journal+journal

=JOURNAL JOURNAL=

4/8/11

Goals for the weekend:

1) Work out if anyone has established definitively why Alzheimer's never affacts the very young. (Reason given in tutorial by Ryan = huge amount of synaptic redundancy in the brain. Loss of synapses much be extensive before there is loss of many neurons. After neurons begin to die, the rate of synaptic loss sky-rockets, causing greater loss of neurons.) 2) See if anyone has come up with a convincing reason why the hippocampus/medial temporal lobe seems to be affected first in AD. 3) See if anyone has worked out why prion diseases tend to have such long latency periods. Can an analogy be drawn with AD? 4) Has anyone ever looked for AD biomarkers in the CSF of very young people? If present, this suggests the disease process might begin a lot earlier than is assumed. 5) Has anyone established that abeta abnormalities definitely occur before the initial synaptic damage? 6) Are there differences in concentration of APP receptors in different parts of the brain? 7) Has APP ever been studied by immunohistochemical staining using brains obtained post-mortem (AD and healthy age-matched controls)? 8) Review alzgene.org 9) Read more about the role of the blood-CSF barrier in AD. 10) Has anyone ever done AD research using primates?

3/8/11

I read Alzheimer's review paper by Ballard et al in Lancet. Found it useful in terms outlining all the different research areas that fit under the category of Alzheimer's disease. Updated this wiki to include new headings based on different things mentioned in the article. Will attach relevant journal articles under each heading as semester progresses. My personal aim is to at least understand "the basics" about each heading included.

Article also contained some very useful information regarding complications in diagnosis--namely, that patients with Alzheimer's also often also have another concomitant neurological/neurodegenerative/neurovascular condition/disease process. This is most common in 80+ year olds for obvious reasons. Now it's hard enough to tell textbook examples of each type of dementia apart in practice (eg diffuse Lewy body v Alzheimer's), so how can we possibly hope to identify and distinguish different disease combinations? And how do we treat such people? The only hope I think is to get in early. If we can consistently diagnose AD early, we increase the likelihood of doing so at a time when only one disease process is at work.

I find it interesting in CSF biomarkers, abeta levels are lower in AD patients than controls. Suggests problem is not so much increased production of abeta, but impaired clearance. Why might clearance be impaired? 1) breakdown in general drainage from brain to CSF, etc. 2) increased aggregation of abeta in brain (eg oligomers + fibrils) so it fails to drain to CSF as monomeric + simple oligomeric forms would. Note that in case 1) you'd expect total tau/hyperphosphorylated tau to be lower in CSF and higher in brain than in case 2) because if drainage in general is impaired, tau presumably won't drain to the CSF well either. In fact, the CSF of such people should be different in other respects too. Has anyone observed two different patterns of biomarkers in AD--ie type 1 = decreased abeta and no real change in total + hyperphosphorylated tau and type 2 = decreased abeta + greatly increased total + HP tau? If so, it suggests there might be different mechanisms at work which would have different pathogeneses. Type 1 would likely be more speedy in progression than type 2, because if tau isn't being cleared well either, more neuronal and synaptic damage would be occurring.

I noticed that nearly all known "risk genes" for Alzheimer's seem to affect abeta concentration/association. For this reason, the amyloid cascade hypothesis has my vote. If tau was the driving factor, wouldn't we expect to observe more tau-related risk genes in the mix? __Note to self: look for tau-related risk genes on http://www.alzgene.org/__ I'm very interested in comparing Alzheimer's with other known tauopathies. Another thought: this doesn't mean a treatment aimed at abeta will necessarily fix everything. While abeta accumulation probably occurs first, maybe the disease becomes destructive/self-perpetuating once tau hyperphosphorylation is somehow dragged into the mix. In other words, once you get past a certain point, abeta's role becomes less relevant to the disease progress, even though it's accumulation is necessary to kickstart the process. This would explain why clinical loss of function doesn't correlate very well with how many senile plaques a person has. It would also mean all this effort to eliminate abeta fibrils/oligomers, etc. would be in vain except in cases where treatment was administered at the very earliest stages (that is, before the disease process gets truly kicked off and you notice anything is wrong). So if all this is true, the best kind of treatment involving abeta would have to be something safe that could be given to everyone... like a vaccine, that would prevent abeta accumulation before it really started to get underway. Let's hope some bright spark can make passive abeta immunisation work. I personally think it has the best hope.

Need to read more about synucleinopathies and the effects of cerebrovascular disease on the brain.

Some questions:

1) Why don't young people ever sporadically get Alzheimer's? Prion with obligatory incubation period? But then what's the source? Meat? But there's no evidence life-long vegetarians are immune. Someone would have noticed that by now. 2) Do people with chromosomal disorders which cause them to "age" faster get Alzheimer's earlier? Why/why not? 3) Why does damage seem to begin in the medial temporal lobe (eg hippocampus, entorhinal cortex, etc.)? Are there differences in these areas that could account for this? 4) How does drainage of "stuff" out of the brain actually work? 5) Ballard mentions a "prodrome" that often precedes AD which involves a reduction in BP and cholesterol. I've never read this elsewhere. Is this true? Why would BP and cholesterol fall? 6) Ballard also mentions: "Almost all patients with severe cerebrovascular disease also have abeta pathology, but only 40% of patients with Alzheimer's have cerebrovasular disease." Evidence in favour of the above type 1/2 characterisation?