Associations of Vascular Risk Factors and APOE Genotype With Perivascular Spaces Among Community‐Dwelling Older Adults

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Association between Subcortical Lesions and Behavioral and Psychological Symptoms in Patients with Alzheimer's Disease.

Background/Aims: The most devastating features of Alz-heimer's disease (AD) are often the behavioral and psychological symptoms in dementia (BPSD). There is controversy as to whether subcortical lesions contribute to BPSD. The aim of this study was to examine the relationship between BPSD and subcortical lesions (white-matter lesions and lacunes) in AD. Methods: CT or MRI from 259 patients with mild-to-moderate AD were assessed with the Age-Related White Matter Changes scale. Linear measures of global and temporal atrophy and Mini-Mental State Examination scores were used to adjust for AD pathology and disease severity in logistic regression models with the BPSD items delusions, hallucinations, agitation, depression, anxiety, apathy and irritability. Results: Lacunes in the left basal ganglia were asso-ciated with delusions (OR 2.57, 95% CI 1.21-5.48) and hallucinations (OR 3.33, 95% CI 1.38-8.01) and lacunes in the right basal ganglia were associated with depression (OR 2.13, 95% CI 1.01-4.51). Conclusion: Lacunes in the basal ganglia resulted in a 2- to 3-fold increased risk of delusions, hallucinations and depression, when adjusting for cognition and atrophy. This suggests that basal ganglia lesions can contribute to BPSD in patients with AD, independently of the AD process

First Administration of the Fc-Attenuated Anti-beta Amyloid Antibody GSK933776 to Patients with Mild Alzheimer's Disease: A Randomized, Placebo-Controlled Study

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Magnetic resonance imaging in dementia : A study of brain white matter changes

Non-specific white matter changes (WMC) in the brain are common findings in the elderly population. Although they are frequently seen in non-demented persons, WMC seem to be more common in demented patients.The significance of these changes, as well as their pathophysiological background is incompletely understood. The aim of this thesis was to study different aspects of WMC using magnetic resonance imaging (MRI) and to investigate the clinical significance of such changes in subjects with mild cognitive impairment or dementia. In study 1 post-mortem MRI of the brain was compared to corresponding neuropathology slices. White matter changes were quantified and found to be more extensive on neuropathology. The areas that appeared normal on MRI but not on histopathology represented only minor changes with increased distance between the myelinated fibres but with preserved axonal network and glial cell density. Study II evaluated the blood-brain barrier (BBB) integrity to investigate if an increased permeability could be shown in WMC areas. A contrast enhanced MRI technique was used to detect small degrees of enhancement. No general increase in BBB could be detected in the WMC areas. In study III the relation between WMC and Apolipoprotein E (APOE) genotype was explored in patients with Alzheimer's disease (AD). Results showed that AD patients who were homozygous for the APOE epsilon4 allele had more WMC than patients with other genotypes. This was most significant for changes in the deep white matter. Results also indicate that in AD patients carrying the epsilon4 allele, WMC are not age related phenomena, but might be related to the aetiology of the disease. Study IV aimed to investigate if WMC in a specific brain region affect cognitive functions related to that area. Periventricular WMC in the left frontal lobe predicted a decrease in initial word fluency, a test thought to reflect left frontal lobe functioning. This indicates that WMC might have specific effects in different brain regions. In study V we evaluated the prognostic significance of WMC in patients with memory impairment, regarding the rate of further global cognitive decline. There was no difference in outcome between patients having extensive WMC and a matched control group, during 2-4 years of follow up, and assessed by the "Mini Mental State Examination". In conclusion, this work has shown and characterised pathological changes in the white matter not visible on conventional MRI. We have also shown that there is no major general increase in BBB permeability in areas of WMC. In addition, homozygosity with regard to the APOE epsilon4 gene allele implies an increased extent of WMC in Alzheimer's disease patients. In AD patients carrying this gene allele WMC are not merely age related phenomena, but might be related to the aetiology of the disease. We also claim that WMC in a specific location might impair cognitive functions that rely on those specific pathways. In contrast, WMC do not seem to have any prognostic value in predicting the rate of global cognitive decline in patients at a memory clinic

Medial Temporal Lobe Atrophy Increases the Specificity of Cerebrospinal Fluid Biomarkers in Alzheimer Disease with Minor Cerebrovascular Changes.

Background: Although cerebrospinal fluid (CSF) biomarkers and medial temporal lobe atrophy (MTA) contribute to the diagnosis of Alzheimer disease (AD), they may not be specific. Relatively little is known about how they correlate with each other. Purpose: To identify the validity of the radiological linear measurements of brain atrophy in AD diagnosis by examining the correlation with CSF biomarkers and by examining if specificity could be improved in classification of AD from controls, when the linear measurements are combined with the CSF biomarkers. Material and Methods: 59 controls (20 male/39 female, age 73 +/- 8 years), 162 pure AD patients (49/113, 74 +/- 7 years), and 86 AD patients with minor cerebrovascular changes (CVC) (31/55, 77 +/- 5 years), aged between 52 and 94 years, were recruited from the Malmo Alzheimer Study. AD patients were subgrouped into opure ADo and oAD + CVCo in order to clarify the possible influence of CVC on atrophy or CSF biomarkers in AD patients. Abeta42, T-tau, and P-tau in CSF were examined. Computed tomography (CT) linear measurements were performed, which included temporal horn ratio and suprasellar cistern ratio that reflect MTA. Results: Compared with the 14 significant correlations between the CT measurements and three CSF biomarkers in the pure AD group, there was only one significant correlation in the AD + CVC group and one in the control group. In particular, P-tau correlates with temporal horn ratio only in pure AD. When the CT measurements were added with CSF biomarkers as independent variables in discriminant analysis, the percentage of correct classification of AD + CVC from controls increased from 79.5% (only CSF biomarkers) to 84.6% (combined CT measurements with CSF biomarkers). However, little was changed in the pure AD group. Conclusion: P-tau correlates with the linear CT measure of MTA only in pure AD without CVC. Combined with the measure of MTA, the specificity of CSF biomarkers can be increased, but only in AD + CVC. The linear measurements of MTA are of value in AD diagnosis

GSK933776 plasma pharmacodynamics.

<p>A) Geometric mean plasma Aβ concentration–time plots over the three dosing intervals (semi-log plot). Plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased in dose-dependent manner. Peak:trough ratios for Aβ decreased with increasing dose of GSK933776. B) Week 12 ratio to baseline for CSF Aβ (Aβ1–42 and AβX–42) concentrations. Presented as individual values and mean (95%CI). There were no significant changes from baseline for Aβ1–42 or AβX–42.</p

Summary of most frequently reported adverse events.

<p>SD = single dose; RD = repeat dose.</p><p>²Amyloid-related imaging abnormality-hemorrhage (ARIA-H)</p><p>¹Amyloid-related imaging abnormality-edema (ARIA-E);</p><p>Summary of most frequently reported adverse events.</p

Summary of patients’ baseline characteristics.

<p>SD = single dose; RD = repeat dose; SE = standard error.</p><p>³Three patients participated in two dose levels of the single dose study and therefore the PGx sample was collected at the first dosing level in which they participated and not the second dosing level. <i>APOE</i> ε4 overall carriage frequency was calculated using the PGx population (n = 15), i.e., patients who participated in more than one dosing level were only taken into account once.</p><p>²Six patients participated in part A and re-entered part B. Therefore the pharmacogenetic (PGx) sample was collected when the patients participated in part A and no PGx sample was collected during part B. <i>APOE</i> ε4 overall carriage frequency was calculated using the PGx population (n = 44), i.e., patients who participated in both parts were only taken into account once.</p><p>¹Values ranged from 20 to 26 for all patients except one, who scored 28.</p><p>Summary of patients’ baseline characteristics.</p