Ever since the initial definitions of psychotic illnesses were introduced into the literature more than 100 years ago, there has been a debate about a morphological substrate of schizophrenia, and both neurodegenerative and neurodevelopmental pathogenetic theories to explain schizophrenia have been offered. Reports on the frequency or severity of neurodegenerative changes such as AD plaques and neurofibrillary tangles continue with some controversy.4,6–9
Further, although the significance of pathological TDP-43 for human disease was appreciated only recently, the presence or degree of TDP-43 pathology in controls have not been systematically addressed.22,30
Also, since the behavioral variant of FTD might overlap clinically with some aspects of schizophrenia, and therefore might be misdiagnosed in life as schizophrenia, we undertook the study described herein to examine the postmortem CNS in a large cohort of patients with chronic SMI, mainly schizophrenia, for the presence of pathological TDP-43, in comparison with control individuals. We found evidence of significant, moderate, or severe pathological TDP-43 in approximately 30% of patients with chronic SMI/schizophrenia and controls 65 years and older, but not in younger individuals; mild pathology was present in approximately another 20% of the elderly study subjects. Moreover, the group with significant TDP-43 pathology was sufficient to create 4 different morphological patterns that sometimes showed overlap in a given case.
A significant proportion of cases showed TDP-43 pathology comprising dystrophic cellular processes and pre-inclusions located closely subjacent to ventricular surfaces with a focal or bandlike appearance. The significance of this finding is unknown, and further studies are needed to define the relationship of TDP-43 lesions with brain surfaces because this might imply an association between mechanisms of TDP-43 with processes involving the ependymal lining and the cerebrospinal fluid system. Mechanistic speculations might thus include a bidirectional interaction of the CNS and the cerebrospinal fluid, and it is known that there is an increase in cerebrospinal fluid TDP-43 levels in patients with FTLD-U and amyotrophic lateral sclerosis compared with controls.47,48
A further morphological pattern comprised single foci of pathology either in the gray matter (often neuronal cells with a cleared nucleus coupled with stained dystrophic cellular processes) or in the white matter (mainly dystrophic cellular processes). Focal gray matter lesions could represent an early stage of TDP-43 pathology formation similar to what has been described for neurofibrillary tangle pathology in the (trans)entorhinal cortex.49
We herein show that patients with chronic SMI and controls show pathological TDP-43 aggregates in different stages of their development ranging from early, more diffuse punctuate immunoreactivity to “mature,” larger and denser inclusions including TDP-43 immunoreactivity in cellular processes. Very upstream stages of inclusion formation may include almost no discernable cytoplasmic pathological TDP-43 aggregates combined with an absence of normal nuclear immunoreactivity (“cleared nuclei”), but it remains to be established if a nucleus devoid of normal TDP-43 without cytoplasmic TDP-43 immunoreactivity might represent incipient TDP-43 pathology. Notably, changes such as this were present in all cohorts including subjects with schizophrenia with and without dementia and controls with and without mild cognitive “issues,” so this might support the idea of very early cellular pathology with the beginning of TDP-43 redistribution into the cytoplasm not severe enough yet to cause significant neuronal loss and reactive changes.
Diffuse TDP-43 pathology was present in the CA1-subiculum area of the hippocampus mainly consisting of abundant short dystrophic cellular processes intermingled with preinclusions or more “mature,” dense inclusions. This was sometimes in the same brain areas as neurofibrillary and neuritic tau pathology, but colocalization of tau and TDP-43 pathology was variable. To our knowledge, we are the first to show that this partial co-localization of tau and TDP-43 pathology does also occur in neuritic plaques. TDP-43 pathology is known to occur in patients with AD and hippocampal sclerosis and this includes abundant dystrophic TDP-43 pathology in the subiculum-CA1 region of the hippocampus.31,35,39,50
Besides the CA1-subiculum pathology, diffuse pathology was found in the amygdala or periamygdaloid cortex and, less frequently, in other cortical areas. The co-localization with tau lesions was also variable. This pattern observed herein is reminiscent of the co-occurrence of TDP-43 pathology in pathologically diagnosed cases of AD.51
Also, in addition to the subiculum-CA1 involvement, TDP-43 pathology has also been reported in the parahippocampal gyrus and entorhinal cortex, whereas the dentate gyrus was affected variably or rarely.50,51
In the present study, cytoplasmic inclusions in the dentate nucleus were uncommon both in the SMI/schizophrenia and control groups similar to a previous report showing infrequent inclusion in the fascia dentata of Guamanian controls.21
This TDP-43 finding is paralleled by published data on robust tau-positive inclusion in the fascia dentata occurring in advanced stages of AD rather than in low-grade cases.49
It was previously suggested that in advanced AD medial temporal lobe limbic structures are vulnerable to TDP-43 pathology, with the amygdala being the most susceptible region, implying a progression of TDP-43 pathology with higher-order association cortices being affected only later on (or in a subset of cases) and other limbic brain areas having an intermediate position.39,51
Neocortical pathology was present only exceptionally in our cohort. The fact that about a quarter of subjects with diffuse pathology in the hippocampus or amygdala also exhibited TDP-43 lesions in other areas, such as the rhombencephalon, deep brain nuclei, or neocortex, corroborates the multisystem concept of TDP-43 proteinopathies.13
In a subset of controls and subjects with schizophrenia, there appeared to be a greater abundance of TDP-43 pathology around blood vessels, ie, in the perivascular white matter or, less frequent, gray matter, but further studies are needed to confirm and extend this association. Moreover, most of these cases had a documented clinical history of cardiovascular problems or pathology related thereto. Considering the high prevalence of chronic vascular changes in elderly individuals, there might not necessarily be a link between ischemia and pathological TDP-43,52
but the findings herein suggest further study of this possibility. Although it also remains to be established what the localization of TDP-43 pathology around blood vessels means in terms of a hypothesized “interaction” between blood and the brain, it has been suggested recently that increased TDP-43 plasma levels occur in FTLD-U and AD and may thereby index TDP-43 pathology within the brain.53
Interestingly, another recent article reported on a “TDP-43 microvasculopathy” in FTLD-U (and familial Lewy body disease) and suggested that abnormal TDP-43 fibrillary inclusions may occur in astrocytic end-feet, raising the possibility of an impairment in the integrity of the blood-brain barrier.54
The finding of a higher age at death in the TDP-43 pathology–positive as compared with the TDP-43 pathology–negative group and, similarly, the steady increase of the frequency of pathological TDP-43 per age decade after the age of 65 years, denotes an aging-related deposition of this pathological protein with the pathology burden being higher in older subjects. This is paralleled by varying degrees of pathology of many disease proteins including tau-, β-amyloid–, and α-synuclein–related pathological aggregates in the CNS of an elderly, neurologic and cognitive normal or only mildly impaired population.15,17
The recent report on an absence of TDP-43 pathology in 8 patients with schizophrenia (or a schizoaffective disorder) might be, at least in part, due to their relatively young age with death occurring in their early 60s.18
The term atypical FTLD-U
was recently coined referring to sporadic early-onset FTD with severe progressive behavioral and personality changes in the absence of aphasia or significant motor features44,45
and was, most recently, associated with FUS inclusion pathology.46
Despite some clinical similarities between schizophrenia with superimposed deterioration in functional and cognitive abilities (dementia) and atypical FTLD-U, the TDP-43 pathology–negative schizophrenia cohort with the clinical presence of dementia did not show any atypical FTLD-U–like FUS pathology, implying different disease mechanisms between these 2 disorders. However, the early nonmemory symptoms in FTD, such as addictive behaviors or disinhibition,55
resembling some aspects of schizophrenia could be due to the TDP-43 pathology in limbic brain areas as shown in a subset of schizophrenia cases in this study.