Objective-To assess the feasibility of using magnetic resonance imaging (MRI) measurements as a surrogate end point for disease progression in a therapeutic trial for Alzheimer's disease (AD).Methods-Three-hundred-sixty-two patients with probable AD from 38 different centers participated in the MRI portion of a 52 week randomized placebo controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI one-year later. Hippocampal volume and temporal horn volume were measured from the MRI scans.Results-The annualized percent change in hippocampal volume (−4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/ cognitive measures (p<0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over one year are: ADASCog 320; MMSE 241; hippocampal volume 21; temporal horn volume fifty-four. Conclusion-The consistency of MRI measurements obtained across sites, and the consistency between the multi-site milameline data and that obtained in prior single site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate end point of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD still awaits a positive trial.The primary outcome measurements for therapeutic trials in Alzheimer's disease (AD) patients are behavioral or cognitive. Due to the inherent test-retest variability in such measurements however, alternatives have been sought. Magnetic resonance imaging (MRI) measurements of rates of whole brain or hippocampal atrophy have been, and are currently being used as outcome measures in several therapeutic trials for AD. Although imaging has been used in clinical trials on AD and vascular disease for diagnostic purposes, to our knowledge, no publication has appeared describing the MRI results of a therapeutic trial in which structural MRI was used as NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript an outcome measure. MRI measures were added to this trial to gain a claim for effects on disease progression as opposed to just symptomatic treatment in those instances where treatment effect was shown on the behavioral/cognitive measures 1-7 .We report the MRI results of a therapeutic trial of milameline, a centrally active muscari...
Treatment with tacrine at doses > 80 mg/d was associated with a reduced likelihood of NHP. These data demonstrate that tacrine's 30-week effects on cognitive function and clinicians' global ratings may generalize to effects on a major milestone of AD. Future studies should attempt to replicate these findings prospectively.
SynopsisPrior research has indicated that the type-token ratio (TTR), a measure of repetition in language, correlates with clinical judgements of thought disorder when spoken language was examined, and differentiates statistically thought-disordered from non-thought-disordered schizophrenics and psychiatric and normal controls. We replicated this finding and examined the clinical sensitivity and specificity of the TTR measure in the diagnosis and in the assessment of thought disorder. The current clinical value of the TTR is limited, but further investigations of the nature of repetition in schizophrenic language are warranted.
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