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Daily use of atogepant (a small-molecule, calcitonin gene–related peptide receptor antagonist) at any of three doses resulted in greater reductions in migraine days per month over a period of 12 weeks than did placebo. Nausea and constipation were side effects in approximately 5% of the participants who received atogepant.

Aim: We sought to identify markers of motor and nonmotor function in Parkinson's disease (PD) using advanced neuroimaging techniques in subjects with PD. Methods: We enrolled 26 nondemented PD subjects and 12 control subjects. All subjects underwent [ 18 F]fluorodeoxyglucose positron emission computed tomography (FDG-PET) and magnetic resonance imaging, and a complete neuropsychological battery. Results: FDG-PET of subjects with PD revealed significant metabolic elevations in the bilateral posterior lentiform nucleus, posterior cingulate, and parahippocampus, and metabolic reductions in the bilateral temporoparietal association cortex and occipital lobe versus controls. PD subjects had significant reductions in executive/attention function, memory/verbal learning, and speed of thinking, and significantly increased depression, anxiety and apathy scores compared with controls. Motor dysfunction correlated with increased metabolism in the posterior lentiform nucleus, pons, and cerebellum, and decreased metabolism in the temporoparietal lobe. Cognitive dysfunction correlated with increased posterior cingulate metabolism and decreased temporoparietal lobe metabolism. Depressive symptoms correlated with increased amygdala metabolism; anxiety scores correlated with decreased caudate metabolism, and apathy scores correlated with increased metabolism in the anterior cingulate and orbitofrontal lobe and decreased metabolism in the temporoparietal association cortex. Conclusions: Our findings showed that motor, cognitive, and emotional dysfunction in PD are associated with distinct patterns of cerebral metabolic changes.

Alien hand syndrome (AHS) is a disorder of involuntary, yet purposeful, hand movements that may be accompanied by agnosia, aphasia, weakness, or sensory loss. We herein review the most reported cases, current understanding of the pathophysiology, and treatments. We performed a PubMed search in July of 2014 using the phrases \"alien hand syndrome,\" \"alien hand syndrome pathophysiology,\" \"alien hand syndrome treatment,\" and \"anarchic hand syndrome.\" The search yielded 141 papers (reviews, case reports, case series, and clinical studies), of which we reviewed 109. Non-English reports without English abstracts were excluded. Accumulating evidence indicates that there are three AHS variants: frontal, callosal, and posterior. Patients may demonstrate symptoms of multiple types; there is a lack of correlation between phenomenology and neuroimaging findings. Most pathologic and functional imaging studies suggest network disruption causing loss of inhibition as the likely cause. Successful interventions include botulinum toxin injections, clonazepam, visuospatial coaching techniques, distracting the affected hand, and cognitive behavioral therapy. The available literature suggests that overlap between AHS subtypes is common. The evidence for effective treatments remains anecdotal, and, given the rarity of AHS, the possibility of performing randomized, placebo-controlled trials seems unlikely. As with many other interventions for movement disorders, identifying the specific functional impairments caused by AHS may provide the best guidance towards individualized supportive care.

In this study, we aimed to evaluate the efficacy, safety, and tolerability of atogepant for the preventive treatment of chronic migraine. We did this randomised, double-blind, placebo-controlled, phase 3 trial at 142 clinical research sites across the USA, the UK, Canada, China, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Poland, Russia, Spain, Sweden, and Taiwan. Adults aged 18−80 years with a 1-year or longer history of chronic migraine were randomly assigned (1:1:1) to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. The primary analysis was done in the modified intent-to-treat population and included all randomly assigned participants who received at least one dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had at least one evaluable post-baseline 4-week period (weeks 1–4, 5–8, and 9–12) of eDiary data during the double-blind period. The safety population consisted of all participants who received at least one dose of study intervention. This trial is registered with ClinicalTrials.gov (NCT03855137). Between March 11, 2019 and Jan 20, 2022, 1489 participants were assessed for eligibility. 711 were excluded, and 778 participants were randomly assigned to atogepant 30 mg twice a day (n=257), atogepant 60 mg once a day (n=262), or placebo (n=259). Participants in the safety population were aged 18–74 years (mean 42·1 years). 459 (59%) of 773 patients were White, 677 (88%) patients were female, and 96 (12%) were male. 84 participants discontinued treatment during the trial, and 755 comprised the modified intent-to-treat population (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246). Baseline mean number of MMDs were 18·6 (SE 5·1) with atogepant 30 mg twice a day, 19·2 (5·3) with atogepant 60 mg once a day, and 18·9 (4·8) with placebo. Change from baseline in mean MMDs across 12 weeks was −7·5 (SE 0·4) with atogepant 30 mg twice a day, −6·9 (0·4) with atogepant 60 mg once a day, and −5·1 (0·4) with placebo. Least squares mean difference from placebo was −2·4 with atogepant 30 mg twice a day (95% CI −3·5 to −1·3; adjusted p<0·0001) and −1·8 with atogepant 60 mg once a day (−2·9 to −0·8; adjusted p=0·0009). Most common adverse events for atogepant were constipation (30 mg twice a day 28 [10·9%]; 60 mg once a day 26 [10%]; and placebo 8 [3%]) and nausea (30 mg twice a day 20 [8%]; 60 mg once a day 25 [10%]; and placebo 9 [4%]). Potentially clinically significant weight decrease (≥7% reduction at any time post-baseline) was observed in each treatment group (atogepant 30 mg twice a day 14 [6%]; atogepant 60 mg once a day 15 [6%]; and placebo 5 [2%]). Atogepant 30 mg twice a day and 60 mg once a day showed clinically relevant reductions in MMDs across 12 weeks in chronic migraine patients. Both atogepant doses were well tolerated, consistent with the known safety profile of atogepant. Allergan (now AbbVie).

Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a migraine attack and is characterised by non-aura symptoms that precede headache onset. The aim of this trial was to evaluate the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome. This PRODROME trial was a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial of ubrogepant 100 mg conducted at 75 research centres and headache clinics in the USA. Eligible participants were adults aged 18–75 years who had at least a 1-year history of migraine with or without aura and a history of two to eight migraine attacks per month with moderate to severe headache in each of the 3 months before screening. Eligible participants were randomly assigned (1:1) to either receive placebo to treat the first qualifying prodrome event and ubrogepant 100 mg to treat the second qualifying prodrome event or to receive ubrogepant 100 mg to treat the first qualifying prodrome event and placebo to treat the second qualifying prodrome event. An automated interactive web-response system used permuted blocks of four to manage randomisation. All people giving interventions and assessing outcomes were masked to group assignment during the study. People doing data analysis, which occurred after study completion, were not masked to group assignment. During the double-blind treatment period, each participant was instructed to orally take two tablets of the study drug at the onset of each qualifying prodrome event. The primary endpoint was absence of moderate or severe intensity headache within 24 h after study-drug dose; efficacy analyses were conducted with the modified intention-to-treat (mITT) population, defined as all randomly assigned participants with at least one headache assessment within 24 h after taking the study drug during the treatment period. The safety population included all treated participants who took at least one administration of study drug. The trial is registered with ClinicalTrials.gov (NCT04492020). Between Aug 21, 2020, and April 19, 2022, 518 participants were randomly assigned to double-blind crossover treatment. The safety population included 480 participants and the mITT population included 477 participants; 421 (88%) of 480 participants were female and 59 (12%) were male. Absence of moderate or severe headache within 24 h after a dose occurred after 190 (46%) of 418 qualifying prodrome events that had been treated with ubrogepant and after 121 (29%) of 423 qualifying prodrome events that had been treated with placebo (odds ratio 2·09, 95% CI 1·63–2·69; p<0·0001). Adverse events that occurred within 48 h after study-drug administration were reported after 77 (17%) of 456 qualifying prodrome events that had been treated with ubrogepant and after 55 (12%) of 462 events that had been treated with placebo. Ubrogepant was effective and well tolerated for the treatment of migraine attacks when taken during the prodrome. AbbVie.

Parkinson’s disease (PD) is an age-related, progressive, multisystem neurodegenerative disorder resulting in significant morbidity and mortality, as well as a growing social and financial burden in an aging population. The hallmark of PD is loss of dopaminergic neurons of the substantia nigra pars compacta, leading to bradykinesia, rigidity and tremor. Current pharmacological treatment is therefore centred upon dopamine replacement to alleviate symptoms. However, two major problems complicate this approach: (i) motor symptoms continue to progress, requiring increasing doses of medication, which result in both short-term adverse effects and intermediate- to long-term motor complications; (ii) dopamine replacement does little to treat non-dopaminergic motor and non-motor symptoms, which are an important source of morbidity, including dementia, sleep disturbances, depression, orthostatic hypotension, and postural instability leading to falls. It is critical, therefore, to develop a broader and more fundamental therapeutic approach to PD, and major research efforts have focused upon developing neuroprotective interventions. Despite many encouraging preclinical data suggesting the possibility of addressing the underlying pathophysiology by slowing cell loss, efforts to translate this into the clinical realm have largely proved disappointing in the past. Barriers to finding neuroprotective or disease-modifying drugs in PD include a lack of validated biomarkers of progression, which hampers clinical trial design and interpretation; difficulties separating symptomatic and neuroprotective effects of candidate neuroprotective therapies; and possibly fundamental flaws in some of the basic preclinical models and testing. However, three recent clinical trials have used a novel delayed-start design in an attempt to overcome some of these roadblocks. While not examining markers of cell loss and function, which would determine neuroprotective effects, this trial design pragmatically tests whether earlier versus later intervention is beneficial. If positive (i.e. if an earlier intervention proves more effective), this demonstrates disease modification, which could result from neuroprotection or from other mechanisms. This strategy therefore provides a first step towards supporting neuroprotection in PD. Of the three delayed-start design clinical trials, two have investigated early versus later start of rasagiline, a specific irreversible monoamine oxidase B inhibitor. Each trial has supported, although not proven, disease-modifying effects. A third delayed-start-design clinical trial examining potential disease-modifying effects of pramipexole has unfortunately reportedly been negative according to preliminary presentations. The suggestion that rasagiline is disease modifying is made all the more compelling by in vitro and PD animal-model studies in which rasagiline was shown to have neuroprotective effects. In this review, we examine efforts to demonstrate neuroprotection in PD to date, describe ongoing neuroprotection trials, and critically discuss the results of the most recent delayed-start clinical trials that test possible disease-modifying activities of rasagiline and pramipexole in PD.

The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding. This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023. Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD – autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive–compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001). Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease. Michael J Fox Foundation for Parkinson's Research.

Some patients with migraine, particularly those in primary care, require effective, well-tolerated, migraine-specific oral preventive treatments. To examine the efficacy of atogepant, an oral, small-molecule, calcitonin gene-related peptide receptor antagonist, using 4 levels of mean monthly migraine-day (MMD) responder rates. This secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial evaluated the efficacy and safety of atogepant for the preventive treatment of migraine from December 14, 2018, to June 19, 2020, in adults with 4 to 14 migraine-days per month at 128 sites in the US. Patients were administered 10 mg of atogepant (n = 222), 30 mg of atogepant (n = 230), 60 mg of atogepant (n = 235), or placebo (n = 223) once daily in a 1:1:1:1 ratio for 12 weeks. These analyses evaluated treatment responder rates, defined as participants achieving 50% or greater (α-controlled, secondary end point) and 25% or greater, 75% or greater, and 100% (prespecified additional end points) reductions in mean MMDs during the 12-week blinded treatment period. Of 902 participants (mean [SD] age, 41.6 [12.3] years; 801 [88.8%] female; 752 [83.4%] White; 825 [91.5%] non-Hispanic), 873 were included in the modified intention-to-treat population (placebo, 214; 10 mg of atogepant, 214; 30 mg of atogepant, 223; and 60 mg of atogepant, 222). For the secondary end point, a 50% or greater reduction in the 12-week mean of MMDs was achieved by 119 of 214 participants (55.6%) treated with 10 mg of atogepant (odds ratio, 3.1; 95% CI, 2.1-4.6), 131 of 223 participants (58.7%) treated with 30 mg atogepant (odds ratio, 3.5; 95% CI, 2.4-5.3), 135 of 222 participants (60.8%) treated with 60 mg of atogepant (odds ratio, 3.8; 95% CI, 2.6-5.7), and 62 of 214 participants (29.0%) given placebo (P < .001). The numbers of participants who reported a 25% or greater reduction in the 12-week mean of MMDs were 157 of 214 (73.4%) for 10 mg of atogepant, 172 of 223 (77.1%) for 30 mg of atogepant, and 180 of 222 (81.1%) for 60 mg of atogepant vs 126 of 214 (58.9%) for placebo (P < .002). The numbers of participants who reported a 75% or greater reduction in mean MMDs were 65 of 214 (30.4%) for 10 mg of atogepant, 66 of 223 (29.6%) for 30 mg of atogepant, and 84 of 222 (37.8%) for 60 mg of atogepant compared with 23 of 214 (10.7%) for placebo (P < .001). The numbers of participants reporting 100% reduction in mean MMDs were 17 of 214 (7.9%) for 10 mg of atogepant (P = .004), 11 of 223 (4.9%) for 30 mg of atogepant (P = .02), and 17 of 222 (7.7%) for 60 mg of atogepant (P = .003) compared with 2 of 214 (0.9%) for placebo. At all doses, atogepant was effective during the 12-week double-blind treatment period beginning in the first 4 weeks, as evidenced by significant reductions in mean MMDs at every responder threshold level. Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses. ClinicalTrials.gov Identifier: NCT03777059.