Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta.
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.
Holton
Janice L
JL
Department of Molecular Pathogenesis, Queen Square Brain Bank, London, United Kingdom.
Lashley
Tammaryn
T
Ghiso
Jorge
J
Braendgaard
Hans
H
Vidal
Ruben
R
Guerin
Christopher J
CJ
Gibb
Graham
G
Hanger
Diane P
DP
Rostagno
Agueda
A
Anderton
Brian H
BH
Strand
Catherine
C
Ayling
Hilary
H
Plant
Gordon
G
Frangione
Blas
B
Bojsen-Møller
Marie
M
Revesz
Tamas
T
D000328:Adult; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D052160:Benzothiazoles; D001808:Blood Vessels / Q000378:metabolism; D001927:Brain Diseases / Q000378:metabolism* / Q000473:pathology; D004396:Coloring Agents; D003224:Congo Red; D003704:Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D003718:Denmark; D005260:Female; D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D010375:Pedigree; D013194:Staining and Labeling; D013844:Thiazoles; D016875:tau Proteins / Q000378:metabolism; D000097382:CD68 Molecule
D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D052160:Benzothiazoles; D004396:Coloring Agents; D003224:Congo Red; D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein; D000949:Histocompatibility Antigens Class II; D013844:Thiazoles; D016875:tau Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C009462:thioflavin T