ABSTRACT
Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.
Subject(s)
Dementia/genetics , Dementia/pathology , Genes, Dominant , Neurofibrillary Tangles/genetics , Neurofibrillary Tangles/pathology , Age of Onset , Aged , Antibody Specificity , Apolipoproteins E/genetics , Dementia/classification , Epitopes/immunology , Female , Genotype , Humans , Immunohistochemistry , Immunophenotyping , Limbic System/chemistry , Limbic System/pathology , Male , Membrane Proteins/genetics , Microscopy, Electron , Middle Aged , Neurofibrillary Tangles/ultrastructure , Neuropil Threads/chemistry , Neuropil Threads/immunology , Neuropil Threads/ultrastructure , Organ Size , Pedigree , Phenotype , Presenilin-2 , tau Proteins/genetics , tau Proteins/immunologyABSTRACT
We have screened a large sample of patients with sporadic late-onset dementia of the Alzheimer type (DAT) and age-matched controls for a mitochondrial tRNA(Gln) variant previously reported to be associated with increased risk of developing Alzheimer's disease (AD). The frequency of an Ava II site gain was determined by restriction analysis of a PCR-amplified mitochondrial DNA product. One of 155 DAT cases and four of 105 age-matched controls carried the variant. Both the affected and control frequencies are statistically different from those previously reported. The mitochondrial lineage of those individuals harboring the variant was determined by sequencing a short region of the hypervariable mitochondrial D-loop. The affected individual and three of the four controls carrying the Ava II variant belong to the same mitochondrial lineage previously reported to be associated with AD.