Regional differences in cerebrovascular reactivity to acetazolamide in Alzheimer's disease

The cerebral blood flow and cerebrovascular reactivity to acetazolamide were investigated in Alzheimer's disease using stable xenon computed tomography (CT). Ten patients with Alzheimer's disease and 10 healthy controls were studied. The regional cerebral blood flow was measured using the xenon delivery and analysis system (AZ-7000 model, Anzai Sogyo, Tokyo, Japan) and CT (PreSage, Yokogawa Medical Systems, Tokyo, Japan). The subjects inhaled room air followed by a mixture of 30% xenon and 50% oxygen for 3 min. Serial scanning was performed once before xenon inhalation, three times in the wash-in process and five times in the washout process of 5 min. The xenon concentration in the end-tidal expired gas was recorded continuously by the thermoconductivity method. The regional cerebral blood flow was measured before and 20 min after i.v. injection of 17 mg/kg acetazolamide. The blood flows in the frontal lobe, parietal lobe and temporal lobe were reduced but the blood flows in the caudate nucleus, putamen and thalamus were normal in the Alzheimer's disease group. The cerebrovascular reactivity to acetazolamide was reduced in the frontal, parietal and temporal cortex but was normal in the other areas. There is a regional difference in the cerebral blood flow and the cerebrovascular reactivity to acetazolamide in Alzheimer's disease     

Protein seeding in Alzheimer's disease and Parkinson's disease: Similarities and differences

Neurodegenerative pathology can be seeded by introduction of misfolded proteins and peptides into the nervous system. Models of Alzheimer's disease(AD) and Parkinson's disease(PD) have both demonstrated susceptibility to this seeding mechanism, emphasizing the role of misfolded conformations of disease-specific proteins and peptides in disease progression. Thinking of the amyloidogenic amyloid-beta peptide(Aβ) and alpha-synuclein(α-syn), of AD and PD, respectively, as prionoids requires a comparison of these molecules and the mechanisms underlying the progression of disease. Aβ and α-syn, despite their size differences, are both natively unstructured and misfold into β-structured conformers. Additionally, several studies implicate the significant role of membrane interactions, such as those with lipid rafts in the plasma membrane, in mediating protein aggregation and transfer of Aβ and α-syn between cells that may be common to both AD and PD. Examination of inter-neuronal transfer of proteins/peptides provides evidence into the core mechanism of neuropathological propagation. Specifically, uptake of aggregates likely occurs by the endocytic pathway, possibly in response to their formation of membrane pores via a mechanism shared with pore-forming toxins. Failure of cellular clearance machinery to degrade misfolded proteins favours their release into the extracellular space, where they can be taken up by directly connected, nearby neurons. Although similarities between AD and PD are frequent and include mechanistically similar transfer processes, what differentiates these diseases, in terms of temporal and spatial patterns of propagation, may be in part due to the differing kinetics of protein misfolding. Several examples of animal models demonstrating seeding and propagation by exogenous treatment with Aβ and α-syn highlight the importance of both the environment in which these seeds are formed as well as the environment into which the seeds are propagated. Although these studies suggest potent seeding effects by both Aβ and α-syn, they emphasize the need for future studies to thoroughly characterize seeds as well as analyze changes in the nervous system in response to exogenous insults.     

Sex differences in Parkinson’s disease

Parkinson’s disease (PD) displays a greater prevalence and earlier age at onset in men. This review addresses the concept that sex differences in PD are determined, largely, by biological sex differences in the NSDA system which, in turn, arise from hormonal, genetic and environmental influences. Current therapies for PD rely on dopamine replacement strategies to treat symptoms, and there is an urgent, unmet need for disease modifying agents. As a significant degree of neuroprotection against the early stages of clinical or experimental PD is seen, respectively, in human and rodent females compared with males, a better understanding of brain sex dimorphisms in the intact and injured NSDA system will shed light on mechanisms which have the potential to delay, or even halt, the progression of PD. Available evidence suggests that sex-specific, hormone-based therapeutic agents hold particular promise for developing treatments with optimal efficacy in men and women.     

Posterior cortical atrophy: clinical characteristics and differences compared to Alzheimer's disease

BACKGROUND: Predominant and progressive complex visual disorders are often due to posterior cortical atrophy (PCA), a rare early-onset dementing syndrome presenting with visual complaints. In clinicopathological studies, PCA is most commonly considered a form of Alzheimer's disease (AD); no prior study has evaluated clinical differences between PCA and AD. METHODS: This study identified 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypoperfusion on SPECT. These patients were retrospectively compared on clinical variables with 30 patients with clinically probable AD matched for gender, age and duration of illness. RESULTS: The PCA patients presented with alexia, elements of Balint's syndrome, apperceptive visual agnosia, dressing apraxia and environmental disorientation along with elements of Gerstmann's syndrome. Compared to the AD patients, the 15 PCA patients (mean age of onset 58 years, range 51-64) had significantly better verbal fluency, less memory difficulty, more depression and greater insight into their illness but similar familial and apolipoprotein E risk factors. In the PCA patients, MRI often showed occipitoparietal atrophy without detectable mesiotemporal atrophy. CONCLUSIONS: PCA is a distinct clinical syndrome and not just AD with prominent visual deficits. Compared to AD controls, PCA patients have better language and memory but more insight and depression and more posterior atrophy on MRI. These results indicate clinical criteria for the diagnosis of PCA and recommend specific interventions such as visual aids and antidepressant medications. Similar risk factors and course suggest that PCA is most commonly an early-onset posteriorly shifted AD variant.     

Sex differences in circadian timing systems: Implications for disease

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic–pituitary–gonadal axis (HPG), the hypothalamic–adrenal–pituitary (HPA) axis, and sleep–arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.     

Sex differences in neuroticism: a quantitative synthesis of published research

The personality trait of neuroticism is thought to be an important risk factor for depression. To ascertain the possible role of neuroticism in producing sex differences in depression, a meta-analysis was carried out on published studies reporting sex- and age-specific norms for neuroticism inventories. A general sex difference was found, with females having higher scores. However, the sex difference was greater in young and middle-aged adults than in children or the very elderly. This age trend in sex differences for neuroticism is similar in form to that previously reported for depression, except that the sex difference for depression completely disappeared in the very young and very old, but the sex difference in neuroticism did not.     

Gender differences in glutathione metabolism in Alzheimer's disease

The mechanism underlying Alzheimer's disease (AD), an age-related neurodegenerative disease, is still an area of significant controversy. Oxidative damage of macromolecules has been suggested to play an important role in the development of AD; however, the underlying mechanism is still unclear. In this study, we showed that the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, was decreased in red blood cells from male AD patients compared with age- and gender-matched controls. However, there was no difference in blood GSH concentration between the female patients and female controls. The decrease in GSH content in red blood cells from male AD patients was associated with reduced activities of glutamate cysteine ligase and glutathione synthase, the two enzymes involved in de novo GSH synthesis, with no change in the amount of oxidized glutathione or the activity of glutathione reductase, suggesting that a decreased de novo GSH synthetic capacity is responsible for the decline in GSH content in AD. These results showed for the first time that GSH metabolism was regulated differently in male and female AD patients.     

Pharmacological models in Alzheimer's disease research

Wider use of pharmacological models would facilitate the development of new drugs for Alzheimer's disease (AD), The two main models currently used are based on the cholinergic and glutamatergic hypotheses of AD, Although they lead to some of the attention and memory impairment observed in AD, they do not fully reproduce the AD pattern. The few studies that used a combination modeling approach, ie, the simultaneous administration of several drugs with the aim of impairing several neurotransmitters or different aspects of a single system, have reported no or marginal cumulative effect. On the basis of current understanding of glutamate and acetylcholine involvement in AD pathophysiology, we suggest that models using selective muscarinic-1 (M(1)) receptor blockers would better mimic the status of the cholinergic system in AD, This kind of model might be suitable for the assessment of drugs that do not act directly on the cholinergic system.     

阿尔茨海默病基因学研究进展

阿尔茨海默病(AD)为老年性痴呆,是由环境因素和遗传因素相互影响而发生的复杂异质性疾病,随着人口的老龄化,痴呆患病率呈不断上升趋势."阿尔茨海默病"的概念最早由德国精神病和神经病理学家Alois Alzheimer于1906年提出.     

Rivastigmine in dementia associated with Parkinson's disease and Alzheimer's disease: similarities and differences

Parkinson's disease dementia (PDD) and Alzheimer's disease (AD) are both characterized by cognitive abnormalities, neuropsychiatric symptoms, and cholinergic deficits. We reviewed data from large, placebo-controlled clinical trials conducted with rivastigmine in patients with PDD and AD to evaluate similarities and differences in response to treatment. In placebo groups, AD patients appeared to show more rapid cognitive decline than those with PDD. Treatment effects (rivastigmine versus placebo) on cognitive performance over 6 months were quantitatively similar in both populations, but qualitatively different: in AD, cognitive abilities were stabilized by rivastigmine compared to declines in placebo groups, whereas in PDD symptomatic improvements above baseline drove treatment effects while placebo patients had limited change. On activities of daily living, stabilization (rather than improvement) was observed in both dementia types. A more aggressive course of placebo decline, and greater treatment differences (rivastigmine versus placebo), were seen in sub-populations of both PDD and AD patients with hallucinations at baseline. The safety and adverse event profiles were comparable in the two populations. In conclusion, the magnitude of effect with rivastigmine versus placebo is quantitatively comparable in patients with AD and PD, but the treatment effect tended to be one of stabilization in AD, while in PDD improvements over baseline were seen. In both populations, hallucinations may identify patients who are likely to be more treatment-responsive.     

Glutamate dysfunction in Alzheimer's disease: an hypothesis

Glutamate is a major excitatory neurotransmitter that has been implicated in memory formation and learning. This acidic amino acid also has neurotoxic properties, and in animals produces lesions reminiscent of human neurodegenerative diseases. Here we present evidence that supports the hypothesis that glutamate dysfunction is involved in the pathophysiology of Alzheimer's disease and can account for many of the neurochemical and behavioral deficits observed in this disease.     

Environmental differences in twin pairs discordant for Alzheimer's disease

The aim of this study was to examine the contribution ofenvironmental factors to the pathogenesis of Alzheimer's disease bycomparing environmental differences in twin pairs discordant forAlzheimer's disease. Seventy four twin pairs discordant for Alzheimer's disease were found by linking the Finnish twin cohort andthe Hospital Discharge Register from years 1972-91. In 50pairs (25 monozygotic and 25 dizygotic pairs), both co-twins had responded to aquestionnaire survey in 1975. Exposure differences were comparedbetween these pairs. A reduced risk of Alzheimer's disease wassignificantly associated with a higher level of schooling (relativerisk 0.3; 95% confidence interval 0.1-0.9, p=0.029). In addition, areduced risk was suggestively associated with ambidextrousness or lefthandedness (p=0.083) and an increased risk with marriage (p=0.052),widowhood (p=0.074), and a history of cholelithiasis (p=0.071). Inconclusion, a reduced risk of Alzheimer's disease was associated witha higher level of schooling.

     

Consent in Alzheimer's disease research: risk/benefit factors

In the era of chronic disease, we are challenged to find therapies that provide symptomatic relief and ideally, alter the course of the underlying disease. In Alzheimer's disease (AD), these issues are complicated by the disease itself, which affects the subject's decision-making capacity for participation in the research. According to established ethical guidelines it is clear that individuals with impaired capacity may participate in research and their risk should be no greater than that which the individual would have in day to day activities with anticipation of benefits within that realm. Decision making processes are complex and involve proxies who themselves have biases about their loved one and the potential for participating in the research. Newer disease-modifying approaches such as immunotherapy have potential for affecting the course of the underlying disease but with greater risk of more significant side effects. Ideally the health care of the subjects is not disadvantaged by research participation. At the same time, trials of potentially riskier therapy are relevant in subjects with the disease. Research for subjects with AD must have appropriate safeguards in place to enable effective progress in innovative therapy for a vulnerable, often elderly population. Recommendations are made which could further our capacity to undertake ethical research in the AD population.     

Sex differences in psychiatric morbidity: an analysis of Victorian data

This study examined relevant Victorian data in the light of overseas findings on sex differences in psychopathology and utilisation of psychiatric treatment resources. Data sources included community health surveys and treatment statistics from the State psychiatric services, general hospitals and general practitioners. It was revealed that more Victorian women than men reported and were treated for psychiatric problems, and that women were most often diagnosed as depressed and otherwise neurotic, whereas men more often had alcohol and personality disorders. Married women had higher rates of mental illness than married men, whereas single and divorced men had higher rates of psychiatric morbidity than their female counterparts. Occupational status was related to men's, but not women's mental health. Various explanations for the findings are discussed, with some stress on the possible contribution of the sex role socialisation and cultural expectations of men and women.