Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Understanding of informed consent by demented individuals.

BACKGROUND: The informed consent process is central to the conduct of research but may be difficult for cognitively impaired participants to understand. The authors developed a brief test addressing the elements of informed consent for a specific minimum-risk nontreatment research protocol. OBJECTIVE: To evaluate and document understanding of informed consent by elderly research participants across a range of dementia severity. METHODS: The elements of informed consent regarding participation in a longitudinal study of healthy aging and dementia were reviewed with both demented (n = 250) and nondemented (n = 165) participants who then completed a short test requiring yes-no responses to assess understanding of these elements. Demented participants had very mild, mild, or moderate dementia as staged by the Clinical Dementia Rating. RESULTS: After adjusting for education, performance on the test varied with dementia severity in mean differences and by correlation. All nondemented and very mildly demented participants and 92% of mildly demented participants provided correct answers for at least 8 of 10 true-false items, whereas only 67% of the moderately demented participants achieved this level of accuracy. CONCLUSIONS: Demented individuals, very mild and mild, understood informed consent information for this nontreatment research study. Understanding notably declined in the moderate stage of dementia. Brief tests may be useful as one method to assess understanding of the consent process for specific studies.

Motor dysfunction in mildly demented AD individuals without extrapyramidal signs.

BACKGROUND: Although not as prominent as cognitive decline, motor dysfunction occurs in AD, particularly in the later stages of the disease. OBJECTIVE: To determine whether early-stage AD is also characterized by motor impairment. METHODS: We examined very mildly (Clinical Dementia Rating [CDR] 0.5) and mildly (CDR 1) demented AD individuals in comparison with healthy elderly control individuals (CDR 0) on a variety of nonmotor cognitive and psychomotor measures and on four motor measures (gait velocity, finger tapping, reaction time, movement time). To minimize the possibility of extrapyramidal dysfunction contaminating the groups, only individuals who were clinically free of extrapyramidal signs were included in the study. RESULTS: Mildly demented AD individuals were slowed on all motor measures except for finger tapping. No evidence of motor dysfunction was found in the very mildly demented AD group. As expected, both AD groups were impaired on the nonmotor cognitive and psychomotor tests. CONCLUSIONS: These results indicate that AD alone, in the absence of clinically confirmed extrapyramidal dysfunction, is associated with motor slowing in a stage-dependent manner. It remains to be determined whether this motor slowing represents a general characteristic of mild AD or indicates other neuropathology such as PD or the Lewy body variant of AD.

Cognitive and motor functioning in Parkinson disease: subjects with and without questionable dementia.

BACKGROUND: The nature of cognitive performance in subjects with Parkinson disease (PD) without dementia is controversial, perhaps because of failure to exclude subjects with unrecognized very mild dementia. OBJECTIVE: To compare cognitive and motor functioning in well-characterized subjects with PD without overt dementia with healthy elderly control subjects. DESIGN: Subjects' conditions were evaluated clinically and psychometrically at entry into a longitudinal study of cognitive and motor performance in elderly subjects. Measures included a global dementia staging scale, the Washington University Clinical Dementia Rating; psychometric tests, including Logical Memory, Digit Span, Associate Learning, Information, Block Design, Digit Symbol, Trail-making A, Crossing-off, Boston Naming Test, and Word Fluency; and motor measures, including finger tapping, gait velocity, reaction time, and movement time. SETTING: A university-based research facility. SUBJECTS: There were 3 groups of subjects: healthy elderly control subjects (n=43), subjects with PD without dementia (n=58), and subjects with PD with questionable dementia (n=22), each evaluated at time of entry. RESULTS: As expected, both PD groups were impaired on motor measures (gait velocity, finger tapping, and movement time) compared with the healthy elderly control group. Neither PD group showed slowing in reaction time. The subjects with PD with questionable dementia were more impaired on Logical Memory, Block Design, Digit Symbol, and Trailmaking A compared with the subjects with PD without dementia. Although free of clinically evident cognitive dysfunction (Clinical Dementia Rating score, 0), the PD group without dementia was impaired with respect to the healthy elderly control group on all measures from the psychometric assessment except Digit Span, Associate Learning, and Word Fluency. CONCLUSIONS: The PD group without dementia showed global cognitive impairments in comparison with the healthy elderly control group, possibly because the healthy elderly control subjects represented idealized aging. Although the deficits were of small magnitude, this finding suggests that PD may predispose to subclinical cognitive impairment. Longitudinal follow-up is required to determine whether subjects with PD destined to develop overt dementia can be distinguished from those who do not.