Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease.

INTRODUCTION: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. METHODS: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. RESULTS: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. DISCUSSION: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure.

Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease.

Identifying which neuropsychological measures detect early cognitive changes associated with Alzheimer disease (AD), brain pathology would be helpful clinically for the diagnosis of early AD and for the design of clinical trials. We evaluated which neuropsychological measures in our cognitive battery are most strongly associated with cerebrospinal fluid (CSF) biomarkers of AD brain pathology. We studied a large cohort (n = 233) of middle-to older-aged community-dwelling individuals (mean age 61 years) who had no clinical symptoms of dementia and underwent baseline CSF collection at baseline. Participants completed a battery of 9 neuropsychological measures at baseline and then every 1 to 3 years. CSF tau/Aß42 was associated with baseline performance on 5/9 neuropsychological measures, especially measures of episodic memory, and longitudinal performance on 7/9 neuropsychological measures, especially measures of global cognition. The free recall portion of the Free and Cued Selective Reminding Task (FCSRT-free) detected declining cognition in the high CSF tau/Aß42 group the earliest, followed by another measure of episodic memory and a sequencing task.

Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

BACKGROUND: Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. METHODS: We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. FINDINGS: The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55·1%, 95% CI 45·7-64·6), aphasia (57·9%, 48·6-67·3), and behavioural changes (61·7%, 51·5-70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9-7·2], aphasia [23·0%, 20·0-26·0], and behavioural changes [31·7%, 28·4-35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8-15·0), and seizures (2·8%, 0·5-5·9) and moderate for parkinsonism (11·2%, 5·3-17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6-22·2 and 15·0%, 12·5-17·6, respectively), parkinsonism (12·5%, 10·1-15·0), and seizures (20·3%, 17·4-23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04-1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90-0·97, p=0·0007; seizures 0·95, 0·92-0·98, p=0·0018; corticobulbar deficits 0·91, 0·86-0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74-0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. INTERPRETATION: The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. FUNDING: National Institutes of Health and German Center for Neurodegenerative Diseases.

Imaging and cerebrospinal fluid biomarkers in early preclinical alzheimer disease.

OBJECTIVE: Deposition of amyloid ß (Aß)-containing plaques as evidenced by amyloid imaging and cerebrospinal fluid (CSF) Aß1-42 (Aß42) is an early indicator of preclinical Alzheimer disease (AD). To better understand their relationship during the earliest preclinical stages, we investigated baseline CSF markers in cognitively normal individuals at different stages of amyloid deposition defined by longitudinal amyloid imaging with Pittsburgh compound B (PIB): (1) PIB-negative at baseline and follow-up (PIB(-) ; normal), (2) PIB-negative at baseline but PIB-positive at follow-up (PIB converters; early preclinical AD), and (3) PIB-positive at baseline and follow-up (PIB(+) ; preclinical AD). METHODS: Cognitively normal individuals (n = 164) who had undergone baseline PIB scan and CSF collection within 1 year of each other and at least 1 additional PIB follow-up were included. Amyloid status was defined dichotomously using an a priori mean cortical cutoff. RESULTS: PIB converters (n = 20) at baseline exhibited significantly lower CSF Aß42 compared to those who remained PIB-negative (n = 123), but higher compared to the PIB(+) group (n = 21). A robust negative correlation (r = -0.879, p = 0.0001) between CSF Aß42 and absolute (but subthreshold) PIB binding was observed during this early preclinical stage. The negative correlation was not as strong once individuals were PIB-positive (r = -0.456, p = 0.038), and there was no correlation in the stable PIB(-) group (p = 0.905) or in the group (n = 10) with early symptomatic AD (p = 0.537). INTERPRETATION: CSF Aß42 levels are tightly coupled with cortical amyloid load in the earliest stages of preclinical AD, and begin to decrease dramatically prior to the point when an abnormal threshold of cortical accumulation is detected with amyloid imaging. Ann Neurol 2016;80:379-387.

Certified normal: Alzheimer's disease biomarkers and normative estimates of cognitive functioning.

Normative samples drawn from older populations may unintentionally include individuals with preclinical Alzheimer's disease (AD) pathology, resulting in reduced means, increased variability, and overestimation of age effects on cognitive performance. A total of 264 cognitively normal (Clinical Dementia Rating = 0) older adults were classified as biomarker negative ("Robust Normal," n = 177) or biomarker positive ("Preclinical Alzheimer's Disease" [PCAD], n = 87) based on amyloid imaging, cerebrospinal fluid biomarkers, and hippocampal volumes. PCAD participants performed worse than robust normals on nearly all cognitive measures. Removing PCAD participants from the normative sample yielded higher means and less variability on episodic memory, visuospatial ability, and executive functioning measures. These results were more pronounced in participants aged 75 years and older. Notably, removing PCAD participants from the sample significantly reduced age effects across all cognitive domains. Applying norms from the robust normal sample to a separate cohort did not improve Clinical Dementia Rating classification when using standard deviation cutoff scores. Overall, removing individuals with biomarker evidence of preclinical AD improves normative sample quality and substantially reduces age effects on cognitive performance but provides no substantive benefit for diagnostic classifications.

Relation of Persistent Depressive Symptoms to Coronary Artery Calcification in Women Aged 46 to 59 Years.

Depressive disorders have been associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis has not been well described, particularly in women and minorities. The relation between repeated episodes of high depressive symptoms and coronary calcium (CAC) is unknown in women at midlife when depression is common. Participants in the Study of Women's Health Across the Nation Heart study were assessed annually for depressive symptoms (Center for Epidemiological Studies Depression Scale [CES-D scale]) over 5 years before CAC assessment and classified as high (CES-D ≥16) or not. CAC, measured by computed tomography, was analyzed as a categorical variable using cumulative logit partial proportional odds models. In these middle-aged women free of CVD and diabetes (194 black, 334 white), high depressive symptoms over 5 years were common; 19% had 1, 9% had 2, and 11% experienced ≥3 episodes. CAC was low; 54% had no CAC, 25% had scores from 0 to 10, and 21% had CAC ≥10 Agatston score. After adjusting for CVD risk factors, women with ≥3 episodes were twice as likely to have significant CAC (≥10 Agatston units) than women with no depressive episodes (odds ratio 2.20, 95% confidence interval 1.13 to 4.28, p = 0.020) with no difference by race. Women with 1 or 2 episodes did not differ from women with no episodes. In conclusion, in healthy women aged 46 to 59 years without clinical CVD or diabetes, persistent depressive symptoms were significantly associated with elevated CAC scores, suggesting that they are more likely to have pathophysiological and behavioral effects on the development of subclinical CVD than does a single episode of elevated depressive symptoms.

Longitudinal relationships among biomarkers for Alzheimer disease in the Adult Children Study.

OBJECTIVE: To determine whether and how longitudinal rates of change in MRI volumetrics, CSF concentrations of Alzheimer-related proteins, molecular imaging of cerebral fibrillar amyloid with PET using the [(11)C] benzothiazole tracer, Pittsburgh compound B (PiB), and cognition were associated among asymptomatic middle-aged to older individuals. METHODS: Multivariate mixed models for repeated measures were used to assess the correlations on the rates of changes across markers. RESULTS: Among 209 asymptomatic middle-aged to older individuals longitudinally followed for up to 11 years (mean 6.7 years), a faster intraindividual decrease in CSF Aß42 was associated with a faster increase in PiB mean cortical standardized uptake value ratio (MCSUVR, p = 0.04), but not others. The rate of change in CSF tau (and Ptau181) was correlated with the rate of change in PiB MCSUVR (p = 0.002), hippocampal volume (p = 0.04), and global cognition (p = 0.008). The rate of change in hippocampal volume was correlated with the rate of change in global cognition (p = 0.04). Only 3 significant correlations were observed at baseline: CSF Aß42 and PiB MCSUVR (p < 0.001), CSF tau and PiB MCSUVR (p < 0.001), and CSF Aß42 and global cognition (p = 0.01). CONCLUSIONS: CSF tau (Ptau181), PiB MCSUVR, and hippocampal volume were all longitudinally correlated with each other, whereas CSF Aß42 was correlated only with PiB binding. Unlike the baseline values, the longitudinal change in CSF tau (Ptau181) and hippocampal volume were correlated with the longitudinal change in global cognition, validating the role of these biomarkers in Alzheimer disease prevention trials.

Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age.

IMPORTANCE: Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined. OBJECTIVE: To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals. DESIGN, SETTING, AND PARTICIPANTS: As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for ß-amyloid 40 (Aß40), Aß42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up. MAIN OUTCOMES AND MEASURES: Changes in Aß40, Aß42, total tau, P-tau181, VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding. RESULTS: While there were no consistent longitudinal patterns in Aß40 (P = .001-.97), longitudinal reductions in Aß42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aß42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau181, and VILIP-1) dramatically increased in some individuals in mid and late middle age (P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P ≤ .003). These patterns were more apparent in at-risk ε4 carriers (Aß42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR. CONCLUSIONS AND RELEVANCE: Longitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.

Absence of practice effects in preclinical Alzheimer's disease.

OBJECTIVE: To describe how practice effects influence cognitive trajectories and determine if a reduction in practice effects is a potential marker of Stage-III preclinical Alzheimer's disease (AD). METHOD: Participants included 263 older adults who were cognitively normal at baseline (i.e., had a Clinical Dementia Rating [CDR] of 0; Morris, 1993) and returned for an average of 9.5 annual visits. Participants completed standard tests of episodic memory, visuospatial ability, semantic memory, and executive function. Progressors (n = 66) converted to CDR > 0 with a diagnosis of symptomatic AD after a minimum of 3 visits and stable participants (n = 197) never progressed to CDR > 0. Practice effects, defined as the slope of performance across Visits 1-3, were compared between groups and used within subjects to predict risk of conversion. Change-point models that accounted for retest were contrasted with linear models that ignored retest. RESULTS: The stable group showed practice effects on episodic-memory measures (ß = 0.14, SE = .02, p < .0001) but the progressor group did not (ß = 0.03, SE = .03, p = .343). Across all participants, practice effects on episodic-memory tests were associated with a decreased risk of progression to AD as indicated by the subdistribution hazards model (SHR; Fine & Gray, 1999); SHR = .110, 95% CI [.032, .384], p = .001). Finally, use of change-point models dramatically altered rate-of-change estimates compared with models that ignored practice. CONCLUSION: Our results indicate that preclinical AD is marked by a reduction in practice effects in episodic memory and that the magnitude of gain from retesting is inversely related to progression risk. Assessment of practice effects may be a face-valid indicator of Stage-III preclinical AD.

Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer's Disease: Results of the DIAN Study.

OBJECTIVE: We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer's disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). METHODS: The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. RESULTS: At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. CONCLUSIONS: The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials.

Remodeling Characteristics and Collagen Distributions of Biologic Scaffold Materials Biopsied From Postmastectomy Breast Reconstruction Sites.

OBJECTIVE: The study purpose was to evaluate the associations between patient characteristics and the histologic remodeling scores of acellular dermal matrices (ADMs) biopsied from breast reconstruction sites in the first attempt to generate a multivariable risk prediction model of nonconstructive remodeling. It was hypothesized that host characteristics and surgical site assessments predict the degree of graft remodeling for ADMs used during breast reconstruction. METHODS: The ADMs were biopsied from the breast reconstruction sites of n = 62 patients during a subsequent breast procedure, stained with hematoxylin-eosin, and evaluated according to a semi-quantitative scoring system for remodeling characteristics (cell types, cell infiltration, extracellular matrix deposition, scaffold degradation, fibrous encapsulation, and neovascularization) and a mean composite score. Biopsies were stained with Sirius Red and Fast Green, and analyzed to determine the collagen I:III ratio. Based on univariate analyses between subject clinical characteristics and the histologic remodeling scores, cohort variables were selected for multivariable regression models using a P value of 0.20 or less. RESULTS: The composite score model yielded 3 variables: pack-year history, corticosteroid use, and radiation timing (r pseudo = 0.81). The model for collagen I yielded 2 variables: corticosteroid use and reason for reoperation (r pseudo = 0.78). The model for collagen III yielded 1 variable: reason for reoperation (r pseudo = 0.35). CONCLUSIONS: These preliminary results constitute the first steps in generating a risk prediction model that predicts the patients and clinical circumstances most likely to experience nonconstructive remodeling of biologic grafts used to reconstruct the breast.

Decreased platelet APP isoform ratios in autosomal dominant Alzheimer's disease: baseline data from a DIAN cohort subset.

INTRODUCTION: This study examines platelet amyloid precursor protein (APP) isoform ratios of 120KDa to 110KDa (APPr) between mutation carriers (MC) carrying a mutation for autosomal dominant Alzheimer's disease (ADAD) and non-carriers (NC). Two previous studies reported no significant difference in APPr between ADAD MC and NC, which may have been due to the small sample size in both studies. The current study examines APPr in MC versus NC in a larger sample. In addition, it investigated whether APPr correlate with neuroimaging data, neuropsychological data and cerebrospinal fluid biomarkers in a cohort subset derived from the Dominantly Inherited Alzheimer Network (DIAN) study. METHODS: APPr were quantified by western blotting. Fifteen MC (symptomatic and asymptomatic) were compared against twelve NC using univariate general linear model. All participants underwent neuroimaging and neuropsychological testing which were correlated with APPr using Pearson's correlation coefficient (r). RESULTS: APPr were lower in MC compared to NC (p=0.003) while Mini-Mental State Examination (MMSE) scores were not significantly different (p>0.1). Furthermore, APPr inversely correlated with amyloid imaging in the Caudate Nucleus (r=-0.505; p<0.05) and Precuneus (r=-0.510; p<0.05). CONCLUSION: APPr are lower in ADAD MC compared to NC, and inversely correlated with brain amyloid load prior to significant differences in cognitive health. However, the use of APPr as a biomarker needs to be explored further.

Covariation of change in bioavailable testosterone and adiposity in midlife women.

OBJECTIVE: To determine whether menopause-related changes in reproductive hormones were associated with change in adiposity and whether these relationships were independent of important covariates. METHODS: Annual assessments of adiposity measures [computed tomography-assessed visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) and dual-energy X-ray absorptiometry-assessed total body fat (TBF)] over 4 years from an ancillary study at the Chicago site of the Study of Women's Health Across the Nation (SWAN) were paired with reproductive hormones collected by SWAN. Included were 243 women (44% African American, 56% Caucasian) who were eligible participants in a population-based cohort with a 72% participation rate. RESULTS: VAT increased by 3.8% annually, and SAT increased by 1.8% per year. Change in bioavailable testosterone was significantly positively associated with changes both in VAT and in SAT but was not related to change in total body fat. The associations were independent of age, race, physical activity, smoking, baseline TBF, baseline bioavailable testosterone, and change in TBF. Change in estradiol was unrelated to changes in any adiposity measure. CONCLUSIONS: Bioavailable testosterone may play an important role in menopause-related redistribution of visceral and subcutaneous fat in the central abdominal region.

Remodeling characteristics and collagen distribution in biological scaffold materials explanted from human subjects after abdominal soft tissue reconstruction: an analysis of scaffold remodeling characteristics by patient risk factors and surgical site classifications.

OBJECTIVE: The study purpose was to evaluate the associations between patient characteristics or surgical site classifications and the histologic remodeling scores of biologic meshes biopsied from abdominal soft tissue repair sites in the first attempt to generate a multivariable risk-prediction model of nonconstructive remodeling. BACKGROUND: Host characteristics and surgical site assessments may predict remodeling degree for biologic meshes used to reinforce abdominal tissue repair sites. METHODS: Biologic meshes were biopsied from the abdominal tissue repair sites of n = 40 patients during an abdominal reexploration, stained with hematoxylin and eosin, and evaluated according to a semi-quantitative scoring system for remodeling characteristics (cell types, cell infiltration, extracellular matrix deposition, scaffold degradation, fibrous encapsulation, and neovascularization) and a mean composite score. Biopsies were stained with Sirius Red and Fast Green and analyzed to determine the collagen I:III ratio. On the basis of univariate analyses between subject clinical characteristics or surgical site classification and the histologic remodeling scores, cohort variables were selected for multivariable regression models using P ≤ 0.200. RESULTS: The model selection process for cell infiltration score yielded 2 variables: age at mesh implantation and mesh classification (C statistic = 0.989). For the mean composite score, the model selection process yielded 2 variables: age at mesh implantation and mesh classification (r = 0.449). CONCLUSIONS: These preliminary results constitute the first steps in generating a risk-prediction model that predicts the patients and clinical circumstances most likely to experience nonconstructive remodeling of abdominal tissue repair sites with biologic mesh reinforcement.

An antidepressant decreases CSF Aß production in healthy individuals and in transgenic AD mice.

Serotonin signaling suppresses generation of amyloid-ß (Aß) in vitro and in animal models of Alzheimer's disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aß in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram's effects on Aß production and Aß concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. Aß production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aß concentrations in the drug-treated group. The ability to safely decrease Aß concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.

Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease.

Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-ß1-42 (Aß1-42) associated with the presence of Aß plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

Remodeling characteristics and collagen distribution in synthetic mesh materials explanted from human subjects after abdominal wall reconstruction: an analysis of remodeling characteristics by patient risk factors and surgical site classifications.

BACKGROUND: The purpose of this study was to evaluate the associations between patient characteristics or surgical site classifications and the histologic remodeling scores of synthetic meshes biopsied from their abdominal wall repair sites in the first attempt to generate a multivariable risk prediction model of non-constructive remodeling. METHODS: Biopsies of the synthetic meshes were obtained from the abdominal wall repair sites of 51 patients during a subsequent abdominal re-exploration. Biopsies were stained with hematoxylin and eosin, and evaluated according to a semi-quantitative scoring system for remodeling characteristics (cell infiltration, cell types, extracellular matrix deposition, inflammation, fibrous encapsulation, and neovascularization) and a mean composite score (CR). Biopsies were also stained with Sirius Red and Fast Green, and analyzed to determine the collagen I:III ratio. Based on univariate analyses between subject clinical characteristics or surgical site classification and the histologic remodeling scores, cohort variables were selected for multivariable regression models using a threshold p value of ≤0.200. RESULTS: The model selection process for the extracellular matrix score yielded two variables: subject age at time of mesh implantation, and mesh classification (c-statistic = 0.842). For CR score, the model selection process yielded two variables: subject age at time of mesh implantation and mesh classification (r (2) = 0.464). The model selection process for the collagen III area yielded a model with two variables: subject body mass index at time of mesh explantation and pack-year history (r (2) = 0.244). CONCLUSION: Host characteristics and surgical site assessments may predict degree of remodeling for synthetic meshes used to reinforce abdominal wall repair sites. These preliminary results constitute the first steps in generating a risk prediction model that predicts the patients and clinical circumstances for which non-constructive remodeling of an abdominal wall repair site with synthetic mesh reinforcement is most likely to occur.

Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.

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-ß1-42 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.