scholarly journals Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative

2020 ◽  
Author(s):  
Thomas K Karikari ◽  
Andréa L. Benedet ◽  
Nicholas J Ashton ◽  
Juan Lantero Rodriguez ◽  
Anniina Snellman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Clinical Stage ◽  
Individual Variability ◽  
Non Invasive ◽  
Longitudinal Measurements ◽  
Dementia Patients ◽  
Positron Emission ◽  
Pet Scans

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-beta and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral amyloid-beta and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1,000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by amyloid-beta PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative amyloid-beta PET scans did not show increased plasma p-tau181. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC=85.3%; 95% CI, 81.4%-89.2%), as well as to distinguish between amyloid-beta-negative and amyloid-beta-positive individuals along the Alzheimer's continuum (AUC=76.9%; 95% CI, 74.0%-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

scholarly journals Detection of amyloid-beta and tau in tear fluid of patients with Alzheimer’s disease

2020 ◽  
Author(s):  
Marlies Gijs ◽  
Inez H.G.B. Ramakers ◽  
Pieter Jelle Visser ◽  
Frans R.J. Verhey ◽  
Marjo P.H. van de Waarenburg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Tear Fluid ◽  
Subjective Cognitive Decline ◽  
Amyloid Beta Peptides ◽  
Non Invasive ◽  
Beta Peptides ◽  
Dementia Patients ◽  
T Tau

Abstract Background There is growing interest in finding non-invasive alternatives to cerebrospinal fluid (CSF) that could serve as front-line diagnostics for Alzheimer’s disease (AD). In this study, we investigated AD-specific biomarkers in tear fluid.Methods Tear fluid was collected from 25 patients with subjective cognitive decline SCD), 24 patients with mild cognitive impairment (MCI), 11 dementia patients and nine controls. Amyloid-beta peptides (AB38, AB40, AB42), t-tau and p-tau levels in tear fluid were determined using multiplex immunoassays.Results Tear t-tau levels in dementia, MCI and SCD patients were higher than in HC (p = 0.002, p = 0.002 and p = 0.013, respectively). A negative correlation between AB42 and t-tau was found in both tear fluid and CSF. Levels of tear p-tau were detectable in patients but not in HC.Conclusions This study shows for the first time presence of amyloid-beta peptides (AB38, AB40, AB42), t-tau and p-tau in tear fluid.

The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer’s Disease Continuum: A Longitudinal Study

2021 ◽  
pp. 1-12
Author(s):  
Heng Zhang ◽  
Diyang Lyu ◽  
Jianping Jia ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Dementia Patients ◽  
Positron Emission ◽  
Potential Biomarker ◽  
Synaptic Degeneration ◽  
Over Time

Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

VANUTIDE CRIDIFICAR (ACC-001) AND QS-21 ADJUVANT IN INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE: AMYLOID IMAGING POSITRON EMISSION TOMOGRAPHY AND SAFETY RESULTS FROM A PHASE 2 STUDY

2016 ◽  
pp. 1-10
Author(s):  
C.H. van Dyck ◽  
C. Sadowsky ◽  
G. Le Prince Leterme ◽  
K. Booth ◽  
Y. Peng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Amyloid Beta ◽  
Standard Uptake Value ◽  
Emission Tomography ◽  
Amyloid Burden ◽  
Treatment Groups ◽  
Positron Emission ◽  
Early Alzheimer’S Disease

BACKGROUNDd: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer’s disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. Trial registration: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer’s disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). Intervention: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.

Neuroimaging in Alzheimer’s Disease

2013 ◽  
pp. 427-431 ◽  
Author(s):  
Hidenao Fukuyama
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Posterior Part ◽  
Lewy Body Disease ◽  
New Drugs ◽  
Amyloid Protein ◽  
Dementia Patients ◽  
Positron Emission ◽  
Occipital Lobes ◽  
The Brain

The diagnosis of Alzheimer’s disease (AD) is often based on clinical and pathological data. Positron emission tomography (PET) using the tracer 18F-FDG revealed findings specific to AD-mainly the posterior part of the brain and the association cortices of the parietal and occipital lobes were affected by a reduction in glucose metabolism. Recent advances in the development of tracers for amyloid protein, which is the key protein in the pathogenesis of AD, enables the pattern of deposition of amyloid protein in the brain to be visualized. Various tracers have been introduced to visualize other aspects of AD pathology. Recent clinical interests on dementia have focused on the early detection of AD and variation of Parkinson’s disease, namely dementia with Lewy body disease (DLB), because the earlier the diagnosis, the better the prognosis. The differential diagnosis of mild AD or mild cognitive impairment (MCI) as well as DLB has been studied using PET and MRI as part of the NIH’s Alzheimer disease Neuroimaging initiative (ADNI). At present, many countries are participating in the ADNI, which is yielding promising results. This chapter’s study will improve the development of new drugs for the treatment of dementia patients by enabling the evaluation of the effect and efficacy of those drugs.

scholarly journals Photobiomodulation for Alzheimer’s Disease: Has the Light Dawned?

Photonics ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 77 ◽  
Author(s):  
Michael Hamblin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Near Infrared ◽  
Infrared Light ◽  
Western World ◽  
Diverse Range ◽  
Non Invasive ◽  
Dementia Patients ◽  
Relieve Pain

Next to cancer, Alzheimer’s disease (AD) and dementia is probably the most worrying health problem facing the Western world today. A large number of clinical trials have failed to show any benefit of the tested drugs in stabilizing or reversing the steady decline in cognitive function that is suffered by dementia patients. Although the pathological features of AD consisting of beta-amyloid plaques and tau tangles are well established, considerable debate exists concerning the genetic or lifestyle factors that predispose individuals to developing dementia. Photobiomodulation (PBM) describes the therapeutic use of red or near-infrared light to stimulate healing, relieve pain and inflammation, and prevent tissue from dying. In recent years PBM has been applied for a diverse range of brain disorders, frequently applied in a non-invasive manner by shining light on the head (transcranial PBM). The present review discusses the mechanisms of action of tPBM in the brain, and summarizes studies that have used tPBM to treat animal models of AD. The results of a limited number of clinical trials that have used tPBM to treat patients with AD and dementia are discussed.

scholarly journals The Challenges of Diagnosis in Alzheimer’s Disease

US Neurology ◽  
2018 ◽  
Vol 14 (1) ◽  
pp. 15 ◽  
Author(s):  
Nenad Bogdanovic
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Amyloid Pet ◽  
Positive Finding ◽  
Positron Emission ◽  
University Of Oslo ◽  
The University ◽  
Study Participants ◽  
The Brain

Current neuropathologic examination of the brain is still the gold standard for diagnosis of Alzheimer’s disease (AD). Postmortem studies, however, have indicated that current methods for the clinical diagnosis of AD are suboptimal.1Recent research has demonstrated the clinical utility of amyloid-beta positron emission tomography (PET) scans, which detect the presence of amyloid-beta plaques in the brain. In a study presented at the Alzheimer’s Association International Conference (AAIC) in London, UK, July 2017, by Nenad Bogdanovic, MD, PhD, of the University of Oslo in Norway, amyloid PET imaging was found to be a fundamental diagnostic tool for AD, establishing a definite diagnosis or excluding AD in all 50 study participants.2 The use of cerebrospinal fluid (CSF) amyloid testing with a higher amyloid-beta plaque threshold than that traditionally used to establish a positive finding also resulted in high diagnostic accuracy, resulting in diagnosis or exclusion in 44 of 50 participants (88%) compared with only 21 individuals (42%) using traditional cutoffs.2

scholarly journals Alzheimer’s Disease-Related Metabolic Pattern in Diverse Forms of Neurodegenerative Diseases

Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2023
Author(s):  
Angus Lau ◽  
Iman Beheshti ◽  
Mandana Modirrousta ◽  
Tiffany A. Kolesar ◽  
Andrew L. Goertzen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lewy Bodies ◽  
Future Research ◽  
Metabolic Pattern ◽  
Dementia Patients ◽  
Positron Emission ◽  
Psychological Dysfunction ◽  
Underlying Causes ◽  
Neuroimaging Biomarkers

Dementia is broadly characterized by cognitive and psychological dysfunction that significantly impairs daily functioning. Dementia has many causes including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). Detection and differential diagnosis in the early stages of dementia remains challenging. Fueled by AD Neuroimaging Initiatives (ADNI) (Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.), a number of neuroimaging biomarkers for AD have been proposed, yet it remains to be seen whether these markers are also sensitive to other types of dementia. We assessed AD-related metabolic patterns in 27 patients with diverse forms of dementia (five had probable/possible AD while others had atypical cases) and 20 non-demented individuals. All participants had positron emission tomography (PET) scans on file. We used a pre-trained machine learning-based AD designation (MAD) framework to investigate the AD-related metabolic pattern among the participants under study. The MAD algorithm showed a sensitivity of 0.67 and specificity of 0.90 for distinguishing dementia patients from non-dementia participants. A total of 18/27 dementia patients and 2/20 non-dementia patients were identified as having AD-like patterns of metabolism. These results highlight that many underlying causes of dementia have similar hypometabolic pattern as AD and this similarity is an interesting avenue for future research.

scholarly journals Repeatability of parametric methods for [18F]florbetapir imaging in Alzheimer’s disease and healthy controls: A test–retest study

2020 ◽  
pp. 0271678X2091540 ◽  
Author(s):  
Sander CJ Verfaillie ◽  
Sandeep SV Golla ◽  
Tessa Timmers ◽  
Hayel Tuncel ◽  
Chris WJ van der Weijden ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Standardized Uptake Value ◽  
Emission Tomography ◽  
Parametric Methods ◽  
Excellent Performance ◽  
Reference Tissue ◽  
Positron Emission ◽  
Arterial Sampling ◽  
Pet Scans

Accumulation of amyloid beta (Aβ) is one of the pathological hallmarks of Alzheimer’s disease (AD), which can be visualized using [18F]florbetapir positron emission tomography (PET). The aim of this study was to evaluate various parametric methods and to assess their test-retest (TRT) reliability. Two 90 min dynamic [18F]florbetapir PET scans, including arterial sampling, were acquired ( n = 8 AD patient, n = 8 controls). The following parametric methods were used; (reference:cerebellum); Logan and spectral analysis (SA), receptor parametric mapping (RPM), simplified reference tissue model2 (SRTM2), reference Logan (rLogan) and standardized uptake value ratios (SUVr(50–70)). BPND+1, DVR, VT and SUVr were compared with corresponding estimates (VT or DVR) from the plasma input reversible two tissue compartmental (2T4k_VB) model with corresponding TRT values for 90-scan duration. RPM ( r2 = 0.92; slope = 0.91), Logan ( r2 = 0.95; slope = 0.84) and rLogan ( r2 = 0.94; slope = 0.88), and SRTM2 ( r2 = 0.91; slope = 0.83), SA ( r2 = 0.91; slope = 0.88), SUVr ( r2 = 0.84; slope = 1.16) correlated well with their 2T4k_VB counterparts. RPM (controls: 1%, AD: 3%), rLogan (controls: 1%, AD: 3%) and SUVr(50–70) (controls: 3%, AD: 8%) showed an excellent TRT reliability. In conclusion, most parametric methods showed excellent performance for [18F]florbetapir, but RPM and rLogan seem the methods of choice, combining the highest accuracy and best TRT reliability.

scholarly journals Positron Emission Tomography in Animal Models of Tauopathies

2022 ◽  
Vol 13 ◽  
Author(s):  
Lei Cao ◽  
Yanyan Kong ◽  
Bin Ji ◽  
Yutong Ren ◽  
Yihui Guan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Time Course ◽  
Neurotransmitter Receptor ◽  
Rat Models ◽  
Non Invasive ◽  
Positron Emission ◽  
Abnormal Accumulation

The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer’s disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer’s disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer’s disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.

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