Translation from Preclinical Research to Clinical Trials: Brain-Gut Photobiomodulation Therapy for Alzheimer's Disease.

Recently, novel non-pharmacological interventions, such as photobiomodulation (PBM) therapy, have shown promise for the treatment of Alzheimer's disease (AD). This article outlines the translation from the preclinical to clinical stages of an innovative brain-gut PBM therapy in a mouse model of AD, a pilot clinical trial involving mild-to-moderate AD patients, and a continuing pivotal clinical trial with a similar patient population. In a mouse model of AD (Aß25-35), daily application of brain-gut PBM therapy to both the head and the abdomen produced a neuroprotective effect against the neurotoxic effects of an Aß25-35 peptide injection by normalizing all the modified behavioral and biochemical parameters. The pilot clinical trial to evaluate brain-gut PBM therapy demonstrated the tolerability and feasibility of the novel PBM-based treatment for mild-to-moderate AD patients. Compared to the sham patients, the PBM-treated patients had lower Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) comprehension sub-scores, higher forward verbal spans, and lower Trail Making Test (TMT) Part B (TMT-B) execution times, which suggest an improvement in cognitive functions. This pilot study provided important information for the design of a novel pivotal clinical trial, currently in progress, to assess the efficacy of brain-gut PBM therapy in a larger sample of AD patients. This pivotal clinical trial could demonstrate that brain-gut PBM therapy is a safe, well-tolerated, and efficient disease-modifying treatment for mild-to-moderate AD patients and that it has medical and economic benefits.

Mild behavioral impairment domains are longitudinally associated with pTAU and metabolic biomarkers in dementia-free older adults.

BACKGROUND: The mechanisms linking mild behavioral impairment (MBI) and Alzheimer's disease (AD) have been insufficiently explored, with conflicting results regarding tau protein and few data on other metabolic markers. We aimed to evaluate the longitudinal association of the MBI domains and a spectrum of plasma biomarkers. METHODS: Our study is a secondary analysis of data from NOLAN. The longitudinal association of the MBI domains with plasma biomarkers, including pTau181, was tested using adjusted linear mixed-effects models. RESULTS: The sample comprised 359 participants (60% female, mean age: 78.3, standard deviation: 0.3 years). After 1 year, the MBI domain of abnormal perception was associated with steeper increases in plasma pTau181. Abnormal perception, decreased motivation, and impulse dyscontrol were associated with homocysteine or insulin dysregulation. DISCUSSION: Apart from the association with plasma pTau181, our results suggest that MBI might also represent metabolic dysregulation, probably contributing to dementia transition among older adults with subjective cognitive decline or mild cognitive impairment. HIGHLIGHTS: Mild behavioral impairment (MBI) psychosis was associated with steeper increases in plasma p. pTau could be a pharmacological target to treat agitation and psychosis symptoms. MBI domains were linked to metabolic dysregulation involving insulin and homocysteine.

Cerebral Metabolic Signature of Chronic Benzodiazepine Use in Nondemented Older Adults: An FDG-PET Study in the MEMENTO Cohort.

OBJECTIVE: We sought to examine the association between chronic Benzodiazepine (BZD) use and brain metabolism obtained from 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in the MEMENTO clinical cohort of nondemented older adults with an isolated memory complaint or mild cognitive impairment at baseline. METHODS: Our analysis focused on 3 levels: (1) the global mean brain standardized uptake value (SUVR), (2) the Alzheimer's disease (AD)-specific regions of interest (ROIs), and (3) the ratio of total SUVR on the brain and different anatomical ROIs. Cerebral metabolism was obtained from 2-deoxy-2-fluoro-D-glucose-FDG-PET and compared between chronic BZD users and nonusers using multiple linear regressions adjusted for age, sex, education, APOE ε 4 copy number, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant use. RESULTS: We found that the SUVR was significantly higher in chronic BZD users (n = 192) than in nonusers (n = 1,122) in the whole brain (beta = 0.03; p = 0.038) and in the right amygdala (beta = 0.32; p = 0.012). Trends were observed for the half-lives of BZDs (short- and long-acting BZDs) (p = 0.051) and Z-drug hypnotic treatments (p = 0.060) on the SUVR of the right amygdala. We found no significant association in the other ROIs. CONCLUSION: Our study is the first to find a greater global metabolism in chronic BZD users and a specific greater metabolism in the right amygdala. Because the acute administration of BZDs tends to reduce brain metabolism, these findings may correspond to a compensatory mechanism while the brain adapts with global metabolism upregulation, with a specific focus on the right amygdala.

Fatigue in Alzheimer's disease: biological basis and clinical management-a narrative review.

BACKGROUND: Fatigue is a common symptom in neurodegenerative diseases and is associated with decreased cognitive performances. A full knowledge of the causes and physiopathological pathways leading to fatigue in Alzheimer's disease could help treating this symptom and obtain positive effects on cognitive functions. OBJECTIVES: To provide an overview of the clinical conditions and the biological mechanisms leading to fatigue in Alzheimer's disease patients. To review the recent advances on fatigue management and describe the landscape of future possibilities. METHODS: We performed a narrative review including all type of studies (e.g. cross-sectional and longitudinal analysis, reviews, clinical trials). RESULTS: We found very few studies considering the symptom fatigue in Alzheimer's disease patients. Populations, designs, and objectives varied across studies rendering comparability across studies difficult to perform. Results from cross-sectional and longitudinal analysis suggest that the amyloid cascade may be involved in the pathogenesis of fatigue and that fatigue may be a prodromal manifestation of Alzheimer's disease. Fatigue and neurodegeneration of Alzheimer's disease could share common brain signatures (i.e. hippocampal atrophy and periventricular leukoaraiosis). Some mechanisms of aging (i.e. inflammation, mitochondrial dysfunction, telomere shortening) may be proposed to play a common underlying role in Alzheimer's disease neurodegeneration and muscle fatigability. Considering treatments, donepezil has been found to reduce cognitive fatigue in a 6-week randomized controlled study. Fatigue is frequently reported as an adverse event in patients treated by anti-amyloid agents in clinical trials. CONCLUSION: The literature is actually inconclusive about the main causes of fatigue in Alzheimer's disease individuals and its potential treatments. Further research is needed to disentangle the role of several components such as comorbidities, depressive symptoms, iatrogenic factors, physical decline and neurodegeneration itself. Given the clinical relevance of this symptom, it seems to be important to systematically assess fatigue by validated tools in Alzheimer's disease clinical trials.

Description of a European memory clinic cohort undergoing amyloid-PET: The AMYPAD Diagnostic and Patient Management Study.

INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results.

Clinical relevance of brain atrophy subtypes categorization in memory clinics.

INTRODUCTION: The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown. METHODS: A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms. RESULTS: Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups. DISCUSSION: Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.

Precision prevention of Alzheimer's and other dementias: Anticipating future needs in the control of risk factors and implementation of disease-modifying therapies.

Empirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular health). While the effect on individuals may be modest, it might have a large societal impact by decreasing overall dementia incidence by up to 35%. Secondary prevention will target cognitively normal persons at high risk of dementia due to Alzheimer's disease pathology with future anti-amyloid, anti-tau, or other drugs. This approach is likely to have major benefits to both individuals and society. Memory clinics will need structural and functional changes to adapt to novel technologies and increased patients' demands, and brand-new services may need to be developed with specific skills on risk profiling, risk communication, and personalized risk reduction plans.

Multidomain intervention and/or omega-3 in nondemented elderly subjects according to amyloid status.

INTRODUCTION: The Multidomain Alzheimer Preventive Trial (MAPT) assessed the efficacy of omega-3 fatty acid supplementation, a multidomain intervention (MI), or a combination of both on cognition. Impact according to cerebral amyloid status was evaluated by PET scan. METHODS: Participants were nondemented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. The primary outcome was a change from baseline in 36 months measured with a cognitive composite Z score. RESULTS: No effect was observed on cognition in the negative amyloid group (n = 167). In the positive amyloid group (n = 102), we observed a difference of 0.708 and 0.471 in the cognitive composite score between the MI plus omega-3 fatty acid group, the MI alone group, and the placebo group, respectively. DISCUSSION: MI alone or in combination with omega-3 fatty acids was associated with improved primary cognitive outcome in subjects with positive amyloid status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252.

Pu Coexists in Three Oxidation States in a Borosilicate Glass: Implications for Pu Solubility.

Pu(III), Pu(IV), and a higher oxidation state of Pu, likely Pu(VI), are for the first time characterized simultaneously present in a borosilicate glass using Pu M5 edge high energy resolution X-ray absorption near edge structure (HR-XANES) technique. We illustrate that the method can be very efficiently used to determine Pu oxidation states, which control the solubility limit of Pu in a glass matrix. HR-XANES results show that the addition of excess Si3N4 is not sufficient for complete reduction of Pu to Pu(III), which has a relatively high solubility limit (9-22 wt % Pu) due to its network-modifying behavior in glasses. We provide evidence that the initially added Pu(VI) might be partly preserved during vitrification at 1200/1400 °C in Ar atmosphere. Pu(VI) could be very advantageous for vitrification of Pu-rich wastes, since it might reach solubility limits of 40 wt % comparable to U(VI).

Apathy as a feature of prodromal Alzheimer's disease: an FDG-PET ADNI study.

OBJECTIVE: The goal of this study is to evaluate brain metabolism in mild cognitive impairment (MCI) patients with and without apathy (as determined by the Neuropsychiatric Inventory Questionnaire). METHODS: Baseline data from 65 MCI participants (11 with apathy and 54 without) from the Alzheimer's Disease (AD) Neuroimaging Initiative study were analyzed. All participants underwent a comprehensive cognitive and neuropsychiatric assessment, volumetric MRI and measures of cerebral glucose metabolism applying (18)F-fluorodeoxyglucose positron emission tomography at baseline. The presence of apathy at baseline was determined by the Neuropsychiatric Inventory Questionnaire. RESULTS: There was no difference between apathy and apathy-free MCI patients regarding cognitive assessment and neuropsychiatric measures when apathy-specific items were removed. Cerebrovascular disease load and cerebral atrophy were equivalent in both groups. Compared with the apathy-free MCI patients, MCI patients with apathy had significantly decreased metabolism in the posterior cingulate cortex. CONCLUSION: The presence of apathy in MCI patients is associated with AD-specific pattern of brain metabolic defect. These results could suggest that apathy belongs to the spectrum of prodromal AD symptoms.

The dental microscope in endodontic education: A feasibility study of a distance learning course.

This study aimed to evaluate the feasibility of preclinical training, specifically in root canal preparation, using a virtual educational system equipped with an operating microscope. Ten postgraduate general dentistry trainees and practitioners undergoing postgraduate training in endodontics participated. The telesimulation course included three steps: theory, demonstration of practical work by the teacher and lastly practical training by the participants. The digital environment including the dental microscope was presented, and the feedback was collected with a questionnaire. The majority of participants considered that the online video conference format allowed them to acquire theoretical content but also practical knowledge and skills, owing to the contribution of the operating microscope. The technical feasibility of endodontic telesimulation was demonstrated. The operating microscope has a potential role in distance education, enabling teaching to occur synchronously and collaboratively. This allows learners to interact with each other and demonstrators in real time.

Integrative Multimodal Metabolomics to Early Predict Cognitive Decline Among Amyloid Positive Community-Dwelling Older Adults.

Alzheimer's disease is strongly linked to metabolic abnormalities. We aimed to distinguish amyloid-positive people who progressed to cognitive decline from those who remained cognitively intact. We performed untargeted metabolomics of blood samples from amyloid-positive individuals, before any sign of cognitive decline, to distinguish individuals who progressed to cognitive decline from those who remained cognitively intact. A plasma-derived metabolite signature was developed from Supercritical Fluid chromatography coupled with high-resolution mass spectrometry (SFC-HRMS) and nuclear magnetic resonance (NMR) metabolomics. The 2 metabolomics data sets were analyzed by Data Integration Analysis for Biomarker discovery using Latent approaches for Omics studies (DIABLO), to identify a minimum set of metabolites that could describe cognitive decline status. NMR or SFC-HRMS data alone cannot predict cognitive decline. However, among the 320 metabolites identified, a statistical method that integrated the 2 data sets enabled the identification of a minimal signature of 9 metabolites (3-hydroxybutyrate, citrate, succinate, acetone, methionine, glucose, serine, sphingomyelin d18:1/C26:0 and triglyceride C48:3) with a statistically significant ability to predict cognitive decline more than 3 years before decline. This metabolic fingerprint obtained during this exploratory study may help to predict amyloid-positive individuals who will develop cognitive decline. Due to the high prevalence of brain amyloid-positivity in older adults, identifying adults who will have cognitive decline will enable the development of personalized and early interventions.

Association Between Years of Education and Amyloid Burden in Patients With Subjective Cognitive Decline, MCI, and Alzheimer Disease.

OBJECTIVES: Higher-educated patients with Alzheimer disease (AD) can harbor greater neuropathologic burden than those with less education despite similar symptom severity. In this study, we assessed whether this observation is also present in potential preclinical AD stages, namely in individuals with subjective cognitive decline and clinical features increasing AD likelihood (SCD+). METHODS: Amyloid-PET information ([18F]Flutemetamol or [18F]Florbetaben) of individuals with SCD+, mild cognitive impairment (MCI), and AD were retrieved from the AMYPAD-DPMS cohort, a multicenter randomized controlled study. Group classification was based on the recommendations by the SCD-I and NIA-AA working groups. Amyloid PET images were acquired within 8 months after initial screening and processed with AMYPYPE. Amyloid load was based on global Centiloid (CL) values. Educational level was indexed by formal schooling and subsequent higher education in years. Using linear regression analysis, the main effect of education on CL values was tested across the entire cohort, followed by the assessment of an education-by-diagnostic-group interaction (covariates: age, sex, and recruiting memory clinic). To account for influences of non-AD pathology and comorbidities concerning the tested amyloid-education association, we compared white matter hyperintensity (WMH) severity, cardiovascular events, depression, and anxiety history between lower-educated and higher-educated groups within each diagnostic category using the Fisher exact test or χ2 test. Education groups were defined using a median split on education (Md = 13 years) in a subsample of the initial cohort, for whom this information was available. RESULTS: Across the cohort of 212 individuals with SCD+ (M(Age) = 69.17 years, F 42.45%), 258 individuals with MCI (M(Age) = 72.93, F 43.80%), and 195 individuals with dementia (M(Age) = 74.07, F 48.72%), no main effect of education (ß = 0.52, 95% CI -0.30 to 1.58), but a significant education-by-group interaction on CL values, was found (p = 0.024) using linear regression modeling. This interaction was driven by a negative association of education and CL values in the SCD+ group (ß = -0.11, 95% CI -4.85 to -0.21) and a positive association in the MCI group (ß = 0.15, 95% CI 0.79-5.22). No education-dependent differences in terms of WMH severity and comorbidities were found in the subsample (100 cases with SCD+, 97 cases with MCI, 72 cases with dementia). DISCUSSION: Education may represent a factor oppositely modulating subjective awareness in preclinical stages and objective severity of ongoing neuropathologic processes in clinical stages.

[Immunotherapies in Alzheimer's disease: state of the art and potential use in the elderly]. / Immunothérapie passive dans la maladie d'Alzheimer : état des lieux et applicabilité en population gériatrique.

The recent positive results of phase III clinical trials evaluating the efficacy of anti-amyloid antibodies in Alzheimer's disease may give hope for an approbation in clinical practice soon. Indeed, lecanemab showed cognitive efficacy but also on functional status, quality of life and caregiver burden in the phase III CLARITY study. Aducanumab has already received marketing authorization in the United States in 2021 for the treatment of Alzheimer's disease. However, these clinical trials include mostly young participants without significant comorbidities who are not fully representative of the real elderly population. It is therefore necessary to examine the potential use of these treatments in routine care in the elderly population and to identify potential barriers to their use. The presence of cerebral microbleeds and anticoagulation, two frequent conditions in the elderly, could limit the use of anti-amyloid immunotherapy in the geriatric population. In this population, another limitation would be the unusually long diagnosis delays given that the anti-amyloid therapies target the earliest stages of the disease. However, the results of the phase III trials and in particular the subgroup analyses seem indicate a superior cognitive efficacy in elderly subjects, especially those over 75. European recommendations on the future use of these treatments are therefore awaited to clarify this situation, which will probably require a precise analysis of the benefit-risk balance. Age alone cannot be a contraindication to the administration of these treatments.

Evaluation of Poly(etheretherketone) Post's Mechanical Strength in Comparison with Three Metal-Free Biomaterials: An In Vitro Study.

The thinking about metallic replacement has begun in a global context of reducing metallic alloys' use in odontology. Among the materials proposed for their replacement, poly(etheretherketone) may present interesting properties, especially in removable dentures' frames. The purpose of this study is to evaluate fracture resistance of PEEK posts-and-cores compared to non-metallic CAD/CAM materials and fiber glass posts. Forty extracted maxillary central incisors were prepared to receive posts. Samples were divided into four groups depending on whether they had been reconstructed with LuxaCam® PEEK, Enamic®, Numerys GF® or LuxaPost®. Samples were submitted to an oblique compressive test and results were statistically analyzed with ANOVA and Student's tests (or non-parametric tests depending on the conditions). Glass fiber posts and Numerys GF® reveal a significantly higher fracture resistance than LuxaCam® PEEK and Enamic®. No exclusively dental fracture has been noted for the Enamic group, which significantly distinguishes these samples from the three other groups. In our study, it appears that the conception of posts and cores with hybrid ceramic never conducts to a unique tooth fracture. By weighting the results according to the materials used, our data, obtained for the first time on this type of PEEK block, cannot confirm the possibility of using PEEK for inlay-core conception, excepted for specific cases when the material is considered in a patient presenting allergies or systemic disease contraindicating resin or metal.

Cognitive impact of multidomain intervention and omega 3 according to blood Aß42/40 ratio: a subgroup analysis from the randomized MAPT trial.

BACKGROUND: In MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET. However, screening eligible patients for multidomain intervention by PET is difficult to generalize in real-world settings. METHODS: MAPT study was a 3-year, randomized, placebo-controlled trial followed by a 2-year observational and optional extension. All participants were non-demented and randomly assigned (1:1:1:1) to the MI plus omega 3, MI plus placebo, omega 3 alone, or placebo alone group. The objectives were to assess the cognitive effect of MAPT interventions (omega 3 supplementation, MI, combined intervention) in non-demented subjects according to amyloid blood status at 12, 36, and 60 months. In this subgroup analysis (n = 483), amyloid status was defined by plasma Aß42/40 ratio (cutoff ≤ 0.0107). The primary outcome measure was the change in cognitive composite score after a 1, 3, and 5-year clinical follow-up. RESULTS: The intention-to-treat (ITT) population included 483 subjects (161 positive and 322 negative amyloid participants based on plasma Aß42/40 ratio). In the positive amyloid ITT population, we showed a positive effect of MI plus omega 3 on the change in composite cognitive score in 12 (raw p = .0350, 0.01917, 95% CI = [0.0136 to 0.3699]) and 36 months (raw p = .0357, 0.2818, 95% CI = [0.0190 to 0.5446]). After correction of multiple comparisons and adjustments, these differences were not significant (adjusted p = .1144 and .0690). In the per-protocol positive amyloid group (n = 154), we observed a significant difference between the combined intervention and placebo groups at 12 (p = .0313, 0.2424, 0.0571 to 0.4276) and 36 months (p = .0195, 0.3747, 0.1055 to 0.6439) persisting after adjustment. In the ITT and per-protocol analyses, no cognitive effect was observed in the positive and negative amyloid group at 60-month visit. CONCLUSIONS: These findings suggest a benefit of MI plus omega 3 in positive blood amyloid subjects. This promising trend needs to be confirmed before using blood biomarkers for screening in preventive trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252 .

Clinical Effect of Early vs Late Amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS Randomized Clinical Trial.

Importance: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect. Objective: To assess the clinical effect of amyloid PET in memory clinic patients. Design, Setting, and Participants: The AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023. Intervention: Amyloid PET. Main Outcome and Measure: The main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months. Results: A total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 (P < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .001). Conclusion and Relevance: In this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients. Trial Registration: EudraCT Number: 2017-002527-21.

'Clinical trials in Alzheimer's disease': immunotherapy approaches.

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid ß (Aß) peptide represents an important molecular target for intervention in Alzheimer's disease. Several types of Aß peptide immunotherapy for Alzheimer's disease are under investigation, direct immunization with synthetic intact Aß(42) , active immunization involving the administration of synthetic fragments of Aß peptide conjugated to a carrier protein and passive administration with monoclonal antibodies directed against Aß peptide. Pre-clinical studies showed that immunization against Aß peptide can provide protection and reversal of the pathology of Alzheimer's disease in animal models. Indeed, several adverse events have been described like meningoencephalitis with AN1792, vasogenic edema and microhemorrhages with bapineuzumab. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several Aß peptide immunotherapy approaches are under investigation but also against tau pathology.

The use of PEEK as an occlusal splint in a patient with histaminosis: A case report.

Poly-(etheretherketone) (PEEK) began to be used in the field of odontology more than 10 years ago, especially in relation to the creation of removable partial dentures. Here we report the case of a 62 years old woman diagnosed with histamine intolerance (or histaminosis), who presented a very particular set of oral symptoms. She described a certain tingling, burning, and swelling of the mucous membranes. These symptoms seem to be linked with the wearing of a resin occlusal splint which was initially prescribed to compensate for the absence of a meniscus in the left temporomandibular joint of the patient. After a multidisciplinary concertation, it was decided to create a new splint with a resin-free material. For this reason, the production of a PEEK prosthesis was considered. Following the installation of the occlusal splint in the patient, and after clinical adjustments, she described the occlusion positioning as correct and a disappearance of the symptomatology. Mechanically, PEEK seems to have higher mechanical resistance than PMMA. Despite these characteristics, the use of PEEK still presents some limitations, especially concerning the overall aesthetic. Additionally, the prescription of the occlusal splint seems to be limited to patients who need special care. The case presented here thus confirms a new perspective concerning the use of PEEK as an occlusal splint.

Plasma MCP-1 and changes on cognitive function in community-dwelling older adults.

BACKGROUND: Monocyte Chemoattractant Protein-1 (MCP-1), a glial-derived chemokine, mediates neuroinflammation and may regulate memory outcomes among older adults. We aimed to explore the associations of plasma MCP-1 levels (alone and in combination with ß-amyloid deposition-Aß42/40) with overall and domain-specific cognitive evolution among older adults. METHODS: Secondary analyses including 1097 subjects (mean age = 75.3 years ± 4.4; 63.8% women) from the Multidomain Alzheimer Preventive Trial (MAPT). MCP-1 (higher is worse) and Aß42/40 (lower is worse) were measured in plasma collected at year 1. MCP-1 in continuous and as a dichotomy (values in the highest quartile (MCP-1+)) were used, as well as a dichotomy of Aß42/40. Outcomes were measured annually over 4 years and included the following: cognitive composite z-score (CCS), the Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) sum of boxes (overall cognitive function); composite executive function z-score, composite attention z-score, Free and Cued Selective Reminding Test (FCSRT - memory). RESULTS: Plasma MCP-1 as a continuous variable was associated with the worsening of episodic memory over 4 years of follow-up, specifically in measures of free and cued delayed recall. MCP-1+ was associated with worse evolution in the CCS (4-year between-group difference: ß = -0.14, 95%CI = -0.26, -0.02) and the CDR sum of boxes (2-year: ß = 0.19, 95%CI = 0.06, 0.32). In domain-specific analyses, MCP-1+ was associated with declines in the FCSRT delayed recall sub-domains. In the presence of low Aß42/40, MCP-1+ was not associated with greater declines in cognitive functions. The interaction with continuous biomarker values Aß42/40× MCP-1 × time was significant in models with CDR sum of boxes and FCSRT DTR as dependent variables. CONCLUSIONS: Baseline plasma MCP-1 levels were associated with longitudinal declines in overall cognitive and episodic memory performance in older adults over a 4-year follow-up. How plasma MCP-1 interacts with Aß42/40 to determine cognitive decline at different stages of cognitive decline/dementia should be clarified by further research. The MCP-1 association on cognitive decline was strongest in those with amyloid plaques, as measured by blood plasma Aß42/40.