It could be that the glucose consumption measurement by PET-scan is perhaps the best tool to measure the possible progress. I would say that Mr. Lawler's brain uses after 12 months on PBT2 more glucose than in the beginning of the study but who knows.
In the mouse study it was very clear that PBT2 lowered the interstitial Abeta (Adlard et al 2008) but do we see it with a PET-scan in humans will be seen soon. It is the primary objective in the Imagine study. It is clear that someting will happen in the Abeta because CSF samples in Ph2 6y ago demonstrated 13 % lower values after the treatment. So most likely the human responce is somehow similar than in the AD mouse but we need to wait still some days.
ALS could be partly an iron issue in brain but perhaps also a Cu, Zn and manganese problem in spinal cord and CSF.
Front Pharmacol. 2014 Feb 17;5:19. eCollection 2014.
Mitochondrial ferritin in the regulation of brain iron homeostasis and neurodegenerative diseases.
Gao G, Chang YZ.
Mitochondrial ferritin (FtMt) is a novel iron-storage protein in mitochondria. Evidences have shown that FtMt is structurally and functionally similar to the cytosolic H-chain ferritin. It protects mitochondria from iron-induced oxidative damage presumably through sequestration of potentially harmful excess free iron. It also participates in the regulation of iron distribution between cytosol and mitochondrial contents. Unlike the ubiquitously expressed H-ferritin, FtMt is mainly expressed in testis and brain, which suggests its tissue-related roles. FtMt is involved in pathogenesis of neurodegenerative diseases, as its increased expression has been observed in Alzheimer's disease, restless legs syndrome and Friedreich's ataxia. Studies from our laboratory showed that in Alzheimer's disease, FtMt overexpression attenuated the β-amyloid induced neurotoxicity, which on the other hand increased significantly when FtMt expression was knocked down. It is also found that, by maintaining mitochondrial iron homeostasis, FtMt could prevent 6-hydroxydopamine induced dopaminergic cell damage in Parkinson's disease. These recent findings on FtMt regarding its functions in regulation of brain iron homeostasis and its protective role in pathogenesis of neurodegenerative diseases are summarized and reviewed.
Gizmo, yes I do believe that we will get positive, succesful results, that is why I have been here over 6 years. But note, I do not know that the results will be fine. Looks like it is only Mr. Lawler and his wife who know. In AD 250mg PBT2 seems to be fine according the earlier study, but perhaps in HD higher dosage could be tested in future. The Reach study gave good results: a new, very safe drug to potentially improve brains function of young HD patients. I am still waiting the iron content subgroup results ( Dr. Rosas does that and I do not think the results were included in the report yet, so we may get more MRI imaging results). I am not a pharmacologist neither a neurologist but I have become interested in AD during these past few years and I try to understand the papers I post here. It is not always easy.
Prana scientists talk about an up-stream problem causing misfolding amyloid and not much of inflammation at all. This misfolding happens in endoplasmatic reticulum when processing APP. Metal balance is important also in endoplasmatic reticulum IMO. Metal balance problem develops gradually by age and most likely is related to age related memory loss aswell. And we know that PBT2 helps also that in mice.
Bill... Go to you tube and find almost 3y old video where Colin Masters tells about oligomers and a-beta, soluble etc. It could help you a bit.
Alzheimers Dement. 2014 Feb 28. pii: S1552-5260(13)02939-7. doi: 10.1016/j.jalz.2013.11.005. [Epub ahead of print]
Aβ and cognitive change: Examining the preclinical and prodromal stages of Alzheimer's disease.
Lim YY1, Maruff P2, Pietrzak RH3, Ellis KA4, Darby D5, Ames D6, Harrington K5, Martins RN7, Masters CL5, Szoeke C8, Savage G9, Villemagne VL10, Rowe CC11; AIBL Research Group.
High β-amyloid (Aβ) is associated with faster memory decline in healthy individuals and adults with mild cognitive impairment (MCI). However, longer prospective studies are required to determine if Aβ-related memory decline continues and whether it is associated with increased rate of disease progression.
Healthy controls (HCs; n = 177) and adults with MCI (n = 48) underwent neuroimaging for Aβ and cognitive assessment at baseline. Cognition was reassessed 18 and 36 months later.
Compared with low-Aβ HCs, high-Aβ HC and MCI groups showed moderate decline in episodic and working memory over 36 months. Those with MCI with low Aβ did not show any cognitive decline. Rates of disease progression were increased in the high-Aβ HC and MCI groups.
In healthy individuals, high Aβ likely indicates that Alzheimer's disease (AD)-related neurodegeneration has begun. Once commenced, the rate of decline in cognitive function remains constant across the preclinical and prodromal stages of AD.
Treatment of cultures with 5 nM FK506 (calcineurin phosphatase inhibitor) resulted in analogous elongation of neurites compared to 50 nM Cu(II)(gtsm), suggesting a potential link between Cu(II)(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes.
PLoS One. 2014 Feb 28;9(2):e90070. doi: 10.1371/journal.pone.0090070. eCollection 2014.
Neuroprotective Copper Bis(thiosemicarbazonato) Complexes Promote Neurite Elongation.
Bica L1, Liddell JR1, Donnelly PS2, Duncan C1, Caragounis A1, Volitakis I3, Paterson BM2, Cappai R4, Grubman A1, Camakaris J5, Crouch PJ6, White AR6.
Abnormal biometal homeostasis is a central feature of many neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease. Recent studies have shown that metal complexing compounds behaving as ionophores such as clioquinol and PBT2 have robust therapeutic activity in animal models of neurodegenerative disease; however, the mechanism of neuroprotective action remains unclear. These neuroprotective or neurogenerative processes may be related to the delivery or redistribution of biometals, such as copper and zinc, by metal ionophores. To investigate this further, we examined the effect of the bis(thiosemicarbazonato)-copper complex, Cu(II)(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that Cu(II)(gtsm) induced robust neurite elongation in PC12 cells when delivered at concentrations of 25 or 50 nM overnight. Analogous effects were observed with an alternative copper bis(thiosemicarbazonato) complex, Cu(II)(atsm), but at a higher concentration. Induction of neurite elongation by Cu(II)(gtsm) was restricted to neurites within the length range of 75-99 µm with a 2.3-fold increase in numbers of neurites in this length range with 50 nM Cu(II)(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that Cu(II)(gtsm) inhibited cellular phosphatase activity. Treatment of cultures with 5 nM FK506 (calcineurin phosphatase inhibitor) resulted in analogous elongation of
The population in Imagine study is more homogenious because everybody was done a PET-scan and it had to be positive. So all are true PET positive AD cases who will develop clinical AD in a "known" speed ( AIBL-study reference). That was not the case in Ph2a study. But prodromal or early AD, I do not know and I do not think it will matter much. The question is the progression speed of each individual and of the group.
If we could trust on mice studies everything would be easy but when Mr. Lawler improves like the mice in the Adlard study in 2011 and when the mouse studies explain how the PBT2 works in the brain ( Bush et all in Cell Sept 2010) and when even normal old mouse improve, then I start to think that these mouse studies really have even "clinical relevance". Mr. Lawler did not improve only in EF as was the case in the Ph2a study, he improved as the mice in the Adladr's 2 papers (in my understanding). So I think that there will be clear change also in his brain MRI and usage of glucose. But all this is speculation until we get the results. In any case it is difficult to think that Mr.Lawler would be the only odd case geting benefit of PBT2.
Thanks Linda, with this info it is easy to understand Mr. Lawler's case. When you add the results of the mouse studies ( Adlard PA et al March 2011 and Adlard PA et al Nov.2013) and the ph2a study it is very evident that Mr. Lawler is not the only one benefitting of PBT2 (excluding his wife). It is evident that in the Imagine study there are many Mr. Lawlers who have been better than the best placebo after 3 months, if we can take the results from the ph2a study to the Imagine study. So to me it is clear that Mr. Lawler is not the only patient benefitting of PBT2. More likely it will be close to 100% of those treated with PBT2 who have improved. This is also why the doctors asked the extension study and why also the placebo cases are now getting PBT2. Efficacy was clear 6 years ago and already with clioquinol years earlier. Exceptional efficacy was demontrated in the mouse studies in AD and even in old normal mice. Now the safety info looks also good. But we need the results and we will get them soon.
Some info about clioquinol and BACE:
Ann Neurol. 2008 Dec;64(6):618-27. doi: 10.1002/ana.21548.
The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.
Xie Z1, Culley DJ, #$%$ Y, Zhang G, Zhang B, Moir RD, Frosch MP, Crosby G, Tanzi RE.
An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed.
We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction.
Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo.
Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.
cont... Performance of the TDP-43 (A315T) in the rotarod test for locomotive function was consistently worse than wild-type mice. These preliminary in vivo data are the first to show that expression of a disease-causing form of TDP-43 is sufficient to disrupt metal ion homeostasis in the central nervous system. Disrupted metal ion homeostasis in the spinal cord but not the brain may explain why the TDP-43 (A315T) mice show symptoms of locomotive decline and not cognitive decline.
Front Aging Neurosci. 2014 Feb 11;6:15. doi: 10.3389/fnagi.2014.00015. eCollection 2014.
Increased metal content in the TDP-43(A315T) transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Dang TN1, Lim NK1, Grubman A1, Li QX2, Volitakis I2, White AR3, Crouch PJ3.
Disrupted metal homeostasis is a consistent feature of neurodegenerative disease in humans and is recapitulated in mouse models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and neuronal ceriod lipofuscinosis. While the definitive pathogenesis of neurodegenerative disease in humans remains to be fully elucidated, disease-like symptoms in the mouse models are all driven by the presence or over-expression of a putative pathogenic protein, indicating an in vivo relationship between expression of these proteins, disrupted metal homeostasis and the symptoms of neuronal failure. Recently it was established that mutant TAR DNA binding protein-43 (TDP-43) is associated with the development of frontotemporal lobar degeneration and ALS. Subsequent development of transgenic mice that express human TDP-43 carrying the disease-causing A315T mutation has provided new opportunity to study the underlying mechanisms of TDP-43-related neurodegenerative disease. We assessed the cognitive and locomotive phenotype of TDP-43 (A315T) mice and their wild-type littermates and also assessed bulk metal content of brain and spinal cord tissues. Metal levels in the brain were not affected by the expression of mutant TDP-43, but zinc, copper, and manganese levels were all increased in the spinal cords of TDP-43 (A315T) mice when compared to wild-type littermates. Performance of the TDP-43 (A315T) mice in the Y-maze test for cognitive function was not significantly different to wild-type mice. By contrast, performance of the TDP-43 (A315T) in the rotarod test for locomotive function was consistently worse than wild-type mic
Alzheimers Res Ther. 2014 Feb 26;6(1):11. [Epub ahead of print]
Assessing THK523 selectivity for tau deposits in Alzheimer's disease and non Alzheimer's disease tauopathies.
Fodero-Tavoletti MT, Furumoto S, Taylor L, McLean CA, Mulligan RS, Birchall I, Harada R, Masters CL, Yanai K, Kudo Y, Rowe CC, Okamura N, Villemagne VL.
The introduction of tau imaging agents such as 18F-THK523, offers new hope for the in vivo assessment of tau deposition in tauopathies such as Alzheimer's disease (AD), where preliminary 18F-THK523-PET studies demonstrated significantly higher cortical retention of 18F-THK523 in AD compared to age-matched healthy individuals. In addition to AD, tau imaging with PET may also be of value to assess non-AD tauopathies, such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease (PiD).
To further investigate the ability of THK523 to recognize tau lesions, we undertook immunohistochemical and fluorescent studies in serial brain sections from AD (n = 3), CBD (n = 2), PSP (n = 1), PiD (n = 2) and Parkinson's disease (PD, n = 2). In addition to the neuropathological analysis, one PSP patient had undergone a 18F-THK523 PET scan five months before death.
While THK523 labeled tau-containing lesions such as neurofibrillary tangles and neuropil threads in the hippocampus and frontal regions of AD brains, it failed to label tau-containing lesions in non-AD tauopathies. Furthermore, while THK523 faintly labeled dense cored amyloid-beta plaques in the AD frontal cortex, it failed to label alpha-synuclein containing Lewy bodies in PD brain sections.
This study suggests that 18F-THK523 selectively binds to paired helical filament-tau in AD brains but does not bind to tau lesions in non-AD tauopathies, nor to alpha-synuclein in PD brains.
Primary prevention with vaccines and also with statins are some how related. Side effect side is important. Vaccinations may have some side effects as have statins and most likely also PBT2 will have, even not difficult ones (?).