6y ago Prana had results of the Euro study and in that 250mg PBT2 reduced abeta 42 significantly in spinal fluid. Now there will be no spinal fluid results but only plasma results. But equally plasma amyloid oligomers are related to alzheimer pathogenesis as demonstrated by this paper by Zhang J et al.
It is evident that when Prana made the the Imagine study plan this was not understood well enough. There is more similar type of evidence than the paper below. This is why prof. Masters also wants now to know the ApoE status. Amyloid deposit measurement is not ready for drug efficacy studies because nobody knows it's pathopysiology.
Neuroimage. 2013 Sep;78:474-80. doi: 10.1016/j.neuroimage.2013.04.048. Epub 2013 Apr 23.
Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth.
Murphy KR1, Landau SM, Choudhury KR, Hostage CA, Shpanskaya KS, Sair HI, Petrella JR, Wong TZ, Doraiswamy PM; Alzheimer's Disease Neuroimaging Initiative.
"Blood biochemistry" generally was included in the study plan. It does not tell that oligomers were included, but I am sure they were studied because they are the most important biochemisty measurements of plasma in AD and Masters is waiting just these measurements. They will be measured also in the extension study but most important is to see if there was reduction of oligomers in the PBT2 group and if the change was different in comparison to the placebo. If so ( as I think will be the case) the PET scan results of non-toxic part of amyloids mean even less.
In his Alzforum interview he tells that this is one thing he is waiting for. I think we will get this answer soon. Here is one article telling why he is waiting this result.
Curr Alzheimer Res. 2014 Mar 16. [Epub ahead of print]
Plasma Amyloid-β Oligomers and Soluble Tumor Necrosis Factor Receptors as Potential Biomarkers of AD.
Zhang J, Peng M, Jia J1.
1Department of Neurology, Xuan Wu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China. firstname.lastname@example.org.
Amyloid beta (Aβ), especially Aβ oligomers, is important in early Alzheimer's disease (AD) pathogenesis. AD-associated inflammation has generally been considered as a secondary response to the pathological lesions evoked by Aβoligomers in the early stage of pathogenesis. We studied the levels of plasma Aβ monomers, Aβ oligomers, and soluble tumor necrosis factor α receptors (sTNFRs) in 120 controls，32 amnestic mild cognitive impairment （aMCI） patients，and 90 mild AD patients. The plasma Aβ monomer, oligomer and sTNFR levels were measured by ELISA. We observed that the Aβ oligomer levels in mild AD patients were significantly higher than those in aMCI (200.8±83.8 versus 93.9±23.3, P
Here is some more new support for the IMAGINE study results about hippocampal atrophy. Some questioned the study finding because there was no difference in the ventricular area, but that develops much later in AD and not yet in the patient population of the IMAGINE study. Hippocampal atrophy is rather a risk factor of future AD.
Minerva Med. 2014 Apr;105(2):157-165.
Automated 3D segmentation of hippocampus based on active appearance model of brain MR images for the early diagnosis of Alzheimer's disease.
Luo ZR1, Zhuang XJ, Zhang RZ, Wang JQ, Yue C, Huang X.
Conclusion: This novel method of automated segmentation of the hippocampus based on AAM has been found to be reliable and accurate in our study, which may be an alternative to manual segmentation. The featured atrophy of hippocampal head can be regarded as an important biomarker for the early diagnosis of AD.
enigmatic, yes, I think that in any case it is essential (?) to correct the metal balance. After that it may well be possible to add some other feature with some other drug ( compare blood pressure medication). But combinations will come much later. Much more research is needed.
With this Imagine study results (more to come) we are much closer than before to get PBT2 to the market. To control development of brain atrophy is a huge issue, much more important than to control non-toxic amyloid and even that may be important. Looks like Wall street does not understand what is brain atrophy.
PBT2 reduced the hippocampus atrophy rate by 35%. In 10y a normal MCI patient looses at 4.0% rate about 1/3 of his hippocampus, but when on 250mg PBT it would take 16 y to loose same amount. In cancer this kind of increase of "survival rate" would be worth billions, but in Pranas case MC lost over 80%.
If the atrophy can be additionally decreased by bigger dosage so with 400mg of PBT2 the atrophy rate could go as low as 1.76 % and it would take some 23 y to loose 1/3 of hippocampus. We do not know it today but while PBT2 has been safe, therepeutic dosage could most likely be much more than 250mg. The whole question in AD is can we push the severe stage of the disease much further in life and the answer is yes we can by PBT2.
Atrophy rate of the brains memory center hippocampus was reduced by 35%. Junk does not do that !
PET-scan method is not error free, just the opposite. It still a new method. But it is not easy to say that there was an error without more info. I think they will look at that more closely and they could even use historical data as a control group to get at least some evidence if PBT2 had any effect on the non-soluble amyloid visualised by PET scan ( to get a bigger control group, when the placebo group was so small ).
But the bigger problem in the Imagine study was to select the PET-scan result as the main target of the study because the PET-scan images do change by them selves and nobody knows why they change. MRI images and area measurements are much more stabile and even a change of 1% can be detected.
So the data may be totally O.K. but nowbody knows what it means, at least it does not mean what it was thought to mean. Fluctuations of PET-scan SURVs are not known enough but they do happen within one year to both directions.
This article below gives more understanding what Tanzi talks and could explain the problem in Imagine study, PiB imaging of amyloid in the selected study population is not behaving as the study planners thought. So in the imagine study they selected a "wrong" primary biomarker IMO and the results can be seen, 80% drop in PPS. In stead of PiB imaging the investors should look at the atrophy rate of hippocampus: 35% reduction by PBT2, unfortunately only a trend in statistical analysis. We will get some more understanding of the atrophy when we get the results of extension study. Can PBT2 reduce the atrophy rate of the previous placebos. Their atrophy rate was 4.0%/y during the first year and the treated group had 2.6%, it is a big difference and most likely a bigger dosage could reduce this rate even more. PBT2 was safe.
The paper is free in the net, pubmed
Brain. 2012 Jul;135(Pt 7):2126-39. doi: 10.1093/brain/aws125. Epub 2012 May 23.
Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer's disease: a voxelwise PiB-PET longitudinal study.
Villain N1, Chételat G, Grassiot B, Bourgeat P, Jones G, Ellis KA, Ames D, Martins RN, Eustache F, Salvado O, Masters CL, Rowe CC, Villemagne VL; AIBL Research Group.
IMO the paper tells that (as we all know) that Abeta accumulation is a risk factor to develop hippocampal degeneration but almost a new thing was that perhaps abeta is only a risk factor but a strong one. Perhaps a bigger news was that neurodegeneration is not a risk factor to abeta accumulation. All patients were cognitively normal so not much help how there parameters related to changes of cognition in the follow-up.
I could expect some related results from IMAGINE study but including cognition and treatment with PBT2 when trying to answer what is essential in the next big study by PBT2.
modified continuation : and Abeta pathophysiology increases or catalyzes neurodegeneration.
Neurology. 2014 Apr 4. [Epub ahead of print]
Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration.
Jack CR Jr1, Wiste HJ, Knopman DS, Vemuri P, Mielke MM, Weigand SD, Senjem ML, Gunter JL, Lowe V, Gregg BE, Pankratz VS, Petersen RC.
To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample.
A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A-) and baseline hippocampal volume (N+ or N-). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups.
At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A-N-), 29 (12%) amyloid negative and neurodegeneration positive (A-N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N-), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+.
We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging-Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiolog
IMO Prana will one day get PBT2 to the market because it can slow down the brain atropy in many neurodegenerative diseases demonstrated by the research Prana is doing. Prana's history is very long, not only 1 week. In near term there can be fluctuation depending on shorts, Wall Street, Prana's news, statements, research etc. Some of us will give up, some new ones will come along and we go forward.
Yes, there is a lot of research supporting that. In fact IMO cognition testing could be not at all so important. We need to have brain tissue, that does the cognition tasks. Without brain cells there is no cognition, to make it simple. Of course cognition testing is needed to know that the brain tissue is working.
The results underscore the importance of identifying structural magnetic resonance imaging (sMRI) markers of functioning in different cognitive domains, as their relative sensitivity depends on the extent to which processing is called upon by different brain networks. The findings have implications for identifying neuroimaging and cognitive outcome measures for use in clinical trials.
My conclusion : Brain imaging explains cognition problems and most likely we can see changes earlier in them than we can find someting strange in the cognition tests. 1 % volume change can be detected in MRI but I do not think we can see yet much difference in naming a ball to be a ball etc.
Brain Behav. 2014 Jan;4(1):29-40. doi: 10.1002/brb3.185. Epub 2013 Nov 13.
Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease.
Harrington DL1, Liu D2, Smith MM2, Mills JA2, Long JD2, Aylward EH3, Paulsen JS4.
The brain mechanisms of cognitive impairment in prodromal Huntington disease (prHD) are not well understood. Although striatal atrophy correlates with some cognitive abilities, few studies of prHD have investigated whether cortical gray matter morphometry correlates in a regionally specific manner with functioning in different cognitive domains. This knowledge would inform the selection of cognitive measures for clinical trials that would be most sensitive to the target of a treatment intervention.
In this study, random forest analysis was used to identify neuroanatomical correlates of functioning in five cognitive domains including attention and information processing speed, working memory, verbal learning and memory, negative emotion recognition, and temporal processing. Participants included 325 prHD individuals with varying levels of disease progression and 119 gene-negative controls with a family history of HD. In intermediate analyses, we identified brain regions that showed significant differences between the prHD and the control groups in cortical thickness and striatal volume. Brain morphometry in these regions was then correlated with cognitive functioning in each of the domains in the prHD group using random forest methods. We hypothesized that different regional patterns of brain morphometry would be associated with performances in distinct cognitive domains.
The results showed that performances in different cognitive domains that are vulnerable to decline in prHD were correlated with regionally specific patterns of cortical and striatal morphometry. Putamen and/or caudate volumes were top-ranked correlates of performance across all
J Biotechnol. 2014 Mar 31. pii: S0168-1656(14)00156-4. doi: 10.1016/j.jbiotec.2014.03.026. [Epub ahead of print]
Metal-Dependent Amyloid β-Degrading Catalytic Antibody Construct.
Nishiyama Y1, Taguchi H1, Hara M1, Planque SA1, Mitsuda Y1, Paul S2.
Catalytic antibodies (catabodies) that degrade target antigens rapidly are rare. We describe the metal-dependence of catabody construct 2E6, an engineered heterodimer of immunoglobulin light chain variable domains that hydrolyzes amyloid β peptides (Aβ) specifically. In addition to the electrophilic phosphonate inhibitor of serine proteases, the metal chelators ethylenediaminetetraacetic acid (EDTA) and 1,10-phenanthroline completely inhibited the hydrolysis of Aβ by catabody 2E6. Formation of catabody-electrophilic phosphonate inhibitor adducts was unaffected by EDTA, suggesting that the metal exerts a favorable effect on a catalytic step after the initial catabody nucleophilic attack on Aβ. The EDTA inactivated catabody failed to disaggregate fibrillar Aβ, indicating the functional importance of the Aβ hydrolytic activity. Treating the EDTA-inactivated catabody with Zn2+ or Co2+ restored the Aβ hydrolytic activity, and Zn2+-induced catabody conformational transitions were evident by fluorescence emission spectroscopy. The studies reveal the absolute catabody dependence on a metal cofactor.
We need it
1. in normal age related memory loss, speed of atrophy 1.4% / year
2. in early alzheimer, speed 4.0 %/ year
3. in alzheimer, speed 4.7 % / year
4. in HD, speed (2-5%)/y , begins early in caudate and putamen
PBT2 250mg / day has reduced the speed in early alzheimer population by 35% to 2.6% (a trend). In HD also some support with the same dosage.
Brain function cannot (?) improve if the atrophy cannot be stopped. 250mg PBT could be enough in normal age related memory loss, but most likely early alzheimer's, alzheimer's and HD need bigger dosage. Early improvement by PBT2 (the euro study 6y ago) could be related to washout of oligomers but stopping the atrophy needs longer treatment. Difficult to find out cognition differences if the placebo and PBT2 group differ only 1.4% in their hippocampus volume. Cognition test are not at this level IMO. But if the difference is some 5% , the tests could find also cognition differences.
IMO Prana has only after this IMAGINE study some real information what perhaps the right dosage of PBT2 needs to be to stop brain atrophy. Before this it has been guess work. But for sure we will get there in these following studies.