Peer Review reports. Pharmacological interventions attempting to counteract the lesions have yet to achieve permanent successful results [ 2 , 3 , 4 ]. Apart from unsatisfactory efficacy, pharmacological treatments are expensive and have a series of adverse effects. As an alternative, scientists have turned to non-pharmacological therapies, with psychosocial therapies being one of the most commonly used. In recent years, the publication of several high-quality meta-analyses, systematic reviews, and randomized controlled trials has increased the overall quality of evidence that psychosocial interventions improve or maintain cognition, function, adaptive behavior, and quality of life.
For example, Epperly et al. Natasha Yuill et al. The findings of Linda Clare et al. It also has not conclusively determined which intervention works best for which service setting, specific behavior, disease stage, or caregiver and patient profile [ 8 ]. In order to offer high-quality evidence for clinical decisions, we performed a Bayesian network meta-analysis to compare and rank different psychosocial interventions in the management of cognitive symptoms in patients with AD.
Included studies were classified according to the type of psychosocial intervention. We searched studies published from inception to August 31, , and compared any psychosocial interventions for cognitive symptoms in patients with AD Additional file 1. Inclusion criteria and exclusion criteria are summarized in Table 1. We included the following psychosocial interventions with usual care as the control: home-based exercise HE , group exercise GE , walking programs WP , reminiscence therapy RT , and art therapy AT.
The review of the main reports and supplementary materials, the extractions of the relevant information from the included trials with a predetermined data extraction sheet, and the assessments of the risk of bias with the Cochrane risk of bias tool were independently performed by three investigators CXW, JLL, YZ.
Any disagreements were resolved through discussion. We evaluated the quality of the included studies with the Cochrane Collaboration Recommendations assessment tool.
Based on these items, studies in which the key domains were all low-risk were considered low-risk, while the remainder were deemed high-risk or unclear-risk, depending on the number of key domains of high or unclear risk. This software is based on the Bayesian framework and the Markov chain Monte Carlo method which can evaluate a priori and process research data.
We used a random-effects model to analyze the effect sizes in this study. The effect sizes for continuous outcomes were the mean difference MD. A consistency assessment drew conclusions on effect sizes of the included interventions and estimated the ranking probabilities for all the interventions.
The consistency test was judged by node-splitting analysis and an inconsistence model. When the p -value of the node-splitting analysis was greater than 0. Otherwise, an inconsistency model was used. Potential scale reduction factor PSRF was used to evaluate the convergence of the model. The closer the PSRF value was to 1, the better the convergence. The convergence of the model was still acceptable if the PSRF value was less than 1. For each intervention, we estimated the ranking probabilities for each treatment at each possible rank.
We ran pair-wise meta-analyses to compare the compliance of different psychosocial therapies because the data included in our study were insufficient for statistical analysis of the network meta-analysis. We conducted the pair-wise meta-analysis with the fixed-effects model with Review Manager RevMan, v 5.
We assessed statistical heterogeneity in the pair-wise comparison with an I 2 statistic and the p -value. In total, citations published between and August 31, was identified by the search. After removing duplicates and unrelated articles, 10 articles describing 11 RCTs including patients were eligible for further quantitative analyses.
A flow chart of the specific screening procedures is shown in Fig. The baseline characteristics of the studies were also extracted Table 2. We evaluated the quality of included studies with the Cochrane Collaboration Recommendations assessment tools [ 12 ]. In attrition bias, 9 studies were deemed to have low-risk outcome data i. Other risks were unclear due to insufficient information in 5 studies. Overall, 1 study was considered high risk and 5 were considered low risk, while 4 were considered unclear risk.
A detailed quality assessment is presented in Additional files 2 and 3. A network meta-analysis was performed to compare and rank the included psychosocial interventions which used usual care as their control. The specific network is presented in Fig. The consistency model was selected for the subsequent network analyses. Meanwhile, the inconsistency model was used to test consistency.
The results of the network meta-analysis for the primary outcomes are presented as a league table in Table 3. The results indicated that WP was significantly more effective than the other treatments in our study. The second and third most effective interventions were RT and HE.
The ranking probability of treatments is presented in Fig. In this subsequent network analysis, we used a consistency model, while an inconsistency model was used to test consistency. The results of the network meta-analyses for the primary outcomes are presented as a league table in Table 4. The three most effective combined interventions were better than the ChEIs. Additional file 4 shows the results of pair-wise meta-analyses of compliance for each intervention.
The included studies which were not analyzed did not have missing data due to patient non-compliance. These findings regarding the comprehensive network meta-analysis represent the most comprehensive synthesis of data for currently available psychosocial AD treatments including the combined treatments of psychosocial therapies and ChEIs. Our study supplements the recommendations of existing guidelines and identifies specific psychosocial interventions with better effects.
When only using psychosocial interventions for AD patients, WP and RT showed better efficacy in the management of cognitive symptoms. WP is a physical activity, which is a type of stimulation-oriented intervention.
Several clinical investigations have shown its cognitive benefits for older individuals who are healthy, but with mild cognitive impairment or dementia [ 13 , 14 , 15 , 16 ]. When WP is applied, the adverse reactions of its application should be taken into consideration.
For personalized needs, the frequency and intensity of WP should be targeted adjustment. Reminiscence therapy is defined as emotion-oriented interventions in which an individual remembers a past event, verbally or nonverbally, alone or with a group.
Reminiscence therapy is another commonly used non-pharmacological application for AD and other types of dementia which benefits cognition and mental health [ 17 , 18 , 19 ]. We also compared and ranked the combination of psychosocial interventions and ChEIs and single used ChEIs, which are the most common used pharmacological interventions. Although there was not enough evidence to prove that psychosocial interventions were better than pharmacological interventions, our study found that the combination of psychosocial interventions and pharmacological interventions was better than treatment with single drugs.
Among the included treatments, CT programs combined with pharmacological treatments that could protect patients from functional deterioration by slowing progressive decline showed the best efficacy for cognitive impairments in AD patients. This revealed that clinical practitioners can try combined therapy, rather than only using drugs. Evidence indicates that pharmacological treatments for AD can benefit patients, but important side effects have led to the development of non-pharmacological interventions and their widespread use.
We confirmed that the efficacy of psychosocial therapies and combined interventions are better than pharmacological therapies used alone. However, the long-term benefits and the potential for translating these approaches into practice remain uncertain. Caring for a person with Alzheimer's disease is physically and emotionally demanding. Feelings of anger and guilt, stress and discouragement, worry and grief, and social isolation are common.
Caregiving can even take a toll on the caregiver's physical health. Paying attention to your own needs and well-being is one of the most important things you can do for yourself and for the person with Alzheimer's. Many people with Alzheimer's and their families benefit from counseling or local support services. Contact your local Alzheimer's Association affiliate to connect with support groups, doctors, occupational therapists, resources and referrals, home care agencies, residential care facilities, a telephone help line, and educational seminars.
Medical care for the loss of memory or other thinking skills usually requires a team or partner strategy. If you're worried about memory loss or related symptoms, ask a close relative or friend to go with you to a doctor's appointment. In addition to providing support, your partner can provide help in answering questions. If you're going with someone to a doctor's appointment, your role may be to provide some history or your thoughts on changes you have seen.
This teamwork is an important part of medical care for initial appointments and throughout a treatment plan. Your primary care doctor may refer you to a neurologist, psychiatrist, neuropsychologist or other specialist for further evaluation.
You can prepare for your appointment by writing down as much information as possible to share. Information may include:.
Your doctor will likely ask a number of the following questions to understand changes in memory or other thinking skills. If you are accompanying someone to an appointment, be prepared to provide your perspective as needed. Your doctor may ask:. Alzheimer's disease care at Mayo Clinic. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. This content does not have an English version.
This content does not have an Arabic version. Diagnosis An important part of diagnosing Alzheimer's disease includes being able to explain your symptoms, as well as perspective from a close family member or friend about symptoms and their impact on daily life. Folic acid supplements: Can they slow cognitive decline? Video: Alzheimer's drug shows early promise Show more related information.
Request an Appointment at Mayo Clinic. Huperzine A: Can it treat Alzheimer's? Phosphatidylserine supplements: Can they improve memory? Vitamin B and Alzheimer's Show more related information. Mediterranean diet. Share on: Facebook Twitter. Show references Daroff RB, et al. Alzheimer's disease and other dementias. In: Bradley's Neurology in Clinical Practice. Philadelphia, Pa. Accessed Nov. Alzheimer's disease fact sheet. National Institute on Aging. Wolk DA, et al. Clincal features and diagnosis of Alzheimer's disease.
Keene CD, et al. Epidemiology, pathology, and pathogenesis of Alzheimer's disease. Albert MS, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's and Dementia. Alzheimer's disease: Common medical problems. What is dementia? Symptoms, types, and diagnosis. Biomarkers for dementia detection and research. Cholinesterase inhibitors in the treatment of dementia.
Press D, et al. Treatment of dementia. Home safety checklist for Alzheimer's disease. Early-stage caregiving. Alzheimer's Association. Alzheimer's disease at a glance.
Extracts from Ginko biloba named as Egb have been found to show cognitive improvement in AD patients and in those with multi-infarct dementia. Similarly Melatonin is found to have antiamyloidogenic activities and is found to reduce neuronal damage caused by reactive oxygen species in AD patients.
Antioxidant therapy with vitamin E though reported in some cases but it does not improve cognitive impairment and its therapeutic use has not been established. Clinical trials with Idebenone, a co-enzyme Q10 analog have been found to attenuate Abeta-induced neurotoxicity and cognitive impairments.
Moreover DHED decreases reactive oxygen species production and cell death induced by Abeta and carboxyterminal peptides of amyloid precursor proteins, thus improving cognitive impairments in AD. Metalloporphyrin antioxidants have been found to delay neuronal death resulting from increased mitochondrial oxidative stress; Mn-salen complexes have been found to be efficacious against oxidative stress [ 35 ].
In AD, neuronal destruction is due to inflammation around Abeta plaques. Drugs under the NSAID groups have anti-inflammatory actions, and found to inhibit cyclooxygenase-1 and cyclooxygenase-2 which are responsible for the oxidation of arachidonic acids to prostaglandins; however due to adverse effects of some NSAIDs on cardiovascular systems, these group of drugs have not found routine use in AD treatment.
Polyunsaturated fatty acids or PUFA have significant biological roles in cellular structure and function. PUFA are the key components of phospholipids, comprising cellular and intracellular membranes. They govern the growth and vitality through oxidation metabolism of food to produce energy required for cellular processes , chemical activities and transportation. In addition to being the structural materials for bio-membranes, PUFA are required for generating and propagating electrical impulses; synthesis of eicosanoids, important signaling hormones with numerous complex functions.
Amongst its wide range of actions include anti-inflammatory, anti-thrombotic and vasodilatory properties, balancing and counteracting pro-inflammatory, vasoconstrictor actions of eicosanoids; the cardiovascular benefits of n-3 PUFA are largely attributed to these eicosanoid properties, and at the same time having significant roles in brain function.
Polyunsaturated fatty acids like alpha linoleic acids ALA , linolenic acids LA , eicosapentaenoic acids EPA or docosahexaenoic acids DHA are not synthesized in the body and hence must be supplied in the diet [ 36 ].
Lipids constitute approximately sixty percent of the dry weight of the brain. DHA is particularly concentrated at neural synapses, retina, brain and nervous system. Though there is a predominance of omega-6 fatty acids in circulation, in contrast to omega-3 fatty acids, however DHA predominates in these vital structures. The amount of DHA levels in the neural phospholipids depend on the amount of dietary intake rich in omega-3 fatty acids.
The n-3 PUFAs have significant biological mechanisms in brain function. Neurotransmitters such as dopamine and serotonin have a role in mental illness, research data have focused on associations between PUFA and central nervous system activity.
Levels of n-3 PUFA have been associated with monoaminergic neurotransmitter levels. There are indications that PUFA are involved in the synthesis and activities of brain peptides, which are involved in modulating the activities of neurotransmitters.
Evidence points to the role of eicosanoids in healthy brain functioning, and phospholipid membranes in neural cell signaling. Results of animal studies have shown that, n-3 deficiency is found to reduce phosphatidylserine PS levels in the brain, which is thought to play an important function in neural signaling activities.
In alcoholics, DHA deficiency has predicted reduced 5-hydroxyindoleacetic acid 5-HIAA concentrations in cerebrospinal fluid, an indicator of low serotonin turnover rate in the frontal cortex. Studies have further indicated that n-3 PUFA may affect receptor properties or activation of signal transduction by receptors. Electrical impulse conduction is dependent on the exchange of ions through the cell membrane, which relies on the fluidity and physiological structure of cell membranes.
Furthermore, n-3 PUFA are also thought to influence gene expression of a range of enzymes required for important neural functions including synaptic transduction, ion channel formation, energy metabolism and formulation of proteins vital for brain development and function.
In this regard, n-3 PUFA are associated with production of nitric oxide, as well as anti-inflammatory and vasodilatory eicosanoids notably PGI 2 , and are known to assist in endothelial-dependent vasodilatation.
They have also been associated with substantially increased transport of glucose across the blood-brain barrier. Therefore, it is also possible that their primary influence on brain function includes improved cerebral blood flow and blood-brain barrier integrity. Increased fish consumption and diets supplemented with omega-3 fatty acids are found to exhibit a protective effect, cognitive improvement and enhancement of learning abilities.
However these findings cannot serve as a basis for general recommendations for treatment of AD with dietary DHA-rich fish oil preparations. Though a number of FDA approved drugs are currently available for the treatment of Alzheimer but there are no such effective treatments to stop the insidious nerve cell death process once the disease begins.
Available drugs can manage and ease some of the symptoms of the disease but the progression of the disease can in no way be slowed down by these treatments. In AD patients there is very less production of neurotransmitter acetylcholine due to the progressive damage of the cells producing acetylcholine.
Most of the FDA approved drugs aim to prevent the breakdown of acetylcholine by inhibiting the enzyme acetyl cholinesterase. But in AD due to rapid destruction of nerve cells, the acetylcholine produced even though protected from further breakdown but the amount produced is significantly insufficient to transmit messages between the brain cells.
This fact necessitates further new drug development. A ligand can bind to the receptor either by hydrophobic, electrostatic or hydrogen bonding interactions and solvation energies of the ligand and receptor sites are the important facts to be considered in this case.
New anti-amyloid agents to prevent fibrillizations can be designed by detailed characterizations of the proto fibrils and fibril formations. Another lucrative approach is to target the APP processing where the three major enzymes are to be targeted: alpha secretase, beta secretase and gamma secretase, the basic aim is to increase the alpha cleavage or to decrease the beta and gamma secretase activities.
Nerve growth factors and neurotrophines can also act as important therapeutic targets. In in -silico drug design approach, computational docking techniques can be used to develop an effective drug to prevent the progression of Alzheimer disease.
Next step is to identify the protease enzyme that cleaves the b-APP so as to prevent the formation of beta-amyloid peptide. Enzyme modeling can be done using packages like Swiss Model, Modeller etc. The most effective protease enzyme with minimum energy conformation can be identified by the above procedure which will act as the potential drug in treating Alzheimer.
Virtually at this point of time there is no cure for Alzheimer. But apart from therapeutic interventions, attempts can be done to manage the disease and treat the symptoms by the care givers in a non-pharmacologic manner. Along with medications, physical exercise, social involvement as well as proper nutrition are essential in treating the symptoms of AD.
The goal of non-pharmacologic treatment in AD though sounds simple but clinically remains a challenge where the care giver has a vital role to play; first thing is to provide a calm structured environment where the comfort, dignity of the afflicted person is maintained and the patient remains functioning as long as possible [ 39 - 41 ]. For AD patients the environment should be so arranged that maximize use of cognitive capacities of AD patients that are intact and compensate for those cognitive capacities that decline.
Treatment in a non-pharmacologic manner aims to improve the quality of life to treat the disease symptoms. It is not a simple task for a care giver to increase functional independence, reduce the need for psychoactive medications, prolong life, reduce the need for restraints, reduce acute hospital admissions, reduce depression and improve morale.
Alzheimer begins in the medial temporal lobe and spreads to other parts of the brain slowly destroying parietal, temporal and frontal lobes, cingulated cortex, hippocampus, amygdale, damaging the tempero-parieto-occipital association cortex leading to memory dysfunction, emotional disturbances, personality changes, visual, language and movement disorders.
Due to damages in the frontal lobes AD patients will have difficulty in performing daily tasks; with the gradual progression of the disease hallucinations, delusions, paranoia, agitation, panic and denial are seen among the afflicted. Among the non-pharmacologic treatment domains include: properly mapped physical environment that removes fear and promotes safety, induce a sense of positive attitude or emotion among the afflicted persons by the care giver while helping in daily activities by helping them to perform the task but not to do the total task for them and make them even more dependent; change negative emotions and promote feelings of purpose and accomplishment.
While treating AD patients in non-pharmacologic manner one of the major corner stone is how we understand the afflicted person and help him to understand himself [ 42 - 44 ]. A person in middle stage of AD should never be attempted to bring back to the realistic world but reduce his fear in all possible stages and help him to move into his sense of the world.
Due to sensory impairment and lack of receptive and expressive language abilities non-verbal perceptual inputs which replace words like familiar music, known food smell, and known touch may be used and afflicted can be communicated with a look, tone or a hug to induce a feeling of care and safety. In case of negative behavior and aggression the triggering agent should be identified and eliminated.
The ultimate outcome of such a treatment approach is to slow the rate of disease progression, delay institutionalization, improve the quality of life and reduce the need for medication [ 39 ]. Below in fig.
Specially designed room for sensory integration therapy Snoezelen ; an emotion oriented psychosocial intervention for people with dementia. There is an increasing emergency in finding a prevention or treatment for AD and dementia because of the aging of the populations and realizing the severity and complications associated with this deadly disease. Fortunately, AD and dementia research is now at a progressing stage.
Availability of improved medical imaging technologies like CT scan, MRI, PET, use of biomarkers helps in early diagnosis of the disease, its progression and severity. Furthermore, pharmacological and non-pharmacological therapies could be directly tested both to prevent and delay the progression of amyloid in the brain and effects on brain morphology and cognitive decline.
Pharmacological therapies that could delay the onset of dementia for several years could result in a substantial reduction in the prevalence of AD because the patients will die of another cause before they develop AD. A second and far more important approach will be the application of these new technologies to understand the etiology of AD. The identification of specific etiological factors is much more likely in the long term to have a major impact on the incidence, prevalence, and disability because of AD and dementia.
Proper understanding the etiology of the disease is essential to develop hypothetical treatment approaches which can be further clinically established. Basing on in-silico drug design approaches it is essential to understand the molecular mechanisms of APP processing, role of folate and homocysteine in neuronal homeostasis.
Main target should be to develop novel therapeutic agents via cost effective, eco-friendly methodologies. Along with specific drug therapy, lifestyle interventions and environmental variables are also to be targeted to reduce the incidence of AD. However in case of new drug research in Alzheimer, ability to utilize the technologies, clinical skills and financial resources to support research studies are of vital importance.
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