Alzheimer's Disease Medications Research Articles

Polypharmacy in Alzheimer's disease patients in Brazil: Guidance for pharmaceutical assistance

Background: Elderly patients frequently have concomitant diseases, triggering the necessity of utilizing several different medications, which can cause adverse events associated with therapy, called polypharmacy. This study aimed to evaluate the main concomitant diseases with Alzheimer's disease (AD) and discuss possible interactions between drugs utilized to treat dementia and its comorbidities, and indicate safe medicines for patients with AD. Methods: 41 individuals with AD who withdraw medicines for dementia from the Brazilian public health system (SUS) participated in this study. Data collection was performed using three questionnaires: 1) Clinical Dementia Rating, to verify disease stage; 2) Mini–mental state examination, to measure cognitive impairment; and 3) Sociodemographic analysis, to evaluate concomitant diseases, utilized drugs, drug-drug interactions, among other demographic variables. Statistical analyses were performed using SPSS and data was presented as relative frequency. Results: The results of this study showed that the most frequent concomitant diseases with AD are: systemic arterial hypertension, depression, diabetes mellitus, and hypercholesterolemia. Polypharmacy was observed in 95.12% of patients. The pharmacologic classes that presented interactions with AD medications were anxiolytics, antidepressants, antipsychotics, antihypertensives, and antidiabetics. Conclusion: In the present study, polypharmacy in patients with AD and other concomitant diseases has been characterized. The average number of drugs that these patients ingested was seven per day, and this leads to drug interactions, which are potentially damaging to the body. Consequently, we have tried to reduce these interactions, by suggesting drugs that are safer, for example furosemide instead of amlodipine to treat hypertension.

Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease.

Background:Effectiveness of Alzheimer’s disease (AD) treatments may depend critically on the timeliness of intervention.Objective:To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline.Methods:Patients with ≥1 prAD diagnosis and ≥1 follow-up visit were selected from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and medication use following prAD diagnosis were compared.Results:Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: ≤3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of ≥3 points in MMSE (median 23.2 versus 23.1 months, p = 0.83), but earlier-diagnosed patients had longer time to a CDR score of ≥2 points, and longer times to initiation of AD medication and antipsychotic agents (all p < 0.01).Conclusion:Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis.

OBSERVATIONAL LONGITUDINAL STUDY OF BRAIN MRI CHARACTERISTICS AND CLINICAL MEASURES OF FUNCTION AND DISEASE PROGRESSION IN PATIENTS WITH DEMENTIA

Longitudinal brain magnetic resonance imaging (MRI) has shown that changes in white matter and medial temporal atrophy are biomarkers of Alzheimer's disease (AD); however, the correlation with MRI findings and progression of AD has not been fully established. In this prospective, 12-month observational study, consecutive dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments included confirmation of AD (brain MRI data), cognitive function, dementia severity, activities of daily living (ADL), and AD medication use. Follow-up assessments were conducted at 6 and 12 months. Among the 899 enrolled patients with dementia, 748 were diagnosed with AD based on MRI assessment; 654 (87%) were using AD medications. In AD patients, changes in cognitive deficit were not correlated with changes in white matter on brain MRI and changes in IADL, but not other cognitive function, correlated with the changes in hippocampal atrophy on brain MRI. These results were more prominent in untreated group. Positive drinking status and higher CDR score were correlated with more severe white matter changes and age, dementia family history, physical exercise, and the results of neuropsychological assessment were correlated with hippocampal atrophy. We confirmed that there is a relationship between the loss of hippocampal volume in MRI and changes in IADL decline with AD patients, especially untreated group, and showed that patient's lifestyle behaviors are more important than non-modifiable factors in the progression of the MRI findings in this study.

Diabetes in a Large Dementia Cohort: Clinical Characteristics and Treatment From the Swedish Dementia Registry.

OBJECTIVEWe aimed to investigate the differences in clinical characteristics and pharmacological treatment associated with the presence of diabetes in a large cohort of patients with dementia.RESEARCH DESIGN AND METHODSA cross-sectional registry-based study was conducted using data from the Swedish Dementia Registry (SveDem). Data on dementia diagnosis, dementia type, and demographic determinants were extracted from SveDem. Data from the Swedish Patient Register and Prescribed Drug Register were combined for the diagnosis of diabetes. Data on antidiabetic, dementia, cardiovascular, and psychotropic medications were extracted from the Swedish Prescribed Drug Register. Logistic regression was used to determine whether the variables were associated with diabetes after adjustment for confounders. In total, 29,630 patients were included in the study, and 4,881 (16.5%) of them received a diagnosis of diabetes.RESULTSIn the fully adjusted model, diabetes was associated with lower age at dementia diagnosis (odds ratio [OR] 0.97 [99% CI 0.97–0.98]), male sex (1.41 [1.27–1.55]), vascular dementia (1.17 [1.01–1.36]), and mixed dementia (1.21 [1.06–1.39]). Dementia with Lewy bodies (0.64 [0.44–0.94]), Parkinson disease dementia (0.46 [0.28–0.75]), and treatment with antidepressants (0.85 [0.77–0.95]) were less common among patients with diabetes. Patients with diabetes who had Alzheimer disease obtained significantly less treatment with cholinesterase inhibitors (0.78 [0.63–0.95]) and memantine (0.68 [0.54–0.85]).CONCLUSIONSPatients with diabetes were younger at dementia diagnosis and obtained less dementia medication for Alzheimer disease, suggesting less optimal dementia treatment. Future research should evaluate survival and differences in metabolic profile in patients with diabetes and different dementia disorders.

The Mechanisms of Action of Curcumin inAlzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. As the prevalence of AD rises in the 21st century, there is an urgent need for the development of effective pharmacotherapies. Currently, drug treatments target the symptoms of the disease and do not modify or halt the disease progress. Thus, natural compounds have been investigated for their ability to treat AD. This review examines the efficacy of curcumin, a polyphenol derived from turmeric herb, to treat AD. We summarize the in vivo and in vitro research describing the mechanisms of action in which curcumin modifies AD pathology: curcumin inhibits the formation and promotes the disaggregation of amyloid-β plaques, attenuates the hyperphosphorylation of tau and enhances its clearance, binds copper, lowers cholesterol, modifies microglial activity, inhibits acetylcholinesterase, mediates the insulin signaling pathway, and is an antioxidant. In conclusion, curcumin has the potential to be more efficacious than current treatments. However, its usefulness as a therapeutic agent may be hindered by its low bioavailability. If the challenge of low bioavailability is overcome, curcumin-based medications for AD may be in the horizon.

Improving medication adherence among community-dwelling seniors with cognitive impairment: a systematic review of interventions.

Background Medication non-adherence may lead to poor therapeutic outcomes. Cognitive functions deteriorate with age, contributing to decreased adherence. Interventions have been tested to improve adherence in seniors with cognitive impairment or Alzheimer disease (AD), but high-quality systematic reviews are lacking. It remains unclear which interventions are promising. Objectives We conducted a systematic review to identify, describe, and evaluate interventions aimed at improving medication adherence among seniors with any type of cognitive impairment. Methods Following NICE guidance, databases and websites were searched using combinations of controlled and free vocabulary. All adherence-enhancing interventions and study designs were considered. Studies had to include community dwelling seniors, aged 65years or older, with cognitive impairment, receiving at least one medication for a chronic condition, and an adherence measure. Study characteristics and methodological quality were assessed. Results We identified 13 interventions, including six RCTs. Two studies were of poor, nine of low/medium and two of high quality. Seven studies had sample sizes below 50 and six interventions focused on adherence to AD medication. Six interventions tested a behavioral, four a medication oriented, two an educational and one a multi-faceted approach. Studies rarely assessed therapeutic outcomes. All but one intervention showed improved adherence. Conclusion Three medium quality studies showed better adherence with patches than with pills for AD treatment. Promising interventions used educational or reminding strategies, including one high quality RCT. Nine studies were of low/moderate quality. High quality RCTs using a theoretical framework for intervention selection are needed to identify strategies for improved adherence in these seniors.

Diabetes mellitus and risk of early-onset Alzheimer's disease: a population-based case-control study.

Previous studies have reported that diabetes is a risk factor for both all-cause and vascular dementia; however, diabetes as a risk factor for Alzheimer's disease (AD) remains controversial. Therefore, the aim was to elucidate the association between diabetes and early-onset AD. A case-control study was conducted using a population-based database that included medical and pharmacy claims and insurance eligibility data, from beneficiaries of corporate employees and their dependent family members. Cases were aged 40-64 years and were first prescribed medications for AD between 2005 and 2016. Up to four controls matched for age, sex and hospital type were included for each case. Data were analyzed using conditional logistic regression and compared between the sexes. Data from 371 patients with AD (mean age 56.3 ± 5.3 years; 48% female) and 1484 controls were analyzed. Use of antidepressants, antipsychotics and antithrombotics during the index month was higher amongst patients with AD (19.4%, 34.5% and 11.3%, respectively) than amongst controls (2.9%, 10.3% and 7.3%, respectively). Our findings suggest no evidence for an association between diabetes and risk of early-onset AD (adjusted odds ratio 1.31; 95% confidence interval 0.90-1.92). In the subgroup analyses, adjusted odds ratios in patients with diabetes were 0.73 (95% confidence interval 0.38-1.39) and 1.68 (95% confidence interval 1.06-2.67) for female and male patients, respectively. There is no apparent association between diabetes and risk of early-onset AD in the total study population, although a weak association was observed amongst male patients.

Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans

Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8h after dosing in humans or 1, 2.5, and 5h in rats. Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.

Development of Clinical Vignettes to Describe Alzheimer's Disease Health States: A Qualitative Study.

AimsTo develop clinical descriptions (vignettes) of life with Alzheimer’s disease (AD), we conducted focus groups of persons with AD (n = 14), family caregivers of persons with AD (n = 20), and clinicians who see persons with AD in their practices (n = 5).MethodsGroup participants read existing descriptions of AD and commented on the realism and comprehensibility of the descriptions. We used thematic framework analysis to code the comments into themes and develop three new vignettes to describe mild, moderate, and severe AD.ResultsThemes included the types of symptoms to mention in the new vignettes, plus the manner in which the vignettes should be written. Since the vignette descriptions were based on focus group participants’ first-hand knowledge of AD, the descriptions can be said to demonstrate content validity.ConclusionMembers of the general public can read the vignettes and estimate their health-related quality-of-life (HRQoL) as if they had AD based on the vignette descriptions. This is especially important for economic evaluations of new AD medications, which require HRQoL to be assessed in a manner that persons with AD often find difficult to undertake. The vignettes will allow the general public to serve as a proxy and provide HRQoL estimates in place of persons with AD.

I'd Do Anything for Research, But I Won't Do That: Interest in Pharmacological Interventions in Older Adults Enrolled in a Longitudinal Aging Study.

Alzheimer’s disease (AD) ranks as the 6th leading cause of death in the United States, yet unlike other diseases in this category, there are no disease-modifying medications for AD. Currently there is significant interest in exploring the benefits of pharmacological treatment before the onset of dementia (e.g., in those with mild cognitive impairment); however, recruitment for such studies is challenging. The current study examined interest in pharmacological intervention trials relative to other types of clinical interventions. A total of 67 non-demented older adults enrolled in a longitudinal cognitive aging study completed a questionnaire assessing interest in participating in a variety of hypothetical research study designs. Consistent with past research, results showed that the opportunities for participants to advance science, receive feedback about their current health, and help themselves or others, were associated with increased interest in clinical trial participation. Some factors were not associated with change in interest (e.g., a doctor not recommending participation) while others were associated with decreased interest (e.g., having to come in for multiple visits each week). Relative to other types of interventions, pharmacological intervention trials were associated with the least interest in participation, despite pharmacological interventions being rated as more likely to result in AD treatment. Decreased interest was not predicted by subjective memory concerns, number of current medications, cardiovascular risk, or beliefs about the likely success of pharmacological treatments. These results highlight the challenges faced by researchers investigating pharmacological treatments in non-demented older individuals, and suggest future research could contribute to more effective ways of recruiting participants in AD-related clinical trials.

The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease.

The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age‐related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS‐related therapies for AD.

The acquisition of medication to treat Alzheimer's disease in Brazil: an analysis of federal purchases, 2008-2013

The demographic transition in Brazil has led to substantial aging of the population and an increased prevalence of age-related diseases such as dementia and Alzheimer's Disease (AD). The Brazilian Ministry of Health finances AD medication and, since 2002, a Clinical Protocol and Therapeutic Guidelines (PCDT) for this condition have been made available. This study investigated the acquisition of medication for AD in the Integrated System of Administration of General Services (SIASG) database. A profile of purchases, expenditures and prices from 2008 to 2013 was prepared. All medication and forms of treatment of AD were investigated, including those not contained in the PCDT protocol. Unit prices were deflated to December 2013 by the IPCA (Brazilian Pricing Index). More than 47 million units of medication for AD were acquired and expenditures attained 90.1 million Brazilian reals. The purchase of the various administration routes of rivastigmine were in the forefront. Medication not listed in the protocol represented 3% of expenditures and purchases resulting from health litigation were negligible. Over the period, a reduction of corrected weighted average prices of PCDT and non-PCDT medication was observed.

No Evidence to Suggest that the Use of Acetylcholinesterase Inhibitors Confounds the Results of Two Blood-Based Biomarker Studies in Alzheimer's Disease.

There is an urgent need to discover Alzheimer's disease (AD) biomarkers that are both easily measured and reliable. Research into blood-based biomarkers for AD using transcriptomics and proteomics has been an attractive and promising area of research. However, to date researchers have not looked into the possibility of AD medication being a confounding factor in these studies. This study explored whether acetylcholinesterase inhibitors (AChEIs), the main class of AD medication, are a confounding factor in AD blood biomarker studies. The most promising blood transcriptomic and proteomic biomarkers from two recent studies were analyzed to determine if they were differentially expressed between AD subjects on AChEIs and subjects that were not. None of the gene or protein biomarkers analyzed were found to be significantly altered between subjects in either group. This study found no evidence that AChEIs are a confounding factor in these published AD blood biomarker studies. Further work is needed to confirm that this is also the case for other proposed biomarkers.

Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study.

The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.

An updated Alzheimer's disease progression model: incorporating non-linearity, beta regression, and a third-level random effect in NONMEM.

Our objective was to expand our understanding of the predictors of Alzheimer's disease (AD) progression to help design a clinical trial on a novel AD medication. We utilized the Coalition Against Major Diseases AD dataset consisting of control-arm data (both placebo and stable background AD medication) from 15 randomized double-blind clinical trials in mild-to-moderate AD patients (4,495 patients; July 2013). Our ADAS-cog longitudinal model incorporates a beta-regression with between-study, -subject, and -residual variability in NONMEM; it suggests that faster AD progression is associated with younger age and higher number of apolipoprotein E type 4 alleles (APOE*4), after accounting for baseline disease severity. APOE*4, in particular, seems to be implicated in the AD pathogenesis. In addition, patients who are already on stable background AD medications appear to have a faster progression relative to those who are not receiving AD medication. The current knowledge does not support a causality relationship between use of background AD medications and higher rate of disease progression, and the correlation is potentially due to confounding covariates. Although causality has not necessarily been demonstrated, this model can inform inclusion criteria and stratification, sample size, and trial duration.

The use of medications approved for Alzheimer's disease in autism spectrum disorder: a systematic review.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects 1 in 68 children in the United States. Even though it is a common disorder, only two medications (risperidone and aripiprazole) are approved by the U.S. Food and Drug Administration (FDA) to treat symptoms associated with ASD. However, these medications are approved to treat irritability, which is not a core symptom of ASD. A number of novel medications, which have not been approved by the FDA to treat ASD have been used off-label in some studies to treat ASD symptoms, including medications approved for Alzheimer’s disease. Interestingly, some of these studies are high-quality, double-blind, placebo-controlled (DBPC) studies. This article systematically reviews studies published through April, 2014, which examined the use of Alzheimer’s medications in ASD, including donepezil (seven studies, two were DBPC, five out of seven reported improvements), galantamine (four studies, two were DBPC, all reported improvements), rivastigmine (one study reporting improvements), tacrine (one study reporting improvements), and memantine (nine studies, one was DBPC, eight reported improvements). An evidence-based scale was used to rank each medication. Collectively, these studies reported improvements in expressive language and communication, receptive language, social interaction, irritability, hyperactivity, attention, eye contact, emotional lability, repetitive or self-stimulatory behaviors, motor planning, disruptive behaviors, obsessive–compulsive symptoms, lethargy, overall ASD behaviors, and increased REM sleep. Reported side effects are reviewed and include irritability, gastrointestinal problems, verbal or behavioral regression, headaches, irritability, rash, tremor, sedation, vomiting, and speech problems. Both galantamine and memantine had sufficient evidence ranking for improving both core and associated symptoms of ASD. Given the lack of medications approved to treat ASD, further studies on novel medications, including Alzheimer’s disease medications, are needed.

Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats.

Alzheimer's disease (AD) has been called the disease of the century with significant clinical and socioeconomic impacts. Pharmacological treatment has limited efficacy and only provides symptomatic relief without long-term cure. Accordingly, there is an urgent need to develop novel and effective medications for AD. Stem cell-based therapy is a promising approach to handling neurodegenerative diseases. Therefore, the current study aimed to explore the possible therapeutic role of single intravenous injection of bone marrow derived mesenchymal stem cells (BM-MSCs) after 4 months in management of AD in the experimental model. The work also extended to compare the therapeutic potential of BM-MSCs with 2 conventional therapies of AD; rivastigmine and cerebrolysin administered daily. BM-MSCs were able to home at the injured brains and produced significant increases in the number of positive cells for choline acetyltransferase (ChAT) and survivin expression, as well as selective AD indicator-1 (seladin-1) and nestin gene expression. Histopathological examination indicated that BM-MSCs could remove beta-amyloid plaques from hippocampus. Significant improvement in these biomarkers was similar to or better sometimes than the reference drugs, clearly showing the potential therapeutic role of BM-MSCs against AD through their anti-apoptotic, neurogenic and immunomodulatory properties.

Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the leading progressive neurodegenerative disorder afflicting 35.6 million people worldwide. There is no therapeutic agent that can slow or stop the progression of AD. Human studies show that besides loss of cognition/learning ability, neuropsychological symptoms such as anxiety and seizures are seen as high as 70 and 17% respectively in AD patients, suggesting dysfunction of GABAergic neurotransmission contributes to pathogenesis of AD. Dihydromyricetin (DHM) is a plant flavonoid and a positive allosteric modulator of GABAARs we developed recently (Shen et al. in J Neurosci 32(1):390-401, 2012 [1]). In this study, transgenic (TG2576) and Swedish transgenic (TG-SwDI) mice with AD-like pathology were treated with DHM (2mg/kg) for 3months. Behaviorally, DHM-treated mice show improved cognition, reduced anxiety level and seizure susceptibility. Pathologically, DHM has high efficacy to reduce amyloid-β (Aβ) peptides in TG-SwDI brain. Further, patch-clamp recordings from dentate gyrus neurons in hippocampal slices from TG-SwDI mice showed reduced frequency and amplitude of GABAAR-mediated miniature inhibitory postsynaptic currents, and decreased extrasynaptic tonic inhibitory current, while DHM restored these GABAAR-mediated currents in TG-SwDI. We found that gephyrin, a postsynaptic GABAAR anchor protein that regulates the formation and plasticity of GABAergic synapses, decreased in hippocampus and cortex in TG-SwDI. DHM treatment restored gephyrin levels. These results suggest that DHM treatment not only improves symptoms, but also reverses progressive neuropathology of mouse models of AD including reducing Aβ peptides, while restoring gephyrin levels, GABAergic transmission and functional synapses. Therefore DHM is a promising candidate medication for AD. We propose a novel target, gephyrin, for treatment of AD.

Kidney Function and Prevalent and Incident Frailty

Kidney disease is associated with physiologic changes that may predispose to frailty. This study sought to investigate whether lower levels of kidney function were associated with prevalent or incident frailty in Cardiovascular Health Study (CHS) participants. CHS enrolled community-dwelling adults age ≥65 years between 1989-1990 and 1992-1993. To examine prevalent frailty, included were 4150 participants without stroke, Parkinson disease, prescribed medications for Alzheimer disease or depression, or severely impaired cognition. To examine incident frailty, included were a subset of 3459 participants without baseline frailty or development of exclusion criteria during follow-up. The primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR(cys)). Secondary analyses examined eGFR using serum creatinine (eGFR(SCr)). Outcomes were prevalent frailty and incident frailty at 4 years of follow-up. Frailty was ascertained on the basis of weight loss, exhaustion, weakness, slowness, and low physical activity. The mean age was 75 years and the median eGFR(cys) was 73 ml/min per 1.73 m(2). Among participants with an eGFR(cys) <45 ml/min per 1.73 m(2), 24% had prevalent frailty. In multivariable analysis and compared with eGFR(cys) ≥90 ml/min per 1.73 m(2), eGFR(cys) categories of 45-59 (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.17 to 2.75) and 15-44 (OR, 2.87; 95% CI, 1.72 to 4.77) were associated with higher odds of frailty, whereas 60-75 (OR, 1.14; 95% CI, 0.76 to 1.70) was not. In multivariable analysis, eGFR(cys) categories of 60-75 (incidence rate ratio [IRR], 1.72; 95% CI, 1.07 to 2.75) and 15-44 (IRR, 2.28; 95% CI, 1.23 to 4.22) were associated with higher incidence of frailty whereas 45-59 (IRR, 1.53; 95% CI, 0.90 to 2.60) was not. Lower levels of eGFR(SCr) were not associated with higher risk of prevalent or incident frailty. In community-dwelling elders, lower eGFR(cys) was associated with a higher risk of prevalent and incident frailty whereas lower eGFR(SCr) was not. These findings highlight the importance of considering non-GFR determinants of kidney function.

Discovering New Treatments for Alzheimer's Disease by Repurposing Approved Medications

Alzheimer's disease (AD) is the most common cause of dementia and a major cause of morbidity and mortality. The greatest risk factor for AD is age and as many countries are experiencing an aging population, the expected rise in AD threatens to have serious medical and socioeconomic impact in the coming decades. The only approved medications for AD are symptomatic and there are no currently available disease modifying treatments. Hence, a disease modifying treatment is desperately needed for AD not only for proper care and management of affected patients, but also to reduce society's socioeconomic burden. Developing novel compounds for any indication is a time, effort, and money consuming endeavor and most treatments never make it to market. Other research and development strategies are needed, especially for the treatment of AD. We provide a review of the current literature in assessing possibilities of repurposing medications currently used for non-AD indications. Many different compounds from many different pharmacological classes have already been studied in an AD context. We provide a "pragmatic drug repurposing score" for each of these compounds based on type of studies conducted, number of possible mechanisms of action, efficacy in AD and other neurodegenerative disease studies, tolerability profile, and their ability to cross the blood brain barrier. The current data suggest several compounds worthy of further study as treatments for AD. Compounds with the highest scores include lithium, minocycline, exenatide, valproic acid, methylene blue, and nicotine.