Differences in rapid eye movement sleep behavior disorder manifestation between synucleinopathies and tauopathies

Rapid eye movement sleep behavior disorder (RBD) frequently occurs in synucleinopathies including multiple system atrophy, Parkinson’s disease, and dementia with Lewy bodies despite the clinical course of RBD being different between these disorders. Comparatively, the existence of RBD symptoms is relatively rare in patients with progressive supranuclear palsy, a tauopathy showing atypical parkinsonism compared with Parkinson’s disease. Moreover, in patients with Alzheimer’s disease, which is another tauopathy, RBD symptoms are less frequent than dementia with Lewy bodies, although both disorders share commonalities in terms of the existence of cortical dementia. Thus, RBD is thought to be relatively specific to synucleinopathies.

     

Neuropathogenesis of AIDS

Neurological disease directly attributable to HIV-1 infection (HIV dementia) is one of the most frequent disorders in persons with AIDS. HIV-1 dementia is associated with neuronal loss, but occurs in the absence of direct viral infection of neurons, suggesting that neurological damage occurs by an indirect mechanism. Recent studies have identified a number of candidate HIV-1 neurotoxins that may cause neuronal damage through common pathways involving the induction of oxidative stress and excitotoxicity. These findings suggest new therapeutic approaches to the prevention and treatment of HIV-1-induced neurological disease.     

Dementia of the Alzheimer Type: An Oral and Biochemical Study1

Alzheimer's disease, or pre-senile dementia, may occur as early as 40 years. Pathologically, there is, besides a loss of brain weight, a conical atrophy with ventricular dilatation and typical microscopic lesions in the cortex and the hippocampus. Previously, the authors [Sanchez & Gonzalez, 1986] have studied the modifications of the amino acids (AA) composition in the cerebrospinal fluid (CSF), Even if some were increased without specificity, three of them were decreased significantly in this type of dementia (Serine, Glutamate and Aspartate). Twenty subjects were studied (15 with Alzheimer's disease and 5 non-patients) having a mean age of 72 years. For each subject, two samples were tested (one blood and one saliva sample). In this study we tried to determine if our results would be similar to those previously obtained in the CSF, but in a different biological fluid, the saliva. Of the 13 AA of the saliva, tested by gas-liquid chromatology (Spectra Physics 7100), 3 were increased significantly, and curiously, these were similar to those found to be decreased in CSF. We attempted to find the possible biological and oral repercussions of this dementia, which is the most frequent type in elderly patients.     

Inflammation,Depression and Dementia: Are they Connected?

Chronic inflammation is now considered to be central to the pathogenesis not only of such medical disorders as cardiovascular disease, multiple sclerosis, diabetes and cancer but also of major depression. If chronic inflammatory changes are a common feature of depression, this could predispose depressed patients to neurodegenerative changes in later life. Indeed there is now clinical evidence that depression is a common antecedent of Alzheimer’s disease and may be an early manifestation of dementia before the cognitive declines becomes apparent. This review summarises the evidence that links chronic low grade inflammation with changes in brain structure that could precipitate neurodegenerative changes associated with Alzheimer’s disease and other dementias. For example, neuronal loss is a common feature of major depression and dementia. It is hypothesised that the progress from depression to dementia could result from the activation of macrophages in the blood, and microglia in the brain, that release pro-inflammatory cytokines. Such cytokines stimulate a cascade of inflammatory changes (such as an increase in prostaglandin E2, nitric oxide in addition to more pro-inflammatory cytokines) and a hypersecretion of cortisol. The latter steroid inhibits protein synthesis thereby reducing the synthesis of neurotrophic factors and preventing reairto damages neuronal networks. In addition, neurotoxic end products of the tryptophan-kynurenine pathway, such as quinolinic acid, accumulate in astrocytes and neurons in both depression and dementia. Thus increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depression and dementia. Such changes may help to explain why major depression is a frequent prelude to dementia in later life. Special issue dedicated to Dr. Moussa Youdim.     

Risk Factors for Aspiration Pneumonia in Older Adults

BackgroundsAspiration pneumonia is a dominant form of community-acquired and healthcare-associated pneumonia, and a leading cause of death among ageing populations. However, the risk factors for developing aspiration pneumonia in older adults have not been fully evaluated. The purpose of the present study was to determine the risk factors for aspiration pneumonia among the elderly.ConclusionThe risk factors for aspiration pneumonia were sputum suctioning, deterioration of swallowing function, dehydration, and dementia. These results could help improve clinical management for preventing repetitive aspiration pneumonia.     

Filarial infection of the breast. Report of a case with diagnosis by fine needle aspiration cytology.

The breast is not a frequent site of filarial infection. We report a case of fine needle aspiration cytologic diagnosis of filariasis of the breast, not previously reported.     

Systemic inflammation and delirium: important co-factors in the progression of dementia

It is widely accepted that inflammation plays some role in the progression of chronic neurodegenerative diseases such as AD (Alzheimer's disease), but its precise role remains elusive. It has been known for many years that systemic inflammatory insults can signal to the brain to induce changes in CNS (central nervous system) function, typically grouped under the syndrome of sickness behaviour. These changes are mediated via systemic and CNS cytokine and prostaglandin synthesis. When patients with dementia suffer similar systemic inflammatory insults, delirium is a frequent consequence. This profound and acute exacerbation of cognitive dysfunction is associated with poor prognosis: accelerating cognitive decline and shortening time to permanent institutionalization and death. Therefore a better understanding of how delirium occurs during dementia and how these episodes impact on existing neurodegeneration are now important priorities. The current review summarizes the relationship between dementia, systemic inflammation and episodes of delirium and addresses the basic scientific approaches currently being pursued with respect to understanding acute cognitive dysfunction during aging and dementia. In addition, despite there being limited studies on this subject, it is becoming increasingly clear that infections and other systemic inflammatory conditions do increase the risk of AD and accelerate the progression of established dementia. These data suggest that systemic inflammation is a major contributor to the progression of dementia and constitutes an important clinical target.     

Aberrantly regulated proteins in frontotemporal dementia

Non-Alzheimer's disease of the frontal type, or frontotemporal dementia (FTD), is the second most common form of dementia. Yet, a detailed characterization of the disease has been especially limiting. To identify mechanisms possibly involved in disease pathology or progression, a proteomic analysis of proteins isolated from human frontal cortex with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was performed. We used 2D gel electrophoresis and MALDI-TOF to identify a total of 24 proteins differentially expressed in FTDP-17. We identified a ubiquitin C-terminal hydrolase, UCHL1, as well as several proteins involved in oxidative stress to be differentially expressed. Data presented implicate UCHL1 and ubiquitin-mediated degradation as well as oxidative stress response in disease pathology or progression.     

A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia?

Because of population ageing, dementias are likely to become a major scourge of the 21st century. Causes of dementia include Alzheimer's disease, cerebrovascular disease, and lesser known entities such as frontotemporal dementia or dementia with Lewy bodies. Neuroinflammation is likely to play an important role in the pathogenesis of dementia by the killing of neurons through inflammatory mechanisms. Such a role of neuroinflammation is well documented for Alzheimer's disease, and it is likely to play a role in other types of dementia as well. Reactive oxygen species (ROS) play a key role in inflammatory tissue destruction. The phagocyte NADPH oxidase NOX2 is the best studied ROS-generating system. In the central nervous system, it is expressed in microglia and--to a lesser extent--in neurons. Indeed, there is emerging experimental evidence for a role of NOX2 in Alzheimer's and cerebrovascular disease. Recently, six novel ROS-generating NADPH oxidases with homology to NOX2 have been discovered. Several of them are also expressed in the central nervous system. In this article, we hypothesize a role of NOX-type NADPH oxidases in inflammatory neuronal loss. We review presently available evidence and suggest that NOX-type NADPH oxidases may become promising pharmacological targets for the treatment and prevention of dementia.     

Maternal lineages and Alzheimer disease risk in the Old Order Amish

Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%) while observed in only 10.6% in outbred American and European populations. Furthermore, haplogroups J and K are less frequent (1.0%) than in the outbred data set (9.4–11.2%). Affected case matrilines and unaffected control lines were chosen from pedigrees to test whether specific haplogroups and their defining SNPs confer risk of AD. We did not observe frequency differences between AD cases compared to controls overall or when stratified by sex. Therefore, we suggest that the genetic effect responsible for AD dementia in the affected Amish pedigrees is unlikely to be of mitochondrial origin and may be caused by nuclear genetic factors.     

Increased Concentrations of the Neurotoxin 3-Hydroxykynurenine in the Frontal Cortex of HIV-1-Positive Patients

Abstract: Human immunodeficiency virus (HIV)-1-associated dementia is a frequent consequence of HIV infection and is associated with neuronal deficits. Increased concentrations of the kynurenine pathway metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) may contribute to this neuronal damage. We measured 3-HK concentrations and the activity of its catabolising enzyme, 3-hydroxykynureninase, in postmortem brain tissue from eight controls and 32 HIV-positive patients, including a group that exhibited dementia. 3-HK concentrations were significantly increased (over threefold) in the HIV-positive group when compared with controls. This increase was greater in those patients with dementia, but it was still apparent in the nondemented cases. 3-Hydroxykynureninase activity was significantly increased in the HIV-infected group compared with the control values. The effect was apparent in both nondementia and dementia cases, although the latter showed a slightly greater increase. The 3-HK content increase is thus unrelated to a reduction in activity of this enzyme and is likely to reflect an overall increase in the kynurenic metabolic pathway. Elevated levels of the neurotoxin 3-HK may contribute to the neuronal deficits underlying HIV-associated dementia.     

Low blood pressure and dementia in elderly people: the Kungsholmen project.

OBJECTIVE--To examine the relation between blood pressure and dementia in elderly people. DESIGN--Cross sectional, population based study. SETTING: Kungsholmen district of Stockholm, Sweden. SUBJECTS-- 1642 subjects aged 75-101 years. MAIN OUTCOME MEASURES--Prevalence and adjusted odds ratio of dementia by blood pressure. RESULTS--People with systolic pressure < or = 140 mm Hg were more often diagnosed as demented than those with systolic pressure >140 mm Hg: odds ratios (95% confidence interval) adjusted for age, sex, and education were 2.98 (2.17 to 4.08) for all dementias, 2.91 (1.93 to 4.38) for Alzheimer''s disease, 2.00 (1.09 to 3.65) for vascular dementia, and 5.07 (2.65 to 9.70) for other dementias. Similar results were seen in subjects with diastolic pressure < or = 75 mm Hg compared with those with higher diastolic pressure. When severity and duration of dementia were taken into account, only moderate and severe dementia were found to be significantly related to relatively low blood pressure, and the association was stronger in subjects with longer disease duration. Use of hypotensive drugs and comorbidity with cardiovascular disease did not modify the results for all dementias, Alzheimer''s disease, and other dementias but slightly reduced the association between vascular dementia and diastolic blood pressure. CONCLUSIONS--Both systolic and diastolic blood pressure were inversely related to prevalence of dementia in elderly people. We think that relatively low blood pressure is probably a complication of the dementia process, particularly Alzheimer''s disease, although it is possible that low blood pressure may predispose a subpopulation to developing dementia.     

基于体素的形态测量学在阿尔茨海默病及轻度认知功能障碍研究中的应用

阿尔茨海默病(Alzheimer's disease,AD)是发生于老年和老年前期、以进行性认知功能障碍和行为异常为特征的中枢神经系统退行性疾病,是老年痴呆中最常见类型。轻度认知功能障碍(mild cognitive impairment,MCI)是介于正常衰老和痴呆之间的一种中间状态,指有轻度的记忆或认知损伤,但尚未达到痴呆程度的一种状态,日常生活和社会功能不受影响,其中很大一部分患者最终进展为AD。临床诊断AD患者多已达中晚期,为了能早期诊断AD及预测MCI的转归,有关AD的生物学标注物的研究成为近年来的科研热点。AD患者颅脑的大体病理特征为脑萎缩,其萎缩有别于正常老龄化所致的退行性改变,有其自身特点,这种特定形式的萎缩有可能成为AD早期诊断的生物学标志物。基于体素的形态测量学(voxel-based morphometry,VBM)是一种基于像素水平对脑核磁图像进行自动、全面、客观分析的技术,可以定量分析全脑结构、刻画出局部脑区结构特征,是一种较好的脑形态分析工具,广泛用于阿尔茨海默病及轻度认知功能障碍的研究中,本文综述了近年来其研究进展,期望为临床及科研提供参考。     

Effects of Alzheimer's amyloid-beta and tau protein on mitochondrial function -- role of glucose metabolism and insulin signalling

Alzheimer's disease (AD) is the most frequent form of dementia among the elderly and is characterized by neuropathological hallmarks of extracellular amyloid-beta (Abeta) plaques and intracellular neurofibrillary tangles composed of abnormally hyperphosphorylated microtubular protein tau in the brains of AD patients. Of note, current data illustrate a complex interplay between the amyloid and tau pathology during the course of the disease. We hypothesize a direct impact of abnormally phosphorylated tau and Abeta on proteins/enzymes involved in metabolism, respiratory chain function and cellular detoxification. Probably at the level of mitochondria, both Alzheimer proteins exhibit synergistic effects finally leading to/accelerating neurodegenerative mechanisms. Moreover, accumulating evidence that mitochondria failure, reduced glucose utilization and deficient energy metabolism occur already very early in the course of the disease suggests a role of impaired insulin signalling in the pathogenesis of AD. Thus, this review addresses also the question if mitochondrial dysfunction may represent a link between diabetes and AD.     

Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia

Background  

Advanced glycation end-products (AGEs) and their receptor (RAGE) occur in dementia of the Alzheimer's type and diabetic microvascular disease. Accumulation of AGEs relates to risk factors for vascular dementia with ageing, including hypertension and diabetes. Cognitive dysfunction in vascular dementia may relate to microvascular disease resembling that in diabetes. We tested if, among people with cerebrovascular disease, (1) those with dementia have higher levels of neuronal and vascular AGEs and (2) if cognitive dysfunction depends on neuronal and/or vascular AGE levels.     

Evaluation of inadequate, indeterminate, falsenegative and false-positive cases in cytological examination for breast cancer according to histological type

ABSTRACT: BACKGROUND: We previously investigated the current status of breast cytology cancer screening at seven institutes in our area of southern Fukuoka Prefecture, and found some differences in diagnostic accuracy among the institutions. In the present study, we evaluated the cases involved and noted possible reasons for their original cytological classification as inadequate, indeterminate, false-negative and false-positive according to histological type. METHODS: We evaluated the histological findings in 5693 individuals who underwent cytological examination for breast cancer (including inadequate, indeterminate, false-negative and falsepositive cases), to determine the most common histological types and/or features in these settings and the usefulness/limitations of cytological examination for the diagnosis of breast cancer. RESULTS: Among 1152 cytologically inadequate cases, histology revealed that 75/173 (43.6%) cases were benign, including mastopathy (fibrocystic disease) in 38.6%, fibroadenoma in 24.0% and papilloma in 5.3%. Ninety-five of 173 (54.9%) cases were histologically malignant, with scirrhous growing type, invasive ductal carcinoma (SIDC) being significantly more frequent (49.5%) than papillotubular growing type (Papi-tub) (P < 0.0001), solid-tubular growing type (P = 0.0001) and ductal carcinoma in situ (DCIS) (P = 0.0001). Among 458 indeterminate cases, 54/139 (38.8%) were histologically benign (mastopathy, 30.0%; fibroadenoma, 27.8%; papilloma, 26.0%) and 73/139 (52.5%) were malignant, with SIDC being the most frequent malignant tumor (37.0%). Among 52 false-negative cases, SIDC was significantly more frequent (42.3%) than DCIS (P = 0.0049) and Papi-tub (P = 0.001). There were three falsepositive cases, with one each of fibroadenoma, epidermal cyst and papilloma. CONCLUSIONS: The inadequate, indeterminate, false-negative and false-positive cases showed similar histological types, notably SIDC for malignant tumors, and mastopathy, fibroadenoma and papilloma for benign cases. We need to pay particular attention to the collection and assessment of aspirates for these histological types of breast disease. In particular, several inadequate, indeterminate and false-negative cases with samples collected by aspiration were diagnosed as SIDC. These findings should encourage the use of needle biopsy rather than aspiration when this histological type is identified on imaging. Namely, good communication between clinicians and pathological staff, and triple assessment (i.e., clinical, pathological and radiological assessment), are important for accurate diagnosis of aspiration samples. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7349809170055423.     

Genetic influences on Alzheimer's disease: evidence of interactions between the genes APOE, APOC1 and ACE in a sample population from the South of Brazil

Alzheimer’s disease is a complex neurodegenerative disorder. Several genes have been suggested as Alzheimer’s susceptibility factors, the apolipoprotein E (APOE) gene being an established susceptibility gene and the genes coding angiotensin-converting enzyme (ACE) and apolipoprotein C1 (APOC1) being considered possible candidate genes for the disease. The objective of this study was to investigate the association of ACE and APOC1 gene polymorphisms with susceptibility to Alzheimer’s disease and dementia in general, both alone and combined with the APOE gene. Forty-seven patients with dementia in general (35 of them with Alzheimer’s disease) and 85 controls were investigated. The haplotypes E*3/−317*ins and E*4/−317*ins of APOE/APOC1 genes were significantly more frequent in the groups with Alzheimer′s disease and dementia in general (P < 0.001). The frequency of the ACE*ins allele was also greater in the groups with Alzheimer’s disease and dementia in general (P = 0.022; P = 0.045), but genotype frequencies were only different in groups without the E*4/−317*ins haplotype (P = 0.012 for Alzheimer’s disease; P = 0.04 for dementia). Our data point to important genetic interactions involved in these diseases.     

Is pulse oximetry a reliable tool for detection of aspiration?

This study was designed to determine whether significant differences in saturation levels existed among patients with aspiration and patients without and wether pulse oximetry can reliably detect aspiration in patients with dysphagia. We also examined the effects of gender and disease (neurologic versus non neurologic) on saturation levels. We studied 38 patients. They all underwent a videofluoroscopic study of swallowing (VFSS). Twenty patients aspirated on videofluoroscopic study of swallowing: ten patients were solid aspirators, ten patients were liquid aspirators. In each group (liquid aspirators, solid aspirators or non aspirators) we found no significant difference in saturation levels. We found however a significant difference in saturation levels between each group before, during and after videofluoroscopic study of swallowing. Both gender and disease had an effect on saturation levels. We conclude that pulse oximetry can not serve as a screening tool for detection of aspiration as saturation levels are dependent on many factors. Therefore one can not reliably predict aspiration with a single saturation screening.