker models (p > 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p < 0.005)., Conclusions: Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms.

The formal role of Certified Peer Specialist (CPS) is a recent addition to the mental health field. CPSs are people in recovery employed within the mental health system, mostly by community mental health centers, to provide support through sharing life experiences with those working toward recovery from mental illness. This brief report examines participant's experiences being a CPS, responsibilities and activities as a CPS, and integration into community mental health centers. Findings suggest that CPSs demonstrate high levels of communal orientation, job satisfaction, workplace integration and organizational support and are well received in mental health centers.

Background: Cross-sectional studies suggest that the cognitive impact of Alzheimer disease pathology varies depending on education and brain size., Objective: To evaluate the combination of cerebrospinal fluid biomarkers of β-amyloid(42) (Aβ(42)), tau, and phosphorylated tau (ptau(181)) with education and normalized whole-brain volume (nWBV) to predict incident cognitive impairment., Design: Longitudinal cohort study., Setting: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri., Participants: A convenience sample of 197 individuals 50 years and older with normal cognition (Clinical Dementia Rating of 0) at baseline observed for a mean of 3.3 years., Main Outcome Measure: Time to Clinical Dementia Rating ≥ 0.5., Results: Three-factor interactions among the baseline biomarker values, education, and nWBV were found for Cox proportional hazards regression models testing tau (P = .02) and ptau (P = .008). In those with lower tau values, nWBV (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.31-0.91; P = .02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (P = .01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment in those with higher ptau values (P = .02)., Conclusion: In individuals with normal cognition and higher levels of cerebrospinal fluid tau and ptau at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.

Objective: To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD., Design: A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT)., Setting: The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri., Participants: One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline., Main Outcome Measure: Progression from CDR 0 to CDR 0.5 status (very mild dementia)., Results: Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0., Conclusion: Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.

Background: Persistent postoperative cognitive decline is thought to be a public health problem, but its severity may have been overestimated because of limitations in statistical methodology. This study assessed whether long-term cognitive decline occurred after surgery or illness by using an innovative approach and including participants with early Alzheimer disease to overcome some limitations., Methods: In this retrospective cohort study, three groups were identified from participants tested annually at the Washington University Alzheimer's Disease Research Center in St. Louis, Missouri: those with noncardiac surgery, illness, or neither. This enabled long-term tracking of cognitive function before and after surgery and illness. The effect of surgery and illness on longitudinal cognitive course was analyzed using a general linear mixed effects model. For participants without initial dementia, time to dementia onset was analyzed using sequential Cox proportional hazards regression., Results: Of the 575 participants, 214 were nondemented and 361 had very mild or mild dementia at enrollment. Cognitive trajectories did not differ among the three groups (surgery, illness, control), although demented participants declined more markedly than nondemented participants. Of the initially nondemented participants, 23% progressed to a clinical dementia rating greater than zero, but this was not more common after surgery or illness., Conclusions: The study did not detect long-term cognitive decline independently attributable to surgery or illness, nor were these events associated with accelerated progression to dementia. The decision to proceed with surgery in elderly people, including those with early Alzheimer disease, may be made without factoring in the specter of persistent cognitive deterioration.

Background: Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease., Objective: To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT)., Design: Retrospective analysis of CSF biomarkers and clinical data., Setting: An academic Alzheimer disease research center., Participants: Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years)., Main Outcome Measures: Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance., Results: The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values., Conclusions: In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

Objective: To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid levels., Design, Setting, and Participants: Uptake of carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) was measured for participants assessed between August 15, 2003, and January 8, 2008, at the Washington University Alzheimer's Disease Research Center and diagnosed either as nondemented (n = 161) or with dementia of the Alzheimer type (n = 37). Multiple regression was used to determine whether [(11)C]PiB uptake interacted with level of educational attainment to predict cognitive function., Main Outcome Measures: Scores on the Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, and Short Blessed Test and individual measures from a psychometric battery., Results: Uptake of [(11)C]PiB interacted with years of education in predicting scores on the Clinical Dementia Rating sum of boxes (P = .003), the Mini-Mental State Examination (P < .001), the Short Blessed Test (P = .03), and a measure of verbal abstract reasoning and conceptualization (P = .02) such that performance on these measures increased with increasing education for participants with elevated PiB uptake. Education was unrelated to global cognitive functioning scores among those with lower PiB uptake., Conclusion: The results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathological burden and cognition.

Purpose: To report two cases of neurofibromatosis type 2 (NF2) initially presenting with isolated bilateral combined hamartomas of the retina and retinal pigment epithelium (RPE)., Methods: Retrospective observational case reports., Results: Two unrelated children presented to ophthalmology with isolated combined hamartomas of the retina and RPE. Patient one presented to ophthalmology at the age of 2 years; by 4 years, he developed what was thought to be a plexiform neurofibroma and, with more than 6 cafe au lait spots, was diagnosed with neurofibromatosis type 1 (NF1). By the age of 5, he had developed bilateral vestibular schwannomas, and was diagnosed with NF2. Subsequent molecular testing revealed a truncating mutation in exon 13 (c.1396C > T; p.R466X) of the NF2 gene. Patient two presented to ophthalmology at the age of 7 months; by age 6 she had developed two subcutaneous masses on her forehead, a mass in her left lower abdomen, and in her gumline. Despite lack of pathological evidence of neurofibroma upon biopsy, molecular testing was initiated at age 6 and revealed a truncating mutation in exon 8 (c.734delA) of the NF2 gene in the blood., Conclusions: Bilateral combined hamartomas of the retina and retinal pigment epithelium (RPE) in a young child should alert the clinician to the possibility of neurofibromatosis type 2. The recognition of this rare finding as a presenting feature of NF2 can lead to earlier diagnosis, which is vital to appropriate surveillance and possible surgical intervention.

Background: Data from neuropathologic studies of the frequency of Alzheimer disease (AD) among African American persons conflict as to whether the neuropathologic phenotype of AD is identical in African American and white persons., Objectives: To examine clinical and neuropathologic phenotypes of AD in African American individuals and to compare AD and vascular burdens between African American and white persons., Design, Setting, and Patients: Ten African American decedents who underwent brain autopsy at the Washington University Alzheimer's Disease Research Center were matched for age, sex, and Clinical Dementia Rating with 10 white decedents between January 1, 1990, and January 1, 2000. The presence and degree of neurofibrillary tangles, senile plaques, Lewy bodies, cerebral infarcts, and cerebral amyloid angiopathy were determined., Results: All 20 individuals had a neuropathologic diagnosis of AD. There were no group differences in the presence or number of infarcts, plaques, tangles, Lewy bodies, or amyloid angiopathy., Conclusion: In this small sample, we found no substantive differences in the neuropathology of AD among African American and white individuals.

Dementia is a common and under-diagnosed problem among the elderly. An accurate screening test would greatly aid the ability of physicians to evaluate dementia and memory problems in clinical practice. We sought to determine whether simple and brief psychometric tests perform similarly to the Mini-Mental State Examination (MMSE) in screening for dementia. Using a retrospective analysis, a series of standard, brief, psychometric tests were compared with each other and to the MMSE as screening tests for very mild dementia, using DSM-III-R criterion as the gold standard. Two independent cohorts from the Baltimore Longitudinal Study of Aging and the Washington University Alzheimer's Disease Research Center were evaluated. We found that two brief and simple-to-administer tests appear to offer similar degrees of sensitivity and specificity to the MMSE. These are the recall of a five-item name and address, "John Brown 42 Market Street Chicago" and the one-minute verbal fluency for animals. Combining these two tests further improves sensitivity and specificity, surpassing the MMSE, to detect dementia in individuals with memory complaints.

Universally accepted neuropathologic criteria for differentiating Alzheimer disease (AD) from healthy brain aging do not exist. We tested the hypothesis that Bielschowsky silver stained total, cored, and neuritic senile plaques (TSPs, CSPs, and NSPs, respectively), rather than neurofibrillary tangles (NFTs), best discriminate between the 2 conditions using rigorously defined nondemented (n = 7) and AD (n = 35) subjects with no known co-morbidities. We compared lesions in 3 neocortical regions, in hippocampal CA1, and in entorhinal cortex in 19 men and 13 women between 74 and 86 years at death. The Clinical Dementia Rating (CDR) was used to assess degree of cognitive impairment within a year of demise. Neocortical TSP measures provided the highest correlation with expiration CDR: area under the curve (AUC) = 0.986 with 97.8% sensitivity at 90% specificity with an estimated cut-point of 6.0 TSP/ mm2. All SP measures yielded higher estimated AUC and sensitivity for 90% specificity compared to NFTs. Derived TSP cut-points applied to 149 persons with clinical AD regardless of their neuropathologic diagnosis yielded a sensitivity of 97% and specificity of 84% for TSPs in the 3 neocortical areas. Thus cut-points based on both diffuse and neuritic SP in neocortical regions distinguished nondemented and AD subjects with high sensitivity and specificity.

Background: Depression can interfere with the normal expression of cognitive abilities in adults of all ages, but it is unclear if depression in demented people, which is common, is associated with reduced cognitive performance beyond the effect of the dementia itself., Objective: To determine if depression adds to the cognitive deficit in dementia., Design: Performance on psychometric tests of memory and other cognitive function was correlated with the number of depressive features reported by the individual and by a knowledgeable collateral source, as well as the judgment of a research clinician as to whether the person was depressed., Setting: An Alzheimer disease research center., Participants: The convenience sample included individuals with very mild (Clinical Dementia Rating, 0.5; n = 167 [mean age, 76.03 years]) or mild (Clinical Dementia Rating, 1; n = 155 [mean age, 78.41 years]) Alzheimer disease who were enrolled in ongoing longitudinal studies at the center., Main Outcome Measures: Psychometric measures of memory and cognition., Results: Depression was present in 15% of the very mild and 24% of the mild dementia groups. There was no relation between the clinicians' diagnoses of depression and psychometric scores. Little relation was found between performance on the cognitive tests and the number of depressive features (maximum, 9) reported by the individual or collateral source. The few statistically significant (P<.05) correlations were modest (< or =0.21)., Conclusion: Depression does not worsen cognitive test performance beyond the effect of dementia.

Our objective was to analyze the lipopolysaccharide (LPS) antitumoral effect upon glioblastoma, including whether the lipid A subunit alone can elicit glioblastoma regression, whether dexamethasone suppresses this response to LPS, whether B and T lymphocytes factor in this response, and whether this antitumoral effect of LPS provides resistance against subsequent challenge with glioblastoma. Mice (BALB/c, nude or SCID) implanted with s.c. DBT glioblastomas were treated with LPS (with or without dexamethasone) or with lipid A. A subset of BALB/c mice in which s.c. DBT glioblastomas had previously been eradicated using LPS were re-implanted with s.c. or intracranial (i.c.) DBT cells. For mice with s.c. tumors, mean tumor masses (MTM) were compared between groups. Survival was compared for mice with i.c. tumors. Lipid A caused near complete tumor regression of DBT glioblastomas in BALB/c mice (p<0.0001). Dexamethasone did not alter the antitumoral effect of LPS (p=0.48). LPS reduced the MTM of s.c. glioblastomas in T lymphocyte-deficient nude mice, but not as effectively as in immunocompetent mice. The antitumoral response to LPS for T and B lymphocyte-deficient SCID mice bearing DBT glioblastomas was similar to that for nude mice. Eradication of s.c. DBT glioblastoma in BALB/c provided partial resistance to subsequent challenge with s.c. or i.c. glioblastoma. We conclude that the LPS-mediated antitumoral response against glioblastoma is dependent upon the lipid A subunit of LPS, partially dependent upon T lymphocytes, independent of B lymphocytes, unaffected by dexamethasone and provides partial protection against subsequent challenges with glioblastoma.

Objectives: To examine the reporting accuracy of collateral sources (knowledgeable informants) regarding very mild and mild dementia of the Alzheimer type (DAT) and to identify characteristics associated with collateral source accuracy., Design: Secondary data analysis of initial visits of individuals enrolled in a longitudinal study of healthy aging and Alzheimer disease., Setting: Urban Alzheimer disease research center., Participants: Pairs of 515 individuals with very mild (n = 203) or mild (n = 312) DAT and their collateral sources., Measurements: Collateral sources were asked separately during a semistructured interview by experienced clinicians to report current ability of the individual with DAT in memory, orientation, and judgment and problem solving. The clinical performance of the individuals with DAT in these domains was compared with these predictions., Results: Collateral sources were consistently and significantly accurate in reporting the cognitive capabilities of individuals with very mild and mild DAT. Although all types of collateral sources performed significantly better than chance, individual variables that correlated with collateral source accuracy included spousal relationship; living with the individual with DAT; frequent exposure to the individual; and age, education level, sex and dementia severity of the individual with DAT., Conclusion: Collateral sources are accurate in reporting the cognitive capabilities of individuals with DAT, even in the very mild stage of dementia.

Objective: To compare rates of progression in the very mildest stages of AD, including the stage currently identified as mild cognitive impairment (MCI), and to identify predictors of those rates., Methods: Demented (n = 289) and nondemented (n = 230) individuals enrolled in longitudinal studies at an Alzheimer Disease Research Center received annual clinical and psychometric examinations for up to 20 years. In order of increasing dementia severity, demented individuals were diagnosed with incipient, very mild, or mild dementia; the incipient stage is equivalent to MCI. Outcome measures included death, nursing home placement, and psychometric scores., Results: Rate of progression increased with dementia severity as staged by the Clinical Dementia Rating at entry into the study. With respect to the dichotomous outcomes, the increase with dementia severity was more dramatic for the endpoint of nursing home entry than it was for the endpoint of death. Increased rates of cognitive decline with increased dementia severity were also obtained for psychometric scores. There was limited evidence of other predictors of progression., Conclusions: The lack of effective predictors of the rate of dementia progression extends to the very earliest stages of the disease, including what is often called MCI. A new approach to the identification of correlates of rates of progression is needed.

Objective: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death., Methods: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance., Results: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5)., Conclusions: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT.

Recently, a dinucleotide repeat polymorphism was identified in the promoter of the nonamyloid component of plaques (NACP) gene, and it was shown that the NACP allele 2 was significantly associated with healthy elderly control individuals with at least one apolipoprotein E epsilon4 allele, suggesting a protective role for this allele in Alzheimer's disease. We genotyped the same NACP polymorphism in a comparable number of individuals diagnosed with dementia of the Alzheimer's type and in healthy, elderly controls. In our analysis, however, no protective effect for NACP allele 2, or any of the other NACP alleles, was observed.

Objective: To examine the earliest cognitive changes associated with the onset of dementia as well as changes associated with normal aging., Design: Longitudinal evaluation of participants with annual clinical and psychometric examinations for up to 15 1/2 years., Setting and Participants: Elderly volunteers (n = 82) enrolled with a Clinical Dementia Rating of 0 (cognitively intact) in longitudinal studies., Interventions: None., Main Outcome Measures: Clinical Dementia Rating and results of a 1 1/2-hour psychometric battery., Results: As estimated with survival analysis, 40% of participants had a Clinical Dementia Rating greater than 0 (cognitive decline) within 12 years of enrollment; 59% of these were judged to have dementia of the Alzheimer type or incipient dementia. Participants with poorer performance on psychometric testing at enrollment were at higher risk for cognitive decline subsequently. The rate of change in psychometric performance before clinically detectable cognitive change occurred was not significantly different between those who eventually developed dementia and those who remained stable, except for performance on the Logical Memory subtest of the Wechsler Memory Scale. When subtle cognitive decline was clinically detected, however, an abrupt deterioration in performance on independently administered psychometric tests was observed., Conclusions: Cognitively healthy elderly people maintain stable cognitive performance when measured longitudinally by both careful clinical evaluation and repeated psychometric testing. This stability is maintained unless and until they develop a dementing illness, at which time a sharp decline in performance is observed.

The presence of senile plaques in the neocortex of apparently nondemented elderly persons often is accepted as part of "normal" aging. Alternatively, because cerebral deposition of beta-amyloid may be a key mechanism in the development of Alzheimer's disease (AD), the presence of beta-amyloid-containing plaques may represent very early AD. To examine the relationships of cognitively normal aging, very mild dementia of the Alzheimer type, and the presence of neocortical senile plaques, we performed clinicopathologic correlation in 21 longitudinally studied healthy elderly subjects (84.5 +/- 6.6 years old at death). Nine subjects had strikingly high plaque densities in the neocortex; two of these subjects died of head injury before which there was no evidence of cognitive impairment. The other seven subjects with high plaque densities had clinical evidence for very mild cognitive impairment (Clinical Dementia Rating score of 0.5) at some time during their course and mildly impaired psychometric performance at last assessment before death. The remaining 12 subjects had no clinical or psychometric impairment and had few or no neocortical AD lesions. These results suggest that senile plaques may not be part of normal aging but instead represent presymptomatic or unrecognized early symptomatic AD. The high density of senile plaques (predominately of the diffuse subtype) in the cortex of subjects just at the threshold of detectable dementia is consistent with the hypothesis that beta-amyloid deposition is an initial pathogenetic event in the development of AD.

Purpose: This study was undertaken to identify the optimum level of stapled ileal pouch-anal anastomosis., Method: A prospective, randomized trial was completed to compare double-stapled ileoanal anastomosis placed at the top of anal columns (high, n = 26) with anastomosis at the dentate line (low, n = 21)., Results: There was no significant difference in the overall complication rate between operations (high, n = 7, vs. low, n = 8; P < 0.21). Pouch-anal functional score (scale 0-12; 0 = excellent, 12 = poor) was significantly better in the high anastomosis group (median (range): 2 (1-9) vs. 5.5 (1-12); P < 0.05). Incontinence occurred in only two patients randomized to high anastomosis compared with six in the low anastomosis group. Nocturnal soiling was reported in three patients after high anastomosis and in six patients after dentate line anastomosis. Both operations caused a significant but comparable reduction of maximum and resting pressure (31 percent after high anastomosis (P < 0.05); 23 percent after low anastomosis (P < 0.05)). However, a significant fall in functional length of the anal canal was only seen after a low pouch-anal anastomosis (P < 0.05)., Conclusion: Stapled pouch-anal anastomosis at the top of anal columns gives better functional results compared with a stapled anastomosis at the dentate line.

Purpose: This study was designed to examine the role of adjuvant internal anal sphincter plication in women with neuropathic fecal incontinence undergoing pelvic floor repair., Methods: We completed a randomized trial with symptomatic and physiologic assessment before and after surgery., Results: There was no symptomatic advantage of adding internal sphincter plication; the mean improvement of functional score was 3.61 +/- 1.82 (standard deviation; P < 0.01) following pelvic floor repair alone compared with 2.80 +/- 1.66 (standard deviation; P < 0.01) when adjuvant internal and sphincter plication was added. The addition of internal sphincter plication was associated with a significant fall in maximum anal resting and squeezing pressures (P < 0.01)., Conclusions: Addition of internal sphincter plication is not advised in women with neuropathic fecal incontinence treated by pelvic floor repair.

Purpose: Conventional assessment of anorectal function with defecating videoproctography is semiquantitative and the high radiation exposure precludes prolonged or repeated testing. The aim of this study was to develop a dynamic scintigraphic method of assessing anorectal function., Methods: Fourteen patients with fecal incontinence, 18 patients with chronic constipation, and 8 control subjects were assessed by scintigraphic defecography. This involves introduction of a technetium-99m-radiolabeled artificial stool into the rectum of the subject and acquisition of gamma camera images during evacuation., Results: Mean evacuation rate was 2.8 percent/second in incontinent patients and 0.9 percent/second in constipated patients (P < 0.001). The mean anorectal angles were 136 degrees and 133 degrees, respectively. There were 18 cases of pelvic floor descent and 6 rectoceles. Scintigraphic defecography provides quantitative information on rectal evacuation. Anorectal angle and pelvic floor movement can be examined. The radiation dose to pelvic organs is significantly less than with videoproctography., Conclusion: We believe that scintigraphic defecography is the investigation of choice for objective and dynamic assessment of anorectal function.

Magnetic resonance imaging detects blood-brain barrier disruption after gadolinium-DTPA enhancement of central nervous system lesions of multiple sclerosis. Experimental allergic encephalomyelitis has many clinical and pathological features in common with multiple sclerosis including alterations in the integrity of the blood-brain barrier. We have compared T2-weighted cranial MR images with Gd-DTPA dimeglumine-enhanced T1-weighted images of myelin basic protein-induced acute (Days 8-42 postimmunization) and central nervous system-induced chronic-progressive (Days 70-95 postimmunization) forms of experimental allergic encephalomyelitis in the guinea pig. Although animals from both groups had abnormal T2-weighted images, only the myelin basic protein-acute-EAE animals (Days 14-24 postimmunization) showed enhancement on postcontrast MR studies. The different responses of the acute and chronic diseases may result from different immunogens, severity of disease, or different permeability of the blood-brain barrier. Therefore, gadolinium-DTPA-enhanced, T1-weighted MR images distinguish acutely active and chronic inflammatory lesions in experimental allergic encephalomyelitis.

Objective: The influence of age on performance on clinical and psychometric assessments is examined in groups of nondemented persons and individuals with either very mild or mild dementia of the Alzheimer type (DAT)., Design: Initial clinical and psychometric assessments of persons enrolled in longitudinal studies of DAT and nondemented control subjects., Setting: Alzheimer's Disease Research Center at Washington University, St Louis, Mo., Participants: Volunteer samples of 108 people (44 men, 64 women) with mild DAT, 61 people (30 men, 31 women) with very mild DAT, and 122 healthy nondemented people (45 men, 77 women) were recruited between 1979 and 1991. Age ranged from 54 to 87 years. Persons with confounding medical, neurologic, or psychiatric disorders were excluded. Dementia severity was staged using the Clinical Dementia Rating scale., Main Outcome Measures: Five brief quantitative clinical tests included in the 90-minute clinician administered protocol, as well as 14 tests included in a 2-hour psychometric test battery., Results: Dementia severity affected performance on all measurements. Age did not influence performance on clinical assessments. There was a significant interaction between age and dementia severity on 10 of 14 psychometric measures. In general, older nondemented individuals performed less well than younger nondemented individuals while older mildly demented persons performed about the same as, or slightly better than, their younger counterparts., Conclusions: Age does not affect performance on brief clinical assessment instruments. However, age affects psychometric performance differently in cognitively intact persons when compared with persons with DAT. As a result, psychometric differentiation between cognitively normal and demented individuals is more difficult in older populations.

Objective: The performance on standard clinical and psychometric assessments of eight elderly individuals with major unipolar depression alone and seven with depression plus mild senile dementia of the Alzheimer type was compared with that of 41 nondepressed subjects suffering from very mild senile dementia of the Alzheimer type, 66 with mild senile dementia of the Alzheimer type, and 83 age-matched subjects without senile dementia., Method: Subjects with depression alone, depression plus mild senile dementia of the Alzheimer type, and very mild and mild senile dementia of the Alzheimer type met strict inclusionary and exclusionary criteria. A 90-minute semistructured interview, including several brief standardized clinical scales, was used to assign a Clinical Dementia Rating to each subject according to published guidelines, and each subject was given a 2-hour psychometric test battery. Data were analyzed by one-way multivariate analysis of variance to ascertain if there was an effect of group on clinical and psychometric test scores., Results: The eight depressed subjects without concurrent dementia performed as well as the 83 nondepressed subjects without dementia on most clinical measures; however, their performance on most psychometric measures closely resembled that of the 41 nondepressed subjects with very mild dementia. The performance of the seven subjects with depression plus mild dementia was comparable to that of the 66 nondepressed subjects with mild dementia on most clinical and psychometric measures., Conclusions: Although depressed subjects performed as well as subjects without dementia on many clinical assessments, psychometric testing was not able to distinguish depressed subjects from those with very mild senile dementia of the Alzheimer type. This demonstrates the need for careful psychiatric evaluation before interpreting deficits on psychometric tests as indicating the presence of very mild senile dementia of the Alzheimer type.