scholarly journals Machine Learning to Predict Brain Amyloid Pathology in Pre-dementia Alzheimer’s Disease Using QEEG Features and Genetic Algorithm Heuristic

2021 ◽  
Vol 15 ◽  
Author(s):  
Nam Heon Kim ◽  
Dong Won Yang ◽  
Seong Hye Choi ◽  
Seung Wan Kang
Keyword(s):  
Alzheimer’S Disease ◽  
Genetic Algorithm ◽  
Alzheimer's Disease ◽  
Amyloid Plaque ◽  
Subjective Cognitive Decline ◽  
Eyes Closed ◽  
Iterative Development ◽  
Positron Emission ◽  
Amyloid Aβ ◽  
Optimal Feature

The use of positron emission tomography (PET) as the initial or sole biomarker of β-amyloid (Aβ) brain pathology may inhibit Alzheimer’s disease (AD) drug development and clinical use due to cost, access, and tolerability. We developed a qEEG-ML algorithm to predict Aβ pathology among subjective cognitive decline (SCD) and mild cognitive impairment (MCI) patients, and validated it using Aβ PET. We compared QEEG data between patients with MCI and those with SCD with and without PET-confirmed beta-amyloid plaque. We compared resting-state eyes-closed electroencephalograms (EEG) patterns between the amyloid positive and negative groups using relative power measures from 19 channels (Fp1, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, O2), divided into eight frequency bands, delta (1–4 Hz), theta (4–8 Hz), alpha 1 (8–10 Hz), alpha 2 (10–12 Hz), beta 1 (12–15 Hz), beta 2 (15–20 Hz), beta 3 (20–30 Hz), and gamma (30–45 Hz) calculated by FFT and denoised by iSyncBrain®. The resulting 152 features were analyzed using a genetic algorithm strategy to identify optimal feature combinations and maximize classification accuracy. Guided by gene modeling methods, we treated each channel and frequency band of EEG power as a gene and modeled it with every possible combination within a given dimension. We then collected the models that showed the best performance and identified the genes that appeared most frequently in the superior models. By repeating this process, we converged on a model that approximates the optimum. We found that the average performance increased as this iterative development of the genetic algorithm progressed. We ultimately achieved 85.7% sensitivity, 89.3% specificity, and 88.6% accuracy in SCD amyloid positive/negative classification, and 83.3% sensitivity, 85.7% specificity, and 84.6% accuracy in MCI amyloid positive/negative classification.

Donanemab (LY3002813) Phase 1b Study in Alzheimer’s Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging

2021 ◽  
pp. 1-11
Author(s):  
S.L Lowe ◽  
C. Duggan Evans ◽  
S. Shcherbinin ◽  
Y.-J. Cheng ◽  
B.A. Willis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Single Dose ◽  
Standard Error ◽  
Amyloid Plaque ◽  
Emission Tomography ◽  
Positron Emission ◽  
Plaque Load ◽  
Antidrug Antibodies

Background: Donanemab (LY3002813) is an IgG1 antibody directed at an N‑terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. Objectives: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. Design: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. Setting: Patients recruited at clinical research sites in the United States and Japan. Participants: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer’s disease and mild-to-moderate Alzheimer’s disease dementia. Intervention: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). Measurements: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. Results: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). Conclusions: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Decreased Alpha Reactivity from Eyes-Closed to Eyes-Open in Non-Demented Older Adults with Alzheimer’s Disease: A Combined EEG and [18F]florbetaben PET Study

2020 ◽  
Vol 77 (4) ◽  
pp. 1681-1692
Author(s):  
Soohyun Chae ◽  
Jinsick Park ◽  
Min Soo Byun ◽  
Dahyun Yi ◽  
Jun Ho Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Memory Function ◽  
Amyloid Β ◽  
Clinical Predictors ◽  
Eyes Closed ◽  
Positron Emission ◽  
Eyes Open ◽  
Early Biomarker

Background: The degree of alpha attenuation from eyes-closed (EC) to eyes-open (EO) has been suggested as a neural marker of cognitive health, and its disruption has been reported in patients with clinically defined Alzheimer’s disease (AD) dementia. Objective: We tested if EC-to-EO alpha reactivity was related to cerebral amyloid-β (Aβ) deposition during the early stage of AD. Methods: Non-demented participants aged ≥55 years who visited the memory clinic between March 2018 and June 2019 (N = 143; 67.8% female; mean age±standard deviation, 74.0±7.6 years) were included in the analyses. Based on the [18F]florbetaben positron emission tomography assessment, the participants were divided into Aβ+ (N = 70) and Aβ- (N = 73) groups. EEG was recorded during the 7 min EC condition followed by a 3 min EO phase, and a Fourier transform spectral analysis was performed. Results: A significant three-way interaction was detected among Aβ positivity, eye condition, and the laterality factor on alpha-band power after adjusting for age, sex, educational years, global cognition, depression, medication use, and white matter hyperintensities on magnetic resonance imaging (F = 5.987, p = 0.016); EC-to-EO alpha reactivity in the left hemisphere was significantly reduced in Aβ+ subjects without dementia compared with the others (F = 3.984, p = 0.048). Conclusion: Among mild cognitive impairment subjects, alpha reactivity additively contributed to predict cerebral Aβ positivity beyond the clinical predictors, including vascular risks, impaired memory function, and apolipoprotein E ɛ4. These findings support that EC-to-EO alpha reactivity acts as an early biomarker of cerebral Aβ deposition and is a useful measurement for screening early-stage AD.

RANDOMIZED, PLACEBO CONTROLLED TRIAL OF NPT088, A PHAGE-DERIVED, AMYLOID-TARGETED TREATMENT FOR ALZHEIMER’S DISEASE

2019 ◽  
pp. 1-4
Author(s):  
D. Michelson ◽  
M. Grundman ◽  
K. Magnuson ◽  
R. Fisher ◽  
J.M. Levenson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Controlled Trial ◽  
Positron Emission Tomography Imaging ◽  
Amyloid Plaque ◽  
Disease Symptoms ◽  
Positron Emission ◽  
Infusion Reactions ◽  
Β Amyloid

The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer’s disease. Previous studies showed that NPT088 treatment reduced β-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer’s disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in β-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer’s disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer’s disease symptoms was observed.

scholarly journals Neuroimaging advances regarding subjective cognitive decline in preclinical Alzheimer’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Xiaoqi Wang ◽  
Weijie Huang ◽  
Li Su ◽  
Yue Xing ◽  
Frank Jessen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Subjective Cognitive Decline ◽  
Imaging Features ◽  
Future Directions ◽  
Positron Emission ◽  
Magnetic Resonance Imaging Mri ◽  
Larger Sample ◽  
Neuroimaging Techniques

Abstract Subjective cognitive decline (SCD) is regarded as the first clinical manifestation in the Alzheimer’s disease (AD) continuum. Investigating populations with SCD is important for understanding the early pathological mechanisms of AD and identifying SCD-related biomarkers, which are critical for the early detection of AD. With the advent of advanced neuroimaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), accumulating evidence has revealed structural and functional brain alterations related to the symptoms of SCD. In this review, we summarize the main imaging features and key findings regarding SCD related to AD, from local and regional data to connectivity-based imaging measures, with the aim of delineating a multimodal imaging signature of SCD due to AD. Additionally, the interaction of SCD with other risk factors for dementia due to AD, such as age and the Apolipoprotein E (ApoE) ɛ4 status, has also been described. Finally, the possible explanations for the inconsistent and heterogeneous neuroimaging findings observed in individuals with SCD are discussed, along with future directions. Overall, the literature reveals a preferential vulnerability of AD signature regions in SCD in the context of AD, supporting the notion that individuals with SCD share a similar pattern of brain alterations with patients with mild cognitive impairment (MCI) and dementia due to AD. We conclude that these neuroimaging techniques, particularly multimodal neuroimaging techniques, have great potential for identifying the underlying pathological alterations associated with SCD. More longitudinal studies with larger sample sizes combined with more advanced imaging modeling approaches such as artificial intelligence are still warranted to establish their clinical utility.

Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1164-1173
Author(s):  
Siju Ellickal Narayanan ◽  
Nikhila Sekhar ◽  
Rajalakshmi Ganesan Rajamma ◽  
Akash Marathakam ◽  
Abdullah Al Mamun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Late Onset ◽  
Precursor Protein ◽  
Brain Disorder ◽  
Amyloid Aβ ◽  
T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

Subjective Spatial Navigation Complaints - A Frequent Symptom Reported by Patients with Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease

2018 ◽  
Vol 15 (3) ◽  
pp. 219-228 ◽  
Author(s):  
Jiri Cerman ◽  
Ross Andel ◽  
Jan Laczo ◽  
Martin Vyhnalek ◽  
Zuzana Nedelska ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Spatial Navigation ◽  
Subjective Cognitive Decline ◽  
Great Effort ◽  
Frequent Symptom ◽  
Normal Controls

Background: Great effort has been put into developing simple and feasible tools capable to detect Alzheimer's disease (AD) in its early clinical stage. Spatial navigation impairment occurs very early in AD and is detectable even in the stage of mild cognitive impairment (MCI). Objective: The aim was to describe the frequency of self-reported spatial navigation complaints in patients with subjective cognitive decline (SCD), amnestic and non-amnestic MCI (aMCI, naMCI) and AD dementia and to assess whether a simple questionnaire based on these complaints may be used to detect early AD. Method: In total 184 subjects: patients with aMCI (n=61), naMCI (n=27), SCD (n=63), dementia due to AD (n=20) and normal controls (n=13) were recruited. The subjects underwent neuropsychological examination and were administered a questionnaire addressing spatial navigation complaints. Responses to the 15 items questionnaire were scaled into four categories (no, minor, moderate and major complaints). Results: 55% of patients with aMCI, 64% with naMCI, 68% with SCD and 72% with AD complained about their spatial navigation. 38-61% of these complaints were moderate or major. Only 33% normal controls expressed complaints and none was ranked as moderate or major. The SCD, aMCI and AD dementia patients were more likely to express complaints than normal controls (p's<0.050) after adjusting for age, education, sex, depressive symptoms (OR for SCD=4.00, aMCI=3.90, AD dementia=7.02) or anxiety (OR for SCD=3.59, aMCI=3.64, AD dementia=6.41). Conclusion: Spatial navigation complaints are a frequent symptom not only in AD, but also in SCD and aMCI and can potentially be detected by a simple and inexpensive questionnaire.

Sign in / Sign up

Export Citation Format

Share Document