Responder rates with eptinezumab over 24 weeks in patients with prior preventive migraine treatment failures: post hoc analysis of the DELIVER randomized clinical trial.

BACKGROUND AND PURPOSE: Eptinezumab reduced monthly migraine days more than placebo in the DELIVER study, a clinical trial with patients with difficult-to-treat migraine and prior preventive treatment failures. This post hoc analysis assesses the sustained response to eptinezumab at the population and patient level and evaluates the potential for response in initial non-responders. METHODS: Adults with chronic or episodic migraine and two to four prior preventive treatment failures were randomized to eptinezumab 100 mg, 300 mg or placebo every 12 weeks. Primary outcomes in this post hoc analysis are the proportion of patients with ≥30%, ≥50% or ≥75% reduction in monthly migraine days (i.e., migraine responder rates [MRRs]) during weeks 1-12 and weeks 13-24 and across 4-week intervals. Secondary outcomes are maintenance and shifts in MRRs from weeks 1-12 to weeks 13-24. RESULTS: Between weeks 1-12 and 13-24, ≥30% MRRs increased from 65.9% to 70.4% (100 mg) and from 71.0% to 74.5% (300 mg), versus 36.9% to 43.1% (placebo). The ≥50% and ≥75% MRRs were sustained or increased over the 24-week period. The largest increase in ≥30% MRRs occurred after the second infusion with eptinezumab. The percentage of initial non-responders (<30% MRRs during weeks 1-12) who experienced response (≥30% MRRs during weeks 13-24) to the second dose was 34.7% (100 mg) and 30.4% (300 mg) with eptinezumab versus 21.1% with placebo. CONCLUSION: Across MRR thresholds, most patients who responded to eptinezumab during weeks 1-12 maintained or improved response during weeks 13-24. More than one-third of initial non-responders became responders after their second infusion.

Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.R406W patients. Over 18 years follow-up, we extended the family with 10 p.R406W carriers and provided an in-depth clinical description of the patients. Additionally, genetic screening was used to identify p.R406W carriers in Belgian cohorts of frontotemporal dementia and Alzheimer's disease patients and to calculate p.R406W frequency. In the frontotemporal dementia cohort, we found four p.R406W carriers (n = 647, 0.62%) and three in the Alzheimer's disease cohort (n = 1134, 0.26%). Haplotype sharing analysis showed evidence of a shared haplotype suggesting that they are descendants of a common ancestor. Of the p.R406W patients, we describe characteristics of neuropsychological, imaging and fluid biomarkers as well as neuropathologic examination. Intriguingly, the phenotypic spectrum among the p.R406W patients ranged from typical behavioural variant frontotemporal dementia to clinical Alzheimer's disease, based on CSF biomarker analysis and amyloid PET scan. Heterogeneous overlap syndromes existed in between, with highly common neuropsychiatric symptoms like disinhibition and aggressiveness, which occurred in 100% of frontotemporal dementia and 58% of clinical Alzheimer's disease patients. This was also the case for memory problems, 89% in frontotemporal dementia and 100% in clinical Alzheimer's disease patients. Median age at death was significantly lower in patients with frontotemporal dementia (68 years) compared to clinical Alzheimer's disease patients (79 years), although the sizes of the sub-cohorts are limited and do not allow prognostic predictions. Post-mortem brain analysis of one p.R406W patient with behavioural variant frontotemporal dementia revealed frontotemporal lobar degeneration with tau pathology. Notably, neuropathological investigation showed only 3R tau isoforms in the absence of 4R tau reactivity, an unusual finding in microtubule-associated protein tau-related frontotemporal lobar degeneration. No traces of amyloid pathology were present. Prevalence of the p.R406W mutation was relatively high in both frontotemporal dementia and Alzheimer's disease Belgian patient cohorts. These findings grant new insights into genotype-phenotype correlations of p.R406W carriers. They may help in further unravelling of the pathophysiology of this tauopathy and in facilitating the identification of patients with p.R406W-related frontotemporal lobar degeneration, both in clinical diagnostic and research settings.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention - part 4: propranolol.

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing propranolol for migraine prophylaxis. METHODS: We report methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared propranolol with placebo for migraine prophylaxis in adults. The outcomes of interest were informed by the Core outcome set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in monthly migraine days, the reduction of monthly migraine days, and the number of adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB (risk of bias) 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded twenty trials (n = 1291 patients) eligible for data synthesis and analysis. The analysis revealed a moderate certainty evidence that propranolol leads to a reduction in monthly migraine days versus placebo (-1.27; 95% CI: -2.25 to -0.3). We found moderate certainty evidence that propranolol increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo with a relative risk of 1.65 (95% CI 1.41 to 1.93); absolute risk difference: 179 more per 1,000 (95% CI 113 to 256). We found high certainty evidence that propranolol increases the proportion of patients who discontinue due to adverse events compared to placebo with a risk difference of 0.02 (95% CI 0.00 to 0.03); absolute risk difference: 20 more per 1,000 (95% CI 0 to 30). CONCLUSIONS: The present meta-analysis shows that propranolol has a prophylactic role in migraine, with an overall acceptable tolerability profile. Combining these results with its long-standing use and its global availability at a low cost confirms its role as a first line agent in the prophylaxis of migraine.

Ten open questions in migraine prophylaxis with monoclonal antibodies blocking the calcitonin-gene related peptide pathway: a narrative review.

The monoclonal antibodies (mAbs) blocking the calcitonin-gene related peptide (CGRP) pathway, collectively called here "anti-CGRP/rec mAbs", have dramatically improved preventive migraine treatment. Although their efficacy and tolerability were proven in a number of randomized controlled trials (RCTs) and, maybe even more convincingly, in real world settings, a number of open questions remain. In this narrative review, we will analyze published data allowing insight in some of the uncertainties related to the use of anti-CGRP/rec mAbs in clinical practice: their differential efficacy in migraine subtypes, outcome predictors, switching between molecules, use in children and adolescents, long-term treatment adherence and persistence, effect persistence after discontinuation, combined treatment with botulinum toxin or gepants, added-value and cost effectiveness, effectiveness in other headache types, and potential contraindications based on known physiological effects of CGRP. While recent studies have already provided hints for some of these questions, many of them will not find reliable and definitive answers before larger studies, registries or dedicated RCTs are available.

The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis.

OBJECTIVE: While there are several trials that support the efficacy of various drugs for migraine prophylaxis against placebo, there is limited evidence addressing the comparative safety and efficacy of these drugs. We conducted a systematic review and network meta-analysis to facilitate comparison between drugs for migraine prophylaxis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to August 13, 2022, for randomized trials of pharmacological treatments for migraine prophylaxis in adults. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist random-effects network meta-analysis and rated the certainty (quality) of evidence as either high, moderate, low, or very low using the GRADE approach. RESULTS: We identified 74 eligible trials, reporting on 32,990 patients. We found high certainty evidence that monoclonal antibodies acting on the calcitonin gene related peptide or its receptor (CGRP(r)mAbs), gepants, and topiramate increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo. We found moderate certainty evidence that beta-blockers, valproate, and amitriptyline increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, and low certainty evidence that gabapentin may not be different from placebo. We found high certainty evidence that, compared to placebo, valproate and amitriptyline lead to substantial adverse events leading to discontinuation, moderate certainty evidence that topiramate, beta-blockers, and gabapentin increase adverse events leading to discontinuation, and moderate to high certainty evidence that (CGRP(r)mAbs) and gepants do not increase adverse events. CONCLUSIONS: (CGRP(r)mAbs) have the best safety and efficacy profile of all drugs for migraine prophylaxis, followed closely by gepants.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 2: flunarizine.

OBJECTIVE: Novel disease-specific and mechanism-based treatments sharing good evidence of efficacy for migraine have been recently marketed. However, reimbursement by insurers depends on treatment failure with classic anti-migraine drugs. In this systematic review and meta-analysis, we aimed to identify and rate the evidence for efficacy of flunarizine, a repurposed, first- or second-line treatment for migraine prophylaxis. METHODS: A systematic search in MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Eligible trials for meta-analysis were randomized, placebo-controlled studies comparing flunarizine with placebo. Outcomes of interest according to the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) were the proportion of patients reaching a 50% or more reduction in monthly migraine days, the change in monthly migraine days (MMDs), and Adverse Events (AEs) leading to discontinuation. RESULTS: Five trials were eligible for narrative description and three for data synthesis and analysis. No studies reported the predefined outcomes, but one study assessed the 50% reduction in monthly migraine attacks with flunarizine as compared to placebo showing a benefit from flunarizine with a low or probably low risk of bias. We found that flunarizine may increase the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.02; 95% CI -0.03 to 0.06). CONCLUSIONS: Published flunarizine trials predate the recommended endpoints for evaluating migraine prophylaxis drugs, hence the lack of an adequate assessment for these endpoints. Further, modern-day, large-scale studies would be valuable in re-evaluating the efficacy of flunarizine for the treatment of migraines, offering additional insights into its potential benefits.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 1: amitriptyline.

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. METHODS: We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more). CONCLUSIONS: Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.

European Headache Federation (EHF) critical reappraisal and meta-analysis of oral drugs in migraine prevention - part 3: topiramate.

OBJECTIVE: Topiramate is a repurposed first-line treatment for migraine prophylaxis. The aim of this systematic review and meta-analysis is to critically re-appraise the existing evidence supporting the efficacy and tolerability of topiramate. METHODS: A systematic search in MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis as of August 13, 2022, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Randomized controlled trials in adult patients that used topiramate for the prophylactic treatment of migraine, with placebo as active comparator, were included. Two reviewers independently screened the retrieved studies and extracted all data. Outcomes of interest were the 50% responder rates, the reduction in monthly migraine days, and adverse events leading to treatment discontinuation. Results were pooled and meta-analyzed, with sensitivity analysis based on the risk of bias of the studies, the monthly migraine days at baseline, and the previous use of other prophylactic treatments. Certainty evidence was judged according to the GRADE framework. RESULTS: Eight out of 10,826 studies fulfilled the inclusion/exclusion criteria, accounting for 2,610 randomized patients. Six studies included patients with episodic migraine and two with chronic migraine. Topiramate dose ranged from 50 to 200 mg/day, and all studies included a placebo arm. There was a high certainty that topiramate: 1) increased the proportion of patients who achieved a 50% responder rate in monthly migraine days, compared to placebo [relative risk: 1.61 (95% confidence interval (CI): 1.29-2.01); absolute risk difference: 168 more per 1,000 (95% CI: 80 to 278 more)]; 2) was associated with 0.99 (95% CI: 1.41-0.58) fewer migraine days than placebo; 3) and had a higher proportion of patients with adverse events leading to treatment discontinuation [absolute risk difference 80 patients more per 1,000 (95% CI: 20 to 140 more patients)]. CONCLUSIONS: There is high-quality evidence of the efficacy of topiramate in the prophylaxis of migraine, albeit its use poses a risk of adverse events that may lead to treatment discontinuation, with a negative effect on patient satisfaction and adherence to care.

A qualitative study with people with young-onset dementia and their family caregivers on advance care planning: A holistic, flexible, and relational approach is recommended.

BACKGROUND: Broad consensus exists on the relevance of advance care planning in dementia. Although people with young-onset dementia and their family are hypothesized to have distinct needs and preferences in this area, they are hardly ever included in studies. AIM: We aim to explore the experiences with and views on advance care planning of people with young-onset dementia and their family caregivers. DESIGN: A qualitative study was conducted, analyzing semi-structured interviews through the method of constant comparative analysis. SETTING/PARTICIPANTS: We included 10 people with young-onset dementia and 10 of their family caregivers in Flanders. RESULTS: Participants lacked awareness about the concept of advance care planning, especially as a communication process. They had not or barely engaged in planning future care yet pointed out possible benefits of doing so. Initially, people with young-onset dementia and their caregivers directly associated advance care planning with planning for the actual end of life. When discussing advance care planning as a communication process, they paid ample attention to non-medical aspects and did not distinguish between medical, mental, and social health. Rather, respondents thought in the overarching framework of what is important to them now and in the future. CONCLUSIONS: Engagement in advance care planning might be hindered if it is too medicalized and exclusively patient-centered. To accommodate advance care planning to people with young-onset dementia's and their caregivers' needs, it should be presented and implemented as a holistic, flexible, and relational communication process. Policy and practice recommendations are provided on how to do so.

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention - 2022 update.

BACKGROUND: A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments. METHODS: The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. RESULTS: We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts' opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives. CONCLUSION: Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure.

BACKGROUND: Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. MAIN BODY: The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient's well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. CONCLUSIONS: The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.

CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs.

BACKGROUND: Several drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor. METHODS: The present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained. RESULTS: Although being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention. CONCLUSIONS: Balancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.

Facial Pain: A Comprehensive Review and Proposal for a Pragmatic Diagnostic Approach.

BACKGROUND: Facial pain, alone or combined with other symptoms, is a frequent complaint. Moreover, it is a symptom situated at, more than any other pain condition, a crosspoint where several disciplines meet, for example, dentists; manual therapists; ophthalmologists; psychologists; and ear-nose-throat, pain, and internal medicine physicians besides neurologists and neurosurgeons. Recently, a new version of the most widely used classification system among neurologists for headache and facial pain, the International Classification of Headache Disorders, has been published. OBJECTIVE: The aims of this study were to provide an overview of the most prevalent etiologies of facial pain and to provide a generic framework for the neurologist on how to manage patients presenting with facial pain. METHODS: An overview of the different etiologies of facial pain is provided from the viewpoint of the respective clinical specialties that are confronted with facial pain. Key message: Caregivers should "think outside their own box" and refer to other disciplines when indicated. If not, a correct diagnosis can be delayed and unnecessary treatments might be given. The presented framework is aimed at excluding life- or organ-threatening diseases, providing several clinical clues and indications for technical investigations, and ultimately leading to the correct diagnosis and/or referral to other disciplines.

Age related metabolic modifications in the migraine brain.

PURPOSE: The aim of this study was to evaluate the possibility that migraine patients exhibit specific age-related metabolic changes in the brain, which occur regardless of disease duration or the frequency of attacks. METHODS: We analysed the relation between brain glucose (18F-fluorodeoxyglucose) uptake and age in healthy volunteers (n = 20) and episodic migraine patients (n = 19). In the latter, we additionally compared the correlation between 18F-fluorodeoxyglucose uptake and disease duration and monthly migraine days. RESULTS: In contrast to controls, in migraine patients advancing age was positively correlated to increased metabolism in the brainstem (especially the posterior pons), hippocampus, fusiform gyrus and parahippocampus. Conversely, no significant correlations between cerebral metabolism and disease duration or migraine days were observed. CONCLUSIONS: Findings of this cross-sectional study show that episodic migraine patients exhibit specific metabolic brain modifications while ageing. As such, age is correlated with metabolic changes in key regions of the brain previously associated with migraine's pathophysiology to a better extent than disease duration or the number of monthly migraine days. More than the repeated headache attacks, the continuous interaction with the environment seemingly models the brain of migraine sufferers in an adaptive manner. A positive control (e.g. chronic pain) is missing in this study and therefore findings cannot be proven to be migraine-specific.

The effect of aerobic exercise on the number of migraine days, duration and pain intensity in migraine: a systematic literature review and meta-analysis.

BACKGROUND: In patients with frequent migraine, prophylactic treatments are used. Patients often request non-pharmacological alternatives. One treatment option can be aerobic exercise. The value of aerobic exercise as prophylactic treatment however needs to be determined. METHODS: A systematic review and meta-analysis was performed to investigate the result of aerobic exercise on the number of migraine days, duration and pain intensity in patients with migraine. After screening three online databases, PubMed, Cochrane library and Web of Science, using predefined in- and exclusion criteria, six studies were retained. Pooling of data was performed when possible. RESULTS: Significant reductions in the number of migraine days after aerobic exercise treatment were found with a mean reduction of 0.6 ± 0.3 migraine days/month. Other outcomes were too variable to pool due to heterogeneity of outcome measurements. Unpooled data revealed small to moderate reductions in attack duration (20-27%) and pain intensity (20-54%) after aerobic exercise intervention. Various exercise intensities are applied. CONCLUSION: There is moderate quality evidence that in patients with migraine aerobic exercise therapy can decrease the number of migraine days. No conclusion for pain intensity or duration of attacks can be drawn. Effect sizes are small due to a lack of uniformity. For future studies, we recommend standardized outcome measures and sufficiently intense training programs. TRIAL REGISTRATION: CRD42018091178 .

3D Shape Perception in Posterior Cortical Atrophy: A Visual Neuroscience Perspective.

Posterior cortical atrophy (PCA) is a rare focal neurodegenerative syndrome characterized by progressive visuoperceptual and visuospatial deficits, most often due to atypical Alzheimer's disease (AD). We applied insights from basic visual neuroscience to analyze 3D shape perception in humans affected by PCA. Thirteen PCA patients and 30 matched healthy controls participated, together with two patient control groups with diffuse Lewy body dementia (DLBD) and an amnestic-dominant phenotype of AD, respectively. The hierarchical study design consisted of 3D shape processing for 4 cues (shading, motion, texture, and binocular disparity) with corresponding 2D and elementary feature extraction control conditions. PCA and DLBD exhibited severe 3D shape-processing deficits and AD to a lesser degree. In PCA, deficient 3D shape-from-shading was associated with volume loss in the right posterior inferior temporal cortex. This region coincided with a region of functional activation during 3D shape-from-shading in healthy controls. In PCA patients who performed the same fMRI paradigm, response amplitude during 3D shape-from-shading was reduced in this region. Gray matter volume in this region also correlated with 3D shape-from-shading in AD. 3D shape-from-disparity in PCA was associated with volume loss slightly more anteriorly in posterior inferior temporal cortex as well as in ventral premotor cortex. The findings in right posterior inferior temporal cortex and right premotor cortex are consistent with neurophysiologically based models of the functional anatomy of 3D shape processing. However, in DLBD, 3D shape deficits rely on mechanisms distinct from inferior temporal structural integrity. SIGNIFICANCE STATEMENT: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visuoperceptual dysfunction and most often an atypical presentation of Alzheimer's disease (AD) affecting the ventral and dorsal visual streams rather than the medial temporal system. We applied insights from fundamental visual neuroscience to analyze 3D shape perception in PCA. 3D shape-processing deficits were affected beyond what could be accounted for by lower-order processing deficits. For shading and disparity, this was related to volume loss in regions previously implicated in 3D shape processing in the intact human and nonhuman primate brain. Typical amnestic-dominant AD patients also exhibited 3D shape deficits. Advanced visual neuroscience provides insight into the pathogenesis of PCA that also bears relevance for vision in typical AD.

Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer's disease.

PURPOSE: The cannabinoid type 2 receptor (CB2R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB2R is primarily found on microglia. CB2R upregulation has been reported in animal models of Alzheimer's disease, with a preferential localization near amyloid beta (Aß) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB2R tracer [11C]NE40 in healthy controls (HC) and in patients with Alzheimer's disease (AD) to investigate whether higher CB2R availability regionally colocalized to Aß deposits is present in vivo. METHODS: Dynamic 90-min [11C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [11C]PIB scan 40 min after injection. In four HC, a retest scan with [11C]NE40 PET was performed within 9 weeks to investigate test-retest characteristics. RESULTS: [11C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time-activity curves best; both binding potential (BPND) and distribution volume (V T) parameters could be used. Brain uptake was generally low with an average K 1 value of 0.07 ml/min/ml tissue. V T and BPND were in the range of 0.7 - 1.8 and 0.6 - 1.6, respectively. Test values in HC were about 30 % for V T and BPND. AD patients showed overall significantly lower CB2R binding. No relationship was found between regional or global amyloid load and CB2R availability. CONCLUSION: Kinetic modelling of [11C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [11C]NE40 PET shows lower CB2R availability in vivo in AD patients, with no relationship to Aß plaques. A possible explanation for these findings is that [11C]NE40 binds to CB2R with lower affinity and/or selectivity than to CB1R.

Diagnostic value of MIBG cardiac scintigraphy for differential dementia diagnosis.

OBJECTIVE: Iodine-123 metaiodobenzylguanidine (MIBG) cardiac scintigraphy has shown the potential to discriminate dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, these studies did not reflect clinical practice, as patients with ischemic heart disease, heart failure, diabetes mellitus, arterial hypertension, and hyperlipidemia and patients treated with antidepressants like trazodone were excluded. METHODS: This study aimed to evaluate the use of MIBG cardiac scintigraphy to diagnose DLB in clinical practice. Moreover, the potential diagnostic value of MIBG cardiac scintigraphy in patients with clinically ambiguous dementia diagnosis (DLB versus AD) was tested. Eighty-five patients with a possible clinical diagnosis of DLB entered the study. MIBG uptake was determined by calculating the heart-to-mediastinum-uptake ratio (H/M). RESULTS: The average H/M ratio was 1.42 ± 0.35. The number of core features for DLB and the H/M ratio were negatively correlated (p = 0.001; r = -0.360). With an H/M ratio cutoff of 1.68 in 20 patients with clinically ambiguous dementia diagnoses (DLB versus AD) at the moment of MIBG cardiac scintigraphy, 95% (19/20) of the patients were correctly classified as compared with clinical or definite diagnosis at follow-up, with sensitivity and specificity values for diagnosing DLB of 100% (16/16) and 75% (3/4), respectively. The H/M ratio was influenced only by age (p = 0.046; r = -0.217) and gender (p = 0.024) and not by any other variable studied. CONCLUSIONS: The MIBG cardiac scintigraphy H/M ratio is a possible diagnostic biomarker for DLB in routine clinical practice and might have an added diagnostic value in case of doubt between DLB and AD.

Oxygen as an abortive therapy in cluster headache: a narrative review and clinical practice aspects.

Cluster headache (International Classification of Headache Disorders third edition, ICHD-3 3.1) is a primary headache disorder affecting around 0.12% of individuals. It is characterized by severe headache attacks causing significant negative impact on the lives of patients. While administration of 100% oxygen is considered to be the first-choice acute treatment, undertreatment also exists. Reasons for undertreatment may entail problems with the correct prescription of oxygen, reimbursement issues or the practical implementation of home oxygen therapy. The aim of this manuscript is to review the scientific evidence on oxygen therapy for cluster headache and provide a practical guidance for both physicians and patients to optimize its use in an acute setting. The current evidence of the administration of 100% oxygen as a safe and effective treatment for cluster headache is strong. Based on several clinical trials and surveys, the recommended flow rates range between 12 and 15 L/min via a non-rebreathing mask, for at least fifteen minutes. The frequency of cluster headache attacks and thus the need for acute treatment can be very high. Fortunately, the Belgian social security system provides a full and lifetime reimbursement of oxygen therapy for cluster headache if the diagnosis and the need for this therapy has been certified by a neurologist, neurosurgeon or neuropsychiatrist.

Brain age as a biomarker for pathological versus healthy ageing - a REMEMBER study.

OBJECTIVES: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. METHODS: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. RESULTS: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. CONCLUSIONS: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.