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BackgroundWe evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.MethodsAmyloid β levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects.ResultsPlasma Aβ levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Aβ40 than disease‐free vessels. Inactivated platelets contained more Aβ peptides than activated ones. Substantially more Aβ was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Aβ.ConclusionsEfforts to use plasma levels of Aβ peptides as AD biomarkers or disease‐staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Aβ values is also due in part to the ability of Aβ to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Aβ plasma levels. Furthermore, the long‐range impact of Aβ immunotherapy on peripheral Aβ sources should also be considered.

ObjectiveTo identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia.Study Design and SettingA multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities.ResultsOperational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study.ConclusionsThe highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials.SignificanceThis document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology.

This investigation examined listener transcriptions of phrases produced by speakers with mild to severe hypokinetic dysarthria to examine individual strategies for the identification of word boundaries in connected speech. It was hypothesized that the most efficient listeners would use syllabic strength information to guide their parsing of the continuous acoustic stream. Six-hundred transcribed phrases (10 listeners ×60 phrases) were coded independently by two judges to identify (1) correct word transcriptions, (2) evidence of accurate lexical parsing, regardless of exact word identification, and (3) the proportions of accurate parsing of strong and weak syllable word onsets. Linear regression analysis of the group data revealed that correct segmentation of strong syllable word onsets predicted listener performance on segmenting weak syllable word onsets [R=0.805, F(1,29)=51.440, p<0.001]. Despite a wide range of listener performance on ``words correct,'' individual strategies for perceptual segmentation were evident only in the transcriptions for the most severe speaker. In this case, the poorest listeners exhibited disproportionate difficulty with the segmentation weak syllable word onsets. Results suggest that a listener's ability to use syllabic strength information in lexical parsing determines, in part, their ability to recognize word onsets. [Work supported by NIDCD, NIH.]

This study is the third in a series that has explored the source of intelligibility decrement in dysarthria by jointly considering signal characteristics and the cognitive–perceptual processes employed by listeners. A paradigm of lexical boundary error analysis was used to examine this interface by manipulating listener constraints with a brief familiarization procedure. If familiarization allows listeners to extract relevant segmental and suprasegmental information from dysarthric speech, they should obtain higher intelligibility scores than nonfamiliarized listeners, and their lexical boundary error patterns should approximate those obtained in misperceptions of normal speech. Listeners transcribed phrases produced by speakers with either hypokinetic or ataxic dysarthria after being familiarized with other phrases produced by these speakers. Data were compared to those of nonfamiliarized listeners [Liss et al., J. Acoust. Soc. Am. 107, 3415–3424 (2000)]. The familiarized groups obtained higher intelligibility scores than nonfamiliarized groups, and the effects were greater when the dysarthria type of the familiarization procedure matched the dysarthria type of the transcription task. Remarkably, no differences in lexical boundary error patterns were discovered between the familiarized and nonfamiliarized groups. Transcribers of the ataxic speech appeared to have difficulty distinguishing strong and weak syllables in spite of the familiarization. Results suggest that intelligibility decrements arise from the perceptual challenges posed by the degraded segmental and suprasegmental aspects of the signal, but that this type of familiarization process may differentially facilitate mapping segmental information onto existing phonological categories.

This investigation evaluated a possible source of reduced intelligibility in hypokinetic dysarthric speech, namely the mismatch between listeners’ perceptual strategies and the acoustic information available in the dysarthric speech signal. A paradigm of error analysis was adopted in which listener transcriptions of phrases were coded for the presence and type of word boundary errors. Seventy listeners heard 60 phrases produced by speakers with hypokinetic dysarthria. The six-syllable phrases alternated strong and weak syllables and ranged in length from three to five words. Lexical boundary violations were defined as erroneous insertions or deletions of lexical boundaries that occurred either before strong or before weak syllables. A total of 1596 lexical boundary errors in the listeners’ transcriptions was identified unanimously by three independent judges. The pattern of errors generally conformed with the predictions of the Metrical Segmentation Strategy hypothesis [Cutler and Norris, J. Exp. Psychol. 14, 113–121 (1988)] which posits that listeners attend to strong syllables to identify word onsets. However, the strength of adherence to this pattern varied across speakers. Comparison of acoustic evidence of syllabic strength to lexical boundary error patterns revealed a source of intelligibility deficit associated with this particular type of dysarthric speech pattern.