Clinical Criteria for a Limbic-Predominant Amnestic Neurodegenerative Syndrome

By Anna S. Nordvig, MD, MS

Assistant Professor of Neurology and Neuroscience, Memory Disorders Clinic, Weill Cornell Medicine

SYNOPSIS: Predominant limbic degeneration in older geriatric patients (ages 75 years and older) with slowly progressive episodic memory loss with fluorodeoxyglucose-positron emission tomography medial temporal hypometabolism limbic-predominant age-related TDP-43 encephalopathy (LATE) involves a progressive degeneration of the amygdala, then hippocampus, then middle frontal gyrus.

SOURCE: Corriveau-Lecavalier N, Botha H, Graff-Radford J, et al. Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome. Brain Commun 2024;6:fcae183.

Predominant limbic degeneration often is a diagnosis of exclusion in older geriatric patients (ages 75 years and older) with slowly progressive episodic memory loss. Neocortical causes of degeneration (such as Alzheimer’s disease [AD], frontotemporal disease, and alpha-synucleinopathies [such as Lewy body disease]) are more widely recognized, and AD has several targeted disease-slowing treatments.

Variable patterns in clinical history (particularly a loss of semantic memory — memory for words, concepts, and overlearned facts), and fluorodeoxyglucose-positron emission tomography (FDG-PET) medial temporal hypometabolism may suggest possible limbic degeneration, most commonly limbic-predominant age-related TDP-43 encephalopathy (LATE) — a progressive degeneration of the amygdala, then hippocampus, then middle frontal gyrus. However, AD and LATE often are comorbid on autopsy, and overlapping clinical presentations often confuse neocortical and limbic degeneration patterns. Neither targeted biomarker testing nor specific treatment exists. This study aims to define clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE, but also with other limbic pathologies.

Of 218 autopsied patients from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had antemortem amnestic syndrome, neuropathology classified 35% with AD, 37% with LATE, and 4% with both in the Mayo cohort, and 30%, 22%, and 9%, respectively, in the ADNI cohort. The following LANS criteria were applied: older age, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory (although this was not incorporated into the analysis), limbic hypometabolism on FDG-PET, and absence of neocortical degeneration and low likelihood of neocortical tau. To validate the LANS criteria, a logistic regression using these criteria was used to calculate the accuracy of these criteria at retrospectively predicting the pathology findings identified.

The LANS criteria predicted TDP-43 pathology with 75% accuracy in the Mayo cohort and 73% accuracy in the external cohort. Patients with autopsy-confirmed AD had the lowest likelihood of meeting LANS criteria, while those with LATE only had the highest likelihood and those with both had intermediate likelihood. Those who met LANS criteria had a milder and slower course but more severe temporo-limbic degeneration (as opposed to the temporo-parietal degeneration classically associated with AD). However, the sample of patients with only LATE neuropathology was small — only nine patients. Patients with AD and LATE co-pathology with low likelihood by LANS criteria had the fastest decline in clinical cognitive score (as measured by the Clinical Dementia Rating [CDR] scale). The CDR measures not only memory but also functional areas such as community involvement, judgment and problem-solving, and personal care.

COMMENTARY

LATE is a common cause of amnestic cognitive decline in older age, but it has a marketing problem — most patients have never heard of it.

LATE is found in more than 40% of autopsies of people older than 85 years of age. While high, this number is nowhere near 100% and, therefore, this cannot be considered “simply a disease of aging.” This newer classification of LANS allows for clinical criteria that can be applied more widely by busy clinicians.

Just as our understanding of AD evolved to distinct clinical syndromes that were found to correlate with specific targetable antigens leading to several U.S. Food and Drug Administration-approved medications, so should our understanding of the pathological entity of LATE. Still, there are some hurdles to face. LANS incorporates LATE pathology but casts a wider net around related pathologies leading to a similar clinical syndrome.

The authors focused on this most common LATE pathology to define LANS criteria to provide construct validity to the criteria. However, by including other pathologies, such as limbic-variant AD, the criteria become slightly less specific for a distinct pathological entity and may introduce more biomarker heterogeneity for these criteria in an age when science is targeting precise biomarkers for drug development. Furthermore, there are several neocortical features, such as visuospatial processing, that are classically impaired in AD, but preserved in LATE; additional clinical features could be investigated in the future as other potential criteria.

It is important to remember that the accuracy of these LANS criteria relies on them being used all together. For example, alone, hippocampal atrophy on magnetic resonance imaging still invokes AD for most clinicians. FDG-PET criteria, such as more medial than lateral temporal lobe atrophy, has limited applicability outside research settings because of the high comorbidity of LATE and AD.¹

We eagerly await the development of TDP-43-specific biomarkers (serum, cerebrospinal fluid, imaging tracers) that can be integrated with the clinical criteria to develop disease-modifying treatment for this common but elusive condition.

REFERENCE

1. Buciuc M, Botha H, Murray ME, et al. Utility of FDG-PET in diagnosis of Alzheimer-related TDP-43 proteinopathy. Neurology 2020;95:e23-e34.