Graff‐Radford, Neill R.

Objectives To investigate whether demographic (age and education) adjustments for the Mini‐Mental State Examination ( MMSE ) attenuate mean score discrepancies between African‐American and Caucasian adults and whether demographically adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African‐American adults over unadjusted MMSE scores. Design Cross‐sectional study. Setting Community‐dwelling adults participating in the Mayo Clinic A lzheimer's Disease Patient Registry and A lzheimer's Disease Research Center. Participants Three thousand two hundred fifty‐four adults (2,819 Caucasian, 435 African American) aged 60 and older. Measurements MMSE score at study entry. Results African‐American adults had significantly lower unadjusted MMSE scores (23.0 ± 7.4) than Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly derived weights. Controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. In African‐American adults, an age‐ and education‐adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African‐American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia. Conclusion Age, dementia severity at study entry, and quality of educational experience are important explanatory factors in understanding the existing discrepancies in MMSE performance between Caucasian and African‐American adults. These findings support the use of unadjusted MMSE scores when screening older African Americans for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15 , in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila , with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.