27 results
Search Results
2. Alzheimer's disease: a review on the current trends of the effective diagnosis and therapeutics.
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Abdul Manap, Aimi Syamima, Almadodi, Reema, Sultana, Shirin, Sebastian, Maheishinii Grace, Kavani, Kenil Sureshbhai, Lyenouq, Vanessa Elle, and Shankar, Aravind
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ALZHEIMER'S disease treatment ,BRAIN physiology ,ALZHEIMER'S disease diagnosis ,SALIVA analysis ,GASTROINTESTINAL system physiology ,TAU proteins ,HETEROCYCLIC compounds ,ANTI-inflammatory agents ,ALZHEIMER'S disease ,MILD cognitive impairment ,BEHAVIOR modification ,PHOSPHORYLATION ,SENSORY stimulation ,CLINICAL trials ,MICRORNA ,ENZYME inhibitors ,IMMUNOTHERAPY ,EICOSAPENTAENOIC acid ,EXERCISE therapy ,GOAL (Psychology) ,PHYTOCHEMICALS ,POSITRON emission tomography ,MAGNETIC resonance imaging ,NEURODEGENERATION ,DRUG approval ,EARLY diagnosis ,DRUG development ,MACROLIDE antibiotics ,STEM cells ,COGNITIVE therapy ,BIOMARKERS ,AMYLOID beta-protein precursor ,TEARS (Body fluid) ,SYMPTOMS - Abstract
The most prevalent cause of dementia is Alzheimer's disease. Cognitive decline and accelerating memory loss characterize it. Alzheimer's disease advances sequentially, starting with preclinical stages, followed by mild cognitive and/or behavioral impairment, and ultimately leading to Alzheimer's disease dementia. In recent years, healthcare providers have been advised to make an earlier diagnosis of Alzheimer's, prior to individuals developing Alzheimer's disease dementia. Regrettably, the identification of early-stage Alzheimer's disease in clinical settings can be arduous due to the tendency of patients and healthcare providers to disregard symptoms as typical signs of aging. Therefore, accurate and prompt diagnosis of Alzheimer's disease is essential in order to facilitate the development of disease-modifying and secondary preventive therapies prior to the onset of symptoms. There has been a notable shift in the goal of the diagnosis process, transitioning from merely confirming the presence of symptomatic AD to recognizing the illness in its early, asymptomatic phases. Understanding the evolution of disease-modifying therapies and putting effective diagnostic and therapeutic management into practice requires an understanding of this concept. The outcomes of this study will enhance indepth knowledge of the current status of Alzheimer's disease's diagnosis and treatment, justifying the necessity for the quest for potential novel biomarkers that can contribute to determining the stage of the disease, particularly in its earliest stages. Interestingly, latest clinical trial status on pharmacological agents, the nonpharmacological treatments such as behavior modification, exercise, and cognitive training as well as alternative approach on phytochemicals as neuroprotective agents have been covered in detailed. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.
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Dubbelman, Mark A., Diez, Ibai, Gonzalez, Christopher, Amariglio, Rebecca E., Becker, J. Alex, Chhatwal, Jasmeer P., Gatchel, Jennifer R., Johnson, Keith A., Locascio, Joseph J., Udeogu, Onyinye J., Wang, Sharon, Papp, Kathryn V., Properzi, Michael J., Rentz, Dorene M., Schultz, Aaron P., Sperling, Reisa A., Vannini, Patrizia, and Marshall, Gad A.
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ALZHEIMER'S disease diagnosis ,TAU proteins ,PROTEIN precursors ,ALZHEIMER'S disease ,RESEARCH funding ,POSITRON emission tomography computed tomography ,DESCRIPTIVE statistics ,COGNITION disorders ,CONFIDENCE intervals ,ACTIVITIES of daily living ,DISEASE progression ,BIOMARKERS ,OLD age - Abstract
Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer’s disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Methods: Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Results: Amyloid [unstandardized partial regression coefficient estimate (β) =-0.007, 95% confidence interval (95% CI) = (-0.013,-0.001)], and medial temporal tau [β =-0.013, 95% CI = (-0.022,-0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Conclusion: Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer’s disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Four Decades of Research in Alzheimer's Disease (1975-2014): A Bibliometric and Scientometric Analysis.
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Serrano-Pozo, Alberto, Aldridge, Georgina M., Qiang Zhang, and Zhang, Qiang
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ALZHEIMER'S disease ,BIBLIOMETRICS ,SCIENTOMETRICS ,NONLINEAR regression ,NEUROSCIENCES ,ALZHEIMER'S disease diagnosis ,ALZHEIMER'S disease treatment ,AGE distribution ,LONGITUDINAL method ,MEDICAL research ,MEDLINE ,ONLINE information services ,RESEARCH funding ,SYSTEMATIC reviews - Abstract
Background: Bibliometric and scientometric methods can be applied to the study of a research field.Objective: We hypothesized that a bibliometric and scientometric analysis of the Alzheimer's disease (AD) research field could render trends that provide researchers and funding agencies valuable insight into the history of the field, current tendencies, and potential future directions.Methods: We performed searches in publicly available databases including PubMed, Scopus, Web of Science, and Alzheimer's Funding Analyzer for the period 1975-2014, and conducted a curve fitting analysis with non-linear regression.Results: While the rate and impact of publications continue to increase, the number of patents per year is currently declining after peaking in the late 2000s, and the funding budget has plateaued in the last 5-10 years analyzed. Genetics is the area growing at a fastest pace, whereas pathophysiology and therapy have not grown further in the last decade. Among the targets of pathophysiology research, amyloid-β continues to be the focus of greatest interest, with tau and apolipoprotein E stagnant after a surge in the 1990s. The role of inflammation, microglia, and the synapse are other research topics with growing interest. Regarding preventative strategies, education attainment, diet, and exercise are recently gaining some momentum, whereas NSAIDs and statins have lost the spotlight they once had.Conclusion: Our bibliometric and scientometric analysis provides distinct trends in AD research in the last four decades, including publication and patent output, funding, impact, and topics. Our findings could inform the decision-making of research funding agencies in the near future. [ABSTRACT FROM AUTHOR]- Published
- 2017
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5. Salivary biomarkers: The early diagnosis of Alzheimer's disease.
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Nazir, Sophia
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ALZHEIMER'S disease diagnosis ,GLYCOPROTEIN analysis ,DIAGNOSIS of brain diseases ,TAU proteins ,EARLY diagnosis ,METABOLOMICS ,BIOMARKERS ,SALIVA ,AMYLOID beta-protein precursor ,ACETYLCHOLINESTERASE ,INTERLEUKINS ,TUMOR necrosis factors - Abstract
The precise identification of Alzheimer's disease and other prevalent neurodegenerative diseases remains a difficult issue that requires the development of early detection of the disease and inexpensive biomarkers that can replace the present cerebrospinal fluid and imaging biomarkers. Blood biomarkers, such as amyloid and neurofilament light, have been emphasized as an important and practical tool in a testing or examination procedure thanks to advancements in ultra‐sensitive detection techniques. Although saliva is not currently being researched for neurodegenerative diseases, it is an important source of biomarkers that can be used for the identification of diseases and has some advantages over other biofluids. While this may be true for most people, getting saliva from elderly people presents some significant challenges. In this overview, we will first discuss how saliva is created and how aging‐related illnesses may affect the amount and kind of saliva produced. The findings support the use of salivary amyloid protein, tau species, and novel biomarkers in the diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Optimization and Biodistribution of [11C]-TKF, An Analog of Tau Protein Imaging Agent [18F]-THK523.
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Yanyan Kong, Yihui Guan, Fengchun Hua, Zhengwei Zhang, Xiuhong Lu, Tengfang Zhu, Bizeng Zhao, Jianhua Zhu, Cong Li, and Jian Chen
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ALZHEIMER'S disease diagnosis ,NEUROFIBRILLARY tangles ,TAU proteins ,POSITRON emission tomography ,LABORATORY mice - Abstract
The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [
18 F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [11 C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [11 C]-TKF can be made by reaction precursor with [11 C]MeOTf or11 CH3 I, but [11 C]MeOTf will give us higher labeling yields and specific activity. [11 C]-TKF presented better brain uptake in normal mouse than [18 F]-THK523 (3.23% ± 1.25% ID.g-1 vs. 2.62% ± 0.39% ID.g-1 at 2 min post-injection). The acute toxicity studies of [11 C]-TKF were unremarkable. [ABSTRACT FROM AUTHOR]- Published
- 2016
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7. Potential Natural Products for Alzheimer's Disease: Targeted Search Using the Internal Ribosome Entry Site of Tau and Amyloid-β Precursor Protein.
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Yun-Chieh Tasi, Ting-Yu Chin, Ying-Ju Chen, Chun-Chih Huang, Shou-Lun Lee, and Tzong-Yuan Wu
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NATURAL products ,ALZHEIMER'S disease diagnosis ,RIBOSOMES ,GENETIC transcription ,TAU proteins - Abstract
Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer's disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES) elements flanked by ß-galactosidase gene (cap-dependent) and secreted alkaline phosphatase (SEAP) (cap-independent) to discern the mechanism of action of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 µM (monitored by SEAP activity) without interfering with the cap-dependent translation as monitored by the ß-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A) and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine) fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE-/-) mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD. [ABSTRACT FROM AUTHOR]
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- 2015
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8. Bayesian workflow for the investigation of hierarchical classification models from tau-PET and structural MRI data across the Alzheimer's disease spectrum.
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Belasso, Clyde J., Zhengchen Cai, Bezgin, Gleb, Pascoal, Tharick, Stevenson, Jenna, Rahmouni, Nesrine, Tissot, Cécile, Lussier, Firoza, Rosa-Neto, Pedro, Soucy, Jean-Paul, Rivaz, Hassan, and Benali, Habib
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BRAIN physiology ,ALZHEIMER'S disease diagnosis ,DISEASE progression ,TAU proteins ,MAGNETIC resonance imaging ,PSYCHOLOGICAL tests ,POSITRON emission tomography ,RESEARCH funding ,STATISTICAL models ,PROBABILITY theory - Abstract
Background: Alzheimer's disease (AD) diagnosis in its early stages remains difficult with current diagnostic approaches. Though tau neurofibrillary tangles (NFTs) generally follow the stereotypical pattern described by the Braak staging scheme, the network degeneration hypothesis (NDH) has suggested that NFTs spread selectively along functional networks of the brain. To evaluate this, we implemented a Bayesian workflow to develop hierarchical multinomial logistic regression models with increasing levels of complexity of the brain from tau-PET and structural MRI data to investigate whether it is beneficial to incorporate network-level information into an ROI-based predictive model for the presence/ absence of AD. Methods: This study included data from the Translational Biomarkers in Aging and Dementia (TRIAD) longitudinal cohort from McGill University's Research Centre for Studies in Aging (MCSA). Baseline and 1year follow-up structural MRI and [18F]MK-6240 tau-PET scans were acquired for 72 cognitive normal (CN), 23 mild cognitive impairment (MCI), and 18 Alzheimer's disease dementia subjects. We constructed the four following hierarchical Bayesian models in order of increasing complexity: (Model 1) a complete-pooling model with observations, (Model 2) a partial-pooling model with observations clustered within ROIs, (Model 3) a partial-pooling model with observations clustered within functional networks, and (Model 4) a partialpooling model with observations clustered within ROIs that are also clustered within functional brain networks. We then investigated which of the models had better predictive performance given tau-PET or structural MRI data as an input, in the form of a relative annualized rate of change. Results: The Bayesian leave-one-out cross-validation (LOO-CV) estimate of the expected log pointwise predictive density (ELPD) results indicated that models 3 and 4 were substantially better than other models for both tau-PET and structural MRI inputs. For tau-PET data, model 3 was slightly better than 4 with an absolute difference in ELPD of 3.10 ± 1.30. For structural MRI data, model 4 was considerably better than other models with an absolute difference in ELPD of 29.83 ± 7.55 relative to model 3, the second-best model. Conclusion: Our results suggest that representing the data generating process in terms of a hierarchical model that encompasses both ROI-level and network-level heterogeneity leads to better predictive ability for both tau-PET and structural MRI inputs over all other model iterations. [ABSTRACT FROM AUTHOR]
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- 2023
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9. The Memory Alteration Test Is Correlated with Clinical, Cerebrospinal Fluid, and Brain Imaging Markers of Alzheimer Disease in Lima, Peru.
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Custodio, Nilton, Malaga, Marco, Montesinos, Rosa, Chambergo-Michilot, Diego, Baca, Fiorella, Carbajal, Juan Carlos, Huilca, Jose Carlos, Herrera-Perez, Eder, Lira, David, Diaz, Monica M., and Lanata, Serggio
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DIAGNOSIS of dementia ,ALZHEIMER'S disease diagnosis ,STATISTICAL correlation ,TAU proteins ,PEARSON correlation (Statistics) ,MIDDLE-income countries ,ALZHEIMER'S disease ,MILD cognitive impairment ,SECONDARY analysis ,RECEIVER operating characteristic curves ,RESEARCH funding ,MAGNETIC resonance imaging ,DESCRIPTIVE statistics ,NEUROPSYCHOLOGICAL tests ,RESEARCH ,MEMORY ,NEURORADIOLOGY ,DEMENTIA ,BIOMARKERS ,AMYLOID beta-protein precursor ,LOW-income countries - Abstract
Introduction: As disease-modifying therapies become available for Alzheimer's disease (AD), detection of AD in early stages of illness (mild cognitive impairment [MCI], early dementia) becomes increasingly important. Biomarkers for AD in low- and middle-income countries (LMICs) are costly and not widely available; hence, it is important to identify cognitive tests that correlate well with AD biomarker status. In this study, we evaluated the memory alteration test (M@T) to detect biomarker-proven AD and quantify its correlation with neurodegeneration and cerebrospinal fluid (CSF) AD biomarkers in a cohort of participants from Lima, Peru. Methods: This is a secondary analysis of a cohort of 185 participants: 63 controls, 53 with amnestic MCI (aMCI), and 69 with dementia due to AD. Participants underwent testing with M@T and a gold standard neuropsychological battery. We measured total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid (β-amyloid) in CSF, and evaluated neurodegeneration via medial temporal atrophy score in MRI. We used receiver-operator curves to determine the discriminative capacity of the total M@T score and its subdomains. We used the Pearson coefficient to correlate M@T score and CSF biomarkers. Results: The M@T had an area under the curve (AUC) of 0.994 to discriminate between controls and cognitively impaired (aMCI or AD) patients, and an AUC of 0.98 to differentiate between aMCI and AD patients. Free-recall and cued recall had the highest AUCs of all subdomains. Total score was strongly correlated with t-tau (−0.77) and p-tau (−0.72), and moderately correlated with β-amyloid (0.66). The AUC for discrimination of neurodegeneration was 0.87. Conclusion: The M@T had excellent discrimination of aMCI and dementia due to AD. It was strongly correlated with CSF biomarkers and had good discrimination of neurodegeneration. In LMICs, the M@T may be a cost-effective screening tool for aMCI and dementia caused by AD. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Editorial: Present and future of biological fluid biomarkers in dementia.
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Frontiñán-Rubio, Javier, Rabanal-Ruiz, Yoana, Peinado, Juan R., and Deierborg, Tomas
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BODY fluid analysis ,DIAGNOSIS of dementia ,CEREBROSPINAL fluid examination ,ALZHEIMER'S disease diagnosis ,SALIVA analysis ,BIOMARKERS ,SERIAL publications ,BLOOD plasma ,TAU proteins ,DEMENTIA patients ,PROTEOMICS ,URINALYSIS - Published
- 2023
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11. Selective Detection of Misfolded Tau From Postmortem Alzheimer's Disease Brains.
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Ling Wu, Zerui Wang, Lad, Shradha, Gilyazova, Nailya, Dougharty, Darren T., Marcus, Madeleine, Henderson, Frances, Ray, W. Keith, Siedlak, Sandra, Jianyong Li, Helm, Richard F., Xiongwei Zhu, Bloom, George S., Shih-Hsiu J. Wang, Wen-Quan Zou, and Bin Xu
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ALZHEIMER'S disease diagnosis ,BRAIN ,BIOMARKERS ,ALZHEIMER'S disease ,TAU proteins ,AUTOPSY ,WESTERN immunoblotting - Abstract
Tau aggregates are present in multiple neurodegenerative diseases known as "tauopathies," including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions. To develop selective markers for AD and related rare tauopathies, we first used an engineered tau protein fragment 4RCF as the substrate for ultrasensitive real-time quaking-induced conversion analyses (RT-QuIC). We showed that misfolded tau from diseased AD and other tauopathy brains were able to seed recombinant 4RCF substrate. We further expanded to use six individual recombinant tau isoforms as substrates to amplify misfolded tau seeds from AD brains. We demonstrated, for the first time to our knowledge, that misfolded tau from the postmortem AD brain tissues was able to specifically seed all six full-length human tau isoforms. Our results demonstrated that RT-QuIC analysis can discriminate AD and other tauopathies from non-AD normal controls. We further uncovered that 3R-tau isoforms displayed significantly faster aggregation kinetics than their 4R-tau counterparts under conditions of both no seeding and seeding with AD brain homogenates. In summary, our work offers potential new avenues of misfolded tau detection as potential biomarkers for diagnosis of AD and related tauopathies and provides new insights into isoform-specific human tau aggregation. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Diffusion tensor imaging of white matter degeneration in Alzheimer’s disease and mild cognitive impairment.
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Amlien, I.K. and Fjell, A.M.
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DIFFUSION tensor imaging , *WHITE matter (Nerve tissue) , *BRAIN degeneration , *ALZHEIMER'S disease diagnosis , *MILD cognitive impairment , *PATHOLOGICAL physiology , *BRAIN imaging , *BIOMARKERS , *DIAGNOSIS - Abstract
Alzheimer’s disease (AD) has traditionally been regarded as a disease of the gray matter (GM). However, the advent of diffusion tensor imaging (DTI) has contributed to new knowledge about how changes in white matter (WM) microstructure in vivo may be directly related to the pathophysiology of AD. It is now evident that WM is heavily affected in AD, even at early stages. Still, our knowledge about WM degeneration in AD is poor compared to what we know about GM atrophy. For instance, it has not been clear if WM can be directly affected in AD independently of GM degeneration, or whether WM changes mainly represent secondary effects of GM atrophy, e.g. through Wallerian degeneration. In this paper, we review recent studies using DTI to study WM alterations in AD. These studies suggest that microstructural WM affection at pre-AD stages cannot completely be accounted for by concomitant GM atrophy. Further, recent research has demonstrated relationships between increased cerebrospinal fluid levels of Tau proteins and changes in WM microstructure indexed by DTI, which could indicate that WM degeneration in pre-AD stages is related to ongoing axonal damage. We conclude that DTI is a promising biomarker for AD, with the potential also to identify subgroups of patients with especially high degree of WM affection, thereby contributing to more differentiated pre-AD diagnoses. However, more research and validation studies are needed before it is realistic to use this information in clinical practice with individual patients. [ABSTRACT FROM AUTHOR]
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- 2014
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13. Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease.
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Jutten, Roos J., Rentz, Dorene M., Fu, Jessie F., Mayblyum, Danielle V., Amariglio, Rebecca E., Buckley, Rachel F., Properzi, Michael J., Maruff, Paul, Stark, Craig E., Yassa, Michael A., Johnson, Keith A., Sperling, Reisa A., and Papp, Kathryn V.
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ALZHEIMER'S disease ,COGNITIVE testing ,RECEIVER operating characteristic curves ,OLDER people ,ENTORHINAL cortex ,POSITRON emission tomography ,CEREBRAL amyloid angiopathy ,ALZHEIMER'S disease diagnosis ,BIOMARKERS ,COGNITION disorders ,STATISTICS ,TEMPORAL lobe ,CONFIDENCE intervals ,TAU proteins ,ASSAULT & battery ,AMYLOID beta-protein precursor ,PSYCHOLOGICAL tests ,QUESTIONNAIRES ,DESCRIPTIVE statistics ,RESEARCH funding ,DATA analysis software ,DATA analysis ,ODDS ratio - Abstract
Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline. Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5. Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02). Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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14. Heterogeneity of Cerebrospinal Fluid Biomarkers Profiles in Individuals with Distinct Levels of Cognitive Decline: A Cross-Sectional Study.
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Pais, Marcos, Loureiro, Júlia, do Vale, Vagner, Radanovic, Marcia, Talib, Leda, Stella, Florindo, Forlenza, Orestes, Pais, Marcos Vasconcelos, Cunha Loureiro, Júlia, Santigado do Vale, Vagner, Talib, Leda Leme, and Vicente Forlenza, Orestes
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CEREBROSPINAL fluid ,OLDER people ,TAU proteins ,COGNITION disorders ,BIOMARKERS ,CEREBRAL amyloid angiopathy ,ALZHEIMER'S disease diagnosis ,DISEASE progression ,RESEARCH ,NERVE tissue proteins ,ALZHEIMER'S disease ,CROSS-sectional method ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,PEPTIDES ,PHOSPHORYLATION - Abstract
Background: Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer's disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice.Objective: To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment.Methods: 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n = 60, 29.4%); MCI (n = 84, 41.2%); or normal cognition (NC, n = 60, 29.4%). CSF concentrations of Aβ42, T-tau, and 181Thr-P-tau were determined, and Aβ42/P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD.Results: The majority (73.7%) of patients in the AD group had the Aβ42/P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A+, 28 (46.7%) as T+, and 23 (38.3%) as N + . In the AD group, 66.7%of the cases were classified as A+, 78.3%as T+, and 80%as N+.Conclusion: Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases. [ABSTRACT FROM AUTHOR]- Published
- 2021
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15. White Matter Hyperintensities Are No Major Confounder for Alzheimer's Disease Cerebrospinal Fluid Biomarkers.
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van Waalwijk van Doorn, Linda J.C., Ghafoorian, Mohsen, van Leijsen, Esther M.C., Claassen, Jurgen A.H.R., Arighi, Andrea, Bozzali, Marco, Cannas, Jorge, Cavedo, Enrica, Eusebi, Paolo, Farotti, Lucia, Fenoglio, Chiara, Fortea, Juan, Frisoni, Giovanni B., Galimberti, Daniela, Greco, Viviana, Herukka, Sanna-Kaisa, Liu, Yawu, Lleó, Alberto, de Mendonça, Alexandre, and Nobili, Flavio M.
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WHITE matter (Nerve tissue) ,CEREBROSPINAL fluid ,ALZHEIMER'S disease ,APOLIPOPROTEIN E4 ,BIOMARKERS ,MAGNETIC resonance imaging ,MILD cognitive impairment ,ALZHEIMER'S disease diagnosis ,DIGITAL image processing ,RESEARCH ,NERVE tissue proteins ,BRAIN diseases ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,PEPTIDES ,PHOSPHORYLATION - Abstract
Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer's disease (AD). However, CSF biomarker levels can be affected by confounding factors.Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels.Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis.Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group.Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment. [ABSTRACT FROM AUTHOR]- Published
- 2021
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16. An evaluation of the amyloid cascade model using in vivo positron emission tomographic imaging.
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Yasuno, Fumihiko, Nakamura, Akinori, Kato, Takashi, Iwata, Kaori, Sakurai, Takashi, Arahata, Yutaka, Washimi, Yukihiko, Hattori, Hideyuki, and Ito, Kengo
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ALZHEIMER'S disease diagnosis ,AMYLOID beta-protein precursor ,MAGNETIC resonance imaging ,MATHEMATICAL models ,MEMORY disorders ,PATH analysis (Statistics) ,REGRESSION analysis ,POSITRON emission tomography ,THEORY ,TAU proteins ,GRAY matter (Nerve tissue) ,IN vivo studies - Abstract
Aim: The amyloid cascade hypothesis posits that the accumulation of amyloid β (Aβ) is the triggering factor for Alzheimer's disease, which consecutively induces aggregation of tau, synaptic loss, and cell death. Most experimental and clinical evidence supports this model, but the available data are largely qualitative. Here, we tested the amyloid cascade hypothesis by using in vivo evaluation of positron emission tomography and magnetic resonance imaging. Methods: Path analysis was used to estimate the relationships among Aβ accumulation (PiB standardized uptake value ratio (SUVR)), tau aggregation and its related neuroinflammation (THK5351 SUVR), grey matter atrophy in the medial temporal region, and memory function in Aβ‐positive subjects. We also performed additional regression analyses to evaluate the effect of Aβ on the toxicity of tau aggregation/neuroinflammation. Results: Path analysis supported our hypothesized model: Aβ accumulation affected tau aggregation/neuroinflammation in the medial temporal region, and these pathological changes caused of the grey matter atrophy and memory dysfunction. In separate regression analyses, THK5351 SUVR had a significant effect on grey matter atrophy only in PiB‐positive subjects. The analysis of the interaction effect showed that the effects of THK5351 SUVR on grey matter atrophy were significantly different between PiB‐positive and PiB‐negative groups. When we included the effect of being an apolipoprotein E ε4 carrier as a covariate, the interaction effect remained significant. Conclusion: Our in vivo evaluation of positron emission tomographic and magnetic resonance imaging data supported the amyloid cascade hypothesis. In addition, it indicated that Aβ not only accelerates tau aggregation/neuroinflammation but promotes its toxicity. Our findings showed the importance of understanding the role and therapeutic potential of the interaction between amyloid and tau aggregation/neuroinflammation in Alzheimer's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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17. Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer's Disease.
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Laugisch, Oliver, Johnen, Andreas, Maldonado, Alejandra, Ehmke, Benjamin, Bürgin, Walter, Olsen, Ingar, Potempa, Jan, Sculean, Anton, Duning, Thomas, Eick, Sigrun, and Walter, Bürgin
- Subjects
PERIODONTITIS ,ALZHEIMER'S disease diagnosis ,PATHOGENIC microorganisms ,VIRAL antibodies ,DEMENTIA ,CEREBROSPINAL fluid ,TAU proteins ,AMYLOID beta-protein - Abstract
Background: Recent studies suggest a link between periodontitis and Alzheimer's disease (AD).Objective: Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD).Methods: Clinical periodontal indices were recorded. Cerebrospinal fluid (CSF) was analyzed for total tau protein (T-tau) and amyloid-β (Aβ1-42). In serum and CSF, antibody levels against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Treponema species were quantified. The presence of selected bacteria and inflammatory biomarkers were determined in periodontium, serum, and CSF.Results: In line with diagnoses, CSF-levels of Aβ1-42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis, T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2.Conclusion: Periodontal pathogens may enter the brain and stimulate a local immune response. However, in patients with dementia at the age up to 70 years, periodontal pathogens do not act as a trigger for developing AD. [ABSTRACT FROM AUTHOR]- Published
- 2018
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18. Relevance of Aβ42/40 Ratio for Detection of Alzheimer Disease Pathology in Clinical Routine: The PLMR Scale.
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Lehmann, Sylvain, Delaby, Constance, Boursier, Guilaine, Catteau, Cindy, Ginestet, Nelly, Tiers, Laurent, Maceski, Aleksandra, Navucet, Sophie, Paquet, Claire, Dumurgier, Julien, Vanmechelen, Eugeen, Vanderstichele, Hugo, and Gabelle, Audrey
- Subjects
ALZHEIMER'S disease diagnosis ,CEREBROSPINAL fluid proteins ,BIOLOGICAL tags ,TAU proteins ,PEPTIDES - Abstract
Background: Cerebrospinal fluid (CSF) biomarkers (Ab peptides and tau proteins) improved the diagnosis of Alzheimer's disease (AD) in research and clinical settings. We previously described the PLM-scale (Paris-Lille-Montpellier study), which combines Ab42, tau, and phosphorylated ptau(181) biomarkers in an easy to use and clinically relevant way. The purpose of this work is to evaluate an optimized PLMR-scale (PLM ratio scale) that now includes the Ab42/Ab40 ratio to detect AD versus non-AD (NAD) participants in clinical routine of memory centers. Methods: Both scales were compared using 904 participants with cognitive impairment recruited from two independent cohorts (Mtp-1 and Mtp-2). The CSF Ab42/Ab40 ratio was measured systematically in Mtp-1, and only on biologically discordant cases in Mtp-2. Two different ELISA kit providers were also employed. The distribution of AD and NAD patients and the discrepancies of biomarker profiles were computed. Receiver Operating Characteristic curves were used to represent clinical sensitivity and specificity for AD detection. The classification of patients with the net reclassification index (NRI) was also evaluated. Results: Nine hundred and four participants (342 AD and 562 NAD) were studied; 400 in Mtp-1 and 504 in Mtp-2. For AD patients, the mean CSF Ab42 and CSF Ab42/40 ratio was 553 ± 216 pg/mL and 0.069 ± 0.022 pg/mL in Mtp-1 and 702 ± 335 pg/mL and 0.045 ± 0.020 pg/mL in Mtp-2. The distribution of AD and NAD differed between the PLM and the PLMR scales (p < 0.0001). The percentage AD well-classified (class 3) increased with PLMR from 38 to 83% in Mpt-1 and from 33 to 53% in Mpt-2. A sharp reduction of the discordant profiles going from 34 to 16.3% and from 37.5 to 19.8%, for Mtp-1 and Mtp-2 respectively, was also observed. The AUC of the PLMR scale was 0.94 in Mtp-1 and 0.87 in Mtp-2. In both cohorts, the PLMR outperformed CSF Ab42 or Ab42/40 ratio. The diagnostic performance was improved with the PLMR with an NRI equal to 44.3% in Mtp-1 and 28.8% in Mtp-2. Conclusion: The integration of the Ab42/Ab40 ratio in the PLM
R scale resulted in an easy-to-use tool which reduced the discrepancies in biologically doubtful cases and increased the confidence in the diagnosis in memory center. [ABSTRACT FROM AUTHOR]- Published
- 2018
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19. Tubulin and Tau: Possible targets for diagnosis of Parkinson’s and Alzheimer’s diseases.
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Salama, Mohamed, Shalash, Ali, Magdy, Alshimaa, Makar, Marianne, Roushdy, Tamer, Elbalkimy, Mahmoud, Elrassas, Hanan, Elkafrawy, Passent, Mohamed, Wael, and Abou Donia, Mohamed B.
- Subjects
PARKINSON'S disease diagnosis ,PARKINSON'S disease & genetics ,ALZHEIMER'S disease diagnosis ,TAU proteins ,TUBULINS ,DISEASE progression - Abstract
Neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by progressive neuronal loss and pathological accumulation of some proteins. Developing new biomarkers for both diseases is highly important for the early diagnosis and possible development of neuro-protective strategies. Serum antibodies (AIAs) against neuronal proteins are potential biomarkers for AD and PD that may be formed in response to their release into systemic circulation after brain damage. In the present study, two AIAs (tubulin and tau) were measured in sera of patients of PD and AD, compared to healthy controls. Results showed that both antibodies were elevated in patients with PD and AD compared to match controls. Curiously, the profile of elevation of antibodies was different in both diseases. In PD cases, tubulin and tau AIAs levels were similar. On the other hand, AD patients showed more elevation of tau AIAs compared to tubulin. Our current results suggested that AIAs panel could be able to identify cases with neuro-degeneration when compared with healthy subjects. More interestingly, it is possible to differentiate between PD and AD cases through identifying specific AIAs profile for each neurodegenerative states. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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20. Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization.
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Lewczuk, Piotr, Lelental, Natalia, Lachmann, Ingolf, Holzer, Max, Flach, Katharina, Brandner, Sebastian, Engelborghs, Sebastiaan, Teunissen, Charlotte E., Zetterberg, Henrik, Molinuevo, Jose Luis, Mroczko, Barbara, Blennow, Kaj, Popp, Julius, Parnetti, Lucilla, Chiasserini, Davide, Perret-Liaudet, Armand, Spitzer, Philipp, Maler, Juan Manuel, Kornhuber, Johannes, and Molinuevo, José Luis
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PHOSPHORYLATION ,ALZHEIMER'S disease diagnosis ,CEREBROSPINAL fluid ,TAU proteins ,OPACITY (Optics) ,ALZHEIMER'S disease ,ANIMAL experimentation ,ANIMALS ,BIOCHEMISTRY ,COLLECTION & preservation of biological specimens ,CELL culture ,ENZYME-linked immunosorbent assay ,IMMUNOGLOBULINS ,IMMUNOLOGY technique ,PHENOMENOLOGY ,MICE ,NERVE tissue proteins ,RESEARCH evaluation ,TEMPERATURE - Abstract
Background: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF).Objective: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF.Methods: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method.Results: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively.Conclusion: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF. [ABSTRACT FROM AUTHOR]- Published
- 2017
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21. A local insult of okadaic acid in wild-type mice induces tau phosphorylation and protein aggregation in anatomically distinct brain regions.
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Baker, Siân and Götz, Jürgen
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ALZHEIMER'S disease diagnosis ,PHOSPHORYLATION ,TAU proteins - Abstract
In Alzheimer's disease (AD), the distribution and density of neurofibrillary tangles, a histological hallmark comprised predominately of phosphorylated tau protein, follows a distinct pattern through anatomically connected brain regions. Studies in transgenic mice engineered to regionally confine tau expression have suggested spreading of tau within neural networks. Furthermore, injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. However, it remains unclear how the initiation of primary aggregation events occurs and what triggers further dissemination throughout the neural system. To consolidate these findings, we pursued an alternative approach to assess the spreading of endogenous phosphorylated tau. To generate endogenous seeds, 130 nl of 100 µM protein phosphatase 2A inhibitor okadaic acid (OA) was injected unilaterally into the amygdala of 8-month-old C57Bl/6 wild-type mice. OA was detected in brain tissue by ELISA, and found to be restricted to the injected hemispheric quadrant, where it remained detectable a week post-injection. OA injection induced tau phosphorylation that was observed not only at the injection site but also in anatomically distinct areas across both hemispheres, including the cortex and hippocampus 24 h post-injection. An increase in insoluble tau was also observed in both hemispheres of injected brains by 7 days. Furthermore, thioflavin-S detected protein aggregation at the injection site and in the cortex of both injected and contralateral hemispheres. OA injection induced no thioflavin-positivity in tau knock-out mice. The data demonstrates that a local OA insult can rapidly initiate changes in protein phosphorylation, solubility and aggregation at anatomically distant sites. This model suggests that tau phosphorylation can be both a primary response to an insult, and a secondary response communicated to non-exposed brains regions. The study highlights the use of OA to assist in understanding the initiation of tau spreading in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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22. Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease.
- Author
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Spiegel, Jonathan, Pirraglia, Elizabeth, Osorio, Ricardo S., Glodzik, Lidia, Li, Yi, Tsui, Wai, Saint Louis, Leslie A., Randall, Catherine, Butler, Tracy, Jinfeng Xu, Zinkowski, Raymond P., Zetterberg, Henrik, Fortea, Juan, Fossati, Silvia, Wisniewski, Thomas, Davies, Peter, Blennow, Kaj, de Leon, Mony J., and Xu, Jinfeng
- Subjects
ALZHEIMER'S disease ,TAU proteins ,CEREBROSPINAL fluid ,PHOSPHORYLATION ,BIOMARKERS ,MEDICAL research ,ALZHEIMER'S disease diagnosis ,NERVE tissue proteins ,PEPTIDES ,RESEARCH funding ,LOGISTIC regression analysis ,CROSS-sectional method ,CASE-control method ,RECEIVER operating characteristic curves - Abstract
Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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23. Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus.
- Author
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Herukka, Sanna-Kaisa, Rummukainen, Jaana, Ihalainen, Jouni, von und zu Fraunberg, Mikael, Koivisto, Anne M., Nerg, Ossi, Puli, Lakshman K., Seppälä, Toni T., Zetterberg, Henrik, Pyykkö, Okko T., Helisalmi, Seppo, Tanila, Heikki, Alafuzoff, Irina, Hiltunen, Mikko, Rinne, Jaakko, Soininen, Hilkka, Jääskeläinen, Juha E., and Leinonen, Ville
- Subjects
HYDROCEPHALUS ,ALZHEIMER'S disease diagnosis ,GENETICS of Alzheimer's disease ,ANIMAL models of Alzheimer's disease ,TAU proteins ,BRAIN metabolism ,APOLIPOPROTEINS ,BRAIN ,CHI-squared test ,COGNITION disorders ,EXTRACELLULAR fluid ,HEMODIALYSIS ,NERVE tissue proteins ,PEPTIDES ,DISEASE complications - Abstract
Background: Amyloid-β (Aβ1 - 42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF.Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF).Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF.Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1 - 42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1 - 42 levels than those six without amyloid pathology.Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease. [ABSTRACT FROM AUTHOR]- Published
- 2015
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24. Preanalytical confounding factors in the analysis of cerebrospinal fluid biomarkers for Alzheimer's disease: the issue of diurnal variation.
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Cicognola, Claudia, Chiasserini, Davide, and Parnetti, Lucilla
- Subjects
ALZHEIMER'S disease diagnosis ,CEREBROSPINAL fluid ,AMYLOID beta-protein ,TAU proteins ,BIOMARKERS ,CLINICAL pathology - Abstract
Given the growing use of cerebrospinal fluid (CSF) beta-amyloid (Aβ) and tau as biomarkers for early diagnosis of Alzheimer's disease (AD), it is essential that the diagnostic procedures are standardized and the results comparable across different laboratories. Preanalytical factors are reported to be the cause of at least 50% of the total variability. Among them, diurnal variability is a key issue and may have an impact on the comparability of the values obtained. The available studies on this issue are not conclusive so far. Fluctuations of CSF biomarkers in young healthy volunteers have been previously reported, while subsequent studies have not confirmed those observations in older subjects, the ones most likely to receive this test. The observed differences in circadian rhythms need to be further assessed not only in classical CSF biomarkers but also in novel forthcoming biomarkers. In this review, the existing data on the issue of diurnal variations of CSF classical biomarkers for AD will be analyzed, also evaluating the available data on new possible biomarkers. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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25. Antibody-Derived In Vivo Imaging of Tau Pathology.
- Author
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Krishnaswamy, Senthilkumar, Yan Lin, Rajamohamedsait, Wajitha J., Rajamohamedsait, Hameetha B., Krishnamurthy, Pavan, and Sigurdsson, Einar M.
- Subjects
ALZHEIMER'S disease diagnosis ,TAU proteins ,IMMUNOGLOBULINS ,AMYLOID beta-protein ,DIAGNOSTIC imaging ,LABORATORY mice ,ENDOSOMES - Abstract
Antibodies or their derivatives as imaging probes for pathological tau protein have great potential, but have not been well studied. In particular, smaller, single-chain-variable antibody fragments (scFv's) are attractive for detecting tau lesions in live subjects. Here, we generated libraries of scFv's and identified numerous phospho-tau-selective scFv's. Peripheral injection of one of these scFv's consistently resulted in a strong in vivo brain signal in transgenic tauopathy mice, but not in wild-type or amyloid-ß plaque mice. The parent tau antibody provided similar results, albeit with a weaker signal intensity. The imaging signal correlated very well with colocalization of the probe with intraneuronal tau aggregates. Both were associated with markers of endosomes, autophagosomes, and lysosomes, suggesting their interaction in these degradation pathways. Such specific antibody-derived imaging probes have great potential as diagnostic markers for Alzheimer's disease and related tauopathies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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26. Tau oligomers as potential targets for Alzheimer's diagnosis and novel drugs.
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Guzmán-Martinez, Leonardo, Farías, Gonzalo A., and Maccioni, Ricardo Benjamin
- Subjects
OLIGOMERS ,TAU proteins ,ALZHEIMER'S disease diagnosis ,ALZHEIMER'S disease treatment ,NEURODEGENERATION ,FULVIC acids - Abstract
A cumulative number of approaches have been carried out to elucidate the pathogenesis of Alzheimer's disease (AD). Tangles formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. Most of recent studies share in common the observation that formation of tau oligomers and the subsequent pathological filaments arrays is a critical step in AD etiopathogenesis. Oligomeric tau species appear to be toxic for neuronal cells, and therefore appear as an appropriate target for the design of molecules that may control morphological and functional alterations leading to cognitive impairment. Thus, cur-rent therapeutic strategies are aimed at three major types of molecules: (1) inhibitors of protein kinases and phosphatases that modify tau and that may control neuronal degeneration, (2) methylene blue, and (3) natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. Only a few polyphenolic molecules have emerged to prevent tau aggregation. In this context, fulvic acid (FA), a humic substance, has potential protective activity cognitive impairment. In fact, formation of paired helical filaments in vitro, is inhibited by FA affecting the length of fibrils and their morphology. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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27. CSF metabolites in the differential diagnosis of Alzheimer's disease from frontal variant of frontotemporal dementia.
- Author
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Rino, Francesca, Martinelli-Boneschi, Filippo, Caso, Francesca, Zuffi, Marta, Zabeo, Matteo, Passerini, Gabriella, Comi, Giancarlo, Magnani, Giuseppe, and Franceschi, Massimo
- Subjects
ALZHEIMER'S disease diagnosis ,FRONTOTEMPORAL dementia ,DIFFERENTIAL diagnosis ,CAREGIVERS ,AMYLOID beta-protein ,TAU proteins ,LONGITUDINAL method ,CEREBROSPINAL fluid ,METABOLITES - Abstract
The early differentiation between Alzheimer's disease (AD) and frontal variant of frontotemporal dementia (fvFTD) is frequently difficult, albeit critical for the adequate management of patients and their caregivers. In order to assess the accuracy of CSF levels of beta-amyloid 1-42 (Aβ), tau (τ) and Thr 181-phosphorilated tau (Pτ) in the early differentiation of AD from fvFTD, we designed a prospective study in which patients have been followed up for at least 2 years. Seventy-two patients with AD and 42 patients with fvFTD showed significantly different CSF levels of Pτ (increased in AD, p = 0.0001), Aβ (reduced in AD, p = 0.03), and ratios of Pτ to Aβ ( p = 0.003). ROC analyses showed that the ratio Pτ/Αβ is able to predict diagnosis with an AUC of 0.73 (optimal level being 0.16) corresponding to a sensitivity of 80% and a specificity of 68%. Our findings suggest that CSF metabolites may be the important tools in the early differential diagnosis between AD and fvFTD, albeit to be correlated with clinical, neuropsychological and bio imaging features. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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