Induction of autoantibodies to glutamate in patients with Alzheimer’s disease

Autoantibodies to glutamate were found in blood plasma from patients with Alzheimer’s disease. The content of autoantibodies to glutamate in blood plasma from patients with moderate and severe dementia was 2-fold higher compared to patients with mild dementia. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 2, pp. 140–141, February, 2007     

Personality and resilience to Alzheimer’s disease neuropathology: a prospective autopsy study

Alzheimer’s disease (AD) neuropathology is found at autopsy in approximately 30% of cognitively normal older individuals. We examined whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (mean 11 ± 7 years) before onset of dementia and up to 30 years (mean 15 ± 7 years) before death in a cohort (n = 111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0; 95% confidence interval, 1.2–3.5), or lower scores on order and competence (conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2–0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r = 0.26), low agreeableness (r = −0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for the extent of neurofibrillary tangles and Aβ neuritic plaques. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology.     

Gng12 is a novel negative regulator of LPS-induced inflammation in the microglial cell line BV-2

Background  

Inflammation plays a central role in many neurodegenerative diseases, including Parkinson’s, Alzheimer’s, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. Microglia are the resident macrophages of the central nervous system and are the cells primarily responsible for the inflammatory component of these diseases.     

Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome

It is known that individuals with Down syndrome develop Alzheimer’s disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer’s disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer’s disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer’s disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer’s disease in Down syndrome.     

Alzheimer’s and prion disease as disorders of protein conformation: implications for the design of novel therapeutic approaches

 Several lines of evidence suggest that a defective protein folding is a central event in both Alzheimer’s and prion disease. Although the two disorders are very different clinically, neuropathologically, and biochemically, the molecular event that may trigger the disease process appears to be the same: the formation of an altered protein conformer composed of a high content of β-sheet structure. Compounds with the ability to prevent and to reverse protein conformational changes may be useful as novel therapeutic approaches for Alzheimer’s disease, prion disease, and other disorders of defective protein folding. Received: 28 December 1998 / Accepted: 8 February 1999     

Relationship satisfaction in couples confronted with colorectal cancer: the interplay of past and current spousal support

Based on attribution theory, this study hypthesized that past spousal supportiveness may act as a moderator of the link between one partner’s current support behavior and the other partner’s relationship satisfaction. A sample of 88 patients with colorectal cancer and their partners completed questionnaires approximately 3 and 9 months after diagnosis. The data were analyzed employing dyadic data analytic approaches. In the short-term, spousal active engagement—which involved discussing feelings and engaging in joint problem solving—was positively associated with relationship satisfaction in patients as well as in partners, but only when past spousal support was relatively low. Spousal protective buffering—which involved hiding worries and fears and avoiding talking about the disease—was negatively associated with relationship satisfaction in patients, again only when past spousal support was relatively low. If past spousal support was high, participants rated the quality of their relationship relatively high, regardless of their partner’s current support behavior. Over time, past spousal supportiveness was not found to mitigate the negative association between spousal protective buffering and relationship satisfaction. Overall, our results indicate that relationship satisfaction can be maintained if past spousal supportiveness is high even if the partner is currently not very responsive to the individual’s needs, at least in the short-term.     

Hostility,conflict and cardiovascular responses in married couples: a focus on the dyad

This study examined the relations of one’s own total trait hostility and one’s spouse’s hostility as influences on cardiovascular (CV) responses to couple interactions (including conflict discussions) in 45 married couples aged 24—50. Systolic blood pressure and cardiac index (CI) reactivity to conflict discussion and recovery after conflict was greater in low hostile males if they were interacting with high hostile wives (p < .02). Vascular resistance index (VRI) reactivity to interactions was greater in high hostile husbands with high hostile wives (p < .05). Women showed no adverse CV effects of having a hostile spouse when their own hostility was low. Instead, seeming to anticipate the subsequent couple interactions, wives from duos in which both partners were high in hostility had higher baseline VRI levels and lower baseline CI compared to wives from duos in which both were low in hostility (ps < .05), and they simply maintained these group differences with no greater CV reactivity during the interactions. Findings suggest that CV responses before, during, and after marital discussions, particularly those characterized by conflict, may be influenced not only by one’s own hostility but by the hostility of one’s partner as well.     

Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits

 Activated microglial cells are concentrated in senile plaques characteristic of Alzheimer’s disease. Such accumulations of activated microglia may contribute towards neurodegeneration via production of cytokines and free radicals. Studies suggesting a link between Alzheimer’s disease and heart disease led us to study microglia immunohistochemically, using monoclonal antibody LN-3, in age-matched nondemented humans with and without heart disease. Using a qualitative staging system for assessing morphological changes occurring in microglia, we found higher microglial activation in the brains of subjects with heart disease than in those without it. Lectin histochemical examination of brains from rabbits maintained on a high-cholesterol diet also revealed increased microglial activation and leukocyte infiltration. Collectively our observations from humans and rabbits suggest that hypercholesterolemia and heart disease accelerate brain aging, and that the formation of senile plaques may be the end result of progressive microglial activation that occurs with aging. Received: 8 October 1996 / Accepted: 4 November 1996     

Effective Metadata Discovery for Dynamic Filtering of Queries to a Radiology Image Search Engine

We sought to demonstrate the effectiveness of techniques to index radiology images using metadata discovered in their free-text figure captions. The ARRS GoldMiner™ image library incorporated 94,256 figures from 11,712 articles published in peer-reviewed online radiology journals. Algorithms were developed to discover metadata—age, sex, and imaging modality—from the figures’ free-text captions. Age was recorded in years, and was classified as infant (less than 2 years), child (2 to 17 years), or adult (18+ years). Each figure was assigned to one of eight imaging modalities. A random sample of 1,000 images was examined to measure accuracy of the metadata. The patient’s age was identified in 58,994 cases (63%), and the patient’s sex was identified in 58,427 cases (62%). An imaging modality was assigned to 80,402 (85%) of the figures. Based on the 1,000 sampled cases, recall values for age, sex, and imaging modality were 97.2%, 99.7%, and 86.4%, respectively. Precision values for age, sex, and imaging modality were 100%, 100%, and 97.2%, respectively. Automated techniques can accurately discover age, sex, and imaging modality metadata from captions of figures published in radiology journals. The metadata can be used to dynamically filter queries for an image search engine.     

Age Differences in Genetic and Environmental Variations in Stress-Coping During Adulthood: A Study of Female Twins

The way people cope with stressors of day to day living has an important influence on health. The aim of the present study was to explore whether genetic and environmental variations in stress-coping differ over time during adulthood. The brief COPE was mailed to a large sample of the UK female twins (N = 4,736) having a wide range of age (20–87 years). Factor analyses of the items of the brief COPE yielded three coping scales: ‘Problem-Solving’, ‘Support Seeking’, and ‘Avoidance’. Monozygotic and dizygotic twin correlations tended to become lower with age for all three scales, suggesting that unique environmental factors may become more important with age during adulthood. Model-fitting results showed that relative influences of unique environmental factors increased from 60 % at age 20 years to 74% at age 87 years for ‘Problem-Solving’ and 56 % at age 20 years to 76% at age 87 years for ‘Avoidance’. During the same age period, genetic factors decreased from 40 to 26 % for ‘Problem-Solving’ and from 44 to 24 % for ‘Avoidance’. For ‘Seeking Support’, the magnitude of genetic and unique environmental factors was not significantly different across the adulthood. For all three scales, shared environmental effects were negligible. Overall, our findings implicate that the effects of environment that stem from idiosyncratic experience of stressful life events accumulate and become increasingly important in adulthood.     

MEG Connectivity Analysis in Patients with Alzheimer’s Disease Using Cross Mutual Information and Spectral Coherence

Alzheimer’s disease (AD) is an irreversible brain disorder which represents the most common form of dementia in western countries. An early and accurate diagnosis of AD would enable to develop new strategies for managing the disease; however, nowadays there is no single test that can accurately predict the development of AD. In this sense, only a few studies have focused on the magnetoencephalographic (MEG) AD connectivity patterns. This study compares brain connectivity in terms of linear and nonlinear couplings by means of spectral coherence and cross mutual information function (CMIF), respectively. The variables defined from these functions provide statistically significant differences (p < 0.05) between AD patients and control subjects, especially the variables obtained from CMIF. The results suggest that AD is characterized by both decreases and increases of functional couplings in different frequency bands as well as by an increase in regularity, that is, more evident statistical deterministic relationships in AD patients’ MEG connectivity. The significant differences obtained indicate that AD could disturb brain interactions causing abnormal brain connectivity and operation. Furthermore, the combination of coherence and CMIF features to perform a diagnostic test based on logistic regression improved the tests based on individual variables for its robustness.     

Spatial frequency domain imaging of intrinsic optical property contrast in a mouse model of Alzheimer's disease

Extensive changes in neural tissue structure and function accompanying Alzheimer’s disease (AD) suggest that intrinsic signal optical imaging can provide new contrast mechanisms and insight for assessing AD appearance and progression. In this work, we report the development of a wide-field spatial frequency domain imaging (SFDI) method for non-contact, quantitative in vivo optical imaging of brain tissue composition and function in a triple transgenic mouse AD model (3xTg). SFDI was used to generate optical absorption and scattering maps at up to 17 wavelengths from 650 to 970 nm in 20-month-old 3xTg mice (n = 4) and age-matched controls (n = 6). Wavelength-dependent optical properties were used to form images of tissue hemoglobin (oxy-, deoxy-, and total), oxygen saturation, and water. Significant baseline contrast was observed with 13–26% higher average scattering values and elevated water content (52 ± 2% vs. 31 ± 1%); reduced total tissue hemoglobin content (127 ± 9 μM vs. 174 ± 6 μM); and lower tissue oxygen saturation (57 ± 2% vs. 69 ± 3%) in AD vs. control mice. Oxygen inhalation challenges (100% oxygen) resulted in increased levels of tissue oxy-hemoglobin (ctO₂Hb) and commensurate reductions in deoxy-hemoglobin (ctHHb), with ~60–70% slower response times and ~7 μM vs. ~14 μM overall changes for 3xTg vs. controls, respectively. Our results show that SFDI is capable of revealing quantitative functional contrast in an AD model and may be a useful method for studying dynamic alterations in AD neural tissue composition and physiology.     

Use of Noben (idebenone) in the Treatment of Dementia and Memory Impairments without Dementia

Noben (idebenone) at a dose of 120 mg per day for six months was used in the treatment of 35 patients aged 60–86 years with Alzheimer’s-type dementia, mixed dementia, and memory impairments not reaching the stage of dementia. Patients were assessed on the basis of data from somatic, neurological, and psychiatric investigations, as well as neuropsychological testing and a series of psychometric and other scales and tests, before and after treatment. Significant improvements in patients’ conditions on the MMSE were seen in patients with mild and moderate dementia. Improvements in daily activities were obtained in 27% of patients. Neuropsychological investigations demonstrated improvements in short-term and long-term memory and attention, with improvements in speech functions, performance of kinesthetic, spatial, and dynamic praxis tests, and in visuospatial gnosis, thought, and writing. On the CGI scale, positive treatment effects were obtained in 37% of patients, while 48% of patients remained in a stable state. Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 108, No. 4, pp. 27–32, April, 2008.     

Oxidative stress and antioxidant enzyme activities in patients with Hashimoto’s thyroiditis

We investigated the parameters of oxidative stress in 71 Hashimoto’s thyroiditis patients. They were divided into three sub-groups according to the thyroid function: group I—euthyroid subjects; group II—hypothyroid subjects; and group III—subjects treated with Levothyroxin. Thirty healthy subjects were studied as controls. The level of lipid peroxidation (malondialdehyde, MDA) in the plasma and the antioxidant defences such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities in erythrocytes were measured. Concentrations of MDA and SOD activity were not different in sub-groups of patients and controls. CAT activity was significantly lower in group II in comparison with both controls (p = 0.01) and group III (p = 0.02) as well as in group I compared to the controls (p = 0.04). Activity of GPX in erythrocytes in hypothyroidism was significantly higher compared to controls (p = 0.02). GPX activity in both groups I and III tended to be lower in comparison with controls. Our results indicate a deficiency of cellular antioxidative defense in Hashimoto’s thyroiditis patients in all stages of disease. Accordingly, we suppose that the supplementation with antioxidants from an early stage of the disease, in addition to thyroid hormone replacement, may have a positive benefit in the treatment.     

Aggregates of denatured proteins stimulate nitric oxide and superoxide production in macrophages

Objective  

Denatured proteins are deposited in damaged tissues, around implanted biomaterials, during natural aging as well as in a heterogeneous group of amyloid diseases, such as Alzheimer’s disease. There is evidence that tissue damage observed in amyloidosis is mediated mainly by factors released from activated macrophages, such as superoxide and nitric oxide (NO), as opposed to direct interaction between amyloid fibrils and nonimmune cells.     

Interactions between short latency afferent inhibition and long interval intracortical inhibition

Peripheral nerve stimulation inhibits the motor cortex and the process has been termed afferent inhibition. Short latency afferent inhibition (SAI) at interstimulus intervals (ISI) of ~20 ms likely involves central cholinergic transmission and was found to be altered in Alzheimer’s disease and Parkinson’s disease. Cholinergic and GABA_A receptors are involved in mediating SAI. The effects of SAI on other intracortical inhibitory and facilitatory circuits have not been examined. The objective of the present study is to test how SAI interacts with long interval cortical inhibition (LICI), a cortical inhibitory circuit likely mediated by GABA_B receptors. We studied 10 healthy volunteers. Surface electromyogram was recorded from the first dorsal interosseous muscle. SAI was elicited by median nerve stimulation at the wrist followed by transcranial magnetic stimulation (TMS) at ISI of N20 somatosensory evoked potential latency + 3 ms. The effects of different test motor-evoked potential (MEP) amplitudes (0.2, 1, and 2 mV) were examined for LICI and SAI. Using paired and triple-pulse paradigms, the interactions between SAI and LICI were investigated. Both LICI and SAI decreased with increasing test MEP amplitude. Afferent stimulation that produced SAI decreased LICI. Thus, the present findings suggest that LICI and SAI have inhibitory interactions.     

Histochemical visualization and diffusion MRI at 7 Tesla in the TgCRND8 transgenic model of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has been characterized by gross cortical atrophy, cellular neurodegeneration, reactive gliosis, and the presence of microscopic extracellular amyloid plaques and intracellular neurofibrillary tangles. Earlier diagnoses of AD would be in the best interest of managing the patient and would allow for earlier therapeutic intervention. By measuring the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI), a type of magnetic resonance imaging (MRI), one can quantify alterations in water diffusivity resulting from microscopic structural changes in the cell at early stages that are associated with pathophysiological processes of brain injury and/or disease progression. Whether or not this methodology is useful for AD is a question under examination. For example, DWI in suspected AD patients has shown increases in mean ADC values in the hippocampus and diminished diffusion anisotropy in the posterior white matter. However, in some cases, hippocampal ADC values appear not to change in AD patients. Moreover, to our knowledge, all DWI studies in suspected AD patients to date are technically incomplete in experimental design, because corresponding histological sections demonstrating actual plaque deposition are lacking and so it is not clear that ADC changes actually correspond to plaque deposition. In our study, we used DWI in the TgCRND8 transgenic model of Alzheimer’s disease in conjunction with histological techniques and found robust plaque deposition in the transgenic strain in older animals (12–16 months old). However, we did not find statistically significant changes (p > 0.05) in ADC values (although ADC values in TgCRND8 mice did decrease in all regions examined) in mice 12–16 months old. Collectively, recent results from human studies and in rodent AD transgenic models support our findings and suggest that amyloid beta plaque load is not likely the major or primary component contributing to diffusional changes, if they occur.     

Odor Identification Deficit as a Predictor of Five-Year Global Cognitive Change: Interactive Effects with Age and ApoE-ε4

Olfactory impairments are present in common neurodegenerative disorders and predict conversion to dementia in non-demented individuals with cognitive impairment. In cognitively intact elderly, evidence is sparse regarding the role of olfactory deficits in predicting cognitive impairment. The present study investigated predictors of 5-year prospective decline in the Mini-Mental State Examination (MMSE) in a large (n = 501), population-based sample of elderly (65–90 years) individuals. All participants were genotyped for the ApoE gene, assessed for health factors, and were non-demented at the baseline assessment. After partialling out the influences of demographic and health-factors at baseline and dementia at follow-up, poor odor identification ability in combination with older age and the ApoE-ε4 allele predicted larger prospective global cognitive decline. This effect could not be produced by a vocabulary test. In sum, the findings suggest that an olfactory deficit can dissociate between benign and malign global cognitive development in non-demented, very old ε4-carriers, who are at high risk of developing dementia. Edited by Tatiana Foroud.     

Cerebrovascular involvement in systemic AA and AL amyloidosis: a clear haematogenic pattern

 Amyloid deposits in cerebral vessels are common in β-amyloid diseases (Alzheimer’s disease, congophilic amyloid angiopathy, Down’s syndrome and hereditary cerebral amyloidosis with haemorrhage of the Dutch type). We report of 20 autopsies on patients who had died with systemic amyloidosis of the AA, Aλ and Aκ types: the brains were examined for the occurrence of amyloid. Vascular amyloid was detected in choroid plexus (in 17 of 20 cases), infundibulum (5 of 8), area postrema (6 of 11), pineal body (3 of 7) and subfornical organ (2 of 3), but not in cortical and leptomeningeal vessels. Immunohistochemical classification of the cerebral amyloid and the systemic amyloid syndrome showed identity proving the same origin of both. The distribution is indicative of a haematogenic pattern of amyloid deposition in systemic amyloidosis and is different from that in Alzheimer’s, prion, ATTR and cystatin C diseases. It corresponds to areas of the brain with a ”leaky” blood–brain barrier. Additionally, all the cases with AA amyloidosis exhibited an Aβ coreactivity in choroid plexus vessels. In one exceptional case, Aβ reactivity of AA amyloid also occurred outside of the brain. Received: 2 November 1998 / Accepted: 25 January 1999     

White matter damage of patients with Alzheimer’s disease correlated with the decreased cognitive function

Increasing evidence demonstrates that there is marked damage and dysfunction in the white matter in Alzheimer’s disease (AD). The present study investigates the nature of white matter damage of patients with Alzheimer’s disease with diffusion tensor magnetic resonance imaging (DTI) and analyses the relationship between the white matter damage and the cognition function. DTI, as well as T1 fluid attenuated inversion recovery (FLAIR) and T2-FLAIR, was performed on probable patients of Alzheimer’s disease, and sex and age matched healthy volunteers to measure the fractional anisotropy (FA) and mean diffusivity (MD) in the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, and the white matter of frontal, temporal, parietal, and occipital lobes. FA was lower in the splenium of corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimer’s disease than in the corresponding region from healthy controls and was strongly positive correlated with MMSE scores, whereas FA appeared no different in the anterior and posterior limbs of internal capsule, occipital lobes white matter, and the genu of corpus callosum between the patients and healthy controls. MD was significantly higher in the splenium of corpus callosum and parietal lobes white matter from patients than in that those from healthy controls and was strongly negative correlated with MMSE scores, whereas MD in the anterior and posterior limbs of internal capsule, as well as in frontal, temporal, occipital lobes white matter and the genu of corpus callosum, was not different between the patients and healthy controls. The most prominent alteration of FA and MD was in the splenium of corpus callosum. Our results suggested that white matter of patients with Alzheimer’s disease was selectively impaired and the extent of damage had a strong correlation with the cognitive function, and that selective impairment reflected the cortico–cortical and cortico–subcortical disconnections in the pathomechanism of Alzheimer’s disease. The values of FA and MD in white matter, especially in the splenium of corpus callosum in AD patients, might be a more appropriate surrogate marker for monitoring the disease progression.