Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I, Attems J, Brayne C, Coyle-Gilchrist IT, Chui HC, Fardo DW, Flanagan ME, Halliday G, Hokkanen SR, Hunter S, Jicha GA, Katsumata Y, Kawas CH, Keene CD, Kovacs GG, Kukull WA, Levey AI, Makkinejad N, Montine TJ, Murayama S, Murray ME, Nag S, Rissman RA, Seeley WW, Sperling RA, White Iii CL, Yu L, Schneider JA. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. 2019 Jun 1;142(6):1503-1527. PubMed.

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Comments

  1. This is a thoughtful summary of the numerous reports and findings over the last decade on TDP-43 pathology restricted to the limbic system common in elderly patients and often associated with hippocampal sclerosis and/or Alzheimer’s disease. While this paper is thought-provoking and important to promote research and awareness of this type of pathology and comorbidities, I also have the following concerns.

    1. I wonder whether it is suitable at the current time point and knowledge to introduce and promote a catchy name for a new disease entity, “Limbic predominant age-related encephalopathy (LATE),” when in fact, all we have is the presence of postmortem neuropathological findings of limbic predominant TDP-43 pathology (often together with other pathological changes). They might be associated with a distinct clinical phenotype that, however, still needs to be defined. So in other words, how useful is the introduction of a new disease that is defined and can be diagnosed so far only by neuropathological findings obtained postmortem? An alternative approach might have been to introduce a consistent term and definition for this type of pathology e.g. “limbic predominant TDP-43 pathology,” followed by describing the next steps towards defining the clinical impact and potentially associated syndrome of this pathological condition.
    2. One important issue which is unfortunately insufficiently addressed is how the neuropathological features in FTLD-TDP should be distinguished from LATE. Based on the proposed LATE-neuropathological change criteria, in my understanding all patients with FTLD-TDP and most with ALS-TDP would fulfill the criteria for LATE-NC.

    View all comments by Manuela Neumann

  2. TDP-43 was first discovered in 2006 as a ubiquitinated protein associated with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Since then it has been found to be associated with many other diseases, including Alzheimer’s.

    I have been involved with TDP-43 research for over a decade, having been the one who first demonstrated that TDP-43 is indeed associated with memory loss in Alzheimer’s disease, way back in 2008 (Josephs et al., 2008). I do believe that TDP-43 is a very important protein, equal to, or greater than, amyloid and tau in importance. TDP-43 has been under-recognized by an Alzheimer’s establishment that can’t seem to get beyond amyloid and tau. The construct of LATE will give TDP-43 the recognition that it deserves and hopefully bring TDP-43 to the forefront of Alzheimer’ disease research. 

    That said, LATE is not a new disease. It may not even be a disease, given that 20 percent of individuals who die with normal cognition will have LATE. Instead, LATE is a rebranding of science, a catchy acronym, but if you can get by all the hype, it is really just TDP-43 in the brains of old people, including those with plaques and tangles.

    References:

    Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, Rademakers R, Boeve BF, Parisi JE, Smith GE, Ivnik RJ, Petersen RC, Jack CR, Dickson DW. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology. 2008 May 6;70(19 Pt 2):1850-7. PubMed.

    View all comments by Keith Josephs

  3. From my perspective as an epidemiologist who has sought to lead studies that provide a platform and insight into what dementia really is in the true population, this work has been incredibly important, and at last begins to move us on from the narrow focus of traditional Alzheimer’s disease neuropathology and their mechanisms.

    It’s clear there is so much more, particularly for the older old populations. For too long, millions of dollars have been chasing an idea of mechanisms with elegant research that is aimed at an assumed pathology instead of looking at what is really there in the population. This paper helps to shift the narrative.

    View all comments by Carol Brayne

  4. In the older population amongst whom most dementia occurs, the relationships between clinically defined dementia and the variety of neuropathologies seen in the brain have long been acknowledged to be complex. There are those with very little pathology and dementia and those with severe pathology and no dementia. Additionally, the majority of those with dementia in the older population have mixed neurodegenerative and vascular pathologies, making the diagnosis of specific dementia-causing processes difficult.

    Beyond the traditional focus on tau and Aβ, TDP-43 is increasingly being seen as an important contributor to the risk of developing dementia. As with the Alzheimer's disease-associated tau and Aβ pathologies, TDP-43 is seen in those with and without dementia. The full range of TDP-43 pathology across the whole brain in relation to dementia in the population has not yet been fully described.

    This lack of clarity, coupled with a lack of biomarkers specific for TDP-43, leads to difficulties in selecting well-defined and meaningful cases and controls both for research and for randomized controlled trials.

    The LATE consensus working report highlights again the complex presentation of dementia in the human population and focuses attention on the need for better research in humans to characterize the wide range of neuropathologies and their contributions to dementia.

    View all comments by Sally Hunter

  5. Hi, a few quick comments ...

    1. The consensus working group report on LATE was that—a distillation of what an international, multidisciplinary group could agree on.

    2. The goal was not to produce a trendy new term. For me personally, a key goal was to have a diagnosis that could be made in a meaningful way. For example, at our center, we just signed out nine cases and four demonstrated what I can now call LATE-NC. It is not meaningful (or rather, it is needlessly puzzling) to patients, clinicians, or anybody else when different diagnosticians apply completely different terms and criteria for a common phenomenon. The best e-mail I got in the past few days was from a respected colleague who wrote, "I already used LATE as a diagnosis today!"

    3. This was not a paper about FTD/FTLD. The commonalities and differences related to LATE-NC and FTLD-TDP were, naturally, a point of discussion among the group. Without getting down in the weeds, a consensus was not reached on that. Here are some differences that were agreed on and are highlighted in the paper: LATE-NC is ~100-fold more prevalent than FTLD-TDP (lifetime risk is 1:4 versus ~1:1000); LATE-NC tends to affect people in a quantumly older age group; persons with FTLD-TDP tend to have language and/or behavioral differences that have not been described in LATE; rather, persons with LATE-NC at autopsy tended to have deficits in episodic memory. I, personally, would guess that those differences will be shown to be correlated with differences in the neuropathology, and other parameters, but time will tell.  MAPT haplotypes make all sorts of tauopathies worse; doesn't make them all FTLD-Tau.  Just as not all tauopathies are AD, not all TDP-43 proteinopathies are FLTD/ALS.

    4. This is a massively underappreciated and understudied disease(s)—and yes, TDP-43 proteinopathy (with or without comorbid AD pathology) is strongly associated with cognitive impairment, although, for a gradually progressive disease that affects >85-year-olds preferentially, a lot of persons die in a presumed preclinical state. 

    It is of course true that this is not the first word on age-related TDP-43 proteinopathy, nor, of course, the last. However, this is the first consensus group effort to address this topic, and it is hoped that this paper will help to move the field forward.

    View all comments by Peter Nelson

  6. It should be considered that the TDP-43 discovered pathological entity could be the neuropathological substrate of accelerated-forgetting syndromes of newly learned information, in particular in transient epileptic amnesia (TEA) and SNAP.

    View all comments by Davide Vito Moretti

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