Multifactorial Hyponatremia: Don't Miss Ruling Out Malignancy.

A 62-year-old male with a history of chronic obstructive pulmonary disease (COPD), schizoaffective disorder treated with Zoloft, type 2 diabetes mellitus, and tobacco use presented with an acute on chronic hyponatremia of 120 mEq/L. He presented with only a mild headache and endorsed recently increasing his free water intake due to a cough. Labs and physical exam findings suggested a true, euvolemic hyponatremia. Polydipsia and Zoloft-induced syndrome of inappropriate antidiuretic hormone (SIADH) were determined to be likely contributors to his hyponatremia. However, given his tobacco use, further workup was done to rule out malignancy causing hyponatremia. Chest CT did ultimately suggest malignancy and further workup was recommended. With the hyponatremia treated, the patient was discharged with recommended outpatient workup. This case serves as a reminder to consider that hyponatremia may be multifactorial and even if there is a likely cause identified, malignancy should be ruled out in patients with risk factors.

A non-catalytic N-terminus domain of WRN prevents mitotic telomere deprotection.

Telomeric ends form a loop structure (T-loop) necessary for the repression of ATM kinase activation throughout the normal cell cycle. However, cells undergoing a prolonged mitotic arrest are prone to lose the T-loop, resulting in Aurora B kinase-dependent mitotic telomere deprotection, which was proposed as an anti-tumor mechanism that eliminates precancerous cells from the population. The mechanism of mitotic telomere deprotection has not been elucidated. Here, we show that WRN, a RECQ helicase family member, can suppress mitotic telomere deprotection independently of its exonuclease and helicase activities. Truncation of WRN revealed that N-terminus amino acids 168-333, a region that contains a coiled-coil motif, is sufficient to suppress mitotic telomere deprotection without affecting both mitotic Aurora B-dependent spindle checkpoint and ATM kinase activity. The suppressive activity of the WRN168-333 fragment is diminished in cells partially depleted of TRF2, while WRN is required for complete suppression of mitotic telomere deprotection by TRF2 overexpression. Finally, we found that phosphomimetic but not alanine mutations of putative Aurora B target sites in the WRN168-333 fragment abolished its suppressive effect. Our findings reveal a non-enzymatic function of WRN, which may be regulated by phosphorylation in cells undergoing mitotic arrest. We propose that WRN enhances the protective function of TRF2 to counteract the hypothetical pathway that resolves the mitotic T-loop.

Mapping Retinal Abnormalities in Psychosis: Meta-analytical Evidence for Focal Peripapillary and Macular Reductions.

BACKGROUND: Several studies have suggested that the retina structure is affected in schizophrenia spectrum disorders (SSD). We aimed to investigate the location and size of the potential differences between patients and healthy controls (HC) in several thickness and volume measures across the retina. STUDY DESIGN: We included cross-sectional studies comparing peripapillary retinal nerve fiber layer (pRNFL) thickness, macular volume, macular thickness (MT), foveal thickness, ganglion cell and inner plexiform layer thickness (GCL+IPL), cup volume, and cup/disc ratio (C/D) in the right and/or left eyes and/or the pRNFL and MT quadrants between patients with SSD and HC. Search databases were MEDLINE, Web of Science, PsycINFO, Cochrane Central, and medrxiv.org. Risk of bias was assessed with the Newcastle-Ottawa Scale. Standardized mean differences (SMD), subgroup analysis, and meta-regression with several variables were computed using the dmetar package in R. PROSPERO: CRD42021287873. STUDY RESULTS: Data from 22 reports (942 patients, 742 HC) were included. We found a retinal thinning in pRNFL (-0.30; 95% CI: -0.46, -0.14), macula (-0.37; 95% CI: -0.61, -0.13), and GCL+IPL (-0.33; 95% CI: -0.57, -0.10). The retinal thinning was especially pronounced in the superior and inferior quadrants of the inner ring of the macula. We also observed a decrease of macular volume (-0.44; 95% CI: -0.68, -0.20) and an increase in C/D ratio (0.35; 95% CI: 0.03, 0.67). CONCLUSIONS: Current evidence demonstrates retinal thinning in SSD, affecting both axonal and cellular structures, specially focused in the inner ring of the macula.

Hypertensive Emergency as the Initial Presentation of Acquired Thrombotic Thrombocytopenic Purpura: A Case Report.

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA) related to a deficiency of ADAMTS13 protein, which could lead to fatal outcomes. TTP presents a vast array of symptoms, making its diagnosis a challenge to physicians. In this report, we discuss the case of an 80-year-old male who presented with abdominal pain and hypertension with underlying severe thrombocytopenia and hemolysis. Although his presentation could also be secondary to malignant hypertension, he was promptly diagnosed with TTP based on these findings. TTP is a hematologic emergency, and it should be kept in the differential diagnosis when a patient presents with thrombocytopenia and hemolysis with or without accompanying symptoms.

Myelodysplastic Syndromes and Modalities of Treatment: An Updated Literature Review.

Myelodysplastic syndromes (MDS) represent a large group of rare and diverse clonal stem cell disorders. These are classified into several different phenotypes and typically arise following a multistep genetic process, whereby genetic mutations alter the DNA damage and cellular stress responses, impacting transcription, RNA splicing, epigenetics, and cytokine signaling. However, despite the advances made regarding molecular pathophysiology and prognostic criteria and the influx of new treatment modalities, management is primarily based on prognostic scores, such as the Revised International Prognostic Scoring System. This poses a significant challenge to current healthcare professionals due to poor comprehension of the underlying pathophysiology. Hence, this review integrates the latest research and treatment modalities for MDS and discusses the different genetic mutations outlined in the revised World Health Organization 2016 MDS classification system and the associated treatment modalities. Additionally, future directions of research and clinical management of MDS are discussed.

Variation in the vulnerability of mice expressing human superoxide dismutase 1 to prion-like seeding: a study of the influence of primary amino acid sequence.

Misfolded forms of superoxide dismutase 1 (SOD1) with mutations associated with familial amyotrophic lateral sclerosis (fALS) exhibit prion characteristics, including the ability to act as seeds to accelerate motor neuron disease in mouse models. A key feature of infectious prion seeding is that the efficiency of transmission is governed by the primary sequence of prion protein (PrP). Isologous seeding, where the sequence of the PrP in the seed matches that of the host, is generally much more efficient than when there is a sequence mis-match. Here, we used paradigms in which mutant SOD1 seeding homogenates were injected intraspinally in newborn mice or into the sciatic nerve of adult mice, to assess the influence of SOD1 primary sequence on seeding efficiency. We observed a spectrum of seeding efficiencies depending upon both the SOD1 expressed by mice injected with seeds and the origin of the seed preparations. Mice expressing WT human SOD1 or the disease variant G37R were resistant to isologous seeding. Mice expressing G93A SOD1 were also largely resistant to isologous seeding, with limited success in one line of mice that express at low levels. By contrast, mice expressing human G85R-SOD1 were highly susceptible to isologous seeding but resistant to heterologous seeding by homogenates from paralyzed mice over-expressing mouse SOD1-G86R. In other seeding experiments with G85R SOD1:YFP mice, we observed that homogenates from paralyzed animals expressing the H46R or G37R variants of human SOD1 were less effective than seeds prepared from mice expressing the human G93A variant. These sequence mis-match effects were less pronounced when we used purified recombinant SOD1 that had been fibrilized in vitro as the seeding preparation. Collectively, our findings demonstrate diversity in the abilities of ALS variants of SOD1 to initiate or sustain prion-like propagation of misfolded conformations that produce motor neuron disease.

Coronary Artery Calcium Score - A Reliable Indicator of Coronary Artery Disease?

Coronary artery disease (CAD) is caused by atheromatous blockage of coronary vessels leading to acute coronary events that usually occur when a plaque ruptures and a thrombus forms. CAD is a known cause of significant cardiovascular events, accounting for more than 50% of the deaths in western countries, and most of the patients with CAD remain asymptomatic. The coronary artery calcium (CAC) score has been created as a measure of coronary atherosclerosis. This article has compiled various studies that conclude the clinical relationship between coronary artery calcium and the development of cardiovascular (CV) events by using the CAC score as a reliable indicator of CAD. This article has reviewed the pathophysiology and risk factors of CAD, along with various methods of CAC scoring. It also underlined the reliability of CAC scoring for early detection of CAD in asymptomatic individuals. We emphasized the importance of age-dependent risk factor analysis combined with practical screening tools like CAC scoring for early diagnosis of CAD can help direct the treatment and prevent deaths in asymptomatic individuals.

Anterior Cruciate Ligament Injury: Conservative Versus Surgical Treatment.

The most frequent type of ligament injury is an anterior cruciate ligament (ACL). The mechanisms of an ACL injury are classified as direct contact, indirect contact, and non-contact. Physical examination for the assessment of the ACL is commonly used in routine care in the evaluation of the knee and is part of the diagnostic process. Due to the high degree of variability in their presentation and outcomes, treatment must be tailored according to factors such as patient demographics, the severity of the damage, and long-term improvement profile. When it comes to ACL injuries, low-quality data have been produced that reveals no difference in patient-reported knee function results between surgical ACL restoration and conservative therapy. However, these results must be evaluated in the perspective of the fact that many individuals with an ACL rupture remained symptomatic after rehabilitation and eventually underwent ACL reconstruction surgery. This article has reviewed the risk factors and the mechanisms that commonly lead to ACL injuries. This article has also discussed the clinical significance of conservative and surgical management and has highlighted the implications of both approaches.

Stroke and Pneumonia: Mechanisms, Risk Factors, Management, and Prevention.

A stroke is a cerebrovascular medical emergency characterized by the sudden loss of neurological function due to interruption to the blood supply. A serious and common complication of stroke is pneumonia. This review article outlined various studies in order to understand the pathogenesis pathways that lead to the development of stroke-associated pneumonia, as well as therapeutic and preventive options to reduce pneumonia. The article looked for risk factors that increase the risk of developing pneumonia among stroke patients. In addition, it has reviewed various therapeutic modalities, such as postural modifications, pharmacological treatment, and other unique treatments, in an attempt to find which of them are efficient to decrease the occurrence of pneumonia and which of them are not. The article also attempts to emphasize the importance of early screening for dysphagia among stroke patients and demonstrates the importance of preventive strategies that can be easily implemented, such as routine oral care and behavioral modifications.

Celiac Disease, Beyond the Bowel: A Review of Its Neurological Manifestations.

Celiac disease (CD) is a multi-systemic autoimmune condition that causes a hyperinflammatory response when gluten is ingested. There has been a shift in the clinical presentation of CD from a mere malabsorption disorder to an autoimmune condition that affects multiple organ systems, which could increase the rate of hospitalizations and a decreased quality of life. This article has compiled various studies that have explored the neurological manifestations of celiac disease, their epidemiology, possible pathogenic mechanisms, diagnosis, and treatment. The most common neurological conditions include gluten ataxia (GA), gluten neuropathy, gluten encephalopathy, and epilepsy which usually present as sporadic diseases which are difficult to diagnose in the absence of gastrointestinal (GI) symptoms. The treatment for most of these conditions is a gluten-free diet (GFD) regardless of GI involvement.

Hereditary Hemochromatosis: A Cardiac Perspective.

Hereditary hemochromatosis (HH) is a common genetic metabolic disorder characterized by excessive iron absorption and elevated serum iron levels, which accumulate in various organs, such as the heart, pancreas, gonads, and damage these organs. There are only a few articles and clinical studies describing the characteristics of cardiac involvement in HH along with the significance of early diagnosis and management in preventing complications. In this review article, we have reviewed multiple pieces of literature and gathered available information regarding the subject. We compiled the data to investigate the importance of early detection of symptoms, regular monitoring, and prompt management with strict adherence to reverse or prevent complications. This article has reviewed different aspects of cardiac hemochromatosis, such as pathogenesis, clinical presentation, diagnosis, and management. Recognition of early symptoms, diagnosis of cardiac involvement with various modalities, and implementation of early treatment are essentially the foundation of better outcomes in HH.

Acromegaly and the Colon: Scoping Beyond the Pituitary.

Acromegaly is a complex endocrinological disorder commonly caused by hypersecretion of growth hormone (GH) typically due to pituitary gland tumors. Patients with acromegaly who are successfully treated and biochemically managed have a reasonably average life expectancy. However, it causes a cascade of multi-systemic involvement throughout the patient's life, including cardiovascular, neuropsychiatric, respiratory, metabolic, neurological, neoplastic, and gastrointestinal involvement, resulting in a higher rate of hospitalization, lower quality of life, and a shorter life expectancy. Although cardiovascular complications are the primary cause of death in patients with acromegaly, malignancy is now emerging as a major killer in these individuals. Colorectal carcinoma has been reported to be prevalent in acromegaly individuals. This review article has compiled studies to demonstrate a link between acromegaly and colorectal neoplasia, intending to provide a strong foundation for their clinical relationship. This article has summarised a potential pathogenic mechanism and provided insights into the clinical presentation of such patients. Furthermore, this article has provided a brief overview of current screening recommendations for colorectal neoplasia in acromegaly patients.

Persistent Pulmonary Hypertension: A Look Into the Future Therapy.

Persistent pulmonary hypertension (PPHN) of the newborn is a lung parenchymal disorder that causes a wide range of hemodynamic changes in the newborn's systemic circulation. Arising from a multifactorial web of etiology, PPHN is one of the most common reasons for neonatal intensive care unit hospitalization and is associated with increased morbidity and mortality. Historically, multiple treatment modalities have been explored, ranging from oxygen and surfactant therapy to newer upcoming medications like magnesium sulfate and adenosine. This review article has discussed the pathogenesis of PPHN and its relationship with the clinical implications of PPHN, such as heart failure and so on. This article has also explored the diagnostic guidelines and analyzed the existing and the upcoming modalities for treating PPHN.

RERE deficiency leads to decreased expression of GATA4 and the development of ventricular septal defects.

Deletions of chromosome 1p36 are associated with a high incidence of congenital heart defects (CHDs). The arginine-glutamic acid dipeptide repeats gene (RERE) is located in a critical region for CHD on chromosome 1p36 and encodes a cardiac-expressed nuclear receptor co-regulator. Mutations affecting RERE cause atrial and ventricular septal defects (VSDs) in humans, and RERE-deficient mice also develop VSDs. During cardiac development, mesenchymal cells destined to form part of the atrioventricular (AV) septum are generated when endocardial cells in the AV canal undergo epithelial-to-mesenchymal transition (EMT) and migrate into the space between the endocardium and the myocardium. These newly generated mesenchymal cells then proliferate to fill the developing AV endocardial cushions. Here, we demonstrate that RERE-deficient mouse embryos have reduced numbers of mesenchymal cells in their AV endocardial cushions owing to decreased levels of EMT and mesenchymal cell proliferation. In the endocardium, RERE colocalizes with GATA4, a transcription factor required for normal levels of EMT and mesenchymal cell proliferation. Using a combination of in vivo and in vitro studies, we show that Rere and Gata4 interact genetically in the development of CHDs, RERE positively regulates transcription from the Gata4 promoter and GATA4 levels are reduced in the AV canals of RERE-deficient embryos. Tissue-specific ablation of Rere in the endocardium leads to hypocellularity of the AV endocardial cushions, defective EMT and VSDs, but does not result in decreased GATA4 expression. We conclude that RERE functions in the AV canal to positively regulate the expression of GATA4, and that deficiency of RERE leads to the development of VSDs through its effects on EMT and mesenchymal cell proliferation. However, the cell-autonomous role of RERE in promoting EMT in the endocardium must be mediated by its effects on the expression of proteins other than GATA4.This article has an associated First Person interview with the first author of the paper.

Vigilancia y análisis de zonas de frontera, puertos de entrada y de población inmigrante / Surveillance and analysis of border areas, ports of entry and immigrant population

RESUMEN Objetivo Realizar una revisión de la literatura sobre los sistemas de información de vigilancia sanitaria y epidemiológica en zonas de frontera y puntos de entrada en Colombia. Materiales y Métodos Se desarrolló una revisión sistemática de literatura mediante la metodología Prisma, términos MeSH y DECS. Para ello, se consultaron, las bases de datos PubMed y BVS entre el 2000 y el 2014. Se incluyeron 51 documentos de acuerdo con los criterios de inclusión-exclusión, a partir de los cuales se discutieron las categorías propuestas: servicios de salud, salud mental, estado de salud y determinantes sociales. Resultados El análisis permite evidenciar que la vigilancia epidemiológica y sanitaria de fronteras y puntos de entrada en el ámbito mundial, está enfocado principalmente en ejes como salud mental, eventos transmisibles y eventos de condiciones no transmisibles. Adicionalmente, se da importancia a la atención integral en los servicios de salud y al análisis del estado de salud de la población inmigrante bajo el enfoque diferencial territorial, étnico y cultural. Sin embargo, hay pocas experiencias con un enfoque intersectorial, así como de determinantes sociales, en los territorios con condiciones de zonas de fronteras y/o puntos de entrada. Conclusiones Las diferencias de contexto, sistemas de salud, sistemas de información y prioridades de cada país, hacen que el intercambio y la cooperación entre las fronteras tengan serios retos. Debido a esto, es necesario contar con instrumentos de cooperación entre países limítrofes y análisis e información, con base en el modelo Determinantes Sociales de la Salud.(AU)

ABSTRACT Objective Perform a literature review about systems of sanitary and epidemiological surveillance for frontier zones and the points of entry of Colombia. Materials and Methods A systematic literature review using the Prisma methodology, MeSH and DECS terms, was developed in PubMed and BVS bibliographic databases between 2000 and 2014. We included 51 documents according to inclusion-exclusion criteria and we proposed and discussed these categories: health services, mental health, health status and social determinants. Results The analysis makes it possible to evidence that the epidemiological and sanitary surveillance of borders and entry points worldwide, focused mainly on axes such as mental health, transmissible events and events of non-communicable conditions. In addition, the importance of comprehensive care in health services, as well as the analysis of the health status of immigrant population under the territorial, ethnic and cultural differential approach. However, there are few experiences with a social determinants analysis in borders zone and / or entry points. Conclusions Differences in the context, health systems, information systems and priorities of each country make the exchange and cooperation between borders challenging. It is necessary to have instruments of cooperation between neighboring countries and a common information based on the Social Determinants of Health.(AU)

[Surveillance and analysis of border areas, ports of entry and immigrant population]. / Vigilancia y análisis de zonas de frontera, puertos de entrada y de población inmigrante.

OBJECTIVE: Perform a literature review about systems of sanitary and epidemiological surveillance for frontier zones and the points of entry of Colombia. MATERIALS AND METHODS: A systematic literature review using the Prisma methodology, MeSH and DECS terms, was developed in PubMed and BVS bibliographic databases between 2000 and 2014. We included 51 documents according to inclusion-exclusion criteria and we proposed and discussed these categories: health services, mental health, health status and social determinants. RESULTS: The analysis makes it possible to evidence that the epidemiological and sanitary surveillance of borders and entry points worldwide, focused mainly on axes such as mental health, transmissible events and events of non-communicable conditions. In addition, the importance of comprehensive care in health services, as well as the analysis of the health status of immigrant population under the territorial, ethnic and cultural differential approach. However, there are few experiences with a social determinants analysis in borders zone and / or entry points. CONCLUSIONS: Differences in the context, health systems, information systems and priorities of each country make the exchange and cooperation between borders challenging. It is necessary to have instruments of cooperation between neighboring countries and a common information based on the Social Determinants of Health.

OBJETIVO: Realizar una revisión de la literatura sobre los sistemas de información de vigilancia sanitaria y epidemiológica en zonas de frontera y puntos de entrada en Colombia. MATERIALES Y MÉTODOS: Se desarrolló una revisión sistemática de literatura mediante la metodología Prisma, términos MeSH y DECS. Para ello, se consultaron, las bases de datos PubMed y BVS entre el 2000 y el 2014. Se incluyeron 51 documentos de acuerdo con los criterios de inclusión-exclusión, a partir de los cuales se discutieron las categorías propuestas: servicios de salud, salud mental, estado de salud y determinantes sociales. RESULTADOS: El análisis permite evidenciar que la vigilancia epidemiológica y sanitaria de fronteras y puntos de entrada en el ámbito mundial, está enfocado principalmente en ejes como salud mental, eventos transmisibles y eventos de condiciones no transmisibles. Adicionalmente, se da importancia a la atención integral en los servicios de salud y al análisis del estado de salud de la población inmigrante bajo el enfoque diferencial territorial, étnico y cultural. Sin embargo, hay pocas experiencias con un enfoque intersectorial, así como de determinantes sociales, en los territorios con condiciones de zonas de fronteras y/o puntos de entrada. CONCLUSIONES: Las diferencias de contexto, sistemas de salud, sistemas de información y prioridades de cada país, hacen que el intercambio y la cooperación entre las fronteras tengan serios retos. Debido a esto, es necesario contar con instrumentos de cooperación entre países limítrofes y análisis e información, con base en el modelo Determinantes Sociales de la Salud.

Suppression of cell migration is promoted by miR-944 through targeting of SIAH1 and PTP4A1 in breast cancer cells.

BACKGROUND: Aberrant expression of microRNAs has been associated with migration of tumor cells. In this study, we aimed to investigate the biological significance of miR-944 whose function is unknown in breast cancer. METHODS: MiR-944 expression in breast cancer cells and tumors was evaluated by Taqman qRT-PCR assays. Transcriptional profiling of MDA-MB-231 cells expressing miR-944 was performed using DNA microarrays. Cell viability, migration and invasion were assessed by MTT, scratch/wound-healing and transwell chamber assays, respectively. The luciferase reporter assay was used to evaluate targeting of SIAH1, PTP4A1 and PRKCA genes by miR-944. SIAH1 protein levels were measured by Western blot. Silencing of SIAH1 gene was performed by RNA interference using shRNAs. RESULTS: Our data showed that miR-944 expression was severely repressed in clinical specimens and breast cancer cell lines. Suppression of miR-944 levels was independent of hormonal status and metastatic potential of breast cancer cells. Gain-of-function analysis indicated that miR-944 altered the actin cytoskeleton dynamics and impaired cell migration and invasion. Genome-wide transcriptional profiling of MDA-MB-231 cells that ectopically express miR-944 showed that 15 genes involved in migration were significantly repressed. Notably, luciferase reporter assays confirmed the ability of miR-944 to bind the 3´UTR of SIAH1 and PTP4A1 genes, but not PRKCA gene. Congruently, an inverse correlation between miR-944 and SIAH1 protein expression was found in breast cancer cells. Moreover, SIAH1 was upregulated in 75 % of miR-944-deficient breast tumors. Finally, SIAH1 gene silencing by RNA interference significantly impaired cell migration of breast cancer cells. CONCLUSIONS: Our results pointed out that miR-944 is a novel upstream negative regulator of SIAH1 and PTP4A1 genes and provided for the first time evidence for its functional role in migration and invasion of breast cancer cells. They also suggest that miR-944 restoration may represent a potential strategy for breast cancer therapy.

Differential proteomic analysis reveals that EGCG inhibits HDGF and activates apoptosis to increase the sensitivity of non-small cells lung cancer to chemotherapy.

PURPOSE: To search for regulated proteins in response to green tea (-)-epigallocatechin-3-gallate (EGCG) in A549 lung cancer cells. EXPERIMENTAL DESIGN: 2DE and ESI/multistage MS (ESI-MS/MS) were performed to identify modulated proteins in A549 cells treated with EGCG. Cell migration was evaluated by transwell assays. RNA interference was used to silence the hepatoma-derived growth factor (HDGF). Caspase-3, caspase-9, and HDGF were immunodetected by Western blot assays. Flow cytometry was used for detection of mitochondrial membrane potential and apoptosis. RESULTS: We found that HDGF expression was threefold suppressed by EGCG treatment. Downregulation of HDGF by EGCG was confirmed using anti-HDGF antibodies in three lung cancer cell lines. EGCG treatment and HDGF abrogation by RNA interference resulted in a decreased migration of A549 cells. In addition, EGCG induced a marked synergistic effect with cisplatin in cell death. Consistently, an enhanced cytotoxicity in HDGF-silenced cells was also found. Cell death was associated to increased apoptosis, disruption of the mitochondrial membrane potential, and activation of caspase-3 and caspase-9. CONCLUSION AND CLINICAL RELEVANCE: Our data suggest for the first time that abrogation of HDGF by EGCG enhances cisplatin-induced apoptosis and sensitize A549 cells to chemotherapy. Therefore, we propose that decreasing the HDGF levels by using EGCG may represent a novel strategy in lung cancer therapy.

Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment.

CONTEXT: The likelihood of conversion to Alzheimer disease (AD) in mild cognitive impairment (MCI) and the "optimal" early markers of conversion need to be established. OBJECTIVES: To evaluate conversion rates to AD in subtypes of MCI and to identify neuropsychological measures most predictive of the time to conversion. DESIGN: Patients were followed up semiannually and controls annually. Subtypes of MCI were determined by using demographically adjusted regression norms on neuropsychological tests. Survival analysis was used to identify the most predictive neuropsychological measures. SETTING: Memory disorders clinic. PARTICIPANTS: One hundred forty-eight patients reporting memory problems and 63 group-matched controls. MAIN OUTCOME MEASURE: A consensus diagnosis of probable AD. RESULTS: At baseline, 108 patients met criteria for amnestic MCI: 87 had memory plus other cognitive domain deficits and 21 had pure memory deficits. The mean duration of follow-up for the 148 patients was 46.6 +/- 24.6 months. In 3 years, 32 (50.0%) of 64 amnestic-"plus" and 2 (10.0%) of 20 "pure" amnestic patients converted to AD (P = .001). In 148 patients, of 5 a priori predictors, the percent savings from immediate to delayed recall on the Selective Reminding Test and the Wechsler Adult Intelligence Scale-Revised Digit Symbol Test were the strongest predictors of time to conversion. From the entire neuropsychological test battery, a stepwise selection procedure retained 2 measures in the final model: total immediate recall on the Selective Reminding Test (odds ratio per 1-point decrease, 1.10; 95% confidence interval, 1.05-1.14; P < .0001) and Digit Symbol Test coding (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P = .01). The combined predictive accuracy of these 2 measures for conversion by 3 years was 86%. CONCLUSIONS: Mild cognitively impaired patients with memory plus other cognitive domain deficits, rather than those with pure amnestic MCI, constituted the high-risk group. Deficits in verbal memory and psychomotor speed/executive function abilities strongly predicted conversion to AD.