In this study of patients with clinical dementia and advanced pathologic changes of AD, we demonstrate the distribution of TDP-43 immunoreactive NCIs and show that the amygdala is the most frequently affected region. In addition, the amygdala had the most abundant TDP-43 pathology for cases in which TDP-43 immunoreactivity was detected in other regions. In a small number of cases (n=6), TDP-43 immunoreactivity was detected only in the amygdala. In the 23 cases with TDP-43 immunoreactivity in the hippocampus as well as the amygdala, involvement of cortical areas was most often detected in temporal lobe, followed by frontal and parietal lobes. Moreover, there was a correlation between the semi-quantitative score of temporal neocortical TDP-43 pathology and the extent of extra-temporal neocortical involvement. Therefore, analysis of the temporal lobar structures, especially the amygdala, remains critical in the identification of TDP-43-associated pathology in AD. Survey of hippocampal or neocortical regions alone would most likely underestimate the number of cases with TDP-43 pathology.
The prominent involvement of medial temporal lobe structures with less often spread to other cortical regions has been noted previously in AD and classified as “limbic” or “diffuse”[1
], with the diffuse type being more frequently associated with pathology that is unique to FTLD-U such as NIIs. Such a step-wise spread may reflect differences in intrinsic susceptibility to TDP-43 associated pathology between neuronal populations, staged degeneration of neurons in associated networks, non-specific vulnerability to inclusion body formation in neurons affected by a primary neurodegenerative process such as Alzheimer disease, or a combination of the processes. As only a small percentage of TDP-43 positive inclusions were positive for phospho-tau[1
], this pattern likely does not represent non-specific immunoreactivity in AD-associated intranuclear pathology. It is not known if this pattern of TDP-43 co-pathology holds true in neurodegenerative disorders with only TDP-43 pathology such as FTLD-U and ALS. An analogous situation exists for α-synuclein in Parkinson’s disease compared to α-synuclein pathology occurring in the setting of advanced AD. In the former there is a predictable progression of pathology from brainstem to limbic lobe to cortex [5
], while in AD some cases have α-synuclein pathology relatively restricted to the medial temporal lobe structures [25
]. The cellular co-localization of tau and TDP-43 originally noted in AD [1
] has now been shown to extend to AD cases with Lewy bodies, and some neurons show co-deposition of all three proteins [10
]. It remains to be determined whether a similar pattern of TDP-43 pathologic distribution we reported here exists in Lewy body disease.
While a staging system of TDP-43 pathology has not been proposed for the primary TDP-43-proteinopathies (FTLD-U and ALS), several lines of evidence point to possible early involvement of amygdala in these disorders. Clinically, severe atrophy of the medial temporal lobe structures, including amygdala and hippocampus, is common in clinically diagnosed behavioral variant frontotemporal dementia and in semantic dementia [7
]. Amygdala atrophy is also common in pathologically confirmed FTLD-U [3
]. At autopsy some cases of ALS also have ubiquitin-positive pathology and neuronal loss in the amygdala [2
]. The extent of ubiquitin-immunoreactive inclusions and neuronal loss also correlate with the severity of clinical cognitive impairment in ALS [15
] Thus, TDP-43 pathology in the amygdala may represent the one of the earliest stages of TDP-43-associated neurodegeneration.
It remains unknown if the presence of TDP-43 immunoreactivity in advanced AD has any clinical significance. Preliminary studies on this same cohort suggests that it is associated with poorer cognitive performance [13
], although it is difficult to determine the cognitive burden of region-specific TDP-43 pathology such as amygdala-only TDP-43 NCIs. It is unlikely that TDP-43 pathology in AD is merely related to severity of AD pathology, as the AD cases in this study that lacked TDP-43 immunoreactivity had very similar AD pathology based upon CERAD plaque and tangle scores and Braak neurofibrillary tangle staging. It may be difficult to unequivocally assign a clinical significance to a particular type of pathology in cases with mixed pathology, and this is true not only for TDP-43 immunoreactivity, but also for ischemic-vascular lesions, Lewy bodies and hippocampal sclerosis [24
]. What can be said is that cases with mixed pathology usually have more severe clinical phenotype [13
]. An approach that might be successful at parsing the contribution of TDP-43 pathology to the clinical syndrome is to examine clinical presentations of patients with and without TDP-43 immunoreactivity who have intermediate- or low-likelihood AD type pathology.
In summary, we present a study on regional distribution of TDP-43-associated pathology in advanced AD. We find that the amygdala is the most frequently affected regions and usually the most severely affected region, suggesting that it may be the earliest affected region in such cases. We hypothesize that TDP-43 associated cortical pathology may spread from limbic structures in the medial temporal lobe (amygdala and hippocampus) to multimodal association cortices in temporal lobe and then to frontal and parietal lobes. How subcortical structures (e.g., basal ganglia, thalamus and brainstem) play into this scheme will require additional studies.