Fibrillar amyloid-beta affects neurofibrillary changes but only in neurons already involved in neurofibrillary degeneration.

The aim of this study of the cerebral cortex of 8 non-demented elderly subjects and of 17 subjects in the severe stage of Alzheimer's disease (AD) (Global Deterioration Scale stage 7/Functional Assessment Staging procedure stage 7a-f) was to examine the relationships between amyloid-beta (Abeta) deposits and neurofibrillary degeneration. The study shows that neuronal processes with neurofibrillary changes are detectable in only a minority of fibrillar plaques: from 31% to 49% of fibrillar plaques within frontal, temporal, parietal, limbic, occipital, and insular cortices. The correlations observed between the numerical densities of neurons with neurofibrillary tangles (NFTs) and the densities of Thioflavin-S-positive fibrillar plaques with neurofibrillary changes (r=0.61; P<0.01) indicate that neurofibrillary pathology in neocortical plaques reflects the topography and rate of neurofibrillary changes in neocortical neurons. The accumulation of abnormally phosphorylated tau in only some plaques indicates that fibrillar Abeta enhances paired helical filament accumulation locally only in dystrophic neurites already involved in neurofibrillary degeneration. The lack of correlation between the number of neurons with neurofibrillary changes and the number of all Thioflavin-S-positive fibrillar plaques (with and without neurofibrillary changes) suggests that beta-amyloidosis does not contribute to initiation of neurofibrillary degeneration in neurons.

Cell-type-specific enhancement of amyloid-beta deposition in a novel presenilin-1 mutation (P117L).

The presenilin-1 (PS1) gene mutation (Pro117Leu), recently identified in a Polish family is characterized by the earliest reported onset (from 24-31 years) of Alzheimer disease (AD) and a very short duration of disease (4-6 years). The neuropathology of 2 subjects with this PS1 mutation (ages at death: 35 and 37 years) was compared to four Down syndrome (DS) patients (mean age at death: 62 years) and 4 sporadic AD patients (mean age at death: 79 years with a mean duration of disease of 18 years). The Polish familial AD (FAD) patients showed a marked increase in the amyloid burden of 2 6-fold in most areas of the brain. The entorhinal cortex was an exception where the amyloid burden was similar in each category of patient. Some brain regions of the Polish FAD patients showed a massive increase of amyloid, such as the molecular layer of the cerebellum where a 7- and 25-fold increase was noted, compared with DS and sporadic AD patients respectively. The cerebellar vessel amyloid burden was also greatly increased in the FAD patients, reflecting a vascular compartment specific increase of amyloid beta deposition. The presence of this PS1 mutation has an even greater effect on both vascular and parenchymal amyloid deposition, than the overexpression of the amyloid beta precursor protein present in DS patients, suggesting that PS mutations can be a critical factor determining amyloid deposition.

Differential susceptibility to neurofibrillary pathology among patients with Down syndrome.

Individual differences in the development of neurofibrillary changes were examined in eight cortical regions in the brains of 43 subjects with Down syndrome (DS; age range, 15-69 years) using sections stained with monoclonal antibodies (mAb) tau-1 and 3-39. Neurofibrillary pathology was found in 4 cases below 36 years of age and in all 20 cases above that age. In the 24 positive cases, numerical density of pretangles stained with tau-1 and 3-39, respectively, was 6.1/mm2 and 0/mm2; early tangles, 5.0/mm2 and 5.3/mm2; mature tangles, 4.0/mm2 and 5.0/mm2 (p < 0.01); and end-stage tangles, 0.04/mm2 and 2.5/mm2 (p < 0.001). Numerical density of pretangles stained with mAb tau-1 and tangles and plaques stained with mAb 3-39 correlates weakly with age (r = 0.43; p< 0.02), and together with the wide range of numerical densities suggested heterogeneity of the population examined. Cluster analysis based on two variables - i.e., numerical density of pretangles stained with mAb tau-1 and neurofibrillary tangles (NFTs) and plaques stained with mAB 3-39, distinguished three groups of subjects with severe, moderate and weak changes. The severely affected group of 5 subject (21%) had an average 54.6/mm2 of neurons and 13.9/mm/ plaques with neurofibrillary changes, whereas the moderately affected group (6 subjects; 25%) showed a significantly lower numerical density of neurons and plaques with neurofibrillary changes (25.7/mm2 and 8.1/mm2, respectively) as compared with the most affected group. Most of the subjects (13; 54%) belong to the third group with only 2.2/mm2 of neurons and 1.4/mm2 plaques with neurofibrillary pathology. Comparison of these three groups of Down syndrome subjects representing high, moderate, and low susceptibility to neurofibrillary changes with the general population suggests that the risk of Alzheimer disease is similar but the onset of pathological changes is earlier in DS.

Alzheimer neuropathology in mentally retarded adults: statistical independence of regional amyloid plaque and neurofibrillary tangle densities.

The densities of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed quantitatively in the brains of 303 mentally retarded adults 23 to 90 years of age at the time of their deaths (mean = 59.5 years). Cases with Down's syndrome, hydrocephalus and metabolic disorders were excluded from the study. Examinations of frontal, temporal, parietal, and occipital cortex, as well as hippocampus and parahippocampal gyrus were made in every case. NPs and/or NFTs were observed within the brains of 163 cases (53.8%). Detailed analyses indicated that NP density within all brain regions examined was positively related to age, with the largest age associated increases in density seen in frontal and temporal regions. In contrast, NFT density increased with age only within hippocampus and parahippocampal gyrus, but not neocortex. In addition, NP lesions within neocortex were more diffusely distributed across regions for older compared to younger cases, while no similar age-associated change in the topography of NFTs was observed. Finally, factor analyses of the combined NP and NFT data indicated that, while strong correlations existed across the various brain regions for measures of NP and NFT densities, considered separately, there was virtually no indication of regional associations between these two types of lesions. While these data, from cases with mental retardation, cannot be generalized directly to the nonretarded population, they provide strong evidence that models of Alzheimer pathogenesis must take into account the fact that regional densities of NPs and NFTs, and, therefore, the underlying processes associated with formation of these lesions, can be largely independent.

Alzheimer neuropathology in non-Down's syndrome mentally retarded adults.

We examined the brains of 385 mentally retarded adults aged 23-90 years without Down's syndrome (DS), metabolic disorder, or hydrocephalus to extend our knowledge about the occurrence of Alzheimer-type neuropathology in this population. Relevant measures of neuropathology also were related to selected information available from clinical records. The presence of one or more neurofibrillary tangles (NFT) and/or neuritic plaques (NP) was observed in 63.4% of all cases and varied with age. The prevalence of positive cases was higher when mental retardation was due to head trauma, congenital malformation, or familial factors and when a history of seizures was reported. Comprehensive morphometric analyses of neocortical, hippocampal and parahippocampal areas indicated that recommended age-specific quantitative criteria for the diagnosis of Alzheimer disease [Khachaturian ZS (1985) Arch Neurol 42:1097-1105] were met in 9.5% of cases less than 50 years of age, 54.2% between 50 and 65, 70% between 66 and 75, and 87% of the cases greater than 75 years of age. However, a limited immunohistochemical study revealed that in most cases the NP did not have a neuritic component containing paired helical filaments and in this respect most of the plaques observed in this population may differ from those most strongly associated with Alzheimer disease. In addition, substantial numbers of NFT were seen in frontal cortex, contrasting with results reported in the literature for nonretarded populations. The number of NP per mm2 consistently increased with age for all areas examined, while the relationship between NFT density and age varied across areas, and was clearly not monotonic.(ABSTRACT TRUNCATED AT 250 WORDS)

Young adult-form of dementia with neurofibrillary changes and Lewy bodies.

Alzheimer's neurofibrillary tangles, Lewy bodies and chromatolytic neurons were found in the brain at autopsy of a 28-year-old male with pyramidal and extrapyramidal signs, and severe dementia of 7-year duration prior to his death. Review of histological material showed generalized changes involving both cortical and subcortical structures. These changes were characterized by the presence of neurofibrillary myelin in long tracts and in subcortical regions. The neurofibrillary tangles were mostly composed of Alzheimer's paired helical filaments (PHF), PHF were immunostained with both polyclonal and monoclonal antibodies to PHF and the microtubule-associated protein tau. Some Lewy bodies were immunolabelled with monoclonal antibodies to PHF. To the best of our knowledge it is the first reported case of a young adult-form of dementia with extensive formation of neurofibrillary changes and Lewy bodies.