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Management, Research Directions and Emerging Therapeutic Approaches of Alzheimer’s disease

Definition:

Alzheimer’s disease (AD) as the most common of all dementia diagnoses has become a major public health concern as our population ages. The American National Institute of Health estimates that by the year of 2030, 8.5 million people will be affected in the United States alone. [1] So far, no preventive drugs have been discovered, but a well controlled blood pressure and an active life, both mentally and socially, are known to delay or lower the risk of AD [2]

 

 

Management:

The goal of research on Alzheimer’s disease is the identification of agents to prevent the occurrence, defer the onset, slow the progression, or improve the symptoms of disease. Progress has been made in this arena, and several agents have been shown to have beneficial effects in the treatment of Alzheimer’s disease.

Current treatments can be divided into pharmaceutical, psychosocial and caregiving.

 

1.Pharmaceutical

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that currently affects millions of Americans. There is no cure at present and no real long-term hope for patients with AD. While partially effective in improving symptoms, currently available treatments approved by the US Food and Drug Administration (FDA) do not halt progression of AD, or address the underlying mechanism of the disease, in part because the etiology of AD is still an active area of investigation

 

Mainly there are 2 classes of drug that are currently approved by the US Food and Drug Administration (FDA) for the treatment of AD, acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartic acid (NMDA) receptor antagonists. [3],[4] As stated above in the Pathophysiology section of this article, current therapies do not target the underlying pathogenesis of AD; rather, they are used to limit disease progression after neuronal damage has occurred. As such, these agents do not directly target the accumulation of amyloid and tau proteins.

 

Cholinesterase inhibitors improve cognitive symptoms or temporarily reduce the rate of cognitive decline. Cholinergic systems are involved in normal memory functions, [5] and cholinergic deficiency has been implicated in the cognitive and behavioral [6] manifestations of AD. Activity of the synthetic enzyme choline acetyltransferase (CAT) and the catabolic enzyme acetylcholinesterase (ACE) are significantly reduced in the cerebral cortex, [7], [8] hippocampus, and amygdala in AD patients.[9] Because cholinergic dysfunction may contribute to the symptoms of AD patients, [5] enhancing cholinergic neurotransmission constitutes a rational basis for symptomatic treatment. Attempts to augment cholinergic activity have employed acetylcholine (ACh) precursors, cholinergic agonists, and drugs inhibiting acetylcholinesterase (AChE), the enzyme responsible for the breakdown of ACh. Precursor therapy, using choline or phosphatidylcholine (lecithin), has been largely unsuccessful. [10] Thus far, cholinergic agonists (bethanechol, pilocarpine, arecoline, RS-86, xanomeline tartrate) have yielded modest results or have been associated with significant side effects. [11], [12]

Various classes of AChE inhibitors have been studied for the treatment of AD. They differ in their mechanism of inhibition (reversible, pseudo-irreversible, or irreversible), metabolism, and brain selectivity. Four Cholinesterase inhibitors (CIs) are currently approved by the FDA for the treatment of AD: tacrine, donepezil, rivastigmine, and galantamine. [3],[10] All of these medications are approved for mild-moderate AD except donepezil, which is approved for mild-severe AD. These medications have never been compared in head-to-head clinical trials; thus, it is difficult to determine which is best for the treatment of patients with AD. Tacrine has significant side effects, such as hepatotoxicity, and is rarely used. [3] The other 3 CIs appear to be equivalent in terms of efficacy and are associated with symptomatic improvement in cognitive function in patients with mild-moderate AD. Improvement generally lasts for 6 to 12 months, followed by a gradual decline in most, but not all, cases. [3]

There is some controversy regarding the duration of use of CIs in the treatment of patients with AD. Some clinicians feel that once a patient has reached the stage of severe AD, CI use should be discontinued. Others feel that CIs may still be useful in managing symptoms in severe AD. This is an active and open area of clinical investigation, but despite this controversy, CIs represent the primary form of treatment for AD. Cholinesterase inhibitors exhibit wide variations in their pharmacology. A clinical study evaluating the concentrations of several biomarkers in Cerebral spinal fluid (CSF) in patients with mild and moderate AD found that long-term treatment with donepezil and galantamine, which are rapidly reversible CIs, significantly upregulated AChE activity and protein levels in cerebral spinal fluid (CSF). In contrast, rivastigmine, a pseudoirreversible CI, caused a significant decrease in AChE activity and no effect on protein levels in CSF. [13] Thus, depending on mechanism of action, CIs can have different effects on CSF activity.

A novel class of AChE inhibitor is currently in development, exemplified by pyrano(3,2-c)quinoline-6-chlorotacrine, a molecule that binds to both peripheral and catalytic sites of AChE.[14] Blocking the peripheral site is expected to affect acetylcholine-induced Aβ aggregation, while blocking the catalytic site is expected to inhibit the production of Ab. The molecule also appears to inhibit BACE1 to some extent. [14] This novel dual-acting drug may emerge as a more effective candidate than those that target either the catalytic or noncatalytic pathways of Aβ production and aggregation.

 

N-Methyl-D-Aspartic Acid (NMDA) receptors Antagonists composed the second main class of drugs that are currently approved by the FDA for the treatment of the AD.

Memantine is currently the only NMDA antagonist that is approved by the FDA for the treatment of AD. N-methyl-Daspartic acid antagonists act by blocking the NMDA receptor. The cognate ligand for the NMDA receptor is glutamate, an excitatory neurotransmitter that may take part in the acceleration of AD.[3],[15-17] In the healthy brain, glutamate binds to NMDA receptors on postsynaptic cells to mediate normal excitory neuronal activity. In brains of patients with AD, dysfunctional regulation leads to excess glutamate, which repeatedly binds to the NMDA receptor causing neuronal excitotoxicity. This dysregulated, sustained neuronal excitotoxicity can eventually lead to neurodegeneration.[15-17] N-methyl-D-aspartic acid antagonists block NMDA receptor binding by glutamate, thereby decreasing neuronal excitotoxicity and slowing the progression of AD (Figure 1). Memantine has been approved for the treatment of all stages of AD but is generally used in moderate-to-severe AD. [3], [4] Administered as a twice-daily dose, compliance is a common issue with memantine, as it is difficult for forgetful patients to remember. Memantine is in no way a cure for AD; however, it has been shown to improve cognitive function and slow the rate of decline in patients with moderate-to-severe AD. [18] The duration and extent of cognitive efficacy is 6 months and possibly greater. [18] Additional studies are needed to determine whether the efficacy of memantine in patients with moderate severe AD lasts beyond 6 months.

 

2.Psychosocial intervention

Psychological interventions are used as an adjunct to pharmacotherapy and fall into four (4) classes: behaviour—, emotion—, cognition— or stimulation—oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general. [19]

Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning,[20] but can help to reduce some specific problem behaviours, such as incontinence.[21] There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.[22],[23]

Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness. [19] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT, it may be beneficial for cognition and mood. [24]

There is little evidence to support the usefulness of these therapies

 

3.Care giving

Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving essentially is the treatment and must be carefully managed over the course of the disease.

Patients with Alzheimer’s disease receive most of their care from family members, and expansion of support services for caregivers is an important aspect of meeting the challenge of Alzheimer’s disease. [25]

 

Prognosis

The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living. [41]

A study by Devanand et al. [26] has reported that “psychotic” symptoms in Alzheimer’s disease show moderate persistence over time. Other studies [27],[28] have shown that even though Alzheimer’s disease patients with delusions deteriorate more rapidly both functionally and in cognitive impairment, they do not die more rapidly.

Life expectancy of the population with the disease is reduced. The mean life expectancy following diagnosis is approximately seven years.[29] Fewer than 3% of patients live more than fourteen years.[30] Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival. Men have a less favorable survival prognosis than women. [30]

 

Research Directions and Emerging Therapeutic Approaches

Alzheimer’s disease (AD) is widely considered to be clinically homogeneous with characteristics profile of neuro-psychological deficits (McKhann et al., 1984; Morris et al., 1989; Locascio et al., 1995). Identification of risk factors and the pathogenic mechanism of AD hold the promise of bringing forth novel treatments and perhaps even a cure. Novel therapeutic strategies such as inhibition of b-amyloid peptide (Ab), tau-mediated pathogenesis, and receptors for advanced glycation end products (RAGE), as well as neuroprotective and anti-inflammatory approaches and the impact of cholesterol-lowering, botanical, and nutritional agents are also reviewed. [31]

Secretase Modulators

This class of medication is composed of drugs that will decrease the formation of Ab through modulation of the enzymes involved in APP processing; they are named α-, β- and γ-secretase. Among these drugs we can find in one hand CTS21166 and posiphen (both β-secretase inhibitors and currently in clinical trials), [32], [33] tarenflurbil (a γ-secretase inhibitots and currently in preclinical studies in patients with mild-moderate AD). [34],[33]

 

Immunotherapeutic Approaches: Anti-Aβ Vaccines and immune Immune Modulation

AN1792 (1st generation active vaccine) were efficient in terms of provoking the immune system to target Aβ, but was stopped in clinical trial due to the increased number of meningoencephalitis in vaccinated patients. [32]

Tramiprosate (1st antiamyloid) was stopped in clinical trial II due to its promotion of the aggregation of tau protein in the brain.[33] Antiamyloid immunoglobulin (IgIV) which is currently in trials, constitutes one of the main passive immunotherapeutic drugs to fight AD.[35]

 

Enzymatic Degradation of Aβ

Neprilysin (NEP) and Insulin degrading enzyme (IDE) are the main drugs of this category. Studies [32],[36] show that NEP and IDE can be emerging therapeutic as the down-regulation of their activity can increase Aβ accumulation.

 

 

Receptor for Advanced Glycation End Products Inhibitors

PF04494700[33], an oral formulation (currently in phase II trials) of Receptor for advanced glycation end products (RAGE) is an emerging drug that reduces Aβ levels in the brain. [34]

 

Chinese Herbs

Chinese herbs show promise in AD treatment because of their cognitive benefits and more importantly, their mechanisms of action with respect to the fundamental pathophysiology of the disease. Below are some Chinese herbs which were found promising for the treatment of AD.

The Chinese herb Uncaria rhynchophyllais a potentially novel therapeutic agent to prevent or treat AD because it has potent inhibitory effects on fibril formation of Aβand can also destabilize preformed Aβ fibrils. [37].

Some researchers found that Tenuigenin (which is a compound extracted from the Chinese herb Polygala tenuifolta) , can inhibit the secretion of Aβ in cultured cells, which may explain its ability to improve cholinergic function degraded through Aβ in rat models. [38]

In some studies, Berberine as an alkaloid isolated from the Chinese herb Coptidis rhizome, can reduce Aβ secretion by altering APP processing in a way to shift from the amyloidogenic to nonamyloidogenic pathway. [39]

An active ingredient of a Chinese herbal formula, Danggui Longhui Wan, Indirubin was found potentially valuable to treat AD patients due to its property of inhibiting two protein kinases involved in abnormal tau phosphorylation in AD. [39]

 

However among all the promising Chinese herbs, G. biloba, Huperzine A (Lycopodium serratum) and Ginseng have been the more reliable ones and have been assessed for their clinical efficacy separetly in six randomized controlled clinical trials

Following the link below we can have an overview of medications for Treatment and Prevention of AD.
http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1157

Conclusion

 

In summary, the anticipated growth of the number of patients with Alzheimer’s disease poses an urgent public health challenge. Improvements in detection, diagnosis, and treatment are needed. There have been marked advances in understanding Alzheimer’s disease, and preliminary steps have been taken to develop new therapies. An expanded research commitment is necessary to accelerate drug discovery, and more translational research is needed to ensure that new discoveries are incorporated into clinical practice.

However, all promising agents will require human testing, and additional funds are needed for this process. Objectives include expanding recruitment of subjects for clinical trials, increasing the number of clinical trials, testing multiple therapeutic agents simultaneously to determine interactive effects, establishing financial incentives for development of drugs that act early in the pathogenic cascade, studying psychotropic agents that reduce behavioral disturbances with few side effects, and investigating the late phases of Alzheimer’s disease to determine how best to treat patients with severe dementia syndromes

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Article By: Guy-Armel BOUNDA, Cosette NGARAMBE
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