Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration

Abstract

TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer’s disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists’ diagnoses from two research centres—University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is ‘Alpha’ versus ‘Beta’ in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively ‘pure’ severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.

Old age genetically confirmed frontotemporal lobar degeneration with TDP‐43 has limbic predominant TDP‐43 deposition

“…Second, not all patients in the pure LATE group had TDP-43 inclusions that extended into neocortex, hence, it is not surprising that cortical burden would be less in those cases compared to the FTLD-TDP cases where in all instances TDP-43 did extended into frontal cortex. 26 Lastly, in contrast to our study that used digital quantitative methods for burden determination, the other study used a semi-quantitative approach to measure the amount of TDP-43 pathology. Our results, therefore, challenge the suggestion made previously that TDP-43 burden in frontal cortex can differentiate FTLD-TDP from non-FTLD TDP-43.…”

“…Most importantly, TDP-43 burden in gFTLD-TDP cases did not differ in the middle frontal cortex, which is discordant with the findings reported from another study where patients with FTLD-TDP, often mutation-associated, had more TDP-43 pathology in the frontal regions compared to mixed AD-TDP/pure-TDP patients referred to as limbic-predominant age-related TDP-43 encephalopathy (LATE). 19,26 There are several explanations for these differences. First, in the above-mentioned study, the patients with FTLD-TDP were on average two decades younger than those with LATE.…”

“…Existing studies investigating the spectrum of pathologic differences among TDP-43 proteinopathies are limited by semi-quantitative methods or confounded by differences in age and differences in TDP-43 stage across comparison groups. 26 It is well known that young-onset FTLD-TDP cases are associated with striking TDP-43 burden in the frontal and temporal cortices. However, little is known about oldage genetically confirmed FTLD-TDP and whether these cases differ from similarly old age-matched sporadic cases with TDP-43 that do not have an FTLD genetic mutation, and may or may not have coexistent AD.…”

“…Patients harbouring mutations have higher TDP-43 burden compared to non-mutation associated TDP-43 proteinopathies in mesocortex; however, mutations in patients who died at older age were not associated with higher TDP-43 burden in neocortical regions compared to non-mutation TDP-43 cases in contrast to younger patients with mutations. 26 Whether these differences are of sufficient magnitude to be clinically impactful is, however, unclear and further research is warranted. There were also similarities between old gFTLD-TDP and sporadic TDP-43 with and without AD that would be in support of the existence of old-age FTLD-TDP (oFTLD-TDP).…”

Random forest-integrated analysis in AD and LATE brain transcriptome-wide data to identify disease-specific gene expression

“…Another type of dementia, frontotemporal dementia (FTD) (Also known as Pick’s disease after Arnold Pick, who first noticed a patient with distinct symptoms affecting language in 1892), is also related to the tau and TDP-43 proteins; however, LATE usually can be distinguished from FTD, because FTD typically affects people under age 60 while LATE affects older people, and LATE neuropathologic change has a relatively restricted neuroanatomical distribution of TDP-43 proteinopathy [ 3 ].…”