Article

Staging TDP-43 pathology in Alzheimer’s disease

Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA, .
Acta Neuropathologica (Impact Factor: 10.76). 11/2013; 127(3). DOI: 10.1007/s00401-013-1211-9
Source: PubMed

ABSTRACT

TDP-43 immunoreactivity occurs in 19-57 % of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.

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Available from: Melissa Erin Murray
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    • "The selection of brain regions of interest was based on key brain regions routinely sampled for neuropathological assessment that are included in the three TDP-43 topographical staging schemes (Brettschneider et al., 2013, 2014; Josephs et al., 2014a) (Table 1). The following regions were included in the analyses: superior prefrontal cortex (Brodmann area 9), motor cortex (precentral gyrus, Brodmann area 4), anterior cingulate cortex (just posterior to genu of corpus callosum; Brodmann area 24), inferior temporal cortex (Brodmann area 20), entorhinal cortex, hippocampal dentate gyrus and CA1 region (at coronal level of lateral geniculate nucleus), amygdala, midbrain (including the substantia nigra and red nucleus), pontine tegmentum at the transverse brainstem level of the locus coeruleus , and medulla oblongata at the transverse level of the hypoglossal nucleus. "
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    • "We were unable to include amygdala slides due to study tissue storage protocols. Amygdala TDP-43 positivity has been reported in AD [13] [16] and cognitively normal older adults [22] in the absence of positivity in other areas. We therefore likely underestimated the prevalence of TDP-43 pathology due to a lack of amygdala tissue. "
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