Amyloid, a protein found in some but not all with dementia, can be targeted in several ways; drug companies have scientists creating specific (monoclonal) antibodies for therapy trials. The Lilly company has one called donanemab, which targets amyloid differently than does aducanumab (Biogen) or solenazumab (also Lilly), and it’s creating some BUZZ for the new year.
This week Lilly released early results of an on-going Phase 2 study that they interpret as looking positive. Subjects were already having dementia symptoms, and some showed “slowing of decline” [not improvement] in both cognition and function. The medication improved PET scans (as have other monoclonals); sadly that doesn’t always correlate with clinical improvement. About a fourth of subjects who received the drug had brain swelling / edema.
Slowing progression would be an admirable and substantial achievement; studies in Sweden show that donepezil and memantine might slow entry to nursing homes but may not affect time to death. It might be the first real step; others might see it as palliation. After all, the monoclonal bevacizumab is FDA approved for slowing the progression of glioblastoma brain tumors, allowing about three more months of survival in a pivotal trial. It did not change overall survival.
Other meds have done well in Phase 2 but don’t make it out of Phase 3. Let’s hope for the best for the new year!
Ever wonder how a neurologist approaches a new diagnosis of dementia? An instructive example was just published; the ultimate diagnosis in this case is rare and tragic (as usual), but the format is revealing.
On the last day of 2020, the NEJM published this: “A 62-year-old, left-handed man was seen in the memory disorders clinic of this hospital because of memory loss, personality changes, and odd behavior.” The format is a “CPC” or Clinicopathological Conference. It presents a medical puzzle to an unsuspecting professor, usually in front of an auditorium full of faculty and trainees.
The way the discussant wows the crowd is by displaying astute medical thinking and describing an extensive differential diagnosis…i.e., listing all the things a certain patient might have, but in the end, making an educated guess at the diagnosis. Usually she or he suggests a definitive diagnostic test. After the discussion, the test result is revealed, and the final diagnosis is presented by pathologists (I think the CPC was invented by a pathologist, they always come out great). So, if you like that kind of thing, the NEJM has presented CPCs for decades.
The behavior by this man included work errors, using a colleague’s vehicle without permission, “…urinating in public on a few occasions and frequently and unexpectedly visiting family members’ workplaces and neighbors’ homes at late hours… The patient was unaware of his inappropriate and unusual behaviors.”
The discussant Dr. Bruce H. Price of McLean Hospital does a nice job displaying how a neurologist might think given these kind of clinical problems. He mentions the nuances of tests like the Montreal Cognitive Assessment (the process might reveal apathy), and the many possibilities in diagnosis, from syphilis, Lewy-body dementia, and the frontal variant of Alzheimer’s.
AdGadfly hopes you can open this link, there are a lot of clinical details: https://www.nejm.org/doi/full/10.1056/NEJMcpc1916251?query=featured_home
Since the link may be behind a “paywall,” (perhaps available through a public library?) here are the answers: TEST: MRI Brain (no PET scans mentioned). CLINICAL: Behavioral variant of frontotemporal dementia; PATHOLOGICAL (at autopsy): Frontotemporal lobar degeneration with tau-positive inclusions (FTLD-tau) consistent with Pick’s Disease. Interestingly, there was very little amyloid. [The picture above is not from the CPC, but looks similar to one of the MRI images shown.]
“Management” for this individual included an anti-depressent sertraline which has many effects, to help with impulsivity, along with a sleeping agent, but generally it was emotional support for the patient and family, since there is no disease-modifying therapy. It is a progressive dementia, but the unusual, regional pattern of brain atrophy in the frontal and temporal lobes begs a lot of unanswered questions. There may be a genetic link for some in the MAPT gene. Normal brain for comparison to picture above:
Frontal Lobe, Pre-frontal cortex (PFC)….sound familiar? There is a fascinating hypothesis about the role of the still-developing PFC in adolescents as an explanation for fun-seeking impulsivity, executive process and judgment issues. Nice contrast to a grumpy old curmudgeon like AdGadfly himself…