Identification of blood biomarkers for use in point of care diagnosis tool for Alzheimer's disease.

Early diagnosis of Alzheimer's Disease (AD) is widely regarded as necessary to allow treatment to be started before irreversible damage to the brain occur and for patients to benefit from new therapies as they become available. Low-cost point-of-care (PoC) diagnostic tools that can be used to routinely diagnose AD in its early stage would facilitate this, but such tools require reliable and accurate biomarkers. However, traditional biomarkers for AD use invasive cerebrospinal fluid (CSF) analysis and/or expensive neuroimaging techniques together with neuropsychological assessments. Blood-based PoC diagnostics tools may provide a more cost and time efficient way to assess AD to complement CSF and neuroimaging techniques. However, evidence to date suggests that only a panel of biomarkers would provide the diagnostic accuracy needed in clinical practice and that the number of biomarkers in such panels can be large. In addition, the biomarkers in a panel vary from study to study. These issues make it difficult to realise a PoC device for diagnosis of AD. An objective of this paper is to find an optimum number of blood biomarkers (in terms of number of biomarkers and sensitivity/specificity) that can be used in a handheld PoC device for AD diagnosis. We used the Alzheimer's disease Neuroimaging Initiative (ADNI) database to identify a small number of blood biomarkers for AD. We identified a 6-biomarker panel (which includes A1Micro, A2Macro, AAT, ApoE, complement C3 and PPP), which when used with age as covariate, was able to discriminate between AD patients and normal subjects with a sensitivity of 85.4% and specificity of 78.6%

Complexity Measures for Quantifying Changes in Electroencephalogram in Alzheimer's Disease

Alzheimer’s disease (AD) is a progressive disorder that affects cognitive brain functions and starts many years before its clinical manifestations. A biomarker that provides a quantitative measure of changes in the brain due to AD in the early stages would be useful for early diagnosis of AD, but this would involve dealing with large numbers of people because up to 50% of dementia sufferers do not receive formal diagnosis. Thus, there is a need for accurate, low-cost, and easy to use biomarkers that could be used to detect AD in its early stages. Potentially, electroencephalogram (EEG) based biomarkers can play a vital role in early diagnosis of AD as they can fulfill these needs. This is a cross-sectional study that aims to demonstrate the usefulness of EEG complexity measures in early AD diagnosis. We have focused on the three complexity methods which have shown the greatest promise in the detection of AD, Tsallis entropy (TsEn), Higuchi Fractal Dimension (HFD), and Lempel-Ziv complexity (LZC) methods. Unlike previous approaches, in this study, the complexity measures are derived from EEG frequency bands (instead of the entire EEG) as EEG activities have significant association with AD and this has led to enhanced performance. The results show that AD patients have significantly lower TsEn, HFD, and LZC values for specific EEG frequency bands and for specific EEG channels and that this information can be used to detect AD with a sensitivity and specificity of more than 90%

Changes in the EEG amplitude as a biomarker for early detection of Alzheimer's disease.

The rapid increase in the number of older people with Alzheimer's disease (AD) and other forms of dementia represents one of the major challenges to the health and social care systems. Early detection of AD makes it possible for patients to access appropriate services and to benefit from new treatments and therapies, as and when they become available. The onset of AD starts many years before the clinical symptoms become clear. A biomarker that can measure the brain changes in this period would be useful for early diagnosis of AD. Potentially, the electroencephalogram (EEG) can play a valuable role in early detection of AD. Damage in the brain due to AD leads to changes in the information processing activity of the brain and the EEG which can be quantified as a biomarker. The objective of the study reported in this paper is to develop robust EEG-based biomarkers for detecting AD in its early stages. We present a new approach to quantify the slowing of the EEG, one of the most consistent features at different stages of dementia, based on changes in the EEG amplitudes (ΔEEGA). The new approach has sensitivity and specificity values of 100% and 88.88%, respectively, and outperformed the Lempel-Ziv Complexity (LZC) approach in discriminating between AD and normal subjects

Early Detection of Alzheimer\u27s Disease with Blood Plasma Proteins Using Support Vector Machines

\ua9 2013 IEEE. The successful development of amyloid-based biomarkers and tests for Alzheimer\u27s disease (AD) represents an important milestone in AD diagnosis. However, two major limitations remain. Amyloid-based diagnostic biomarkers and tests provide limited information about the disease process and they are unable to identify individuals with the disease before significant amyloid-beta accumulation in the brain develops. The objective in this study is to develop a method to identify potential blood-based non-amyloid biomarkers for early AD detection. The use of blood is attractive because it is accessible and relatively inexpensive. Our method is mainly based on machine learning (ML) techniques (support vector machines in particular) because of their ability to create multivariable models by learning patterns from complex data. Using novel feature selection and evaluation modalities, we identified 5 novel panels of non-amyloid proteins with the potential to serve as biomarkers of early AD. In particular, we found that the combination of A2M, ApoE, BNP, Eot3, RAGE and SGOT may be a key biomarker profile of early disease. Disease detection models based on the identified panels achieved sensitivity (SN) > 80%, specificity (SP) > 70%, and area under receiver operating curve (AUC) of at least 0.80 at prodromal stage (with higher performance at later stages) of the disease. Existing ML models performed poorly in comparison at this stage of the disease, suggesting that the underlying protein panels may not be suitable for early disease detection. Our results demonstrate the feasibility of early detection of AD using non-amyloid based biomarkers

Higuchi fractal dimension of the electroencephalogram as a biomarker for early detection of Alzheimer's disease

It is widely accepted that early diagnosis of Alzheimer's disease (AD) makes it possible for patients to gain access to appropriate health care services and would facilitate the development of new therapies. AD starts many years before its clinical manifestations and a biomarker that provides a measure of changes in the brain in this period would be useful for early diagnosis of AD. Given the rapid increase in the number of older people suffering from AD, there is a need for an accurate, low-cost and easy to use biomarkers that could be used to detect AD in its early stages. Potentially, the electroencephalogram (EEG) can play a vital role in this but at present, no reliable EEG biomarker exists for early diagnosis of AD. The gradual slowing of brain activity caused by AD starts from the back of the brain and spreads out towards other parts. Consequently, determining the brain regions that are first affected by AD may be useful in its early diagnosis. Higuchi fractal dimension (HFD) has characteristics which make it suited to capturing region-specific neural changes due to AD. The aim of this study is to investigate the potential of HFD of the EEG as a biomarker which is associated with the brain region first affected by AD. Mean HFD value was calculated for all channels of EEG signals recorded from 52 subjects (20-AD and 32-normal). Then, p-values were calculated between the two groups (AD and normal) to detect EEG channels that have a significant association with AD. k-nearest neighbor (KNN) algorithm was used to compute the distance between AD patients and normal subjects in the classification. Our results show that AD patients have significantly lower HFD values in the parietal areas. HFD values for channels in these areas were used to discriminate between AD and normal subjects with a sensitivity and specificity values of 100% and 80%, respectively

Tsallis entropy as a biomarker for detection of Alzheimer's disease.

Alzheimer's disease (AD) and other forms of dementia are one of the major public health and social challenges of our time because of the large number of people affected. Early diagnosis is important for patients and their families to get maximum benefits from access to health and social care services and to plan for the future. EEG provides useful insight into brain functions and can play a useful role as a first line of decision-support tool for early detection and diagnosis of dementia. It is non-invasive, low-cost and has a high temporal resolution. The functions of brain cells are affected by damage caused by dementia and this in turn causes changes in the features of the EEG. Information theoretic methods have emerged as a potentially useful way to quantify changes in the EEG as biomarkers of dementia. Tsallis entropy has been shown to be one of the most promising information theoretic methods for quantifying changes in the EEG. In this paper, we develop the approach further. This has yielded an enhanced performance compared to existing approaches

Prevalence of rickets-like bone deformities in rural Gambian children.

The aim of this study was to estimate the burden of childhood rickets-like bone deformity in a rural region of West Africa where rickets has been reported in association with a low calcium intake. A population-based survey of children aged 0.5-17.9 years living in the province of West Kiang, The Gambia was conducted in 2007. 6221 children, 92% of those recorded in a recent census, were screened for physical signs of rickets by a trained survey team with clinical referral of suspected cases. Several objective measures were tested as potential screening tools. The prevalence of bone deformity in children <18.0 years was 3.3%. The prevalence was greater in males (M = 4.3%, F = 2.3%, p < 0.001) and in children <5.0 years (5.7%, M = 8.3%, F = 2.9%). Knock-knee was more common (58%) than bow-leg (31%) or windswept deformity (9%). Of the 196 examined clinically, 36 were confirmed to have a deformity outside normal variation (47% knock-knee, 53% bow-leg), resulting in more conservative prevalence estimates of bone deformity: 0.6% for children <18.0 years (M = 0.9%, F = 0.2%), 1.5% for children < 5.0 years (M = 2.3%, F = 0.6%). Three of these children (9% of those with clinically-confirmed deformity, 0.05% of those screened) had active rickets on X-ray at the time of medical examination. This emphasises the difficulties in comparing prevalence estimates of rickets-like bone deformities from population surveys and clinic-based studies. Interpopliteal distance showed promise as an objective screening measure for bow-leg deformity. In conclusion, this population survey in a rural region of West Africa with a low calcium diet has demonstrated a significant burden of rickets-like bone deformity, whether based on physical signs under survey conditions or after clinical examination, especially in boys < 5.0 years

Assessment of Alzheimer-related pathologies of dementia using machine learning feature selection

Although a variety of brain lesions may contribute to the pathological assessment of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remains uncertain. Systematically assessing neuropathological measures by their degree of association with dementia may lead to better diagnostic systems and treatment targets. This study aims to apply machine learning approaches to feature selection in order to identify critical features of Alzheimer-related pathologies associated with dementia. We applied machine learning techniques for feature ranking and classification to objectively compare neuropathological features and their relationship to dementia status during life using a cohort (n=186) from the Cognitive Function and Ageing Study (CFAS). We first tested Alzheimer’s Disease and tau markers and then other neuropathologies associated with dementia. Seven feature ranking methods using different information criteria consistently ranked 22 out of the 34 neuropathology features for importance to dementia classification. Although highly correlated, Braak neurofibrillary tangle stage, beta-amyloid and cerebral amyloid angiopathy features were ranked the highest. The best-performing dementia classifier using the top eight neuropathological features achieved 79% sensitivity, 69% specificity and 75% precision. However, when assessing all seven classifiers and the 22 ranked features, a substantial proportion (40.4%) of dementia cases was consistently misclassified. These results highlight the benefits of using machine learning to identify critical indices of plaque, tangle and cerebral amyloid angiopathy burdens that may be useful for classifying dementia

Robust EEG Based Biomarkers to Detect Alzheimer’s Disease

Biomarkers to detect Alzheimer’s disease (AD) would enable patients to gain access to appropriate services and may facilitate the development of new therapies. Given the large numbers of people affected by AD, there is a need for a low-cost, easy to use method to detect AD patients. Potentially, the electroencephalogram (EEG) can play a valuable role in this, but at present no single EEG biomarker is robust enough for use in practice. This study aims to provide a methodological framework for the development of robust EEG biomarkers to detect AD with a clinically acceptable performance by exploiting the combined strengths of key biomarkers. A large number of existing and novel EEG biomarkers associated with slowing of EEG, reduction in EEG complexity and decrease in EEG connectivity were investigated. Support vector machine and linear discriminate analysis methods were used to find the best combination of the EEG biomarkers to detect AD with significant performance. A total of 325,567 EEG biomarkers were investigated, and a panel of six biomarkers was identified and used to create a diagnostic model with high performance (≥85% for sensitivity and 100% for specificity).</jats:p