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Prana Biotechnology Limited Message Board

pivalde 153 posts  |  Last Activity: 10 hours ago Member since: Feb 15, 2001
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  • Reply to

    Three Questions

    by goutah3006 13 hours ago

    The extension study could be very valuable. The placebo group atrophy rate was 4.0% and if it will get lower (35% or more ??) now when on PBT2 it would practically mean that PBT2 is effective in reducing atrophy rate. Every person would have his atrophy rate measured before and after being on PBT2. Some how the results of the first year and the results of the second year can be pooled aswell.

  • Reply to

    Three Questions

    by goutah3006 13 hours ago

    goutah, here is one estimate:

    Mov Disord. 2011 Dec;26(14):2544-51. doi: 10.1002/mds.23912. Epub 2011 Sep 19.

    Basal ganglia atrophy in prodromal Huntington's disease is detectable over one year using automated segmentation.

    Majid DS1, Aron AR, Thompson W, Sheldon S, Hamza S, Stoffers D, Holland D, Goldstein J, Corey-Bloom J, Dale AM.

    Future clinical trials of neuroprotection in prodromal Huntington's (known as preHD) will require sensitive in vivo imaging biomarkers to track disease progression over the shortest period. Since basal ganglia atrophy is the most prominent structural characteristic of Huntington's pathology, systematic assessment of longitudinal subcortical atrophy holds great potential for future biomarker development. We studied 36 preHD and 22 age-matched controls using a novel method to quantify regional change from T(1) -weighted structural images acquired 1 year apart. We assessed cross-sectional volume differences and longitudinal volumetric change in 7 subcortical structures-the accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. At baseline, accumbens, caudate, pallidum, and putamen volumes were reduced in preHD versus controls (all P

  • Thank you pierreluke, it worked.

  • Reply to

    This Will Rock When They Release The Plan

    by tb00tb00a Apr 23, 2014 10:56 AM
    pivalde pivalde Apr 23, 2014 12:04 PM Flag

    The most important thing is to solve why the placebo group improved in the Imagine study. If it is the ApoE4 problem as suggested by Masters, it is easy to solve and look at the results again in this new light. We have no info about the metabolic biomarkers and so that info will also come later. There could be something else explaining the results (if anything) but this needs to be studied and informed to the investors. The results were "preliminary" and they may differ from the final. Before these final results I would not say that PBT2 does not work in AD, because it reduced hippocampus atrophy 35% (trend), a thing not an other drug has ever done, dosage 250mg. But what PBT2 did not do according the preliminary results was that it did not reduce one risk factor ( not the cause) of hippocampus atrophy. PET scan demonstrating amyloid is only a risk factor of AD !!!! This has been demonstrated in many studies. Hippocampus atrophy, however, is a start of AD. Compare with stains: they reduce incidence of vascular diseases by reducing one risk factor but they do not prevent people getting vascular catastrophies, they only reduce the number of them. PBT2 works directly on the end organ : Brain. It reduced the brain atrophy, neural degeneration resulting gradually AD and that starts from hippocampus.

  • Reply to

    Tanzi info posted on Hot Copper....

    by interestingtome Apr 22, 2014 5:46 PM
    pivalde pivalde Apr 23, 2014 11:24 AM Flag

    Prana is a MPAC company, not a Gamma-Secretase Modulator company. Prana develops MPACs for very many different diseases. Mpacs are very different than GSMs. There is 9 people working in Prana and they have dedicated themselves to MPACs. Some companies are manufacturing vitamines and some antibiotics etc, Prana works with MPACs and I think it is almost alone in this business, all 9 persons are most likely busy with that, no need to go anywhere else as to GSMs, which are very different chemically, in their action and also most likely in their different indications. AD is just one possibility where both could work but again in very different way.

  • Reply to

    Tanzi info posted on Hot Copper....

    by interestingtome Apr 22, 2014 5:46 PM
    pivalde pivalde Apr 23, 2014 10:52 AM Flag

    I think Prana is a MPAC company with over 1000 different molecules. there will be many different indications for these drugs.

  • pivalde pivalde Apr 22, 2014 1:14 PM Flag

    It should be. Without brain, no cognition. There are drugs to preserve bone mass, drugs to preserve muscle mass, drugs to prevent skin atrophy, drugs to prevent hair loss, drugs to prevent what ever, but there has not been a drug , that could prevent brain loss ever before but with PBT2 we can prevent loss of brain tissue, 250mg /day results 35% less loss of hippocampus (the memory center) in early AD.

  • pivalde by pivalde Apr 22, 2014 11:45 AM Flag

    The published Imagine study results are "preliminary" and looks like they need further analyses before they can be trusted and published. ApoE4 was a concern of prof. Masters because it is just a very big risk factor in developing AD and if ( and when as it looks like) ApoE4 factor has not been corrected in these preliminary results, the result will possibly look very different (?) after correcting by ApoE4 factor. To speculate further it looks like the placebo group would have too few ApoE4 cases and PBT2 perhaps too many of them.
    So if this is the case and results will be corrected by ApoE4 factor, it will increse the difference in the atrophy rate of PBT2 treated and placebo, perhaps over 35% and perhaps the difference becomes significant. It could be also that the primary outcome could become positive. But this is speculation. This speculation is based on these preliminary results, which looked that we can not trust on them because a possible biasis between the PBT2 and placebo group.

  • pivalde pivalde Apr 22, 2014 3:29 AM Flag

    Conclusion: Glucose hypometabolism and brain atrophy were associated with concurrent cognitive function, whereas brain amyloid was not. Amyloid deposition and glucose hypometabolism were predictors for decline of a wide variety of cognitive functions, while brain atrophy specifically predicted memory deterioration.

  • Neurology. 2014 Apr 18. [Epub ahead of print]

    Long-term effects of amyloid, hypometabolism, and atrophy on neuropsychological functions.

    Ossenkoppele R1, van der Flier WM, Verfaillie SC, Vrenken H, Versteeg A, van Schijndel RA, Sikkes SA, Twisk J, Adriaanse SM, Zwan MD, Boellaard R, Windhorst AD, Barkhof F, Scheltens P, Lammertsma AA, van Berckel BN.
    OBJECTIVE:

    To assess how amyloid deposition, glucose hypometabolism, and cerebral atrophy affect neuropsychological performance in patients with Alzheimer disease (AD) dementia, patients with mild cognitive impairment (MCI), and controls over time.

    METHODS:

    A total of 41 patients with AD dementia, 28 patients with MCI, and 19 controls underwent [11C]-Pittsburgh compound B (11C-PiB) and [18F]-2-fluoro-2-deoxy-d-glucose (18F-FDG)-PET and MRI scans at baseline. We extracted global binding potential for 11C-PiB, the number of abnormal voxels for 18F-FDG, and gray matter volumes using SIENAX for MRI as measures of amyloid, hypometabolism, and atrophy. In addition, repeat neuropsychological testing was performed, including memory, attention, language, and executive tasks (mean follow-up 2.2 ± 0.7 years). Cross-sectional and longitudinal relationships between imaging markers and cognition were assessed using linear mixed models, including terms for the imaging markers, time, sex, age, diagnosis, and interactions for imaging marker × time and imaging marker × time × diagnosis.

    RESULTS:

    Linear mixed models showed that baseline hypometabolism and atrophy were associated with poorer baseline performance on attention and executive functions (p

  • Reply to

    ApoE4 and amyloid in normals

    by pivalde Apr 22, 2014 2:35 AM
    pivalde pivalde Apr 22, 2014 3:18 AM Flag

    Conclusions: normal individuals who are APOE ε4+ and have high Aβ showed the highest cognitive decline. These results suggest that Aβ and APOE ε4 are not redundant contributors of decline in aging but rather interact to promote decline during the short follow-up period examined in this study. Longer follow-up periods will be essential to fully elucidate the influence of Alzheimer disease risk factors on cognitive decline in aging.

  • Neurology. 2014 Apr 18. [Epub ahead of print]

    Amyloid and APOE {varepsilon}4 interact to influence short-term decline in preclinical Alzheimer disease.

    Mormino EC1, Betensky RA, Hedden T, Schultz AP, Ward A, Huijbers W, Rentz DM, Johnson KA, Sperling RA; For the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing, and the Harvard Aging Brain Study.

    OBJECTIVE:

    To examine whether β-amyloid (Aβ) and APOE ε4 status independently contribute or interact to influence longitudinal cognitive decline in clinically normal older individuals (CN).

    METHODS:

    Data from 490 CNs were aggregated across 3 observational cohort studies (Harvard Aging Brain Study, Alzheimer's Disease Neuroimaging Initiative, and Australian Imaging Biomarkers and Lifestyle Study of Ageing; median age = 75.0 years, 255 female), and the contributions of APOE ε4 and Aβ on longitudinal change over a median of 1.49 years were examined. Cognitive decline was assessed with the Mini-Mental State Examination (MMSE) and Logical Memory (immediate and delayed recall scores).

    RESULTS:

    High Aβ participants were more likely to be APOE ε4+ than low Aβ participants. CNs who were both high Aβ and APOE ε4+ showed greater decline in Logical Memory immediate recall (p

  • pivalde pivalde Apr 21, 2014 3:12 PM Flag

    Cognitive improval was seen already in the Euro-study 6y ago in a study with totally some 78 (?) people in the 3 groups. In the Imagine study the placebo group was clearly smaller (almost only half of the Euro study) but treatment time was 4 times longer. The placebo-group problem could influence also the cognition result at least if the problem relates to ApoE4. The difference in hippocampal atrophy rate was so small (1.4%) that it in spite it was 35% less in PBT2 treated patients it could be not visible in cognition tests. One factor is also "resilience" of hippocampus but it's effect is difficult to estimate. Best to wait what will be found behind this "placebo group" problem. If it is ApoE4 related, it could be that by correcting the data analyses with this factor more statistical significant results could be seen (??)

  • pivalde pivalde Apr 21, 2014 2:50 PM Flag

    ApoE4 is one risk factor and about some 50% of the AD patients have it and the other half of AD patients have not it. When you have it, you will usually get AD much younger than if you do not have this risk factor. But ApoE4 is only a risk factor, it is not the cause of AD.

  • pivalde pivalde Apr 21, 2014 2:41 PM Flag

    I do not think they will change the study plan and sure it is best to do as it has been planned, so it will be MRI and PIB pet scans and I think also FDG Pet scan. The most interesting thing to me will be if the previous placebo group will have slower atrophy rate of hippocampus when it will now get PBT2. So we know their previous atrophy rate individually and now 1 y later with PBT2. Correspindingly there is a possibility to compare Pet scans and plasma metabolites as oligomers reflecting somehow the atrophy rate.

  • pivalde pivalde Apr 21, 2014 1:25 PM Flag

    goutah, I agree. IMO the Imagine study was not at all an efficacy study but a study to find best imaging modality for efficacy studies and it looks like MRI is the best and PIB Pet scan is worthless.

  • pivalde pivalde Apr 21, 2014 11:58 AM Flag

    clarken.... I do not remember that from the conference call. One week is a long time but not enough to get the ApoE4 thing cleared if ApoE4 has not yet been analysed. In any case at the moment Prana needs to clear the mess and I think prof. Masters has advised them to look at also the plasma oligomers which relate to atrophy speed. Of course there may be other problems what cannot be seen yet.

  • pivalde pivalde Apr 21, 2014 10:14 AM Flag

    alwood, Prana was given these results by the company which did the analyses and prana only reported these results they got just on the last minute. Seemingly these who analysed the results were totally ingnorat of AD and that some 50% of AD patients have a genetic risk factor ApoE4 that speeds up the amyloid accumulation, development of AD, hippocampus atrophy, cognition etc and the rest does not have this factor and in whom PET scanning result of SUVR can go also down. In ApoE4 cases SUVR goes up but not in always in non-carriers. In this kind of case the analysers shoud control this big risk factor influencing so much to the results of an efficacy study. But according to the comments of Colin Masters this was not done and PPS dropped over 80%. The mess needs to be solved and soon. I cannot be quite sure that the problem is what I think, but to me this is the only possibility to explain the placebo group results. But I agree with you that Prana should inform what they intend to do and already have done and also who is resposible of this mess. I think we were lucky that the effect on hippocampus was so strong that we could get "the trend " visible. If this ApoE4 thing will clear up these results, I would predict that the hippocampus results will become significant. To me that is the most important biomarker and it will also be reflected in cognition.

  • pivalde pivalde Apr 21, 2014 6:38 AM Flag

    There is not an other possible factor than just this ApoE4 which could explain why placebo group SUVR did not increase but went down. Prana needs do everything to solve this problem as soon as possible. It was a mistake of the study plan not to control ApoE4 as it is so prevalent risk factor of AD, amyloid accumulation etc. But IMO ApoE4 factor will clear this mess.

  • There were only 15 patients and about 7 or 8 of them should be the number of ApoE4 carriers ( in normal AD population) but by change there could be only 5 or even less and so 10 or 11 could be without this important risk factor of AD, PIB accumulation, progression speed of AD and hippocampal atrophy. In the bigger PBT2 treated group it is more likely to get close to 50% of ApoE4 carriers but in that there could be a bias to other direction (??).
    If we have in the placebo group clearly less these ApoE4 cases it is not a wonder if the PET scan did not demonstrate increasing accumulation of amyloid but even lower accumulation, because the non-carriers have demonstrated fluctuation of PET scan results but the ApoE carriers do accumulated with double speed amyloid.
    This would also explain that hippocampus atrophy rate was quite low 4.0 % when the expected value would be 4.7 %. This possible unfortunate random thing could explain even the fact that study could not find any difference in cognition.
    Because ApoE4 is just so strong risk factor, some authorities do recommend that in efficacy studies this problem needs to be controlled, more so in studies with small number of patients. It is no wonder Collin
    Masters wants to se the ApoE4 status of these patients.

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