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Washington University Experience | NEURODEGENERATION | Alzheimer Disease | Gross Pathology | 9B Case 9 Denouement
Neuro Microscopic Description: There is mild to focally moderate neuronal loss and microvacuolation of superficial laminae in the sections of frontal lobe sampled. Frequent diffuse beta-amyloid plaques are seen and there are a few cored plaques. Neuritic plaques are seen at varying densities from mild to focally numerous. Tau immunohistochemistry reveals neuritic plaques and neurofibrillary tangles and pre-tangles (diffusely immunoreactive neurons). Several alpha-synuclein-positive inclusions (Lewy bodies and, Lewy neurites) are present in the anterior cingulate gyrus but they are less numerous in other frontal cortical areas. There are no TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCIs) in the frontal lobe. There is no cerebral amyloid angiopathy (CAA, defined here as immunoreactivity for amyloid-beta peptide within vessel walls) and no significant arteriolosclerosis. ---- Neuro Diagnosis Comment: The main neuropathological findings of this case are diffuse Lewy body disease (pathological correlate of dementia with Lewy bodies) and Alzheimer disease. Other minor pathologies include modest TDP-43 proteinopathy and modest small vessel disease. Frequent beta-amyloid plaques, frequent neurofibrillary tangles, and few to focally frequent neuritic plaques are present in distributions and densities consistent with AD using Khachaturian, CERAD and NIA-Reagan grading schemes. In the more recent NIA-AA criteria, this case has neuropathological change consistent with AD (A3B3C3). This case displays alpha-synuclein-positive inclusions in the form of Lewy bodies and Lewy neurites in brain stem, limbic, and neocortical areas. The density and distribution of these lesions are sufficient to meet the criteria for the clinicopathological entity called ‘dementia with Lewy bodies (DLB)’ and given the distribution of Lewy bodies this is consistent with a neocortical stage). In the staging of Lewy body pathology in Parkinson’s disease according to Braak et al., this case is stage 6 (range: 1-6). In addition to diagnostic features of AD, this case also shows some TDP-43-immunoreactive NCI in the amygdala and adjacent structures. Neuronal cytoplasmic inclusions (NCI) containing TDP-43 protein represent hallmark features of several diseases, (e.g. amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and have also been described as a co-morbidity in other more common diseases, including AD. The distribution of TDP-43 positive NCIs seen here in the temporal lobe and adjacent limbic areas, in combination with the AD pathology described above, is consistent with a recently described entity, tentatively called ‘AD with limbic TDP-43 proteinopathy'. The contribution of these few TDP-43 positive inclusions to cognitive impairment in this context is not entirely clear, but has been reported in one study (PMID: 18401022). Finally, vascular pathology in the form of mild to moderate arteriolosclerosis was present. In conclusion, in this Participant there is evidence of four molecular pathologies: beta-amyloidosis, tauopathy, synucleinopathy, and TDP-43 proteinopathy. The presence of both AD and DLB most likely explain the progressive cognitive impairment and atypical clinical features.
