International Society for Frontotemporal Dementia Conference – Vancouver

The bi-annual international conference on FTD that features content for both scientist/clinicians and caregivers has begun again.

In the pursuit of blood tests that can detect mutations responsible for FTD, Dr. Rosa Rademakers has found a disconnect between levels of blood markers for Chromosome 9 mutation orf72 and levels in brain tissue markers. This means that testing for this mutation’s severity won’t be possible through a relatively easy-to-obtain blood sample. Such may not be the case for other genetic mutations associated with FTD, but it is an important new point to guide the search for early detection methods.

Dr. Rademakers’ lab has done all sorts of work to elucidate how that C9orf72 gene can lead to the brain deterioration, and one important new clue is that homeobox genes, which work neuronal repair and regeneration, seem to respond to the C9orf72 abnormality. Do those homeobox (“HOX” if you want to google or pubmed search it) genes need a boost in order for patients to compensate for their dementia? These results are so fresh that they are being presented in posters at the conference, which often precedes their publication in a medical journal for 6-12 months.

International collaboration to consolidate progranulin mutation carriers (different chromosome and gene from C9orf72) has brought 555 mutation carriers DNA together for analysis – more to come in the future. The largest families with FTD have yielded the previously described progranulin, C9orf72, fused in sarcoma (FUS), MAPT (tau), CHMP2B, or valosin-containing protein (VCP) mutations. This is roughly 20% of known FTD cases followed in Antwerp.
The Mayo Clinic (Dr. Rademakers’ home base) has 170 brains from patients with TDP-43 proteinopathy (frequently a result of progranulin mutation), and whole-genome sequencing is under way. This has identified 2 new mutations related to the ALS-variant of FTD, a mutation on chromosome *10* in a gene that codes for protein optineurin (OPTN). A candidate gene under examination but NOT YET PROVEN to have a strong or likely causal association to FTD is KIF-17.

Dr. Christine van Broeckhoven from the Univ of Antwerp reported from her lab:

  • in their search for which genetic factors determine the earlier ages at onset of FTD, they have not seen a role for serum levels of progranulin protein. Instead, it seems that one particular part of the genome may be responsible for assigning a person’s onset age. The next steps are to correlate this with something more easily identifiable in either serum or cerebrospinal fluid (obtained through lumbar puncture).
  • Among cases with C9orf72 mutations, they report that short repeat sequences seem to be more associated with anticipation between generations, which is the phenomenon of a child having earlier onset age than an affected parent. This is significant as the opposite of what happens in a disease like Huntington’s, in which more repeats means earlier onset of illness. If you’re a genetics junkie, you may be interested to know that the degree of repeats affects the methylation status of the DNA processing.
  • another candidate gene, FLNC, makes protein filamin C. The expression of this gene is increased in TDP-43 patients, so it may be a secondary villain in taking down the integrity of cell structure and ability to communicate.
  • another candidate gene: VPS13C may work independent of the aforementioned genetic mutations. It’s been identified in a few families and some patients without family history. Dr. Stephanie Philtjens reported further on the clinical presentations of patients with this mutation. Onset ages were 62 years on average, with two cases manifesting in their early 40s. About half of patients were women, no gender bias. There is decreased VPS13C protein in patients with the mutation, but what the protein is normally doing in relation to preventing dementia remains unclear. There may be a link to Alzheimer’s disease as well. Genetics junkies may recall that CHMP2B is another gene for VPS, which has an established link to FTD.
  • work continues to understand how mutations in SQSTM1 lead to ALS or other neurodegenerative disorders. This one doesn’t have a single association to illness; variants in the mutation lead patients to different fates.

    Carrying on from the SQSTM1 theme above, Dr. Paul Taylor described ongoing work on the association between inclusion body myopathy (IBM), Paget’s disease of bone, and familial cases of ALS. Matrin 3 mutations can be responsible for this presentation, but Dr. Taylor has been working most on VCP. The protein will ordinarily act as the remodeler of multimeric complexes. That’s a mouthful that I can really only translate for you as helping to keep working surfaces within the cell functioning to traffic proteins appropriately. In the presence of the mutation, cells pocket TDP-43. For genetics junkies, VCP in this context is gumming up hnRNPA species 1 and 2B1.
    The exciting part of this work is the similarity of glycine-rich segments of the hnRNPAs to yeast prions. You may have heard of prions before, in the context of mad cow disease or Creutzfeld-Jakob disease. Neil Cashman out here at UBC has been arguing in favor of a prion mechanism turning dementias (not just FTD) on at a certain point in life, based on genetic vulnerabiltiies and environmental exposures. Dr. Taylor explained that the prion-like portions of the hnRNPAs may be the place where that switching-on may transpire, resulting immediately (at least in his videos) of key proteins precipitating out of solution into granules loaded with proteinopathy! The good news is that the switch can go in the other direction, OFF, so his lab is hot on the trail of how to control that switch. In a Petri dish, they can use a laser to disassemble the granules, but the presence of VCP locks the switch to ON.

  • Follow-Up Report for Non-Fluent PPA Intervention

    I’ve posted before about the promising work of Dr. Roy Hamilton at Penn. In Spring, he described an ongoing trial of tDCS (a form of non-invasive brain stimulation) to suppress a small area of the brain’s right hemisphere to enhance speech. At that time, he had positive effects on fluency when an instrument called the Western Aphasia Battery was used before and after the treatments. A paper on this same intervention used in the context of aphasia resulting from stroke has already been published. I hope there will be a further update for PNFA at the international FTD conference, which starts tomorrow in Vancouver.

    Having a Conversation with a Patient

    There are many times that friends or family members would like to visit the patient but don’t quite know how to start a conversation that will be meaningful or adapted to the patient’s communication ability. There’s help available: Very specific how-to info in Claudia Strauss’ Talking to Alzheimer’s: Simple Ways to Connect When You Visit with a Family Member or Friend. It’s actually been around since 2001, but the advice holds true.

    A New Insomnia Intervention

    In August, 2014, the FDA approved suvorexant, which has a different mechanism of action from other “sleepers” available through prescription or over the counter.

    At the American Academy of Neurology meeting in Philly, May, 2014, investigators announced the results of a year-long trial of the new oral medication in patients with insomnia of a wide range of ages. Some of you already know through experience that most of the “sleeper” medications we prescribe either lose efficacy after a few months or have intolerable side effects of daytime sleepiness or enhance rebound insomnia on cessation of the drug.

    The intriguing mechanism of action of the new agent is that it interferes with a brain chemical called orexin. Orexin is secreted and taken up by target neuron receptors to keep one awake. The drug has anti-orexin activity that might sidestep some of the problems in currently available sleepers. The data support not only shorter time to fall asleep, but also ability to stay asleep through the 2nd and last thirds of the night. And the drug worked for study participants for the entire year-long study period (not just a few months).


  • Patients with narcolepsy have the opposite problem – they can’t get enough orexin connection in the brain. The studies on suvorexant thus far have had no participants develop narcolepsy or cataplexy (related condition).
  • There are many non-pharmacologic considerations that should be addressed before we resort to a sleeping pill, regardless of the side effect profile. We need to make sure that we are not putting a bandaid on an underlying, treatable problem that causes insomnia as a sidenote.
  • Knowing many of your stories, it is not yet clear to me whether the patient with insomnia, the caregiver who’s being woken up by that patient, or both should get prescriptions for this agent.

  • What Will You Do When You Can’t Drive?

    Breaking my wrist last year grounded me from driving my stick shift car. Luckily, I was living very close to a major public transportation hub and I had lots of friends with cars whose schedules coincided with mine. I considered it a reminder to plan ahead for retirement, when my eyes or reflexes or mind might not be up to the task of independent driving.

    The NY times gave this topic some good air time/column space recently. Click here for important considerations for either your aging parent or your own future. I especially like the idea of driving others now for future ride credits!

    Tech to Support People with Cognitive Impairment

    This device requires that the person can still read:

    but might be helpful for those families who feel they’re repeating information constantly. There are other setups out there on the market, and I do not at all intend to be endorsing this one above the others- I have not personally compared them! I do like that they realize that patients with traumatic brain injury and with dementia may have some needs in common. And that there’s very little setup for caregiver to do, device supposedly turnkey.


    Care near End of Life

    Kudos to the Dutch team that is raising awareness about how pain and agitation are seldom relieved in the last week of a patient’s life. See comments by Drs. Jenny van der Steen and Shega in Neurology Today. Beware of pain medications appearing on the nursing list  to be given only “as needed” or prn; if the patient doesn’t ask for it, s/he doesn’t get it, and what patient at that stage of illness can ask?

    This article is part of a growing movement to acknowledge that most of what we do after making a diagnosis of dementia is palliative, that is, meant to enhance quality of life where there is no cure. I am hoping that we can destigmatize the word “palliative” over time.

    UK-Based Early Onset Dementia Online Resource

    In the UK, they call it Young Onset Dementia (YOD), as opposed to Early-Onset Dementia. Here’s a link to their information and support. Includes personal stories, blogs and poetry written by patients and their carers, plus links to relevant publications and other useful websites.

    Editorial comment: this is the first site I’ve seen that has video content and invites patients to share from their own experiences, although I do know the Alzheimer Society in Canada has created in-person support groups for patients with mild stages of early- and late-onset dementia.