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BACKGROUND: The effect of calcium channel blockers (CCB) on mortality and ischaemic stroke risk in dementia patients is understudied. OBJECTIVES: To calculate the risk of death and ischaemic stroke in dementia patients treated with CCBs, considering individual agents and dose response. METHODS: Longitudinal cohort study with 18 906 hypertensive dementia patients from the Swedish Dementia Registry (SveDem), 2008-2014. Other Swedish national registries contributed information on comorbidities, dispensed medication and outcomes. Individual CCB agents and cumulative defined daily doses (cDDD) were considered. RESULTS: In patients with hypertension and dementia, nifedipine was associated with increased mortality risk (aHR 1.32; CI 1.01-1.73; P < 0.05) compared to non-CCB users. Patients diagnosed with Alzheimer's dementia (AD) or dementia with Lewy bodies/Parkinson's disease dementia (DLB-PDD) taking amlodipine had lower mortality risk (aHR, 0.89; CI, 0.80-0.98; P < 0.05 and aHR 0.58; CI, 0.38-0.86; P < 0.01, respectively), than those taking other CCBs. Amlodipine was associated with lower stroke risk in patients with Alzheimer's dementia compared to other CCBs (aHR 0.63; CI, 0.44-0.89; P < 0.05). Sensitivity analyses with propensity score-matched cohorts repeated the results for nifedipine (aHR 1.35; 95% CI, 1.02-1.78; P < 0.05) and amlodipine in AD (aHR, 0.87; CI, 0.78-0.97; P < 0.05) and DLB-PDD (aHR, 0.56, 95%CI, 0.37-0.85; P < 0.05). CONCLUSION: Amlodipine was associated with reduced mortality risk in dementia patients diagnosed with AD and DLB-PDD. AD patients using amlodipine had a lower risk of ischaemic stroke compared to other CCB users.
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Enfermedad de Alzheimer , Isquemia Encefálica , Bloqueadores de los Canales de Calcio , Hipertensión , Accidente Cerebrovascular Isquémico , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/epidemiología , Amlodipino/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/epidemiología , Bloqueadores de los Canales de Calcio/uso terapéutico , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/epidemiología , Estudios Longitudinales , Nifedipino/uso terapéutico , Sistema de Registros , Suecia/epidemiologíaRESUMEN
BACKGROUND AND PURPOSE: Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow-up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia. METHODS: A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated. RESULTS: Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk-benefit ratio should be performed at regular intervals. Regular, preplanned medical follow-up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non-pharmacological measures have been proven to be without benefit or in the case of severe self-harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first-line therapy (Good Practice statement). CONCLUSION: This GRADE-based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas.
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Enfermedad de Alzheimer , Demencia , Neurología , Academias e Institutos , Anciano , Analgésicos , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Traumatic brain injury (TBI) is clinically divided into a spectrum of severities, with mild TBI being the least severe form and a frequent occurrence in contact sports, such as ice hockey, American football, rugby, horse riding and boxing. Mild TBI is caused by blunt nonpenetrating head trauma that causes movement of the brain and stretching and tearing of axons, with diffuse axonal injury being a central pathogenic mechanism. Mild TBI is in principle synonymous with concussion; both have similar criteria in which the most important elements are acute alteration or loss of consciousness and/or post-traumatic amnesia following head trauma and no apparent brain changes on standard neuroimaging. Symptoms in mild TBI are highly variable and there are no validated imaging or fluid biomarkers to determine whether or not a patient with a normal computerized tomography scan of the brain has neuronal damage. Mild TBI typically resolves within a few weeks but 10-15% of concussion patients develop postconcussive syndrome. Repetitive mild TBI, which is frequent in contact sports, is a risk factor for a complicated recovery process. This overview paper discusses the relationships between repetitive head impacts in contact sports, mild TBI and chronic neurological symptoms. What are these conditions, how common are they, how are they linked and can they be objectified using imaging or fluid-based biomarkers? It gives an update on the current state of research on these questions with a specific focus on clinical characteristics, epidemiology and biomarkers.
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Traumatismos en Atletas/diagnóstico , Traumatismos en Atletas/epidemiología , Conmoción Encefálica/diagnóstico , Conmoción Encefálica/epidemiología , Adolescente , Adulto , Traumatismos en Atletas/rehabilitación , Biomarcadores/análisis , Conmoción Encefálica/rehabilitación , Niño , Humanos , Puntaje de Gravedad del TraumatismoRESUMEN
Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aß) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aß and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.
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Enfermedad de Alzheimer/tratamiento farmacológico , Terapia Molecular Dirigida , Péptidos beta-Amiloides , Tratamiento Basado en Trasplante de Células y Tejidos , Terapia Combinada , Terapia Genética , Humanos , Proteínas tauRESUMEN
Millions of people worldwide receive agents targeting the renin-angiotensin system (RAS) to treat hypertension or statins to lower cholesterol. The RAS and cholesterol metabolic pathways in the brain are autonomous from their systemic counterparts and are interrelated through the cholesterol metabolite 27-hydroxycholesterol (27-OHC). These systems contribute to memory and dementia pathogenesis through interference in the amyloid-beta cascade, vascular mechanisms, glucose metabolism, apoptosis, neuroinflammation and oxidative stress. Previous studies examining the relationship between these treatments and cognition and dementia risk have produced inconsistent results. Defining the blood-brain barrier penetration of these medications has been challenging, and the mechanisms of action on cognition are not clearly established. Potential biases are apparent in epidemiological and clinical studies, such as reverse epidemiology, indication bias, problems defining medication exposure, uncertain and changing doses, and inappropriate grouping of outcomes and medications. This review summarizes current knowledge of the brain cholesterol and RAS metabolism and the mechanisms by which these pathways affect neurodegeneration. The putative mechanisms of action of statins and medications inhibiting the RAS will be examined, together with prior clinical and animal studies on their effects on cognition. We review prior epidemiological studies, analysing their strengths and biases, and identify areas for future research. Understanding the pathophysiology of the brain cholesterol system and RAS and their links to neurodegeneration has enormous potential. In future, well-designed epidemiological studies could identify potential treatments for Alzheimer's disease (AD) amongst medications that are already in use for other indications.
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Encéfalo/metabolismo , Colesterol/metabolismo , Demencia/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Encéfalo/fisiopatología , Colesterol/fisiología , Cognición/efectos de los fármacos , Demencia/metabolismo , Demencia/fisiopatología , Humanos , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Alzheimer's disease (AD) causes dementia in both young and old people affecting more than 40 million people worldwide. The two neuropathological hallmarks of the disease, amyloid beta (Aß) plaques and neurofibrillary tangles consisting of protein tau are considered the major contributors to the disease. However, a more complete picture reveals significant neurodegeneration and decreased cell survival, neuroinflammation, changes in protein and energy homeostasis and alterations in lipid and cholesterol metabolism. In addition, gene and cell therapies for severe neurodegenerative disorders have recently improved technically in terms of safety and efficiency and have translated to the clinic showing encouraging results. Here, we review broadly current data within the field for potential targets that could modify AD through gene and cell therapy strategies. We envision that not only Aß will be targeted in a disease-modifying treatment strategy but rather that a combination of treatments, possibly at different intervention times may prove beneficial in curing this devastating disease. These include decreased tau pathology, neuronal growth factors to support neurons and modulation of neuroinflammation for an appropriate immune response. Furthermore, cell based therapies may represent potential strategies in the future.
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Enfermedad de Alzheimer/terapia , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Terapia Genética/métodos , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Terapia Combinada , Expresión Génica/genética , Humanos , Neprilisina/genética , Neurogénesis/fisiología , Proteínas tauRESUMEN
OBJECTIVE: Depression is associated with accelerated aging and age-related diseases. However, mechanisms underlying this relationship remain unclear. The aim of this study was to longitudinally assess the link between depressive symptoms, brain atrophy, and cortisol levels. METHOD: Participants from the Betula prospective cohort study (mean age = 59 years, SD = 13.4 years) underwent clinical, neuropsychological and brain 3T MRI assessments at baseline and a 4-year follow-up. Cortisol levels were measured at baseline in four saliva samples. Cortical and hippocampal atrophy rates were estimated and compared between participants with and without depressive symptoms (n = 81) and correlated with cortisol levels (n = 49). RESULTS: Atrophy in the left superior frontal gyrus and right lingual gyrus developed in parallel with depressive symptoms, and in the left temporal pole, superior temporal cortex, and supramarginal cortex after the onset of depressive symptom. Depression-related atrophy was significantly associated with elevated cortisol levels. Elevated cortisol levels were also associated with widespread prefrontal, parietal, lateral, and medial temporal atrophy. CONCLUSION: Depressive symptoms and elevated cortisol levels are associated with atrophy of the prefrontal and limbic areas of the brain.
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Depresión/metabolismo , Depresión/patología , Trastorno Depresivo/metabolismo , Trastorno Depresivo/patología , Hipocampo/patología , Hidrocortisona/metabolismo , Neocórtex/patología , Adulto , Anciano , Atrofia/patología , Depresión/diagnóstico por imagen , Trastorno Depresivo/diagnóstico por imagen , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neocórtex/diagnóstico por imagen , Saliva , SueciaRESUMEN
An estimated 10% of stroke patients have an underlying dementia. As a consequence, health professionals often face the challenge of managing patients with dementia presenting with an acute stroke. Patients with dementia are less likely to receive thrombolysis (0.56-10% vs. 1-16% thrombolysis rates in the general population), be admitted to a stroke unit or receive some types of care. Anticoagulation for secondary stroke prevention is sometimes withheld, despite dementia not being listed as an exclusion criterion in current guidelines. Studies in this population are scarce, and results have been contradictory. Three observational studies have examined intravenous thrombolysis for treatment of acute ischaemic stroke in patients with dementia. In the two largest matched case-control studies, there were no significant differences between patients with and without dementia in the risks of intracerebral haemorrhage or mortality. The risk of intracerebral haemorrhage ranged between 14% and 19% for patients with dementia. Studies of other interventions for stroke are lacking for this population. Patients with dementia are less likely to be discharged home compared with controls (19% vs. 41%) and more likely to be disabled (64% vs. 59%) or die during hospitalization (22% vs. 11%). The aim of this review was to summarize current knowledge about the management of ischaemic stroke in patients with pre-existing dementia, including organizational aspects of stroke care, intravenous thrombolysis, access to stroke unit care and use of supportive treatment. Evidence to support anticoagulation for secondary prevention of stroke in patients with atrial fibrillation and antiplatelet therapy in nonembolic stroke will be discussed, as well as rehabilitation and how these factors influence patient outcomes. Finally, ethical issues, knowledge gaps and pathways for future research will be considered.
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Isquemia Encefálica/complicaciones , Isquemia Encefálica/tratamiento farmacológico , Demencia/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Isquemia Encefálica/epidemiología , Isquemia Encefálica/fisiopatología , Humanos , Calidad de la Atención de Salud/ética , Prevención Secundaria , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/fisiopatología , Terapia Trombolítica , Resultado del TratamientoRESUMEN
Previous work indicates that erythrocytes (RBCs) accumulate ß-amyloid X-40 (Aß40) in individuals with Alzheimer disease (AD) and to a lesser extent in healthy elderly. The toxin damages RBCs and increases their mean corpuscular volume (MCV). Furthermore, AD platelets demonstrate lower reactivity. This study investigated interactions between RBCs and platelets. Older individuals with moderate hypertension (n = 57) were classified into two groups, depending on MCV in whole blood: The MCVhigh group comprised individuals with higher MCV (n = 27; 97 ± 3(SD) fl) and MCVlow group had relatively lower MCV (n = 30; 90 ± 3(SD) fl). Flow cytometry was used to determine platelet reactivity, i.e., the surface binding of fibrinogen after provocation. Adenosine diphosphate (ADP) and a thrombin receptor-activating protein (TRAP-6) were used as agonists. Subsequently, blood cells were divided according to density into 17 subfractions. Intra-RBC Aß40 content was analyzed and in all platelet populations surface-bound fibrinogen was determined to estimate platelet in vivo activity. We found Aß40 inside RBCs of approximately 50% of participants, but the toxin did not affect MCV and platelet reactivity. In contrast, MCV associated inversely with platelet reactivity as judged from surface-attached fibrinogen after ADP (1.7 µmol/L) (p < 0.05) and TRAP-6 provocation (57 µmol/L (p = 0.01) and 74 µmol/L (p < 0.05)). In several density fractions (nos. 3, 4, 8, 11-13 (p < 0.05) and nos. 5-7 (p < 0.01)) MCV linked inversely with platelet-attached fibrinogen. In our community-dwelling sample, enhanced MCV associated with decreased platelet reactivity and lower in vivo platelet activity. It resembles RBCs and platelet behavior in AD-type dementia.
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Envejecimiento/sangre , Plaquetas/fisiología , Eritrocitos/citología , Activación Plaquetaria , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores , Tamaño de la Célula , Índices de Eritrocitos , Femenino , Citometría de Flujo , Humanos , MasculinoRESUMEN
There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-ß-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid ß-peptide (Aß) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aß formation and aggregation or to enhance Aß clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aß aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.
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Amiloidosis/terapia , Enfermedad de Alzheimer/terapia , Amiloide/fisiología , Amiloidosis/fisiopatología , Animales , Diabetes Mellitus Tipo 2/terapia , Humanos , Trasplante de Hígado , Prealbúmina/fisiologíaRESUMEN
BACKGROUND: The association between mortality risk and use of antidepressants in people with dementia is unknown. OBJECTIVE: To describe the use of antidepressants in people with different dementia diagnoses and to explore mortality risk associated with use of antidepressants 3 years before a dementia diagnosis. METHODS: Study population included 20 050 memory clinic patients from the Swedish Dementia Registry (SveDem) diagnosed with incident dementia. Data on antidepressants dispensed at the time of dementia diagnosis and during 3-year period before dementia diagnosis were obtained from the Swedish Prescribed Drug Register. Cox regression models were used. RESULTS: During a median follow-up of 2 years from dementia diagnosis, 25.8% of dementia patients died. A quarter (25.0%) of patients were on antidepressants at the time of dementia diagnosis, while 21.6% used antidepressants at some point during a 3-year period before a dementia diagnosis. Use of antidepressant treatment for 3 consecutive years before a dementia diagnosis was associated with a lower mortality risk for all dementia disorders and in Alzheimer's disease. CONCLUSION: Antidepressant treatment is common among patients with dementia. Use of antidepressants during prodromal stages may reduce mortality in dementia and specifically in Alzheimer's disease.
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Antidepresivos/uso terapéutico , Demencia/diagnóstico , Demencia/mortalidad , Anciano , Anciano de 80 o más Años , Demencia/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Suecia/epidemiologíaRESUMEN
It has recently been proposed that heart failure is a risk factor for Alzheimer's disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer's disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.
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Enfermedad de Alzheimer/epidemiología , Insuficiencia Cardíaca/epidemiología , Animales , Fibrilación Atrial/epidemiología , Circulación Cerebrovascular , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertensión/fisiopatología , Arteriosclerosis Intracraneal/epidemiología , Infarto del Miocardio/epidemiología , Factores de Riesgo , Síndromes de la Apnea del Sueño/epidemiología , Volumen SistólicoRESUMEN
Recent trials of anti-amyloid agents have not produced convincing improvements in clinical outcome in Alzheimer's disease; however, the reason for these poor or inconclusive results remains unclear. Recent genetic data continue to support the amyloid hypothesis of Alzheimer's disease with protective variants being found in the amyloid gene and both common low-risk and rare high-risk variants for disease being discovered in genes that are part of the amyloid response pathways. These data support the view that genetic variability in how the brain responds to amyloid deposition is a potential therapeutic target for the disease, and are consistent with the notion that anti-amyloid therapies should be initiated early in the disease process.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/antagonistas & inhibidores , Amiloide , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Amiloide/genética , Amiloide/metabolismo , Encéfalo/metabolismo , Intervención Médica Temprana , Predisposición Genética a la Enfermedad , Humanos , Inmunoterapia/métodosRESUMEN
The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
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Enfermedad de Alzheimer , Biomarcadores/análisis , Inhibidores de la Colinesterasa/uso terapéutico , Memantina/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Nootrópicos/uso terapéutico , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Dopaminérgicos/uso terapéutico , Monitoreo de Drogas/métodos , Humanos , Administración del Tratamiento Farmacológico , Trastornos de la Memoria/etiología , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Recent developments in blood biomarkers (BBM) have shown promising results in diagnosing amyloid pathology in Alzheimer's Disease (AD). However, information on how these BBMs can best be used in clinical settings to optimise clinical decision-making and long-term health outcomes for individuals with AD is still lacking. OBJECTIVES: We aim to assess the potential value of BBM in AD diagnosis within the context of disease-modifying treatment (DMT). DESIGN: We developed a decision analytic model to evaluate the long-term health outcomes using BBM in AD diagnosis. We compared standard of care (SOC) diagnosis workflow to the integration of BBM as a (1) referral decision tool in primary health center (PHC) and (2) triaging tool for invasive CSF examination in specialist memory clinic (MC). We combined a decision tree and a Markov model to simulate the patient's diagnostic journey, treatment decisions following diagnosis and long-term health outcomes. Input parameters for the model were identified from published literature and registry data analysis. We conducted a cost-utility analysis from the societal perspective using a one-year cycle length and a 30-year (lifetime) horizon. MEASUREMENTS: We reported the simulated outcomes in the percentage of correct diagnosis, costs (in 2022 Euros), quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICER) associated with each diagnosis strategy. RESULTS: Compared to SOC, integrating BBM in PHC increased patient referrals by 8% and true positive AD diagnoses by 10.4%. The lifetime costs for individuals diagnosed with AD were 249,685 and 250,287, and QALYs were 9.5 and 9.52 in SOC and PHC pathways, respectively. The cost increments were 603, and QALYs gained were 0.01, resulting in an ICER of 48,296. Using BBM in MC reduced the exposure to invasive CSF procedures and costs but also reduced true positive AD diagnoses and QALYs. CONCLUSIONS: Using BBM at PHC to make referral decisions might increase initial diagnostic costs but can prevent high costs associated with disease progression, providing a cost-effective DMT is available, whereas using BBM in MC could reduce the initial evaluation cost but incur high costs associated with disease progression.
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Enfermedad de Alzheimer , Biomarcadores , Análisis Costo-Beneficio , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/economía , Enfermedad de Alzheimer/tratamiento farmacológico , Biomarcadores/sangre , Años de Vida Ajustados por Calidad de Vida , Toma de Decisiones Clínicas , Técnicas de Apoyo para la Decisión , Árboles de Decisión , Cadenas de Markov , AncianoRESUMEN
BACKGROUND: The emergence of disease-modifying Alzheimer's (AD) treatments provides new hope to patients and families but concerns have been raised about the preparedness of healthcare systems to provide timely access to such treatments because of a combination of a complex diagnostic process and a large prevalent pool. OBJECTIVES: We assess the preparedness of Sweden, a high-income country known for its dementia-friendly policies, to diagnose AD patients eligible for treatment within a six-month window, given current capacity for specialist evaluations and biomarker testing. We calculate the investment requirements for Sweden to achieve this target over a timeframe of 20 years. DESIGN: Desk research to identify data for population, mortality, disease burden, cost of services and current capacity, expert consultation to inform assumptions about patient journey, and use of a Markov model to predict waiting times. The model simulates the patients' journey through different evaluation stages: initial evaluation by a primary care specialist, neurocognitive testing by an AD specialist, and confirmatory biomarker testing with PET scanning or cerebrospinal fluid (CSF) testing. The model assumes specialist appointments and PET scans are capacity constrained, and patients progress from cognitively normal to MCI and from MCI to dementia in the resulting waiting times. MEASUREMENTS: Projected waiting times for diagnosis of eligibility for disease-modifying Alzheimer's treatment from 2023 to 2042 assuming current capacity, assuming 20% of Swedish residents aged 60 years and above would seek an evaluation for cognitive decline. Investments required to scale capacity up to reach target of providing diagnosis within six months on average. RESULTS: Initial average waiting times for AD specialist appointments would be around 21 months in 2023 and remain around 55 months through 2042, as demand would continue to outstrip supply throughout the 20-year model horizon. Waiting times for biomarker testing would be stable at less than four weeks, as patients would be held up in the queue for their first specialist consultations, and use of CSF testing is widely accepted in Sweden. An additional 25% of AD specialists would have to be added above the current growth trend to reduce waiting times to less than 6 months at an average annual cost of approximately 805 million SEK. The increased cost of volume of biomarker testing would amount to about 106 million SEK per year. CONCLUSIONS: At current capacity, the Swedish healthcare system is unable to provide timely diagnosis of patients eligible for disease-modifying AD treatment. Although future diagnostic technologies, such as digital cognitive assessments and blood tests for the AD pathology, might decrease demand for capacity-constrained services, substantial investments will be required to meet a target of less than six months of waiting time for a diagnosis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/psicología , Suecia/epidemiología , Disfunción Cognitiva/diagnóstico , Tomografía de Emisión de Positrones , BiomarcadoresRESUMEN
Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Mutación Puntual , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Secuencia de Bases , Encéfalo/patología , Codón/genética , Exones , Femenino , Ligamiento Genético , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Linaje , Transcripción GenéticaRESUMEN
OBJECTIVES: To examine the associations between serum homocysteine (tHcy), holotranscobalamin (holoTC, the biologically active fraction of vitamin B12) and folate and cognitive functioning in a longitudinal population-based study of Finnish elderly subjects. SUBJECTS AND DESIGN: tHcy, holoTC and folate were measured at baseline in 274 dementia-free subjects aged 65-79years from the Cardiovascular Risk Factors, Aging and Dementia study. Subjects were re-examined 7years later, and global cognition, episodic memory, executive functioning, verbal expression and psychomotor speed were assessed. RESULTS: Higher baseline tHcy levels were associated with poorer performance in global cognition, relative difference: 0.90 [95% confidence interval (CI) 0.81-0.99]; episodic memory: 0.87 (95% CI 0.77-0.99); executive functions: 0.86 (95% CI 0.75-0.98); and verbal expression: 0.89 (95% CI 0.81-0.97) at follow-up. Increased holoTC levels were related to better performance on global cognition: 1.09 (95% CI 1.00-1.19); executive functions: 1.11 (95% CI 1.01-1.21); and psychomotor speed: 1.13 (95% CI 1.01-1.26). After excluding 20 cases of incident dementia, increased tHcy remained associated with poorer performance in episodic memory, execution functions and verbal expression. Higher holoTC levels tended to be related to better performance in executive functions and psychomotor speed, while elevated serum folate concentrations were significantly related to higher scores in global cognition and verbal expression tests. CONCLUSIONS: tHcy, holoTC and folate levels are related to cognitive performance 7years later even in nondemented elderly subjects. Randomized trials are needed to determine the impact of vitamin B12 and folate supplementation on preventing cognitive decline in the elderly.
Asunto(s)
Trastornos del Conocimiento/sangre , Ácido Fólico/sangre , Homocisteína/sangre , Transcobalaminas/metabolismo , Anciano , Función Ejecutiva/fisiología , Femenino , Humanos , Masculino , Memoria Episódica , Estudios Prospectivos , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiología , Habla/fisiologíaRESUMEN
Platelets contain a substantial quantity of amyloid-precursor protein (APP) and ß-amyloid. However, despite the large importance of APP and ß-amyloid to dementia, little is known about platelets in sporadic Alzheimer dementia (AD). Furthermore, platelet heterogeneity influences human pathology and has been described to affect the progression of AD. This study investigated AD platelets with respect to density diversity and in vivo activity associated with density sub-fractions. We included 39 AD patients and used, as controls, 22 elderly individuals without apparent memory disorder. A continuous Percoll™ gradient covering the density span 1.04-1.09 kg/l provided the basis to divide platelets of whole blood into density fractions (n = 16). All platelet populations were evaluated accordingly. Platelet counts were determined electronically. A flow-cytometer was put to use to measure surface-bound fibrinogen as a measure of platelet in vivo activity. Samples obtained from patients diagnosed with sporadic AD contained platelets (fractions numbers 4-16) that circulated with significantly less surface-bound fibrinogen, i.e., their platelet activation in vivo was reduced, compared with controls. In particular, highly significant differences (p < 0.001) were obtained for the six less dense platelet populations (fractions numbers 11-16) when comparing sporadic AD with controls. In contrast, the densest AD platelets in fractions numbers 1-3 did not differ significantly from control cells with respect to in vivo platelet-bound fibrinogen. It is concluded that sporadic AD is characterized by lower density platelet populations that, while circulating, exhibited reduced activation. The clinical significance of this finding is unclear but these results suggest the importance of platelet heterogeneity in dementia as a topic for further investigation.