Spinal and bulbar muscular atrophy is an adult-onset, hereditary motor neuron disease caused by the expansion of a trinucleotide CAG repeat within the gene encoding the androgen receptor. To date, several agents have been shown to prevent or slow disease progression in animal models of this disease. For the translational research of these agents, it is necessary to perform the detailed analysis of natural history with quantitative outcome measures and to establish sensitive and validated disease-specific endpoints in the clinical trials. To this end, we performed a prospective observation of disease progression over 3 years in 34 genetically confirmed Japanese patients with spinal and bulbar muscular atrophy by using quantitative outcome measures, including functional and blood parameters. The baseline evaluation revealed that CAG repeat length in the androgen receptor gene correlated not only with the age of onset but also with the timing of substantial changes in activity of daily living. Multiple regression analyses indicated that the serum level of creatinine is the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy. In 3-year prospective analyses, a slow but steady progression was affirmed in most of the outcome measures we examined. In the analyses using random coefficient models that summarize the individual data into a representative line, disease progression was not affected by CAG repeat length or onset age. These models showed large interindividual variation, which was also independent of the differences of CAG repeat size. Analyses using these models also demonstrated that the subtle neurological deficits at an early or preclinical stage were more likely to be detected by objective motor functional tests such as the 6-min walk test and grip power or serum creatinine levels than by functional rating scales, such as the revised amyotrophic lateral sclerosis functional rating scale or modified Norris scale. Categorization of the clinical phenotypes using factor analysis showed that upper limb function is closely related to bulbar function, but not to lower limb function at baseline, whereas the site of onset had no substantial effects on disease progression. These results suggest that patients with spinal and bulbar muscular atrophy show a slow but steady progression of motor dysfunction over time that is independent of CAG repeat length or clinical phenotype, and that objective outcome measures may be used to evaluate disease severity at an early stage of this disease.

KEY WORDSDegradation / SEC Column / Styrene / m-Divinylbenzene / Ultrahigh Molecular Weight / Network-Polymer Precursor / As an extension of our continuing studies concerned with the mechanistic discussion of the three-dimensional network formation in the freeradical polymerization and copolymerization of multivinyl compounds, 1 the preceding article 2 dealt with the crosslinking copolymerization of styrene (St) with m-divinylbenzene (m-DVB) as a most typical monovinyl/divinyl system. Thus, the reasons for the greatly delayed gelation from Flory-Stockmayer gelation theory (FS theory) 3 have been discussed extensively in order to clarify the crosslinking polymerization mechanism of multivinyl compounds. 1 The actual gel point should be close to the theoretical one if the experiment were done under the polymerization conditions in which the polymer concentration, at the theoretical gel point, would be high enough to reduce the significance of a thermodynamic excluded volume effect as a primary factor and, furthermore, the intramolecular crosslinking preceded by the intermolecular crosslinking could be suppressed. Our interpretations are verified for monomethacrylate/dimethacrylate, 4, 5 monoacrylate/diacrylate, 6 and St/m-DVB 2 copolymerizations, in which the results obtained are discussed in terms of ideal network formation according to FS theory.In a series of these investigations, the detailed pursuit of the variation of molecular-weight distribution (MWD) curves with conversion is inevitable for a full understanding of crosslinking polymerization because the MWD curves should rapidly broaden towards a higher molecular weight side with conversion as a result of exclusive occurrence of intermolecular crosslinking reaction leading to ideal network formation. 3,7,8 Here it is worthy to note that a size-exclusion chromatography (SEC) is commonly used to determine † To whom correspondence should be addressed. the molecular weight and the MWD of resulting prepolymers. However, as a technique it is not always applicable to our crosslinking polymerization systems because the structure of prepolymer changes from a linear to a branched form with progressing polymerization and, moreover, the content of ring or loop structure introduced into the linear portion or primary chain and the content of multiple crosslink or network structure in the branched form depend on the polymerization conditions. On the other hand, SEC equipped with a multiangle laser light scattering (MALLS) device (SEC-MALLS) is expected to be a very useful and efficient tool in characterizing our prepolymers because the use of MALLS, as an absolute detector, enables the molecular weight and MWD to be determined directly without any calibration. 5 During the progress of our investigation, we noticed that the degradation of poly(St-co-m-DVB) prepolymer of ultrahigh molecular weight obtained at the conversion close to the gel point occurred significantly in SEC columns. That is, the molecular weights determined by both SEC-MALLS and light scattering (LS) me...

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Network-polymer precursors obtained in various crosslinking monovinyl/divinyl copolymerization systems, including benzyl methacrylate/1,6-hexanediol dimethacrylate, benzyl acrylate (BzA)/1,6-hexanediol diacrylate (HDDA), and vinyl benzoate/divinyl adipate, were subjected to degradation during elution through size exclusion chromatography (SEC) columns, although the copolymerizations were conducted under specified conditions where the factors for the greatly delayed gelation from the Flory-Stockmayer gelation theory were reduced. The most remarkable degradation was observed for the BzA/HDDA copolymerization, which provided prepolymers with the most flexible backbone chains. Thus, the BzA/HDDA precopolymers were chosen, and their degradation behavior during elution through SEC columns was explored in detail as one of the representatives of vinyl-type network-polymer precursors. The results were correlated with the structural parameters of network-polymer precursors, including primary polymer chain length, branched structure, and multiple crosslink or network structure. The degradation became more remarkable with decreased primary polymer chain length, that is, the increment of branching, whereas reduced degradation was observed with the incorporation of loop and network structures into the prepolymer.