How to Read the Newspaper

This is excerpted from The Memory Clinic. Although published back in 2013, I find myself circulating this to folks who email about articles they see in the paper.

Appendix 1

Do-It-Yourself—Believing the Newspaper Headlines

 If I could wave my magic wand, I would imbue each caregiver with the ability to sort critically through the information on dementia “breakthroughs” available on the Internet. Although they are reading with some caution, caregivers forward all sorts of cure claims they find on the Internet to me for an opinion. Some of this spurious material even makes its way as links onto otherwise trustworthy websites.

Here are some general rules of thumb you can use to evaluate whether the information is valid. If the article is about diagnostic testing, you’d like to see:

  • Validation of the test between people who have the illness confirmed by autopsy and an age-matched sample without the illness
  • Validation among participants who resemble your demographics (age, sex, race, ethnicity) and risk for dementia (presence or absence of family history)
  • Availability of the test to the general public—It may be exciting and promising, but where is it being conducted and what does it cost? New technology typically comes at a price and is not necessarily covered by your health insurance

If the article is about a new “breakthrough” treatment, it should explain:

  • Were the participants included in the study affected by the target illness? Was the diagnosis made by the same guidelines that your doctor is using for you? There is a difference to you in results from a study conducted on patients at risk for a disease versus patients already diagnosed with the disease. Both types of studies may be valid, but the applicability of the results to you may differ. My patient Mimi recounts on every visit the findings of a Reader’s Digest article in which a patient with Alzheimer’s disease had a curative surgery. She insists she wants “someone to go in there [knocking on her head] and fiddle around, to bring back aaaaaall my memories.” But even if the surgical result had been replicated in a decent number of Alzheimer’s patients (it hasn’t), Mimi doesn’t understand that she does not have Alzheimer’s disease. The article doesn’t pertain to her.
  • Is there a good rationale behind the use of the test drug? Researchers try to use logical means against the target illness—if we can’t justify that the intervention acts on something with a known association to the disease mechanism (e.g., the abnormal protein, or a biochemical process known to be deranged in the dementia), you’d need to be sure the study was soundly designed to take much meaning from the study. Sometimes the rationale is based on observation; the curcumin trials arose from the observation that those who have an East Indian diet with a large amount of curcumin were at lower risk than others internationally for Alzheimer’s disease. This led to a diet intervention trial and simultaneous bench studies checking the effects of curcumin on phosphorylated (sticky) tau.
  • Was the study designed to test the drug against a placebo or another drug considered the current standard? The FDA and other public health drug agencies typically will not approve the drug unless it has shown clear superiority over a placebo or at least equivalence against another drug already available.
  • Were the outcomes of all the enrolled participants detailed? Sometimes the study is positive only for a small segment of the population and the other participants dropped out before the study ended, which skews the final statistical analysis. It’s important to know who dropped out in case you more closely match that group than you do the study-completers.
  • If there were a lot of study drop-outs, did the investigators calculate the results by bringing the last observation forward? This is the authors’ way of acknowledging that there were some hold-ups in the study for participants.
  • Sometimes participants leave a study early because they are experiencing adverse effects. What were the side effects of the drug reported in the study? Are they life-threatening? Did they occur with the same frequency in the placebo group? Even if there is a high risk of a few side effects, the benefit of the drug may outweigh the risk in individual decision-making. The relative economics of pharmaceutical drug decision-making is a new science unto itself. The fact that most dementias occur in elderly persons who are at high risk of mortality due to age alone can shift the decision-making algorithm for some families.
  • Is this article aimed at caregivers seeking affordable treatment, or at venture capitalists looking to invest in a drug that will sell well? The time from the end of Phase I to the end of Phase III when the drug can be widely accessible with a prescription can run 10–15 years minimum. When the newspaper headline proclaims, “Breakthrough!”, check to see if they’re talking about a pre-clinical, Phase I, or Phase III result. A breakthrough announcement in the newspaper may predate a prescription drug on your pharmacist’s shelf by 20 years.
  • There’s a difference between “statistically significant” and “clinically significant.” If you can afford to enroll thousands of patients in a clinical trial, that number can influence the statistics to highlight a very small difference that would not be just a chance finding. That is a statistically significant difference. If my experimental intervention were to wave hello to each patient every morning in passing, and 1,800 of the 2,000 patients showed a change in blood pressure from 170/85 to 165/85, the investigators could report a statistically significant reduction in blood pressure (it did go down!) from a “therapeutic wave.” This amount of change in blood pressure doesn’t make much of a difference in life outcomes like stroke, heart attack, or sudden death. This finding therefore wouldn’t necessarily be clinically The most responsible of investigators would choose a clinically significant amount of change (e.g., a larger drop from 170 to 140 in systolic blood pressure) before performing the study, then would report that they found only statistically significant change at a level below clinical significance when they published the results. A responsible scientific journal’s peer reviewers would insist that the results be stated in this balanced way.
  • Is the newspaper or a health website the only place where the results have been published? If so, peer researchers may not have agreed with the design, results, or phrasing of the report from the
  • “What is the drug?” is important, but emerging work is also proving that “When is the drug useful?” is just as important. Consider the complexity of estrogen supplementation, for instance. We are still at the stage of discovering which abnormal protein collections are key to target with treatment first. Although Alzheimer’s disease patients have abnormal tau and amyloid, it is not clear which target should be the priority, and the answer may differ depending upon the age of the patient or level of cognitive impairment already in place.
  • Whether it’s a drug or a lifestyle intervention, the same questions above should be applied to the There are some suggestions that will seem like “common sense,” such as, more exercise is better for you, but this may not be applicable to a patient with terrible arthritic pain on walking, or it may have greater impact at a different time of the lifespan than the one you’re now in.

Newspaper articles often bear word limits and cannot express all these details. They will tell whether the study was an open-label drug study (implying no placebo arm) or placebo-controlled. To answer the critique questions, you may have to go to the original articles themselves, which are often available online through a hospital or university library. To get into print, studies must detail all of these parameters. Peer reviewers demand it. When in doubt, ask your doctor to help you interpret the applicability of the new findings to you specifically. It’s what we are trained to do.

 

 

San Diego Still Serious about Tracking Wanderers

Blogged about this in September of last year – they’re still offering FREE GPS trackers to patients with dementia. Please click here for more info! Sponsored by a grant to the Alzheimer San Diego group. Bravo!

I have written a few caveats about the use of GPS trackers previously in this blog-

https://drchowftd.wordpress.com/2014/08/07/wandering-unfortunately-unpredictable/

https://drchowftd.wordpress.com/2013/08/24/whereabouts-gps-for-locating-patients/

Is There a Science to Forgiveness?

 

I would argue that Forgiveness is more of an Art than a Science, but I do like evidence presented by Dezutter et al. that older adults who have been able to forgive are less likely to have significant depression. And we should all keep in mind that depression has a definite effect on dementia risk and dementia symptom severity.

See a very nice lay summary of the scientific paper here. I especially like the idea of “making peace” before a final peace is enforced upon us.

Men and Women Doctors – Is there a difference?

blog_20161220It’s been forever since I heard this question posed or discussed. 20+yrs ago, there was a lot of support and mistaken assumption that women physicians were uniformly more compassionate than their male counterparts, and I’m delighted to see in the conversation in this recent NPR piece that men were spoken for favorably. But interesting finding: women Internists (note, this isn’t neurologists or surgeons) had better 30-day hospital (not outpatient) mortality rates than the men.

See the paper: Tsugawa et al. Comparison of Hospital Mortality and Readmission Rates for Medicare Patients Treated by Male vs Female Physicians. JAMA Intern Med. 2016.

 

Tau PET Imaging with AV-1451 Related to PSP and CBD

Maybe not so helpful for PSP since only deep basal ganglia areas were marked, creating non-specific results. 

Corticobasal degeneration cases thus far are showing variable patterns- raising questions of whether better diagnosis was Alzheimer’s disease for some patients, why the more atrophied side of brain didn’t show more tau deposition? The latter would imply lack of correlation between radioligand binding to target proteinopathy and disease severity. 

Click here for more about the expectations for tau PET. For more detailed results, see Smith et al. in press with Acta Neuropathologica 

I’m Changing my Mind about Stem Cells

stemcell

Image from http://americanregen.com/stem-cells-therapy/. Use of this image is not an endorsement of this business

Whereas I had previously been quite doubtful that researchers would ever be able to grow fresh brain that could meaningfully connect and restore function to a brain with Alzheimer’s disease, I now see that the goals of stem cell infusion have shifted. Presenters here at CTAD are showing that an IV infusion of human mesenchymal stem cells can change the inflammatory conditions within the brain. This is a very different goal from creating an internal brain transplant. Researchers from Lausanne, Switzerland; University of Miami; and UC Irvine were all invited to present during this symposium.

  • Mesenchymal stem cells (MSCs) tend to settle into lung and liver first after infused…but after that first pass through circulation, they may land closer to areas relevant to Alzheimer’s disease, such as in the hippocampus (deep medial part of the brain that is an epicenter of Alzheimer’s changes)
  • They don’t seem to evolve into teratomas (turn into tumors) over time in the first human studies thus far; no more serious adverse events related to cancer or tumor than in placebo groups
  • Even if the MSCs stay below the neck, there is emerging evidence that an inflammatory reaction down in the gut may be related to amyloid processing problems in the brain. Harach and Bolmont suggest that cooling off the gastrointestinal inflammatory response might change the course of Alzheimer’s pathology. I haven’t seen enough about this to applaud thinking way out of the box or to poopoo, but we are progressing so slowly along other therapeutic streams that tempered open-mindedness is likely to help  move our field along
  • We’ll need to see if there’s consistent and trackable crossing from bloodstream into the brain, and if this is a necessary process for benefits to Alzheimer’s disease to arise
  • I was very pleased that Dr. Pierce (UCI) began her talk with reiterated warnings that the evidence is still at a very preliminary stage. We still do not encourage patients to go within or outside of the US and pay privately (and handsomely) for stem cell administration. See prior post.

Animal Model Work (Next Stop, Human Patients?)

lab-mouseAlso presented at CTAD 2016 in San Diego:

XG-102 inhibits toxic kinases (PKR and JNK3). Transgenic mice seem to respond well to administration of the inhibitor. Mechanism of action may work on neuronal apoptosis due to pTau, neuroinflammation, and enhance BACE inhibition. Has only been tested in health males, proved tolerable thus far…

New method of drug delivery? Nanowires may provide a way to get a compound across the blood brain barrier. Sharma et al. have introduced cerebrolysin (a neurotrophin “cocktail”) and neprilysin into the brain via nanowires, that is tiny titanium “yarnballs” infused with the drug of interest are floated in a solution which can then be injected into the ventriclesfantastic-v of the brain or even into the bloodstream. This reminds me of the Fantastic Voyage,
but 1) it’s not clear what the best molecules to deliver as a long-term continuous-release for Alzheimer’s disease might be and 2) whether we need to get those yarnballs back out after a certain period of time and how we would do so.

Radiation oncology is exploring in mouse models whether cranial irradiation (as if the person has a brain tumor) addresses amyloid buildup. That of course raises issues about increasing the risk of brain tumors, but per Dr. Fontanesi, there is evidence that Down Syndrome adults who had radiation early in childhood did not have the expected levels of amyloid (most Down Syndrome adults older than 33 develop Alzheimer’s disease that is amyloid-heavy). Watch for work by the Michigan group in Farmington Hills. Given study participant hesitation to undergo PET imaging because of radiation concerns, I’m not sure whethe rthis potential therapy has legs, but let’s see.