Part of the problem in finding drugs which may be effective for dementia is that our ideas about what constitutes dementia have been undergoing radical change in recent years. It had been traditional to distinguish between Alzheimer's dementia, or senile dementia of the Alzheimer's type (SDAT) and multi-infarct dementia (MID), which is theoretically caused by small strokes which insidiously pick off brain tissue to the point where an individual's cognitive function is compromised.
It was originally thought that MID accounted for 60%+ of the dementias. Accordingly, early attempts to treat the dementias concentrated on the multi-infarct dementias. The initial hypothesis was that these multiple small strokes were being caused by a process of hardening of the arteries, sometimes called arteriosclerosis and sometimes atherosclerosis (although these terms refer to two quite different disorders) which impaired blood supply to the brain. The logical treatment, therefore, for this condition was to attempt to dilate blood vessels. This led to the use of a wide number of vasodilating drugs such as hydralazine.
It is quite rare now for such drugs to be used for this purpose. Arguably, if anything, such treatment may have made the condition somewhat worse in that a potential effect of vasodilators is the reduction of blood pressure and reducing blood pressure would mean that the brain would be less perfused with blood, as one of the functions of blood pressure in the first instance is to provide the propulsive force to send blood up against the force of gravity to perfuse the brain.
Stage 2
More recent attempts to treat the dementias have proceeded on the basis that Alzheimer's dementia is the commonest form of dementia. For many years, the term Alzheimer's dementia was reserved for dementias that came on before the age of 65 (for this reason it was also called persenile dementia), which were not obviously caused by strokes. It was conceded that there was another dementia that was like Alzheimer's dementia, which appeared to come on after the age of 65 but this was thought to be less common. Distinctions on the basis of age have now collapsed and both dementias of the Alzheimer type are now called senile dementia of the Alzheimer type. The amalgamation of these two groups led to an awareness that Alzheimer's-type dementia is the commonest form. The primary therapeutic focus in the field, therefore, has been on an attempt to reverse the deficits which are supposed to be present in SDAT.
In particular, it has been held that in Alzheimer's, there is a dysfunction of cholinergic pathways in the brain, for which there are both historical and clinical reason. Historically, when early work in psychopharmacology began, there were only four known neurotransmitters - noradrenaline, 5-HT, dopamine and acetylcholine (ACh). Noradrenaline quickly became the neurotransmitter involved in depression and mood disorders. Dopamine was known to be involved in Parkinson's disease, and, when it became clear that neuroleptics acted on it, schizophrenia, after which the psychoses in general came to be seen as disorders of dopamine neurotransmission. For the most part, 5-HT was associated with either depression or anxiety. This left ACh without a function. It seemed convenient to parcel it out to the dementias.
There was, in addition, some clinical evidence in favour of an association between the cholinergic system and dementia. Part of the reason for this claim can be seen in a number of the chapters of this blog, in which drugs with anticholinergic effects have been noted as potentially causing amnesia or confusion (see The Management of Side Effects & Side Effects of Antidepressants articles).
Stage 3
In the last 5 years, a number of other dementias have been described. A distinction has been drawn between cortical and subcortical dementias. The cortex of the brain is the area responsible for higher cognitive functions, such as speaking, reading, planning and executing actions, etc In the cortical dementias, memory is usually the function most noticeably affected but those who are affected also have problems with planning even simple functions such as dressing and they typically cannot read, draw or execute any complex tasks. Alzheimer's and MID are cortical dementias. There are also subcortical parts to the brain which are common to humans and other mammals. They involve a number of what are termed midbrain and brainstem structures.
It was originally thought that MID accounted for 60%+ of the dementias. Accordingly, early attempts to treat the dementias concentrated on the multi-infarct dementias. The initial hypothesis was that these multiple small strokes were being caused by a process of hardening of the arteries, sometimes called arteriosclerosis and sometimes atherosclerosis (although these terms refer to two quite different disorders) which impaired blood supply to the brain. The logical treatment, therefore, for this condition was to attempt to dilate blood vessels. This led to the use of a wide number of vasodilating drugs such as hydralazine.
It is quite rare now for such drugs to be used for this purpose. Arguably, if anything, such treatment may have made the condition somewhat worse in that a potential effect of vasodilators is the reduction of blood pressure and reducing blood pressure would mean that the brain would be less perfused with blood, as one of the functions of blood pressure in the first instance is to provide the propulsive force to send blood up against the force of gravity to perfuse the brain.
Stage 2
More recent attempts to treat the dementias have proceeded on the basis that Alzheimer's dementia is the commonest form of dementia. For many years, the term Alzheimer's dementia was reserved for dementias that came on before the age of 65 (for this reason it was also called persenile dementia), which were not obviously caused by strokes. It was conceded that there was another dementia that was like Alzheimer's dementia, which appeared to come on after the age of 65 but this was thought to be less common. Distinctions on the basis of age have now collapsed and both dementias of the Alzheimer type are now called senile dementia of the Alzheimer type. The amalgamation of these two groups led to an awareness that Alzheimer's-type dementia is the commonest form. The primary therapeutic focus in the field, therefore, has been on an attempt to reverse the deficits which are supposed to be present in SDAT.
In particular, it has been held that in Alzheimer's, there is a dysfunction of cholinergic pathways in the brain, for which there are both historical and clinical reason. Historically, when early work in psychopharmacology began, there were only four known neurotransmitters - noradrenaline, 5-HT, dopamine and acetylcholine (ACh). Noradrenaline quickly became the neurotransmitter involved in depression and mood disorders. Dopamine was known to be involved in Parkinson's disease, and, when it became clear that neuroleptics acted on it, schizophrenia, after which the psychoses in general came to be seen as disorders of dopamine neurotransmission. For the most part, 5-HT was associated with either depression or anxiety. This left ACh without a function. It seemed convenient to parcel it out to the dementias.
There was, in addition, some clinical evidence in favour of an association between the cholinergic system and dementia. Part of the reason for this claim can be seen in a number of the chapters of this blog, in which drugs with anticholinergic effects have been noted as potentially causing amnesia or confusion (see The Management of Side Effects & Side Effects of Antidepressants articles).
Stage 3
In the last 5 years, a number of other dementias have been described. A distinction has been drawn between cortical and subcortical dementias. The cortex of the brain is the area responsible for higher cognitive functions, such as speaking, reading, planning and executing actions, etc In the cortical dementias, memory is usually the function most noticeably affected but those who are affected also have problems with planning even simple functions such as dressing and they typically cannot read, draw or execute any complex tasks. Alzheimer's and MID are cortical dementias. There are also subcortical parts to the brain which are common to humans and other mammals. They involve a number of what are termed midbrain and brainstem structures.
