DISEASE INFLUENCING FACTORS : DIET, LIFE STYLE, ENVIRONMENT, SMOAKING, ALCOHOL, DRUG ABUSE & LACK OF EXERCISE
Medical Care: Therapeutic approaches to AD are based on developing theories of its pathogenesis and on the need to alleviate its cognitive and behavioral manifestations. The predominantly symptomatic approach preceded, by many decades, the more recent interventions based on our improving understanding of the pathogenesis and pathophysiology of AD.
To date, no interventions have been shown to convincingly prevent AD or slow its progression. Medical treatments for AD include psychotropic medications and behavioral interventions, cholinesterase inhibitors (ChEIs) and the avoidance of centrally acting anticholinergic medications, N-methyl-D-aspartate (NMDA) antagonists, and other and new therapeutic interventions.
Psychotropic medications and behavioral interventions
A variety of behavioral and pharmacologic interventions can temporarily alleviate clinical manifestations of AD, such as anxiety, agitation, depression, and psychotic behavior, which are best approached symptomatically. These interventions are useful in managing AD, though their effectiveness is often modest and temporary, and they do not prevent the eventual deterioration of the patient's condition.
Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of AD. These interventions are often combined with the more widely used pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage).
No specific agent or dose of individual agents is unanimously accepted for the wide array of clinical manifestations. At present, the US Food and Drug Administration (FDA) has not approved any agent for the treatment of AD. However, medications that many practitioners prefer are haloperidol, risperidone, olanzapine, and (more recently) quetiapine. The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients.
Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the manifestations of dementia with cortical Lewy bodies (DCLB), also known as Lewy body dementia (LBD), because patients with DCLB may be extremely sensitive to these agents. Adverse reactions to conventional neuroleptics have fueled the search for new agents that alleviate disruptive behavior while minimizing the occurrence of extrapyramidal manifestations and worsening of motor and behavioral performance, which is frequently observed in DCLB. This is the basis for the recent trend to use new-generation agents to alleviate the behavioral manifestations of AD, with therapy usually extending into the more advanced stages of the disorder.
Results of several studies indicate that anticonvulsants (eg, gabapentin) may have a role in the treatment of behavioral problems in patients with AD.
Cholinesterase inhibitors
A strategy widely used to address the symptoms of AD is palliating the deficiency in cholinergic innervation to the cerebral cortex. Numerous lines of evidence indicate that the corticipetal cholinergic system is targeted relatively early and more or less selectively in AD. For over 2 decades, AD has been characterized by substantial loss of acetylcholine (ACh) in the cerebral cortex, progressive decline in cortical levels of choline acetyltransferase (biosynthetic enzyme necessary for the synthesis of ACh), and severe loss of neurons in the subcortical cholinergic nuclei that project to the cerebral neocortex (ie, basal nucleus of Meynert) and hippocampus (ie, medial septal nuclei).
These observations have led to the theory that some of the clinical manifestations of AD are due to loss of the cholinergic innervation to the cerebral cortex. In turn, this theory led to development of an increasing number of compounds capable of palliating the cholinergic defect by interfering with the degradation of ACh by acetylcholinesterase (AChE), the synaptic, or specific, form of cholinesterase. More recent compounds include substances capable of blocking the nonsynaptic, or nonspecific, cholinesterases; these are frequently called butyrylcholinesterases (BuChEs).
An often neglected aspect of palliation of cholinergic deficits is the avoidance of centrally acting anticholinergic medications. Patients not uncommonly receive both ChEIs and anticholinergic agents, which negate or at least counteracting the effects of the former. Therefore, a careful listing of the patient's medications is important to reduce the doses of, or ideally eliminate, all centrally acting anticholinergic agents.
See also the Medication section below.
N-methyl-D-aspartate antagonists: A relatively new category of drugs, NMDA antagonists, is based on an entirely different mechanism of action. Memantine is the first NMDA antagonist approved in the United States. This agent is approved for treating the advanced stages of AD, in contrast with ChEIs, which are approved for only the early and intermediate stages. Of interest, memantine may also be helpful in other neurodegenerative conditions, such as Huntington disease, AIDS-related dementia, and vascular dementia.
Antidepressants: The role of antidepressants in the treatment of mood disorders, and especially depression, cannot be overemphasized. Depression is observed in more than 30% of patients with AD, and it frequently begins before AD is clinically diagnosed. Therefore, palliation of this frequent comorbid condition can considerably improve their cognitive and noncognitive performance. Other mood modulators, such as valproic acid, can be helpful for the treatment of disruptive behaviors and outbursts of anger, which patients with moderately advanced or advanced stages of AD may have.
Other and new therapeutic interventions: Other agents proposed for the treatment of AD and new drugs being developed are free-radical scavengers, and estrogen- or selective estrogen-receptor agonists, anti-inflammatories, and clioquinoline and other drugs.
The proposal that oxidative stress causes AD and evidence suggesting that estrogen has a trophic effect on certain neuronal populations that is lost after menopause were the bases for previous recommendations to give high doses of tocopherol (1000 IU PO bid) to all patients and estrogen replacement therapy to postmenopausal women with AD. Federal and institutional policies do not mandate use of these agents; their common use reflects the widespread belief that they may be beneficial. Because findings show that estrogen supplementation may be associated with cognitive impairment and that high-dose tocopherol may cause adverse cardiovascular events, the entire body of evidence is being re-evaluated, and few (if any) now recommend these treatments. Results to date indicate that patients with clinical dementia do not benefit from estrogen replacement therapy.
An additional treatment, the use of anti-inflammatory agents, is based on the postulation that inflammation is needed for many AD lesions, especially SPs, to develop and progress through the theoretical stages of increasing severity. This theory has received considerable support, and many studies purportedly show improvement or a lack of progression of the manifestations of AD over relatively short periods of anti-inflammatory therapy. No present recommendations require the use of anti-inflammatories in AD; results of large-scale trials still underway have not been published.
New drugs under development include clioquinoline, an antibiotic that may help reduce brain amyloid deposition in patients with AD. Other, unrelated compounds under development and are also expected to reduce or eliminate cerebral amyloid deposition and possibly NFTs.
The mainstay of therapy is the use of centrally acting cholinesterase inhibitors to palliate the depletion of ACh in the cerebral cortex and hippocampus. Because the clinical manifestations of AD are believed to be partly due to a loss of the cholinergic innervation to the cerebral cortex, compounds have been developed to palliate the cholinergic defect by interfering with the degradation of ACh by AChE, the synaptic (or specific) form of cholinesterase. Some of the more recently available compounds are substances that inhibit also the nonsynaptic (or nonspecific) cholinesterases, which are frequently called BuChE.
AChE inhibitors approved by the FDA for use in the early and intermediate stages of AD are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (galanthamine, Reminyl). Among these, only tacrine and rivastigmine also inhibit BuChE. This may be important for their therapeutic efficacy because BuChE levels increase during the course of AD and are present in some AD lesions, including senile plaques. At present, tacrine, is used seldom if at all because it has been superseded by the other 3. To date, the ChEIs is the only class of drugs that has been formally approved for use in AD.
An increasing number of clinical studies demonstrate that cholinesterase inhibition can have modest but detectable effects, such as improvement in cognitive performance, as measured by tools such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). More recent evidence indicates that ChEIs may also alleviate the noncognitive manifestations of AD. For example, they can ameliorate behavioral manifestations, as assessed by using tools such as the Neuropsychiatric Inventory, and they may improve the performance of activities of daily living, as evaluated by using the Progressive Deterioration Scale.
DRUG TREATMENT :
1. CENTRALLY ACTING AChE INHIBITORS -- These agents are used to palliate cholinergic deficiency
- RIVASTIGMINE (Exelon) -- Centrally acting AChE and BuChE inhibitor.
- DONEPEZIL
- GALANTAMINE
2. NMDA antagonists -- The newest class of agents indicated for the treatment of AD. As of October 2003, the only approved drug in this class is memantine. These agents may be used alone or combined with AChE inhibitors. Most believe that combination therapy offers superior benefits compared with results of either category of agent alone.
- MEMANTINE