The Value of Pre-Screening in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease Trial.

The Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) trial evaluates the anti-amyloid-ß antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre-screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed pre-screening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD.

Doxepin and cognitive behavioural therapy for insomnia in patients with Parkinson's disease -- a randomized study.

INTRODUCTION: Although a variety of pharmacologic and non-pharmacologic treatments are effective for insomnia in the general population, insomnia in Parkinson's disease differs in important ways and may need different treatments. No studies have conclusively demonstrated effective insomnia treatments in Parkinson's disease. METHODS: We conducted a three-arm six-week randomized pilot study assessing non-pharmacologic treatment (cognitive behavioural therapy with bright light therapy) or doxepin (10 mg daily), compared to an inactive placebo in Parkinson's patients with insomnia. Sleep outcomes included insomnia scales, clinical global impression, sleep diaries and actigraphy. Secondary outcomes included motor severity, fatigue, depression and quality of life. RESULTS: 18 patients were randomized, 6 to each group. Compared to placebo, doxepin improved the Insomnia Severity Index (-9 ± 5.4 vs. -2 ± 3.9, p = 0.03), the SCOPA-night score (-5.2 ± 1.5 vs. -2.3 ± 2.8, p = 0.049), the Pittsburgh Sleep Quality Index-sleep disturbances subscale (-0.5 ± 0.5 vs 0.2 ± 0.4, p = 0.02), and both patient and examiner-rated clinical global impression of change (1.7 ± 0.8 vs. 0.5 ± 0.8, p = 0.03 and 1.4 ± 0.5 vs. 0.3 ± 0.5, p = 0.003). On secondary outcomes doxepin reduced the fatigue severity scale (p = 0.02) and improved scores on the Montreal Cognitive Assessment (p = 0.007). Non-pharmacological treatment reduced the Insomnia Severity Index (-7.8 ± 3.8 vs. -2.0 ± 3.9, p = 0.03), and the examiner-reported clinical global impression of change (p = 0.006), but was associated with decline in Parkinson Disease Questionnaire-39. There were no changes in other primary and secondary outcomes, including actigraphy outcomes. Adverse events were comparable in all groups. CONCLUSION: Doxepin and non-pharmacologic treatment substantially improved insomnia in Parkinson's disease. These potential benefits must be replicated in a full confirmatory randomized controlled trial.

Restless legs syndrome outside the blood-brain barrier--exacerbation by domperidone in Parkinson's disease.

INTRODUCTION: Models of dopaminergic function in restless legs focus on central dopaminergic neurons. Domperidone, a peripheral dopamine blocker that cannot cross the blood-brain barrier, is commonly used in Parkinson's disease. After encountering a case of restless legs syndrome that dramatically worsened with domperidone, we assessed whether Parkinson's patients may have exacerbation of restless legs with domperidone. METHODS: From two Parkinson's disease cohorts, we assessed restless legs prevalence according to standard criteria, in patients taking vs. not taking domperidone. Regression analysis was performed, adjusting for age, sex, disease duration, UPDRS, dopaminergic medications and other medications. RESULTS: One hundred eighty four patients were assessed, of whom 46 (25%) had restless legs. Thirteen out of twenty seven (48%) patients on domperidone had restless legs compared to 33/157 (21%) without (p = 0.010). Other medications were not associated with restless legs. CONCLUSION: This unexpected finding suggests that dopaminergic neurons outside of the blood-brain barrier may be important in restless legs syndrome pathophysiology.

[Pharmacotherapy of the cognitive sequelae secondary to traumatic brain injury]. / Farmacoterapia de las secuelas cognitivas secundarias a traumatismo craneoencefálico.

AIM: To review and correlate the most common cognitive disorders secondary to traumatic brain injuries (TBI), the neurobiology of these deficits and their possible modulation by neuropharmacological means. DEVELOPMENT: As of a complex cascade of injuries to the brain, patients with TBI may experience alterations that affect the cognitive domain on different levels and to varying degrees, the most common being alteration of the level of alertness; slowing of the speed at which information is processed; attention, memory and learning deficits; language and communication disorders; and impaired executive functions. Brain damage may be caused by a range of pathological mechanisms, such as focal bruising, diffuse axonal damage, cytotoxic damage and neurotransmitter excitotoxicity. Certain pharmacological agents have an effect on the cognitive functions. Pharmacological agents that improve cognitive performance include dopaminergic agents, psychostimulants, some antidepressants and cholinesterase inhibitors. CONCLUSIONS: Studies into the pharmacological neuromodulation of the cognitive disorders secondary to TBI are currently in the early stages. The information we have available on the neurochemical bases of cognition and cognitive disorders due to TBI suggest that the most important goals of pharmacological intervention in this group of patients are the stimulation of the catecholaminic and cholinergic functions.