Category Archives: Science

Gum Disease And/Or Herpes: Alzheimer’s Culprits?

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Science doesn’t always proceed linearly straight-forward. Quite often, it zigs and zags between competing hypotheses which can even be contradictory. Evidence is beginning to accumulate that this may indeed be the case with Alzheimer’s research. For over thirty years, from the early 1980’s, the dominant hypothesis has been that the accumulations of amyloid and tau protein plaques found in the brains of Alzheimer’s patients are abnormal and are the cause of the mental decline of those patients. So research focused on how to directly halt or mitigate the growth of those plaques, and that work has been strikingly disappointing. Quite large amounts of money have been invested in attempting to develop drugs which function directly against the plaque accumulation, yet none have been successful in human trials.

The hypothesis that there might be an external physical cause for the plaque accumulation, that there might be a bacterial or viral agent prompting the amyloid and tau accumulations, that the plaque accumulations might actually be a way the brain fights back against certain invaders, was regarded a heresy. But now there is developing evidence that there might be one or two or even more invading agents against which the brain attempts to fight back with the amyloid and tau plaques. (For the story of one of the herpes researchers, see How an outsider in Alzheimer’s research bucked the prevailing theory — and clawed for validation.)

We posted earlier (Herpes & Alzheimer’s and Herpes & Alzheimer’s — More) about studies strongly suggesting that the Herpes virus may be one of the causative agents. Separately, other studies (Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III and
Inflammation and Alzheimer’s disease: Possible role of periodontal diseases
) have suggested Periodontal diseases as similar agents. Now a new study strongly suggests that this may indeed be the case.

Here are four media articles about the newest work:
We may finally know what causes Alzheimer’s – and how to stop it
Gum Disease Bacteria Found in Alzheimer’s Brains
How gum disease could lead to Alzheimer’s

And here is the research report on the work:
Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

All links have been added to Alzheimer’s > Risk Factors and Neuro-Psych

Zombie Mice Brain Cells: Clearance Stops Cognitive Decline

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Bodies, both mice and human, have a natural anti-cancer defense. Cells which have accumulated so many mutations that might lead to uncontrolled growth (i.e., cancer) move into senescent mode; they cease dividing and are eventually eliminated by the immune system.

Recently published research on mice has demonstrated the rather striking finding occurring when clearing or flushing all senescent cells from the brains of mice genetically bred to exhibit signs of dementia: “When senescent cells were removed, we found that the diseased animals retained the ability to form memories, eliminated signs of inflammation, did not develop [protein] tangles, and had maintained normal brain mass.”

Below are links to three media articles on the work, together with a link to the research article abstract.

Removing faulty brain cells staves off dementia in mice
Over-the-hill cells may cause trouble in the aging brain
Zombie cells found in brains of mice prior to cognitive loss
Research abstract:
Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

All links have been added to
Alzheimer’s > Neurology & Neuroplasticity

Scientific Support for Mental Exercises: Battle of the Open Letters

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When is a purported consensus not in fact a consensus?
On October 15, 2014, the Stanford Institute for Longevity and the Max Planck Institute for Human Development released a purported “Consensus on the Brain Training Industry from the Scientific Community” [1], which broadly asserted that there was no evidence that any cognitive training regimen can improve cognitive function, and was signed by 75 academics, mostly psychologists.

Then on December 17, 2014, a second group of doctors and scientists published a responding open letter, “COGNITIVE TRAINING DATA” [2] (henceforth, CTD), which stated: “Given our significant reservations with the [Stanford] statement, we strongly disagree with your assertion that it is a “consensus” from the scientific community.” As the press release issued in connection with that response [3] (referenced in [3a]) notes: “The [responding] letter is signed by 127 doctors and sci­en­tists, many of whom are lumi­nar­ies in the field of neu­ro­plas­tic­ity – the dis­ci­pline that examines the brain’s ability to change. Sig­na­to­ries include mem­bers of the National Acad­emy of Sci­ences, mem­bers of the Insti­tute of Med­i­cine, depart­ment chairs and direc­tors of pro­grams and insti­tutes, as well as sci­en­tists who are founders of neu­ro­science com­pa­nies. The sig­na­to­ries include sci­en­tists from 18 countries around the world.”

That answers the opening question: The purported consensus in the Stanford letter is not a consensus of the scientific community, despite it’s claim to be such.

Given the level of difference, and the significance to ordinary people concerned with their own aging processes, it’s worth looking into this a bit.

First, who are the authorities? From [4] we can gain a breakdown of the scientists constituting each group:

Of the 75 scientists who signed the “anti” brain-training statement, 54 are behavioural researchers while only 11 are neuroscientific/medical researchers. This means the majority of scientists (72%) who argue brain training does not work have explored this topic from a behavioural performance point of view (for example, using explicit tests to measure memory, learning, comprehension). A minority (~15%) of “anti” brain-training scientists have explored this topic from a physiological point of view (for example, using brain scans to measure brain function, structure, connectivity).

Conversely, of the 131 scientists who signed the “pro” brain-training statement, only 29 are behavioural researchers while 88 are neuroscientific/medical researchers. This means the majority of scientists (67%) who argue brain training does work have explored this topic from a physiological point of view, while the minority (22%) have explored this topic from a behavioral performance point of view.

Second, let’s look at the character of the Stanford open letter. The focus of concern, stated at the beginning of the Stanford letter, is:

Computer-based cognitive-training software — popularly known as brain games

while the final summary statement is:

We object to the claim that brain games offer consumers a scientifically grounded avenue to reduce or reverse cognitive decline when there is no compelling scientific evidence to date that they do.

From first to last, the Stanford letter only discusses “brain games”, and admits no distinction whatever between possibly different implementations of “computer-based cognitive-training software”.  That’s an extremely broad brush, indeed, covering everything from systems like Cogmed and Lumosity to the many sites with crossword puzzles or arithmetic practice, or combinations of such (e.g. Strong Brain), to sites like Posit Science/BrainHQ, founded by major neuroscientists, and boasting extensive scientific studies (cf [5] and [5a]).  Moreover, such a broad brush would tar (second)-language learning sites as well. Yet [6] and related papers demonstrate the power of second languages in cognition.

Rather sloppy for presumed serious scientists.

The Stanford letter neither reviews the scientific evidence claimed by some of the sites, nor does it dig in to the details of the games. It is indeed likely that some of the “brain games” provided by some of the brain training sites do not in fact have direct specific scientific studies validating that particular brain game. It does not follow that such brain games could not be scientifically validated, only that they have not so been validated. Other games on the sites may well have scientific backing.

Again, quite sloppy for presumed serious scientists.

Third, let’s look at the presence or absence of data.  The Stanford letter’s concluding statement is extremely strong:

there is no compelling scientific evidence to date that they [brain-games] do [reduce or reverse cognitive decline]

Wow! In court a judge will tell you that “Ignorance of the law is no defense.” And in every science classroom, you will be told that “Ignorance of the literature is no defense!”  The Stanford letter lists only seven references, and three of them are not concerned with brain-games (The effects of cardiovascular exercise on human memoryAerobic exercise and neurocognitive performance; Bridging animal and human models of exercise-induced brain plasticity), leaving only four references concerned with the topic of the “Consensus”.  On the other hand, the CTD site [2] has a link [7] to a partial list of 132 published studies on cognitive training benefits. Now, to establish the assertion

there is no compelling scientific evidence to date that they [brain-games] do [reduce or reverse cognitive decline]

the Stanford letter would have to refute substantially all of the CTD 132 studies (and more), which it in no way even attempts to do.

Moreover, the Stanford letter would need to refute the work of Kawashima and his group (cf [8]), also not addressed. One can make the case that Kawashima’s 2003 publication of Train Your Brain: 60 Days to a Better Brain in Japan (cf [9] for the English language version) and its subsequent implementation on Nintendo DS as Brain Age: Train Your Brain in Minutes a Day! kicked off the entire world-wide brain-training phenomena. It is worth observing that Kawashima’s original research leading to Train Your Brain, as well as the current work (cf [8]), relies on two non-computerized tasks:  elementary mathematical calculations and reading aloud.  Both of these, of course, can be implemented on computers in a wide variety of ways.

Establishing negative vs positive study results. In a setting in which there are potentially many (or unlimited) ways of accomplishing a given task, how does one prove that there is no method of achieving that task? One must explicitly or implicitly examine every possible method, and show that it will not work. When there are only finitely many conceivable methods, it is potentially possible to enumerate them and demonstrate that each does not achieve the task. But when there are an unlimited number of methods — as there are in brain training settings — much more is required.

The classic, gold standard for such arguments is found in mathematics and computer science, wherein it is proved that certain algorithms cannot exist (e.g. Gödel’s theorem on non-axiomatizability of arithmetic [10] and Turing’s proof of the unsolvability of the halting problem [11]). In these settings, an infinite number of possible algorithms for the problem exist, and it must be shown that each fails. The core of the arguments is to assume that solutions do exist, and then derive a contradiction. The bedrock of the arguments is that the underlying concepts — formal arithmetic (Gödel’s theorem) or computer programs and machines (Halting problem) — are given precise definitions, enabling contradictions to be derived.

Of course, nothing in the fields of human psychology or neuroscience even approaches such gold standards of precise definition and proof. But the principle remains: if one is to assert that no method can achieve a given task, one must at least create sound arguments attempting to enumerate and deal with all possible solutions, or to argue that no such method could possibly exist, even if not with the precision of mathematics.

The four brain-game-related references cited by the Stanford letter are, to one degree or another, concerned with the transferability of training effects of particular tasks to other (presumably related) cognitive areas such as fluid intelligence; in most cases, the task trained was working memory. All four papers performed an analysis of related studies, as well as direct experiments. Broadly, the results leaned towards finding some (but not many) short-term transfer effects, with no long-term transfer effects being observed. However, all that can be inferred from these is that the single memory training method employed in these experiments does not produce any long-lasting transference.

Implicit in the language of these papers and in their being cited in the Stanford letter is the conclusion that no training method for short term memory would transfer to other brain systems. But as noted above, all that follows is that the particular training method described in each of the papers does not provoke long-lasting transfers.

The basic question here is this: Does there exist a sufficient precise definition of “working memory” (or other cognitive subsystems) to support negative inferences as described above? The evidence would suggest: No. “Working memory” is typically defined in terms of or in contrast to “short-term memory”, which is typically defined in terms such as “faculties of the human mind that can hold a limited amount of information in a very accessible state temporarily.” (cf. [12])

Despite the belief that working memory is deeply entwined with many cognitive systems, why or how would the training of a subsystem such as working memory have transfer effects to other brain subsystems? It might be the case for certain subsystems. But without established neurological theories of the activity of the subsystems and their neurological interaction, it seems like guesswork to assert that training one subsystem will or will not produce long-lasting transfer effects to another, much less to be able to quantify the extent of such transfer.

The implicit assertion in these four papers is that since the training methods used did not produce long-lasting transfer effects, no other training methods would either. This, of course, is suspect.

One other (somewhat simple) criticism (which may not apply to all the papers) concerns the measurement of long-term effects some time after cessation of the training. That is, looking to see if the training effects “stick” without maintenance. This seems silly, rather like giving someone reasonable athletic training for some months, then letting them stop training, and after six months of being a couch potato, measuring the effects of the athletic training.

Charitably, it would seem that the Stanford/Max Planck letter was somewhat ill-considered, and that at least some, if not many, of the signatories did not give it serious consideration before signing. That there always has been hype and hucksterism, if not outright fraud, around human development and medicine is obvious to everyone. Certainly, most of the Stanford letter signatories must have been concerned that the brain-game hype is getting overheated, and wanted to try to cool it off. However, to err as badly as shown above was just not wise. Much better to have carefully studied all the literature, developed a truly broad world-wide consortium of researchers and clinicians, and worked with regulatory authorities to develop and enforce standards of evaluation.


[1] A Consensus on the Brain Training Industry from the Scientific Community


[3] Scientists to Stanford: Research Shows Brain Exercises Can Work

[3a] 127 scientists challenge the purported brain training “consensus” released by the Stanford Center for Longevity

[4] What Science Really Tells Us About Brain Training Games

[5] 100+ Published Research Studies

[5a] A Response to “A Consensus on the Brain Training Industry from the Scientific Community”

[6] Bilingualism, Aging, and Cognitive Control: Evidence From the Simon Task

[7] View a partial list of published studies on cognitive training benefits

[8] Reading Aloud and Arithmetic Calculation Improve Frontal Function of People With Dementia

[9] Dr. Ryuta Kawashima, Train Your Brain: 60 Days to a Better Brain, [2005]
Kumon Publishing North America, 172 pp.

[10] Gödel’s incompleteness theorems

[11] Halting problem

[12] Nelson Cowan What are the differences between long-term, short-term, and working memory?, in Progress in Brain Research, Volume 169, 2008, Pages 323–338.

Category: Mental Agility, Science

Science and Exercise

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Science is incredibly important.  Without it, we wouldn’t be very far out of the caves.   But one does not necessarily need formal science to make rational decisions and take sensible actions. Don’t get me wrong — formal medical and biological studies are immensely valuable and important. However, we don’t have to wait for a formal study to confirm many of the things we intuitively know from experience.  (And in fact, formal studies are increasing confirming the main points discussed below.)

High school coaches don’t need a collection of formal double-blind trials to know how to build school sports teams. At the beginning of fall (or spring) practice, they know that the young players will need strength and endurance, and that many of the players haven’t necessarily worked out (or worked jobs) over the summer or winter to build that strength and endurance. And so every day of practice typically begins with pushups, situps, kneebends, laps around the track, pushups, situps, knee bends, laps around the track, … you get the idea.

Coaches everywhere certainly get that idea, and their players initially ache and groan.  But then after a few weeks, the players tighten up and 50 pushups or two miles around the track, all in full gear, become simply a normal day’s event.

Other high school teachers have typically had similar ideas about strengthening their students’ minds, quite notably language teachers (say of Latin, French, German, Spanish, etc.) and math teachers, especially geometry teachers.  They and many other people in the education world have thought that mastering a language (yes, even Latin!) and/or  mastering geometry will strengthen thinking, never mind whether these things will directly help in getting a job later.

For a long period, those sorts of views of intellectual exercise — Latin and other languages, geometry, and all sorts of similar mental activities — fell out of educational favor, partly because they could not easily be subjected to formal controlled studies with  definable outcomes, whether those outcomes were functionally measurable behaviors or biologically-based measures — at that time it was just too hard to  get inside people’s skulls and count the neurons!.

But some surprising things have happened in the last 35 years. The development of sophisticated non-invasisve scanning techniques for soft tissue have effectively allowed researchers to open up our skulls and see at least a bit of what is going on inside. The biggest surprise is that the previous orthodoxy that  brain neurons are fixed by the end of adolescence and decline thereever after turned out not to be true. Neurogenesis is real! Under the right kinds of stimulus, the brain can and does regenerate neurons to replace others which may have been damaged. Sometimes it also appears to press other neurons (loafing nearby?) into such service. And part of the surprise is that our old Latin and geometry teachers have been vindicated: learning languages and acquiring intellectual and physical skills are the kinds of stimulae which push brains grow or rebuild themselves.  And so both mental and physical exercise turn out to be important throughout life.

We’ll return to all this in future posts.