Mixture of regressions with multivariate responses for discovering subtypes in Alzheimer's biomarkers with detection limits.

There is no gold standard for the diagnosis of Alzheimer's disease (AD), except from autopsies, which motivates the use of unsupervised learning. A mixture of regressions is an unsupervised method that can simultaneously identify clusters from multiple biomarkers while learning within-cluster demographic effects. Cerebrospinal fluid (CSF) biomarkers for AD have detection limits, which create additional challenges. We apply a mixture of regressions with a multivariate truncated Gaussian distribution (also called a censored multivariate Gaussian mixture of regressions or a mixture of multivariate tobit regressions) to over 3,000 participants from the Emory Goizueta Alzheimer's Disease Research Center and Emory Healthy Brain Study to examine amyloid-beta peptide 1-42 (Abeta42), total tau protein and phosphorylated tau protein in CSF with known detection limits. We address three gaps in the literature on mixture of regressions with a truncated multivariate Gaussian distribution: software availability; inference; and clustering accuracy. We discovered three clusters that tend to align with an AD group, a normal control profile and non-AD pathology. The CSF profiles differed by race, gender and the genetic marker ApoE4, highlighting the importance of considering demographic factors in unsupervised learning with detection limits. Notably, African American participants in the AD-like group had significantly lower tau burden.

Exploration of potential immune mechanisms in cervical dystonia.

BACKGROUND: Although there are many possible causes for cervical dystonia (CD), a specific etiology cannot be identified in most cases. Prior studies have suggested a relationship between autoimmune disease and some cases of CD, pointing to possible immunological mechanisms. OBJECTIVE: The goal was to explore the potential role of multiple different immunological mechanisms in CD. METHODS: First, a broad screening test compared neuronal antibodies in controls and CD. Second, unbiased blood plasma proteomics provided a broad screen for potential biologic differences between controls and CD. Third, a multiplex immunoassay compared 37 markers associated with immunological processes in controls and CD. Fourth, relative immune cell frequencies were investigated in blood samples of controls and CD. Finally, sequencing studies investigated the association of HLA DQB1 and DRB1 alleles in controls versus CD. RESULTS: Screens for anti-neuronal antibodies did not reveal any obvious abnormalities. Plasma proteomics pointed towards certain abnormalities of immune mechanisms, and the multiplex assay pointed more specifically towards abnormalities in T lymphocytes. Abnormal immune cell frequencies were identified for some CD cases, and these cases clustered together as a potential subgroup. Studies of HLA alleles indicated a possible association between CD and DRB1*15:03, which is reported to mediate the penetrance of autoimmune disorders. CONCLUSIONS: Altogether, the association of CD with multiple different blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of individuals with CD.

Latent Class Proportional Hazards Regression with Heterogeneous Survival Data.

Heterogeneous survival data are commonly present in chronic disease studies. Delineating meaningful disease subtypes directly linked to a survival outcome can generate useful scientific implications. In this work, we develop a latent class proportional hazards (PH) regression framework to address such an interest. We propose mixture proportional hazards modeling, which flexibly accommodates class-specific covariate effects while allowing for the baseline hazard function to vary across latent classes. Adapting the strategy of nonparametric maximum likelihood estimation, we derive an Expectation-Maximization (E-M) algorithm to estimate the proposed model. We establish the theoretical properties of the resulting estimators. Extensive simulation studies are conducted, demonstrating satisfactory finite-sample performance of the proposed method as well as the predictive benefit from accounting for the heterogeneity across latent classes. We further illustrate the practical utility of the proposed method through an application to a mild cognitive impairment (MCI) cohort in the Uniform Data Set.

Predictors of Cognitive Decline in Healthy Middle-Aged Individuals with Asymptomatic Alzheimer's Disease.

Alzheimer's disease (AD) progresses through a lengthy asymptomatic period during which pathological changes accumulate prior to development of clinical symptoms. As disease-modifying treatments are developed, tools to stratify risk of clinical disease will be required to guide their use. In this study, we examine the relationship of AD biomarkers in healthy middle-aged individuals to health history, family history, and neuropsychological measures and identify cerebrospinal fluid (CSF) biomarkers to stratify risk of progression from asymptomatic to symptomatic AD. CSF from cognitively normal (CN) individuals (N=1149) in the Emory Healthy Brain Study were assayed for Aß42, total Tau (tTau), and phospho181-Tau (pTau), and a subset of 134 cognitively normal, but biomarker-positive, individuals were identified with asymptomatic AD (AsymAD) based on a locally-determined cutoff value for ratio of tTau to Aß42. These AsymAD cases were matched for demographic features with 134 biomarker-negative controls (CN/BM-) and compared for differences in medical comorbidities and family history. Dyslipidemia emerged as a distinguishing feature between AsymAD and CN/BM-groups with significant association with personal and family history of dyslipidemia. A weaker relationship was seen with diabetes, but there was no association with hypertension. Examination of the full cohort by median regression revealed a significant relationship of CSF Aß42 (but not tTau or pTau) with dyslipidemia and diabetes. On neuropsychological tests, CSF Aß42 was not correlated with performance on any measures, but tTau and pTau were strongly correlated with visuospatial perception and visual episodic memory. In addition to traditional CSF AD biomarkers, a panel of AD biomarker peptides derived from integrating brain and CSF proteomes were evaluated using machine learning strategies to identify a set of 8 peptides that accurately classified CN/BM- and symptomatic AD CSF samples with AUC of 0.982. Using these 8 peptides in a low dimensional t-distributed Stochastic Neighbor Embedding analysis and k-Nearest Neighbor (k=5) algorithm, AsymAD cases were stratified into "Control-like" and "AD-like" subgroups based on their proximity to CN/BM- or AD CSF profiles. Independent analysis of these cases using a Joint Mutual Information algorithm selected a set of 5 peptides with 81% accuracy in stratifying cases into AD-like and Control-like subgroups. Performance of both sets of peptides was evaluated and validated in an independent data set from the Alzheimer's Disease Neuroimaging Initiative. Based on our findings, we conclude that there is an important role of lipid metabolism in asymptomatic stages of AD. Visuospatial perception and visual episodic memory may be more sensitive than language-based abilities to earliest stages of cognitive decline in AD. Finally, candidate CSF peptides show promise as next generation biomarkers for predicting progression from asymptomatic to symptomatic stages of AD.

Thyroid disease in cervical dystonia.

There are many possible etiologies for cervical dystonia (CD), but a cause cannot be identified in most cases. Most recent attention has focused on genetic causes, although a few prior studies have highlighted autoimmune mechanisms instead. Because autoimmune disorders frequently co-exist, the current study evaluated the hypothesis that autoimmune disorders might be more common in CD than neurological controls. The frequency of 32 common autoimmune disorders was evaluated using a systematic survey comparing 300 subjects with CD with 391 neurological controls. The frequency of thyroid disease was significantly higher in CD (20%) compared with controls (6%). Regression analyses that accounted for age and sex revealed an odds ratio of 4.5 (95% CI 2.5-8.1, p < 0.001). All other autoimmune disorders occurred with similar frequencies in CD and controls. Although these studies do not establish a mechanistic link between CD and autoimmune disease, they suggest the need for further attention to a potential relationship, and more specifically with thyroid disease.

Evaluating the association between latent classes and competing risks outcomes with multiphenotype data.

Latent class analysis is an intuitive tool to characterize disease phenotype heterogeneity. With data more frequently collected on multiple phenotypes in chronic disease studies, it is of rising interest to investigate how the latent classes embedded in one phenotype are related to another phenotype. Motivated by a cohort with mild cognitive impairment (MCI) from the Uniform Data Set (UDS), we propose and study a time-dependent structural model to evaluate the association between latent classes and competing risk outcomes that are subject to missing failure types. We develop a two-step estimation procedure which circumvents latent class membership assignment and is rigorously justified in terms of accounting for the uncertainty in classifying latent classes. The new method also properly addresses the realistic complications for competing risks outcomes, including random censoring and missing failure types. The asymptotic properties of the resulting estimator are established. Given that the standard bootstrapping inference is not feasible in the current problem setting, we develop analytical inference procedures, which are easy to implement. Our simulation studies demonstrate the advantages of the proposed method over benchmark approaches. We present an application to the MCI data from UDS, which uncovers a detailed picture of the neuropathological relevance of the baseline MCI subgroups.

Semiparametric Latent Class Analysis of Recurrent Event Data.

Recurrent events data frequently arise in chronic disease studies, providing rich information on disease progression. The concept of latent class offers a sensible perspective to characterize complex population heterogeneity in recurrent event trajectories that may not be adequately captured by a single regression model. However, the development of latent class methods for recurrent events data has been sparse, typically requiring strong parametric assumptions and involving algorithmic issues. In this work, we investigate latent class analysis of recurrent events data based on flexible semiparametric multiplicative modeling. We derive a robust estimation procedure through novelly adapting the conditional score technique and utilizing the special characteristics of multiplicative intensity modeling. The proposed estimation procedure can be stably and efficiently implemented based on existing computational routines. We provide solid theoretical underpinnings for the proposed method, and demonstrate its satisfactory finite sample performance via extensive simulation studies. An application to a dataset from research participants at Goizueta Alzheimer's Disease Research Center illustrates the practical utility of our proposals.

An Exploration of Subgroups of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Their Risks of Conversion to Dementia or Death.

OBJECTIVE: To explore the heterogeneity of neuropsychiatric symptom (NPS) complexes in individuals with mild cognitive impairment (MCI) and assess the relative risks of converting to dementia or dying. DESIGN: Latent class analysis using 7,971 participants with MCI. SETTING: Participants in the Uniform Data Set (UDS) from 39 NIH Alzheimer's Disease Centers. PARTICIPANTS: Persons with a diagnosis of MCI at initial visit from each center and with either a Mini-Mental State Examination (MMSE) score of 22 or greater or an equivalent education-adjusted Montreal Cognitive Assessment (MoCA) score of 16 or greater. MEASUREMENTS: Neuropsychiatric Inventory Questionnaire (NPI-Q) administered at initial visit. RESULTS: In addition to a subgroup with mild or no NPS (relative frequency, 50%), three empirically-based subgroups of NPS were identified: 1) an "affect" or "negative mood" subgroup (27%) with depression, anxiety, apathy, nighttime disturbance, and change in appetite; 2) a "hyperactive" subgroup (14%) with agitation, irritability, and disinhibition; and 3) a "psychotic with additional severe NPS" subgroup (9%) with the highest risk of delusions and hallucinations, as well as highest risk of all other NPS. Each of these three subgroups had significantly higher risk of converting to dementia than the "mild NPS" class, with the "psychotic with additional severe NPS" subgroup possessing a 64% greater risk. The subgroups did not differ in their risks of death without dementia. CONCLUSION: Our findings of three NPS subgroups in MCI characterized by affect, hyperactive, or psychotic features are largely consistent with a previous 3-factor model of NPS found in a demented population. The consistency of these findings across studies and samples, coupled with our results on the associated risks of converting to dementia, suggests that the NPS structure is robust, and warrants further consideration in classification models of MCI.

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial.

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2 . One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).

Scalable and robust latent trajectory class analysis using artificial likelihood.

Latent trajectory class analysis is a powerful technique to elucidate the structure underlying population heterogeneity. The standard approach relies on fully parametric modeling and is computationally impractical when the data include a large collection of non-Gaussian longitudinal features. We introduce a new approach, the first based on artificial likelihood concepts, that avoids undue modeling assumptions and is computationally tractable. We show that this new method provides reliable estimates of the underlying population structure and is from 20 to 200 times faster than conventional methods when the longitudinal features are non-Gaussian. We apply the approach to explore subgroups among research participants in the early stages of neurodegeneration.

Correction to: Low-chloride- versus high-chloride-containing hypertonic solution for the treatment of subarachnoid hemorrhage-related complications: The ACETatE (A low ChloriE hyperTonic solution for brain Edema) randomized trial.

[This corrects the article DOI: 10.1186/s40560-020-00449-0.].

Low-chloride- versus high-chloride-containing hypertonic solution for the treatment of subarachnoid hemorrhage-related complications: The ACETatE (A low ChloriE hyperTonic solution for brain Edema) randomized trial.

BACKGROUND: Recent reports have demonstrated that among patients with subarachnoid hemorrhage (SAH) treated with hypertonic NaCl, resultant hyperchloremia has been associated with the development of acute kidney injury (AKI). We report a trial comparing the effect of two hypertonic solutions with different chloride contents on the resultant serum chloride concentrations in SAH patients, with a primary outcome aimed at limiting chloride elevation. METHODS: A low ChloridE hyperTonic solution for brain Edema (ACETatE) trial is a single-center, double-blinded, double-dummy, randomized pilot trial comparing bolus infusions of 23.4% NaCl and 16.4% NaCl/Na-acetate for the treatment of cerebral edema in patients with SAH. Randomization occurred when patients developed hyperchloremia (serum Cl- ≥ 109 mmol/L) and required hyperosmolar treatment. RESULTS: We enrolled 59 patients, of which 32 developed hyperchloremia and required hyperosmolar treatment. 15 patients were randomized to the 23.4% NaCl group, and 17 patients were randomized to the 16.4% NaCl/Na-acetate group. Although serum chloride levels increased similarly in both groups, the NaCl/Acetate group showed a significantly lower Cl- load at the end of the study period (978mEq vs. 2,464mEq, p < 0.01). Secondary outcome analysis revealed a reduced rate of AKI in the Na-acetate group (53.3% in the NaCl group vs. 11.8% in the Na-acetate group, p = 0.01). Both solutions had similar effects on ICP reduction, but NaCl/Acetate treatment had a more prominent effect on immediate post-infusion Na+ concentrations (increase of 2.2 ± 2.8 vs. 1.4 ± 2.6, (p < 0.01)). Proximal tubule renal biomarkers differed in concentration between the two groups. CONCLUSIONS: Our pilot trial showed the feasibility and safety of replacing 23.4% NaCl infusions with 16.4% NaCl/Na-acetate infusions to treat cerebral edema in patients with SAH. The degree of hyperchloremia was similar in the two groups. 16.4% NaCl/Na-acetate infusions led to lower Cl- load and AKI rates than 23.4% NaCl infusions. Further multi-center studies are needed to corroborate these results. TRIAL REGISTRATION: clinicaltrials.gov # NCT03204955, registered on 6/28/2017.

Subjective Memory Complaints in White and African American Participants.

OBJECTIVE: Subjective memory complaints (SMCs) are associated with mild cognitive impairment and dementia but are understudied in African Americans (AAs). We compared SMC endorsement in white and AA participants and evaluated predictors of diagnostic progression. METHODS: Initial visit variables, including SMC and memory performance, were compared within a cognitively normal race-matched sample of white and AA participants (Ntotal = 912; 456each race) to assess the presence and predictors of SMC, the predictors of future diagnostic progression, and the change in memory performance over time. RESULTS: More white (32.9%) than AA (24.3%) participants reported SMC (P < .01, ϕ = -.10). Subjective memory complaint was predicted by memory performance (B = -0.03, standard error [SE] = 0.013, odds ratio [OR] = .968, P < .05) and race (B = -0.99, SE = 0.080, OR = .373, P < .001). Subjective memory complaints and memory performance were associated with progression, χ2 (3, n = 912) = 102.37, P < .001. African American race (-2.05 ± 0.24 SE) and SMC (-0.45 ± 0.21 SE) were associated with worse memory performance at baseline and over time, χ2(3) = 13.54, P < .01. CONCLUSIONS: In contrast to previous research, our study found that SMC is associated with diagnostic progression and objective memory declines in both white and AA participants.

Rationale and Design of the Emory Healthy Aging and Emory Healthy Brain Studies.

Understanding the relationships between health and aging is essential for delaying morbidity and maximizing independence in aging populations as life expectancies increase. Loss of cognitive function is a feared age-associated condition and growing public health concern. Alzheimer's disease (AD), the most common cause of dementia, has no curative therapies. Characterizing the relationships between risk factors, biomarkers, and AD progression is critical for the development of effective disease prediction, clinical intervention, and ultimately, disease prevention. The Emory Healthy Aging Study (EHAS) and the Emory Healthy Brain Study (EHBS), which is nested within EHAS, aim to further the understanding of healthy aging and the pathogenesis of age-related illnesses in well-characterized, community-based prospective cohorts and to identify biomarkers for the earliest manifestations of AD for the facilitation of preventative interventions. The EHAS is an innovative, longitudinal, web-based study enrolling English-speaking adults in the U.S. who agree to be contacted for future studies. Using validated instruments, the annual questionnaire enquires about demographics, socioeconomics, self-reported cognitive function, personal and family medical history, lifestyle, and psychosocial factors. Cognitive assessments are also obtained using an ambulatory device. Nested within EHAS, the EHBS is enrolling up to 2,500 EHAS participants, 50-75 years old, who do not have a diagnosis of AD, mild cognitive impairment, or any other memory disorder. EHBS in-person, biennial study visits, include neuropsychological testing, cardiovascular measures, retinal and brain imaging, biospecimen collection (blood, cerebrospinal fluid, gut microbiome), and other assessments. Since spring 2016, EHAS and EHBS have enrolled 12,500 and 863 participants with completed baseline assessments, respectively. Data and biospecimens from EHBS participants will support a broad range of AD biomarker discovery efforts, and follow-up of EHAS participants will enable assessment of self-reported cognitive trajectories and accumulation of incident cases of a variety of health conditions. The EHAS design supports the interval deployment of new study instruments and targeted sampling for ancillary studies. This project will increase our knowledge about healthy aging, improve our understanding of risk factors for cognitive impairment and dementias, support development of biomarkers, and facilitate studies of age-associated disorders including AD.

Psychological Distress and Subsequent Cardiovascular Events in Individuals With Coronary Artery Disease.

Background Higher symptom levels of a variety of measures of emotional distress have been associated with cardiovascular disease ( CVD ), especially among women. Here, our goal was to investigate the association between a composite measure of psychological distress and incident cardiovascular events. Methods and Results In a prospective cohort study, we assessed 662 individuals (28% women; 30% blacks) with stable coronary artery disease. We used a composite score of psychological distress derived through summation of Z-transformed psychological distress symptom scales (depression, posttraumatic stress, anxiety, anger, hostility, and perceived stress) as a predictor of an adjudicated composite end point of adverse events (cardiovascular death, myocardial infarction, stroke, heart failure, or unstable angina). During a mean follow-up of 2.8 years, 120 (18%) subjects developed CVD events. In the overall population, there was no association between the psychological distress measure and CVD events, but there was a sex-based interaction ( P=0.004). In women, higher psychological distress was associated with a higher incidence of CVD events; each SD increase in the composite score of psychological distress was associated with 1.44 times adjusted hazard of CVD events (95% CI, 1.09-1.92). No such association was found in men. Conclusions Among patients with coronary artery disease, higher psychological distress is associated with future cardiovascular events in women only.

The Relation of Psychosocial Distress With Myocardial Perfusion and Stress-Induced Myocardial Ischemia.

OBJECTIVE: Mental stress-induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease (CAD). The link between an integrated measure of chronic psychosocial distress and mental stress-induced myocardial ischemia, and whether it differs by sex, has not been examined before. METHODS: We used latent class analysis to derive a composite measure of psychosocial distress integrating scales of depression, posttraumatic stress, anxiety, anger, hostility, and perceived stress in 665 individuals with stable CAD. Participants underwent myocardial perfusion imaging with mental stress and perfusion defects were quantified at rest (summed rest score), with mental stress (summed stress score), and their difference (summed difference score), the latter being an index of inducible ischemia. RESULTS: The M (SD) age was 63 (9) years, and 185 (28%) were women. Latent class analysis characterized the study sample into four distinct classes of incremental psychosocial distress. In women, class 4 (highest distress) had an adjusted 4.0-point higher summed rest score (95% confidence interval = 0.2-7.7) as compared with class 1 (lowest distress), whereas no difference was observed in men (-0.87 points, 95% confidence interval = -3.74 to 1.99, p = .04 for interaction). There was no association between the psychosocial distress latent variable and summed difference score in either women or men. CONCLUSIONS: Among patients with CAD, a higher level of psychosocial distress is not associated with mental stress ischemia, but it is associated with more resting (fixed) perfusion abnormalities in women only, as well as with blunted hemodynamic response to mental stress in both men and women.

Low-chloride versus high-chloride hypertonic solution for the treatment of subarachnoid hemorrhage-related complications (The ACETatE trial): study protocol for a pilot randomized controlled trial.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition that results from a ruptured cerebral vessel. Cerebral edema and vasospasm are common complications and frequently require treatment with hypertonic solutions, in particular hypertonic sodium chloride (NaCl). We have previously shown that hyperchloremia in patients with aSAH given hypertonic NaCl is associated with the development of acute kidney injury (AKI), which leads to higher morbidity and mortality. Our current trial aims to study the effect of two hypertonic solutions with different chloride content on serum chloride concentrations in patients with aSAH who are at risk for AKI. METHODS: A low ChloridE hyperTonic solution for brain Edema (ACETatE) is a single center, double-blinded, double-dummy pilot trial comparing bolus doses of 23.4% NaCl and 16.4% NaCl/Na-Acetate for the treatment of cerebral edema in patients with aSAH. All patients will be enrolled within 36 h following admission. Randomization will occur once patients who receive hypertonic treatment for cerebral edema develop hyperchloremia (serum Cl- concentration ≥ 109 mmol/L). Subsequent treatment will consist of either NaCl 23.4% or NaCl/Na-Acetate 16.4%. The primary outcome of this study will be the change in serum Cl- concentrations during treatment. Secondary outcomes will include incidence of AKI, mortality, changes in intracranial pressure, and extent of hypernatremia. DISCUSSION: In patients with aSAH, hyperchloremia is a known risk factor for subsequent development of AKI. The primary goal of this pilot study is to determine the effect of two hypertonic solutions with different Cl- content on serum Cl- concentrations in patients with aSAH who have already developed hyperchloremia. Data will be collected prospectively to determine the extent to which the choice of hypertonic saline solution affects subsequent serum Cl- concentrations and the occurrence of AKI. This approach will allow us to obtain preliminary data to design a large randomized trial assessing the effects of chloride-sparing hypertonic solutions on development of AKI in patients with SAH. This pilot study is the first to prospectively evaluate the relationship between hypertonic solution chloride content and its effect on serum electrolytes and renal function in aSAH patients at risk of AKI due to hyperchloremia. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03204955 . Registered on 28 June 2017.

Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center.

Given the importance of identifying prodromes of dementia with specific etiologies, we assessed whether seven latent classes of mild cognitive impairment (MCI), defined empirically based on cognitive, functional, and neuropsychiatric information at initial visit, are associated with distinct clinical outcomes and neuropathological features. We separated 6034 participants with a baseline diagnosis of MCI into seven latent classes using previously defined criteria. We found that these latent classes of MCI differed significantly in their clinical outcomes, survival time, and neuropathology. Two amnestic multi-domain subgroups, as well as two other subgroups with functional impairments and neuropsychiatric disturbances, were at higher risk of not only a 'pure' form of Alzheimer's disease (AD) pathology, but also a 'mixed' pathology consisting of both AD and vascular features. Moreover, the seven latent classes had different risks of Lewy bodies, hippocampal sclerosis, and frontotemporal lobar degeneration (FTLD). This study indicates that data-driven subgroups of MCI are clinicopathologically informative and, with refinement, could lead to targeted interventions focused on each etiology.