Coastal Neurological
Medical Group, Inc.

UNDERSTANDING THE DIAGNOSIS AND TREATMENT OF MEMORY LOSS

Alzheimer's disease is more than just a memory loss. Alzheimer's disease is a progressive neurodegenerative disease like the other neurodegenerative diseases such as Parkinson's, ALS, prion disease and frontal temporal dementia. Alzheimer's involves the loss of memory and other cognitive functions and also a significant decline in ability to perform activities of daily living. There are oftentimes changes in personality and behavior and these changes in the patient bring about a significant increase in resource utilization and eventual nursing home placement. The approach currently for treating Alzheimer's disease is to treat the disease aggressively with the three drugs that we have available, Aricept, Exelon and Reminyl. We treat the patients aggressively with these drugs so we can improve quality of life, improve activities of daily living, improve motor function, improve behavior and improve cognitive ability. This ability to improve the patient allows for reduced caregiver time, reduced caregiver depression, reduce full time care, delay of nursing placement and studies have shown that these drugs are cost effective.

Alzheimer's is the fourth leading cause of death in the disease for people 65 years of age or older in the United States. About 4-5 million people in the United States have Alzheimer's disease, but probably for every one diagnosed there is another one that is not diagnosed. It is a very costly disease and it is about 100-120 billion a year in cost and that is slightly less than cancer and about the same cost as diabetes. Other costs for diseases are for depression 60 billion, Parkinson's 30-40 billion. The cost of Alzheimer's per patient is variable depending on where the patient obtains care and how much the family participates. The average patient with mild Alzheimer's costs about 18-20 thousand a year. For a moderate Alzheimer's it is about 30 and for a severe Alzheimer's it can be 35-40 thousand a year depending on the expense of the nursing home. There is a significant opportunity to help Alzheimer's patients and their families. What we would like to do is improve patient management programs and it is thought that this can be done by improving early diagnosis, using effective Alzheimer's treatment medication, enhance coordination of care and improve management of comorbidities and complications and also improve caregiver education and support.

The key points in understanding the concepts of treatment today with memory loss is to understand that there are a number of irreversible causes of dementia. The most common cause of dementia is Alzheimer's disease. The next most common cause is probably mixed Alzheimer's and vascular disease. Then next is vascular disease, Lewy body disease and frontal temporal dementias and other types of dementias make up a small percent of the other irreversible dementias. An important consideration for treating dementias today is that for Alzheimer's disease and possibly some other dementias we have three effective medications; Aricept, Exelon and Reminyl. The key important aspect today is to remember that early diagnosis is extremely important and early treatment is also very important. Today, studies document clearly that these three medications, all of the acetylcholinesterase inhibitors have good strong efficacy documented in clinical trials. To make the diagnosis early and to treat early we have to consider screening patients in our office and to screen patients that have a likely chance of having dementia. The reasons we treat patients with acetylcholinesterase inhibitors early now is because the studies show that they improve cognition, improve behavior, they are cost effective, they delay time to nursing home placement, they reduce caregiver time and caregiver depression and they reduce costly antipsychotic drugs. These drugs also help treat not only mild to moderate Alzheimer's disease but also they are effective in advance Alzheimer's disease. We know that neurodegenerative diseases are a group and that group is mainly composed of Alzheimer's disease, Parkinson's disease, anterior horn cell disease, or ALS, and frontal tempora disease.

There are many reasons to aggressively diagnose and treat dementias. Some of the practical reasons today are the legal issues that occur for the family and for the patient.

Dementia of the Alzheimer's types characteristics are noted to be dementia, depression; oftentimes a third of patients will have depression before the diagnosis of the development of dementia. They also have behavioral disturbances, autonomic dysfunction, sleep disorders and a third of the patients later will have motor impairment mainly consisting of rigidity and akinesia.

We aggressively treat so we can improve quality of life. This is to improve activities of daily living, improve motor function. improve behavior, improve cognitive ability to reduce caregiver time and depression and to reduce other drugs that are costly. These drugs, without question, have been shown that they are cost effective. There are definite indications for the evaluation of Alzheimer's disease. Patients who have difficulty with learning or retaining new information should be evaluated as should patients who have difficulty in performing complex tasks, who have impaired reasoning ability, or patients who have problems with orientation and spatial abilities. Language difficulty such as an expressive aphasia or a receptive aphasia should be also evaluated and Alzheimer's disease should be considered or a frontal temporal dementia should be considered. Depression and behavior changes can often precede dementia in patients with Alzheimer's disease and in these patients definitely dementia should be considered.

Risk factors for dementia are age, Apo E-4 genotype, family history, head injury, smoking, hypertension, diabetes and elevated homocysteine levels. An inverse relationship to the risk factors have been now noted to be estrogen, statins and NSAIDs.

The pathology of dementias of the Alzheimer's type is noted to be senile plaques, neurofibrillary tangles, amyloid angiopathy, reduced acetylcholine, reduced dopamine and reduced serotonin levels. The cholinergic hypothesis is thought to be an important aspect of the underlying pathophysiology and abnormal transmission that occurs in Alzheimer's patients. There is the presynaptic neuron which has a presynaptic terminal where acetylcholine is stored and released into the synaptic cleft. In the synaptic cleft there is acetylcholine that is released, there is acetylcholinesterase and butyrylcholinesterase. It is the acetylcholinesterase and the butyrylcholinesterase that reduces the acetylcholine in the synaptic cleft and does not allow it to reach the acetylcholine receptors on the postsynaptic membrane of the postsynaptic neuron or the postsynaptic terminal. Hence, the effect and benefit of the acetylcholinesterase inhibitors like Aricept, Exelon and Reminyl is that they inhibit the acetylcholinesterases and allow more available acetylcholine to reach the postsynaptic terminals and attach to the acetylcholine receptors. In Alzheimer's disease cognitive decline is expected over time and in one year the Mini-Mental State Exam declines by 2-4 points and the ASB cog will decline by 5-7 points per year. Cognitive function scores remain at baseline when using drugs like Aricept as measured by the Mini-Mental State Exam for almost one year and then decline. The pathology of Alzheimer's disease has three consistent neuropathological hallmarks. They are amyloid-rich senile plaques, neurofibrillary tangles and neuronal degeneration. These changes eventually lead to clinical symptoms but the pathological changes oftentimes occur many years before the onset of symptoms. It is known that in autopsies on people who have no evidence of dementia clinically that there is oftentimes found senile plaques and neurofibrillary tangles. The treatment of neurodegenerative diseases, which as mentioned were Parkinson's, Alzheimer's, ALS and frontal temporal dementias, is very important and early treatment as mentioned is important because it has an opportunity to improve quality of life and improve other aspects of the patient's disease process. It is important to remember that patients with neurodegenerative disease do not die of their disease. They usually die of infections, subdurals, ruptured bowel or stroke or heart disease. Oftentimes they will fall and have injury and those complications will lead to further medical complications and demise. So it is important manage cognitive aspects, behavior and motor impairment early in neurodegenerative disease. It is important to support the patient who has dysphagia, who falls, who wanders, who has bladder incontinence, who has hypertension, sleep disturbances and bowel difficulties. In these patients it is important to avoid narcotics and sedatives and other medicines that will make them more likely to have complications. Alzheimer's disease is often misdiagnosed and usually the patient can be diagnosed as some other cause of dementia, or in about 15% they are diagnosed at first as having depression or just normal aging. Oftentimes vascular dementia is a dementia that is in the differential diagnosis of Alzheimer's disease. Vascular dementia is the second most common cause of dementia and oftentimes vascular dementia and Alzheimer's are pathologically seen in one patient and they have an overlap disease. Many patients will have what we call mixed dementia. In pathological studies it is shown that this is the case and people with vascular dementia will oftentimes have microinfarcts or lacunar infarcts. They will have cortical infarcts. They will have white matter T2 changes on MRI and they will also have other evidence of peripheral vascular disease. Frontal temporal dementia is another dementia that is seen in the differential diagnosis. This is a chromosome 17 Q21-22 localization genetically. It is due to mutations in the microtubule associated with protein Tau. Frontal temporal dementias can be autosomal dominant, autosomal recessive, even sex-linked autosomal dominant and autosomal recessive. Pick's disease is probably the old term for frontal temporal dementia. It really is a spectrum of dementias and one of the interesting clinical pictures is that of someone presenting with primary progressive aphasia. Their main problem that they present with is difficulty getting words out or expressive aphasia. Other people with this clinical picture can be those patients who have cortical basal ganglia degeneration and progressive supranuclear palsy. Not all of these people have Tau. Many of them have an overlap pathology and it has been shown now in some centers that a third of patients with ALS will have a frontal temporal dementia. It is important to make this diagnosis because they usually don't respond as well to acetylcholinesterase inhibitors and some of them, it is noted, have serotonin receptor reduction and sometimes SSRIs can be of benefit. If they don't respond to SSRIs and there has been a careful use of acetylcholinesterase inhibitors and they have been ineffective, then atypical neuroleptics oftentimes need to be used.

Another disease that is infrequently seen, but in the differential of dementias, is prion disease. Dr. Stanley Prusner won the Nobel Prize for the investigation of this disease. It is an infectious agent that has a protein deposition like the other neurodegenerative diseases and the protein that is deposited is PRP 24 to PRP SC. Dr. Prusner is now researching many drugs for the possibility of treating this disease that really has three important forms. These forms are sporadic, familial, and new variant CJ disease, or known as Mad Cow disease.

Treatment today for Alzheimer's disease is well-known and, as mentioned before, should be done aggressively. Donepezil, which is a drug that improves cognition and global function in patients with mild to moderate Alzheimer's disease, has been used the longest of the three that are commonly used today. The first 24-week study showed efficacy and improvement not only in cognition but in the Mini-Mental State Exam and in activities of daily and also in behavior. Long term efficacy with donepezil, or Aricept, is now out as far as 4-5 years showing an improvement over the natural history of the disease process. Other drugs have been shown to be of benefit such as galantamine which was used in a 6-month double blind study and showed that it had improvement in functional performance and also in ABS cog scores over five months. It also showed improvement of activities of daily living over five months when compared to placebo. The long term cognitive benefit of galantamine was shown at six months using the highest doses, which were 24 mg per day as compared to a lower dose of placebo and when patients who had been on placebo for six months took the medication at six months they never caught up to the patients who had been on the drug from the beginning. This phenomenon definitely supports the concept of early diagnosis and early treatment pushing the drug to the highest dose possible. It has also been shown that there has been significant caregiver time reduction in caregivers of patients with Alzheimer's disease, especially when assisting with activities of daily living. There has also been a reduction in time by the caregiver in supervising the patient with Alzheimer's disease and this has been documented in numbers of studies. Aricept did a nursing home placement study which showed a delay 21 months, almost two years, for patients who used Aricept for at least 36 weeks or longer. There have been a number of studies which have shown that in severe dementia patients with Mini-Mental State Exams less than ten that these drugs are efficacious and improve the patients' behavior, activity, improve their neuropsychiatric symptoms and allow them to participate more and to have improved activities of daily living. There was a one-year preservation of function trial which showed that the median time to functional decline was 72% longer when patients were on donepezil, or Aricept, as compared to those patients on placebo. Patients who had severe dementia showed significant MMSE improvement when the patient's Mini-Mental State Exam was monitored and it had a more robust improvement in more severely demented patients.

It has been known in another neurodegenerative disease, Parkinson's disease, that the concept of continuous stimulation may play a role in the patient's Parkinson symptoms. The concept of continuous stimulation is the thought that having more available neurotransmitter, in Parkinson's it is dopamine, available at the postsynaptic receptor sites allows the reduction of abnormal movement that can be seen in Parkinson patients, which is dyskinesia. This concept of continuous stimulation is important in Parkinson's but how important it is in Alzheimer's is not certain. It is known that when using a more continuous stimulating drug at the postsynaptic receptor site in Parkinson's disease, such as a dopamine agonist, that there is a reduction in dyskinesias. This was shown when comparing a shorter acting drug, L-dopa, to the longer acting dopamine agonist, that dyskinesias occurred much less frequently at the end of five years in patients on dopamine agonists as compared to those on L-dopa. This is thought to be case because of changes that occur downstream. Dr. Tom Chase at NIH has felt that this occurred in the striatal medium spiny neurons where dopamine has its action. This striatal medium spiny neuron has receptor sites for dopamine but when the dopamine neuron has lost its capacity to store dopamine then it goes into other neurons, possibly a serotonin neuron and is not released in a continuous or physiological manner. This causes abnormalities in signaling in the medium spiny neuron dendrite and there are changes that take place in certain receptors and certain NMDA signaling processes. This may explain why patients on a longer acting, more continuous stimulating drug have less dyskinesia. The question is does this apply to Alzheimer's disease and if so, how does it affect the disease signs and symptoms. We know now by PET scanners and SPECT scanners in Parkinson patients that there does appear to be less neuronal loss in the substantia nigra in patients who were studied in the dopamine agonist studies that developed less dyskinesia.

The acetylcholinesterase inhibitors have been used in patients that have Alzheimer's plus Parkinson symptoms and these patients had improvement also with their Mini-Mental State Exam and it was uncertain whether they had Parkinson's disease or just Alzheimer's and Parkinson's signs but there was definitely an improvement in these patients' Mini-Mental State Exam. The efficacy of Aricept in this population for improvement of cognitive aspects was as good as in the Alzheimer's patients. There was no worsening of any of the Parkinson symptoms.

Treating Alzheimer's today for cognitive improvement and behavioral improvement is very important and the studies have shown in these drugs that we can improve quality of life, improve activities of daily living, improve motor function, improve behavior and improve cognitive ability. We also can with these drugs reduce caregiver time, caregiver depression and it has been documented that these drugs are cost effective.

There is a significant amount of research being done in Alzheimer's disease, not only in the basic science aspect, but also in the pathology and in the treatment of Alzheimer's disease. We have much to be encouraged about because these treatment formats should only get better and our understanding of Alzheimer's disease should also get better. Any advance in the treatment of any of these diseases, such as Alzheimer's, Parkinson's, prion disease, will probably be of benefit and will help in the understanding of any of the diseases.

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Coastal Neurological Medical Group
9850 Genesee Avenue
Suite 860
La Jolla, CA 92037
Tel: 858.453.3842
Fax: 858.535.9390

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