Autosomal dominant dementia with widespread neurofibrillary tangles.
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.
Reed
L A
LA
Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City 52242, USA.
Grabowski
T J
TJ
Schmidt
M L
ML
Morris
J C
JC
Goate
A
A
Solodkin
A
A
Van Hoesen
G W
GW
Schelper
R L
RL
Talbot
C J
CJ
Wragg
M A
MA
Trojanowski
J Q
JQ
D017668:Age of Onset; D000368:Aged; D000918:Antibody Specificity; D001057:Apolipoproteins E / Q000235:genetics; D003704:Dementia / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008032:Limbic System / Q000737:chemistry / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008854:Microscopy, Electron; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology* / Q000648:ultrastructure; D019600:Neuropil Threads / Q000737:chemistry / Q000276:immunology / Q000648:ultrastructure; D009929:Organ Size; D010375:Pedigree; D010641:Phenotype; D053766:Presenilin-2; D016875:tau Proteins / Q000235:genetics / Q000276:immunology
D001057:Apolipoproteins E; D000939:Epitopes; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D016875:tau Proteins