Dynamic amyloid and metabolic signatures of delayed recall performance within the clinical spectrum of Alzheimer’s disease

Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer’s disease (AD). In this study, we assessed patients’ scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer’s Disease Neuroimaging Initiative. Subjects were classified as cognitively normal (CN), or with early (EMCI) or late (LMCI) mild cognitive impairment, or AD dementia. The memory outcome measures of interest were logical memory 30 min delayed recall (LM30) and Rey Auditory Verbal Learning Test 30 min delayed recall (RAVLT30). Voxel-based [18F]florbetapir and [18F]FDG uptake-ratio maps were constructed and correlations between PET images and cognitive scores were calculated. We found that EMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake on the right parieto-occipital region. LMCI individuals had LM30 scores positively associated with left lateral temporal lobe [18F]FDG uptake, and RAVLT30 scores positively associated with [18F]FDG uptake in the left parietal lobe and in the right enthorhinal cortex. Additionally, LMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake in the right frontal lobe. For the AD group, [18F]FDG uptake was positively correlated with LM30 in the left temporal lobe and with RAVLT30 in the right frontal lobe, and [18F]florbetapir uptake was negatively correlated with LM30 scores in the right parietal and left frontal lobes. The results show that the association between regional brain metabolism and the severity of episodic memory deficits is dependent on the clinical disease stage, suggesting a dynamic relationship between verbal episodic memory deficits, AD pathophysiology, and clinical disease stages

Assessment of treatment outcomes of multidrug-resistant tuberculosis patients in D R Congo: A study based on drug regimens used between 2007 to 2017: Évaluation des issues thérapeutiques des patients atteints de la tuberculose à bacilles multi résistants : étude basée sur les régimes de médicaments utilisés en République Démocratique du Congo de 2007 à 2017

Context. Little is known about therapeutic successes in MDR-TB patients under regimens containing second-line molecules. The present study aimed to assess therapeutic outcomes in patients under therapeutic regimens applied in DR Congo. Methods. This historical cohort study has included confirmed MDR-TB patients who received treatment between 2007 and 2017 in 218 TB centers in DR Congo. Treatment outcome and survival at 36 months were analyzed using Zscore and chi square test. Kaplan-Meier method was performed to describe survival and Log Rank test helped in comparing curve based on the therapeutical regimen. Factors associated with therapeutic success and mortality predictors were assessed using multivariate logistic regression and Cox regression analysis, respectively. Results. The therapeutic success in the study group (n=1,724) was 72% (range 68-74%) for all regimen combined. The average death rate was 12.8% although the group of patients receiving Cyclosérine and Ofloxacine was the most affected (16%). The death rate was significantly higher in patients living in urban areas (15.2% versus 14.9%, p = 0.013) and also among MDR-TB/HIV co-infected patients (28.4% vs 15.7%, p<0.001) patients. The median survival of the study group was 722.7 days compared to 601.1 days for MDR-TB/HIV co-infected patients, and 736.7 days for HIV negative patients (p<0.001). Conclusion. Therapeutic successes are significant for the short regimen. However, the death rate remains high when Cycloserine and Ofloxacin are included in the regimen. The predictors of mortality are HIV infection and living in urban areas. Contexte. L’issue thérapeutique de la tuberculose multi résistante (TB-MR) sous les molécules de deuxième intention n’est pas très bien connue. La présente étude a évalué les régimes thérapeutiques appliqués, en termes de succès thérapeutique et de survie. Méthodes. L’étude de cohorte historique a inclu les patients TB-MR confirmés et traités entre 2007 et 2017 dans 218 centres de tuberculose en RD Congo. L’issue thérapeutique et la survie à 36 mois ont été analysées. Le score Z ou le test de chi carré ont comparé des issues. La méthode de Kaplan-Meier a décrit les courbes de survie et le test de Log Rank a comparé la survie en fonction du regime therapeutique. Les facteurs associés au succès thérapeutique et les prédicteurs de mortalité ont été analysés respectivement, par l’analyse multivariée de régression logistique et de Cox. Résultats. Dans le groupe étudié (n=1724), le succès thérapeutique a été de 72% (68-74%) pour l’ensemble des régimes. Le taux était plus élevé pour le régime court (74%) et plus faible pour le régime contenant la Cyclosérine et l’Ofloxacine (68%). La moyenne de décès était de 12,8% ; mais plus élevée dans le groupe sous regime contenant la Cyclosérine et l’Ofloxacine (16%). Le taux de décès était significativement plus élevé en milieu urbain (15,2% versus 14,9 %, p = 0,013) et également chez les sujets co-infectés par la MDR-TB  et le VIH (28.4% vs 15.7%, p <0,001). La survie médiane dans le groupe était de 722,7 jours contre 601,1 jours chez les co-infectés MDR-TB/VIH, et de 736,7 jours) chez les patients VIH négatifs (p<0,001). Conclusion. Les succès thérapeutiques sont acceptables en particulier, pour le régime court ; toutefois, le taux de décès demeure encore très élevé dans le groupe sous Cyclosérine et Ofloxacine. Les prédicteurs de mortalité sont l’infection à VIH et la vie citadine. &nbsp

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

Collaborative research between academia and industry using a large clinical trial database: a case study in Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Large clinical trials databases, developed over the course of a comprehensive clinical trial programme, represent an invaluable resource for clinical researchers. Data mining projects sponsored by industry that use these databases, however, are often not viewed favourably in the academic medical community because of concerns that commercial, rather than scientific, goals are the primary purpose of such endeavours. Thus, there are few examples of sustained collaboration between leading academic clinical researchers and industry professionals in a large-scale data mining project. We present here a successful example of this type of collaboration in the field of dementia.</p> <p>Methods</p> <p>The Donepezil Data Repository comprised 18 randomised, controlled trials conducted between 1991 and 2005. The project team at Pfizer determined that the data mining process should be guided by a diverse group of leading Alzheimer's disease clinical researchers called the "Expert Working Group." After development of a list of potential faculty members, invitations were extended and a group of seven members was assembled. The Working Group met regularly with Eisai/Pfizer clinicians and statisticians to discuss the data, identify issues that were currently of interest in the academic and clinical communities that might lend themselves to investigation using these data, and note gaps in understanding or knowledge of Alzheimer's disease that these data could address. Leadership was provided by the Pfizer Clinical Development team leader; Working Group members rotated responsibility for being lead and co-lead for each investigation and resultant publication.</p> <p>Results</p> <p>Six manuscripts, each published in a leading subspecialty journal, resulted from the group's work. Another project resulted in poster presentations at international congresses and two were cancelled due to resource constraints.</p> <p>Conclusions</p> <p>The experience represents a particular approach to optimising the value of data mining of large clinical trial databases for the combined purpose of furthering clinical research and improving patient care. Fruitful collaboration between industry and academia was fostered while the donepezil data repository was used to advance clinical and scientific knowledge. The Expert Working Group approach warrants consideration as a blueprint for conducting similar research ventures in the future.</p

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease : Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial

The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-170560. The study was sponsored by TauRx Therapeutics (Singapore). We thank Lon Schneider and Howard Feldman for their contribution to the Scientific Advisory Board. We gratefully acknowledge study investigators and the generosity of study participants. Authors’ disclosures available online (http://j-alz.com/manuscript disclosures/17-0560r3).Peer reviewedPublisher PD

Recommendations for the use of Serious Games in people with Alzheimer's Disease, related disorders and frailty.

International audienceAlzheimer's disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimer's Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

IMPORTANCE: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles. OBJECTIVE: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET). DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded. EXPOSURES: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES: Associations between p-tau biomarkers with amyloid PET and tau PET. RESULTS: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts. CONCLUSIONS AND RELEVANCE: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework

Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ ([18F]AZD4694) and tau ([18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice