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A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer’s disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n= 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T−and A−T−groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+(hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9–33.7), A+TMTL+(HR = 14.6, 95% CI = 8.1–26.4) and A+T−(HR = 2.4, 95% CI = 1.4–4.3) groups versus the A−T−(reference) group. Both A+TMTL+(HR = 6.0, 95% CI = 3.4–10.6) and A+TNEO-T+(HR = 7.9, 95% CI = 4.7–13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T−group. Linear mixed-effect models indicated that the A+TNEO-T+(β= −0.056 ± 0.005, T= −11.55, P< 0.001), A+TMTL+(β= −0.024 ± 0.005, T= −4.72, P< 0.001) and A+T−(β= −0.008 ± 0.002, T= −3.46, P< 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A−T−(reference) group (all P< 0.001). Both A+TNEO-T+(P< 0.001) and A+TMTL+(P= 0.002) groups also progressed faster than the A+T−group. In summary, evidence of advanced Alzheimer’s disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3–5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

IMPORTANCE: A National Institute on Aging–Alzheimer’s Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker evidence of β-amyloid plaques and tau tangles and not by clinical symptoms. OBJECTIVES: To estimate the sex- and age-specific prevalence of 3 imaging biomarker–based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and to compare these entities with clinically defined diagnostic entities commonly linked with Alzheimer disease. DESIGN, SETTING, AND PARTICIPANTS: The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging in Olmsted County, Minnesota. The MCSA in-person participants (n = 4660) and passively ascertained (ie, through the medical record rather than in-person) individuals with dementia (n = 553) aged 60 to 89 years were included. Subsets underwent amyloid positron emission tomography (PET) (n = 1524) or both amyloid and tau PET (n = 576). Therefore, this study included 3 nested cohorts examined between November 29, 2004, and June 5, 2018. Data were analyzed between February 19, 2018, and March 26, 2019. MAIN OUTCOMES AND MEASURES: The sex- and age-specific prevalence of the following 3 biologically defined diagnostic entities was estimated: Alzheimer continuum (abnormal amyloid regardless of tau status), Alzheimer pathologic change (abnormal amyloid but normal tau), and Alzheimer disease (abnormal amyloid and tau). These were compared with the prevalence of 3 clinically defined diagnostic groups (mild cognitive impairment or dementia, dementia, and clinically defined probable Alzheimer disease). RESULTS: The median (interquartile range) age was 77 (72-83) years in the clinical cohort (n = 5213 participants), 77 (70-83) years in the amyloid PET cohort (n = 1524 participants), and 77 (69-83) years in the tau PET cohort (n = 576 participants). There were roughly equal numbers of women and men. The prevalence of all diagnostic entities (biological and clinical) increased rapidly with age, with the exception of Alzheimer pathologic change. The prevalence of biological Alzheimer disease was greater than clinically defined probable Alzheimer disease for women and men. Among women, these values were 10% (95% CI, 6%-14%) vs 1% (95% CI, 1%-1%) at age 70 years and 33% (95% CI, 25%-41%) vs 10% (95% CI, 9%-12%) at age 85 years (P &lt; .001). Among men, these values were 9% (95% CI, 5%-12%) vs 1% (95% CI, 0%-1%) at age 70 years and 31% (95% CI, 24%-38%) vs 9% (95% CI, 8%-11%) at age 85 years (P &lt; .001). The only notable difference by sex was a greater prevalence of the mild cognitive impairment or dementia clinical category among men than women. CONCLUSIONS AND RELEVANCE: Results of this study suggest that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men. This difference is mostly driven by asymptomatic individuals with biological Alzheimer disease. These findings illustrate the magnitude of the consequences on public health that potentially exist by intervening with disease-specific treatments to prevent symptom onset.

Functionally related brain regions are selectively vulnerable to Alzheimer's disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer's disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivomolecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer's disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer's disease dementia, we found several distinct spatial patterns of tau deposition, including ‘Braak-like’ and ‘non-Braak-like’, across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with ‘non-Braak-like’ patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer's disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer's disease.

Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (p<0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithium-treated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk.

IMPORTANCE: The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain. OBJECTIVE: To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers. DESIGN, SETTING, AND PARTICIPANTS: A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated. MAIN OUTCOMES AND MEASURES: Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures. RESULTS: At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB− noncarriers). These associations were largely independent of APOE4. CONCLUSIONS AND RELEVANCE: In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.

The strategy that hotels employ to design the properties is a reflection of the socio-demographic changes in the society. Based on a review of the history of urban hotel design, the article argues that the social changes brought about by the advancement of technology as well as the popularity of social media, the newly emerged business and services in the sharing economy, as well as the scarcity of land resources in urban area contribute to the emergence of the component hotel. The component hotel is defined as an urban hotel property that has satellite guest services (referred to as components) such as accommodation, food and beverage, and wellness located outside of a central core facility which is located within an urban centre. The design details were also discussed in the paper.

IMPORTANCE: To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI). OBJECTIVE: To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer’s Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A−) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N−), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease–like pattern on 18fluorodeoxyglucose (FDG)–positron emission tomography. MAIN OUTCOMES AND MEASURES: Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions. RESULTS: In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N− group (n = 17) (all 4 ROIs; P &lt; .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P &lt; .01) compared with the A−N− group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P &lt; .001) compared with either the A+N− group or A−N− group. The A+N+ group showed large longitudinal declines in FDG SUVR (P &lt; .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P &lt; .05 for medial temporal and lateral temporal regions) compared with the A−N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A−N− group on FDG SUVR (P &lt; .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P &lt; .05) compared with the A+N− group. The A−N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N− or A−N− groups. CONCLUSIONS AND RELEVANCE: Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A−N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.

IMPORTANCE: Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging. OBJECTIVE: To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old. MAIN OUTCOMES AND MEASURES: Memory, HVa, and amyloid PET. RESULTS: Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P &lt; .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P &lt; .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 status at any age. From age 70 years onward, APOE ε4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers. CONCLUSIONS AND RELEVANCE: Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.

To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of -amyloid (A) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample.

Constrictive pericarditis is a potentially reversible cause of heart failure that may be difficult to differentiate from restrictive myocardial disease and severe tricuspid regurgitation. Echocardiography provides an important opportunity to evaluate for constrictive pericarditis, and definite diagnostic criteria are needed.

We determined whether head trauma was associated with amyloid deposition and neurodegeneration among individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI).

To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.

We assessed whether hypertension in pregnancy is associated with elevated C-reactive protein (CRP) levels in later life, possibly reflecting an increased risk of cardiovascular disease (CVD).

IMPORTANCE The appearance of β-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer disease (AD), but their interaction is poorly understood. OBJECTIVE To test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration. DESIGN Longitudinal cohort study. SETTING Population-based Mayo Clinic Study of Aging. PARTICIPANTS One hundred ninety-one CN persons (median age, 77 years; range, 71-93 years) in the Mayo Clinic Study of Aging who underwent magnetic resonance, fludeoxyglucose F 18 (FDG) positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET imaging at least twice 15 months apart. Participants were grouped according to the recommendations of the National Institute on Aging–Alzheimer Association preclinical AD criteria based on the presence of β-amyloidosis, defined as a PiB PET standardized uptake value ratio (SUVr) greater than 1.5, alone (stage 1) or with brain injury (stage 2 + 3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of patients with mild cognitive impairment (n = 17) or dementia (n = 9) from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had undergone comparable imaging and had a PiB PET SUVr greater than 1.5. MAIN OUTCOMES AND MEASURES Rate of change of cortical volume on volumetric magnetic resonance images and rate of change of glucose metabolism on FDG PET scan results. RESULTS There were 25 CN participants with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (preclinical AD stages 2 + 3). On follow-up scans, the preclinical AD stage 2 + 3 participants had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared with the other CN groups. The changes were similar to those in the cognitively impaired participants. Extratemporal regions did not show similar changes. CONCLUSIONS AND RELEVANCE Higher rates of medial temporal neurodegeneration occur in CN individuals who, on their initial scans, had abnormal levels of both β-amyloid and brain injury biomarkers. Although preclinical AD is currently only a research topic, the description of its brain structural changes will be critical for trials designed to prevent or forestall dementia due to AD.

To model the temporal trajectory of -amyloid accumulation using serial amyloid PET imaging.

Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.

OBJECTIVE To characterize the shape of the trajectories of Alzheimer disease biomarkers as a function of Mini-Mental State Examination (MMSE) score. DESIGN AND SETTING Longitudinal registries from the Mayo Clinic and the Alzheimer's Disease Neuroimaging Initiative. PATIENTS Two different samples (n = 343 and n = 598) were created that spanned the cognitive spectrum from normal to Alzheimer disease dementia. Subgroup analyses were performed in members of both cohorts (n = 243 and n = 328) who were amyloid positive at baseline. MAIN OUTCOME MEASURES The shape of biomarker trajectories as a function of MMSE score, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebrospinal fluid (CSF) Aβ42 and tau levels, amyloid and fluorodeoxyglucose positron emission tomography imaging, and structural magnetic resonance imaging. RESULTS Baseline biomarker values generally worsened (ie, nonzero slope) with lower baseline MMSE score. Baseline hippocampal volume, amyloid positron emission tomography, and fluorodeoxyglucose positron emission tomography values plateaued (ie, nonlinear slope) with lower MMSE score in 1 or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE score. Nonconstant within-subject rates (deceleration) of biomarker change were found in only 1 model. CONCLUSIONS Biomarker trajectory shapes by MMSE score were complex and were affected by interactions with age and APOE status. Nonlinearity was found in several baseline effects models. Nonconstant within-subject rates of biomarker change were found in only 1 model, likely owing to limited within-subject longitudinal follow-up. Creating reliable models that describe the full trajectories of Alzheimer disease biomarkers will require significant additional longitudinal data in individual participants.

Recommendations for the diagnosis of preclinical Alzheimer disease (AD) have been formulated by a workgroup of the National Institute on Aging and Alzheimer's Association. Three stages of preclinical AD were described. Stage 1 is characterized by abnormal levels of -amyloid. Stage 2 represents abnormal levels of -amyloid and evidence of brain neurodegeneration. Stage 3 includes the features of stage 2 plus subtle cognitive changes. Stage 0, not explicitly defined in the criteria, represents subjects with normal biomarkers and normal cognition. The ability of the recommended criteria to predict progression to cognitive impairment is the crux of their validity.

OBJECTIVE To determine whether magnetic resonance imaging measurements observed in the Alzheimer Disease Neuroimaging Initiative (ADNI) convenience sample differ from those observed in the Mayo Clinic Study of Aging (MCSA) population-based sample. DESIGN Comparison of 2 samples. SETTING Fifty-nine recruiting sites for the ADNI in the United States and Canada and the MCSA, a population-based cohort in Olmsted County, Minnesota. PATIENTS Cognitively normal subjects and amnestic subjects with mild cognitive impairment were selected from the ADNI convenience cohort and MCSA population-based cohort. A simple random sample of subjects from both cohorts in the same age range was selected, and a second sample applied matching for age, sex, educational level, apolipoprotein E genotype, and Mini-Mental State Examination score. MAIN OUTCOME MEASURES Baseline hippocampal volumes and annual percentage of decline in hippocampal volume. RESULTS In the population-based sample, MCSA subjects were older, had less education, performed worse on the Mini-Mental State Examination, and had a family history of Alzheimer disease less often than did ADNI subjects. Baseline hippocampal volumes were larger in ADNI compared with MCSA cognitively normal subjects in the random sample, although no differences were observed after matching. Rates of decline in hippocampal volume were greater in the ADNI compared with the MCSA for cognitively normal subjects and those with amnestic mild cognitive impairment, even after matching. CONCLUSIONS Rates of decline in hippocampal volume suggest that ADNI subjects have a more aggressive brain pathologic process than MCSA subjects and hence may not be representative of the general population. These findings have implications for treatment trials that use ADNI-like recruitment mechanisms and for studies validating new diagnostic criteria for Alzheimer disease in its various stages.

The Surgical Treatment for Ischemic Heart Failure (STICH) randomized trial was designed to identify an optimal management strategy for patients with ischemic cardiomyopathy. Baseline echocardiographic examinations were required for all patients. The primary aim of this report is to describe the baseline STICH Echocardiography Core Laboratory data. The secondary aim is to provide recommendations regarding how echocardiography should be used in clinical practice and research on the basis of the experience gained from echocardiography in STICH.

OBJECTIVE To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner. DESIGN Validation sample. SETTING Multisite, referral centers. PARTICIPANTS A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples. MAIN OUTCOME MEASURES Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume). RESULTS Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months. CONCLUSIONS A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

The aim of this study was to investigate the incidence and predictors of neuropsychiatric (NP) symptoms during 24 hours after dobutamine-atropine stress testing (DST).

To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOEgenotype, and sample sizes for clinical trials.

The association between hypertension in pregnancy and future cardiovascular disease (CVD) increasingly is recognized. We aimed to assess the role of hypertension in pregnancy as an independent risk factor for hypertension, coronary heart disease (CHD), and stroke later in life.

OBJECTIVE To assess the effect of R0 resection margin status and R0 en bloc resection in pancreatoduodenectomy outcomes. DESIGN Retrospective medical record review. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS Patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma at our institution between January 1, 1981, and December 31, 2007, were identified and their medical records were reviewed. MAIN OUTCOME MEASURE Median survival times. RESULTS A total of 617 patients underwent pancreatoduodenectomy. Median survival times after R0 en bloc resection (n = 411), R0 non–en bloc resection (n = 57), R1 resection (n = 127), and R2 resection (n = 22) were 19, 18, 15, and 10 months, respectively (P &lt; .001). A positive resection margin was associated with death (P = .01). No difference in survival time was found between patients undergoing R0 en bloc and R0 resections after reexcision of an initial positive margin (hazard ratio, 1.19; 95% confidence interval, 0.87-1.64; P = .28). CONCLUSIONS R0 resection remains an important prognostic factor. Achieving R0 status by initial en bloc resection or reexcision results in similar long-term survival.Arch Surg. 2010;145(2):167-172--

To investigate the relationship between baseline MRI and CSF biomarkers and subsequent change in continuous measures of cognitive and functional abilities in cognitively normal (CN) subjects and patients with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD) and to examine the ability of these biomarkers to predict time to conversion from aMCI to AD.

To determine whether treatments guidelines for lower extremity venous thrombosis (DVT) could be applied to patients with cerebral venous sinus thrombosis (CVST), the rates of recurrent venous thrombosis and survival for these two diseases were compared.

State Highway 130 is the largest highway project the Texas Department of Transportation has ever undertaken. By combining its first design/build contract with innovative financing techniques, the department compressed the project’s time frame from 25 years into less than 5.

The role of cholecystokinin (CCK) inpostprandial control of colonic motility iscontroversial. To test the hypothesis that CCKstimulates colonic tone, motility, and transit wemeasured these colonic functions in 16 healthy subjects using intraluminalmanometry, barostatic balloon measurements, andradioscintigraphy. This was a randomized-order,double-blind, sequential study design in each subject ofsaline and either atropine (0.01 mg/kg stat and 0.01mg/kg/hr by infusion) or CCK-octapeptide (OP, 30 ng/kgstat and 60 ng/kg/hr by infusion). Atropine was used ascontrol to demonstrate responsiveness of selected parameters of colonic motility. Atropinesignificantly reduced whole colon (change from fasting= 52 ± 11%) and left colon (change from fasting61 ± 8%) phasic pressure activity and transversecolon tone (change from fasting 159 ± 40%); CCK-OP had nosignificant effects on phasic contractility, tone ortransit. Thus, a CCK-OP infusion that maximallystimulates pancreatic exocrine secretion and gallbladdercontraction has no effect on motor function or transit inprepared colon of healthy subjects.

This paper describes the design and performance of a new prosthetic hand capable of multiple grasp configurations, and capable of fingertip forces and speeds comparable to those used by healthy subjects in typical activities of daily living. The hand incorporates four motor units within the palm, which together drive sixteen joints through tendon actuation. Each motor unit consists of a brushless motor that drives one or more tendons through a custom two-way clutch and pulley assembly. After presenting the design of the prosthesis, the paper presents a characterization of the hand’s performance. This includes its ability to provide eight grasp postures, as well as its ability to provide fingertip forces and finger speeds comparable to those described in the biomechanics literature corresponding to activities of daily living.