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1.
JCI Insight ; 8(22)2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37815864

RESUMO

Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.


Assuntos
Mitocôndrias Musculares , Músculo Esquelético , Atrofia Muscular , Animais , Humanos , Camundongos , Envelhecimento , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Mitocôndrias Musculares/metabolismo , Debilidade Muscular/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia
2.
Nat Commun ; 14(1): 3392, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37296100

RESUMO

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2's known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.


Assuntos
Amidoidrolases , Arginina , Camundongos , Animais , Amidoidrolases/metabolismo , Arginina/metabolismo , Óxido Nítrico/metabolismo
3.
Mol Metab ; 68: 101670, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36642217

RESUMO

OBJECTIVE: Skeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen-related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function. METHODS: We assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity. RESULTS: ERRs were induced in human skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRß and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis. CONCLUSIONS: Our findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles.


Assuntos
Músculo Esquelético , Doenças Musculares , Humanos , Camundongos , Animais , Músculo Esquelético/metabolismo , Metabolismo Energético , Isoformas de Proteínas/metabolismo , Estrogênios/metabolismo , Lipídeos
4.
J Biomed Mater Res B Appl Biomater ; 110(7): 1535-1544, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35090200

RESUMO

Brain aneurysms can be treated with embolic coils using minimally invasive approaches. It is advantageous to modulate the biologic response of platinum embolic coils. Our previous studies demonstrated that shape memory polymer (SMP) foam coated embolization coils (FCC) devices demonstrate enhanced healing responses in animal models compared with standard bare platinum coil (BPC) devices. Macrophages are the most prevalent immune cell type that coordinate the greater immune response to implanted materials. Hence, we hypothesized that the highly porous SMP foam coatings on embolic coils activate a pro-regenerative healing phenotype. To test this hypothesis, we analyzed the number and type of infiltrating macrophages in FCC or BPC devices implanted in a rabbit elastase aneurysm model. FCC devices elicited a great number of infiltration macrophages, skewed significantly to a pro-regenerative M2-like phenotype 90 days following implantation. We devised an in vitro assay, where monocyte-derived macrophages were placed in close association with FCC or BPC devices for 6-72 h. Macrophages encountering SMP FCC-devices demonstrated highly mixed activation phenotypes at 6 h, heavily skewing toward an M2-like phenotype by 72 h, compared with macrophages encountering BPC devices. Macrophage activation was evaluated using gene expression analysis, and secreted cytokine evaluation. Together, our results demonstrate that FCC devices promoted a pro-regenerative macrophage activation phenotype, compared with BPC devices. Our in vitro findings corroborate with in vivo observations that SMP-based modification of embolic coils can promote better healing of the aneurysm site, by sustaining a pro-healing macrophage phenotype.


Assuntos
Embolização Terapêutica , Aneurisma Intracraniano , Materiais Inteligentes , Animais , Prótese Vascular , Aneurisma Intracraniano/cirurgia , Ativação de Macrófagos , Platina , Coelhos
5.
Nutrients ; 13(1)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466705

RESUMO

Obesity prevention involves promoting healthy eating and physical activity across all children. Can we leverage technology to feasibly survey children's health behaviors and deliver theory-based and user-tailored messages for brief clinical encounters? We assessed the acceptability and utility of an online pediatric-adapted liking survey (PALS) and tailored messages among children receiving non-urgent care in a pediatric emergency department (PED). Two hundred and forty-five children (average age = 10 years, racially/ethnically diverse, 34% overweight/obese from measured indices, 25% of families reporting food insecurity) and their parents/caregivers participated. Each reported the child's activity and behaviors using the online PALS and received two to three messages tailored to the responses (aligned with elaboration likelihood and transtheoretical models) to motivate behavioral improvements or reinforce healthy behaviors. Most children and parents (>90%) agreed the PALS was easy to complete, encouraging thought about their own/child's behaviors. The child's PALS responses appeared reasonable (fair-to-good child-parent intraclass correlations). Most children and parents (≥75%) reported the tailored messages to be helpful and favorable for improving or maintaining the targeted behavior. Neither message type (motivating/reinforcing) nor favorability responses varied significantly by the child's weight or family's food security status. In summary, children and parents found the PALS with tailored messages acceptable and useful. The message types and responses could help focus brief clinical encounters.


Assuntos
Comportamentos Relacionados com a Saúde/fisiologia , Promoção da Saúde/métodos , Obesidade Infantil , Adolescente , Criança , Pré-Escolar , Exercício Físico/fisiologia , Feminino , Humanos , Internet , Masculino , Pais , Satisfação do Paciente , Obesidade Infantil/diagnóstico , Obesidade Infantil/prevenção & controle , Inquéritos e Questionários , Telemedicina/métodos
6.
JACC Basic Transl Sci ; 4(2): 147-157, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31061916

RESUMO

Negative alterations of mitochondria are known to occur in heart failure (HF). This study investigated the novel mitochondrial-targeted therapeutic agent elamipretide on mitochondrial and supercomplex function in failing human hearts ex vivo. Freshly explanted failing and nonfailing ventricular tissue from children and adults was treated with elamipretide. Mitochondrial oxygen flux, complex (C) I and CIV activities, and in-gel activity of supercomplex assembly were measured. Mitochondrial function was impaired in the failing human heart, and mitochondrial oxygen flux, CI and CIV activities, and supercomplex-associated CIV activity significantly improved in response to elamipretide treatment. Elamipretide significantly improved failing human mitochondrial function.

7.
Can Geriatr J ; 21(2): 139-142, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29977428

RESUMO

BACKGROUND: The purpose of this pilot study was to explore the potential of eye-tracking technology in monitoring symptoms and predicting outcomes in apathetic Alzheimer's disease (AD) patients treated with methylphenidate (MTP). METHODS: Neuropsychological tests and eye-tracking measurements were completed at baseline and following at least four weeks of treatment with MTP (5-10 mg BID). Eye-movements were measured while patients viewed novel and social stimuli. Cognition, behavior, and apathy were assessed using the Standardized Mini-Mental State Exam (sMMSE), Neuropsychiatric Inventory, and Apathy Evaluation Scale (AES), respectively. RESULTS: Nine patients were included in the analysis (age: median=75, interquartile range=8; sMMSE: median=22, interquartile range=14). Spearman correlations showed that improvement on the AES was associated with increased visual attention towards novel stimuli (ρ7=-0.809, p=.008). Additionally, lower baseline attention towards social images was associated with improvement on the AES (ρ7=0.905, p=.001). CONCLUSIONS: Eye-tracking techniques can be developed as an objective and nonverbal method of monitoring symptoms and treatment outcomes in AD patients.

8.
Am J Physiol Heart Circ Physiol ; 315(4): H1051-H1062, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30028197

RESUMO

Sudden cardiac death from ventricular arrhythmias is more common in adult patients with with heart failure compared with pediatric patients with heart failure. We identified age-specific differences in arrhythmogenesis using a guinea pig model of acute ß-adrenergic stimulation. Young and adult guinea pigs were exposed to the ß-adrenergic agonist isoproterenol (ISO; 0.7 mg/kg) for 30 min in the absence or presence of flecainide (20 mg/kg), an antiarrhythmic that blocks Na+ and ryanodine channels. Implanted cardiac monitors (Reveal LINQ, Medtronic) were used to monitor heart rhythm. Alterations in phosphorylation and oxidation of ryanodine receptor 2 (RyR2) were measured in left ventricular tissue. There were age-specific differences in arrhythmogenesis and sudden death associated with acute ß-adrenergic stimulation in guinea pigs. Young and adult guinea pigs developed arrhythmias in response to ISO; however, adult animals developed significantly more premature ventricular contractions and experienced higher arrhythmia-related mortality than young guinea pigs treated with ISO. Although there were no significant differences in the phosphorylation of left ventricular RyR2 between young and adult guinea pigs, adult guinea pigs exposed to acute ISO had significantly more oxidation of RyR2. Flecainide treatment significantly improved survival and decreased the number of premature ventricular contractions in young and adult animals in association with lower RyR2 oxidation. Adult guinea pigs had a greater propensity to develop arrhythmias and suffer sudden death than young guinea pigs when acutely exposed to ISO. This was associated with higher oxidation of RyR2. The incidence of sudden death can be rescued with flecainide treatment, which decreases RyR2 oxidation. NEW & NOTEWORTHY Clinically, adult patients with heart failure are more likely to develop arrhythmias and sudden death than pediatric patients with heart failure. In the present study, older guinea pigs also showed a greater propensity to arrhythmias and sudden death than young guinea pigs when acutely exposed to isoproterenol. Although there are well-described age-related cardiac structural changes that predispose patients to arrhythmogenesis, the present data suggest contributions from dynamic changes in cellular signaling also play an important role in arrhythmogenesis.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Morte Súbita Cardíaca/etiologia , Frequência Cardíaca , Ventrículos do Coração/fisiopatologia , Isoproterenol , Função Ventricular Esquerda , Potenciais de Ação , Fatores Etários , Animais , Antiarrítmicos/farmacologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/prevenção & controle , Morte Súbita Cardíaca/prevenção & controle , Modelos Animais de Doenças , Feminino , Flecainida/farmacologia , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Masculino , Oxirredução , Fosforilação , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos
9.
iScience ; 2: 221-237, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29888756

RESUMO

Adrenergic stimulation of brown adipose tissue (BAT) induces acute and long-term responses. The acute adrenergic response activates thermogenesis by uncoupling oxidative phosphorylation and enabling increased substrate oxidation. Long-term, adrenergic signaling remodels BAT, inducing adaptive transcriptional changes that expand thermogenic capacity. Here, we show that the estrogen-related receptors alpha and gamma (ERRα, ERRγ) are collectively critical effectors of adrenergically stimulated transcriptional reprogramming of BAT. Mice lacking adipose ERRs (ERRαγAd-/-) have reduced oxidative and thermogenic capacity and rapidly become hypothermic when exposed to cold. ERRαγAd-/- mice treated long term with a ß3-adrenergic agonist fail to expand oxidative or thermogenic capacity and do not increase energy expenditure in response to norepinephrine (NE). Furthermore, ERRαγAd-/- mice fed a high-fat diet do not lose weight or show improved glucose tolerance when dosed with ß3-adrenergic agonists. The molecular basis of these defects is the finding that ERRs mediate the bulk of the transcriptional response to adrenergic stimulation.

10.
J Alzheimers Dis ; 55(4): 1339-1349, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27834775

RESUMO

BACKGROUND: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Using visual scanning parameters, selective attention toward novel stimuli, or novelty preference, can be measured by a non-verbal, non-invasive method that may be of value in predicting disease progression. OBJECTIVE: In this longitudinal study, we explored whether novelty preference can predict cognitive decline in AD patients. METHODS: Mild to moderate AD patients viewed slides containing both novel and repeat images. The number of fixations, the average fixation time, and the relative fixation time on the two types of images were measured by an eye-tracking system. Novelty preference was estimated by the differences between the visual scanning parameters on novel and repeat images. Cognition and attention were assessed using the Standardized Mini-Mental Status Examination (sMMSE) and the Conners' Continuous Performance Test (CPT), respectively. Cognition was re-assessed every 6 months for up to 2 years. RESULTS: Multivariate linear regressions of 32 AD patients (14 females, age = 77.9±7.8, baseline sMMSE = 22.2±4.4) indicated that reduced time spent on novel images (t = 2.78, p = 0.010) was also associated with greater decline in sMMSE scores (R2 = 0.41, Adjusted R2 = 0.35, F3,28 = 6.51, p = 0.002), adjusting for attention and baseline sMMSE. CONCLUSION: These results suggest that novelty preference, measured by visual attention scanning technology, may reflect pathophysiological processes that could predict disease progression in the cognitively-impaired.


Assuntos
Doença de Alzheimer/complicações , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Comportamento de Escolha/fisiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Feminino , Fixação Ocular , Humanos , Estudos Longitudinais , Masculino , Entrevista Psiquiátrica Padronizada , Testes Neuropsicológicos , Estimulação Luminosa , Valor Preditivo dos Testes , Adulto Jovem
11.
Curr Alzheimer Res ; 13(10): 1134-44, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27137221

RESUMO

Agitation and aggression are common neuropsychiatric symptoms of Alzheimer's disease and are highly prevalent in people with dementia. When pharmacological intervention becomes necessary, current clinical practice guidelines recommend antipsychotics, cholinesterase inhibitors, and some antidepressants. However, those interventions have modest to low efficacy, and those with the highest demonstrated efficacy have significant safety concerns. As a result, current research is focusing on novel compounds that have different mechanisms of action and that may have a better balance of efficacy over safety. The purpose of this review is to evaluate novel pharmacological therapies for the management of agitation and aggression in AD patients. We performed a comprehensive literature search to identify recent novel drugs that are not included in most clinical practice guidelines or are currently undergoing clinical trials for the treatment of agitation and/or aggression in AD. This review suggests that novel treatments, such as cannabinoids, lithium, non-steroidal anti-inflammatory drugs, analgesics, narcotics, and newer antiepileptic drugs, may provide a safer alternative treatment option for the management of agitation and aggression in AD and requires further study in order to clarify their risks and benefits.


Assuntos
Agressão/psicologia , Doença de Alzheimer/complicações , Doença de Alzheimer/psicologia , Antipsicóticos/uso terapêutico , Agitação Psicomotora/tratamento farmacológico , Agressão/efeitos dos fármacos , Bases de Dados Bibliográficas/estatística & dados numéricos , Humanos , Agitação Psicomotora/etiologia
12.
Lipids ; 51(5): 561-9, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26846325

RESUMO

Huntington's Disease (HD) is an autosomal dominant disease that occurs as a result of expansion of the trinucleotide repeat CAG (glutamine) on the HTT gene. HD patients exhibit various forms of mitochondrial dysfunction within neurons and peripheral tissues. Cardiolipin (Ptd2Gro) is a polyglycerophospholipid found exclusively in mitochondria and is important for maintaining mitochondrial function. We examined if altered Ptd2Gro metabolism was involved in the mitochondrial dysfunction associated with HD. Mitochondrial basal respiration, spare respiratory capacity, ATP coupling efficiency and rate of glycolysis were markedly diminished in Epstein-Barr virus transformed HD lymphoblasts compared to controls (CTRL). Mitochondrial supercomplex formation and Complex I activity within these supercomplexes did not vary between HD patients with different length of CAG repeats and appeared unaltered compared to CTRL. In contrast, in vitro Complex I enzyme activity in mitochondrial enriched samples was reduced in HD lymphoblasts compared to CTRL. The total cellular pool size of Ptd2Gro and its synthesis/remodeling from [(3)H]acetate/[(14)C]oleate were unaltered in HD lymphoblasts compared to CTRL. In addition, the molecular species of Ptd2Gro were essentially unaltered in HD lymphoblasts compared to CTRL. We conclude that compared to CTRL lymphoblasts, HD lymphoblasts display impaired mitochondrial basal respiration, spare respiratory capacity, ATP coupling efficiency and rate of glycolysis with any pathological CAG repeat length, but this is not due to alterations in Ptd2Gro metabolism. We suggest that HD patient lymphoblasts may be a useful model to study defective energy metabolism that does not involve alterations in Ptd2Gro metabolism.


Assuntos
Cardiolipinas/metabolismo , Doença de Huntington/metabolismo , Linfócitos/patologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Trifosfato de Adenosina/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Glicólise , Herpesvirus Humano 4/isolamento & purificação , Humanos , Doença de Huntington/patologia , Doença de Huntington/virologia , Linfócitos/metabolismo , Mitocôndrias/patologia
13.
J Alzheimers Dis ; 51(3): 837-46, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26890774

RESUMO

BACKGROUND: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation. OBJECTIVE: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients. METHODS: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured. RESULTS: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023). CONCLUSION: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy.


Assuntos
Doença de Alzheimer/psicologia , Apatia , Viés de Atenção , Idoso , Doença de Alzheimer/fisiopatologia , Cognição , Estudos Transversais , Emoções , Medições dos Movimentos Oculares , Movimentos Oculares , Feminino , Humanos , Modelos Lineares , Masculino , Testes Neuropsicológicos , Estimulação Luminosa , Índice de Gravidade de Doença , Percepção Social
14.
CNS Drugs ; 29(8): 615-23, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26271310

RESUMO

Alzheimer's disease (AD) is frequently associated with neuropsychiatric symptoms (NPS) such as agitation and aggression, especially in the moderate to severe stages of the illness. The limited efficacy and high-risk profiles of current pharmacotherapies for the management of agitation and aggression in AD have driven the search for safer pharmacological alternatives. Over the past few years, there has been a growing interest in the therapeutic potential of medications that target the endocannabinoid system (ECS). The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD. This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD. Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids­dronabinol or nabilone­on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Canabinoides/farmacologia , Agitação Psicomotora/tratamento farmacológico , Agressão/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Animais , Canabinoides/efeitos adversos , Endocanabinoides/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Agitação Psicomotora/etiologia
15.
Cochrane Database Syst Rev ; (4): CD009524, 2015 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-25897825

RESUMO

BACKGROUND: Current treatments for Alzheimer's disease (AD) provide modest symptomatic relief but do not slow the progression of the disease. Latrepirdine may modulate several targets involved in AD pathology, including lipid peroxidation, mitochondrial permeability, voltage-gated calcium ion channels as well as neurotransmitter receptor activity, and thus potentially represents both a symptomatic and disease-modifying intervention. Several randomized, placebo-controlled trials have sought to evaluate the effect of latrepirdine on cognition, function and behaviour in patients with AD. OBJECTIVES: To evaluate the efficacy and safety of latrepirdine for the treatment of AD. SEARCH METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 4 June 2014 using the terms: latrepirdine OR dimebon OR dimebolin OR 2,3,4,5-tetrahydro-2,8-dimethyl-5- (2-(6-methyl-3-pyridyl)ethyl)-1H-pyrido(4,3-b)indole. SELECTION CRITERIA: We included all randomized, double-blind, placebo-controlled trials where latrepirdine was administered to patients with mild, moderate or severe AD. DATA COLLECTION AND ANALYSIS: We assessed the quality of studies and two authors extracted data. We calculated mean difference (MD), risk ratio (RR) and 95% confidence interval (CI) on an intention-to-treat (ITT) basis for all relevant outcome measures. MAIN RESULTS: Seven trials involving a total of 1697 participants were found and six were included in the quantitative analyses. No data were available from the seventh trial. Three trials involving 1243 patients were included in analyses of efficacy outcomes, and four trials involving 1034 patients were included in analyses of safety and tolerability outcomes. We judged five trials to be at high risk of bias due to selective outcome reporting and three to be at high risk of attrition bias. There was low quality evidence favouring latrepirdine on the Clinician's Interview - Based Impression of Change Plus Caregiver Input after 26 weeks (CIBIC-Plus) (MD -0.60, 95% CI -0.89 to -0.31, 1 study, P < 0.001). Due to imprecision in the results, it was not possible to determine whether latrepirdine had any effect on cognition measured with the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog) (MD -1.49, 95% CI -3.47 to 0.49, 3 studies, P = 0.14) or the Mini-Mental State Examination (MMSE) (MD 0.59, 95% CI -0.94 to 2.11, 3 studies, P = 0.45), or on function measured with the Alzheimer's Disease Co-operative Study - Activities of Daily Living scale (ADCS-ADL) (MD 1.00, 95% CI -1.15 to 3.15, 3 studies, P = 0.36) at study endpoint (26 or 52 weeks). We considered the evidence provided on these outcomes to be of overall low quality. However, there was some high quality evidence showing a very small benefit of latrepirdine on the Neuropsychiatric Inventory (NPI) (MD -1.77, 95% CI -3.09 to -0.45, 3 studies, P = 0.009) at study endpoint (26 or 52 weeks). Additionally, moderate quality evidence suggested that latrepirdine and placebo were comparable in adverse events (RR 1.03, 95% CI 0.93 to 1.14, P = 0.51), serious adverse events (RR 0.86, 95% CI 0.55 to 1.35, P = 0.52), dropouts (RR 0.91, 95% CI 0.65 to 1.27, P = 0.57) and dropouts due to adverse events (RR 0.98, 95% CI 0.57 to 1.67, P = 0.93). AUTHORS' CONCLUSIONS: Our meta-analysis is limited by the small number of studies, imprecision, inconsistencies between studies and likelihood of bias. Nevertheless, the evidence to date suggests that while not associated with an increased risk of adverse events compared with placebo, there is no effect of latrepirdine on cognition and function in mild-to-moderate AD patients, though there appears to be a modest benefit for behaviour. Further studies should investigate the potential benefit of latrepirdine on neuropsychiatric symptoms in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Indóis/uso terapêutico , Nootrópicos/uso terapêutico , Doença de Alzheimer/psicologia , Comportamento/efeitos dos fármacos , Cognição/efeitos dos fármacos , Humanos , Indóis/efeitos adversos , Nootrópicos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Dement Geriatr Cogn Dis Extra ; 5(3): 492-502, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26955382

RESUMO

BACKGROUND: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Selective attention can be explored through examination of novelty preference. AIMS: In this study, we quantified novelty preference in AD patients by measuring visual scanning behaviour using an eye tracking paradigm. METHODS: Mild-to-moderate AD patients and elderly controls viewed slides containing novel and repeated images simultaneously. The outcome measure was time spent on specific images, with novelty preference defined by greater relative fixation time (RFT) on novel versus repeated images. Cognitive status (Standardized Mini-Mental State Examination, SMMSE) and attention (Digit Span, DS) were also measured. RESULTS: AD patients (age 79.2 ± 6.7 years, SMMSE 22.2 ± 4.0, n = 41) and controls (age 76.2 ± 6.4 years, SMMSE 28.1 ± 2.0, n = 24) were similar in age, education and sex. Compared with controls, AD patients had lower RFT on novel than on repeated images (F1,63 = 11.18, p = 0.001). Further, reduced RFT was associated with lower scores on SMMSE (r63 = 0.288, p = 0.020) and DS (r63 = 0.269, p = 0.030). Within individuals, novelty preference was detected in 92.3% of patients and in 100% of controls. CONCLUSION: These findings suggest that novelty preference, measured by visual scanning behaviour, can differentiate cognitively healthy and impaired people and may offer a nonverbal, less cognitively demanding method of assessing selective attention.

17.
Int Psychogeriatr ; 26(2): 239-46, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24169147

RESUMO

BACKGROUND: Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses. METHODS: MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale--Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6-DS baseline)) - (placebo (DS week 6-DS baseline)). RESULTS: In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06-1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09-1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment. CONCLUSION: These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.


Assuntos
Doença de Alzheimer , Apatia/efeitos dos fármacos , Atenção/efeitos dos fármacos , Metilfenidato , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Metilfenidato/efeitos adversos , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
18.
Neurobiol Aging ; 33(7): 1482.e17-29, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22305186

RESUMO

BACKGROUND: Higher intake of omega-3 fatty acids (n-3 FAs) is associated with a reduced risk of Alzheimer's disease (AD) and milder forms of cognitive impairment (e.g. cognitive impairment no dementia [CIND]); however, findings from interventional trials are inconsistent. This meta-analysis examined the neuropsychological benefit of n-3 FAs in randomized double-blind placebo-controlled studies (RCTs) including healthy, CIND, or AD subjects. METHODS: Literature was searched using Medline, Embase, PsycInfo, Cochrane Library, Allied and Complementary Medicine Database (AMED), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to September 2011. Treatment effects were summarized across cognitive subdomains, and effect sizes were estimated using Hedge's g and random effects modeling. RESULTS: Ten RCTs were combined quantitatively. There was no effect of n-3 FAs on composite memory (g = 0.04 [95% CI: -0.06-0.14], N = 934/812, p = 0.452). When examined by domain, no overall benefit for immediate recall (0.04 [-0.05-0.13], N = 934/812, p = 0.358) was detected; however, an effect in CIND subjects (0.16 [0.01-0.31], N = 349/327, p = 0.034) was found. A benefit for attention and processing speed was also detected in CIND (0.30 [0.02-0.57], N = 107/86, p = 0.035), but not healthy subjects. Benefits for delayed recall, recognition memory, or working memory and executive function were not observed. Treatment did not benefit AD patients as measured by the Mini-Mental State Examination (MMSE) or Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog). No differences in adverse events (AE), dropout, or dropout due to AE between groups were observed. CONCLUSIONS: These results suggest an effect of n-3 FAs within specific cognitive domains in CIND, but not in healthy or AD subjects.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Ácidos Graxos Ômega-3/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/psicologia , Transtornos Cognitivos/epidemiologia , Humanos , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento
19.
Drugs ; 71(15): 2031-65, 2011 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-21985169

RESUMO

Alzheimer's disease (AD) is a progressive and ultimately fatal condition that causes debilitating memory loss and extensive deterioration of cognitive and functional abilities. Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. These therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability. The search for disease-modifying interventions has focused largely on compounds targeting the amyloid-ß pathway. To date, the treatments targeting this pathway, such as tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in clinical stages of testing. At this point, it is likely that not only amyloid-ß aggregation but other possible neuronal mechanisms - such as hyperphosphorylated tau, neuro-inflammation and other processes - play important roles in the pathophysiology of this multifactorial disorder. Development of better disease models and biomarkers is essential for the advancement of knowledge of the disease mechanisms. This systematic review critically examines the efficacy and safety data for currently approved drugs and emerging treatments in AD, as well as discussing the present and future directions of innovation in this field.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Nootrópicos/uso terapêutico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Proteínas tau/efeitos dos fármacos
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