De Novo PS1 Mutation (Pro436Gln) in a Very Early-Onset Posterior Variant of Alzheimer’s Disease Associated with Spasticity: A Case Report

2021 ◽  
pp. 1-6
Author(s):  
Pablo Agüero ◽  
María José Sainz ◽  
Raquel Téllez ◽  
Isabel Lorda ◽  
Almudena Ávila ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Clinical Phenotype ◽  
Brain Mri ◽  
Amyloid Β ◽  
Strong Impact ◽  
Amyloid Pet ◽  
Posterior Cortex ◽  
Cerebrospinal Fluid Biomarkers

We report a patient with sporadic Alzheimer’s disease with onset in his twenties found to carry the de novo Pro436Gln mutation in the presenilin 1 gene (PS1). Clinical phenotype featured a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. Brain MRI and FDG-PET scans revealed severe parieto-occipital atrophy/hypometabolism. Cerebrospinal fluid biomarkers showed a decrease in Aβ 42 level and Aβ 42/40 ratio, increased phospho-tau, and normal total tau. Amyloid PET identified a very high burden of amyloid-β neuritic plaques in the posterior cortex. Similarities between this and two previously reported cases with this variant support that this mutation has a very strong impact on the clinical phenotype and is consistently associated with spasticity.

scholarly journals Olfactory Impairment is Related to Tau Pathology and Neuroinflammation in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Julia Klein ◽  
Xinyu Yan ◽  
Aubrey Johnson ◽  
Zeljko Tomljanovic ◽  
James Zou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Mri ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Odor Identification ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Olfactory Impairment ◽  
T Tau

Background: Olfactory impairment is evident in Alzheimer’s disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ 42). Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p <  0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p <  0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p <  0.01). Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration. NCT Registration Numbers: NCT03373604; NCT02831283

scholarly journals Case of early-onset Alzheimer’s disease with atypical manifestation

2021 ◽  
Vol 34 (1) ◽  
pp. e100283
Author(s):  
Lin Zhu ◽  
Limin Sun ◽  
Lin Sun ◽  
Shifu Xiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Manifestation ◽  
Early Onset ◽  
Short Term Memory ◽  
Brain Mri ◽  
Memory Loss ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Fluent Aphasia

Short-term memory decline is the typical clinical manifestation of Alzheimer’s disease (AD). However, early-onset AD usually has atypical symptoms and may get misdiagnosed. In the present case study, we reported a patient who experienced symptoms of memory loss with progressive non-fluent aphasia accompanied by gradual social withdrawal. He did not meet the diagnostic criteria of AD based on the clinical manifestation and brain MRI. However, his cerebrospinal fluid examination showed a decreased level of beta-amyloid 42, and increased total tau and phosphorylated tau. Massive amyloid β-protein deposition by 11C-Pittsburgh positron emission tomography confirmed the diagnosis of frontal variant AD. This case indicated that early-onset AD may have progressive non-fluent aphasia as the core manifestation. The combination of individual and precision diagnosis would be beneficial for similar cases.

scholarly journals Decreased salivary lactoferrin levels are specific to Alzheimer’s disease

2020 ◽  
Author(s):  
Marta González-Sánchez ◽  
Fernando Bartolome ◽  
Desiree Antequera ◽  
Veronica Puertas-Martín ◽  
Pilar González ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Diagnostic Performance ◽  
Group Versus ◽  
Amyloid Β ◽  
University Hospital ◽  
Control Group ◽  
Amyloid Pet ◽  
Prodromal Ad ◽  
Study Participants

Abstract Background Efforts focused on developing new less invasive biomarkers for early Alzheimer’s disease (AD) diagnosis are substantial. Evidences of infectious pathogens in AD brains may suggest a deteriorated innate immune system in AD pathophysiology. We previously demonstrated reduced salivary levels of Lf in AD patients, one of the major antimicrobial peptides. Methods To assess the clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid-β (Aβ) load in two different cross-sectional cohorts including patients with different neurodegenerative disorders. Study participants for cohort 1 (n = 116) were enrolled from the 12 de Octubre University Hospital Neurology Service in Madrid (Spain) and Pablo de Olavide University in Sevilla (Spain). Study participants for cohort 2 (n = 142) were enrolled as part of the Atherobrain - Heart to Head (H2H) project. Participants underwent neurological and neuropsychological examination, saliva sampling, and amyloid-Positron-Emission Tomography (PET) neuroimaging. Results The diagnostic performance of salivary Lf in the cohort 1 had an area under the curve [AUC] of 0.95 (0.911-0.992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET + ) versus healthy group, and 0.97 (0.924-1) versus the frontotemporal dementia (FTD) group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0.93 (95% CI 0.876-0.989). Salivary Lf detected prodromal AD and AD dementia distinguishing them from other dementias as FTD with over 87% sensitivity and 91% specificity. Conclusion Therefore, salivary Lf seems to have a very good diagnostic performance to detect AD. Our findings support the possible utility of salivary Lf as a new non-invasive and cost-effective AD biomarker.

scholarly journals Deep Learning in Brain MRI: Effect of Data Leakage Due to Slice-level Split Using 2D Convolutional Neural Networks

2021 ◽  
Author(s):  
Ekin Yagis ◽  
Selamawet Workalemahu Atnafu ◽  
Alba García Seco de Herrera ◽  
Chiara Marzi ◽  
Marco Giannelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Neural Networks ◽  
Alzheimer's Disease ◽  
Convolutional Neural Networks ◽  
De Novo ◽  
Neurological Diseases ◽  
Brain Mri ◽  
Progression Markers ◽  
Magnetic Resonance Imaging Mri

Abstract In recent years, 2D convolutional neural networks (CNNs) have been extensively used for the diagnosis of neurological diseases from magnetic resonance imaging (MRI) data due to their potential to discern subtle and intricate patterns. Despite the high performances reported in numerous studies, developing CNN models with good generalization abilities is still a challenging task due to possible data leakage introduced during cross-validation (CV). In this study, we quantitatively assessed the effect of a data leakage caused by 3D MRI data splitting based on a 2D slice-level using three 2D CNN models for the classification of patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our experiments showed that slice-level CV erroneously boosted the average slice level accuracy on the test set by 30% on Open Access Series of Imaging Studies (OASIS), 29% on Alzheimer’s Disease Neuroimaging Initiative (ADNI), 48% on Parkinson's Progression Markers Initiative (PPMI) and 55% on a local de-novo PD Versilia dataset. Further tests on a randomly labeled OASIS-derived dataset produced about 96% of (erroneous) accuracy (slice-level split) and 50% accuracy (subject-level split), as expected from a randomized experiment. Overall, the extent of the effect of an erroneous slice-based CV is severe, especially for small datasets.

scholarly journals Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

2020 ◽  
Author(s):  
Michael J. Lucas ◽  
Henry S. Pan ◽  
Eric J. Verbeke ◽  
Lauren J. Webb ◽  
David W. Taylor ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Amyloid Β ◽  
Mesoporous Silicas ◽  
Aggregation Kinetics ◽  
Central Feature ◽  
Relative Population ◽  
Aβ Fibrils

AbstractThe aggregation of Amyloid-β (Aβ) is associated with the onset of Alzheimer’s Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of Aβ1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from Aβ1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Aβ1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of Aβ1-40 and other amyloidogenic proteins.Significance StatementA major challenge in understanding the progression of Alzheimer’s Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-β (Aβ). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that Aβ fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge this gap, we used surface-functionalized mesoporous silicas to influence the formation of Aβ1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of Aβ fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific Aβ polymorphs.

scholarly journals Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

2021 ◽  
Vol 39 (3) ◽  
pp. 214-218
Author(s):  
Min Hye Kim ◽  
Joonho Lee ◽  
Hong Nam Kim ◽  
In Ja Shin ◽  
Keun Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Early Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Emission Tomography ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Positron Emission

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed <sup>18</sup>F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

Elevated Tau PET Signal Depends on Abnormal Amyloid Levels and Correlates with Cognitive Impairment in Elderly Persons without Dementia

2020 ◽  
Vol 78 (1) ◽  
pp. 395-404 ◽  
Author(s):  
Rui-Qi Zhang ◽  
Shi-Dong Chen ◽  
Xue-Ning Shen ◽  
Yu-Xiang Yang ◽  
Jia-Ying Lu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Function ◽  
Amyloid Β ◽  
Amyloid Pet ◽  
Elderly Persons ◽  
Cross Sectional ◽  
Memory Decline ◽  
Tau Pet

Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ– subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented subjects.

Unravelling the Association Between Amyloid-PET and Cerebrospinal Fluid Biomarkers in the Alzheimer’s Disease Spectrum: Who Really Deserves an A+?

2021 ◽  
pp. 1-12
Author(s):  
Luca Sacchi ◽  
Tiziana Carandini ◽  
Giorgio Giulio Fumagalli ◽  
Anna Margherita Pietroboni ◽  
Valeria Elisa Contarino ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Linear Regression Models ◽  
Csf Analysis ◽  
Disease Spectrum

Background: Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)42 and amyloid-PET measures is inconstant across the Alzheimer’s disease (AD) spectrum. However, they are considered interchangeable, along with Aβ 42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+). Objective: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. Methods: We include ed 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ 42 within a 365-days interval. Thresholds used for dichotomization were: Aβ 42 <  640 pg/mL (Aβ 42+); pTau >  61 pg/mL (pTau+); and Aβ 42/40 <  0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). Results: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93–0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho = 0.56, p = 0.0063) and Aβ 42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho = –0.56, p = 0.0058; rho = –0.52, p = 0.0117 respectively). No correlations between CSF-Aβ 42 and global SUVRs were observed. In subregion analysis, both pTau and Aβ 42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2 = 0.55–0.59, p <  0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ 42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ 42 or using Aβ 42/40, instead of Aβ 42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. Conclusion: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ 42/40 and secondarily pTau rather than Aβ 42 levels.

P4-314: Discordance Between Amyloid-PET and CSF Amyloid-β for Diagnosing Alzheimer’S Disease in a Clinical Setting

2016 ◽  
Vol 12 ◽  
pp. P1154-P1154
Author(s):  
Ellis Niemantsverdriet ◽  
Tobi Van den Bossche ◽  
Sara Van Mossevelde ◽  
Julie Ottoy ◽  
Jeroen Verhaeghe ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Setting ◽  
Amyloid Β ◽  
Amyloid Pet

scholarly journals Plasmon-Activated Water Reduces Amyloid Burden and Improves Memory in Animals with Alzheimer’s Disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chia-Hsiung Cheng ◽  
Kun-Ju Lin ◽  
Chien-Tai Hong ◽  
Dean Wu ◽  
Hung-Ming Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Memory Performance ◽  
Memory Function ◽  
Amyloid Β ◽  
Amyloid Pet ◽  
Amyloid Burden ◽  
Daily Consumption ◽  
Innovative Strategy

Abstract With the great extension of the human lifespan in recent times, many aging diseases have inevitably followed. Dementia is one of the most-commom neurodegenerative aging diseases, in which inflammation-related Alzheimer’s disease (AD) is the most prevalent cause of dementia. Amyloid accumulation in the brain, which occurs before any clinical presentations, might be the first and key step in the development of AD. However, many clinical trials have attempted to remove amyloid from brains of AD patients, but none has so far been successful. Negatively charged plasmon-activated water (PAW) is created by resonantly illuminated gold (Au) nanoparticles (NPs), which reduce the hydrogen-bonded (HB) structure of water. PAW was found to possess anti-oxidative and anti-inflammatory effects. Herein, we report on an innovative strategy to retard the progression of AD by the daily consumption of PAW instead of normal deionized (DI) water. APPswe/PS1dE9 transgenic mice were treated with PAW or DI water from the age of 5 months for the next 9 months. Encouragingly, compared to DI water-treated mice, mice treated with PAW presented better memory performance on a test of novel object recognition and had a significantly lower amyloid burden according to 18F-florbetapir amyloid-PET and phosphorylated (p)-tau burden according to Western blotting and immunohistochemistry measurements. There were no obvious side effects in PAW-treated mice. Collectively, our findings support that PAW was able to reduce the amyloid and p-tau burden and improve memory in an AD mouse model. However, the protein levels of molecules involved in amyloid metabolism and oligomeric amyloid did not change. We propose that the effects of PAW of reducing the amyloid burden and improving memory function cannot be attributed to synthesis/degradation of amyloid-βprotein but probably in preventing aggregation of amyloid-β proteins or other mechanisms, including anti-inflammation. Further applications of PAW in clinical trials to prevent the progression of AD are being designed.

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