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Washington University Experience | NEURODEGENERATION | Alzheimer Disease | Gross Pathology | 8B Case 8 Denouement
Neuro Microscopic Summary: Neuronal loss and gliosis are focally mild to moderate. Frequent diffuse beta amyloid plaques are seen and there are frequent neurofibrillary tangles and more variable numbers of neuritic plaques. Tau immunohistochemistry reveals frequent neurofibrillary tangles or pre-tangles (diffusely immunoreactive neurons), few neuritic plaques but numerous neuropil threads which make the appreciation of neuritic plaques more difficult. A few alpha-synuclein-positive Lewy bodies are seen in the anterior cingulate gyrus. There are no TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCIs) in the frontal lobe. There is modest cerebral amyloid angiopathy (CAA, defined here as immunoreactivity for amyloid beta peptide within vessel walls) and mild arteriosclerosis. ---- Neuro Diagnosis Comment: The main neuropathological finding of this case is severe Alzheimer disease. Supporting a diagnosis of Alzheimer disease (AD), beta-amyloid plaques, neuritic plaques, and neurofibrillary tangles support a neuropathological diagnosis of AD by Khachaturian criteria, CERAD, and NIA-Reagan Institute criteria. In the more recent NIA-AA criteria, this case has neuropathological change consistent with AD (A3B3C3). In addition to beta-amyloidosis and tauopathy, this case also displays alpha-synuclein-positive Lewy bodies and Lewy neurites in limbic and paralimbic areas with almost none in the neocortex. The substantia nigra was relatively well-populated. Because there was only modest loss of neurons from the brain stem nuclei, there was insufficient Lewy body pathology to cause parkinsonism or an entity called 'dementia with Lewy bodies'. In the staging of Lewy body pathology according to Braak et al. this case is not readily graded as there is a dearth of brainstem Lewy bodies. The high density and distribution of Lewy bodies in limbic areas is most consistent with an entity called 'Alzheimer disease with amygdala Lewy bodies’. It is unlikely that the Lewy body pathology had advanced sufficiently to have caused any significant motor or cognitive deficits. In addition to diagnostic features of AD and Lewy body disease, this case also shows a few TDP-43-immunoreactive NCIs in the amygdala. 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 comorbidity in other more common diseases, including Alzheimer disease. The distribution of TDP-43 positive NCIs seen in the temporal lobe, 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 TDP-43 positive inclusions to cognitive impairment in this context is not entirely clear but has been reported. Finally, vascular pathology in the forms of mild cerebral amyloid angiopathy and mild to moderate arteriolosclerosis were additional findings in this case. However, no infarcts were seen so these changes are unlikely to have contributed significantly to cognitive dysfunction. In conclusion, this patient had the neuropathologic stigmata of very severe AD. Lewy body disease and TDP-43 proteinopathy were at a relatively early stage and unlikely to have contributed significantly to any loss of cognitive functions.
