Our understanding of how genes eventually relate to brain disorders continues to evolve, and along with it, the terminology:

Genome: it started here. Technology at first let us have brief peeks at “neighborhoods” of genes. As we developed methods for looking at neighborhoods with relation to each other and their relative production rates, we became able to consider

Proteome (integrity of finished protein product’s structure) and Transcriptome (how RNA plays its middleman role) make sense as factors in how much impact the genome could have on an individual’s health. But wait, there’s more, lots more:

Metabolome: the flip side of that productivity coin: if the protein made from the genetic instruction manual is being broken down in an abnormal way, you might have too little or too much of the protein, even if your body knows how to make it.

Connectome: specific to neuroscience. How your brain regions are physically connected to one another (which includes what structure you were born with and what structure you may acquire from stroke or head injury or infection) plays a role in how well or not well the proteins function in that brain.

Epigenome: I used to conflate this with the next section. This refers to the methylation process, which is a way to flip a railroad track signal to enhance or inhibit the transcriptome.

Interactome: the interactions  of genes with each other (2 wrongs can make a right or there can be some wonderful synergies)

Exposome: a way to throw environmental exposure, life changes, accidents into one category.

For more, see Dr. Andy Saykin (and ADNI Genetics Core)’s review.

The title for this post refers to how we medically name tumors (rapid unintentional growths) after the cell type + oma, e.g., meningioma.

Learning from Biotrial

Some of you may be hearing about the 6 participants in a French study of a new drug to act within the brain. Our institute is not involved with that study, but the developments of serious brain injuries from a drug trial that had actually been going along without problems for the last half of 2015 have certainly served
to let me run through what processes we have in place for similar emergencies in our studies. 
This type of thing, where 6 participants are hospitalized, is more likely to happen in Phase I trials where the drug’s safety in humans is first being tested. Our portfolio of trials are all at least in the Phase II stage, but to have adverse effects in the older target populations with dementia may be significant (become serious) because of their age and other coincident health status. 

I read through a major investigational review of a similar incident from the ’90s and was relieved that there can be a clear protocol for safety after the unexpected has struck: both internal and external reviews of the drug risk and the participants’ conditions start immediately, and any prior history of similar reactions during trials of the same drug are brought forward for pattern recognition. Ethics, safety, and protocol reviews go on simultaneously to right what can be remedied and protect any participants who are still in the study but potentially at risk. 

One newspaper article about the current dilemma quoted an external researcher as warning that volunteer participants for Phase I studies might not have the education to understand what they’re signing on for but the money to be made is compelling. From another article, it doesn’t seem like an unusual sum was given for the study in question. Time will tell what we can do better in future. I’m hoping we’ll find ways to reassure our recruits that we are watchdogging for safety from the point of designing the study, right on through.

Confirmation: Estrogen Supplementation is NOT a Treatment for Alzheimer’s Disease

older-womanFormer USC colleague, Dr. Vic Henderson, and his group at Stanford published results of their randomized, placebo-controlled clinical trial of a selective estrogen receptor modulator for those women who already have mild-moderate Alzheimer’s disease.

In a nutshell, there were no differences in the progression of the illness after a year, whether participants were on placebo or raloxifene. This confirms the ongoing consensus that estrogen may play more of a role in cognitive health based on what happens earlier in life BEFORE memory problems of aging take place.

The article: Henderson V et al. Raloxifene for women with Alzheimer disease. Neurology 2015; 85: 1937-1944.

NEW Resource for Canadian Caregivers

elizzFor a while, the only caregiver resource I knew of on-call in North America was the US-based Alzheimer’s Association helpline, 1.800.272.3900.

I am delighted to learn that just as of October, 2015, St. Elizabeth’s launched Finally, Canadian caregivers can either call in 1-855-ask-elizz, or start a chat to be triaged to services 24/7. The Nurse Advisor is available 24/7; behavioural health professionals who work fulltime for Elizz are available on more of a bankers’ schedule. Anything beyond the chatline does come at a fee, but family members can set up payment for one primary caregiver to have access anytime s/he needs it! They don’t have a gift card system set up at this time, but call 1-855-ask-elizz to make arrangements.

And if the patient could benefit from a “Virtual Visit,” for $49/mo., an Elizz professional will call him/her regularly. See Toronto Star story.

I am hoping they will discover some Elder Care law professionals who will collaborate. To my eye, that’s the only missing piece at this point. Lucky you, Canada. With time, maybe this can arise in more places.

First Aid for Mental Health!!

  I was slow to pick up on this, but I’m thinking a one-day, 8-hour course on Mental Health First Aid might be VERY handy training for caregivers. Although designed to address all manners of psychiatric events, much of the information to de-stigmatize and to operationalize letting someone know you care for him/her is broadly applicable. See to see where you can sign up for a course in the United States!

And just as with CPR classes, it’s worth discussing if there is such a thing as “too young” to start learning about this. 

Remember the Cabernet “Treatment” for Rats?

  The resveratrol story continues…

You may have seen in my book that a study on rats about benefits of red wine for Alzheimer’s prevention had two important findings:

1) it seemed to work

2) the dose translation into humans was not sustainable as a Cabernet daily supplement (too high)

Researchers/nutraceutical companies have been working to create a supplement for humans that would give all the benefit (seemingly attached to resveratrol molecule) without any of the alcoholic toxicity. Turner et al. report in Neurology 2015; 85:1383-1391 that they’ve amped up the human dose and administered it safely to older humans. And a very preliminary look at effects on the brain, while not overwhelmingly different between treatment and placebo groups, show a glimmer of hope. 

Most importantly, note that the dose was up to 2,000mg/D, which is MUCH higher than what’s on the store shelves currently. But don’t start swallowing it by the handfuls yet, ok?

The Hypothalamus in FTD

Interesting news from “Down Under” [Piguet lab]:
I had been glossing over explaining insatiability or preference for sweets in patients with FTD by saying that the part of the brain in the frontal and temporal lobes that would inhibit oral intake was offline, but that is not the whole story. 

 A deeper (sorry, couldn’t help that one) look by Ahmed et al., published in Neurology 2015;85:1310-1317, revealed good evidence that the hypothalamic segments that secrete appetite stimulating hormones run out of control, in part because the back end of the hypothalamus shrinks akin to the frontal and temporal lobes in FTD. These findings were more frequent among those patients with the TDP-43 type of abnormal protein deposition than tauopathy, so future studies may confirm whether the presence of overeating and oral disinhibition are diagnostic for TDP-43. 

Most importantly, identifying roles for agouti-related peptide and leptin creates new targets for symptomatic FTD pharmacotherapy…and it may not be a stretch to think any developed interventions might become weight-loss aids.

Can Older Women Predict Their Own Dementia?

Interesting paper by Kaup et al. (Kristin Yaffe’s lab) in Nov 24, 2015 issue of Neurology

Women followed for 20 years starting on average at their age 70 seemed able to recognize their own vulnerability at that first time point. Specifically, those 8% of women in the study who felt at age 70 they had memory problems tended to be right in worrying — they were more likely than non-complainers to have either mild cognitive impairment (MCI) or dementia 20 years later. DEAR MOM, PLEASE NOTE, THEY DID NOT ALL PROCEED TO ALZHEIMER’S DISEASE!

Also, please note that the 8% were more likely to have history of heart attack by age 70 and more depressive symptoms than the rest of the cohort followed. IF YOU ARE A 70 YEAR OLD WOMAN WHO THINKS SHE’S “LOSING IT,” THIS STUDY’S FINDINGS MAY NOT APPLY TO YOU, IF YOU DO NOT ALSO HAVE CONCURRENT DEPRESSION OR SIGNIFICANT CARDIOVASCULAR DISEASE.

Another important finding in this study was that women who continued to have concerns about their memory function were at high risk for developing MCI or dementia –*please note again, not all getting Alzheimer’s disease. 

I’m not sure why a survival curve to show how quickly the 8% descended in function over time wasn’t shown. I’m also feeling curious about how men have done in a similar inquiry. The question of whether women are more in touch with their cognition has NOT been asked or answered by this study. 

Memory complaints and risk of cognitive impairment after nearly 2 decades among older women. Kaup AR1, Nettiksimmons J2, LeBlanc ES2, Yaffe K2. Neurology 2015; 85:1852-1858