β-amyloid (Aβ) deposition in cognitively normal brain, dementia with Lewy bodies, and Alzheimer's disease:a study using principal components analysis

The densities of diffuse, primitive, and classic ß-amyloid (Aß) deposits were studied in the temporal lobe in cognitively normal brain, dementia with Lewy bodies (DLB), familial Alzheimer’s disease (FAD), and sporadic AD (SAD). Principal components analysis (PCA) was used to determine whether there were distinct differences between groups or whether Aß pathology was more continuously distributed from group to group. Three principal components (PC) were extracted from the data accounting for 56% of the total variance. Plots of cases in relation to the PC did not result in distinct groups but suggested overlap in Aß deposition between the groups. In addition, there were linear correlations between the densities of Aß deposits and the distribution of the cases along the PC in specific brain regions suggesting continuous variation from group to group. PC1 was associated with the degree of maturation of Aß deposits, PC2 with differences between FAD and SAD, and PC3 with the degree of spread of Aß pathology into the hippocampus. Apolipoprotein E (APOE) genotype was not associated with variation in Aß deposition between cases. PCA may be a useful method of studying the pathological interface between closely related neurodegenerative disorders.

Further studies on the patterns of senile plaques in senile dementia of the Alzheimer type (SDAT) with a hypothesis on the colonization of the cortex

The pattern of senile plaques was investigated in various brain regions of six SDAT brains. In 91 pattern analyses, the regularly spaced clump was the most common pattern found in 64.8% of analyses. Clumping due to large aggregations of uncored plaques in sulci was also common. Regularly spaced clumps were equally common in the hippocampus and neocortex. The pattern of plaques varied in different tissue sections from the same brain region. Cored and uncored plaques presented a similar range of patterns but their pattern varied when they were both present in the same tissue section. Both clump diameter and the intensity of clumping were positively correlated with cored but unrelated to uncored plaque density. Plaques may develop in regular clumps on subcortical afferents and during development of the disease the clumps may spread laterally and ultimately coalesce.

Longitudinal diffusion tensor imaging in dementia with Lewy bodies and Alzheimer's disease

Copyright © 2016 Elsevier Ltd. All rights reserved. Acknowledgements The study was supported by the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Elijah Mak was in receipt of a Gates Cambridge PhD studentship.

Whole-brain patterns of 1H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies

Acknowledgments We thank Craig Lambert for his help in processing the MRS data. The study was funded by the Sir Jules Thorn Charitable Trust (grant ref: 05/JTA) and was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre and the Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust and Newcastle University and the NIHR Biomedical Research Centre and Biomedical Research Unit in Dementia based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Whole Cortical And Default Mode Network Mean Functional Connectivity As Potential Biomarkers For Mild Alzheimer's Disease.

The search for an Alzheimer's disease (AD) biomarker is one of the most relevant contemporary research topics due to the high prevalence and social costs of the disease. Functional connectivity (FC) of the default mode network (DMN) is a plausible candidate for such a biomarker. We evaluated 22 patients with mild AD and 26 age- and gender-matched healthy controls. All subjects underwent resting functional magnetic resonance imaging (fMRI) in a 3.0 T scanner. To identify the DMN, seed-based FC of the posterior cingulate was calculated. We also measured the sensitivity/specificity of the method, and verified a correlation with cognitive performance. We found a significant difference between patients with mild AD and controls in average z-scores: DMN, whole cortical positive (WCP) and absolute values. DMN individual values showed a sensitivity of 77.3% and specificity of 70%. DMN and WCP values were correlated to global cognition and episodic memory performance. We showed that individual measures of DMN connectivity could be considered a promising method to differentiate AD, even at an early phase, from normal aging. Further studies with larger numbers of participants, as well as validation of normal values, are needed for more definitive conclusions.

Subclinical hyperthyroidism and dementia: the Sao Paulo Ageing & Health Study (SPAH)

Background: Several epidemiologic studies have shown a possible association between thyroid function and cognitive decline. Our aim was to evaluate the association of subclinical hyperthyroidism and dementia in a population sample of older people Methods: A cross-sectional study - Sao Paulo Ageing & Health Study (SPAH) - in a population sample of low-income elderly people >= 65 years-old to evaluate presence of subclinical thyroid disease as a risk factor for dementia. Thyroid function was assessed using thyrotropic hormone and free-thyroxine as well as routine use of thyroid hormones or antithyroid medications. Cases of dementia were assessed using a harmonized one-phase dementia diagnostic procedure by the ""10/66 Dementia Research Group"" including Alzheimer's disease and vascular dementia. Logistic regression models were used to test a possible association between subclinical hyperthyroidism and dementia. Results and discussion: Prevalence of dementia and of subclinical hyperthyroidism were respectively of 4.4% and 3.0%. After age adjustment, we found an association of subclinical hyperthyroidism and any type of dementia and vascular dementia (Odds Ratio, 4.1, 95% Confidence Interval [95% CI] 1.3-13.1, and 5.3 95% CI, 1.1-26.4; respectively). Analyzing data by gender, we found an association of subclinical hyperthyroidism with dementia and Alzheimer's disease only for men (OR, 8.0; 95% CI, 1.5-43.4; OR, 12.4; 95% CI, 1.2-128.4; respectively). No women with subclinical hypothyroidism presented Alzheimer's disease in the sample. Conclusion: The results suggest a consistent association among people with subclinical hyperthyroidism and dementia.

The accuracy of the Clock Drawing Test compared to that of standard screening tests for Alzheimer`s disease: results from a study of Brazilian elderly with heterogeneous educational backgrounds

Background: Although the Clock Drawing Test (CDT) is the second most used test in the world for the screening of dementia, there is still debate over its sensitivity specificity, application and interpretation in dementia diagnosis. This study has three main aims: to evaluate the sensitivity and specificity of the CDT in a sample composed of older adults with Alzheimer`s disease (AD) and normal controls; to compare CDT accuracy to the that of the Mini-mental State Examination (MMSE) and the Cambridge Cognitive Examination (CAMCOG), and to test whether the association of the MMSE with the CDT leads to higher or comparable accuracy as that reported for the CAMCOG. Methods: Cross-sectional assessment was carried out for 121 AD and 99 elderly controls with heterogeneous educational levels from a geriatric outpatient clinic who completed the Cambridge Examination for Mental Disorder of the Elderly (CAMDEX). The CDT was evaluated according to the Shulman, Mendez and Sunderland scales. Results: The CDT showed high sensitivity and specificity. There were significant correlations between the CDT and the MMSE (0.700-0.730; p < 0.001) and between the CDT and the CAMCOG (0.753-0.779; p < 0.001). The combination of the CDT with the MMSE improved sensitivity and specificity (SE = 89.2-90%; SP = 71.7-79.8%). Subgroup analysis indicated that for elderly people with lower education, sensitivity and specificity were both adequate and high. Conclusions: The CDT is a robust screening test when compared with the MMSE or the CAMCOG, independent of the scale used for its interpretation. The combination with the MMSE improves its performance significantly, becoming equivalent to the CAMCOG.

Stress and coping in older people with Alzheimer`s disease

To investigate stress intensity and coping style in older people with mild Alzheimer`s disease. The potential risk assessment of a stress event and the devising of coping strategies are dependent on cognitive function. Although older individuals with Alzheimer`s disease present significant cognitive impairment, little is known about how these individuals experience stress events and select coping strategies in stress situations. Survey. A convenient sample of 30 cognitively healthy older people and 30 individuals with mild Alzheimer`s disease were given an assessment battery of stress indicators (Symptom Stress List, Cornell Scale for Depression in Dementia, State-Trait Anxiety Inventory), coping style (Jalowiec Coping Scale) and cognitive performance (mini-mental state exam) were applied in both groups. Statistical analysis of the data employed the Mann-Whitney test to compare medians of stress indicators and coping style, Fischer`s exact test to compare proportions when expected frequencies were lower than five, and Spearman`s correlation coefficient to verify correlation between coping style and cognitive performance. Both groups suffered from the same stress intensity (p = 0.254). Regarding coping styles, although differences were not statistically significant (p = 0.124), emotion-oriented coping was predominant in the patients with Alzheimer`s disease. However, those individuals displaying better cognitive performance in the Alzheimer`s disease group had selected coping strategies focused on problem solving (p = 0.0074). Despite a tendency for older people with Alzheimer`s disease to select escape strategies and emotional control, rather than attempting to resolve or lesser the consequences arising from a problem, coping ultimately depends on cognitive performance of the individual. The findings of this study provide information and data to assist planning of appropriate support care for individuals with Alzheimer`s disease who experience stress situations, based on their cognitive performance.

Memory with emotional content, brain amygdala and Alzheimer`s disease

Objectives - A highly adaptive aspect of human memory is the enhancement of explicit, consciously accessible memory by emotional stimuli. We studied the performance of Alzheimer`s disease (AD) patients and elderly controls using a memory battery with emotional content, and we correlated these results with the amygdala and hippocampus volume. Methods - Twenty controls and 20 early AD patients were subjected to the International Affective Picture System (IAPS) and to magnetic resonance imaging-based volumetric measurements of the medial temporal lobe structures. Results - The results show that excluding control group subjects with 5 or more years of schooling, both groups showed improvement with pleasant or unpleasant figures for the IAPS in an immediate free recall test. Likewise, in a delayed free recall test, both the controls and the AD group showed improvement for pleasant pictures, when education factor was not controlled. The AD group showed improvement in the immediate and delayed free recall test proportional to the medial temporal lobe structures, with no significant clinical correlation between affective valence and amygdala volume. Conclusion - AD patients can correctly identify emotions, at least at this early stage, but this does not improve their memory performance.

The clinical utility of the Hopkins Verbal Learning Test as a screening test for mild dementia

Objective. The purpose of this study was to determine whether the Hopkins Verbal Learning Test (HVLT) could be used as a valid and reliable screening test for mild dementia in older people, and to compare its performance to that of the Mini-Mental State Examination (MMSE). Method. Using a cross-sectional design, we studied three groups of older subjects recruited from a district geriatric psychiatry service: (1) 26 patients with DSM-IV dementia and MMSE scores of 18 or better; (2) 15 patients with psychiatric diagnoses other than dementia; and (3) 15 normal controls. The relationship of each potential cutting point on the HVLT and the MMSE was examined against the independently ascertained DSM-IV diagnoses of dementia using a Receiver Operating Characteristic (ROC) analysis. Results. The subjects consisted of 21 (37.5%) males and 35 (62.5%) females with a mean age of 74.7 (SD 6.1) years and a mean of 8.5 (SD 1.8) years of formal education. ROC analysis indicated that the optimal cutting point for detecting mild dementia in this group of subjects using the HVLT was 18/19 (sensitivity = 0.96, specificity = 0.80) and using the MMSE was 25/26 (sensitivity = 0.88, specificity = 0.93). Conclusions. The HVLT can be recommended as a valid and reliable screening test for mild dementia and as an adjunct in the clinical assessment of older people. The HVLT had better sensitivity than the MMSE in detecting patients with mild dementia, whereas the MMSE had better specificity. Copyright (C) 2000 John Wiley & Sons, Ltd.

Homocysteine, Alzheimer genes and proteins, and measures of cognition and depression in older men

The epsilon4 allele of apolipoprotem E (APOE), and the plasma levels of APOE, amyloid beta-protein precursor, arnyloid beta1-40 (Abeta40) and homocysteine, (Hcy) have all been correlated with the presence of dementia. Mutations in the methylnetetrahydrofolate reductase enzyme (MTHFR) have been associated with elevated levels of Hcy. This study explored the association of these factors with cognition and depression in community dwelling older men. Two hundred and ninety-nine men, mean age 78.9 years (SD 2.8), were studied in this cross-sectional survey. Mean plasma Hcy was 13.5 (SD 5.3) mumol/L. The MTHFR genotype had no obvious impact on Hey levels. Ln Hcy and Ln Abeta40 were both inversely correlated with calculated glomerular filtration rate (cGFR), r = -0.41 (p < 0.001) and r = -0.28 (p < 0.001), respectively. There was a positive correlation between Ln Hey and Ln Abeta40, r = 0.19 (p < 0.001), which remained significant after adjusting for cGFR, with a doubling of Hcy associated with a 24% increase of Abeta40. The e4 allele was associated with increased depressive symptoms as measured by the Geriatric Depression Scale-15, Odds ratio (OR) = 2.59 (95% CI 1.06-6.34) and poorer performance on the Clock Drawing Test, OR = 2.32 (95% CI: 1.25-4.29). There was a positive association between Abeta40 and Hcy, even after adjustment for cGFR in this sample of well, community dwelling older men. This association may help elucidate the link between elevated levels of Hey and Alzheimer's disease.

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood and adult-onset schizophrenia, bipolar disorder, attention-deficit/ hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages. (C) 2004 Published by Elsevier Inc.

Estimate of Dementia Prevalence in a Community Sample from Sao Paulo, Brazil

Aims: To estimate dementia prevalence and describe the etiology of dementia in a community sample from the city of Sao Paulo, Brazil. Methods: A sample of subjects older than 60 years was screened for dementia in the first phase. During the second phase, the diagnostic workup included a structured interview, physical and neurological examination, laboratory exams, a brain scan, and DSM-IV criteria diagnosis. Results: Mean age was 71.5 years (n = 1,563) and 58.3% had up to 4 years of schooling (68.7% female). Dementia was diagnosed in 107 subjects with an observed prevalence of 6.8%. The estimate of dementia prevalence was 12.9%, considering design effect, nonresponse during the community phase, and positive and negative predictive values. Alzheimer`s disease was the most frequent cause of dementia (59.8%), followed by vascular dementia (15.9%). Older age and illiteracy were significantly associated with dementia. Conclusions: The estimate of dementia prevalence was higher than previously reported in Brazil, with Alzheimer`s disease and vascular dementia being the most frequent causes of dementia. Dementia prevalence in Brazil and in other Latin American countries should be addressed by additional studies to confirm these higher dementia rates which might have a sizable impact on countries` health services. Copyright (C) 2008 S. Karger AG, Basel

Improving Alzheimer`s Disease Diagnosis with Machine Learning Techniques

There is not a specific test to diagnose Alzheimer`s disease (AD). Its diagnosis should be based upon clinical history, neuropsychological and laboratory tests, neuroimaging and electroencephalography (EEG). Therefore, new approaches are necessary to enable earlier and more accurate diagnosis and to follow treatment results. In this study we used a Machine Learning (ML) technique, named Support Vector Machine (SVM), to search patterns in EEG epochs to differentiate AD patients from controls. As a result, we developed a quantitative EEG (qEEG) processing method for automatic differentiation of patients with AD from normal individuals, as a complement to the diagnosis of probable dementia. We studied EEGs from 19 normal subjects (14 females/5 males, mean age 71.6 years) and 16 probable mild to moderate symptoms AD patients (14 females/2 males, mean age 73.4 years. The results obtained from analysis of EEG epochs were accuracy 79.9% and sensitivity 83.2%. The analysis considering the diagnosis of each individual patient reached 87.0% accuracy and 91.7% sensitivity.