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.

Resveratrol Update, December 2016

“Broadcasting” from the Clinical Trials in Alzheimer’s Disease (CTAD):

Dr. Scott Turner from Georgetown University presented more results of a multicenter resveratrol study. He and the investigative group had already published initial results in 2015, but in this presentation,  some intriguing explanations were offered for the finding that those taking the resveratrol (as opposed to placebo) showed more brain volume loss (3% shrinkage vs 1% in placebo group). Multiple sclerosis researchers encouraged Dr. Turner to see  this result as a different kind of drug efficacy in anti-inflammation. When they examined markers of inflammatory processes, they believe that the baseline brain volumes may be indicative of swelling (think of how your knee blows up when irritated or injured) and that the decreases in brain volumes show a normalization, as opposed to a worsening, with resveratrol.

sketch-drawing-wine-bottle-glass-vector-illustration-33426233The type of resveratrol used was a capsule of synthesized product, not an extract, administered in doses up to 2000mg per day (1000 bottles of red wine worth of resveratrol daily). The study length was 1 year in patients diagnosed with AD (average 4 yrs duration). Poor bioavailability is one reason for the high dose necessary.

Another piece of the study that might or might not support the anti-inflammatory efficacy of resveratrol was the observation that the drug group had lower incidence of cancer over the yearlong study than the placebo group.

Analyses, planning  for follow-up study pending. Not yet available on shelves.

Some fun facts:

  1. Dr. Turner’s audiovisuals were completely interrupted mid-talk, keeping the audience of edge of seats for over 20 minutes. He’d only just turned to the first of his Results slides! I’m archiving this demonstration of grace under fire into my presenter memory bank. As if in compensation, he received email during this attempted talk from the editors at Journal of Inflammation: the anti-inflammatory slant on their results have been accepted for publication.
  2. Dr. Rissman at UCSD handled the inflammatory biomarker assays that may ultimately bear out the story above. When they were setting up the trial design, needing to anticipate the blood levels of resveratrol after ingestion of the supplement required some creative maneuvers. Dr. Rissman sacrificed himself (he’s that kind of guy) by chowing down on a few Wine Time chocolate bars with resveratrol (sorry, may no longer be in biz), then drawing his own blood at regular time intervals to develop the pharmacokinetics for the study.

Methylene Blue Trial Conclusions

One therapy that aims at abnormal tau and therefore might be useful both in contexts of Alzheimer’s disease and FTD has unfortunately NOT shown significant efficacy in either dementia. The anti-tau agent was leuco-methylthioninium aka LMTM.

You may recall some buzz about this in late July: a trial in Alzheimer’s disease was negative, but the investigators were criticized for trying to make a case that a sub-analysis showed some good effects in  those participants who were taking only the investigational product and NOT typical Alzheimer’s standard of care. The level of evidence provided was NOT enough to get this drug approved by the FDA or for clinicians to stop FDA-approved medication to institute LMTM instead.

At the Munich International FTD Conference last month, results of a similar clinical trial but for participants with behavioral variant FTD were announced.  The CEO of the pharma company , Claude Wischik, reported no significant benefit for this group either.  Dedicated groups will continue the search.

Bloodtests for Tracking FTD Progression

For similar report applicable to Alzheimer’s disease, click here

Rohrer et al., an international collaborative that has been studying biomarkers and genetics in FTD, reported in late September that assaying serum for neurofilament light chain protein still holds promise. The UCSF group had presented some preliminary work in this area a few years ago, based on measurements from cerebrospinal fluid (which typically requires lumbar puncture to obtain). Now, just 2 years later, there may be a way to get this useful information through a blood draw.

The authors warned:

  • there was a lot of variability seen in measurements subgrouped by type of FTD (e.g., behavioral variant vs PPA)
  • while the serum level of neurofilament light chains increases as the size of the frontal lobes shrinks, more work is needed to know how predictive or diagnostic this measure can be.

The Paper: Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology. 2016 Sep 27; 87(13): 1329–1336. doi:  10.1212/WNL.0000000000003154

Frontotemporal Dementia: Tracking Changes over the Course of Illness

O’Connor et al. (Australian group) followed and compared participants with behavioral variant FTD and semantic dementia (AKA semantic variant PPA) for 2- 4 years. In addition to looking at worsening of behavioral symptoms over time as we had done with data from UCSF, then Baycrest, these authors drew correlations between particular behavioral disturbances and ability to maintain one’s own activities of daily living. Of interest, but probably not news to you caregivers, was the finding that disability was not so related to disinhibition, but very much correlated with apathy. And counterintuitively, mental rigidity and compulsions in participants with semantic dementia (not bvFTD) seemed to bolster activity engagement.

I regret we don’t yet have a good symptomatic therapy for apathy despite its fairly unanimous priority as a symptom to target in therapy.

The paper:  Longitudinal change in everyday function and behavioral symptoms in frontotemporal dementia. Neurology Clinical Practice