The beta‐site amyloid precursor protein cleaving enzyme‐1 (BACE‐1) initiates the generation of amyloid‐β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti‐Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE‐1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP‐transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose‐dependent Aβ reduction in the cerebrospinal fluid. Thus, long‐term, pivotal studies with CNP520 have been initiated in the Generation Program.

Introduction Alzheimer's disease (AD) pathology, including the accumulation of amyloid beta (Aβ) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer's Prevention Initiative Generation Program, therapies targeting Aβ, including CNP520 (umibecestat), a β-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aβ immunotherapy, are in clinical development in preclinical AD. Methods The Alzheimer's Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60–75 years), APOE4 genotype, and, for heterozygotes ( APOE ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer's Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging. Discussion The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.

Background In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified. Methods In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo. Results The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo ( p < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher ( p = 0.003) on the VIP day compared to the placebo day. The difference in headache intensity scores was more evident in the post-infusion period (120–200 min, p = 0.034) and in the post-hospital phase (4–12 h, p = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo ( p = 0.033). Conclusion Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03989817).

Diacutaneous fibrolysis may be an effective and safe therapeutic option to improve active range of motion in patients suffering from painful shoulder.

In the early stage after stroke, within the first 2 weeks, physical therapy (PT) has 2 main goals: prevent immobilityrelated events and stimulate motor control recovery. However, the amount of PT to provide and the time after stroke for provision remain unclear.The organization of care in multidisciplinary stroke units has reduced the risk of death and dependency after stroke, with early mobilization and rehabilitation having an important role.1-3 Very early mobilization (VEM) was defined by the AVERT group (A Very Early Rehabilitation Trial): within the first 24 hours, focusing on out-of-bed activity (sitting, standing, walking), provided at least 3× more than usual care, by physical therapists or nurses. VEM has been found safe and feasible, 4 with a significant positive effect on recovery of walking 50 m unassisted, good functional prognosis on Barthel index at 3 months, 5 and for the frequency of severe complications. 6 Hemorrhagic stroke patients showed a better level of function (walking >15.24 m). 7 The recent European recommendations 8 and those from the American Stroke Association 9 promote VEM, although how early and how much a patient should be mobilized remains controversial. Some negative impact of early (<24 hours) versus delayed (<48 hours) physical rehabilitation has been reported, with increased risk of death. 10Background and Purpose-Intensive physical therapy (PT) facilitates motor recovery when provided during a subacute stage after stroke. The efficiency of very early intensive PT has been less investigated. We aimed to investigate whether intensive PT conducted within the first 2 weeks could aid recovery of motor control. Methods-This multicentre randomized controlled trial compared soft PT (20-min/d apart from respiratory needs) and intensive PT (idem+45 minutes of intensive exercises/day) initiated within the first 72 hours after a first hemispheric stroke. The primary outcome was change in motor control between day (D) 90 and D0 assessed by the Fugl-Meyer score. Main secondary outcomes were number of days to walking 10 m unassisted, balance, autonomy, quality of life, and unexpected medical events. All analyses were by intent to treat. Results-We could analyze data for 103 of the 104 included patients (51 control and 52 experimental group; 64 males; median age overall 67 [interquartile range 59-77], 67 right hemispheric lesions, 80 ischemic lesions, National Institutes of Health Stroke Scale score ≥8 for 82%). Fugl-Meyer score increased over time (P<0.0001), with no significant effect of treatment (P=0.29) or interaction between treatment and time (P=0.40). The median change in score between D90 and D0 was 27.5 (12-40) and 22.0 (12-56) for control and experimental groups (P=0.69). Similar results were found for the secondary criteria. Conclusions-Very early after stroke, intensive exercises may not be efficient in improving motor control. This conclusion may apply to mainly severe stroke. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01520636.