Familial Danish Dementia: A Novel Form of Cerebral Amyloidosis Associated with Deposition of Both Amyloid-Dan and Amyloid-Beta

Abstract

Familial Danish dementia (FDD) is pathologically characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal protein deposits, and neurofibrillary degeneration. FDD is associated with a mutation of the BRI2 gene located on chromosome 13. In FDD there is a decamer duplication, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan. The aim of this study was to describe the major neuropathological changes in FDD and to assess the distribution of ADan lesions, neurofibrillary pathology, glial, and microglial response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non-fibrillary) lesions was found. Abeta was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive neurofibrillary degeneration occurring with parenchymal, predominantly pre-amyloid rather than amyloid, deposition. These findings support the notion that parenchymal amyloid fibril formation is not a prerequisite for the development of neurofibrillary tangles. The significance of concurrent ADan and Abeta deposition in FDD is under further investigation.

Familial Danish Dementia

“…Transient ischemic attacks occurred at the age of 31. After the development of double vision, ataxia, and dementia with threatening behavior, he died at the age of 43 from bronchopneumonia (5). In this patient, the TTTAATTTGT decamer insertion at codon 265 of the BRI2 gene, characteristic of FDD, was previously confirmed and reported (4), and his ApoE genotype, tested as described below, was found to be ⑀4/⑀3.…”

“…The parenchymal lesions are usually Thioflavin S/Congo red-negative and ultrastructurally appear as mostly amorphous (nonfibrillar) electron-dense material with sparse fibrils, whereas the vascular deposits are of amyloid nature. The presence of A␤, sometimes co-localizing with ADan deposits, was previously localized immunohistochemically in three affected family members belonging to different generations (5) and is further illustrated below.…”

“…As judged by their paired helical filament ultrastructure, their reactivity in immunohistochemical analysis, and their hyperphosphorylated tau pattern in Western blot analysis, these tangles are strikingly similar (if not identical) to those present in AD (5). Surprisingly, a detailed anti-A␤ immunohistochemical survey of different brain areas from all available FDD autopsy cases (three family members from different generations, including the case analyzed in the present study (5)) unequivocally identified A␤ co-deposited with ADan mainly in vascular and perivascular amyloid lesions, although on a smaller scale the co-deposition was also observed in parenchymal preamyloid deposits (5). The fact that A␤ co-deposition was a constant feature of all three FDD cases available argues against a coincidental nonspecific interaction between two hydrophobic peptides.…”

“…Neuropathologically, FDD shares several features with Alzheimer disease (AD), among them widespread cerebrovascular amyloidosis, parenchymal amyloid and preamyloid lesions, and neurofibrillary degeneration (4,5). Vascular and perivascular amyloid, parenchymal preamyloid lesions, and scarce neuritic plaques in the hippocampus are mainly composed of ADan peptides (4).…”

Clinical phenotypes of Cerebral Amyloid Angiopathy

“…There is some recognized phenotypic variability where the clinical characteristics within the hereditary group include a broader spectrum of presentations than within sporadic disease, usually with a younger age of onset (Table 1). Clinical signs in the hereditary forms can include spastic paraparesis, extrapyramidal signs, progressive ataxia or ocular disturbances, features that have not been part of the spectrum of sporadic cases [66][67][68][69][70][71][72][73][74][75].…”