Abstract
In the course of a published, large molecular study of Alzheimer disease in Turkey, the Presenilin 1 (PSEN1) variant GCC to ACC was identified at c.1186 in the coding region of Exon 11. The same DNA change was found by analyzing archival brain tissue obtained by the National Cell Repository for Alzheimer’s Disease. A re-examination of the brain was carried out and available clinical records reviewed. DNA was isolated from frozen brain tissue and the APP and PSEN1 genes were sequenced. For histology, the following methods were used: Hematoxylin Eosin, Woelcke-Heidenhain, and Bielschowsky; for immunohistochemistry, antibodies against tau (ALZ-50), amyloid β (10D5), and α-synuclein were used. A 58 year old male complained of problems of concentration. At age 60, he noted word finding problems. An MRI, at age 61, showed atrophy and white matter changes more pronounced in the right occipital lobe; a SPECT scan at age 62 showed decreased perfusion in the right parietal lobe. The subject died at age 66. The subject’s father developed a dementing illness after age 65. The fresh brain weighed 1200 grams. The left hemibrain was examined neuropathologically, while the right hemibrain was frozen for molecular studies. Histologic and immuno-histochemical studies revealed numerous Lewy bodies and neurites in cingulate, frontal, insular, temporal, parietal and occipital cortices, in hippocampus, caudate nucleus, putamen, substantia innominata, amygdala, thalamus, substantia nigra, ocular motor nerve nucleus, locus coeruleus, and nucleus ambiguus. Numerous neurofibrillary tangles and neuritic plaques, tau immuno-positive neurons and neuropril threads, as well as Aβ immuno-positive plaques were also present in the above mentioned anatomical regions. Aβ angiopathy was noted. DNA analysis revealed a GCC>ACC point mutation predicting an amino acid substitution of Alanine (A) to Threonine (T) at residue 396 in Presenilin 1. This is the first study of the neuropathologic features associated with the PSEN1 A396T mutation. The neuropathologic diagnoses established prior to molecular analysis were: 1) Lewy body disease and 2) Alzheimer disease. The reexamination forces us to reconsider the neuropathologic diagnosis and potential pathogenetic mechanisms operating in the presence of PSEN1 mutations. Acknowledgements: P30 AG 010133; U24 AG 21886.
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