LANS
Our group (led by Nick Corriveau-Lecavalier, Ph.D. )recently put out a detailed description of and criteria for ‘LANS’ - Limbic-predominant amnestic neurodegenerative syndrome (1). I think it is worthwhile? to review how we, as a field, got here, and to provide some nuance to the LANS media coverage of which there has been plenty. Fair warning - this gets into some behavioral neurology weeds!!!
For a long time we defined ‘Alzheimer’s disease’ (AD) based only on symptoms. This led to it often being used synonymously with dementia (not ideal) or applied to anyone with what was felt to be a ‘typical’ presentation of Alzheimer’s disease - slowly progressive memory loss, eventually impacting non memory domains, and leading to dementia. Along this same vein, amnestic mild cognitive impairment (MCI) - defined as objective memory loss without significant limitations in activities of daily living - was viewed as an ‘early stage’ of AD, with several papers documenting ‘progression’ of MCI to ‘AD’.
We always knew AD is characterized by plaques (amyloid) and tangles (tau) under the microscope - we were just using clinical symptoms and course as a proxy for these. As tests for these during life (biomarkers) became available, the definition of AD gradually became more biological. In 2010, Cliff Jack at Mayo Clinic put out a seminal paper documenting the change in biomarkers over time (2). The curves from that paper - which have since been updated - are known as the ‘Jack curves’, and it is basically impossible to attend an AD or AD-adjacent conference without seeing them. The main points that are relevant for our present discussion is the fact that amyloid accumulates in the brain - and can be detected on spinal fluid, PET scans, or more recently blood - 10-15 years before someone develops symptoms? from AD. Tau, the other defining protein, starts accumulating close to symptom onset, and then evidence of neurodegeneration happens most proximal to symptoms.
Cliff followed up this work with his ATN (for amyloid, tau, neurodegeneration) classification scheme for AD spectrum diseases in 2016 (3). Around this time the field was already moving away from calling progressive memory loss ‘AD’ and instead relying on biomarkers to call something ‘AD’ regardless of symptoms. But that same year an important paper documented findings in patients who clinically had ‘AD’ but lacked AD biomarkers by Ga?l Chételat and colleagues (4). The documented that clinical ‘AD’ cases that lacked amyloid had limbic hypometabolism, which made sense with their symptoms, but they didn’t go beyond it to a different non-AD etiology.
We had noticed these cases too. Patients who clinically looked just like your ’typical’ AD patient, but who sometimes lacked AD biomarkers. In fact, in 2006 Ron Petersen at Mayo had published an autopsy series of aMCI showing that there are cases that resemble AD clinically but progress very slowly and lack AD at autopsy or with a low stage of AD(5). What united these cases was that they had prominent neurodegeneration of the medial temporal (limbic) areas. Some of the oldest patients had hippocampal sclerosis, a finding we have known since the 90s to be common in dementia among the oldest patients (6). However, we had recently learned that degenerative hippocampal sclerosis was associated with a non-AD protein called TDP-43. This protein was often present with AD, and seemed critical for the degree of limbic neurodegeneration seen in some cases, with some even going so far as to say it was critical for the core symptoms in AD (7). It is also worth noting that around this time Pete Nelson put out a paper noting that age related TDP-43 with hippocampal sclerosis should be it’s own disease and used the term CARTs - Cerebral Age-Related TDP-43 With Sclerosis (CARTS) (8).
In 2018 we decided to publish a brief case series of cases that clinically were indistinguishable from AD (9), but who didn’t have biological AD (meaning, they were not amyloid and tau positive, or A+T+ per ATN).? Despite being a very short report it remains one of my favorite papers because of the single-case examples showing that someone can have severe limbic atrophy and amnestic dementia without any tau. This mirrored the Chételat paper from before. We then followed it up with a larger paper showing that those cases - the tau negative, amnestic dementia cases - had a distinct pattern of limbic restricted neurodegeneration and mimicid what was seen in autopsy confirmed hippocampal sclerosis of aging (or CARTS) cases (10). This work was subsequently corroborated in another Mayo cohort (11) and a non-Mayo cohort by an independent team (12).
Because of the growing momentum behind this limbic predominant non-AD disease being important a large group of researchers led by Pete Nelson put out criteria for LATE - Limbic age-related TDP-43 encephalopathy. It was a rebrand of CARTS and hippocampal sclerosis of aging to encompass limbic TDP-43 and related atrophy and symptoms (13). It was … controversial, because it wasn’t really a new thing, and furthermore many people had TDP without symptoms, so ‘encephalopathy’ seemed rich.? However, it has led to more research into this phenomenon which is good.
Our group felt strongly that there was a gap that was evident since Ron’s 2006 paper and our 2018 papers that was not filled by LATE - there are patients who present with a distinct clinical syndrome who have imaging suggesting restricted limbic neurodegeneration. These cases often have LATE, but not always, and many patients have LATE without symptoms. They also often have AD at autopsy, but we don’t think AD is the driving factor in all. Many have a specific flavor of AD called ‘limbic AD’. Others have argyrophilic grain disease?- which is neither AD not anything TDP-43 related! Since we could often recognize these patients clinically we decided that a clinical-imaging-pathological concept was needed. This is how LANS was born.
领英推荐
I think the idea behind LANS is important, and I don’t think the alternative to LANS is to use LATE or LATE-NC, and certainly we cannot go without any term for these limbic predominant cases. I personally take issue with the media coverage suggesting LANS is a ‘new cause’ of memory loss - it is not, we have known about this concept for decades, as evidenced by this quote from the 2006 Jicha paper (14):
‘Several of the aMCI cases had evidence of hippocampal sclerosis or AGD in addition to Alzheimer-type pathologic abnormalities, suggesting that anatomy of neurodegeneration is more predictive of the clinical syndrome than the specific pathologic process. That which unites these various processes is their predilection for the medial temporal lobe.’
It is new in the sense of a new name and proposed criteria for it, naturally.
I also take issue with the fact that it is presented as LANS being ‘confused’ with AD - most LANS cases will have AD at autopsy, and AD is defined biologically these days. Instead, patients are suspected of having AD as their ‘main’ issue when it is often another process. Talks of a better prognosis in LANS is also a bit premature in my opinion, as are the implications for treatment decisions or upcoming cures.
In any event, I do think the idea behind LANS - decades in the making - is important and that every neurologist, neuroradiologist, and researcher working in aging and dementia needs to be aware of it!
Epidemiologist, focused on the future of health through data science, precision medicine, and artificial intelligence
7 个月Excellent review—underscores how emerging technology, coupled with rigorous rethinking that shifts paradigms, leads to what we need to ‘know now that we didn’t know then’.
Professor of Biostatistics Research on Hidden Curriculum, Health Equity Engineering
8 个月I really appreciate this summary of key changes in the field. Thanks!
Assistant Professor of Psychology and Neurology at Mayo Clinic
8 个月Thanks for the important nuances, Hugo! Many things to chat about at some other time and place. I just want to clarify that of course we knew about pathological findings and clinical features of these patients for a long time. Those obviously always existed even before we studied them. But the fact that we now have a framework, criteria, and a name for a neurological syndrome that can be differentiated from other neurodegenerative entities (eg Alzheimer's dementia, ie clinical + biomarkers) is definitely new! This is not overplayed in the media IMO.