Over 1200 patients with motor neuron disease have been carefully diagnosed, followed, and included in a detailed database delineating characteristics of the disease. Of these patients, 831 were identified as exhibiting typical, sporadic amyotrophic lateral sclerosis (ALS). The progression of the disease in these patients has been followed with our scoring system, and the ALS score was verified as a significant covariate of survival. Age at first symptom, delay from first symptom to entering ALS clinic, and rate of change of respiratory function were also identified as significant covariates of survival. These measures, applied to the Cox proportional hazards model, were used to develop a mathematical model for prediction of survival time in ALS, which proved highly accurate for the 80% of patients at intermediate risk. For those patients, a second model was developed which accurately predicts, after an initial period of observation, the time over which ALS patients will decline a set number of points in total ALS score. Such validation permits initial trials for drug therapies in ALS by comparison of relatively small groups of treated patients to this historical control group, based on the model of predicted time to a particular decrement in total ALS score.

In the course of analyzing the chemical composition of Alzheimer's disease neuritic and vascular amyloid, we have purified stable dimeric and trimeric components of A␤ peptides. These peptides (molecular mass 9.0 and 13.5 kDa) were separated by size exclusion chromatography in the presence of 80% formic acid or 5 M guanidine thiocyanate, pH 7.4. The average ratio of monomers, dimers, and trimers was 55:30:15, respectively. Similar structures were produced over time upon incubation of synthetic A␤-(1-42) at pH 7.4. The stability of these oligomeric forms was also demonstrated by Western blot and mass spectrometry. Atomic force microscopy and electron microscopy rotary shadowing revealed that the monomers polymerized into 8 -10-nm filaments, whereas the dimers generated prolate ellipsoids measuring 3-4 nm in diameter. Although evidence implicates ␤-amyloid peptide (A␤) in the pathogenesis of Alzheimer's disease (AD) 1 (reviewed in Ref. 1), little is known about the nature of the A␤ mediating the pathology. Toxicity initially was attributed to aggregated A␤ in amyloid plaques (1), the morphological hallmarks of AD brains. A␤-(1-42) is the major peptide constituent of amyloid plaques (2), and increased production of the 42-amino acid peptide correlates with an earlier onset of AD (1). However, recent studies show that small quantities of A␤-(1-42) also exists as soluble peptide in the plasma, cerebrospinal fluid, and cerebral cortex of AD and normal individuals and are also secreted by cells in tissue culture (3-13). Utilizing ultracentrifugation, graded membrane filtration, and ELISA, we have recently isolated and quantitated the oligomeric water-soluble A␤ present in the brains of AD and control individuals (13). The levels of insoluble A␤ in AD brains are at least 100 times higher than those found in control brains. The amounts of water-soluble A␤ in AD brains are approximately six times higher than those detected in control brains. Interestingly, we isolated an A␤ fraction, from the A␤ water-soluble oligomeric pool, with a molecular mass of Ͻ10 kDa containing monomeric and/or dimeric forms of A␤ peptide (13). In all probability these peptides represent the initial building blocks that may ultimately aggregate into insoluble A␤ filaments. In the course of analyzing the chemical composition of AD neuritic plaque and vascular amyloid, we have purified stable dimeric and trimeric components of A␤-(1-40/42) (2, 14 -15). In the present study we report the chemical and morphological characteristics of the dimeric A␤ as elucidated by atomic force microscopy and transmission electron microscopy techniques. In addition, the potential for toxicity of the AD brain-derived A␤-(1-40/42) dimer was assessed on glial-neuronal cell cultures. MATERIALS AND METHODSPurification of A␤-(1-42) from AD Brain-Brains were obtained from eight patients who died of AD (postmortem delay 3-6 h). After separation of the leptomeninges, the right hemispheres were frozen at Ϫ70°C. Examination of the left hemispheres revealed numerous neuritic plaq...

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Objective-To determine the prevalence and correlates of neuropsychological impairment in a large cohort (n =