TDP-43 proteinopathies: pathological identification of brain regions differentiating clinical phenotypes

Abstract

The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.

TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia

“…Family history for ALS was more prevalent in pure bvFTD cases with TDP-43 in the hypoglossal nucleus, but this did not reach significance compared to other bvFTD cohorts (p = 0.06). The recent topographical staging of TDP-43 pathology in bvFTD and ALS [6,7] demonstrated that TDP-43 initiated in the motor system network in ALS is also seen in the majority of bvFTD cases, despite the absence of ALS in over 50% of these [6,21]. In a recent analysis [21], we identified the hypoglossal nucleus as a key brain region in discriminating between cases with and without ALS and the present study corroborates this finding in bvFTD cases.…”

“…The recent topographical staging of TDP-43 pathology in bvFTD and ALS [6,7] demonstrated that TDP-43 initiated in the motor system network in ALS is also seen in the majority of bvFTD cases, despite the absence of ALS in over 50% of these [6,21]. In a recent analysis [21], we identified the hypoglossal nucleus as a key brain region in discriminating between cases with and without ALS and the present study corroborates this finding in bvFTD cases. Further support for the segregation of bvFTD cases by TDP-43 inclusions in the hypoglossal nucleus was evidenced here by differences in disease duration and postmortem brain weights, with 'intermediate' levels of atrophy in bvFTD cases with end-stage ALS (Figure 2).…”

“…This research project was approved by the Human Research Ethics Committee of the University of New South Wales. Cases with neuropathological FTLD-TDP and clinical bvFTD not previously analysed in [20] were included in this study (n=27) as well as two bvFTD cases previously assessed that met clinical criteria for possible ALS by endstage (n=2/22 from [20] Figure 2c). Of these 29 bvFTD cases, 59% (n=17) did not have a clinical diagnosis of possible or probable ALS at onset and are referred to here as 'pure bvFTD' while the others had both bvFTD and possible or probable ALS at onset (n=12, 41%).…”

“…However, TDP-43 pathology was seen in the hypoglossal nucleus of 13% of the bvFTD cohort assessed [20]. Based on the premise that pathological deposition precedes clinical symptomology [4], the present study set out to determine if bvFTD cases with TDP-43 pathology in the hypoglossal nucleus had developed or were developing ALS by endstage.…”

“…In our recent analysis, the hypoglossal nucleus emerged as a key brain region in which the presence of TDP-43 pathology could accurately discriminate 'TDP-43opathy' cases with coexistent clinical features of ALS [20]. However, TDP-43 pathology was seen in the hypoglossal nucleus of 13% of the bvFTD cohort assessed [20].…”