Samuel Wilks on the need for multidisciplinary neurologic research (in 1864)

A history of dementia often starts in 1907 with the work of Alois Alzheimer, but in reality it should start much sooner. In 1864 Samuel Wilks wrote “Clinical Notes on the Atrophy of the Brain,” which was one of the first studies to point out gross atrophy of the sulci in the brains of persons who had dementia prior to death. This is a great paper! I loved the intro:

WERE an occasional comparison instituted between the experiences of those who practise in special but different departments of the profession, it would conduce not only to the fulfilment of some higher general truths than we now possess, but afford to the individual labourer in his department a more just and less narrow view of the field of observation which is always more immediately before his eye. A close observance to one section of medicine may produce much accurate and minute knowledge, but since the division of our art into branches is artificial rather than real, the knowledge therein obtained is regarded apart from its natural relations, and becomes so distorted as to lose much of its value as truth. If the various sciences into which we divide nature for the purposes of study are artificial, and it be true that an exclusive devotion to one of them can never give to its follower a correct insight into the operations of nature, so more true must it be that the general laws of human pathology can scarcely be gleaned in an exclusive practice in one single department.

It may seem almost impertinent to make these remarks in a Journal devoted to a special object, nor were they, indeed, intended to apply to the study of mental disorders, which must be undertaken in an almost isolated manner; and yet an opinion has obtained hold of me (which, however, may be erroneous) that even here some too narrow views may be held of cerebral pathology, and this opinion, right or wrong, has suggested the remarks in the present communication. To be more explicit: I have thought that those who are occupied in the practice and study of any one department might possibly look upon some morbid condition or other feature in a case, as peculiar to a certain form of disease. Thus, in connection with the subject on which I purpose to make a few remarks, it has seemed to be inferred that a certain morbid phenomenon has been found exclusively in lunatic asylums; and, at the same time, to be inferred by a writer on infantile diseases, and who is probably destitute of the knowledge just mentioned, that this phenomenon is intimately connected with the cerebral affections of children. So, also, with the general subject of the following observations, atrophy of the brain: this has appeared to me to have been regarded by some as a condition attaching to those who have died of mental affections, and not only so, but of some special form of insanity; others would describe a similar condition as resulting from repeated attacks of delirium tremens; whilst others write of a state not distinguishable from these as the ordinary result of old age. From having no inclination towards any of these special departments, I have endeavoured to take a comprehensive view of such pathological changes, and, as regards the subject before us, to discover at what stage our knowledge has reached of this morbid condition, and what is its true pathological significance; leaving it for further research to elucidate its varieties and the different methods by which these are brought about.

Is progeria related to aging in the same way that familial AD is related to sporadic AD?

Attention conservation notice: Someone has probably made this point before.


Progeria is a genetic disorder caused by mutations in the lamin A nuclear lamina protein. Since it manifests in several ways that resemble an aged state (eg wrinkled skin, atherosclerosis, kidney failure, loss of eyesight), it is widely believed to be an early-onset version of aging.

Yet, few people think that nuclear membranes are the only thing that is altered in aging, as aging is generally considered too complicated for that. Instead, nuclear membranes are recognized to be one aspect within a larger pathway that is altered in aging.

Familial Alzheimer’s disease (AD) is a genetic disorder caused by mutations in APP, PSEN1, or PSEN2, which are all part of the APP processing pathway and thus (among other things) amyloid plaque production. Since it manifests in several ways that resemble sporadic AD (episodic memory loss, Aβ plaques, tau tangles), it is widely believed to be a an early-onset version of sporadic AD.

In contrast to progeria and aging, familial AD is generally thought to be a model of sporadic AD that captures almost all of the key pathways involved. As a result, one of the major justifications for clinical trials to treat sporadic AD by removing amyloid plaques is that the genetics of familial AD are all related to APP processing and thus amyloid plaque production.

There are probably several good arguments for why this progeria:aging::familial AD:sporadic AD contrast doesn’t make sense, but I still thought it might be interesting.

Arterial aging and its relation to Alzheimer’s dementia

I’m a big proponent of the role of arterial aging in explaining dementia risk variance, in large part because it explains the large role that vascular-related risk factors have in promoting the likelihood of Alzheimer’s disease (AD). However, some data suggests that the burden of ischemic events and stroke cannot explain all of the vascular-related AD risk. Recently, Gutierrez et al. published a nice paper which suggests that non-atherosclerotic artery changes with age may explain some of this residual vascular-related risk of AD. In particular, they used 194 autopsied brains and found five arterial features which strongly correlated with aging, including decreased elastin and concentric intimal thickening. Importantly, these features also correlated with AD risk independently of age.

The authors propose that the arterial aging features are a consequence of mechanical blood flow damage that accumulates over the years. If it is true that the damage is mechanical, it suggests that it may be difficult to reverse with existing cellular and molecular anti-aging therapies. For those people who are interested in slowing down aging, the brain must be a top priority because it cannot be replaced even by highly advanced tissue engineering approaches to replace the other organs. Thus, this sort arterial damage needs to be addressed, but to the best of my knowledge it has not been, which is one of the many reasons that I expect that serious anti-aging therapies are much further out than are commonly speculated in the popular press.

Are four postulated disease spectra due to evolutionary trade-offs?

I recently read Crespi et al.’s interesting paper on this subject. They describe eight diseases as due to four underlying diametric sets that can be explained by evolutionary/genetic trade-offs:

  1. Autism spectrum vs psychotic-affective conditions
  2. Osteoarthritis vs osteoporosis
  3. Cancer vs neurodegenerative disorders
  4. Autoimmunity vs infectious disease

Of these, #2 and #4 seem obviously correct to me based on my fairly limited med school exposure, and they describe the evidence in a systematic way. I don’t know enough about the subject matter to speculate on #1, but I would like to see more genetic evidence.

Finally, I found their postulated explanations for #3 somewhat weak and I personally think that it is a selection bias trade-off, i.e. a case of Berkson’s bias as applied to trade-off. That is, since both cancer and neurodegeneration are age-related conditions, you could think of aging as the “agent” that selects either neurodegeneration or cancer as the ultimate cause of age-related death. I could be persuaded to change my mind on the basis of genetic predisposition evidence or some other mechanism, but I found the mechanism of apoptosis to be weak since apoptosis occurs (or doesn’t occur when it should) in many, many diseases, and moreover it is far from clear that neurodegeneration is mostly due to apoptosis as opposed to some other mechanism of cell death. A mechanism that might be most persuasive to me is one related to immune cells, since they clearly play a large role in regulating cancer growth, and also have high expression for the most GWAS risk factors for Alzheimer’s disease. But I still suspect that the selection bias is primary.

A clinical trial for omental transposition in early stage AD

A couple of years ago I wrote about treating AD with omental transposition, a radical therapy with success in ~ 35% of patients in one case series. Today I just noticed that there is a non-randomized, single-arm clinical trial on its use in patients with early stage AD (MoCA score 11-18), in Salt Lake City, UT. Estimated study completion date: May 2019.

This is especially interesting because they have a relatively thorough explanation of how the surgery works. In the general surgery portion of the procedure, an omental flap is created, which receives blood supply from the right gastric and gastroepiploic arteries. Next, a subcutaneous tunnel is created that travels up the chest wall and neck to behind the ear.

In the neurosurgery portion of the procedure, a portion of bone is removed near the temporal-frontal area, followed by removal of the dura and arachnoid membrane. The omentum is then placed on the parietal-temporal-frontal area of one cerebral hemisphere, and connected to the dura via a suture.

Besides this tissue grafting approach, other neurosurgical approaches to Alzheimer’s have included:

  1. CSF shunts (to the atria or ventricles)
  2. Intraventricular infusions (of bethanecol, NGF, or GM1)
  3. Gene therapy with infusion of NGF-expressing cells
  4. Electrical stimulation (of the vagus nerve, nucleus basalis of Meynert, or the fornix)

Clinical trial evidence related to calling Alzheimer’s “Type 3 Diabetes”

Attention conservation notice: These are just a few impressions from only 2-3 years of following the AD field — I’m certainly not an expert in any of this. Also, I am not a doctor.


The evidence behind calling Alzheimer’s “type 3 diabetes” is at least two-fold. First, insulin and insulin-like growth factor pathways are thought to decrease in levels in AD patients. Second, diet and vascular risk factors are strongly linked to AD diagnosis.

The purpose of this post is that I’m trying to learn about the idea and how valuable I think it is as a framework for AD.

First, let’s look at some history. On Pubmed, there are 48 results for “type 3 diabetes” OR “type III diabetes”. Which, out of 83658 total hits for “Alzheimer’s”, is not that many.

The first mention on PubMed is in 2000. Although I don’t have access to the full-text, I don’t think it’s about Alzheimer’s.

Instead, it seems that the first mention is in 2005, by Steen et al. [1] — and indeed, in their abstract they say that they are coining the term. Their argument is that insulin-related proteins, especially IGF-I and IGF-II, have reduced expression in postmortem human brain tissue from AD patients, suggesting a lack of sufficient insulin in the brain.

To get a sense of how it has seeped into the public consciousness, let’s look at how much people are searching for this term using Google trends:

Screen Shot 2015-11-25 at 8.35.27 PM

searches for “type 3 diabetes” on Google trends

So I don’t think it is old news.

Yesterday, Gabrielle Strobel from AlzForum reported on two pieces of data from CTAD 2015 that seem relevant to the case for Alzheimer’s as type 3 diabetes:

  1. Metformin (a drug that increases insulin sensitivity and is used to treat type 2 diabetes) was ineffective in improving cerebral perfusion in 20 patients with mild-to-moderate AD.
  2. Intranasal Determir (an insulin analog) did not have an improvement on memory or MRI volume, but regular insulin did.

There are also a couple of other relevant pieces of data:

  1. Previously, numerous studies have shown that intranasal insulin leads to memory improvements in AD patients (e.g., here, here, and here).
  2. The SNIFF trial is a study of year-long treatment of twice-daily intranasal insulin with 240 enrollees nation-wide. The results are set to be in in February 2016, so we should hear about it soon.

Notably, intranasal insulin has also been shown to improve cognition in non-AD trials:

  1. It improves cognition in people with type 2 diabetes (e.g., here).
  2. In rats, it improves cognition in normal aging (here).
  3. It improves some measures of cognition in healthy subjects age 18-34 (n = 38; here; note: this study did not correct for multiple hypothesis tests).

Since mixed vascular and Alzheimer’s dementia is probably the most common form of dementia (e.g. see here), and vascular dementia is often related to poor perfusion in part due to insulin-related metabolic problems, it makes total sense that intranasal insulin would help to improve cerebral vascular function and thus appear to be helping the memory of AD patients, when in reality it is helping the mixed vascular dementia component.

So although I definitely hope that the SNIFF trial receives positive results on cognition, I don’t think it’s fair even in that case to call it as necessarily a “win” for the case for Alzheimer’s as type 3 diabetes.

For that to be the case, I’d want to see better data that not only is cognition improving following insulin treatment, but also that measures of AD pathology such as amyloid and tau are improving. This seems to be one of the major goals of the SNIFF trial, since they are also measuring amyloid and tau in the CSF of the enrollees.

So, in an attempt to quantify my actual beliefs, and knowing absolutely nothing about the SNIFF trial itself (i.e., this is based solely on public info, mostly listed above), I predict with 60% probability that the trial will show a significant improvement in cognition. I also predict that neither CSF Abeta nor Abeta/tau ratios will change significantly based on treatment, this time with 75% probability.

Since the results are meant to be completed in February 2016, we should know the actual results by the end of 2016 latest.

Although the terminology, classification, and mechanisms around AD are extremely important for research priorities, the most important thing is to get better therapies for all types of dementia into clinical practice ASAP. And on that note, hopefully intranasal insulin will turn out to be a really valuable therapy for patients.

 

Why Clinical Biomarkers for AD Matter

Frisoni et al. make this interesting point: In HIV and cancer, success in fighting the disease was heralded by biomarkers — CD4 counts and viral load for HIV, and a wide variety of tumor markers in cancer — that allowed researchers to do much faster iterations in clinical trials. The problem is that regulators don’t have good reason to trust these unless a useful agent can be shown to affect that biomarker while also improving clinical symptoms in AD. Once this has been shown — and the effect on that biomarker is fairly specific and/or biologically meaningful — then beyond the obvious clinical use, it will speed up drug development for AD tremendously. This, to me, is a big part of why candidate biomarker research in AD is so important.

Twelve Interesting Recent Papers

1) Wootla et al. discussing naturally occurring antibodies for treatment of CNS disorders. Naturally occurring antibodies are mainly IgM and bind to many different types of antigens with low affinity (that’s what happens when you don’t do any affinity maturation). One idea is that elderly people without AD (but with, say, risk factors such as APOE) may have more of these antibodies, that help clear amyloid, and that’s why they haven’t developed AD. In fact, one of the more promising current treatments for AD in trials, aducanumab, was originally derived from elderly donors without AD based on this hypothesis. A similar procedure is also being done in MS — e.g., the authors describe some antibodies that bind specifically to oligodendrocytes with the goal of promoting remyelination.

2) Cummings et al. describing good phase II trial results for dextromethorphan + quinidine for agitation in AD. Aside from being excited about a potential new treatment for an aspect of AD, I find this particularly interesting since I was previously involved in a project that evaluated the effects of recreational doses of DXM in the comments of YouTube videos. However, the recreational doses are much higher than the doses in this study (> 200 mg vs 30 mg, respectively), so the effects are probably radically different — as always, the dose makes the poison.

3) A couple of papers recently came out purporting to explain the role of the ApoE risk variant in AD, which is very important but still very much unknown. First, a really interesting paper from Zhu et al. shows that in APOE ɛ4 carriers, synj1 expression increases, which decreases the expression of phospholipids such as PIP2. This is similar to an ApoE-null phenotype, suggesting a loss of function phenotype. Second, Cudaback et al. show that ApoE allele status affects the astrocyte secretion of the microglial chemotaxis factor CCl3. Interestingly, the ɛ4 and ɛ2 alleles have a more similar effect than ɛ3 in their data.

4) Turner et al. present results from an RCT of resveratrol for AD, which finds some good effects in biomarkers, but is not a home run clinically. Although with only 119 participants, it is likely underpowered, and one of the four clinical measures had a p = 0.03 effect in the correct direction.

5) Tom Fagan at AlzForum does nice reporting on results from PET and neuropathology showing that, by both measures, around 25% of people clinically diagnosed with AD do not have high amyloid levels. This is higher in ApoE e4 non-carriers, which is what you’d expect based on conditional probability and clinicians not taking into account ApoE allele status into account when making their diagnosis. In the absence of amyloid, neurodegeneration appears to be fairly slow or absent.

6) Dale Bredesen continues his innovative work in AD, describing here case reports suggesting that there are three types of AD, one inflammatory, one metabolic (e.g., related to insulin resistance), and one related to zinc deficiency.

7) Moran et al. use ADNI data to show that Type 2 Diabetes is associated with CSF tau (explaining 15% of the T2DM-associated cortical thickness loss), but not CSF amyloid, suggesting that T2DM might be related to tau-only AD cases, and/or tau increases that are independent of amyloid.

8) Not AD, but still neurological, in frontotemporal dementia, Ahmed et al. report that fasting blood levels of agouti-related peptide (AgRP) are much higher in patients (~66.5 +/- 85) than in controls (~23 +/- 20). Furher, AgRP levels are correlated with BMI, suggesting that AgRP levels account for the increased eating behavior seen in some variants of FTD. Just interesting to see an example where the effect of hormones on eating behavior could be very strong.

9) Petrovski et al. used WGS data to define an interesting measure of “how tolerant a gene’s regulatory region has been to mutation across evolution.” Specifically, their measure (the “noncoding Residual Variation Intolerance Score”) measures how many common variants a gene has in its regulatory region compared to other genes with a similar mutation rate. They found that higher levels of this measure were significantly associated with genes that are annotated as haploinsufficient, meaning that this is a good way of describing how much cells care about what relative expression levels a gene has.

10) Zheng et al. also used WGS data and found that rare variants in the gene EN1 are significantly associated with the risk of bone fracture. To quantify the effects of rare variants (< 5% MAF) they also used an association test — SKAT — to measure associations of these variants with bone marrow density in windows of 30 bp’s, and found one significant gene with this procedure. Refreshingly they put their code for this analysis online, available here, I haven’t ran it but just want to say +1 to them for putting their wrapper code online. Interestingly, both this paper and the Petrovski paper use the GERP++ score for their evolutionary inference — that seems to be a common tool, check it out here.

11) In influenza news, Lakdawala et al. show that influenza A does a large amount (most?) of its replication in the soft palate, which is the fleshy, soft part in the back of your mouth. Total hindsight bias, but this “makes sense” to me when I think back to the times when I think I had the flu myself — that part of my mouth gets very irritated, and now this makes slightly more sense.

Children with genetic risk of autosomal AD have higher plasma abeta levels

Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD… [M]utation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001).

That’s an extract from the abstract of an interesting study from the June issue of JAMA Neurology.

Age-related changes in white matter are likely not due to demyelination?

That’s the conclusion of an important new paper from Billiet et al that integrated a bunch of different imaging modalities.

First, they used DTI to measure fractional anisotropy, which is a non-specific measure of white matter, measuring axon density, axon diameter, and myelin content. They also used myelin water fraction (MWF) to measure myelin content and the orientation dispersion index (ODI) to measure dendrite/axon dispersion. These were their findings:

  • Total white matter volume does not change in aging
  • Myelin content (via MWF) is not significantly altered in aging in most regions, and in the regions where there is a change, it increases
  • There is a widespread decrease in fractional anisotropy in aging that is especially strong in frontal regions
  • Changes in myelin content (MWF) do not correlate well with this decrease in fractional anisotropy
  • Changes in neurite orientation (ODI) dispersion do correlate with this decrease in fractional anisotropy

Thus, their conclusion is that age-related decreases in the “diffusibility” of white matter (or whatever fractional anisotropy is measuring) are due to changes in axons rather than to changes in myelin.

It’s all cross-sectional, n = 59, and they call this conclusion “highly speculative,” but if true it suggests that axons changes are more early/causal/fundamental to aging than changes in myelin. We need more data on this, especially from older individuals (their study went up to only 70) and from people with dementias, such as Alzheimer’s disease.


Billiet T, Vandenbulcke M, Mädler B, et al. Age-related microstructural differences quantified using myelin water imaging and advanced diffusion MRI. Neurobiol Aging. 2015