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(American Journal of Pathology. 2001;158:515-526.)
© 2001 American Society for Investigative Pathology

Regular Article

Regional Distribution of Amyloid-Bri Deposition and Its Association with Neurofibrillary Degeneration in Familial British Dementia

Janice L. Holton^*, Jorge Ghiso, Tammaryn Lashley^*, Agueda Rostagno, Christopher J. Guerin^§, Graham Gibb, Henry Houlden, Hilary Ayling^*, Lillian Martinian^*, Brian H. Anderton, Nicholas W. Wood, Ruben Vidal, Gordon Plant^||, Blas Frangione and Tamas Revesz^*

From the Departments of Neuropathology^*
and Clinical Neurology,
Institute of Neurology, University College London; London, United Kingdom; The National Hospital for Neurology and Neurosurgery,^||
London, United Kingdom; the Neurotoxicology Group,^§
MRC Toxicology Unit, Leicester, United Kingdom; the Department of Neuroscience,
Institute of Psychiatry, London, United Kingdom; and the Department of Pathology,
New York University School of Medicine, New York, New York

Familial British dementia (FBD), pathologically characterized by cerebral amyloid angiopathy (CAA), amyloid plaques, and neurofibrillary degeneration, is associated with a stop codon mutation in the BRI gene resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri). The aim of this study was to assess the distribution of ABri fibrillar and nonfibrillar lesions and their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and immunoelectron microscopy in five cases of FBD. Abnormal tau was studied with immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and pre-amyloid (nonfibrillar) lesions are formed. Ultrastructurally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consist of amorphous electron-dense material with sparse, dispersed fibrils. In contrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil threads occurring mainly in limbic structures, are found in areas affected by all types of ABri lesions whereas abnormal neurites are present around amyloid lesions. Immunoblotting for tau revealed a triplet electrophoretic migration pattern. Our observations confirm a close link between ABri deposition and neurodegeneration in FBD.

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