That's interesting!

View all comments by Jun Xu

Wow!

View all comments by Larry Nault

Unfortunately I couldn't make this conference but the reports are fascinating. We have argued for some time that certain plaque types are particularly dense (e.g. fibrillar and dense-core plaques) and act as microscopic 'space-forming' lesions. Double-labelling immunohistochemical experiments have shown that the denser plaques effectively displace normal axons and dendrites, with the aberrant regenerative axonal pathology likely to follow from squeezing and constriction of axons (eg Dickson et al., 1999; Vickers et al., 2000; Adlard et al., 2002). Removing the plaques may be effective at reducing the aberrant regenerative response, but won't alleviate damage already done to the neurons of origin of these axons. Thus, it is unlikely that there will be significant therapeutic benefit for established AD cases (i.e., damage is already done).

In light of the data regarding increased atrophy in A-beta immunized individuals, it may not be due to the absolute loss in weight of the deposit, rather the reduction in space that follows clearance of thousands (if not millions) of...  Read more

Unfortunately I couldn't make this conference but the reports are fascinating. We have argued for some time that certain plaque types are particularly dense (e.g. fibrillar and dense-core plaques) and act as microscopic 'space-forming' lesions. Double-labelling immunohistochemical experiments have shown that the denser plaques effectively displace normal axons and dendrites, with the aberrant regenerative axonal pathology likely to follow from squeezing and constriction of axons (eg Dickson et al., 1999; Vickers et al., 2000; Adlard et al., 2002). Removing the plaques may be effective at reducing the aberrant regenerative response, but won't alleviate damage already done to the neurons of origin of these axons. Thus, it is unlikely that there will be significant therapeutic benefit for established AD cases (i.e., damage is already done).

In light of the data regarding increased atrophy in A-beta immunized individuals, it may not be due to the absolute loss in weight of the deposit, rather the reduction in space that follows clearance of thousands (if not millions) of space-forming lesions, perhaps also accompanied by a reduced inflammatory reaction associated with the damage done by the space-forming lesion. It would be fascinating to examine the morphology of nerve cells following removal of the dense plaques.

References:
Dickson, T.C., King, C.E., McCormack, G.H. and Vickers, J.C. (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Experimental Neurology 156, 100-110. Abstract

Vickers, J.C., Dickson, T.C., Adlard, P.A., Saunders, H.L., King, C.E. and McCormack, G. (2000) The cause of neuronal degeneration in Alzheimer’s disease. Progress in Neurobiology 60, 139-165. Abstract

Adlard, P.A., King, C.E. and Vickers, J.C. (2000) The effects of taxol on the central nervous system response to physical injury. Acta Neuropathologica 100, 183-188. Abstract

View all comments by James Vickers

I believe it is the time to finally admit that Elan’s AN-1792 trial is a failure! There is no clear evidence on cognitive benefits, neither on global measures nor on neuropsychological tests; moreover, in a subset of subjects a potentially fatal complication emerged (encephalitis) and, now, after Nick Fox's report we became aware that vaccination seems to accelerate the rate of brain atrophy... The major unsolved problem is the mechanism and, hopefully, it will be vigorously looked for before anybody starts a new trial. Maybe cases of encephalitis might give us a hint on the mechanism of the vaccine toxicity. Isn't it possible that in fact an inflammatory response (of one sort or another) occurs invariably in all vaccinated subjects but only in some leads to clinically significant symptoms? By the way, very interesting and mostly ignored results were shown on Tuesday the 20th with oral vaccination by the Japanese group (Takeshi Tabira, Hideo Hara; oral session 03-06). What is really impressive about this particular research group is that they're NOT planning an immediate...  Read more

I believe it is the time to finally admit that Elan’s AN-1792 trial is a failure! There is no clear evidence on cognitive benefits, neither on global measures nor on neuropsychological tests; moreover, in a subset of subjects a potentially fatal complication emerged (encephalitis) and, now, after Nick Fox's report we became aware that vaccination seems to accelerate the rate of brain atrophy... The major unsolved problem is the mechanism and, hopefully, it will be vigorously looked for before anybody starts a new trial. Maybe cases of encephalitis might give us a hint on the mechanism of the vaccine toxicity. Isn't it possible that in fact an inflammatory response (of one sort or another) occurs invariably in all vaccinated subjects but only in some leads to clinically significant symptoms? By the way, very interesting and mostly ignored results were shown on Tuesday the 20th with oral vaccination by the Japanese group (Takeshi Tabira, Hideo Hara; oral session 03-06). What is really impressive about this particular research group is that they're NOT planning an immediate trial in humans once highly promising results in mice have been achieved (notably, no signs of an inflammatory response whatsoever..). They have decided to go to primates first, a very reasonable and cautious approach.

View all comments by Tomasz Sobow

The summary by Gabrielle Strobel was nicely done. One further aspect from Sid Gilman's talk was that although a Z score for all cognitive tests showed the treatment group better than placebo as summarized, the ADAS-Cog score for the responder immunized group was -3.8, compared to -2.7 for placebo. Thus, a widely accepted test more focused on cognitive decline in Alzheimer disease correlates with the loss of brain volume. Immunization against a protein that has a natural function seems inadvisable with 3 strikes: greater cognitive decline, even more brain loss and risk of encephalitis. In baseball, wiser managers try new talent. Perhaps it's time for better funding for competitors of the amyloid hypothesis.

View all comments by Gregory J Brewer

The brain volume changes in patients who were immunized and developed antibodies is interesting, but perhaps not so surprising in retrospect when the information available from the neuropathology is taken into account. You might predict (1) an initial transient phase (days to weeks) of brain swelling due to activation of microglia and edema (fluid retention), followed by (2) a reduction in brain volume due partly to resolution of this inital reaction and partly due to removal of plaques (Aβ and all the other plaque-associated proteins), and shrinkage and/or removal of the microglia and plaque-associated astrocytes, followed by (3) stabilization or even increased volume if regeneration occurs. This sequence of events would seem to fit with what we know so far from the imaging and the neuropathology.

View all comments by James Nicoll