Association of the ATN Research Framework With Clinical Profile, Cognitive Decline, and Mortality in Patients With Dementia With Lewy Bodies

Abstract

Background and Objectives:The ATN framework has been developed to categorize biological processes within the Alzheimer’s disease (AD) continuum. Since AD pathology often coincides with dementia with Lewy Bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN-profiles in DLB to prognosis.Methods:We included 202 DLB patients from the Amsterdam Dementia Cohort (68±7yrs, 19%F, MMSE: 24±3, DAT-SPECT abnormal: 105/119). Patients were classified into eight profiles according to the ATN framework, using CSF Aβ42 (A), CSF p-tau (T) and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2yrs for n=139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on both the eight profiles, as well as three clustered categories (normal AD biomarkers, non-AD pathologic change, AD continuum).Results:Fifty (25%) DLB patients had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N-: 10%/A-T-N+: 6%/A-T+N+: 3%) and 115 (57%) were classified within the AD continuum (A+T-N-: 20%/A+T+N-: 16%/A+T-N+: 10%/A+T+N+: 9%). A+T+N+ patients were older and least often had RBD symptoms. Parkinsonism was more often present in A+T-, compared to A-T+ (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers.Discussion:In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within DLB patients aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies, e.g. AD modifying treatment. Expanding the framework by incorporating markers for alpha-synucleinopathy would improve the use of the framework to characterize dementia patients with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium

“…ATN categories were stratified by AD pathologic change without p‐Tau pathology (A+T−N−, A+T−N+), AD pathologic change with p‐Tau (A+T+N−, A+T+N+), non‐AD pathologic change (A−T+N−, A−T−N+, A−T+N+), and normal AD biomarkers (A−T−N−). Interestingly, the same ATN distribution as in our study was previously reported, 30% A+T− and 26% A+T+ 17 . This suggests that not only is there a large proportion of A+ individuals in DLB as previously described, 3,10,17 but many of the A+ individuals do not meet criteria for p‐Tau biomarker thresholds.…”

Association of Plasma Phosphorylated Tau With the Response to Neflamapimod Treatment in Patients With Dementia With Lewy Bodies

“…With respect to the association between plasma ptau181 and treatment response, it is important to note that, in DLB, such elevated plasma levels of phosphorylated tau are associated with more extensive neurodegeneration 6,7,28 and more rapid clinical disease progression. 17,29 This literature is compatible with our observation that elevated plasma ptau181 is associated with poorer cognitive function and greater dementia severity. These findings are also consistent with prior reports of pathology and/or MRI data indicating that patients with DLB and without AD copathology (cortical tau pathology and/or neuritic amyloid plaques) have minimal cortical atrophy, particularly in the medial temporal lobe.…”

Association between ATN profiles and mortality in a clinical cohort of patients with cognitive disorders

“…Few studies have previously examined the association between biomarkers in the ATN classification and mortality. A previous study in a population of patients with Lewy body dementia showed that those within the AD continuum had a steeper cognitive decline and shorter survival [ 24 ]. Two studies have also reported an association of brain amyloidopathy assessed on PET amyloid [ 25 ] or neurodegeneration assessed by brain MRI atrophy with a higher risk of mortality [ 25 , 26 ].…”