Senile Dementia is an acquired cognitive deficit, especially memory,found among 5% of people aged 60 years or more. This means for Thailandthat up to 250 000 people may suffer from this disease. This number mayshow a fast increase along the aging of the Thai population at mid-term.
The most frequent etiologies of Senile Dementia are Vascular Dementiaand Alzheimer's disease. To-date, one can take prophylactic measures totreat Vascular Dementia, such as administering low doses of aspirin whichprevent blood clotting. This decreases the risks of further brain insults.Drugs improving the cognitive abilities of patients with Alzheimer's diseaseare available since recently. Let us mention the acetyl-cholinesteraseinhibitors donepezil (ARICEPT) from Esai and Pfizer, as well as finasteride(EXELON) from Novartis. However, much research remains to be done for improvingsignificantly the disease management of Senile Dementia.

1. Introduction

Senile Dementia is an acquired cognitive deficit found among 5% - 7%of people aged 65 years or more. This disease may also encountered in younger ages between 50 and 65 years of age. It is usually define as Pre-senileDementia. Their number may represent 10% of those suffering from SenileDementia. The most frequent etiologies of Senile Dementia are VascularDementia and Alzheimer's disease.

The acquired cognitive deficit is characterized by a loss of memory;for instance patients cannot recognize their friends and familiar surroundings anymore. While the disease progresses they even loose the remembrance oftheir closest family relatives such own children or even their spouse orget lost when they leave their home for only 5 minutes. This impairmentis sufficient to interfere with their daily activities to an extent thatthese persons cannot live anymore an independent and self-sufficient life.They must rely on the continuous support of their next family members.More severely affected patients may need to be placed in specialized institutionsoffering a 24-h care.
 
 

2. Epidemiology of Senile Dementia

While epidemiological data on Senile Dementia, particularly Alzheimer's disease, start to be more comprehensive in Western Countries, they arestill scarce in Asian countries. However, the data that follows will bebased on some publication from Asia because they are thought to be morerelevant for Thailand.

According to epidemiological data from Japan (1. Ueda,1992), among 7.2% residents aged 65 + years, 6.7% had Dementia. Vascular Dementia was found among 56% of demented people and Alzheimer's disease in 26%. Also in Japan (2. Yamada,1999), 7.2 % of people 60 years or more had Dementia (community based study). Vascular Dementia was predominant among male demented people and Alzheimer's disease among female demented people.
In Western Countries, about 2.5% of persons aged 60 years or more haveVascular Dementia. However Vascular Dementia was more frequent in Chinaand in Japan than in the Western Countries (3.Desmond, 1998).
Stroke is the most common cause of Vascular Dementia. Cumulative frequency of dementia in a Japanese community based study was 27.2% with patientswith a history of Stroke and 3.4% in the control population (1.). The incidence of Vascular Dementia is increasing with age. After 1 year the probability of new-onset Dementia is 5.4% in patients over 60 years and 10.4% in patients over 90 years. (4.Van Koten, 1988). Cumulative effect of cerebrovascularlesions increases the occurrence of Vascular Dementia. Furthermore Strokemay induce an earlier expression of Alzheimer's disease.

Generally spoken, the risks for Vascular Dementia are high blood pressure, cardiac disorders, and hematocrit superior to 45%, carotid bruit and Diabetes mellitus.
3. Association of Vascular Dementia and Alzheimer's disease.
The E 4 allele of the apolipoproteins E gene (APOE) is associated witha higher risk of Ischemic Stroke or Coronary Heart Disease. (5. Leys, 1998)The allele is also associated to a higher risk of late onset Alzheimer'sDisease. 10 - 20% of Alzheimer's patients have cerebrovvascular lesionssuggesting Vascular Dementia. Also 20% of Vascular Dementia patients haveassociated Alzheimer's Disease.
 

4.Role of demographic characteristics for Senile Dementia

Increasing age, previous myocardial infarction, lower educational level, Diabetes mellitus and current cigarette smoking are associated with anincreased risk of dementia in Stroke patients. Cerebral hypoperfusion leadingto hypoxemia (lack of oxygen) and cardiogenic hypotension can be a potentialfactor for the occurrence of Vascular Dementia. (5.)

The recognition of vascular component in dementia syndrome may be useful in terms of prevention. Hence, control of hypertension and general lifehygienic measures as low fat diet and regular exercise may reduce the riskof both diseases namely Vascular Dementia and Alzheimer's disease.

In Thailand an estimated 5.5 million people are aged 60 years or overwhich represents a share of 8% of the total population.(WHO, 1999) Thisshare is about half that found in Western Countries and in Japan. To-dateepidemiological data on Senile Dementia is lacking. However, based on epidemiologicaldata from abroad, it can be realistic to assume the 5% of the people aged60 years or over may suffer from this disease. Hence, we may estimate thenumber of people with Senile Dementia and related disorders up to 250 000in Thailand.

For estimating the affected persons by etiology, we can roughly usethe following key:
 

This distribution may changed more or less soon since in Japan for instance there is a shift in favor to Alzheimer's disease, may be because of anincreasing population of old women where Alzheimer's disease is predominant.Moreover a better prophylaxis of Stroke among men and an increased awarenessof Alzheimer's disease among Japanese doctors with improved skills to diagnosethat disease what may contribute to this change. (2.)

As final remark to that section, it would be highly desirable to start epidemiological studies in Thailand as soon as possible.

5. Diagnosis of Dementia

Dementia develops cognitive deficits, particularly loss of memory, which are sufficient to interfere with social functioning and daily activities. (7. DSM IV, ICD 10)

Vascular Dementia (VAD) occurs with a number of syndromes, which areassociated with cerebrovascular disesase. The development of the diseaseis generally characterized by sudden onset, stepwise decline, impairedfunction to plan its own life, gait disorder (i.e. abnormal walking), andunstable mood (angry agitated episodes followed by apathy). There are clinicalor neuroimaging evidence of cerebrovascular disorders. There is usuallya time-relationship between a cerebrovascular event and the onset of thecognitive decline.

Alzheimer's disease (AD) is characterized by neurodegenerative process, which is gradual and extends over years. There is a continuous declineof memory, particularly the remembrance of recent events and other cognitive functions such as language disturbance, impaired manual skills, loss oforientation in familiar sites, the person cannot find her/his home againafter shopping, inability to plan and manage her/his own life. More severelystruck persons cannot recognize her/his children and spouse.

Further Dementia of various etiologies can be mentioned:

Frontemporal Dementia (FTD) There is an insidious onset and slow progression of behavioral disturbances such as loss of social awareness, disinhibition triggering inconvenient behavior, and mental rigidity, loss of insight,and loss of hygienic standard; impaired language.

Dementia with Lewy bodies: resembles to Alzheimer's disease with progressive cognitive decline associated to Parkinson's disease. In neuroimaging, one recognizes the typical lewy bodies in the brain.

6. Treatment of Senile Dementia

In this paper we shall focus on the drug treatment of Vascular Dementia and of Alzheimer's disease.

6.1 Drug treatment of Vascular Dementia

The current prophylactic treatment of Vascular Dementia is the sameas for the prevention of Stroke in order to slow down further brain insults. Let us mention, control of hypertension, low fat diet, antithrombotic treatment, such as low-dose aspirin for preventing blood clotting, thrombolytic andhemorheological treatments, the latte aim to improve blood flow in thebrain. (8. Meyer, 1989)

To-date, there is still a lack of effective and well-tolerated neuroprotectants, although much research is currently undertaken in this domain and may bring new drugs in the future. The neuroprotectants are potentially active during the ischemic and hypoxic episode following stroke, the ischemic penumbria. Inflammatory brain damages take place within few hours up to a few daysgenerating edema and a lot of radicals and peroxides. Research is aimingto develop drugs, which act at different stages of the cascade that resultsto neuronal damages. Let us mention a few of them: modulators of the EAA(excitatory amino acids) release, modulators of calcium influx, metabolicactivators, inhibitors of leukocyte adhesion and migration, free radicalscavengers, antioxidants, and neuronal growth factors. (9. Dorman, 1996)For example, nimodipine (NIMOTOP) from Bayer is a calcium channel blocker,which has been registered for the treatment of ischemic deficits in theUSA in 1997. ( PDR, 21) Elsewhere, it is used in cerebrovascular diseases.

There are alternative medicines, which may be useful. Let us mentionChinese and Japanese tea extraction of herbs such as Gou Teng San, a mixtureof gamber, ginseng, and gypsin. (10. Meditopia, 1996) Western science isnow aiming at investigating the rationale of efficacy of natural plantextracts from traditional Asian medicines based on millenary empiricalobservation. Researchers have found that ginsenosides extracted from theginseng root attenuated glutamate induced neurotoxicity. (11. Kim, 1998)
It would be worthwhile to investigate the traditional Thai pharmacopoeiain Samun Phrai in order to find which drugs may be recommended for VascularDementia.

6.2 Treatment of Alzheimer's disease.

The drug treatment of Alzheimer's disease is somewhat more advancedthan that of Vascular Dementia, because the former disease is much moreprominent in Western Countries. Hence, the drug research is more activein that domain. The drug treatment of the cognitive decline in Alzheimer'sdisease aims at two therapeutic concepts:

1. The symptomatic treatment in order to get a cognitive and functional improvement.
2. The slowing down of the disease progression.

6.2.1 The symptomatic treatment of Alzheimer's disease

It has been observed that one of the main brain systems being deteriorated in the Alzheimer's patient, is the cholinergic system. There is a lackof acetylcholine that is one of the neurotransmitters linked to memory.In improving this system, one hopes that patients have an improved cognitionand better functioning in daily activities. (12. Feldman, 1996) The drugcompanies hope to demonstrate that they can prevent the institutionalizationof patients by one year, which in turn may represent important savingsto the Health System of a country. It is estimated that the cost of one-yeartreatment per patient may exceed 50 000 USD in the USA. (13. NIA)

The main groups of drugs with symptomatic action are: the acetylcholinesterase inhibitors, the muscarinic agonists, the choline receptor agonists, thenootropics including rheoactive drugs (increasing cerebral blood flow),the metabolic stimulators (increasing glucose assimilation and oxygen consumptionat the level of mitochondria). The acetylcholinesterase inhibitors andmuscarinic agonists increase the availability of acetyl-choline at synapses.The choline receptor agonists had deceiving results and the developmentof many is discontinued. The older nootropics are considered to be ineffective.

At present, the most promising drugs are the acetyl-cholinesterase inhibitors of which 3 have been introduced internationally for the treatment of Alzheimer's disease: the leading one is donepezil (ARICEPT) marketed by Pfizer andEsai. Rivastigmine (EXELON) from Novartis is still in the introductoryphase. Tacrine (COGNEX) from Warner Lambert, the first introduced of thisclass of drugs- is now phasing out because of its liver toxicity. The benefitof those drugs is moderate because relevant clinical improvement among40 - 50% of treated patients. (14. Roger, 1996) (15. Kopman, 1996) (16.Cutler, 1996) This performance would be insufficient for drugs in othertherapeutic areas. For instance, an antidepressant must show a significantclinical improvement in at least 60% of unselected depressed patients forbeing registered by Western Health Authorities. This means that much researchremains to be done in the drug treatment of Alzheimer's disease.

6.2.2 The slowing of the disease progression

The therapeutic concept of agents slowing the disease progression isbased on their neuroprotectant activity, particularly protecting neuronsto oxygen stress. (17. Gray, 1996) Here, drugs useful for Alzheimer's diseasemay also be useful for Vascular Dementia. The pathological base is dueto the observation that senile amyloid plaques and the neurofibrillarytangles are sites of inflammation, which generate peroxides and oxygeneradicals which destroy the surrounding tissue. Compound investigated forneuroprotection are Ca-antagonists, phosphodiesterase inhibitors, EAA-(excitatory aminoacid antagonists, AMPA-antagonists, adenosine receptorligands, free radical scavengers, NMDA-antagonists, nicotinic receptor antagonists, MAOB-inhibitors, antiinflammatories and estrogens.

This list is not exhaustive, and all drugs, even those introduced asnootropics, are still in their development phase for demonstrating theireffectiveness in Alzheimer's disease. With regard to nicotine receptorsantagonists, antiinflammatories and estrogens, one has incidently observedthat smokers, patients with arthritic conditons treated with NSAIDS(non-steroidalantiinflammatory drugs) and steroids, as well as post-menauposic womenreceiving hormonal replacement therapy showed a lower prevalence of Alzheimer'sdisease. However, the mode of action preventing this disease is as yetunknown. Some exploratory trials are under way. (18. Green, 1995) (19.Rother, 1996) Generally spoken, most of these compounds have the liabilityto have less marked symptomatic improvement than the symptomatic drugs.They would only be able to prevail if clinical documentation can prove that they have significantly better disease stabilizing properties compared to symptomatic drugs on the long run. Also, they find a place, if theyallow lower doses of symptomatic agents, thus better tolerated, with equivalent therapeutic efficacy in combined therapies, thus an improved managementof the Alzheimer's patient.

In that context, let us mention that selegiline (a MAO-inhibitor) andvitamin E may slow down the progression of Alzheimer's disease by about7 months. (20. Sano, 1997)

Alternative medicine useful in Vascular Dementia may also be usefulin Alzheimer's disease such as Chinese and Japanese tea extraction(forexample Gou Teng San mentioned in the chapter 6 ). Here also, Samun Phraimay offer interesting ways of treatment.

Note on the author:

Dr Ph.D. Jan Favre is a Swiss citizen borne in Bern in 1942, He promoted as a Ph.D. in Microbiology at the Federal Institute ofTechnology in Zurich, Switzerland in 1975. Then, he worked for severalinternational drug companies, managing medical information for the Researchand Development Divisions, as well as for their Marketing Division.
Dr Jan Favre retired from the pharmaceutical companiesat mid year 1997 and recently settled with his Thai wife in Thailand nearBangkok.
 

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