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Washington University Experience | NEURODEGENERATION | Argyrophilic Grain Disease (AGD) | 6D0 Case 6 Denouement
Neuro Final Diagnosis: Alzheimer's disease ; Dementia with Lewy bodies ; Argyrophilic grain disease ; TDP-43 proteinopathy in medial temporal lobe; Cerebral amyloid angiopathy; Arteriolosclerosis, mild ---- Neuro Diagnosis Comment: : The main neuropathological finding in this case is Alzheimer's disease (AD). There is a minor contribution from diffuse Lewy body disease (dementia with Lewy bodies), argyrophilic grain disease, and TDP-43 proteinopathy. Frequent beta-amyloid plaques and few to focally moderate numbers of neuritic plaques and neurofibrillary tangles are present consistent with Braak and Braak neurofibrillary tangle stage III (range: 0, I-VI) and amyloid stage C (range: 0, A-C). These findings indicate the presence of Alzheimer's disease (AD) by Khachaturian criteria, 'probable' AD by CERAD criteria, and there is an 'intermediate' probability' that the dementia is caused by AD according to the NIA-Reagan Institute criteria. In addition to beta-amyloid pathology, this case also displayed alpha-synuclein-positive inclusions in the form of Lewy bodies and Lewy neurites in brainstem and limbic areas. The density and distribution of these lesions is sufficient to meet the criteria for dementia with Lewy bodies (limbic type). In the staging of Lewy body pathology in Parkinson’s disease according to Braak et al. this case is stage 3 (range: 0,1-6). In the revised criteria which take into account Lewy bodies and Alzheimer’s disease, there is an “intermediate” probability that the cognitive deficits are caused by DLB (McKeith et al. PMID: 28592453). Together with the pathological changes described above, the presence of tau-positive inclusions in both neurons and glial cells (astrocytes and coiled bodies in oligodendrocytes, also called argyrophilic grains when impregnated with silver salts) in cingulate gyrus and amygdala support the diagnosis of argyrophilic grain disease (AGD), stage 2. It typically presents as a late-onset dementia and may account for ~12% of demented individuals older than 65. This case has four molecular pathologies: beta-amyloidosis, tauopathy, synucleinopathy, and TDP-43 proteinopathy in the medial temporal lobe, one of an expanding group of neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). TDP-43 proteinopathy has been described as a co-morbidity in other more common diseases, including Alzheimer’s disease, but the presence of four molecular pathologies, largely in one brain area, raises the possibility that this is a recently described entity, tentatively called AD with limbic TDP-43 proteinopathy (Higashi et al., PMID: 17963732). These changes were modest in this case and unlikely to have contributed significantly to the cognitive impairment. Vascular pathology in the form of mild arteriolosclerosis was also a feature of this brain. These lesions were relatively modest and unlikely to have contributed to motor or cognitive symptoms. In conclusion, the cognitive deficits experienced during life may be explained by Alzheimer's disease and a modest contribution from diffuse Lewy body disease (also called dementia with Lewy bodies) with a very modest contribution from argyrophilic grain disease and TDP-43 proteinopathy.
