If I remember right the CFS amyloid went down in the Euro-study. Usually when amyloid is accumulating CFS amyloid goes also down. This is usually explaned with amyloid elimination problem. As you say chemistry is complicated and brain chemistry looks to be more complicated that brain surgery.
There should be now enough cases (including AIBL cases) to find out what are these cases getting sometimes lower SUVRs. But looking the AIBL cases there are no cases which get constantly lower values. After one lower value the suvrs go up again in the follow-up. So if the previous placebos get their mean value down some 2.5% or more it can be regarded as significant drug effect. But all placebos will not get lower values during this 1st year on PBT2 and most likely some will get their suvr down even some 7%. One interesting thing in this extension study is to find out who will respond well and who worse both in the PET scan and of course in the hippocampus atrophy speed.
abakeraaa3, I expect PET-scan results improve from -2.5% level to 5-8 % level and hippocampus atrophy speed to slow down at least some, perhaps to 50-60% level during the 2nd year. The mouse study does not talk about what happens when brain gets rid of amyloid but when it is accumulating amyloid. But we have now a human study, the Imagine study demonstrating that during the second 6 months human brain gets rid of 2.5% of the amyloid. I would think that during the 1st 6 months something corresponding or else was happening in the PBT2 treated as was happening in the mouse study, perhaps only in reverse oder.
ITM, thanks. looks like it could even much more complex process to brake down all different types of amyloids: low nanoM, 200 nanoM, low microM and real plaques (taken from masters's July 17th presentation).
Biol Psychiatry. 2015 Apr 14. pii: S0006-3223(15)00312-1. doi: 10.1016/j.biopsych.2015.04.005.
Brain Glutathione Levels - A Novel Biomarker for Mild Cognitive Impairment and Alzheimer's Disease.
Mandal PK1, Saharan S2, Tripathi M3, Murari G2.
Extant data from in vivo animal models and postmortem studies indicate that Alzheimer's disease (AD) pathology is associated with reduction of the brain antioxidant glutathione (GSH), yet direct clinical evidence has been lacking. In this study, we investigated GSH modulation in the brain with AD and assessed the diagnostic potential of GSH estimation in hippocampi (HP) and frontal cortices (FC) as a biomarker for AD and its prodromal stage, mild cognitive impairment (MCI).
Brain GSH levels were measured in HP of 21 AD, 22 MCI, and 21 healthy old controls (HC) and FC of 19 AD, 19 MCI, and 28 HC with in vivo proton magnetic resonance spectroscopy. The association between GSH levels and clinical measures of AD progression was tested. Linear regression models were used to determine the best combination of GSH estimation in these brain regions for discrimination between AD, MCI, and HC.
AD-dependent reduction of GSH was observed in both HP and FC (p
Patients with MCI with APOEε4, abnormal CSF τ level, hippocampal and medial temporal lobe atrophy, entorhinal atrophy, depression, diabetes, hypertension, older age, female gender, lower MMSE score and higher ADAS-cog score, had a high risk for the progression to AD.
J Neurol Neurosurg Psychiatry. 2015 May 22. pii: jnnp-2014-310095. doi: 10.1136/jnnp-2014-310095. [Epub ahead of print]
Risk factors for predicting progression from mild cognitive impairment to Alzheimer's disease: a systematic review and meta-analysis of cohort studies.
Li JQ1, Tan L2, Wang HF3, Tan MS4, Tan L4, Xu W1, Zhao QF1, Wang J1, Jiang T3, Yu JT5.
We sought to identify the risk factors for predicting the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD).
We searched 6 electronic databases for cohort studies published from January 1966 to March 2015. Eligible studies were required to be relevant to the subject and provide sufficient data for our needs.
60 cohort studies with 14 821 participants from 16 countries were included in the meta-analysis. The strongest positive associations between risk factors and the progression from MCI to AD were found for abnormal cerebrospinal fluid (CSF), phosphorylated τ (p-τ) (relative risk (RR)=2.43, 95% CI=1.70 to 3.48), abnormal CSF τ/Aβ1-42 (RR=3.77, 95% CI=2.34 to 6.09), hippocampal atrophy (RR=2.59, 95% CI=1.95 to 3.44), medial temporal lobe atrophy (RR=2.11, 95% CI=1.70 to 2.63) and entorhinal atrophy (RR=2.03, 95% CI=1.57 to 2.62). Further positive associations were found for the presence of apolipoprotein E (APOE)ε4ε4 and at least 1 APOEε4 allele, CSF total-τ (t-τ), white matter hyperintensity volume, depression, diabetes, hypertension, older age, female gender, lower mini-mental state examination (MMSE) score and higher AD assessment scale cognitive subscale (ADAS-cog) score. Negative associations were found for high body mass index (RR=0.85, 95% CI=0.76 to 0.96) and higher auditory verbal learning test delay score (RR=0.86, 95% CI=0.77 to 0.96).
Patients with MCI with APOEε4, abnormal CSF τ level, hippocampal and medial temporal lobe atrophy, entorhinal atrophy, depression, diabetes, hyp
The imagine extension study will ( I do hope ) demonstrate that PBT2 is a disease modifier ( SUVRs going down, brain srinking stopped and perhaps glucose consumption of brain increased). I am talking about those days when PBT2 is given to patients as their treatment in AD. You need to have a test to demonstrate that PBT2 works. This test ( Lee EJ et al) would be quite simple and inexpensive ( compared with PET scan or MRI ) and it deals nicely with brain function and it looks to be very specific to the metal balance in the synapses according this study.
But kadaicher, you are right, at the moment Prana needs evidence with biomarkers, but perhaps it would not be a bad idea to start the next study with much bigger dosage than 250mg, may be only for 2-3 days and do the brain function tests already after these 3 days. Brain function could change quickly when the metal balance is normalised. To get rid of harmless amyloid (98% of the amyloid) will take time ( 1-2y) and there is no tool to observe separately what happens to the harmful part of amyloid ( 2% of it). Hippocampus atrophy is also a very slow thing and glucose consumption measurement did not have enough power in the early analyses of the Imagine study. So there is a need for better biomarkers (perhaps EEG ??) if it is not clear just by observing the patient in his daily living as it was in these mice. The results of the Euro study could be caused just by this quick effect on metal balance. Most likely it was not caused by reduction of total amyloid or stopping the hippocampus atrophy.
An other important thing in this paper was IMO that PBT2 could possibly be used in autistic people to improve their brain function . 1% of population in the world has this problem.
It think this could be the only test needed when testing old people for AD. This is very close what canadianhegemony has presented here. To me it is evident that if PBT2 clears brain function in few days ( may be even only in hours) there is a metal balance problem, a clear Zn balance problem. Why to use PET-scan in spite it is a diagnostic imaging modality, but it looks to be so far away from the memory function. Hippocampus is somehow closer the problem, but even that is much more far when you compare the amount of trans-synaptic Zn which relates immediately to the memory. And PBT2 can improve that Zn balance.
The paper below (posted earlier) tells how to "measure" it in mice. IMO it could be measured in the corresponding way in humans: Big dosage of PBT2 for a couple of days and brain function measures before and after. If there is enough Zn, no improvement in function but if brain function will increase there has been a problem in Zn- level and has been improved by PBT2. Looks like autism is a very related problem with AD. The paper is free on the net.
Nat Commun. 2015 May 18;6:7168. doi: 10.1038/ncomms8168.
Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation.
Lee EJ1, Lee H2, Huang TN3, Chung C2, Shin W2, Kim K2, Koh JY4, Hsueh YP3, Kim E2.
Kadaicher, yes I do remember those studies. In this new study they had also info about Zn and how everything was changed in a very short time. That is what perhaps you would expect when we are dealing with metals in synapses. I started to think that perhaps the results of Euro-study were based just on the same phenomen as in this study. In any case it is more and more clear that we have at least 2 important areas clioquinol and PBT2 works. First there is this synapsis level where PBT2 will normalise metalbalance and will get almost immediate improvement in function and then there is this slower phenomen in which PBT2 prevents brain tissue atrophy and hopefully regenerates neural tissue not only in mice but also in humans. But of course these 2 things relate to each other very strongly.
This paper below ( already posted here 3 days ago) can possibly tell what kind of a problem there is in the synapsis on the level of metal balance and how it can be treated by cloiquinol ( and most likely with PBT2).
Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation
Eun-Jae Lee, Hyejin Lee, Tzyy-Nan Huang, Changuk Chung, Wangyong Shin,Kyungdeok Kim, Jae-Young Koh, Yi-Ping Hsueh & Eunjoon Kim
These changes included increased glutamate release probability (P smaller than 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P smaller than 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease.
Brain. 2015 May 16. pii: awv127. [Epub ahead of print]
First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.
Cummings DM1, Liu W1, Portelius E2, Bayram S3, Yasvoina M1, Ho SH1, Smits H1, Ali SS1, Steinberg R1, Pegasiou CM1, James OT1, Matarin M4, Richardson JC5, Zetterberg H6, Blennow K2, Hardy JA7, Salih DA1, Edwards FA8.
Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P smaller than 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action poten
Nat Commun. 2015 May 19;6:6760. doi: 10.1038/ncomms7760.
Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE.
Ayton S, Faux NG, Bush AI; Alzheimer's Disease Neuroimaging Initiative.
Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.