Calculating stage duration statistics in multistage diseases

Many human diseases are characterized by multiple stages of progression. While the typical sequence of disease progression can be identified, there may be large individual variations among patients. Identifying mean stage durations and their variations is critical for statistical hypothesis testing needed to determine if treatment is having a significant effect on the progression, or if a new therapy is showing a delay of progression through a multistage disease. In this paper we focus on two methods for extracting stage duration statistics from longitudinal datasets: an extension of the linear regression technique, and a counting algorithm. Both are non-iterative, non-parametric and computationally cheap methods, which makes them invaluable tools for studying the epidemiology of diseases, with a goal of identifying different patterns of progression by using bioinformatics methodologies. Here we show that the regression method performs well for calculating the mean stage durations under a wide variety of assumptions, however, its generalization to variance calculations fails under realistic assumptions about the data collection procedure. On the other hand, the counting method yields reliable estimations for both means and variances of stage durations. Applications to Alzheimer disease progression are discussed.     

Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer's disease

Postmortem demonstration of increased expression of biologically active S100B in Alzheimer's disease (AD) and its relation to progression of neuropathological changes across the cortical regions suggests involvement of this astrocytic cytokine in the pathophysiology of AD. The hypothesis that the overexpression of S100B in Alzheimer brain is related to the progression of clinical symptoms was addressed in living persons by measuring S100B concentrations in cerebrospinal fluid (CSF) from AD patients with a broad range of clinical dementia severity and from healthy older persons. The effect of normal aging on CSF S100B concentrations also was estimated. CSF S100B did not differ between all 68 AD subjects (0.98±0.09 ng/ml (mean±S.E.M.)) and 25 healthy older subjects (0.81±0.13 ng/ml). When AD subjects were divided into mild/moderate stage and advanced stage clinical dementia severity by the established Clinical Dementia Rating Scale (CDR) criteria, S100B was significantly higher in the 46 mild/moderate stage AD subjects (1.17±0.11 ng/ml) than in either the 22 advanced stage AD subjects (0.60±0.12 ng/ml) or the healthy older subjects. Consistent with higher CSF S100B in mild to moderate AD, there was a significant correlation among all AD subjects between CSF S100B and cognitive status as measured by the Mini Mental State Exam (MMSE) score. CSF S100B did not differ between healthy older subjects and healthy young subjects. These results suggest increased CNS expression of S100B in the earlier stages of AD, and are consistent with a role for S100B in the initiation and/or facilitation of neuritic plaque formation in AD brain.     

Plasma prion protein concentration and progression of Alzheimer disease

Background/Objective: Recently, PrP^c has been linked to AD pathogenesis. Second, a relation of PrP^c plasma levels with cognitive status and decline of healthy elderly subjects has been reported. Therefore, we hypothesized baseline plasma levels of PrP^c to be associated with AD progression in cognitive and functional domains.Materials and Methods: AD patients (n = 84) were included into an observational study at time of diagnosis. Baseline plasma PrP^c levels were determined. Decline was assessed annually (mean follow-up time 3 years) with the aid of different standardized tests (MMSE, iADL, bADL, GDS, UPDRSIII). Multiple regression analyses were used to uncover potential associations between decline and PrP^c levels.Results: No association of PrP^c and decline could be established. Presence of diabetes mellitus was linked to slower deterioration. Intake of neuroleptic drugs or memantine was associated with faster progression.Conclusion: Plasma PrP^c at baseline could not be shown to be related to AD progression in this study. An interesting association of diabetes mellitus and decline warrants further investigation.     

¹²⁵I]SD-7015 reveals fine modalities of CB₁ cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer's disease

The cannabinoid type-1 receptor (CB₁R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB₁Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB₁R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB₁R radioligand to investigate regional variations in CB₁R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer’s disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB₁Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB₁R autoradiography with [¹²⁵I]SD-7015 as radioligand. Regional concentration of [¹²⁵I]SD-7015, corresponding to, and thereby representing, regional CB₁R densities, were expressed in fM/g_tissue. The results show that CB₁R density inversely correlates with Braak tau pathology with the following tendency: controls 1R radioligand [¹²⁵I]SD7015 in human brains, allowing the detection of fine modalities of receptor expression and radioligand binding during the progression of AD.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

The importance of individual developmental variation in stage‐structured population models

Population stage structure is fundamental to ecology, and models of this structure have proven useful in many different systems. Many ecological variables other than stage, such as habitat type, site occupancy and metapopulation status are also modelled using transitions among discrete states. Transitions among life stages can be characterised by the distribution of time spent in each stage, including the mean and variance of each stage duration and within‐individual correlations among multiple stage durations. Three modelling traditions represent stage durations differently. Matrix models can be derived as a long‐run approximation from any distribution of stage durations, but they are often interpreted directly as a Markov model for stage transitions. Statistical stage‐duration distribution models accommodate the variation typical of cohort development data, but such realism has rarely been incorporated in population theory or statistical population models. Delay‐differential equation models include lags but no variation, except in limited cases. We synthesise these models in one framework and illustrate how individual variation and correlations in development can impact population growth. Furthermore, different development models can yield the same long‐term matrix transition rates but different sensitivities and elasticities. Finally, we discuss future directions for estimating realistic stage duration models from data.     

Note on a method for analyzing stage-frequency data

A new method for analyzing stage-frequency data is proposed which is based on the estimation of rates of transition between one stage and the next highest stage in one unit of time, and a unit time survival rate that is assumed to be constant. Once these estimates are calculated it becomes possible to also estimate the mean durations of stages, stage-specific survival rates, and numbers entering stages. An advantage of the method is that it can be applied with any distribution of entry times to stage 1, and any distribution of numbers in stages when sampling begins. Use of the method is illustrated on data from a copepod population in a Canadian lake.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Sensory and skeletal development and growth in relation to the duration of the embryonic and larval stages in damselfishes (Pomacentridae)

Several trends were found in comparisons of rates of growth and development of larvae of four coral-reef damselfishes ( Chromis atripectoralis, Pomacentrus amboinensis, Premnas biaculeatus, Acanthochromis polyacanthus ), which were reared under constant temperature conditions in the laboratory, and which varied in their early life stage durations (respectively, egg stage durations were 2, 4, 7, 16; larval stage durations were 25, 23, 14, 0). Parameters measured included standard length, muscle area, eye diameter, and selected stages of retinal development, olfactory development, and skeletal ossification. Rates of ossification and olfactory development were inversely related to growth rate (in length and muscle area) among most species. Rates of eye growth and retinal development were also negatively correlated among all species. These results are consistent with the concept of a trade-off between growth and development. We observed a positive relationship between egg stage duration and developmental rate, and a negative correlation between larval stage duration and developmental rate. Acanthochromis developed slower than predicted by the general trends, although retinal development was very rapid. Specific retinal stages correlated with settlement, regardless of ontogenetic rates. Olfactory development was especially rapid in the anemonefish Premnas biaculeatus , which imprints to olfactory cues as an embryo. Skeletal ossification was rapid in species with pelagic larvae, and much slower in the benthic brooder. Literature-derived data on size and age at hatching and settlement from > 40 species of tropical pomacentrids were transformed into growth and developmental rates; correlations of these literature-derived parameters were mostly consistent with our controlled four-species comparison.  © 2003 The Linnean Society of London, The Biological Journal of the Linnean Society , 2003, 80 , 187−206.     

Changes in the temporal pattern of antennal drumming behavior across the <Emphasis Type="Italic">Polistes fuscatus</Emphasis> colony cycle (Hymenoptera,Vespidae)

Social wasps in several genera exhibit a diverse array of conspicuous vibrational behavior patterns closely associated with larval feeding. Polistes, as the only genus in which these substrate-borne mechanical signals have been studied in some detail, is a useful system for understanding their functions. Most Polistes species examined perform antennal drumming (AD) in the context of feeding prey liquid to larvae. Two existing hypotheses on the function of AD propose that it is a behavioral releaser signal that regulates the release of larval saliva, but with opposite effects. One proposes that AD stimulates larvae to release their saliva for the drumming adult to imbibe, whereas the other proposes that AD inhibits saliva release. A recently proposed third hypothesis argues instead that AD has a modulatory effect on development: exposure to high levels of AD biases larvae toward a worker phenotype as adults. While the larval-saliva-release hypothesis for AD function has little support, predictions made by both the inhibition hypothesis and the mechanical switch hypothesis are yet to be tested within the broader ontogenetic framework of the Polistes colony cycle. We investigated the contexts, rates of performance, and actors associated with AD across 13 weeks of the P. fuscatus colony cycle. Mean colony-wide rates of AD were high during pre-emergence and early post-emergence stages, but dropped dramatically following the third week after the first workers emerged. This variation in the temporal pattern of AD was correlated neither with the rate at which larvae were fed liquid, the number of larvae on the nest, nor with the adult-to-larva ratio, but was solely a function of colony stage. In contrast, rates of feeding liquid to larvae varied only as a function of the number of larvae in the nest. Queens drummed and fed liquid to larvae at much higher rates than did workers. Queen AD and feed-liquid rates decreased after the third week of worker emergence. During the same period, total feed-liquid rates of workers became as high as levels of queens during pre-emergence. Colony-wide AD rates dropped dramatically because workers seldom drummed while feeding liquid to larvae. The mean duration of AD bursts for queens also decreased after the second week of worker emergence. These results fail to support the salivary inhibition hypothesis, but provide indirect support for the mechanical switch hypothesis on AD function.     

The relationship between subcortical tau pathology and Alzheimer's disease

The stepwise progression of tau pathology [NFTs (neurofibrillary tangles) and NTs (neuropil threads)] in AD (Alzheimer's disease) is generally assumed to begin in the transentorhinal region (entorhinal stage) from which it progresses to the hippocampus (limbic stage) and to neocortical regions (neocortical stage). This stepwise progression is reflected in the NFT Braak stages. However, it has been shown recently that tau pathology is frequently seen in subcortical nuclei, in particular the LC (locus coeruleus) in over 90% of individuals under 30 years of age, suggesting that AD-associated tau pathology begins in the LC and not in the transentorhinal region. On the other hand, only minimal amounts of tau pathology are seen in the LC in cases with considerable entorhinal tau pathology, while the severity of tau pathology in the LC significantly increases with increasing NFT Braak stages. These findings suggest that the LC becomes increasingly involved during AD progression rather than representing the site initially affected. Further studies are warranted to answer the question of whether tau pathology in the LC of young individuals is associated with AD or whether it rather reflects non-specific neuronal damage.     

Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo

Antimicrobial peptides are an integral part of the epithelial innate defense system. Dermcidin (DCD) is a recently discovered antimicrobial peptide with a broad spectrum of activity. It is constitutively expressed in human eccrine sweat glands and secreted into sweat. Patients with atopic dermatitis (AD) have recurrent bacterial or viral skin infections and pronounced colonization with Staphylococcus aureus. We hypothesized that patients with AD have a reduced amount of DCD peptides in sweat contributing to the compromised constitutive innate skin defense. Therefore, we performed semiquantitative and quantitative analyses of DCD peptides in sweat of AD patients and healthy subjects using surface-enhanced laser desorption ionization time-of-flight mass spectrometry and ELISA. The data indicate that the amount of several DCD-derived peptides in sweat of patients with AD is significantly reduced. Furthermore, compared with atopic patients without previous infectious complications, AD patients with a history of bacterial and viral skin infections were found to have significantly less DCD-1 and DCD-1L in their sweat. To analyze whether the reduced amount of DCD in sweat of AD patients correlates with a decreased innate defense, we determined the antimicrobial activity of sweat in vivo. We showed that in healthy subjects, sweating leads to a reduction of viable bacteria on the skin surface, but this does not occur in patients with AD. These data indicate that reduced expression of DCD in sweat of patients with AD may contribute to the high susceptibility of these patients to skin infections and altered skin colonization.     

Chromosomal axis formation and meiotic progression in chicken oocytes: a quantitative analysis

The assembly and disassembly of the synaptonemal complexes (SCs) correlate with the progression of meiotic prophase I. Using immunostaining of the cohesin component SMC3, which is present in the axial elements of the SC, we characterized the synaptic process in chicken oocytes and quantified the frequency of the different prophase stages at hatching and at 3 different ages after hatching. The analysis provides detailed quantitative data regarding the meiotic stages in the chicken ovary showing that the maximum amount of pachytene oocytes is found around hatching and that oocytes reach the diplotene stage 5 days after entering into meiosis. We confirmed the asynchrony of the meiotic development in the female chicken gonad showing that the ovary has a composite population of cells at different stages from day 17 before hatching and for several days after hatching. The significance of these results is discussed in relationship to functional experimental procedures that involve avian oocytes.     

Aβ seeding potency peaks in the early stages of cerebral β‐amyloidosis

Little is known about the extent to which pathogenic factors drive the development of Alzheimer's disease (AD) at different stages of the long preclinical and clinical phases. Given that the aggregation of the β‐amyloid peptide (Aβ) is an important factor in AD pathogenesis, we asked whether Aβ seeds from brain extracts of mice at different stages of amyloid deposition differ in their biological activity. Specifically, we assessed the effect of age on Aβ seeding activity in two mouse models of cerebral Aβ amyloidosis (APPPS1 and APP23) with different ages of onset and rates of progression of Aβ deposition. Brain extracts from these mice were serially diluted and inoculated into host mice. Strikingly, the seeding activity (seeding dose SD₅₀) in extracts from donor mice of both models reached a plateau relatively early in the amyloidogenic process. When normalized to total brain Aβ, the resulting specific seeding activity sharply peaked at the initial phase of Aβ deposition, which in turn is characterized by a temporary several‐fold increase in the Aβ42/Aβ40 ratio. At all stages, the specific seeding activity of the APPPS1 extract was higher compared to that of APP23 brain extract, consistent with a more important contribution of Aβ42 than Aβ40 to seed activity. Our findings indicate that the Aβ seeding potency is greatest early in the pathogenic cascade and diminishes as Aβ increasingly accumulates in brain. The present results provide experimental support for directing anti‐Aβ therapeutics to the earliest stage of the pathogenic cascade, preferably before the onset of amyloid deposition.     

东方田鼠种群密度制约的迟滞效应

本研究中用成年东方田鼠不同时间不同密度笼养后（笼内雌雄各半）,低密度配对饲养,观察各阶段东方田鼠繁殖指标的差异。试鼠144只,处理时分为LL（低密度长时间）（2只/笼,共20笼,90d）、HL（高密度长时间）（8只/笼,共5笼,90d）、HM（高密度中等时间）（8只/笼,共4笼,20d）与HS（高密度短时间）（8只/笼,共4笼,10d）4组。处理后在低密度条件下观察繁殖情况（胎仔数、怀孕率、分娩频率以及产仔间隔等）,直至180 d。实验数据按时间划分为3个部分统计：0~90 d为第一阶段(不同密度处理期),90~109 d为过渡阶段（处理后的过渡期）,109 d以后为第二阶段（正常低密度配对繁殖期）。结果表明：经过长时间高密度处理后,平均产仔数显著减少,组间平均分娩频率无显著差异。怀孕率由HL组到HM组,再到LL和HS组显著增加。在第一阶段,除了LL组之外,其余各组都未发现繁殖。过渡阶段的怀孕率组间差异显著,LL组以及HM组显著高于HL组。第二阶段的怀孕率以及胎仔数的组间差异显著,都为LL、HS两组较高,HL、HM两组较低。平均分娩频率、平均胎仔数以及产仔间隔各组间无显著差异。结论：不同持续时间的密度效应有较大差别。对于东方田鼠,20d的高密度处理相比于10d更能对其繁殖起到抑制作用。恢复低密度后,存在种群的迟滞性密度制约。     

Measurement of quality of life in patients with dementia of Alzheimer type and their caregivers: Schedule for the Evaluation of Individual Quality of Life (SEIQoL)

Twelve patients with mild to moderate Alzheimer's Disease (AD) and their caregivers were interviewed with the SEIQoL. The SEIQoL measures quality of life by taking into account the relevant determinants for a particular individual. The subject rates 5 areas in life most important to the quality of life. The relative contribution of each area to the overall quality of life is then calculated with a multiple regression analysis programme developed for the purpose. Next the SEIQoL Index score, validity and reliability are computed. One patient was unable to complete the interview. The remaining (8 women, 3 men, mean age 71.3 years) had a mean SEIQoL Index score of 79.9 (median: 85.4), which is comparable to healthy Dutch elderly. The caregivers (10 spouses, 2 daughters; mean age 67.4 years), on the other hand, had a lower SEIQoL Index score: 62.2 (median: 63.8). Validity and reliability were good for both groups. Thus, caregivers in this pilot study experienced a lower quality of life than AD patients and healthy Dutch elderly. The SEIQoL allows quantitative measurement of completely individualised quality of life for AD patients and their caregivers.     

Abeta toxicity in Alzheimer's disease: globular oligomers (ADDLs) as new vaccine and drug targets

Over the past several years, experiments with synthetic amyloid-beta peptide (Abeta) and animal models have strongly suggested that pathogenesis of Alzheimer's disease (AD) involves soluble assemblies of Abeta peptides (Trends Neurosci. 24 (2001) 219). These soluble neurotoxins (known as ADDLs and protofibrils) seem likely to account for the imperfect correlation between insoluble fibrillar amyloid deposits and AD progression. Recent experiments have detected the presence of ADDLs in AD-afflicted brain tissue and in transgenic-mice models of AD. The presence of high affinity ADDL binding proteins in hippocampus and frontal cortex but not cerebellum parallels the regional specificity of AD pathology and suggests involvement of a toxin receptor-mediated mechanism. The properties of ADDLs and their presence in AD-afflicted brain are consistent with their putative role even in the earliest stages of AD, including forms of mild cognitive impairment.     

Quantitative Analysis of β-Amyloid Peptides Expressed in Human Cerebrospinal Fluid by an Improved Method of Antibody-Assisted Time-of-Flight Mass Spectrometry

Establishment of diagnostic measures for early stage Alzheimer’s disease (AD) and mild cognitive impairment (MCI) is of crucial importance. Using surface enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS), antibody-assisted MS of cerebrospinal fluid (CSF) has enabled quantitative analysis of the ratio of β-amyloid (Aβ) peptides, Aβ1-42/Aβ1-40, which has a diagnostic value for AD/MCI. To apply the MS analysis to a far wider range of CSF samples, we have established a method to analyze Aβ peptides expressed in 100 μl CSF samples quantitatively. Pretreatment of CSF samples by limit-filtration to condense peptides, and modified washing procedure using urea as denaturant, Aβ peptides of interest can be assessed with higher sensitivity by five to tenfolds to the original method. This improvement enables quantitative analysis of Aβ species from a residual amount of CSF samples, which will be occasionally obtained in case of lumbar anesthesia prior to operation and spinal tap performed for routine diagnostic purposes. Prevalence of the new procedure as laboratory test, especially among the elderly consulting for neurological clinic, will enhance the number of subjects diagnosed at early stage of AD/MCI.     

Oral health behaviour and socio-demographic profile of subjects with Alzheimer's disease as reported by their family caregivers

Objective: To evaluate the oral health care provided to subjects with Alzheimer's disease (AD) as reported by their family caregivers. Method: Structured interviews were performed with 56 Alzheimer caregivers from the Group of relatives and friends of subjects with AD of the Hospital de Clínicas de Porto Alegre. Spearman and Pearson correlations were performed. Results: The mean age of the subjects with AD was 76.09 (±7.76) years, 53.6% were female and 58.9% were in the advanced stage of AD. The mean number of teeth present was 11.66 (±10.94), and oral hygiene was performed 2.21 (±1.04) times/day. The provision of oral health care to subjects with AD was carried out by caregivers in 85.7%. Oral hygiene was provided by the caregivers to the subjects with AD with the aid of a toothbrush and/or gauze embedded with non‐fluoridated mouthwash in the majority of the cases. Complete dental prostheses were cleaned with the aid of mouthwashes instead of denture brushes by 44% of the subjects/caregivers. There was a significant association between the number of teeth in the subjects with AD and the number of oral hygiene procedures performed per day and current smoking. Conclusion: Oral health care planning for subjects with AD should take into account caregivers’ perceptions and knowledge about oral health and hygiene as caregivers represent the primary providers to these patients when the disease progresses from early to more advanced stages.