Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer's disease.

Kathy Y Liu,Paul Francis,Kirsty E McAleese,Robert Howard,Johannes Attems,Suzanne Reeves,Alan Thomas

doi:10.1093/brain/awaa315

Abstract

There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease. It has been suggested that the combination of Alzheimer's disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom burden, compared to either pathology alone. Longitudinal Neuropsychiatric Inventory and psychotropic medication prescription data from neuropathologically diagnosed pure ADNC (n = 78), pure LATE-NC (n = 14) and mixed ADNC/LATE-NC (n = 39) brain bank donors were analysed using analysis of variance and linear mixed effects regression models to examine the relationship between diagnostic group and neuropsychiatric symptom burden. Nearly all donors had dementia; three (two pure LATE-NC and one pure ADNC) donors had mild cognitive impairment and another two donors with LATE-NC did not have dementia. The mixed ADNC/LATE-NC group was older than the pure ADNC group, had a higher proportion of females compared to the pure ADNC and LATE-NC groups, and had more severe dementia versus the pure LATE-NC group. After adjustment for length of follow-up, cognitive and demographic factors, mixed ADNC/LATE-NC was associated with lower total Neuropsychiatric Inventory and agitation factor scores than pure ADNC, and lower frontal factor scores than pure LATE-NC. Our findings indicate that concomitant LATE pathology in Alzheimer's disease is not associated with greater neuropsychiatric symptom burden. Future longitudinal studies are needed to further investigate whether mixed ADNC/LATE-NC may be protective against agitation and frontal symptoms in dementia caused by Alzheimer's disease or LATE pathology.

Highlights

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently recognized disease entity, commonly affecting individuals over 80 years and diagnosed at autopsy (Nelson et al, 2019)
Previous neuropathological studies have suggested that individuals with ‘pure’ LATE, show slower clinical decline compared to those with ‘pure’ Alzheimer’s disease pathology, known as Alzheimer’s disease neuropathological change (ADNC) [where the combined presence of hyperphosphorylated tau, amyloid-b protein and neuritic plaques account for cognitive impairment (Boyle et al, 2017; Josephs et al, 2017)]
The current study investigated the relationship between LATE-neuropathological change (LATE-NC) and neuropsychiatric symptoms, by comparing clinical data between neuropathologically confirmed cases of pure LATE-NC, pure ADNC and mixed ADNC/LATE-NC

Summary

Introduction

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently recognized disease entity, commonly affecting individuals over 80 years and diagnosed at autopsy (Nelson et al, 2019). Previous neuropathological studies have suggested that individuals with ‘pure’ LATE (where the sole presence of LATE-NC accounts for cognitive impairment), show slower clinical decline compared to those with ‘pure’ Alzheimer’s disease pathology, known as Alzheimer’s disease neuropathological change (ADNC) [where the combined presence of hyperphosphorylated tau, amyloid-b protein and neuritic plaques account for cognitive impairment (Boyle et al, 2017; Josephs et al, 2017)] Those with mixed ADNC and LATE-NC, i.e. both pathologies are present and fulfil specific pathological criteria, show greater cognitive impairment and faster decline compared to ‘pure’ LATE and ‘pure’ Alzheimer’s disease cases (Josephs et al, 2014, 2015). As an important contributing factor to neurodegeneration with significant impact on public health, a greater understanding of LATE and its clinical features is needed

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