Friday, July 29, 2016

Clinical Trial for Alzheimer's Disease - Is LMTX Ineffective or Unprecedented?

So which is it? Ineffective or unprecedented?

TauRx Alzheimer's Drug LMTX Fails in Large Study Although Some Benefit Seen

Wednesday, 27 Jul 2016 | 11:23 AM ET

TauRx Pharmaceuticals' experimental Alzheimer's drug LMTX failed to improve cognitive and functional skills in patients with mild to moderate Alzheimer's disease, a large, late-stage study showed.

But in a perplexing twist, the drug did show a significant benefit in about 15 percent of patients in the trial who were not taking other standard Alzheimer's drugs, according to the findings released on Wednesday at the Alzheimer's Association International Conference in Toronto.

LMTX was ineffective in a clinical trial of 891 patients with Alzheimer's disease (AD), although a post hoc analysis in a small subgroup of patients showed a benefit for those taking no other medications for AD (when compared to an inappropriate control group).

Ben Goldacre, Chris Chambers, and others on Twitter took the UK media to task for their misleading articles on the outcome of the trial conducted by TauRx Pharmaceuticals.

As the name implies, TauRx is developing Alzheimer's treatments based on disrupting tau protein, which accumulates in pathological tangles in the brain. Tau aggregation inhibitors are presumed to disrupt these tangles, thereby slowing neurodegeneration and memory loss. The degradation of tau aggregates in vitro was first demonstrated 20 years ago (Wischik et al., 1996), using the stain methylene blueLMTX is a variant of methylene blue, which turns urine blue. For that reason, the placebo group in the TauRx trial received a tiny amount of the drug for blinding purposes.

The clinical trial protocol is NCT01689246, Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild to Moderate Alzheimer's Disease. The original enrollment across 121 sites was estimated at 833, and the original duration was 12 months. The duration was changed to 15 months about a year later, and five other outcome measures were added. And a secondary outcome measure (ADCS-ADL23) and a primary outcome measure (ADCS-CGIC) were swapped.

The company press release used a vague headline (TauRx Reports First Phase 3 Results for LMTX®) to announce the results, but led off with the subgroup analysis (no surprise):

TauRx Therapeutics Ltd today announced Phase 3 clinical trial results that show treatment with LMTX®, the company's novel tau aggregation inhibitor, had a marked beneficial effect on key measures of Alzheimer's disease in patients with mild or moderate forms of the disease.

While the TRx-237-015 study in 891 subjects failed to meet its co-primary endpoints, clinically meaningful and statistically significant reductions in the rate of disease progression were observed across three key measures in patients who were treated with LMTX® as their only Alzheimer's disease medication. These three key measures comprised a cognitive assessment (ADAS-Cog), a functional assessment (ADCS-ADL) and an assessment of the level of brain atrophy (lateral ventricular volume, LVV, as measured by MRI). An abstract of the results will be presented during an open session at the 2016 Alzheimer's Association International Conference (AAIC) in Toronto, Canada this afternoon by Dr. Serge Gauthier, CM, MD.

The ADCS-ADL was originally a secondary outcome measure, and hippocampal volume (not reported) was included as an “Other” outcome measure along with the lateral ventricle volume measurements. Keep in mind these results are preliminary (not peer-reviewed). However, given the possibility of a true positive treatment effect, I can understand why publication would be of secondary importance. There should be no delay in starting AD patients on an effective new and proven treatment (which this is not).

It took a while to find the conference abstract by Gaultier et al. (2016), but an excerpt is below. The actual results were not included the abstract aimed to “highlight the potential therapeutic value” of LMTX (also called LMTM and TRx-0237)  but the text did mention the “85% were taking approved AD treatments” aspect of the study.

Gaultier et al., AAIC 2016

LMTM (TRx-0237) is a novel stabilized reduced form of the methylthioninium moiety with potential for efficacy in treatment of Alzheimer's disease. ... It acts as a selective tau aggregation inhibitor in vitro and in transgenic mouse models  The present 15-month double-blind, placebo-controlled trial (NCT01689246) was performed in patients with probable AD, MMSE score in the range 14-26, Clinical Dementia Rating 1-2 and age < 90 years. Patients were randomized 3:3:4 to receive oral LMTM at doses of 150 or 250 mg/day or placebo (containing 8 mg/day, to maintain blinding) respectively. Primary efficacy outcomes were change from baseline on cognitive (ADAS-Cog) and functional (ADCS-ADL) scores. Three-monthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results: A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). ... The study efficacy and safety outcomes will be reported. The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.

[The entire abstract with authors and affiliations is at the end of this post.]

The 15% who benefited from LMTX® were the patients who were not taking any other medications for dementia (e.g., acetylcholinesterase inhibitors). This monotherapy subgroup was compared to the entire placebo group, not to the subgroup of placebo patients not on any other dementia meds (as pointed out by @bengoldacre). It was nice to read critical coverage of the TauRx spin (and media reporting) at Forbes, BuzzFeed, and Quartz.

Meanwhile, New Scientist updated their headline (and url) to more accurately reflect reality.

Is it worthwhile for TauRx to pursue a proper clinical trial of LMTX as a monotherapy?  Maybe. The big mystery is why LMTX didn't work in patients taking the usual medications for dementia. There's no convincing mechanism to explain that odd result (Wischik: “other Alzheimer’s treatments help to clear toxic material out of the brain, and may also clear away LMTX too”). Or it could be a p-hacked false positive, or a function of milder severity or diagnostic issues or study site in the 15%. If TauRx is truly confident that LMTX taken alone can slow the progression of AD by 80%, then run another randomized controlled study where LMTX + no AD meds is compared to placebo + no AD meds.

Meanwhile, exaggerated reporting on “the first drug to halt Alzheimer’s” is highly unethical.

ADDENDUM (Aug 2 2016): A damning article at Alzforum says, In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period.
On the main primary results slide, disease progression curves for both doses of drug and the placebo were practically identical. Scientists’ disappointment at this finding soon turned into disbelief when Gauthier went on to present a subgroup analysis that held no statistical credence yet purported to show a strong benefit on cognition and brain atrophy.
Thanks to @MaikWallas for the link.

AAIC Conference Abstract

Phase 3 Trial of the Tau Aggregation Inhibitor Leuco-Methylthioninium-Bis(hydromethanesulfonate) (LMTM) in Mild to Moderate Alzheimer's Disease

Serge Gauthier, MD1; Howard H Feldman, MD2; Lon S Schneider, MD, MS3; Gordon Wilcock, MD4; Giovanni B Frisoni, MD5; Jiri Hardlund, MD6; Karin Kook, PhD7; Damon J Wischik, PhD6; Bjoern O Schelter, PhD8; John M Storey, PhD6,8; Charles R Harrington, PhD6,8 and Claude M Wischik, MD, PhD6,8, (1)McGill University Research Centre for Studies in Aging, Verdun, QC, Canada, (2)University of British Columbia, Vancouver, BC, Canada, (3)Keck School of Medicine of USC, Los Angeles, CA, USA, (4)Oxford University, Oxford, United Kingdom, (5)Universite de Geneve, Geneve, Switzerland, (6)TauRx Therapeutics Ltd, Aberdeen, United Kingdom, (7)Salamandra LLC, Bethesda, MD, USA, (8)University of Aberdeen, Aberdeen, United Kingdom

Background: Leuco-methylthioninium-bis(hydromethanesulfonate) (LMTM; TRx-0237) is a novel stabilized reduced form of the methylthioninium (MT) moiety (Harrington et al. J Biol Chem 2015;290:10862) with potential for efficacy in treatment of Alzheimer's disease (AD). A previous trial using the oxidized form of MT identified dose dependent absorption limitations (Wischik et al. J Alzheimers Dis 2015;44:705). LMTM is better absorbed and tolerated (Baddeley et al. J Pharmacol Exptl Therapeutics 2015;352:110) permitting higher doses to be tested. It acts as a selective tau aggregation inhibitor in vitro (Harrington et al. J Biol Chem 2015;290:10862) and in transgenic mouse models (Melis et al. Behav Pharmacol 2015;26:353). Methods: The present 15-month double-blind, placebo-controlled trial (NCT01689246) was performed in patients with probable AD, Mini-Mental State Examination (MMSE) score in the range 14-26, Clinical Dementia Rating (CDR) 1-2 and age < 90 years. Patients were randomized 3:3:4 to receive oral LMTM at doses of 150 or 250 mg/day or placebo (containing 8 mg/day, to maintain blinding) respectively. Primary efficacy outcomes were change from baseline on cognitive (Alzheimer's Disease Assessment Scale cognitive subscale; ADAS-Cog) and functional (Alzheimer's Disease Cooperative Study Activities of Daily Living; ADCS-ADL) scores. Three-monthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results: A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). Dementia was of moderate severity (MMSE score 14-19) in 61%. The study efficacy and safety outcomes will be reported. Conclusions: The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.

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Friday, July 22, 2016

A New Twist on Some Old Brain Myths

1. We only use 4 to 5% of our brains.

The usual ten percent myth is wrong, according to Brain Vizion. We have even more untapped potential waiting to be unlocked!
Brain is the most complex organ in the human body & serves as the center of the nervous system. Brain is the amazing organ as we go deeper we realize the miracles of the GOD. If all information of all books in the world is loaded into the brain, human brain will never be full. Do you know, we are using at the most 4% to 5% of potential of our brain?. Potential of human brain is beyond our imagination. Full potential is a result of proper education (mental development). Think what will happen if we use whole brain?

2. Left Brain, Right Brain, Mid Brain

Everyone knows the left brain/right brain myth. But did you know that you should stimulate your mid brain?
Mid-brain activation is a method to stimulate and balance the left and right brains. Mid brain Activation allows the middle brain act as a control panel for left and right hemispheres. This activates both parts of the brain and enhances the capacity and ability to learn.

What is the middle brain?
Mid brain manages functions of left and right brain. Mid brain is the ‘bridge’ between left and right hemispheres. [No, that would be the corpus callosum.] Once the mid brain gets activated, information will exchange more efficiently in between both hemispheres which leads to more efficient in learning and absorbing information.Mid brain activation allows the brain to function as a whole, rather than only utilizing one part of the brain.

3. Left Brain is Beta, Right Brain is Alpha.

Did you know that each hemisphere has a unique pattern of oscillatory brain activity, operating at separate frequency bands?
One type of brain function belongs to left brain which operates at Beta wave frequency (14Hz to 30Hz cycles/sec). This is the brain we are most familiar with, having developed this brain in traditional academy settings. ... The right brain works at Alpha wave frequency (8 to 13 hertz cycles per second). This is the frequency of the brain associated with a relaxed alert state of mind such as in meditation, just before getting out of bed or while listening to music. It is not the type of brain activity which determines whether something is right or left brain oriented, but rather the brain wave that is operating at the time (Alpha or Beta).

4. Move over theta, it's time for THEATA wave learning.

Back to our magical friend, Mid Brain Activation:
In order to awaken this part of the brain, it is necessary to stimulate a hormonal discharge by sending a special vibration. For this scientific alpha-theta level music are played where apparently only children can receive these waves effectively. In general, theta and alpha waves belong to babies and children. Since these waves belong to the subconscious mind babies and children feel easier to learn something or receive and follow somebody else’s words.  

Wait, I thought alpha waves belong to the right hemisphere...

Mystical brain training outlet Brain Vizion has clearly moved from common brain myths into ESP territory here:
During the mid-brain activation, a child learns how to enter the condition of meditative trans in order to be able to ”see” with eyes closed (Blind-folded).
. . .

Blindfold activation ... is a form of extra sensory perception.Our activated mid-brain’s brain-wave may detect objects nearby & appears in our mind as a form of visualization.Science have proven that even animals are able to perform such ability when moving around or looking for food.e.g.Bats.In human beings , in Blind-fold activation intuition play an important role.

OK then. What can THEATA wave training do for you?
Children will be given an opportunity to do activities of ALPHA & THEATA level vigorously throughout the workshop.Conventional school emphasize predominantly on BETA waves & neglect the importance of ALPHA & THEATA wave learning environment which are for more conducive.

The benefits of their Brain Stimulation program also include improvements in attention, mood, motivation, energy, pain, sleep, performance enhancement, and stress reduction.

It gets even weirder, with the quackery known as the Dermatoglyphics Multiple Intelligence Test (DMIT).

What is the Relation between Human Brain and Fingerprints? Don't click unless you want to see pictures of anencephalic babies. Instead, if you really want to read more about DMIT, Hand Reading News & Reports has a comprehensive review of its history, pseudoscientific claims, and scams.

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Saturday, July 16, 2016

Professor Richard Frackowiak on Retirement (and the Human Brain Project)

A neuroimaging pioneer, distinguished Professor Richard Frackowiak, has come out in favor of retirement:
I retired aged 65 – I am known for being very pro-retirement. Older scientists should advise, if asked, by the next generation, which they trained. They should refrain from occupying leadership positions or directing implementation – the time for that is past.

This is an important public stance to take in a time of dwindling resources and opportunities for junior scientists. On the one hand, with the steady increase in life expectancy since 1935, many aging Boomers plan to work well into their 70s. But on the other hand, this glut of working elders deprives many talented young researchers entrée into tenure track positions. The fact that a senior scientist wants to move aside to allow the next generation to occupy leadership positions is notable, in my view.

Prof Frackowiak's opinion on retirement was included in his comment on a post about Henry Markam and the Human Brain Project (HBP). In The laborious delivery of Markram’s brainchild, science journalist Leonid Schneider takes Markram to task for his dictatorial HBP leadership, his publishing empire (Frontiers), and most of all his hubris (e.g., 2009 TED talk):
“I hope that you are at least partly convinced that it is not impossible to build a brain. We can do it within 10 years, and if we do succeed, we will send to TED, in 10 years, a hologram to talk to you”.

Frackowiak found the post “scurrilous” and specifically objected to Schneider's mischaracterization of his own retirement as “resigning” from the HBP:
I note one mistake that could easily have been checked. Makes me wonder about the accuracy of this scurrilous blog. I did not resign from the HBP. I remain a task leader in the Medical Informatics Platform.  

But many have objected to the goals and governance of the HBP from the very beginning. In fact, two years ago, 156 Principal Investigators (eligible for HBP funding) and 660 others signed an Open message to the European Commission concerning the Human Brain Project. I won't rehash those issues (see further reading below).

Schneider ends with some pointed links to highly embarrassing Frontiers papers, including one endorsing chemtrail conspiracy theories. Frontiers has issued an Expression of Concern about this paper:
An expression of concern on
Human and Environmental Dangers Posed by Ongoing Global Tropospheric Aerosolized Particulates for Weather Modification
by Herndon, J.M. (2016). Front. Public Health 4:139. doi: 10.3389/fpubh.2016.00139

With this notice, Frontiers states its awareness of several complaints and serious allegations surrounding the article “Human and Environmental Dangers Posed by Ongoing Global Tropospheric Aerosolized Particulates for Weather Modification” published on 30 June 2016. Our Chief Editors, Joav Merrick and Anwar Huq, will direct an investigation in full accordance with our complaints procedures. The situation will be updated as soon as the investigation is complete.

UPDATE (17 July 2016): The chemtrails article has been retracted by Frontiers (via @Neuro_Skeptic):
Based on information discovered after publication and reported to Frontiers in July 2016, the article was examined, revealing that the complaints were valid and that the article does not meet the standards of editorial and scientific soundness for Frontiers in Public Health. The retraction of the article was approved by the Field Chief Editor of Frontiers in Public Health and the Specialty Chief Editor of Environmental Health. The author considers the retraction to be unwarranted and therefore does not agree to the statement. 

What does this have to do with the HBP?? Nothing. It came along as part of the larger anti-Markram package.

Further Reading

Guest post: Dirty Rant About The Human Brain Project

Interview: What’s wrong with the Human Brain Project?

Markram et al. (2015). Reconstruction and Simulation of Neocortical Microcircuitry. Cell. 2015 Oct 8;163(2):456-92.

Behold, The Blue Brain

More Fringe Science from Borderline Publisher Frontiers

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Friday, July 01, 2016

Newly Discovered EEG Rhythm Related to Texting, or Cell Phone Artifact?

Texting Zombie (by Ian Aberle)

Contemporary consumers of science infotainment “need” to understand that the brain responds to modern technology in an unprecedented and potentially sinister way. Or at least, that's what you'd think, based on the number of books and essays on how The Internet and Digital Technologies are destroying our brains. The latest entrée into this lucrative genre of mild techno-paranoid is from Elsevier, with their press release about a poorly controlled observational study in a relatively obscure journal:

Sending text messages on a smartphone can change the rhythm of brain waves, according to a new study published in Epilepsy & Behavior.
. . .

Dr. Tatum, professor of neurology and director of the epilepsy monitoring unit and epilepsy center at Mayo Clinic in Jacksonville, Florida found a unique 'texting rhythm' in approximately 1 in 5 patients who were using their smartphone to text message while having their brain waves monitored.

The publishing giant spawned a flood of news stories which claim that texting triggers a Unique, Never-Before-Seen Brain Rhythm that Actually Changes the Way Your Brain Thinks.

But here's what we don't know about the 'texting rhythm'. We don't know:
  • That the signal represents brain activity, rather than a biological artifact (e.g., eye movements) or an electromagnetically-induced artifact produced by the smartphone
  • That the 'texting rhythm' has never been seen before, given the lack of systematic studies
  • That it occurs in people without epilepsy
  • That it has any direct relation to how we think

In a series of two [largely overlapping] studies, Tatum and colleagues (2016a, 2016b) recorded noninvasive EEG (brainwave) activity from inpatients undergoing continuous video monitoring for potential seizure activity. In the more recent paper (2016b), records from 129 texting patients were reviewed for the presence of a reproducible texting rhythm (TR), defined as “a distinct, paroxysmal, time-synched, rhythmic, generalized, frontocentral, 5–6 Hz, monomorphic, theta rhythm repeatedly induced by text messaging” (based on their 2016a study with 100 patients).

Fig. 1 (adapted from Tatum et al., 2016b). (B) unilateral texting with the right hand (picture insert) during video-EEG monitoring. Note the presence of the TR as a 5–6-Hz frontocentral monomorphic rhythm (blue boxes) at the start and termination of texting (solid blue arrows).

It's hard to see what's going on here, so I've zoomed in on the lower box, which shows activity from two bipolar derivations. The Fp1-F3 trace shows eye movements and the F3-C3 trace shows the TR. It appears to be more rhythmic in these left hemisphere electrodes contralateral to the texting hand, but the TR can also be seen in the F4-C4 derivation in Fig 1B.

Although I'm just making qualitative guesses here, I don't think the EEG was quantified with spectral power or time-frequency analyses. In other words, epochs of EEG during texting vs. other activities (audio telephone use, thumb/finger movements, cognitive testing/calculation, scanning eye movements, and speech/language tasks) were eyeballed for the presence or absence of TR. We learn that the TR lasted from 2 sec to continuous runs of  >10 sec. We don't know the number or duration of epochs during the various control activities, but the authors declared a startling significance level:
The TR was highly specific to this text messaging (p < 0.0001). A similar waveform during baseline activation with motor, speech/language, and cognitive tasks performed independently was absent in all patients and was not observed during auditory–verbal smartphone communication (p < 0.0001).

The TR didn't habituate with repeated texting, wasn't specific to iPhone vs. Android, and “was observed in a patient using an iPad, though we did not observe it during the use of a laptop.”

But most texting patients undergoing video EEG monitoring did not show a TR. The percentage of patients with a TR was 24.5% (24 out of 98) and 22.6% (7 out of 31) in a separate Chicago cohort (Tatum et al, 2016a), and only 20.9% (27 of 129) in the 2016b paper. Having a TR wasn't related to age, sex, type of seizure (focal, generalized, epileptic, non-epileptic), or presence/absence of brain lesion on MRI. And we have absolutely no explanation for why that might be, which inspired this hilarious, overly honest headline:

Neuroscientists just found that texting alters your brainwaves, but they can’t explain why

Does using a smartphone fundamentally alter the way that your brain works? ...a group of researchers at the Mayo Clinic recently discovered that text messaging elicits a change in the regular rhythm of brain waves, completely different than the waveforms created by any other activity.

“The big deal with discovering this ‘texting rhythm’ is that the number of new brain waves that are identified on EEG are extremely rare at this point in time,” Dr. William Tatum, the lead author of the study, tells Digital Trends.

Dr. Tatum says that the new brain waves were discovered by accident when analyzing the day-to-day cortical rhythms of people suffering from epilepsy. This discovery triggered an investigation into the neurological effects of smartphone use, which ultimately grew to include nearly 130 participants over a period of 16 months. Only around one in five participants demonstrated the “texting rhythm,” although it didn’t appear to conform to any single gender, ethnicity or age group. Nor is it known exactly what aspect of texting prompts the effect: since text messaging includes a variety of different skills, such as finger dexterity, formulating succinct communications and more.

What we do know is that cell phones and other devices can produce artifacts in EEG recordings (Sethi et al., 2007; Rasquinha et al., 2012; Myers et al., 2016), and this was not discussed in the paper.

Dr. Ranjith Polusani, Artifacts in EEG

EEG Artifact Recognition: Electrical and Environmental Artifacts [cellphone]

But I don't mean to be so pedantic. William O. Tatum, D.O. is a neurologist and member of the American Board of Clinical Neurophysiology who has published Handbook of EEG Interpretation, Second Edition, How not to read an EEG (Neurology, 2013), Artifact-related epilepsy (Neurology, 2013), and more (see References). In fact, here's another image of a telephone artifact from Tatum et al. (2011). Dr. Tatum presumably knows a non-physiological artifact when he sees one.

So does that mean I believe the TR is real? I'll withhold judgment until the results from carefully controlled, quantitatively analyzed, statistically rigorous experiments in participants with and without epilepsy are in. Meanwhile, speculating on the origin, meaning, or relevance of the 'texting rhythm' is premature...

“The question we’re trying to answer right now is whether this is a destructive process or an active process,” Dr. Tatum says. “We think it’s probably an active process through an entrainment of normal cortical rhythms. What’s strange is that it appears to be a destructive frequency that’s more typically identified in people that have a slowing of their brain waves.”


Myers KA (2016). Cell Phone Saccades: EEG Artifact for the 21st Century. Pediatric Neurology. Available online 25 June 2016.

Rasquinha RJ, Moszczynski AJ, Murray BJ. (2012). A modern artifact in the sleep laboratory. J Clin Sleep Med. 8(2):225-6.

Sethi NK, Sethi PK, Torgovnick J, Arsura E. (2007). Telephone artifact in EEG recordings. The Internet Journal of Neuromonitoring. 5(1).

Tatum WO, Dworetzky BA, Schomer DL. (2011). Artifact and recording concepts in EEG. J Clin Neurophysiol. 28(3):252-63.

Tatum WO. (2013). How not to read an EEG: introductory statements. Neurology 80(1 Suppl 1):S1-3.

Tatum WO. (2013). Artifact-related epilepsy. Neurology 80(1 Suppl 1):S12-25.

Tatum WO, DiCiaccio B, Kipta JA, Yelvington KH, Stein MA. (2016a). The Texting Rhythm: A Novel EEG Waveform Using Smartphones. J Clin Neurophysiol. Jan 7. [Epub ahead of print]

Tatum WO, DiCiaccio B, Yelvington KH. (2016b). Cortical processing during smartphone text messaging. Epilepsy Behav. 59:117-21.

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