...... that higher F2 isoprostane levels in smokers were related to smaller hippocampal volume. These findings provide additional novel evidence that a history of chronic smoking during adulthood is associated with adverse effects on the human brain that are potentially enduring even with extended smoking cessation.
Drug Alcohol Depend. 2014 Jul 3. pii: S0376-8716(14)00957-0. doi: 10.1016/j.drugalcdep.2014.06.030. [Epub ahead of print]
History of cigarette smoking in cognitively-normal elders is associated with elevated cerebrospinal fluid biomarkers of oxidative stress.
Durazzo TC1, Mattsson N2, Weiner MW3, Korecka M4, Trojanowski JQ4, Shaw LM4; for the Alzheimer's Disease Neuroimaging Initiative.
Cigarette smoking in adults is associated with abnormalities in brain neurobiology. Smoking-induced central nervous system oxidative stress (OxS) is a potential mechanism associated with these abnormalities. The goal of this study was to compare cognitively-normal elders on cerebrospinal fluid (CSF) levels of F2-isoprostane biomarkers of OxS.
Elders with a lifetime history of smoking (smokers; n=50; 75±5 years of age; 34±28 pack-years; approximately 12% were actively smoking at the time of study) were compared to never-smokers (n=61; 76±6 years of age) on CSF iPF2α-III and 8,12, iso-iPF2α-VI F2-isoprostanes levels. F2-isoprostanes levels were quantitated with HPLC-atmospheric pressure chemical ionization-tandem mass spectrometry. Associations between F2-isoprostanes levels, hippocampal volumes, and cigarette exposure measures were also evaluated.
Smokers showed higher iPF2α-III level than never-smokers. An age×smoking status interaction was observed for 8,12, iso-iPF2α-VI, where smokers demonstrate a significantly greater concentration with increasing age than never-smokers. In smokers only, higher 8,12, iso-iPF2α-VI concentration was associated with smaller hippocampal volume, and greater iPF2α-III level was related to greater pack years.
This is the first study to demonstrate that a history of cigarette smoking in cognitively-normal elders was associated with significantly elevated CSF F2-isoprostane levels and greater age-related increases in F2-isoprostanes, and that higher F2-isop
Safety of PBT2 is a marvellous thing when thinking any partnerships. AD is a brain disoder and a complex one. Brain controls everything. No side effects ( just some minor ones) is a almost a miracle. Think about almost any medicine, they all have side effects. Those treating brain disoders have quite a lot of them but PBT2 seems to have very little of them if any. With this kind of record ( the treated numbers are still quite low) it is not a big risk to big pharma to partner.
6y ago we were waiting a deal with a big pharma after the positive Euro-study results. There were rumors that a deal was very close but all fell apart after the world wide economic turmoil started.
Before the Imagine study results it was apparent that Prana was also looking possible partners but at this time perhaps the initial poor results have stopped the negotiations, or have they been stopped ???
Now at least when there is better understanding about the Imagine study results (that they were not so poor at all), I would think there could again be something going on.
There has been a lot of new information about PBT2 during the past 6 years and independent research about clioquinols ( S Lindquist et al) that at this time there is much more to sell than 6y ago. HD and age related memory loss are totally new possible indications for PBT2.
We all know that Prana needs a partner to do big AD and age related memory loss studies. I can not understand that " the company remains enthusiastic about the prospects of a large trial powered to demonstrate cognitive benefit" if it would not have something real in it's plans, perhaps a partner IMO.
This not very important but may still interest some of us.
Acta Neuropathol. 2014 Jun;127(6):803-10. doi: 10.1007/s00401-014-1290-2. Epub 2014 May 7.
Do current therapeutic anti-Aβ antibodies for Alzheimer's disease engage the target?
Watt AD1, Crespi GA, Down RA, Ascher DB, Gunn A, Perez KA, McLean CA, Villemagne VL, Parker MW, Barnham KJ, Miles LA
Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.
Esoteric, thank you ! IMO Data mining is very essential in research when we try to get forward in unknown territories as in AD research. All big follow-up studies as AIBL etc are all data mining studies, but very valuable when trying to find new solutions. In them lot of data is collected, even irrelevant at the moment of collecting but even irrelevant data can later become valuable.
AF`s goal is not to find an AD drug. His goal is to play with pps.
What Masters actually did was that he made a litterature review about drugs designed to lower Abeta. In that PBT2 seems to be the best and even looks like it could lower the hippocampus atrophy rate related to memory. Other drug designers have not yet found that hippocampus vol measure is much better than measuring total Abeta by PET-scan when evaluating drug efficacy. In fact it looks like most of AD researchers believed in that still in last year ( read Canadianhegemony's comment ). Only now we know that PET scan is perhaps only for diagnostics (Ong et al 2014) and that result was made by data mining AIBL data.
Seems that AF is still talking about Abeta visible by PET and not about much more relevant biomeasure hippocampus vol. The fact that the Imagine study found a clear trend in slowering hippocampus atrophy was not a finding made by data mining and it was IMO the most essential finding of the Imagine study, even still only a statistical trend. The effect of PBT2 on more relevant spinal fluid oligomers has been known for years.
He explained different pools of Abeta (unpublished data of Roberts and Ryan) and told ( I think to to Big Pharma) that PBT2 is the only of the developed drugs targetting the toxic abeta oligomers by inhibiting their formation and promoting their clearance and so in the end reducing hippocampal atrophy ( only trend) and improving cognition (Euro study)
PBT2 seems to have effect on total Abeta (as was the hypothesis in the Imagine study), best effect if Abeta in brain is on very high level. By using historical data ( published about the best drug Bapi reperted to lower Abeta) Masters demonstrates that PBT2 was better than that even in this respect. So PBT2 could have some effect also on a bigger pool of abeta and not only the oligomers (but the most important in AD). But when Bapi does not target the oligomers (only few % of the total Abeta) there is no help in cognition.
The table of the hippocampus atrophy demonstrates well how the mean atrophy rate in treated is smaller than that of placebo but that the numbers are too small for statistical significance (placebo population). It is evident that genetics has a role both in developing brain atrophy and also when trying to slow down it by a drug, but these numbers were too small for these analyses.
Now when Masters is a consultant of both Lilly and Prana, I would think that there will be some consultations about co-operation aswell.
Here is one, it is free on the net:
PLoS One. 2012;7(3):e33552. doi: 10.1371/journal.pone.0033552. Epub 2012 Mar 23.
The zinc dyshomeostasis hypothesis of Alzheimer's disease.
Craddock TJ1, Tuszynski JA, Chopra D, Casey N, Goldstein LE, Hameroff SR, Tanzi RE.
pjemmet, I think that there is a mistake in the tables. I think the triangles are the ApoE4 carriers, but in any case you are reading the tables right. I think this should be asked from Prana.
In the Masters's presentation, there was also APOE presented, but the numbers were very small. 3 ApoE4 cases in the placebo group,( 20%) and 6 in PBT2 treated group (24%). Looks like ApoE4 was not the factor in explaining placebo group amyloid measurements.
interestingtome, thank you ! The papers you have seen in Copenhagen will be published in some 2 years in various journals. You will be now at least 1y ahead of us who did not travel to the meeting. Thanks for posting !
Interestingtome, thanks again ! This is a very important paper again explaining also the role of ApoE in iron metabolism of the brain.
The biggest risk factor of AD is related to metal balance !!! ( Hot copper has all of the abstract posted by interestingto me).
interestingtome, I am only splitting the title of his talk you gave us few weeks ago. Plenary session talks are not always in the abstract booklet and so they can include even the latest info.
IMO there will be many different aspects in his talk as is usual in plenary sessions and I do not think the talk will relate directly to Imagine study, but there may be indirect issues as he has been one person supporting small control group (his vdeo on youtube) and also to target amyloid. We are supposed to get answers to:
- How to change the rate of Abeta accumulation ??
- How to change the rate of cognitive decline??
- How to monitore the rate of Abeta accumulation??
- How to monitore the rate of cognitive decline ??
I think it is too simplistic to think that he will give an answer we Prana investors would like to get, but if there is also a press release from Prana telling more about the Imagine study results, he perhaps could tell more about hippocampus atrophy as one parameter to monitore and perhaps blood oligomers aswell. The role of ApoE4 will be one issue even without any Imagine study results. We will get the info tomorrow!
AD patients are more likely to be anemic or have lower hemoglobin, MCHC and higher ESR, not explained by dietary iron deficiency. This suggests that hemoglobin production, possibly as a result of altered iron metabolism, is deficient in AD patients.
Hippocampus. 2014 Jun 30. doi: 10.1002/hipo.22322. [Epub ahead of print]
Intracellular Zn2+ signaling in the dentate gyrus is required for object recognition memory.
Takeda A1, Tamano H, Ogawa T, Takada S, Nakamura M, Fujii H, Ando M.
1Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan; Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
The role of perforant pathway-dentate granule cell synapses in cognitive behavior was examined focusing on synaptic Zn2+ signaling in the dentate gyrus. Object recognition memory was transiently impaired when extracellular Zn2+ levels were decreased by injection of clioquinol and N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylendediamine. To pursue the effect of the loss and/or blockade of Zn2+ signaling in dentate granule cells, ZnAF-2DA (100 pmol, 0.1 mM/1 µl), an intracellular Zn2+ chelator, was locally injected into the dentate molecular layer of rats. ZnAF-2DA injection, which was estimated to chelate intracellular Zn2+ signaling only in the dentate gyrus, affected object recognition memory 1 h after training without affecting intracellular Ca2+ signaling in the dentate molecular layer. In vivo dentate gyrus long-term potentiation (LTP) was affected under the local perfusion of the recording region (the dentate granule cell layer) with 0.1 mM ZnAF-2DA, but not with 1-10 mM CaEDTA, an extracellular Zn2+ chelator, suggesting that the blockade of intracellular Zn2+ signaling in dentate granule cells affects dentate gyrus LTP. The present study demonstrates that intracellular Zn2+ signaling in the dentate gyrus is required for object recognition memory, probably via dentate gyrus LTP expression.
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 6-14 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.
Mol Neurodegener. 2014 Jul 10;9(1):27. [Epub ahead of print]
Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease.
Ayton S, Lei P, Adlard PA, Volitakis I, Cherny RA, Bush AI, Finkelstein DI.
The substantia nigra (SN) midbrain nucleus is constitutively iron rich. Iron levels elevate further with age, and pathologically in Parkinson's disease (PD). Iron accumulation in PD SN involves dysfunction of ceruloplasmin (CP), which normally promotes iron export. We previously showed that ceruloplasmin knockout (CP KO) mice exhibit Parkinsonian neurodegeneration (~30% nigral loss) by 6 months, which is prevented by iron chelation. Here, we explored whether known iron-stressors of the SN (1) aging and (2) MPTP, would exaggerate the lesion severity of CP KO mice.
We show that while 5 month old CP KO mice exhibited nigral iron elevation and loss of SN neurons, surprisingly, aging CP KO mice to 14 months did not exacerbate iron elevation or SN neuronal loss. Unlike young mice, iron chelation therapy in CP KO mice between 9-14 months did not rescue neuronal loss. MPTP exaggerated iron elevation in young CP KO mice but did not increase cell death when compared to WTs.
We conclude that there may exist a proportion of substantia nigra neurons that depend on CP for protection against iron neurotoxicity and could be protected by iron-based therapeutics. Death of the remaining neurons in Parkinson's disease is likely caused by parallel disease mechanisms, which may call for additional therapeutic options.