Should We Cheat (note not Treat) Senior Moments with Cognitive Enhancers?

JAMA published an article online today that may revive debates about whether people who are healthy and NOT cognitively impaired should be  able to use cognitive enhancing drugs (e.g., modafinil) as they need, to get through a sleepy day or even to enhance performance. The authors were surprised to find that talented chess players were able to perform better after taking drug; they’d expected no improvement beyond their typical outlier performances without drug!

More pertinent to this readership, however,  were the comments from experts in the field about use of such cognitive enhancers in the case of mild cognitive impairment. I was happy to see them reiterate messages of caution:

“Let’s say you are in your 60s and 70s,” said Sahakian. “You don’t have dementia, but you’re losing some sharpness. You just want to get some of your old faculties back. Is that enhancement? Or is it restoration?”

Sharon Straus, MD, MSc, a gerontologist at the University of Toronto, is wary of prescribing CEs for mild cognitive impairment in the elderly because of adverse effects, including diarrhea, vomiting, fatigue, insomnia, and weight loss that have been noted among patients with Alzheimer disease.

“There is no high-quality evidence to support use of cognitive enhancers in healthy people,” said Straus, who is director of the Knowledge Translation Program at St Michael’s Hospital in Toronto. “I would advise clinicians to avoid their use.”

She notes that there are alternative interventions known to stave off cognitive decline, including exercise, tobacco cessation, and weight loss, though she acknowledges that they are difficult to implement.

Seizures in Alzheimer’s Disease

Image courtesy of http://what-when-how.com/acp-medicine/epilepsy-part-1/

This is a long-brewing topic on which I have changed my mind (a few times!), based on the evidence as it rolls out.

The Questions:

1. Does Alzheimer’s disease cause patients to have seizures?
2. If it does, how often should we treat with anti-seizure medication to improve the cognition or behavior of someone with Alzheimer’s disease?

Evolving Answers:

Because the pathology of Alzheimer’s disease affects the cortex of the brain (AKA gray matter), there is always a potential for abnormal cortical electrical activity to arise and propagate over areas of the brain, that might be focal (e.g., causing momentary speech arrest) or generalized throughout the brain. We have an easier time of recognizing generalized seizures (loss of consciousness, often with major involuntary jerking or shaking as you see in the movies). Those patients, regardless of whether they have Alzheimer’s disease (AD), do get treated so that we can prevent additional generalized seizures, which can cause injury but are not typically fatal. The literature  contains reports of anywhere from 20-50% of AD patients at given  centers showing seizure activity. But anti-seizure medications (AKA anti-epileptic drugs) can have adverse effects on cognition, and the risk:benefit ratio has been difficult to distinguish in this seizure context. For a long time, I did not treat with anti-seizure medication unless a generalized seizure had occurred or a patient’s severe agitation warranted treatment with valproic acid. Over time, some patients slept better, avoided seizures and seemed a bit more clear to their caregivers; others progressed into end stages of AD and it was hard to tell if there were further seizures unless convulsions were observed by caregivers. [Not all seizures manifest with convulsions; it depends on the part of the brain with abnormal electrical activity and synchronization.] Here’s a 2016 review paper.

Then clinical trials did not show clear benefit of valproic acid for agitation, so I shied away from that second indication for prescribing anti-seizure medication.

From 2014-2015, I was reading EEGs in my small, Hawai’ian private practice, and I saw with my own skeptical eyes that many of my patients with Alzheimer’s disease did have indications of seizure activity, even if none of them had a seizure during the 1.5 hour recording session  (e.g., the tracing shown above).

It was hard to tell from the few patients who could tolerate regular administration of an anti-seizure medication (and believe me, we tried several in sequence on the off-chance that we could clear cognition, even if a little bit), if this improved their lot.

The latest study I’ve seen, which triggered writing this post, seems to back up what I’ve experienced less formally in clinic: Keith Vossel at UCSF  et al. published work showing that patients with early stages of AD are 4 times more likely than age-matched healthy folks to show that evidence of seizure activity on EEG over a 3.3-year period. And those 42.4% of patients in the study with the EEG abnormalities proceeded  into  more severe stages of AD more quickly over the course of the study than the 58% of AD patients in the study with normal EEGs. My takehome messages from this important paper are:

• there may be a role for doing at least one EEG on each patient with AD, even if in an early stage of illness
• it might not be worth doing  that from a cost-benefit point of view unless we can determine a tolerable anti-seizure medication for this population of patients first. As an example, despite warnings that levetiracetam can cause irritability in older patients, there has been some work to show efficacy as an anti-agitation agent.

The Nose Knows?

Parfumier Edmond Roudnitska 1969, Courtesy of Michel Roudnitska cafleurebon.com

Back in the 1990s, loss of sense of smell (anosmia) seemed to correlate with higher incidence of Parkinson’s disease. The literature then seemed to go back and forth indecisively about whether this might also herald Alzheimer’s disease. A Feb 2017 article by Woodward et al. indicates that loss of olfactory sensation, as measured by the authors’ clinical instrument, the UPSIT, has decent sensitivity and specificity for predicting who will evolve from mild cognitive impairment to develop dementia due to Alzheimer’s disease over at least a year’s time. Please note:

• This is not for determining who WITHOUT memory problems yet will develop Alzheimer’s in the future
• This does not distinctly conclude you will know what will happen over the next 12 months if  you have mild cognitive impairment now.

While a completely non-invasive and potentially fun test, it was notable to me that this is not as good a predictor as structural MRI investigations for atrophy (loss of brain volume) but apparently AS good as spinal fluid biomarkers obtained from patients through relatively more invasive lumbar puncture.

Not all doctors’ offices will keep the UPSIT in stock for this clinical use, but feel free to print this and bring it to your doctor to see if s/he recommends you obtain and take the scratch and sniff test. I don’t think insurance will cover this yet.

Agitating for Treatment of Agitation

Treatment-resistant agitation is horrible for both patient and caregiver (professional and informal) quality of life. Dr. Helen Kales, of the WeCare group at UMich has been investigating how we are doing from many points of view, from complementary medicine to the economics of how we try to treat.

As part of her exploration of the why of certain interventions, she reports the Number Needed to Harm, which is the flip side of the coin from Number Needed to Treat. While a low number needed to treat indicates a widespread efficacy of an intervention (pharmacologic or ecopsychosocial), a low number needed to harm indicates high adverse effect rates that might keep you from resorting to that intervention.

Many clinicians (including me) have been loathe to prescribe Haldol, an old “typical” antipsychotic medication, and her statistics bear this out with low number needed to harm (NNH) of 8. Translation: of 8 consecutive Haldol-takers, one will have an adverse event that is clinically significant. Other antipsychotic preparations in common use for dementia have a NNH  = 20-31. Relatively better, but still not ideal.

Despite this NNH info, US nursing homes have NOT been shifting away from psychotropics to better caregiver training, and there is more evidence to support that than any of the psychotropics.

Her group has developed a web-based WeCare advisor resource to try to disseminate the right type of caregiver training. One benefit is to get around the rate-limiting step of treating physician offices not being reimbursed for time spent on this type of caregiver support. The DICE method taught by WeCare reminds me of Baycrest’s ABC approach (Dmitro Rewilak).

What Do Older People Want to Learn?

I was going to add this to the Diversity post, but I think it’s worth knowing across all communities. For those of us interested in developing programs that might be considered perks by research volunteers in Alzheimer’s research, whether taking the investigational product or acting as study partners to those who are, Fabu Carter at the University of Wisconsin ADRC Retention Project reported that the top 3 requests for education from their local Black community were:

• Finances for elders – of course this makes sense, who doesn’t want to learn how to budget with a fixed income?
• Computer skills – could extend to mobile device use. Adult children will breathe a sigh of relief not to have to act as IT help desks for their parents! The researchers brilliantly teamed up with university comp sci folks so they could make use of an already-existing computer lab. The program has been so popular that folks were waitlisted. 
• Gentle exercise

[Note nothing to directly to do with cognitive reserve-building or dementia!!]

Progress in Diversity in Dementia Reported at AAIC

• In a 2016 paper by Elizabeth Mayeda et al.,  a Kaiser health system population was explored for racial dementia rates. Asian Americans had the lowest 14-year dementia incidence (how many new cases are diagnosed for the 14-year period following initial assessment) after age 64 compared to African-Americans, Latinos and whites.  Pacific Islanders, considered separately from Asian Americans (usually lumped together!) were almost as low.
• Corrada has studied “the oldest old” (over 90), and found that 15% live in poverty, and more likely if they belong to minority groups. 25% of oldest old African Americans live in poverty.
• Amy Kind of the Univ of Wisconsin further reported that toxic exposure, access to healthy food options play into the definition of disadvantaged neighborhoods (socioeconomic grouping). Phosphorylated tau (which is the main ingredient of neurofibrillary tangles in Alzheimer pathology) levels are higher from the neighborhoods most challenged by poverty.
• Sebastian Koehler was able follow people who were able to use vouchers to move to better neighborhoods, with good resulting impact on health. 
• Of 110 million people worldwide with dementia, 70% live in low- and middle-income countries. Mortality rates for n= 1488 patients diagnosed with dementia from 8 of those countries (China, India, DR, Mexico, Venezuela, Cuba, PR, and Peru) were followed for 4 years:

1. Male sex, malnutrition and physical impairment figured high in hazard ratios across countries. Of course, severity of dementia also played a role.
2. Mortality ratio  (+dementia vs same age but without dementia) was worst for Puerto Rico and lowest in Mexico.
3. Mortality rate (how many with dementia die per unit of time, typically one year) was highest in China, double the other countries’ rates (not receiving adequate support or care?).

• This report made it into the newspapers during the AAIC week: Zuellsdorf also from UW found: “African Americans (n=82) reported significantly more (mean=4.5) stressful experiences during their lifetime than non-Hispanic whites (n=1,232; mean=2.8, p<.001).” And the effect of the stress was negative predication of frontal lobe functions such as processing speed in later life. Yet to be distinguished: whether that effect is modulated by stroke or by Alzheimer’s disease.
• Hazzouri reported that African Americans aged 45-55 are more adversely affected by elevated blood pressure than other groups are, although Chinese manifested the largest proportion of elevated systolic blood pressure from ages 45-90. Please also keep in mind that researchers have found that having LOW blood pressure is not better for you as you age than higher blood pressure is. 
• Dr. Levinia Lim of Singapore reported on a new mental status test for Asians (work published last year): useful for distinguishing MCI and AD in  Singapore, Malaysia, Indonesia and the Philippines, this instrument is more visually based (language ability less likely to disadvantage the patient), and  lay people can be trained to administer it (one problem in these countries is lack of health care personnel who can provide tertiary care). North American tests currently in use can be less valid among those speaking Asian languages that use pictographs and with lower education levels (not long ago, the statistics showed that 1 of every 5 people on the planet is a Chinese peasant).

Holding our Breath

Travel to Beijing and to New Delhi have been eye-openers in terms of air pollution conditions outside of Los Angeles or Toronto. The World Health Organization has warned that regions with the worst air pollution have major health disparities as well, and this may not just be explained by poverty, low socioeconomic status. Dr Marta Cross-Bou enlightened us on air pollution as a correlate of dementia. How does that risk for dementia work? Data from the ALFA study (based in Barcelona) show that regional metrics for pollution consisting of 1) nitrogen dioxide and 2) oxide, 3) particulate matter, and 4) exposure to noise were compared as negative risks for dementia; access to green spaces was hypothesized as the positive risk. After adjusting for smoking and other known risk factors for dementia, the relatively young sample (mean age 57 years, which is younger than the age at which most people will manifest dementia), revealed a surprise: 

People living in regions with high nitrogen dioxide levels showed BETTER performance on one cognitive test. Particulate matter didn’t show any association with memory performance.  But both correlated with lower parietal lobe brain volume. One interpretation of this finding is that this young sample will not age as well cognitively during the follow-up to this study.

If you’re interested in reading more about the Spanish cohort: The ALFA (ALzheimer and FAmilies) study is a prospective cohort of 2,743 cognitively healthy subjects, aged 45-74, many of them AD patients’ offspring. Anthropometric, sociodemographic and epidemiological characteristics are available for all participants. Episodic memory measured by means of the Memory Binding Test, as well as executive and reasoning functions assessed by WAIS-IV, were administered to assess cognitive performance of participants. Land Use Regression models were used to estimate residential exposure to air pollutants (PM2.5, PM10, PM2.5-abs, PM-coarse, NO2, NOx) and to measure the greenness of the area (Normalized Difference Vegetation
Index).

Frontotemporal Dementia Items from AAIC 2017

My practice in Hawaii and my current position with ATRI have taken me out of the FTD loop for a little while, so it was good to try to catch up with progress in frontotemporal degeneration.

• I see I had missed another change in the nomenclature: FTLD-FET. The majority of FTLDs are linked to either abnormal collections of TDP-43 or of tau, but there is another group called FUS (fused in sarcoma). Enough FTD cases are coming to post-mortem study to allow a re-classification that subsumed FUS: last year, Ian Mackenzie at the Univ of British Columbia published a suggested grouping called “FET” which represents FUS (the F in FET), Ewing’s sarcoma protein, and TATA-binding protein associated factor 15 (TAF15), because the 3 can (but don’t always) travel together. This family of DNA/RNA binding proteins  share functional similarities and can interact with each other. “In all FTLD-FUS subtypes [of his published sample], FUS-positive pathology was also labeled for TAF15 and EWS and cells with inclusions showed a reduction in the normal nuclear staining of all FET proteins.” In contrast, in cases of ALS due to FUS, TAF15 and EWS remained separate from FUS-positive collection.
• Masato Hasegawa presented his work demonstrating a prion mechanism for TDP-43’s spread through brain regions in FTD. This mechanism implies that anti-prion therapy (underway for treatment of multi-systems atrophy) might also work for this type of FTLD-TDP-43. Earlier this year, discussions began on how the undesired protein collections may shift from a liquid phase (theoretically more vulnerable to intervention) to a gel phase (which might prove irreversible). Keep an eye peeled for further discoveries and developments!

The Latest on Cognitive Training’s Efficacy for Dementia Prevention

Elizabeth Stine-Morrow gave her spirited and knowledgeable review of The Perils and Pitfalls of Cognitive Training in Late Life. As noted before in this blog, we’ve been having trouble showing improvement in performance beyond the context of test-taking, to difficulty with finding a transfer of over-practiced skills into real life ability.

Some of these cognitive training activities, if you’re new to this subject, include reading, diversifying one’s repertoire of activities, like learning a new language. One piece of evidence to support these activities, albeit indirectly, is Rohwedder and Willis’ finding from 2010 that older adults in countries with tax policies that discourage retirement show relatively smaller cognitive declines. The title of the paper is Mental Retirement(!).

I liked her explanation of  Senior Odyssey‘s goal for a reverse transfer trial. That is, what if you supervise problem solving activities, will that improve cognitive test scores?  Creative problem-solving or inductive reasoning training as a daily exercise was offered for 6 months prior to a competition. Kinda like camp, with costume design and skits. Those participants then tested better on cognitive instruments! At the very least, this sounds like a worthwhile activity that encouraged socialization along with the training.

Dr. Stine-Morrow was part of the team that systematically reviewed 132 papers after Lumosity claimed to have proven efficacy in dementia prevention. The paper, Do Brain-Training Programs Work? reported that the studies were mainly correlational and not proving cognitive training as a cause for lowered dementia incidence/risk. Many studies didn’t include adequate controls are only measured practice effects (follow-up testing too close to training).

Despite the encouraging findings from the Senior Odyssey project, Dr. Stine-Morrow’s bottom line remained: the evidence is still insufficient  to drive cognitive training as a proven deterrent against dementia.

Good News, Bad News about our Progress in Prevention for the Aging

I was caught in a freakishly large wad of travelers through Oslo’s airport yesterday afternoon. It is so beautiful here in Norway on the fjords, that I understand why. And an upside of the long line was that I had time to speak with those near me. A couple from Alabama asked whether we were any nearer to a cure for Alzheimer’s. The quick answer is no, but the more encouraging piece of news, I think, is from  Dr. Carol Brayne and her group.

Those who were elderly (let’s say over 70) in the 1990s were exposed to different stressors and wellness information, when compared to those who’ve been over 70 in the last 5 years. The  good news in the comparison: The incident rate* of cases between recent and 90s cohorts dropped by 20%.

*Please recall that prevalence refers to how  many people now have a disease (regardless of how long they’ve had it, diagnosed yesterday or diagnosed 5 years ago). Incidence is a more up-to-the-minute look at how often a diagnosis is being made per population group (typically per 100,000 people) per year.

Dr. Brayne explained that even when loss to follow up or death is accounted for (survivorship bias is removed), that difference still holds. Dementia prevalence has declined too. The reason that you may not be seeing this in your own experience is that the absolute numbers of people affected are higher, because the proportion of aged population has grown.

Important note that was echoed throughout the conference: the most socially disadvantaged groups among us have not seen this improvement from one cohort of elderly to the next. More on that in another post.

Amnestic mild cognitive impairment (MCI), meanwhile has increased in prevalence between 1991 and 2011.

The data don’t allow us to jump to the conclusion that people are doing better more recently because we are holding them back from dementia within an early stage of amnestic MCI, but it is tempting and wishful to think that way.

• Head injury, depression and diabetes as risk factors for dementia haven’t changed in 20 yrs.
• Female sex now has relative risk of > +1.2 (was -0.4 before)! So I will have to change my tune. I have long maintained that the prevalence was higher in women but incidence rates were the same as for men.
• Smoking now worse as a relative risk also. 
• Lack of friendships no longer appears to bear risk. (But don’t turn people away if you do have friends! Dr. Fiona Matthews explained that decrease in relative risk occurs as any attribute becomes more commonly found in a cohort. The flip side of the same explanatory coin is that smoking isn’t now worse for people than it ever was; it’s just that with fewer smokers, the formula for relative risk (RR) within a study group will result in a higher RR number. The same logic may apply to RR of being a woman…)
• By the same token, please don’t believe that NOT drinking has a negative effect on dementia risk (yes, I am purposefully writing in double negative)…This was further explained by the acknowledgment that people who don’t drink may not do so because of other poor health conditions that make more sense as dementia risk factors.

Bottom line: Beware attribution of causality where it doesn’t belong! Many epidemiologic studies show us correlations, as opposed to confirming causes.