interestingtome, I wrote to Prana to check if the lifestyle change ( exrecise+ diet) could have some influence explaining the placebo group. They may have all the data collected but in any case it can be only 41 phone calls to get that info. This evidence of exercise is so strong that it needs to be controlled also in the future studies.
Kempler has been talking about odds one or two statsitical possibilities in 1000 when explaining the placebo group behavior in the Imagine study. Masters thought that apoE4 or some other genetic factor could explain it. We do not know today what is the reason. After these Interestingtome calculations and hypothesis that the placebos increasing their hippocampus volume and the placebos decreasing their suvrs in Pet scans could be the same individuals, it is well possible that these few cases have changed their physical activity level.
What would you do if you are told you are just about loose your brain but we know that increasing exercises could help. It is easy to think that some 3 cases of 41 could increase their activity and even quite much, either in the placebo group or in the PBT2 group. In this kind of a small material these few cases could have the effect we have seen in the results. To me it is clear that the role of increased exercise needs to be examined. It is very clear that exercise can increase hippocampus volume and lower the srvrs of PET scan.
Interestingtome, yes, thanks again. If the odd cases differ much from others in daily exercises, I think it would be reasonable to eliminate them from the analyses.
This indicates that in the intervention studies the physical exercise should be controlled (?). It could be one factor increasing hippocampal volume in the placebo group and also in the treatment group and possibly a reason not to get significant results.
IMO in an under powered study you need to do this kind of speculative analyses to get new thoughts to get forward and it is very obvious that Prana has been doing similar type of analyses (as was Masters). To me the Imagine study was unfortunately only a pilot study.
Interestingtome has only less information than Prana has and he has no access to the info possibly explaining these odd cases he is eliminating. When I was looking the hippocampus vol slide of Masters, I did also eliminate in my mind the placebo case increasing hippocampus vol to srink the standard error of mean. Unfortunately we had also in the PBT2 group a similar "Mr. Lawler" case, but because the number of cases was bigger the effect of one odd case on standard error of mean was not so big as in the placebo group.
15 cases in the placebo group was clearly too small number but IMO it is useful to do what interestingtome did to see the possible background trends. When you can see a statistical trend in this kind of small material it is a very strong signal that the drug works. It is much more difficult to demonstrate that a drug does not work. In the 2care study it took some 3000 patient years and 1500 in the placebo group. Now with 15 patient years in the placebo group we have a strong trend. There will be never a study telling that PBT2 does not work and interestingtome's analyses are helpful to us to see this in spite the definitive proof will come only later.
Front Aging Neurosci. 2014 Aug 4;6:170. doi: 10.3389/fnagi.2014.00170. eCollection 2014.
Not only cardiovascular, but also coordinative exercise increases hippocampal volume in older adults.
Niemann C1, Godde B2, Voelcker-Rehage C2.
Cardiovascular activity has been shown to be positively associated with gray and white matter volume of, amongst others, frontal and temporal brain regions in older adults. This is particularly true for the hippocampus, a brain structure that plays an important role in learning and memory, and whose decline has been related to the development of Alzheimer's disease. In the current study, we were interested in whether not only cardiovascular activity but also other types of physical activity, i.e., coordination training, were also positively associated with the volume of the hippocampus in older adults. For this purpose we first collected cross-sectional data on "metabolic fitness" (cardiovascular fitness and muscular strength) and "motor fitness" (e.g., balance, movement speed, fine coordination). Second, we performed a 12-month randomized controlled trial. Results revealed that motor fitness but not metabolic fitness was associated with hippocampal volume. After the 12-month intervention period, both, cardiovascular and coordination training led to increases in hippocampal volume. Our findings suggest that a high motor fitness level as well as different types of physical activity were beneficial to diminish age-related hippocampal volume shrinkage or even increase hippocampal volume.
Slenium in HD by Bush:
Neurobiol Dis. 2014 Jul 8. pii: S0969-9961(14)00186-7. doi: 10.1016/j.nbd.2014.06.022. [Epub ahead of print]
Altered selenium status in Huntington's disease: Neuroprotection by selenite in the N171-82Q mouse model.
Lu Z1, Marks E1, Chen J1, Moline J2, Barrows L2, Raisbeck M2, Volitakis I3, Cherny RA3, Chopra V4, Bush AI3, Hersch S4, Fox JH5.
Disruption of redox homeostasis is a prominent feature in the pathogenesis of Huntington's disease (HD). Selenium an essential element nutrient that modulates redox pathways and has been reported to provide protection against both acute neurotoxicity (e.g. methamphetamine) and chronic neurodegeneration (e.g. tauopathy) in mice. The objective of our study was to investigate the effect of sodium selenite, an inorganic form of selenium, on behavioral, brain degeneration and biochemical outcomes in the N171-82Q Huntington's disease mouse model. HD mice, which were supplemented with sodium selenite from 6 to 14 weeks of age, demonstrated increased motor endurance, decreased loss of brain weight, decreased mutant huntingtin aggregate burden and decreased brain oxidized glutathione levels. Biochemical studies revealed that selenite treatment reverted HD-associated changes in liver selenium and plasma glutathione in N171-82Q mice and had effects on brain selenoprotein transcript expression. Further, we found decreased brain selenium content in human autopsy brain. Taken together, we demonstrate a decreased selenium phenotype in human and mouse HD and additionally show some protective effects of selenite in N171-82Q HD mice. Modification of selenium metabolism results in beneficial effects in mouse HD and thus may represent a therapeutic strategy.
ACS Chem Neurosci. 2014 Aug 22. [Epub ahead of print]
Design, Synthesis, and Evaluation of Multitarget-Directed Selenium-Containing Clioquinol Derivatives for the Treatment of Alzheimer's Disease.
Wang Z1, Wang Y, Li W, Mao F, Sun Y, Huang L, Li X.
A series of selenium-containing clioquinol derivatives were designed, synthesized, and evaluated as multifunctional anti-Alzheimer's disease (AD) agents. In vitro examination showed that several target compounds exhibited activities such as inhibition of metal-induced Aβ aggregation, antioxidative properties, hydrogen peroxide scavenging, and the prevention of copper redox cycling. A parallel artificial membrane permeation assay indicated that selenium-containing clioquinol derivatives possessed significant blood-brain barrier (BBB) permeability. Compound 8a, with a propynylselanyl group linked to the oxine, demonstrated higher hydrogen peroxide scavenging and intracellular antioxidant activity than clioquinol. Furthermore, 8a exhibited significant inhibition of Cu(II)-induced Aβ1-42 aggregation and was capable of disassembling the preformed Cu(II)-induced Aβ aggregates. Therefore, 8a is an excellent multifunctional promising compound for development of novel drugs for AD.
I think in the same way and we had already the Euro study results. I am almost sure that the extension study will give Prana new evidence.
There is a lot of information that those with intact hippocampus have better memory than those who have atrofied hippocampus. The role of hippocampus in memory is quite well understood. I do not think FDA will question it's role in cognition and memory. So an less atrofied hippocampus will unequivocally reflect tangible benefit to a patient, IMO.
Now we have only a trend in the Imagine study and I do not think that it would be not enough for FDA. But if the extension study gives more evidence, IMO it would be difficult not to let those with early hippocampus atrophy to get on a safe drug to reduce the progression of the atrophy. The extension study could provide more evidence of the total brain atrophy.
I think Ira Shoulson has an interesting job trying to get PBT2 approved in FDA.
Interestingtome, hippocampus volume was an endpoint, not the primary endpoint but anyhow an endpoint decided before the study started. So there is no need to change any endpoints.
Interestingtome, there has been a hunt after surrogates because nobody could find a tissue lesion ( but Abeta) behind AD symptoms. Now no surrogate is needed because we can now demostrate a real tissue lesion ( brain atrophy) behind the poor function. Surrogates are comon in medicine as CRP as an indicator of bacterial infection and it was believed that some kind of surrogate could be found also in AD. PET scan is a surrogate but hippocampus atrophy is not, it is the real reason why brain does not work well.
The Imagine study was a pilot study to find best possible biomarkers. It does not matter what biomarker was placed as primary endpoint. When the study was planned Abeta was thought to be the best but only now later we know that hippocampus atrophy vol is better correlated with loss of memory. Formalities are worthless when the hunt for AD drug is costing billions to societies. FDA wants a safe drug and in PBT2 it will get one that most likely slows down the atrophy rate of brain. To demonstrate that we may need to wait the results of extension study or perhaps start ph3 study, but IMO now when Prana knows that hippocampus atrophy is the best imaging biomarker a multicenter study can be made much sooner than in 5y years. Because of the safety record it is perhaps more likely that FDA can accept PBT2 to be used when early hippocampus atrophy has been found, perhaps by screening the left hippocampus volume.
Interestingtome, MY POINT is that HIPPOCAMPUS atrophy is NOT a surrogate at all. It is reason that brain does not work, it is one anatomic structure memory functon is based on. Our body needs an organ to perform a function. if a man has not a left leg we will understand immediately that he has difficulties to walk. If a person has a srinken hippocampus I am sure that FDA understand that he has poor memory.
As you may remember AIBL study just confirmed that it is hippocampal atrophy and not Abeta driving memory loss ( Ong KT et al 2014). So hippocampus vol can well become the best biomarker for any treatment study and Masters slide no 12 demonstrates that this atrophy starts clearly before loss of memory. So if there is a srinking hippocampus it is a sign that memory will be deteriating in next few years (and it is time to start PBT2). To measure the hippocampus vol is not a surrogate of memory loss, it is the reason to memory loss = less brain tissue means less memory. It sure that FDA understands this !!!
Extension study will give more support to this IMO.
J Clin Neurosci. 2014 Aug 20. pii: S0967-5868(14)00304-X. doi: 10.1016/j.jocn.2014.03.036. [Epub ahead of print]
Diagnostic value of Alzheimer's disease-related individual structural volume measurements using IBASPM.
Han SH1, Lee MA2, An SS2, Ahn SW1, Youn YC3, Park KY1.
We validated the use of medial temporal volume measurements via the automated volumetric method of Individual Brain Atlases using Statistical Parametric Mapping (IBASPM) in screening for Alzheimer's disease (AD). We also determined the optimal cut-off values for hippocampal volumes. This study included T1-weighted MRI of 89 patients with AD and 33 normal controls. To determine age-specific cut-off values we grouped subjects according to age. The regional structural volumes of each group were measured using individual atlas-based volumetry with IBASPM. The normalized value of left hippocampal volume in patients with AD was significantly lower than that of normal controls in all age groups. The area under the curve values of the left hippocampus in receiver operating characteristic curves were also the largest in the medial temporal lobe, indicating that left hippocampal volume is the most useful factor in AD screening. The optimal cut-off values of the left hippocampus for diagnosing AD were 4.06 in the 60-64year age group, 4.05 in the 65-69 group, 4.07 in the 70-74 group and 3.63 in patients older than 75. Measurements of left hippocampal volume using the IBASPM may be useful for AD screening in clinical practice, and could provide a useful biomarker for AD.
Yes, interestingtome, and we have much more:
- cognition improvement in Euro study
- hippocampus atrophy decline in the Imagine study ( a trend)
- cognition improvement in reach2HD
All these are much more than surv changes in the Imagine study.
So it is a big job to demonstrate that a drug does not work. It took some 3000 patient years before that was obvious enough in the 2care study. The imagine study used 41 patient years, only 1.4% of the amount what there was in the 2care study, not even close what is needed to demonstrate that a drug does not work. Unfortunately Wall Street and many investors did not understand that. You can demonstrate that a drug works in much smaller patient population ( Reach2HD) but small numbers are not enough to demonstrate that a drug does not work. With a very small numbers we have a possibility to see possible positive trends ( hippocampus atrophy rate in the Imagine study).