Acute acalculous cholecystitis as an early manifestation of COVID-19: case report and literature review.

Background: The novel coronavirus disease 2019 (COVID-19) has rapidly spread worldwide since the outbreak in Wuhan, China, in 2019, becoming a major threat to public health. The most common symptoms are fever, dry cough, shortness of breath, but subjects with COVID-19 may also manifest gastrointestinal symptoms, and in a few cases an involvement of the gallbladder has been observed. Case report: Here we present a case of 50-year-old male with SARS-CoV-2 infection who had abdominal pain, vomiting and diarrhea without respiratory symptoms and was finally diagnosed as acute acalculous cholecystitis (AAC). Laparoscopic cholecystectomy was performed and found a gangrenous gallbladder; the real-time reverse transcription polymerase chain reaction SARS-CoV-2 nucleic acid assay of the bile was negative. We also made a review of the literature and try to understand the hypothetic role of SARS-CoV-2 in the pathogenesis of AAC. Conclusions: We highlighted that it is noteworthy to look at gastrointestinal symptoms in patients with SARS-CoV-2 infection and take into account AAC as a possible complication of COVID-19. Although more evidence is needed to better elucidate the role of the pathogenic mechanisms of the SARS-CoV-2 in AAC, it is conceivable that the hepatobiliary system could be a potential target of SARS-CoV-2.

Predictive Machine Learning Models and Survival Analysis for COVID-19 Prognosis Based on Hematochemical Parameters.

The coronavirus disease 2019 (COVID-19) pandemic has affected hundreds of millions of individuals and caused millions of deaths worldwide. Predicting the clinical course of the disease is of pivotal importance to manage patients. Several studies have found hematochemical alterations in COVID-19 patients, such as inflammatory markers. We retrospectively analyzed the anamnestic data and laboratory parameters of 303 patients diagnosed with COVID-19 who were admitted to the Polyclinic Hospital of Bari during the first phase of the COVID-19 global pandemic. After the pre-processing phase, we performed a survival analysis with Kaplan-Meier curves and Cox Regression, with the aim to discover the most unfavorable predictors. The target outcomes were mortality or admission to the intensive care unit (ICU). Different machine learning models were also compared to realize a robust classifier relying on a low number of strongly significant factors to estimate the risk of death or admission to ICU. From the survival analysis, it emerged that the most significant laboratory parameters for both outcomes was C-reactive protein min; HR=17.963 (95% CI 6.548-49.277, p < 0.001) for death, HR=1.789 (95% CI 1.000-3.200, p = 0.050) for admission to ICU. The second most important parameter was Erythrocytes max; HR=1.765 (95% CI 1.141-2.729, p < 0.05) for death, HR=1.481 (95% CI 0.895-2.452, p = 0.127) for admission to ICU. The best model for predicting the risk of death was the decision tree, which resulted in ROC-AUC of 89.66%, whereas the best model for predicting the admission to ICU was support vector machine, which had ROC-AUC of 95.07%. The hematochemical predictors identified in this study can be utilized as a strong prognostic signature to characterize the severity of the disease in COVID-19 patients.

Antiphospholipid syndrome: a case report with an unusual wide spectrum of clinical manifestations.

BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the occurrence of venous and/or arterial thrombosis, and the detection of circulating antiphospholipid antibodies. The classification criteria for definite APS are actually met when at least one clinical criterion (thrombosis or pregnancy morbidity) is present in association of one laboratory criterion (LAC, aCL antibody or aß2GPI antibody present on two or more occasions, at least 12 weeks a part), and thrombosis should be confirmed by objective validated criteria. The average age of primary APS patients has been reported to be about 35-40 years and the disease is more common in women than in men. CASE PRESENTATION: In this report, we described a rare case of an adult male who presented over a period of 9 years with a wide spectrum of clinical manifestations involving different organs that were not initially diagnosed as APS. Dizziness and syncope were his first clinical symptoms, and a non-bacterial thrombotic endocarditis (NBTE) involving the mitral valve was at first diagnosed. Subsequently, the patient also presented with generalized seizures and subsequent head injury. When the patient was admitted to our clinic with bilateral epistaxis and fever, thrombocytopenia was revealed. Moreover, laboratory examinations showed acute pancreatitis with an increase of levels of inflammation markers. CONCLUSION: Based on the patient's medical history and all the examination results, it was possible to make a diagnosis of primary APS and, starting from diagnosis of thrombocytopenia, we were allowed to conclude that all of manifestation were epi-phenomena of a unique clinical entity, rather than unrelated diseases. Though APS is one of the most common thrombocytophilias, unfortunately, it is not recognized often enough. The lack of prevention in undiagnosed patients may cause severe complications which can in turn result in the death of those patients.

Corticosteroids for Acute and Recurrent Idiopathic Pericarditis: Unexpected Evidences.

Pericarditis is a common disease, often postviral or "idiopathic," diagnosed in about 5% of emergency room visits for non-ischemic chest pain. Although pericarditis often occurs as a benign and self-limiting disease, it may present recurrences. The first-line therapy includes aspirin/nonsteroidal anti-inflammatory drugs (ASA/NSAIDs) plus colchicine. Steroids especially at high-dose have been associated with a higher recurrence rate. In this retrospective study, we evaluated efficacy and safety of ASA/NSAIDs and prednisone in the treatment of acute or recurrent idiopathic pericarditis (colchicine was off-label in the period of the study). The cohort included 276 patients diagnosed with acute idiopathic pericarditis. Mean age was 45.4 ± 12.7 years, and males were significantly higher in number and younger than females. Sixty-one patients (22.1%) were treated with prednisone and 215 with ASA/NSAIDs (77.9%). 171 patients experienced at least one recurrence (62%). No difference in recurrence rate was observed (p=0.257) between the groups treated with prednisone (55.7%) vs. ASA/NSAIDs (63.7%). The recurrences were treated with steroids at low doses and very gradual tapering, and the dose reduction was slower as the number of relapses was higher. Steroids alone were administered to about 80% of patients, while in the remaining 20% of cases, they were associated with ASA/NSDAIDs or colchicine. Approximately 90% of patients had a very favorable course, that is no more than 2 relapses and no patients presented serious side effects. Steroids at low dose, did not act, surprisingly, as an independent risk factor for recurrences and therefore may be considered a successful and safe treatment for acute and recurrent idiopathic pericarditis.

Assessment of physical performance and body composition in male renal transplant patients.

BACKGROUND: Renal transplant (RTX) recipients seem to experience a better quality of life compared to dialysis patients. However, the factors responsible for this positive effect are not completely defined. Conceivably, a change in the physical performance of these patients could play a role. METHODS: To assess this, we measured: (1) waist circumference, fat mass and appendicular fat-free mass (aFFM) by dual-energy X-ray densitometry, (2) physical performance with the Short Physical Performance Battery, and (3) muscle strength with the handgrip test, in 59 male RTX, 11 chronic kidney disease in conservative treatment (CKD) and 10 peritoneal dialysis (PD) patients. RESULTS: Surprisingly, anthropometric characteristics and body composition were similar among the three groups. However, despite a low aFFM, muscle strength was higher in stable RTX recipients > 5 years after transplantation than in dialyzed patients. Instead, CKD (wait-listed for RTX) had similar muscle strength to RTX patients. Waist circumference in RTX recipients showed a redistribution of body fat with increased central adipose tissue allocation compared to PD. At linear regression analysis, age, weight, height, aFFM, hemoglobin and transplant age were independent predictors of handgrip strength, explaining about 37% of the variance. Age and transplant age accounted for 18 and 12% of variance, respectively. CONCLUSIONS: Our study demonstrates, for the first time, that clinically stable RTX recipients have greater muscle strength than dialyzed patients and suggests that the handgrip test could be an effective and easy-to-perform tool to assess changes in physical performance in this large patient population.

The Potential of ß-Hydroxy-ß-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity.

Sarcopenia is defined as an age-related loss of skeletal muscle mass and function and is recognized as a major clinical problem for older people. Essential amino acid supplementation, particularly ß-hydroxy-ß-methylbutyrate (HMB), a metabolite of leucine that is produced in skeletal muscle, has been evaluated in several studies as a nutritional approach to enhancing muscle protein synthesis in healthy or frail elderly subjects. Studies performed in in vitro conditions show that HMB may be effective in the treatment of muscle wasting, increasing myogenesis, reducing muscle apoptosis, and having a positive effect on muscle protein turnover; however, studies of the effects of HMB conducted in old animals have reported conflicting results. Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects. HMB supplementation results in an increase in skeletal muscle mass and strength in the elderly and its effect is even greater when combined with physical exercise. The role of HMB in sarcopenic obesity management is still under debate and a general lack of intervention studies in this population must be recognized. In conclusion, HMB appears to be effective for enhancing muscle mass and strength in the elderly. Less certain is the role of HMB supplementation in reducing fat mass and, thus, in the treatment of sarcopenic obesity.

Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review.

In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

An unusual association of three autoimmune disorders: celiac disease, systemic lupus erythematosus and Hashimoto's thyroiditis.

Autoimmune disorders are known to be more frequent in women and often associated each others, but it is rare to see multiple autoimmune diseases in a single patient. Recently, the concept of multiple autoimmune syndrome has been introduced to describe patients with at least three autoimmune diseases. We describe a case of a young man with a clinical history of psychiatric symptoms and celiac disease (CD) who was diagnosed to have other two autoimmune disorders: systemic lupus erythematosus (SLE) and Hashimoto's thyroiditis. This case is unusual upon different patterns: the rare combination of the three autoimmune diseases, their appearance in a man and the atypical onset of the diseases with psychiatric symptoms likely to be related either to CD or to SLE.

Coffee Consumption Habits and the Risk of Mild Cognitive Impairment: The Italian Longitudinal Study on Aging.

Coffee, tea, or caffeine consumption may be protective against cognitive impairment and dementia. We estimated the association between change or constant habits in coffee consumption and the incidence of mild cognitive impairment (MCI). We evaluated 1,445 individuals recruited from 5,632 subjects, aged 65-84 year old, from the Italian Longitudinal Study on Aging, a population-based sample from eight Italian municipalities with a 3.5-year median follow-up. Cognitively normal older individuals who habitually consumed moderate amount of coffee (from 1 to 2 cups of coffee/day) had a lower rate of the incidence of MCI than those who never or rarely consumed coffee [1 cup/day: hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.211 to 1.02 or 1-2 cups/day: HR: 0.31 95% CI: 0.13 to 0.75]. For cognitively normal older subjects who changed their coffee consumption habits, those increasing coffee consumption (>1 cup of coffee/day) had higher rate of the incidence of MCI compared to those with constant habits (up to ±1 cup of coffee/day) (HR: 1.80, 95% CI: 1.11 to 2.92) or those with reduced consumption (<1 cup of coffee/day) (HR: 2.17, 95% CI: 1.16 to 4.08). Finally, there was no significant association between subjects with higher levels of coffee consumption (>2 cups of coffee/day) and the incidence of MCI in comparison with those who never or rarely consumed coffee (HR: 0.26, 95% CI: 0.03 to 2.11). In conclusion, cognitively normal older individuals who increased their coffee consumption had a higher rate of developing MCI, while a constant in time moderate coffee consumption was associated to a reduced rate of the incidence of MCI.

Metabolic syndrome, mild cognitive impairment, and progression to dementia. The Italian Longitudinal Study on Aging.

We investigated the relationship of metabolic syndrome (MetS) and its individual components with incidence of mild cognitive impairment (MCI) and its progression to dementia in a large longitudinal Italian population-based sample with a 3.5-year follow-up. A total of 2097 participants from a sample of 5632 65-84-year-old subjects from the Italian Longitudinal Study on Aging were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. MCI, dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were classified using current published criteria. Among MCI patients those with MetS (N=49) had a higher risk of progression to dementia (HR, 4.40; 95% CI, 1.30-14.82) compared with those without MetS (N=72). After a multivariate adjustment, the risk in MCI patients with MetS approximately doubled (multivariate adjusted HR, 7.80, 95% CI 1.29-47.20) compared with those MCI without MetS. Finally, among non-cognitively impaired individuals there were no significant differences in risks of developing MCI in those who were affected by MetS (N=608) in comparison with those without MetS (N=837), as well as excluding those individuals with undernutrition or low inflammatory status with or without undernutrition. In our population, among MCI patients the presence of MetS independently predicted an increased risk of progression to dementia over 3.5 years of follow-up.

Late-life depression, mild cognitive impairment, and dementia: possible continuum?

Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%-83%) than in population-based studies (median: 15.7%, range: 3%-63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.

Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing.

OBJECTIVE: The authors investigated the relationship of metabolic syndrome (MetS) and its individual components with incident dementia in a prospective population-based study with a 3.5-year follow-up. METHODS: A total of 2097 participants from a sample of 5632 subjects (65-84 years old) from the Italian Longitudinal Study on Ageing were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Dementia, Alzheimer disease (AD) and vascular dementia (VaD) were classified using current published criteria. RESULTS: MetS subjects (N=918) compared with those without MetS (N=1179) had an increased risk for VaD (1.63% vs 0.85%, adjusted hazard ratio (HR) 3.71, 95% CI 1.40 to 9.83). After excluding 338 subjects with baseline undernutrition, MetS subjects compared with those without MetS had an elevated risk of VaD (adjusted HR, 3.82; 95% CI 1.32 to 11.06). Moreover, those with MetS and high inflammation had a still further higher risk of VaD (multivariate adjusted HR, 9.55; 95% CI 1.17 to 78.17) compared with those without MetS and high inflammation. On the other hand, those with MetS and low inflammation compared with those without MetS and low inflammation did not exhibit a significant increased risk of VaD (adjusted HR, 3.31, 95% CI 0.91 to 12.14). Finally, a synergistic MetS effect versus its individual component effects was verified on the risk of VaD. CONCLUSION: In our population, MetS subjects had an elevated risk of VaD that increased after excluding patients with baseline undernutrition and selecting MetS subjects with high inflammation.

Interleukin 6-174 G/C promoter and variable number of tandem repeats (VNTR) gene polymorphisms in sporadic Alzheimer's disease.

BACKGROUND: Previous studies examining the association between the interleukin 6 (IL-6)-174 C/G polymorphism and Alzheimer's disease (AD) have yielded conflicting results. Furthermore, the C allele of the IL-6 variable number of tandem repeats (VNTR) polymorphism was associated with a delayed onset and a decreased risk of AD. METHODS: A total sample of 149 AD patients, and 298 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotyped for the apolipoprotein E (APOE) polymorphism, the VNTR polymorphism in the 3' flanking region, and the -174G/C single-nucleotide polymorphism (SNP) in the promoter region of IL-6 gene on chromosome 7. Furthermore, we performed a haplotype analysis on these two polymorphisms on IL-6 locus. RESULTS: IL-6 VNTR and -174G/C allele and genotype frequencies were similar between AD patients and controls, also after stratification for late-onset (> or =65 years) and early-onset (<65 years) or APOE epsilon4 status. Furthermore, there was no evidence of linkage disequilibrium between the VNTR and -174G/C polymorphisms, not supporting a previous reported additive effect of both IL-6 polymorphisms on AD risk. CONCLUSIONS: Our findings did not support a role of IL-6-174 G/C and IL-6 VNTR polymorphisms in the risk of sporadic AD in southern Italy, suggesting that these polymorphisms of IL-6 gene were at most weak genetic determinants of AD.

Dietary fatty acids in dementia and predementia syndromes: epidemiological evidence and possible underlying mechanisms.

Drugs currently used in the treatment of cognitive impairment and dementia have a very limited therapeutic value, suggesting the necessity to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. An increasing body of epidemiological evidence suggested that elevated saturated fatty acids (SFA) could have negative effects on age-related cognitive decline (ARCD) and mild cognitive impairment (MCI). Furthermore, a clear reduction of risk for cognitive decline has been found in population samples with elevated fish consumption, high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. Epidemiological findings demonstrated that high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. Several hypotheses could explain the association between dietary unsaturated fatty acids and cognitive functioning, including mechanisms through the co-presence of antioxidant compounds in food groups rich in fatty acids, via atherosclerosis and thrombosis, inflammation, accumulation of b-amyloid, or via an effect in maintaining the structural integrity of neuronal membranes, determining the fluidity of synaptosomal membranes that thereby regulate neuronal transmission. However, recent findings from clinical trials with n-3 PUFA supplementation showed efficacy on depressive symptoms only in non-apolipoprotein E (APOE) epsilon4 carriers, and on cognitive symptoms only in very mild Alzheimer's disease (AD) subgroups, MCI patients, and cognitively unimpaired subjects non-APOE epsilon4 carriers. These data together with epidemiological evidence support a possible role of fatty acid intake in maintaining adequate cognitive functioning and possibly for the prevention and management of cognitive decline and dementia, but not when the AD process has already taken over.

All-cause mortality and competing risks of fatal and nonfatal vascular events in the Italian longitudinal study on aging: impact of lipoprotein(a).

Among possible determinants of vascular events, the role of high lipoprotein(a) (Lp[a]) serum levels represents a still uncertain independent risk factor in elderly populations. Moreover, the cumulative incidence of nonfatal vascular events due to high Lp(a) serum levels is conditioned by the competing risk of death from any causes that are a function of age. After a 6.3-year median follow up, we tested the competing risks of all-cause mortality, cumulative fatal-nonfatal stroke events, cumulative fatal-nonfatal coronary artery disease (CAD) events, and nonfatal stroke or CAD events due to high Lp(a) serum levels in a population-based, prospective study conducted in one of the eight centers of the Italian Longitudinal Study on Aging (ILSA), Casamassima, Bari, Italy. Of 704 elderly individuals (65-84 years), 372 (169 women and 203 men) agreed to participate in the study. As compared with those in the lowest Lp(a) tertile serum levels, subjects in the highest tertile (>20 mg/dL) had a higher partially adjusted risk of nonfatal CAD (hazard ratio, 4.19; 95% confidence interval [CI], 1.36-12.94) and nonfatal stroke (hazard ratio, 3.38; 95% CI, 1.00-11.56). Compared with those in the lowest tertile, subjects in the highest tertile had a higher fully adjusted risk of nonfatal CAD (hazard ratio, 3.41; 95% CI, 1.08-10.78). Finally, overall no statistically significant association was found between Lp(a) and the risk of all-cause mortality, cumulative fatal-nonfatal stroke, and cumulative fatal-nonfatal CAD events. In our population, Lp(a) was not a significant independent predictor of stroke and death from all causes, but it was an independent predictor of nonfatal CAD. Finally competing risk, conditioning the timing and occurrence of vascular events in our study population, could be a correct approach for evaluating the role of Lp(a) lipoprotein in vascular disease among elderly people.

Dietary fatty acids and predementia syndromes.

An increasing body of epidemiological evidence suggests that elevated saturated fatty acids (SFA) could have negative effects on age-related cognitive decline (ARCD). Furthermore, a reduction of risk for cognitive decline and mild cognitive impairment (MCI) has been found in population samples with elevated fish consumption, and high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. However, recent findings from clinical trials with n-3 PUFA supplementation showed efficacy on depressive symptoms in non-apolipoprotein E (APOE) epsilon4 carriers, and on cognitive symptoms only in very mild Alzheimer's disease (AD) subgroups, MCI patients, and cognitively unimpaired non-APOE epsilon4 carriers. These data, together with epidemiological evidence, support the idea that n-3 PUFA may play a role in maintaining adequate cognitive functioning in predementia syndromes, but not when the AD process has already taken over. Therefore, at present, no definitive dietary recommendations on fish and unsaturated fatty acids consumption, or lower intake of saturated fat, in relation to the risk for dementia and cognitive decline are possible.

Disease-modifying approach to the treatment of Alzheimer's disease: from alpha-secretase activators to gamma-secretase inhibitors and modulators.

In the last decade, advances in understanding the neurobiology of Alzheimer's disease (AD) have translated into an increase in clinical trials assessing various potential AD treatments. At present, drugs used for the treatment of AD only slightly delay the inevitable symptomatic progression of the disease and do not affect the main neuropathological hallmarks of the disease, i.e. senile plaques and neurofibrillary tangles. Brain accumulation of oligomeric species of beta-amyloid (A beta) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being made to identify drugs able to interfere with proteases regulating A beta formation from amyloid precursor protein (APP). Compounds that stimulate alpha-secretase, the enzyme responsible for non-amyloidogenic metabolism of APP, are being developed and one of these, EHT-0202, has recently commenced evaluation in a phase II study. The discovery of inhibitors of beta-secretase (memapsin-2, beta-amyloid cleaving enzyme-1 [BACE-1]), the enzyme that regulates the first step of amyloidogenic APP metabolism, has proved to be particularly difficult because of inherent medicinal chemistry issues and only one compound (CTS-21166) has proceeded to clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates A beta, have been identified, the most advanced being LY-450139 (semagacestat), presently in phase III clinical development. There has been considerable disappointment over the failure of a phase III study of tarenflurbil, a compound believed to modulate the activity of gamma-secretase, after encouraging phase II findings. Nevertheless, other promising gamma-secretase modulators are being developed and are approaching clinical testing. All these therapeutic approaches increase the hope of slowing the rate of decline in patients with AD and modifying the natural history of this devastating disease within the next 5 years.