Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome

Abstract

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

Keywords: Alzheimer’s disease; amnestic syndrome; behavioural neurology; limbic age-related 43 encephalopathy; limbic-predominant amnestic neurodegenerative syndrome.

Graphical Abstract

Figure 1

Primary neuropathological diagnoses associated with a predominant and progressive neurodegenerative amnestic syndrome in the Mayo and ADNI cohorts. ADNCs, Alzheimer’s disease neuropathological changes; LATE-NCs, limbic-predominant age-associated TDP-43 encephalopathy neuropathological changes; LBD, Lewy body disease; AGD, argyrophilic grain disease; FTLD, fronto-temporal lobar degeneration; PART, primary age-related tauopathy; VaD, vascular disease.

Figure 2

FDG-PET findings between ADNC, ADNC/LATE-NC, LATE-NC and CU controls. The ‘less than’ sign reflects less metabolism in a given group relative to the other and vice versa. Contrasts were generated using SPM12 using pairwise t-comparisons between groups at the voxel level and involved 53 ADNC cases, 33 ADNC/LATE-NC cases, 4 LATE-NC cases and 112 CUs. ADNCs, Alzheimer’s disease neuropathological changes; LATE-NCs, limbic-predominant age-associated TDP-43 encephalopathy neuropathological changes; CU, cognitively unimpaired; FDR, false discovery rate; N.S., non-significant; FDG-PET, fluorodeoxyglucose-PET.

Figure 3

FDG-PET and longitudinal CDR-SB findings across LANS likelihoods. (A) FDG-PET findings comparing LANS likelihoods to CUs. Contrasts were generated using SPM12 using pairwise t-comparisons between groups at the voxel level and involved 42 cases with a low likelihood, 25 cases with a moderate likelihood, 15 cases with a highest/high likelihood and 112 CUs. (B) Longitudinal CDR-SB trajectories at the individual and group level are displayed on the right. CU, cognitively unimpaired; FDR, false discovery rate; CDR-SB, Clinical Dementia Rating Scale Sum of Boxes.

Figure 4

FDG-PET and longitudinal CDR-SB findings in ADNC/LATE-NC according to LANS likelihoods relative to other groups. (A) FDG-PET findings comparing ADNC/LATE-NC to CUs. Contrasts were generated using SPM12 using pairwise t-comparisons between groups at the voxel level and involved 12 ADNC/LATE-NC cases with a low likelihood, 8 ADNC/LATE-NC cases with a moderate likelihood, 13 ADNC/LATE-NC cases with a high/highest likelihood and 112 CUs. (B) Longitudinal CDR-SB trajectories at the individual and group level are displayed on the right. ADNCs, Alzheimer’s disease neuropathological changes; LATE-NCs, limbic-predominant age-associated TDP-43 encephalopathy pathological changes; CU, cognitively unimpaired; FDR, false discovery rate; CDR-SB, Clinical Dementia Rating Scale Sum of Boxes.

Figure 5

Case example of a prospective use of the LANS criteria in clinical settings. This patient was seen at Mayo Clinic, Rochester, to determine eligibility for an anti-amyloid monoclonal antibody therapy, and the LANS criteria were internally defined at the time of evaluation. The criteria were operationalized using clinical judgement of available data including visual reads of neuroimaging as is the current standard in clinical practice. This patient was a female over the age of 75 with a history of memory problems for several years. She lived alone, managed her instrumental activities of daily living independently and was still working part-time. Neuropsychological testing revealed moderate to severe impairment on measures of delayed recall and fragility of salient semantic knowledge (i.e. she could not recall details about the events occurring on 11 September 2001; she named another building than the World Trade Center and did not know how many buildings were hit). Performance was also mildly low on a task of object naming. The remainder of the assessment (i.e. global cognition, executive functions, visuospatial processing and language) was within or above expectations from a normative standpoint. The profile was consistent with single-domain amnestic mild cognitive impairment. MRI revealed disproportionate bilateral hippocampal atrophy, and she was assigned a moderate likelihood LANS diagnosis. Subsequently, a brain FDG-PET revealed prominent temporo-limbic and milder inferior frontal hypometabolism in the absence of a neocortical degenerative pattern by visual read. Amyloid-PET was read as negative. She thus met all core, standard and advanced criteria for LANS, corresponding to the highest likelihood. She did not meet criteria for an anti-amyloid monoclonal antibody therapy and was counselled about diagnosis, prognosis and most likely underlying aetiology.