Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Abstract

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Keywords: FTLD; MRI; PET; SNAP; epidemiology.

Figure 1

LATE neuropathological changes (LATE-NC). (A–E) Coronally sectioned human hippocampi stained using haematoxylin and eosin (H&E). Note that the photomicrographs in A–C are presented at the same magnification. (A) LATE-NC with hippocampal sclerosis (HS). The hippocampus is atrophic and the neuropil rarefied. (D) Higher magnification in CA1 subfield, with lack of normal cellular architecture and with extensive gliosis. (C) Control age-matched hippocampus. (E) CA1 of the control hippocampus to demonstrate the normal cellular architecture and intact eosinophilic neuropil (asterisk). The hippocampus shown in B is less atrophic, with less obvious neuropil disruption, in comparison to the case in A at low magnification; however, an adjacent section revealed TDP-43 proteinopathy. Hippocampal fields are labelled in B: dg = dentate granule layer; Sub = subiculum. TDP-43 proteinopathy can be recognized using antibodies raised against either non-phosphorylated or phosphorylated TDP-43 epitopes. (F) Dentate granule cells in a case lacking TDP-43 pathology. Note that cell nuclei are normally immunopositive for non-phosphorylated TDP-43 protein. In a case with LATE-NC (G), by contrast, an antibody against phosphorylated TDP-43 protein recognizes only the pathological inclusions in the nucleus (green arrow) and cytoplasm (red arrow). Unlike the antibody against non-phosphorylated TDP-43, the antibody against phosphorylated TDP-43 is negative in non-affected cells. Most cells in G are visualized with the counterstain, haematoxylin, which stains cell nuclei blue. The Venn diagram in H illustrates schematically the imperfect overlap between cases with TDP-43 proteinopathy, hippocampal sclerosis, and LATE-NC. A subset of cases with TDP-43 pathology have comorbid hippocampal sclerosis pathology; the change zone between non-hippocampal sclerosis and hippocampal sclerosis cases is indistinct because many cases seem to be in transition with incipient hippocampal neuron loss and gliosis. Importantly, cases with hippocampal sclerosis pathology but no TDP-43 proteinopathy (e.g. hippocampal sclerosis pathology associated with anoxia or epilepsy) are not classified as LATE-NC. (I) Phospho-TDP-43 proteinopathy in two neurons in hippocampal CA1, along with phospho-TDP-43 immunoreactive dystrophic neurites. (J) Tangle-like phospho-TDP-43 immunoreactive cytoplasmic inclusions in amygdala (red arrows) with fewer phospho-TDP-43 immunoreactive neurites in the background. (K) An intraneuronal phospho-TDP-43 inclusion (red arrow) and a phospho-TDP-43 deposit (green arrow) surrounding a capillary (shown with blue arrows); these TDP-43 immunoreactive structures have been demonstrated to exist within astrocyte end-feet (Lin et al., 2009). Note also the presence of a cell with cytoplasmic puncta (green arrow), perhaps in an early phase of phosphorylated TDP-43 proteinopathy. Scale bar in A = 4 mm for A–C; D = 200 μm; E = 100 μm; F = 30 μm; G = 35 μm; I = 30 μm; and K = 25 μm.

Figure 2

Statistical analyses on data related to LATE from the Rush University community-based autopsy cohort depicting the results of pathway analyses. Data were analysed from research volunteers (total n = 1309) in two clinical‐pathological studies of ageing from Rush University as described previously (Power et al., 2018). In this sample, the mean age of death was 89.7 years [standard deviation (SD) 6.5 years, range 65–108 years]. These analyses incorporated age, density of amyloid-β neuritic amyloid plaques (to factor in ADNC), TDP-43 proteinopathy, hippocampal sclerosis pathology, and the endpoint of Alzheimer’s-type clinical dementia. The components of the pathway analyses most strongly associated with LATE-NC are shown in red. The numbers are path coefficients with standard error in parentheses (shown in purple). These numbers help to quantify the effects of individual pathways. For instance, the data are compatible with there being two pathways from TDP-43 proteinopathy to dementia, one direct pathway (TDP-43 proteinopathy→dementia) and the other indirect pathway that includes hippocampal sclerosis pathology (TDP-43 proteinopathy→hippocampal sclerosis→dementia): in the statistical model, the TDP-43 proteinopathy is independently associated with both hippocampal sclerosis pathology and clinical dementia status. Further, the data indicate that a subset of TDP-43 proteinopathy is ‘downstream’ of ADNC-type neuritic amyloid plaque pathology. In a practical sense, this means that brains with more neuritic amyloid plaques are more likely to have TDP-43 proteinopathy, with all other known factors being the same. Aβ = amyloid-β.

Figure 3

Brain regions that are affected in LATE. (A) Post-mortem MRI with autopsy confirmation allows discrimination of regions of brain atrophy associated with LATE-NC. These data indicate grey matter regions inside and outside of the medial temporal lobe with atrophy in cases with autopsy-confirmed LATE-NC from a community-based autopsy sample. The figure was prepared similarly to the methods used in Kotrotsou et al. (2015), with some modifications. Cerebral hemispheres from 539 participants of two cohort studies of ageing (Rush Memory and Aging Project and Religious Orders Study) were imaged with MRI ex vivo and also underwent detailed neuropathological characterization. The cortical and subcortical grey matter were segmented into 41 regions. Linear regression was used to investigate the association of regional volumes (normalized by height) with the score of LATE-NC at autopsy (scores: 0 = no TDP-43 inclusions, or inclusions in amygdala only; 1 = TDP-43 inclusions in amygdala as well as entorhinal cortex or hippocampus CA1, and neocortex; 2 = TDP-43 inclusions in amygdala, entorhinal cortex or hippocampus CA1, and neocortex, and hippocampal sclerosis pathology) controlling for amyloid plaques and neurofibrillary tangles, Lewy bodies, gross and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, as well as age, sex, years of education, post-mortem interval to fixation and to imaging, and scanners. Unique colours have been assigned to different model estimates (units: mm²) for grey matter regions with significant negative correlation between their volumes and LATE pathology (P < 0.05, false discovery rate-corrected); darker colours indicate greater brain atrophy in that region. Results are overlaid on both hemispheres of the T₁-weighted template of the IIT Human Brain Atlas (v.4.2). Lateral, medial and inferior to superior 3D views of the results are also shown. (B) Classification of LATE-NC according to anatomical region(s) affected by TDP-43 proteinopathy. The present working group recommended a simplified staging scheme for routine assessment of LATE-NC. This requires sampling and TDP-43 immunohistochemical staining of amygdala, hippocampus, and middle frontal gyrus. More detailed TDP-43 immunohistochemical staging schemes that are directly relevant to LATE-NC were previously published by Josephs et al. (2014a, 2016) and Nag et al. (2018). MFG = middle frontal gyrus.

Figure 4

Different neurodegenerative disease conditions stratified by age: LATE-NC, severe ADNC, and FTD. FTD/FTLD cases were not present in data shown in A–D. Note that published studies to estimate disease prevalence for the various diseases have used importantly different study designs—thus, E is a clinical (no autopsy) study because population-based autopsy cohorts lack substantial numbers of FTD/FTLD cases. (A and B) Data from a community-based autopsy cohort—the Rush University ROS-MAP cohort (overall n = 1376). The TDP-43 pathology is operationalized using standard methods as described previously (Nag et al., 2018) and then the current paper’s suggested simplified staging system was applied; sample sizes for each age group (in years) are: <75 (n = 34); 75–80 (n = 82); 80–85 (n = 192); 85–90 (n = 375); 90–95 (n = 407); 95–100 (n = 222); and >100 (n = 64). Note that in this community-based sample, the proportion of cases with advanced ADNC is <50% in all age groups. (C and D) Data from the National Alzheimer’s Coordinating Center (NACC), which derives from 27 different research centres, as described previously (Besser et al., 2018; Katsumata et al., 2018). Overall sample size is n = 806, stratified thus by age groups (in years): <75 (n = 155); 75–80 (n = 118); 80–85 (n = 165); 85–90 (n = 170); 90–95 (n = 122); 95–100 (n = 57); and >100 (n = 19). The NACC research subjects were more likely to come to autopsy after being followed in dementia clinics, and the sample includes a higher percentage of subjects with severe ADNC. The percentage of subjects with LATE-NC is still >20% in each age group. Note that in both the community-based cohort (A and B) and clinic-based cohort (C and D), the proportion of subjects with severe ADNC decreased in advanced old age, while in the same cases the proportion of subjects with LATE-NC increased. (E) Epidemiological data on FTD syndromes for comparison to LATE. Data are provided about crude prevalence rates for FTD syndromes that have been associated with FTLD-TDP. Several of these clinical syndromes are likely to have considerable numbers of cases with FTLD-tau (bvFTD and nfvPPA) or ADNC (other PPA) rather than FTLD-TDP, so the actual prevalence of FTLD-TDP pathology is probably lower than these data suggest. Note that the clinical syndromes associated with FTLD-TDP have a prevalence that are several orders of magnitude lower than LATE-NC. These data, described in detail previously (Coyle-Gilchrist et al., 2016), derive from multisource referral over 2 years, which identified all diagnosed or suspected cases of FTD subtypes in two UK counties comprising the PiPPIN (Pick’s Disease and Progressive Supranuclear Palsy: Prevalence and Incidence) catchment area in the East of England. Two cities in the PiPPIN catchment area were Norfolk and Cambridge. Diagnostic confirmation used current consensus diagnostic criteria after interview and re-examination. Total sample size was n = 986 483 subjects. Shown are crude prevalence rates for the major FTLD-TDP associated syndromes by age and syndrome. bvFTD = behavioural variant frontotemporal dementia; nfvPPA = non-fluent agrammatic variant primary progressive aphasia; svPPA = semantic variant PPA. Note that subjects between ages 55 and 80 are at greatest risk for FTD, and, the FTLD-TDP associated FTD syndrome prevalence is <30 per 100 000 (E), in sharp contrast to the data shown in A–D.

Figure 5

Biomarkers are currently not specific to LATE-NC. (A) Radiological scans from an 86-year-old female who suffered amnestic cognitive impairment compatible with ‘Probable Alzheimer’s disease’ diagnosis. However, the amyloid-β PET scan was negative, tau PET scan was also negative, and the MRI showed appreciable atrophy of the medial temporal lobes bilaterally. This combination is considered ‘A−T−N+’ and was diagnosed during life as ‘suspected non-Alzheimer’s pathology’ (SNAP). Autopsy within a year of the brain scans confirmed the presence of TDP-43 pathology and hippocampal sclerosis, which now is diagnosable as LATE-NC. (B) Another common biomarker combination, in the brain of a 91-year-old male with dementia. In this subject, the amyloid PET scan was positive, yet the tau PET scan was negative. The MRI again showed atrophy of the medial temporal lobes. The combination of pathologies—in this case presumed early ADNC and comorbid LATE-NC—is common, especially in the brains of subjects in advanced age.