Alzheimer's and the Brain

We're very fortunate to be joined by Dr Peter Nestor. He is from Cambridge University and he works on mild cognitive impairment and also specializes in Alzheimer's: investigating what brain processes occur to give someone the disease in the first place and how we can actually try and prevent it. Hello Peter!

Peter - Hi.

Chris - So if I was to do a brain scan on someone who had Alzheimer's disease, what would I see?

Peter - Well, it depends on the kind of brain scan. If you do a structural brain scan such as a CAT (CT) scan or an MRI scan, the answer can be not very much. There's shrinkage of the brain and particularly certain areas such as the hippocampi. However, our brains shrink as we get older so it's not such a great discriminator. If you do functional brain scans such as a PET scan (positron emission tomography) and look at brain metabolism then you typically see reduced brain metabolism in areas of what we call polymodal association cortex - particularly around the back of the temporal lobes and parietal lobes.

Chris - What do those bits of the brain do?

Peter - Lots of different things. Interestingly, given that the key deficit is memory impairment or amnesia with Alzheimer's those particular areas that we see easily on the brain scan are not so important for memory. Other areas that are important for memory such as the hippocampus and an area we've been doing a lot of work on called a posterior cingulate cortex are important for memory. Of those the posterior cingulate seems to become dysfunctional first of all, at the start of the illness.

Chris - There are lots of different diseases though, that constitute senile dementia, aren't there? We tend to use an umbrella terms and say, 'this person's got dementia,' or lots of people say, 'this person's got Alzheimer's,' but can you see differences between these different diseases on your scans?

Peter - Yes, you can. You're absolutely right. Dementia is just a generic term for losing mental abilities and obviously that can be due to all sorts of pathological processes of which Alzheimer's is the most common. But other common dementias include what's called 'Dementia with Lewy Bodies' or Fronto-Temporal Dementia. They tend to have different signatures in terms of the location, the topography if you like, of the damage in the brain.

Chris - Presumably as we get better at spotting these disease early and come up with treatments it will become very important to be able to discriminate between them because you can put someone on a certain drug and therefore, if you know what the disease is in the first place, you can get the drug right and slow the disease down.

Peter - Yeah, that's absolutely right and it's a very important point. It's a very important point because of trial research because obviously one doesn't want to include people with the wrong kind of pathology if your therapeutic agent that you're experimenting with is thought to work on a particular pathological pathway. Having people with the wrong kind of dementia syndrome in the trial is a big problem. That's a major incentive to work at the moment.

Chris - We've mentioned some of the symptoms and signs of Alzheimer's disease so far but what are the cardinal features of people who are going to get the disease tend to show?

Peter - Well, the hallmark is memory impairment, forgetfulness, which brings up this term you mentioned earlier, 'cognitive impairment.' This is this isolated memory impairment. There's a sort of a programme which can last for many years where someone has memory problems without having impairments in other mental abilities such as language or spatial abilities and so forth. Ultimately those other things do catch up with the patient. As the disease progresses one gets impairments in all mental abilities but for a long time it's just focussed on memory.

Chris - So, as we become better at working out what these things are and who's got what disease what are we going to do about trying to treat people? Are we at any stage where we can intervene in these disorders?

Peter - Well, there's nothing that's available yet as a treatment that's been proven to work but there are a number of trials underway. I think you mentioned before in the previous article about vaccines and one strategy that has been tried is to give a vaccine against those amyloid deposits, the cause pathology in the brain. The jury's still out on that. The first trial was stopped because one or two people had some quite severe side-effects from it. It's not really clear yet whether it may actually be helpful. That's one but there are lots of others that are trying to modify the sort of molecular pathology, if you like.

Chris - Do some of the drugs try to correct the chemical imbalance that you get in the brain? As far as we know people who develop Alzheimer's disease lose signalling from a chemical called acetylcholine and any of these drugs that you get given seem to boost that drug in the brain and can make people improve for a while.

Peter - Yes it's an interesting story, acetylcholine. That is the only drug that we have that as treatment for Alzheimer's at the moment but it's not a disease-modifying treatment, it's replacing the cholinergic activity. Interestingly, though it's been rather disappointing as a symptomatic treatment. Most people do find that it helps a little bit but it doesn't dramatically restore memory or anything like that. Interestingly, the work that was done that showed there was a cholinergic deficit in Alzheimer's disease over 25 years ago was done on end-stage disease (post-mortem brains of people who'd died at the ends of the illness). That showed the deficit. Recent evidence suggests that it's probably not a major feature of the very early clinical course of the illness.

Chris - So by putting people on drug that effect that, we might be barking up the wrong tree?

Peter - Well, it's a symptomatic treatment so it could be if someone has the deficit. Given that it's a symptomatic treatment and you're trying to improve someone's symptoms you can always give it a go. If it doesn't work you can stop it again. Interestingly though, another condition related to Parkinson's disease called Dementia with Lewy Body turns out to have a much more profound cholinergic effect early on in the illness. That condition seems to respond much more dramatically to cholinesterase that does Alzheimer's disease.

Chris - It sort of flies in the face of the fact that haven't the government been quite difficult to persuade that these drugs are good for people who have this condition? I know that people who care for people who have these conditions find these drugs very helpful.

Peter - Yeah. In the case of Lewy Body disease it's disappointing they haven't looked at that one because I think there is enough evidence now to say that's very useful. Certainly I know from my own practice of seeing patients that it can very significantly help. I guess with regard to the bigger issue of Alzheimer's disease one of the other problems we have is how does one measure accurately that there's been an improvement? I think one of the problems in the trials that the government have used for evidence is that they've used fairly old and antiquated methods of measuring cognition. It is sometimes those measures are somewhat at odds with what the actual families report. They do see some improvement but that said it has to be acknowledged that the improvements are not dramatic. It's a little bit of an improvement.

Chris - Just to finish off, what do you think the long-term effects are going to be here? We've got an ageing population, at the moment 1 person in 5, roughly gets Alzheimer's disease but there's going to be a hell of a lot more people over the age of 80 who are therefore in that risk group before too long. What's going to happen?

Peter - Well, yeah. It's a huge problem and a huge financial problem to say nothing of the huge distress it causes the families and patients. Yes, as the population ages the prevalence is going to go up and up. Already it's estimated in the United States that Alzheimer's disease costs more than all of cancer combined. If you factor in all the indirect costs such as needing to look after people, people needing to stop working to stay at home and care for someone and that kind of thing. Yes, that's an enormous potential problem for the future.