Dementia not due to Alzheimer's disease

Although Alzheimer's disease is the most common of the dementias, clinicians should look out for other possible causes, some of them reversible, that would affect cognitive function. There are dozens of unusual causes of dementing diseases in older individuals, the following conditions are relatively common, either alone or in combination with other aetiologies.

A simple standardised cognitive rating scale is the Mini-Mental State Examination (MMSE). The MMSE includes 11 questions, requires 5 to 10 minutes and minimal training to administer. The first section calls for verbal responses to assess orientation, memory, and attention. The remaining sections examine simple naming, the ability to follow verbal and written commands, to write a sentence spontaneously, and to copy a geometrical figure. The maximum score is 30. Originally, scores below 24 were interpreted to suggest some degree of dementia. (The Hong Kong version of the MMSE uses 20 points as cut off). It is now clear that mild cognitive impairment may be seen with higher scores (26 or 27) in highly educated persons. For the illiterate, the cut off point is suggested by some to be 18.

Besides cognitive impairment, depression is also a common problem in older adults. They present frequently with somatic symptoms, sleep problems and memory difficulties. The clinician can explore these complaints by asking tactful questions about mood and probing for vegetative signs, such as loss of interests, appetite and libido.

Diagnosis

The ICD 10 general criteria for dementia is extracted below in Box 1.

The definite diagnosis of AD can only be made after the death of the patient by histopathological examination of the brain. However, the diagnosis of AD can be made in life with good sensitivity (between 80% and 100%). The NINCDS-ADRDA criteria for the clinical diagnosis of AD is given in Box 2.

Genetics

Alzheimer's disease has an important genetic component.

Familial Alzheimer's disease (FAD) is usually indistinguishable from the typical forms except for the earlier age of onset. Deterministic AD mutations have been identified in three regions:

Families with FAD are of great scientific interest, but these families are quite rare, constituting less than 5% of the families who have AD. In more typical AD cases, it is suggested that multiple susceptibility genes mix and match with environmental risk factors to develop AD. The most well-established of these susceptibility genes in AD are the polymorphisms associated with the ApoE protein.

Apolipoprotein E is a plasma protein synthesized by the liver and also produced by the glial cells in the central nervous system. It transports cholesterol and lipids between cells, is involved in the building and re-innervation of neuronal cells following injury, and may be associated with the production or deposition of amyloid, the binding of tau, and the pathophysiology of AD. The gene (APOE) that codes for the ApoE protein has 3 alleles, designated e2,e3, and e4. The inheritance of the e4 allele is a powerful risk factor for AD.

In comparison to the most common combination (e3/e3), the presence of a single e4 allele triples the risk of having AD, whereas the presence of two e4 alleles increases that risk by about 15 fold. Under some circumstances, APOE genotyping may be helpful in the diagnostic workup of demented patients, but is currently not recommended for predictive risk assessment except within highly controlled research environments.

Neuropathology

There are numerous neuropathological changes in the brain of patients with AD, but the major histopathologic hallmarks of AD are:

Neurofibrillary tangles are masses of abnormal filaments within the cytoplasm of neurons that are made up of "paired helical filaments". The major protein abnormality in NFTs is the presence of a highly insoluble protein called tau. The intracellular deposition of tau and its disruption of the normal cytoskeletal architecture may be an important factor in the death of neurons. (Figure 1)

Amyloid deposition appears to play a critical role in the pathophysiology of AD. The amyloid precursor protein (APP) molecule is a transmembrane protein of unknown function. The metabolism of APP involves an enzyme, termed the alpha secretase, that cuts the molecule and produce a long protein known as the soluble APP alpha. (Figure 2)

In AD, this normal metabolism is altered. The APP molecule is cut at a different extracelluar site by beta secretase and within the transmembrane region by another enzyme gamma secretase. The molecular fragments produced by these cuts is either 40 or 42 amino acids in length, and is termed the Ab or beta amyloid. In AD, the alternative cleavage pattern of APP and the resulting production of beta amyloid are increased, resulting in the deposition of beta amyloid in senile plaques and blood vessels.

Senile plaques are spherical structures composed of degenerative neuronal processes, extracellular Ab, microglia and astrocytes.

Neuronal death occurs in normal aging, but patients with AD lose more neurons than normal at an earlier age. In AD, the effects of tau or Ab deposition may accelerate this process. Another factor that may accelerate cell death is inflammation of the brain of AD patients.

Neurotransmitter system abnormalities

The cholinergic system: The discovery that cortically projecting cholinergic cells in the basal forebrain's Nucleus Basalis of Meynert are devastated in AD have contributed to the notion of this disease as a cholinergic dementia. The activity of choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of acetylcholine, is markedly reduced in the cortices of AD patients. Researchers have since developed strategies to enhance the cholinergic system and they included dietary choline, muscarinic receptor agonists and cholinesterase inhibitors (ChEI). The ChEIs are now widely used in the treatment of mild to moderate Alzheimer's disease.

Other neurotransmitter systems: It is found that noradrenergic neurons, serotonergic neurons are also depleted in AD patients. Abnormalities of other neurotransmitters and neuropeptides are also documented.

The cholinergic hypothesis

The cholinergic system was the first neurotransmitter system to be described. The first cholinesterase inhibitor, physostigmine, is more than one hundred years old. In the CNS, acetylcholine has been considered to act as an overall modulator and moderator in the cerebral cortex, and amongst other things enhances the effects of glutamate.

The cholinergic hypothesis suggests that AD results from a selective loss in cholinergic neurons with decreased acetylcholine levels. Patients with severe AD show AchE (esterase) and ChAT (transferase) levels 85-90% lower than normal. Meanwhile, BuChE (butyrylcholinesterase) increases, possibly due to higher synthesis or gliosis. These patients therefore have very little residual AChE in their cortex. This suggests that perhaps the increased BuChE would be a better therapeutic target than AChE.

The nicotinic system is also relevant in this context. AD patients show clear deficits in nicotinic binding sites and this led to hopes for the development of new nicotinic drugs.

Treatments that increase the level of acetylcholine would be expected to provide clinical benefit, but clinical trials of dietary precursors of acetylcholine and muscarinic receptor agonists have been unsuccessful. Until recently, the most successful approach is to increase Ach levels by the inhibiting cholinesterase function through the use of cholinesterase inhibitors.

However, it is found that cholinergic activity is probably not lost to any significant degree until later in the course of AD, so it makes sense to explore other options.

The glutamatergic system

Glutamate is the major transmitter of the brain and is involved in all aspects of cognitive function since it is the transmitter of cortical and hippocampal pyramidal neurons. Disturbance of excitatory glutamatergic neurotransmission is believed to be associated with many neurological disorders, including Alzheimer's disease.

There are two main classes of glutamate receptors, the ionotropic (including NMDA and AMPA) receptors and the metabotropic receptors. The current interests lie in the study of NMDA receptors, which are involved in learning and memory.

It is known physiologically, NMDA receptors are transiently activated by glutamate, whereas during pathological activation such as that occurring in AD, NMDA receptors are likely activated by lower concentrations of glutamate but more or less continuously. Under such conditions, temporally uncoordinated, continuous stimulation of NMDA receptors produces enhanced noise, decreasing the probability of detecting the relevant signal once it arrives. This produces a progressive deficit in cognitive functions. This overactivation of glutamate receptors and continuous calcium ion influx ultimately leads to damage of neurons not able to compensate and further decline of cognitive functions. (Figure 3)

As a result of the above argument, a search for a NMDA antagonist is thought to be able to counteract this deficit. The high affinity antagonist MK801 (dizocilpine) has long been known but produces numerous side effects. Memantine, a new compound and a low affinity antagonist, is found to serve the purpose well. Following strong synaptic activation, memantine can leave the NMDA receptor channel due to its voltage dependency and fast unblocking kinetics. As such, memantine suppresses synaptic noise but allows the relevant physiological synaptic signal to be detected. This provides both neuroprotective and symptomatic restoration of synaptic plasticity.

The neuropathogenesis of Alzheimer's disease

The exact underlying mechanism for development of Alzheimer's disease is still unkown. A sequence of pathologic events is hypothesized as follows.

The first component of the disease cascade is a dysfunctional gene that produces amyloid. Amyloid (the toxic Ab 42) produces inflammation around the senile plaques, and the inflammation sets up a cascade of seemingly uncontrollable changes in specific areas of the brain (more so in the aged brain than in the younger brain).

Damaged neurons and neurites and highly insoluble b amyloid peptide deposits and neurofibrillary tangles provide stimuli for inflammation.

Chronic inflammation may contribute to the initial stages of cellular dysfunction, increase cellular vulnerability, cause a decline in choline transferase activity, deplete acetylcholine, and the appearance of activated microglia.

Patients with Alzheimer's disease have reductions in the glutamate transporter for glial cells, which is important because the transporter helps to mop up excess glutamate in the extracellular fluid. These changes lead to an increase in the extracellular concentration of glutamate. The increased level of glutamate contributes to the ultimate death of neurons (see the preceding paragraph).

Non-pharmacological interventions

There are a number of non-cognitive symptoms in dementia that provide problems not only for the person with dementia, but for the carer and in clinical management.

The most obvious are agitation, aggressive mood disorder, psychosis, sexual disinhibition, eating problem and abnormal vocalization.

Besides using medications, there are a number of non-pharmacological approaches to the management of these types of problems, interested readers are advised to consult special articles in this field. A brief outline is given below: