There is no recent data addressing the long term survival of cirrhosis patients without transplantation, but with the availability of optimal pharmacological and endoscopic therapies. We compared the long term transplant free survival of alcoholic (AC) and cryptogenic (CC) cirrhosis patients in a setting where liver transplantation was, until very recently, not available. AC and CC patient details were extracted from our database, maintained since 1995. For those who had not attended clinics within the past 4 weeks, the patient or families were contacted to obtain survival status. If deceased, cause of death was ascertained from death certificates and patient records. Survival was compared using Kaplan-Meier curves.Complete details were available in 549/651 (84.3%) patients . Mean follow up duration (SD) (months) was 29.9 (32.6). 82/96 deaths (85.4%) among AC and 80/94 deaths (85.1%) among CC were liver related. Multivariate analysis showed age at diagnosis and Child’s class predicted overall survival among all groups. The median survival in Child’s class B and C were 53.5 and 25.3 months respectively. Survival was similar among AC and CC. Among AC survival was improved by abstinence [HR = 0.63 (95% CI: 0.40-1.00)] and was worse with diabetes [HR=1.59 (95% CI: 1.02- 2.48)] irrespective of alcohol status.The overall survival of AC was similar to CC. Death in both groups were predominantly liver related, and was predicated by age at diagnosis and Child class. Among AC, presence of diabetes and non-abstinence from alcohol were independent predictors for poor survival. The long term survival of cirrhotic patients is an important issue in management, from the initial counseling of the patients at diagnosis to finally planning liver transplantation. This beLiver transplantation is in its infancy in Sri Lanka. Until recently only very few patients with the means of getting the procedure performed abroad had a liver transplant. It is still not widely available for most cirrhotic patients attending state sector hospitals. This has provided an opportunity to study the natural history of the disease in a setting where patients have the benefit of most modern therapies, with the exception of transplantation. The main causes of cirrhosis in Sri Lanka are alcohol induced and cryptogenic. The long term comparative survival of these two causes of cirrhosis has been poorly studied especially during the last twenty years-12. We rThe study was conducted in the Gastroenterology Clinic of the University Medical Unit, Colombo North Teaching Hospital, Ragama, Sri Lanka, which serves as a major referral center for cirrhosis. Details of all cirrhotic patients in our clinic have been maintained since 1995.All patients diagnosed with AC and CC registered in our clinic were eligible for inclusion in the study. Cirrhosis was diagnosed on clinical, biochemical, abdominal imaging, and endoscopic criteria and, when possible or required, confirmed by liver biopsy. Patients who were found to have hepatocellular carcinoma at diagnosis were excluded from the study. AC had a history of consuming alcohol above the accepted safe limits  prior to the diagnosis of cirrhosis. CC were patients who did not drink alcohol above the safe limit, had no history of contributory drug or herbal product use and in whom Hepatitis B and C, autoimmune disease, haemachromatosis, Wilson’s disease, and alpha-1 antitrypsin deficiency were excluded. Patients in whom cirrhosis was diagnosed prior to availability of Hepatitis C testing were subjected to the test once it became available. Therefore, all patients attending the clinic had their Hepatitis B and C status assessed at some time during follow-up.This was a retrospective cohort study. Patients diagnosed with AC and CC registered in our clinic since January 1995 were included. This study was conducted over a period of 4 weeks in June 2010. Patients who had not attended the clinic within 4 weeks of the study were identified, and either the patients or their families were contacted by telephone or post to obtain survival status, and if deceased, details of death. The cause of death was confirmed from death certificates and patient records. Clinical details of AC and CC were obtained, and included the date of diagnosis of cirrhosis, liver biochemistry with INR and Child Pugh grade at diagnosis.Patients with AC and their families were interviewed for details of alcohol consumption following the diagnosis of cirrhosis. ‘Alcohol abstinence’ was defined as patents who claimed that they never consumed alcohol, following the diagnosis of cirrhosis. Details of abstinence were confirmed from family members after consent from the patient. If the individual patient or the family claimed that alcohol (of any quantity) was consumed on one or more occasions following diagnosis of cirrhosis, the patient was defined as ‘non – abstinent’.In those whom this information was available, abstinence or non-abstinence for alcohol was recorded. The presence of diabetes anytime during the follow up period was recorded in all patients.Prior ethics approval for this study was obtained from the Ethics Review Committee of the Faculty of medicine, University of Kelaniya. Informed consent was taken from all participating patients and their families regarding obtaining information as well as follow up data.Unadjusted and adjusted hazard ratios and 95% confidence intervals were estimated using Cox’s proportional hazards modeling for the association between mortality and associated factors. Potential confounding variables considered in the model were age, sex, BMI, diabetes mellitus, Child-Pugh Grade at diagnosis and the aetiology of cirrhosis (AC or CC). All potential confounding variables were included in the multivariate model.Survival was compared using Kaplan-Meier curves using SPSS (version 16.0) and predictors of survival in each group were sought. The mean and median survival of cirrhotics was calculated according to Child’s Pugh class.Of the 696 registered cirrhotic patients, AC and CC accounted for 651 (93.53%)  . Demographic and clinical characteristics in these patients are given in Table % (AC 306Deaths among both AC and CC were predominantly liver related (85.3%). There were 96 deaths [82 (85.4%) liver related] in the AC group and 94 deaths [80 (85.1%) liver related] in the CC group  volunteerd information regarding alcohol consumption after diagnosis. For deceased patients this information was obtained from the family members. The percentage of AC claming to be abstinent was 75.8%. Among AC claiming abstinence (n=150), 50 patients (33.3%) had died during follow up. Among AC who were not abstaining (n=48), 30 62.5%) had died. The survival of AC who continued to drink, AC who claimed abstinence and CC was compared  ] and was worse in the presence of diabetes [HR=1.59 (95% CI: 1.02- 2.48)].In our sample, none of the patients had the option of being listed for liver transplantation as this was not available in Sri Lanka at the time of the study, and none of the study population could afford transplantation abroad. Despite this, they were all provided with optimal pharmacological and endoscopic therapy. This provided an unique opportunity for us to study true transplant free survival in the current context.et al. uses “competing risk analyses” as an alternative method of analysis, but admits that “Kaplan-Meier estimates may be the most appropriate to answer certain ‘what if’ questions, for example, when counseling a patient about their future course without transplantation”[Previous studies on the natural history of patients in settings where transplantation is available are fundamentally different from our study for several reasons. Firstly, patient populations of those studies comprised only of patients who qualified for a liver transplant,7. Seconntation”. This isOur results indicate that the median overall survival of Child’s B and C cirrhotics was 53.5 months and 25.3 months respectively. This is in contrast to older estimates,5. This There was a relatively short mean follow period up of 29.9 months for this study. The reason for this is that as our centre became established as a national referral centre for liver diseases the number of patients referred to it during recent times has been far greater than in the initial stages.et al. in 1968 reported that AC appeared to have a better outlook than CC[et al. reported that survival of AC was poorer than CC[et al. reported non-liver related causes of death to be 8%[We found that the survival of patients with AC and CC was similar. The survival of these two groups has been poorly compared during the last twenty years. Stone  than CC. Later,  than CC. The inv than CC. Our finto be 8%.We found, predictably, that abstinence from alcohol significantly improves long term survival among AC. This has been established in previous studies-15. ThisNumerous studies have reported a high prevalence of obesity and diabetes among patient with CC and suggested that most of these patients represent non alcoholic steatohepatitis (NASH) related cirrhosis-18. It het al. recently reported no association between diabetes and the in–hospital mortality of cirrhosis patients, although they too found that a significant proportion of cirrhotic patients had diabetes[et al. also reported a similar association between diabetes, abstinence and mortality among cirrhotics who had refractory ascites[In our study, diabetes was found to be an independent predictor of mortality among AC, but not among CC. Diabetes may be an aggravating factor in the evolution of cirrhosis or may occur as a consequence of cirrhosis - termed “hepatogenous diabetes”,23. Althdiabetes. The ass ascites.Demographically, the two groups of patients in our study were similar except that there were far fewer females with AC than CC. This is representative of the drinking habits in an average Sri Lankan population where, for possible cultural reasons, heavy alcohol consumption among females is very uncommon. However sex was not a significant predictor of survival when other factors  were adjusted for, and hence did not seem to affect survival in these two groups.Among co-morbidities only diabetes and obesity were assessed as predictors of survival. Socio-economic status as a predictor of outcome was not assessed in this study. These are limitations of our study.We assessed survival of our patients according to the Child-Pugh class. Assessing survival according to their MELD score would have been advantageous. The MELD score only came into wide use in 2002, when it was adopted as the criteria by which donor organs are distributed by UNOS (United Network for Organ Sharing),30. Our Ours was a retrospective study. A prospective study such as this would not have been possible in the current context because liver transplantation has commenced in our center in Sri Lanka.We were able to contact 84.3% of the total registered population of cirrhotic patients. This represents the difficulties encountered during long term follow up of patients in a setting where hospitals and death registries are not linked electronically. In many cases, changes in addresses and phone numbers limited our ability to contact patients. Follow up of a large number of alcoholic cirrhotic patients whose compliance with clinic attendance is usually erratic is bound to be difficult in any setting.In a setting where liver transplantation is not readily available, we found that the overall survival of AC was similar to CC. Death in both groups were predominantly liver related, and was predicated by age at diagnosis and Child Pugh class, although survival was longer than that suggested in older studies. This may reflect better pharmacotherapy and endotherapy which is currently available altering the natural history of the disease. Among AC, those who continued to drink had the worst survival, and the presence of diabetes and non-abstinence from alcohol were independent predictors of mortality.AC: Alcoholic cirrhosis; CC: Cryptogenic cirrhosis; MELD: Model For End-Stage Liver Disease.The authors declare that there are no competing interests.HJdeS designed the research. SMS, MAN, SKW, JPdeA, APdeS, ASD, HJdeS carried out the research. AK annalized the data. SMS, MA and HJdeS wrote the final paper. All authors read and approved the final manuscript.SMS (MBBS MD), Senior Registrar in Gastroenterology, University Medical Unit, Colombo North Teaching Hospital, RagamaMAN , MRCP(Lond)), Consultant Gastroenterologist, University Medical Unit, Colombo North Teaching Hospital, RagamaSKW(MBBS), Demonstrator, Department of Medicine, Faculty of Medicine, University of Kalaniya, Ragama,AK (MBBS MD), Senior Lecturer, Department of Public Health, Faculty of Medicine, University of Kalaniya, Ragama,JPdeA (MBBS), Demonstrator, Department of Medicine, Faculty of Medicine, University of Kalaniya, Ragama,APdeS , MRCP(UK), FRCP(Lond), FCCP), Professor in Medicine, Department of Medicine, Faculty of Medicine, University of Kalaniya, Ragama and Consultant Physician, University Medical Unit, Colombo North Teaching Hospital, RagamaASD , Senior Lecturer, Department of Pharmacology, Faculty of Medicine, University of Kalaniya, Ragama,HJdeS , FRCP (Lond), FCCP, FNatAcadSci (SL), Hon. FRACP) Professor of Medicine, Department of Medicine, Faculty of Medicine, University of Kalaniya, Ragama and Consultant Physician, University Medical Unit, Colombo North Teaching Hospital, Ragama


Noun and verb comparison shows differences in regions of activation in the left Inferior Frontal cortex and in the extent of the same areas. We have found specific areas of activation for object noun, and similarities in the pattern of activation for event noun and verb. The activations induced by pseudowords highly resembled the areas activated by the corresponding word category. The implications of the results are discussed in light of the recent debate on the role of grammatical category in the brain.In a functional MRI (fMRI) study, we have investigated the grammatical categories of object noun, event noun and verb in order to assess the cortical regions of activation supporting their processing. Twelve Italian healthy participants performed a lexical decision task. They had to decide whether a string was an Italian word or not. Words could be objects like  Noun and verb are indicated as distinct grammatical classes across different languages.In neuropsychology it has long been known that the mental processing of noun and verb involves different steps. This fact is immediately evident when language impairments are taken into account. For example, agrammatic patients often experience greater difficulties in the production of verbs rather than nouns, whereas anomic patients often show the opposite pattern Neuroimaging studies are only partially consistent with neuropsychological observations. Verb processing is often associated, across studies, with the activation of frontal/prefrontal and parietal areas Activation for noun has been shown by Fujimaki et al. the chase/to chase, the bombardment/to bombard, the theft/to steal. In Italian, with very few exceptions, event nouns are nominalizations derived from verbs through suffixes , and therefore these nouns are, in general, morphologically complex.The grammatical class of noun can semantically refer to at least two different categories: object noun and event noun. The latter refers to events, and its morphology may or may not recall the semantically related verb, like cavalcare/to ride). Along with the target, participants were presented with a distracter word, which was either an event noun or a verb, and could be semantically close or far from the target . The semantically close words produced a reliable interference effect on picture naming, regardless of grammatical class.According to most linguists, event nouns have the same semantic and thematic structure as the verbs from which they derive Batteria per l’Analisi dei Deficit Afasici/Battery for the Analysis of Aphasic Deficitsmedaglia/medal), event nouns , one-place argument verbs (e.g. dormire/to sleep), and two-place argument verbs (e.g. distruggere/to destroy). As expected, errors in the production of object nouns were statistically fewer than in the production of verbs. In addition, patients made fewer errors with one-place than with two-place argument verbs. Interestingly, their performance was significantly better with object nouns than event nouns. The latter did not differ from verbs.Neuropsychological evidence also suggests that patients may treat event noun and object noun differently. Collina et al. In a similar vein, Tabossi et al. galoppa/s/he gallops) or event nouns (e.g. corsa/run) and referring either to sensation (e.g. solletico/tickle) or motion (e.g. giravolta/twirl). The results indicated specific areas of activation for sensory words in the anterior temporal cortex and for motion words in the primary motor cortex. However, no significant difference was found specifically for noun and verb.In a PET study conducted in Italian mangiare/to eat) or in the present third person singular (e.g. mangia-s/he eats), or using a noun (e.g. mangiata/eating). This task produced a global activation in the area of the left inferior frontal gyrus, but no specific areas of activation for noun and verb.Likewise, in an fMRI study Both many doors, he sweeps) in response to words (noun or verb) or pseudowords (to be used as noun or verb in the context). In comparison to verb, noun production elicited greater activation in the left inferior temporal lobe. In comparison to noun, verb processing produced greater activation in pre-frontal areas and in the left superior parietal lobule. This pattern was consistent for words and pseudowords, abstract and concrete words, and regularly and irregularly inflected words. The authors suggest that these areas are involved in the representation of core conceptual properties of noun and verb. These abstract properties may show that all nouns refer to an identifiable thing, whereas all verbs refer an event taking place in time. Although in their studies Shapiro et al. did not use event nouns, they explicitly claim that their abstract characterization of noun concepts includes abstract nouns, mass nouns, and nominalizations.Shapiro and colleagues proposed an alternative view Thus, while according to Vigliocco et al. nuvola/cloud) and pseudowords selected to resemble simple object nouns (e.g. grincipe), event nouns (e.g. liberazione/freeing) and pseudowords with event nouns suffixes (e.g. sbinamento), and verbs (e.g. brillare/to shine) and pseudoverbs with verb suffixes -are, -ere, -ire (e.g. adevare). Nouns and pseudonouns were in the singular form, and verbs and pseudoverbs were in the infinitive form. The three groups of words were matched for frequency, concreteness, imageability, familiarity, and syllable length. All pseudowords were legal.As already observed, nouns could also refer to events, and event nouns have not been systematically investigated, with few exceptions The task was a lexical decision. There is debate about the sensitivity of the lexical decision task to study grammatical categories If Vigliocco and colleagues’ hypothesis is correct, then no different areas of activation should be observed for event noun and verb. On the other hand, if Shapiro’s hypothesis is correct, noun classes should produce similar patterns of activation, and this activation should differ from that produced by verb.Behavioral data on the correct execution of the task reveal that all subjects performed the three experimental conditions with a low number of errors, ranging from 0% to 5% across subjects (mean 2.3%). The errors for each experimental condition were 4% (N0), 1.5% (N1) and 1.5% (V). More errors were observed in pseudoword than in word presentation, with a rate of 8.25 ; the maximum number of wrong answers per stimulus among subjects was 2.The results are reported in terms of anatomical label, activation center coordinates  in MNI space, Z-score, and corresponding Brodmann Area (BA) in the left (L) or right (R) hemisphere. Due to the relevant number of areas of activation, a full description of all the results is available as Supporting Information S1.The global effect for all classes of words, masked by the effect of pseudowords, includes activations in the left inferior frontal gyrus (BA 44L), bilateral superior temporal gyrus (BA 22), bilateral inferior parietal lobule (BA 40), and postcentral gyrus (BA 43).Object nouns only activated the left inferior parietal lobule toward the postcentral gyrus (BA 40L).Event nouns activated Brodmann areas 46/10 and 45 in the left IFG, the transverse temporal gyrus toward the postcentral gyrus bilaterally (BA 40/41/42), and the right middle temporal gyrus (BA 39R).Verbs activated the left IFG (BA 44L/45L/13L), the left inferior parietal lobule (BA 40L) and postcentral gyrus (BA 43L), the superior temporal gyrus bilaterally (BA 22), right middle temporal gyrus (BA 37R). The activations resulting from the three conditions are superimposed on the same background in The cross-comparison among the three classes revealed a higher number of activations. During analysis, we observed that the pattern of activation of pseudowords versus null baseline for each class partially recalled the pattern obtained for the corresponding class of words under the same condition. Cross-comparison therefore allowed us to identify areas which were previously shadowed by imposing mask and threshold on the map of activation of each class.Compared to verb, noun elicits greater activation in a portion of the left insula (BA 13L) and IFG (BA 44L), the left inferior parietal lobule (BA 40L) and anterior cingulate cortex (BA 32L), plus the right middle temporal gyrus (BA 39R). In the opposite comparison, verb activates a wider portion of the left insula (BA 13L) and a number of areas in the left IFG including Brodmann areas 47, 46, 10, a portion of the anterior cingulate cortex (BA 32L) with a different center of activation from the previous comparison, the left inferior parietal lobule and superior temporal gyrus ; the pattern on the right hemisphere is very similar  with the exception of BA 46 and 32. The results are shown in Object and event nouns share activations in same areas in the left IFG and parietal lobules, but with different centers and extent. Object noun activates Brodmann area 44 in the left inferior frontal gyrus, the insula (BA 13L), and the inferior parietal lobule bilaterally (BA 40). Event noun shows a similar pattern of activation , plus different activations in the left middle frontal gyrus (BA 46/10R), the right IFG , the superior temporal gyrus bilaterally  and the left parahippocampal gyrus (BA 27/30L). The results are described in The patterns of activation of the two classes are almost entirely different; therefore the comparison reveals patterns recalling the results of the analyses of the separate classes. Masked with the map of activation for verb, object noun reveal an exclusive activation of Brodmann area 44L, which cannot be observed in the opposite comparison, and the insula. Conversely, verb elicits greater activation in areas 47 and 10 in the IFG bilaterally , left area 46, 45/13/47, the insula, the anterior cingulate cortex , and bilaterally the inferior parietal lobule (BA 39/40) and superior temporal gyrus .Compared to verb, event noun shows cortical activation in Brodmann area 44, 46 and the insula bilaterally, plus right area 45, the superior temporal gyrus bilaterally (BA 42) though more extensively in the right hemisphere, and the left parahippocampal gyrus (BA 27/30L). The opposite comparison results in the activation of the left IFG , toward the anterior cingulate gyrus , and of the middle and superior temporal gyrus bilaterally .The specific activation for object noun involves the inferior parietal lobule, postcentral gyrus and medial frontal gyrus bilaterally , the insula (BA 13L), and the right anterior cingulate cortex (BA 24R). Event words, either verb or noun, recruit numerous areas bilaterally in the inferior frontal gyrus , the anterior cingulate cortex (BA 32) and a relevant portion of the temporal lobe spreading towards the surrounding structures .In this study, we aimed to investigate the issue of the representation of grammatical classes in the mental lexicon. To this end, we performed a direct comparison involving object noun, event noun and verb.The results of our study have evidenced specific areas of activation for object noun compared to verb, involving the inferior frontal gyrus, the left insula, and the left inferior parietal lobule. This pattern of activation contradicts the hypothesis according to which noun activation, when compared to verb, depends on the amount of morphological and syntactic processing required by the task porta-s/he brings; porta-door).Indeed, cross-linguistic variables could explain the magnitude of the differences in the observed patterns of activation. In English, grammatical class differences mainly emerge when morpho-syntactic operations are engaged. When a word is presented in isolation  it can either be a noun or a verb. In order to solve the ambiguity, a morphological or syntactic context is necessary. In two lexical decision experiments, Vigliocco and colleagues found a grammatical class effect only when the primes, either verb or noun, were preceded by a grammatical context . However, when bare primes were presented, no grammatical class effect was observed. In a rich morphological language as Italian, this problem is strongly reduced and principally limited to verbs in the present form, third singular person, which may be morphologically identical to a noun , right-handed, and had no visual defects. All the subjects were fully informed on the modality and execution of the scans before signing an informed consent agreement in accordance with the Declaration of Helsinki. Subjects could leave the experiment at any time, although all completed the experimental sessions, and gave written permission to the treatment of personal data. Approval from the Ethics Committee of the University of Trieste was also obtained for this study.medaglia-medal), 20 argumental nouns (N1) (e.g. pianto-cry), 20 verbs (V) (e.g. dormire-to sleep). The complete lists can be found in Three lists of experimental words were selected: 20 non-argumental nouns (N0)  and frequency . They were also matched for familiarity, based on ratings collected from a panel of 18 Italian speakers on a 7-point scale .In addition, two new groups, each of 18 Italian speakers, were interviewed to collect, on a 7-point scale, ratings on concreteness and imageability. Based on the scorings obtained, the lists were also matched for concreteness  and imageability .grincipe for N0, darcerazione for N1, prigiare for V) to match with the experimental lists.Finally, an equal number of pseudo-nouns and verbs were selected . The interval between subsequent words was semi-randomized to 3, 4, 5 seconds to avoid expectance. The subjects were asked to read the stimuli and to perform a lexical decision task. In order to obtain a measure of this decision, the subjects were instructed to push a comfortable and very sensitive button only when recognizing the word to be part of their vocabulary. Stimuli were presented in three sessions, each including one of the experimental lists and the matching pseudowords. The correctness of the response to stimuli was recorded for further analysis. To minimize head movements during task execution, a number of small cushions were inserted between the subjects’ skull and the head coil after the best and most comfortable position for visual cue was reached.All images were acquired with a 1.5 Tesla Philips Gyroscan Intera MRI scanner using a multi-channel coil (maximum gradient amplitude: 30 mT/m). The sequence used ramp sampling to minimize distortion and image artifacts. Each f-MRI session consisted in 3750 images  acquired in about 8 minutes. Parameters were as follow: Fast Field Echo Planar; orientation: axial; TR/TE = 3200/45 ms; flip: 90 degrees; phase encoding: AP; Field of View 210×210 mm; plane resolution: 64×64 pixels; slice thickness: 4 mm; resulting voxel size: 3.28×3.28×4 mm.Raw images were processed with SPM 5 . We decided to correct for Slice Timing first and then Realign and Unwrap images, because the realignment of raw images showed very little spatial correction  thus allowing to correct the temporal signal for each voxel without dramatically losing spatial localization www.ihb.spb.ru). The portion of space surrounding each local maximum was then explored with T2T-Muenster Converter  to ensure proper identification of Brodmann areas in large clusters with more local maxima and clusters in a gap between two contiguous areas.Pre-processed images were analyzed on an event-related protocol. Pseudowords were taken as baseline. Realignment correction parameters were used as multiple regressors. A high pass temporal filter (cut-off: 128 seconds) was applied to the time series. In1st level analysis, the time series were convolved with the canonical hemodynamic response function (HRF); as the real shape of the HRF may differ from the canonically defined function, the time and dispersion partial derivatives of the HRF were also modeled, in order to identify variations in time occurrence and width of the response to the submitted stimuli, thus increasing detection power Information S11. Global effect 2. Words masked by pseudowords, for each class of words  3. Cross comparisons among classes of words  4. Coupled cross comparisons among classes of words  5. Pseudowords masked by words, for each class of words .(DOC)Click here for additional data file.Appendix S1Words and pseudowords as presented in the three experimental sessions (English translation provided for meaningful words).(DOC)Click here for additional data file.


The intraindividual variability (IIV) of cognitive performance has been shown to increase with aging. While brain research has generally focused on mean performance, little is known about neural correlates of cognitive IIV. Nevertheless, some studies suggest that IIV relates more strongly than mean level of performance to the quality of white matter (WM). Our study aims to explore the relation between WM integrity and cognitive IIV by combining functional (fMRI) and structural  imaging. Twelve young adults (aged 18–30 years) and thirteen older adults (61–82 years) underwent a battery of neuropsychological tasks, along with fMRI and DTI imaging. Their behavioral data were analyzed and correlated with the imaging data at WM regions of interest defined on the basis of (1) the fMRI-activated areas and (2) the Johns Hopkins University (JHU) WM tractography atlas. For both methods, fractional anisotropy, along with the mean, radial, and axial diffusivity parameters, was computed. In accord with previous studies, our results showed that the DTI parameters were more related to IIV than to mean performance. Results also indicated that age differences in the DTI parameters were more pronounced in the regions activated primarily by young adults during a choice reaction-time task than in those also activated in older adults. Cognitive aging is typically described in terms of a general decline of cognitive performance, in particular a general slowing of processing speed based on the mean performance of individuals . More reinconsistency, which denotes transient and rapid fluctuations that occur over short-term time scales ; (b) intraindividual variability across tasks, or dispersion; (c) relatively permanent alterations that evolve slowly over relatively long-term time scales , through training, or development, that is, intraindividual change; (d) interindividual or between-individual variability, also termed diversity [Behavioral individual variability has been described in various ways, which can be summarized in four main types: (a) short-term or trial-to-trial, within-task variability, or iversity , 8, 9.In this paper, we will focus on inconsistency, that is, on within-task short-term variability (and we will refer to this as IIV). Several studies have observed that inconsistency increases with age during adulthood and support the idea that it is a stable and meaningful indicator of individual differences , 10, 11.Despite the growth of recent studies, little is known about inconsistency in aging, and still less about its neural underpinnings. As Hultsch et al.  mentionehttp://cmrm.med.jhmi.edu/) [The objective of the present study was to further explore the relationships between IIV and the quality of the white matter, by combining DTI and fMRI in young and older adults. Regions of interest (ROI) were defined in two ways: by inspection of age differences in regions activated in a simple reaction time paradigm administered in the scanner, and by the usual means of a dedicated protocol (John Hopkins University (JHU) white-matter tractography atlas-JHU, mi.edu/) , 24. Sevmi.edu/) . FA refemi.edu/) –30. Somemi.edu/) , 32, whimi.edu/) , 34. In  Twelve young adults  and thirteen older adults  participated in the experiment see  are stanThe study was approved by the ethics committee of the Faculty of Psychology and Educational Sciences of the University of Geneva. All participants gave written informed consent, and older adults received a small amount of money as a compensation for their transportation fees.The behavioral tasks were administered in our laboratory during two sessions lasting about 1.5 hours, one week apart, for the older adults, and one session of roughly 2 hours for young adults. The older adults are part of a longitudinal study, using a rather extensive experimental protocol. The tasks presented here are a subset of this larger study. All experimental tasks were individually administered on a Dell computer, using E-Prime .The Cross-Square (CrossSquare) Task. This choice reaction time task, adapted from Hultsch et al. [h et al. , was admLetters Comparison Task (LetterComp). This task of processing speed was adapted from Salthouse [Yes or a No key on the response keypad.althouse . ParticiStroop Color Word Task (Stroop). In this widely used task [sed task , meant tIn order to control for processing speed, an index of resistance to interference was computed as follows: /mean RT in the neutral condition). The lower the index (relative ratio), the more resistant to interference.Working Memory Tasks. Two tasks of working memory were used: the Reading Span task, a verbal task [bal task , and thebal task  presentiReading Span task (RSpan), participants were instructed to read a series of sentences  on the computer screen and to decide whether each sentence was semantically correct or not (press a Yes or a No key on the keypad), while retaining the last word. Recall of the last words in their order of presentation was asked at the end of each series. The test consisted of twenty trials—ten at the participant's span level  and ten at the span level +1 (ten series of 5 sentences). Response times for the semantic judgment were recorded, and the order and accuracy of oral responses were recorded manually by the experimenter.In the Matrices task (Matrices) consisted of a 5 × 5 grid containing either a number of blackened cells  or of words written within the cells . The number of black cells or of words ranged from two to eight, depending on the participants' span. In the visuo-spatial condition (simple positions), participants had to recall the position of the black cells and to replace them on a blank grid using a touch screen. In the verbal-spatial condition (words in the cells), participants had to recall both the words  and their positions . The visuo-spatial condition consisted of ten trials at span level and ten trials at span level +1; the verbal-spatial condition comprised ten trials at span level +1 and ten trials at span level +2. The The number of correctly recalled words in the RSpan, regardless of their order, and the number of correctly recalled positions and words in the Matrices task were used as scores in the present study.For reaction times (RTs) tasks, participants gave their response on a response pad with the forefinger of either hand (right/left or same/different), except for the Stroop Color Word task, for which a voice key was used. Accuracy in the working memory tasks was recorded by the experimenter. Several practice trials were given prior to each task (from 6 to 10 depending on the task complexity). In addition to these tasks, measures of fluid   and crysb value = 1000 s/mm2, and voxel size 2.0 × 2.0 × 2.0 mm). The two DTI acquisitions, which presented a high correlation with each other (higher than .95), were concatenated to increase the signal-to-noise ratio during the postprocessing.Participants were scanned in a Siemens Trio 3T magnet. They underwent one fMRI task sequence, as well as two fMRI sequences in a resting condition (not used in the present study), and two DTI sequences. The BOLD fMRI task-rest sequence was administered first, using a reaction time paradigm, where the participant had to indicate on which side a cross was changing into a square, as fast as possible (see CrossSquare above). The task consisted of eight experimental blocks, interspersed with eight resting blocks . The BOLD activity was obtained using an echo planar imaging acquisition . Then a structural T1-weighted MRI was acquired (time echo (TE) = 2.27 ms, time repetition (TR) = 1900 ms, field of view (FOV) = 256 mm, and voxel size 1.0 × 1.0 × 1.0 mm). Finally, two sequences of 30 directions DTI were acquired  and extremely slow responses . As mentioned above, working memory performance was scored in terms of the number of correctly recalled items (words and/or positions) by trial.Age group effects as well as systematic time-related effects (practice or fatigue effects) were removed from the working memory and RT data by regressing age group, item rank, block rank, and their interactions on each trial, in each task. Data were then standardized and transformed into T-scores. Mean performance and within-person variability (inconsistency) were considered for the analyses. Within-person variability was assessed by computing intraindividual standard deviations (iSDs) on the T-scores. As concerns the Stroop task, residuals were computed for the raw RTs and transformed in T-scores. Then, resistance to interference was computed (relative ratio) on these T-scores, for each block; iSD was computed on the basis of these nine block indices.In order to diminish the number of variables to correlate with brain data, and based on the between-task correlations observed, scores were further regrouped. Two combined working memory scores were used: (a) verbal working memory, assessing verbal aspects of working memory and regrouping scores obtained in the two conditions of RSpan and in the verbal part of Matrices ; (b) spatial working memory, regrouping the four conditions of the spatial aspect of Matrices . This leaves altogether five behavioral scores: (1) simple reaction time (CrossSquare); (2) complex processing speed (LetterComp); (3) verbal working memory (vWM); (4) spatial working memory (sWM); and (5) resistance to interference (int). Univariate analyses of variance (ANOVAs) were conducted on iSDs for each of these five dimensions. As data were residualized for age group effects, no effects of age were expected on mean performance, except possibly for the Stroop, since for this task residuals were computed on the raw RTs, and not on the index of interference.http://www.fmrib.ox.ac.uk/fsl) [ Image analysis was done using FSL (.uk/fsl) . The firThe two sessions of DTI were concatenated for each subject. Each DTI volume was registered to the T1-weighted image (patient space) using FLIRT. An eddy-current correction was done. The nonbrain tissue was removed from the image (skull-striped), and least-square fits were performed to estimate the FA and eigenvector maps. The individual FA volumes were skeletonized and transformed into a common space (the fMRI58_FA template supplied by FSL) using TBSS and FNIRT. The skeletons were binarized to reduce the partial volumes between tissues borders (threshold for FA > 0.2). At every step, the warped/coregistered volumes were inspected visually for accuracy. Two methods were used to define ROIs for structural imaging analyses as follows.Z = 2.3, P = 0.05). We selected six different maps of activation on the basis of age group differences: significantly activated in young adults, significantly activated in old adults, significantly greater in young than in old ((1) The first method used activated fMRI clusters as regions of interest (ROI). After a classical fMRI preprocessing, activation regions were computed as a group analysis (old versus young) contrasting the experimental and the rest blocks when the RT task was administered  to include the white matter surrounding them and masked, with a grey matter mask, to exclude the cortex . In orde(2) In order to be able to compare our data to the literature, we decided to use an atlas that had previously been used in aging studies and to apply it to our data –46. TherFor both methods of ROIs definition, one-way analyses of variance (ANOVAs) were conducted on each of the four DTI parameters  with age group as a between factor to assess age-related differences in the white matter quality . BonferrF = 7.233; P = .013; η2 = .24), older adults showing less resistance to interference than younger adults. As expected, ANOVAs conducted on mean performance for simple RTs, complex RTs, verbal working memory, and spatial working memory yielded no significant results. Note, however, that raw results  did present significant age differences in all tasks, as usual in cognitive aging studies: young adults were faster and less variable in RT tasks and had better performances in the spatial working memory task; they were, however, not significantly better in the RSpan task. Regarding resistance to interference, results showed a significant main effect of age group,  = 24.346; P < .001; η2 = .51), RTs in complex processing speed tasks  = 7.89; P = .01; η2 = .25), and in spatial working memory  = 6.858; P = .015; η2 = .23). Within-person variability was not significantly different between age groups in verbal working memory  = 1.05; P = .749; η2 = .005), nor in resistance to interference  = 0.135; P = .717; η2 = .006). ANOVAs conducted on iSDs revealed that younger adults were less variable than older adults regarding RTs in simple tasks . The older adults presented greater activation in the right insula and in larger bifrontal/biparietal regions than the younger adults. As mentioned above, we analyzed six different networks: the regions activated (1) by the young adults , (2) by the older adults , (3) more strongly in the young than in the older adults , the left middle temporal gyrus, the right angular gyrus, and the right middle frontal gyrus anteriorly. Finally, each activated area was enlarged to capture the WM adjacent to it; then the cortex was excluded using a mask since diffusivity values are only interesting in white matter. F = 14.77; P = .001; η2 = .40), MD  = 13.403; P = .001; η2 = .38) and RD  = 19.405; P < .001; η2 = .47). In addition, age effects were observed in regions activated more by young adults than by older adults in both MD  = 12.558; P = .002; η2 = .36) and RD  = 11.647; P = .002; η2 = .35). RD in regions only activated by both groups (union) also showed an age effect  = 9.076; P = .006; η2 = 29). Results showed significant effects of age in regions exclusively activated in young adults in FA (No age effects were observed for the DTI parameters either in regions activated by older adults (exclusively or more powerfully than in young adults) or in the conjunction of the regions activated by both young and older adults. We only examined correlations with the CrossSquare (RT) task, that is, the task for which regions of functional activation were analyzed, whether administered in the scanner or in the laboratory. With regard to CrossSquare administered in the laboratory, there was a significant negative correlation between iSD and FA (−0.47), as well as a positive correlation between iSD and RD (0.46); both DTI values were obtained in the regions activated by the young adults only. However, those results were not significant in the same task repeated in the magnet.r = −.40 and r = −.72, all P < .05). A similar relation was observed for iSD in the simple task and FA in the forceps minor  and between iSD in spatial working memory and FA in bilateral IFO . A few correlations were also significant between mean performance and FA values. iM in the complex processing speed task was positively related to FA in bilateral SLF  ; and mean level of resistance to interference significantly correlated with FA in the forceps minor and in the left cingulum .Correlation analyses were carried out between the four DTI parameters and mean performance, on the one hand, and between the four DTI parameters and iSDs, on the other hand, for the tasks administered in the laboratory. r = .42, P < .05 and r = .68, P < .01), and in most tracks for the simple RT task , with the exception of left IFO for MD, and bilateral ILF, and forceps minor for RD. Variability in spatial working memory also correlated significantly with RD in left IFO and left CS . Fewer significant correlations between mean performance, on the one hand, and mean or radial diffusivity, on the other hand, were observed , our results also showed strong significant correlations between the degree of diffusivity and iSD in most tasks. Cognitive intraindividual variability was positively and significantly related to MD and RD in all tracks  for the complex RT task . Interestingly, all significant correlations were with tracks showing no age differences in AD. In tracks showing age differences, AD was significantly related to cognitive IIV in both simple and complex RT tasks , and positively related to mean performance in both simple and complex RT tasks in bilateral ATR . Results concerning axial diffusivity (AD) were slightly different see . They diThis study aimed to assess age differences in the quality of white matter and to explore its relationships with cognitive performance; in particular, the “inconsistency” . WM was studied using diffusion tensor imaging (DTI), by using two methods to define relevant regions: regions defined by age differences in functional activation in response to a choice reaction time (RT) task and regions defined a priori on the basis of the JHU atlas. Four DTI parameters were computed: fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity. On the basis of fMRI, six sets of regions were defined: significant activation in younger adults, significant activation in older adults, significantly greater activation in younger than in older adults, significantly greater activation in older than in younger adults, regions significantly activated in both age groups (conjunction), and regions activated either by one group or the other (union). Interestingly, age differences in FA, as well as in MD and RD, were only significant for those regions more strongly or uniquely activated in young adults; FA values were higher in young adults, while MD and RD values were higher in older adults. In contrast, there were no age differences in those regions which were also strongly activated in older adults. We will return to this point below. On the basis of the JHU atlas, 20 regions were defined and a mean value was computed, for each of the four DTI parameters. When presenting a significant age difference, FA was higher in young adults; this was the case for forceps major and forceps minor, the bilateral inferior fronto-occipital fasciculi (IFO), as well as the right inferior longitudinal fasciculus (ILF), and the overall mean. MD, RD, and AD indices, when differing between the two groups, were higher in older adults, and this concerned the bilateral anterior thalamic radiation (ATR) and the bilateral superior longitudinal fasciculi (SLF—only the left one for AD). MD and RD were higher in the left ILF; RD showed additional differences: left cingulum/cingulate gyri, right IFO. MD and RD mean values were also significantly higher. Our results converge with those of Madden and colleagues  who showWe also observed a small anterior posterior gradient  as seen in the literature and explained by an increased susceptibility of the anterior white matter to age-related alterations , 48–50. The behavioral performance was studied by means of a choice reaction time task administered in the scanner (CrossSquare task), on the one hand, and by a battery of several cognitive tasks, varying in complexity, administered in our laboratory: reaction time (CrossSquare), more complex processing speed (LetterComp), inhibition (interference score in the Stroop task), verbal working memory (a score combining RSpan and Matrices), and spatial working memory . Age differences were observed in all the tasks as concerns the mean raw scores. However, the focus was placed here on residual scores, once age and trial and block order (practice effect), as well as their interactions, had been controlled . ObviousGlobally, quality of WM was mostly related with IIV and not with mean performance . Variability in the Letter Comparison task was negatively related to FA in almost all regions and was positively related to MD and RD in regions showing age differences. IIV in the Cross Square task performed outside the scanner correlated with FA only in the forceps minor and with MD and RD in bilateral ATR and SLF, in addition to the cingulum/cingulate gyrus for RD. It is true, as one of the reviewers rightly commented, that the difference in correlations was not directly tested. Note, however, that the sheer number of significant correlations was clearly higher with IIV than with the mean, in particular as concerns the FA values. These observations are consistent with Fjell and collaborators' report of a stronger relation between WM quality and IIV than with average performance . They alThe relationship between WM quality and IIV in simple RT tasks was, however, less important than in the complex processing speed task. Complex cognitive tasks typically involve increasing interplay between multiple areas, spatially distributed , 56. ProIf IIV does increase with complexity, one might also expect a significant relation between DTI parameters and working memory tasks, which are certainly more complex than our RT tasks. This was not the case in this study. IIV in spatial working memory did correlate with FA in bilateral IFO, as well as with RD in the left IFO and left CS tracks, but IIV in verbal working memory showed no correlation with any of the DTI parameters. As already mentioned above, IIV might behave differently depending on whether the cognitive performance is scored in terms of RT or of accuracy. Also, verbal performance does not present the same aging pattern, altogether, as other cognitive abilities such as speed or spatial cognition. Walhovd and Fjell  reportedNote that, as mentioned above, other studies also report a link between mean performance and DTI parameters , 48, 60. Obviously, the present study is not without some limitations. First, as already mentioned, the sample is still small, and results await replication with a larger number of participants. Because the older participants are examined within a broader, longitudinal study, data collection is still ongoing and has to wait for a given time interval before a new assessment can be conducted. Therefore, increase in the sample size takes time to evolve within the population being studied. It is worth stressing that significant associations were already observed with a small sample size in the present study and that the effects' size was often large. Nevertheless, an increase in the sample size should help clarifying a few issues, or, in the case of somewhat different results, would point to the importance of interindividual differences. Second, as just mentioned, although yielding interesting results, the analysis of region-based DTI parameters based on brain activity is task dependent. The results in terms of age differences might differ if the task used in the scanner was more complex. It is, however, difficult to adopt a more extensive protocol in the scanner. Future analyses, based on a larger sample, will focus on the relationship between white matter and observed change over the three waves to which the older adults were submitted. Lastly, some studies have shown that IIV was a strong predictor of cognitive decline, including mild cognitive impairment or dementia , 10, 61.To summarize, the present study provides further empirical support to the proposal that IIV in cognitive behavior increases with age  and brin


The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with ‘real-world’ treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication.Participants prescribed either conventional mood stabilizers  alone, or olanzapine with, or without, CMS  were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale – Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data.On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone  and the olanzapine ± CMS  cohorts.Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome. Bipolar disorder (BD) is a complex and severe mental illness, with a fluctuating course, characterized by acute, affective episodes with full or partial inter-episode remissions. Adding to the complexity of BD is the “mixed” affective syndrome, in which the person experiences both depressive and manic symptoms simultaneously. The lifThe global burden of BD is significant as it represents the sixth leading cause of years lived with disability. IndividDue to the varying mood-states and different expressions of the illness, management of BD is complicated. For decades, lithium was considered the cornerstone of pharmacologic treatment for BD and remaSeveral large observational studies of patients with BD and schizoaffective disorder (SAD) have been conducted and subsequently published-24. AmonThe observational design was chosen for the BCOS to complement information available from other study designs, such as randomized controlled trials (RCTs). While RCTs have higher internal validity, observational studies offer several advantages over RCTs including: a) lower cost; b) increased timeliness; c) fewer inclusion and exclusion criteria, thus providing an opportunity to study a more diverse patient population over longer periods of time in a naturalistic setting; and most importantly, d) the ability to identify risk factors and prognostic indicators in situations which would be impossible or unethical for RCTs,27-30. WThe broad objective of BCOS was to better understand the long-term clinical, functional, social and economic outcomes achieved by participants being treated for BD I or SAD. As part of this objective, we aimed to evaluate current clinical practices, including pharmacological treatment. Specifically, we were interested in examining the 2-year outcomes for participants following treatment with either conventional mood stabilizers (CMS) alone, or olanzapine with, or without, CMS (olanzapine ± CMS).Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR)); 100%;  for mood stabilizers, 96.7%;  for antipsychotics, 6.1%;  for antidepressants, and 1.1%;  for benzodiazepines/hypnotics.Despite the majority of participants experiencing mild depressive and manic symptoms at study entry, study participants reported considerable functional impairment and comorbidities. Approximately 40%; of participants were in a permanent relationship, and 63%; had considered suicide in the previous month Table . FurtherOverall, participants experienced some improvements in quality of life during the course of the study. The SF-36 mental health component scores improved significantly over 24 months  and refusal of consent or being unable to participate ; however, post-enrollment participant retention was very high . Unlike those in more restrictive RCT settings, BCOS participants were not excluded based on comorbidities, and were free to use any adjunctive medications or therapies. However, the requirement to be receiving at least one of the pre-specified agents as a mood stabilizer at study entry excluded patients receiving other treatment regimens.In considering the clinical correlates of BD, we found high symptomatic remission rates for mania and depression , demonstrating that participants experienced adequate symptom control across both poles during the study. However, the high relapse rate for depression  suggests that maintaining long-term management of depressive symptoms is more difficult to achieve. This aligns with results from a long-term follow up study of BD I patients, in which patients were symptomatically ill 47%; of the time, with depressive symptoms predominating.A major finding from this study was the extent of polypharmacy used in treating people with BD. The pre-specified comparison between the symptomatic relapse rate of participants prescribed olanzapine ± CMS or CMS alone at study entry was confounded by the complexity of the treatment that participants received over time. Polypharmacy is also prevalent in other countries; a large US study of patients with BD (n = 7406), revealed that, although 33%; of patients received an initial prescription for more than one psychotropic agent, 12 months later, the polypharmacy rate among those still receiving treatment had risen to 50%;.The key finding with respect to social outcomes and quality of life was that while unemployment rates improved over the 24-month study period, the rate was still higher than in the general Australian population. In addia priori. Second, the participants were required to provide consent at study entry, thus excluding many of the most severely ill patients, although 19%; of participants in this study were manic and 25.4%; were suffering severe depression , however, more participants with a diagnosis of SAD were in the olanzapine ± CMS cohort  as compared with the CMS alone cohort ; since the BD indication was new for olanzapine, these participants may not reflect those currently using this medication.As mentioned previously, observational studies offer several advantages over RCTs including: a) the opportunity to study a more diverse patient population, over longer periods of time and; b) the ability to identify risk factors and prognostic indicators in situations in which it would be impossible or unethical for RCTs to do so,27-30. Sore ≥19;). Third,Our naturalistic data suggest that participants were receiving diverse, complex medication treatments that led to some overall clinical and functional improvement. However, not all participants achieved remission of symptoms or syndrome. Persistent depressive symptoms were common for this sample, with 58%; of participants experiencing symptomatic relapse of depression at some point. Given the complexity of treatment, we split participants into PT cohorts to explore the comparative treatment effectiveness but with limited success. Few differences were observed between the treatment cohorts; the use of multiple mood stabilizers and other concomitant medications made it difficult to attribute reported outcomes to any one treatment group, and thus elucidate the role of individual medications. This is an important limitation, particularly in terms of making recommendations on prescribing practices. It should be noted that a recent multiple-treatment meta-analysis (data from 68 RCTs) which ranked efficacy and acceptability of drugs used to treat mania concluded that olanzapine was one of two antipsychotic drugs that ranked superior in terms of efficacy and acceptability,51. An aThe findings from the BCOS describe a complex patient population receiving treatment regimens that were often discordant with recommendations made in the major treatment guidelines for either BD or SAD. The polypharmacy approach used to treat many of the study participants was associated with some improvement in clinical and functional outcomes. However, this raises a series of questions regarding the pragmatic utility of current clinical guidelines. The abuFunding for this study was provided by Eli Lilly Australia. The chief study investigators (J. Kulkarni and M. Berk) are independent academic clinicians and directed the study design and conduct. Lilly Medical employees were involved in study design, analysis and interpretation of data, and in the writing of the report. The Lilly authors listed  participated in the decision to submit the paper for publication. Lilly had no role in data collection.J. Kulkarni, P.B. Fitzgerald, A. de Castella, and S. Dodd have received research funding and/or speaker's fees and/or funding to attend conferences from Eli Lilly. M. Berk has received grant/research support from the Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma and Servier; has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Pfizer, Sanofi Synthelabo, Servier, Solvay, Wyeth and acted as a consultant for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, and Servier. L. Berk is supported by an NHMRC scholarship. W. Montgomery, K. Kelin, and A.J. Lowry are employees of Eli Lilly Australia. A. Brnabic was employed by Eli Lilly Australia at the time of manuscript development.AB was involved in study design, statistical planning, analysis, interpretation and presentation of results. LB was involved in conducting the assessments with participants and editing the manuscript. MB was a principle investigator on the study and was involved in editing the manuscript. AD was involved in the design and conduct of the study, and has contributed to the analysis and presentation of results. AL was involved in the data interpretation and drafting of the manuscript. KF was involved in the project coordination and data collection for this study, and contributed to the overall study design and preparation and review of this manuscript. SF was involved in the project coordination and data collection for this study, and contributed to the overall study design and preparation and review of this manuscript. JK was a principle investigator on the study and was involved in editing the manuscript. KK was involved in the study design, data interpretation and critical review of the manuscript. SD was involved in study design and management, data interpretation and manuscript preparation. WM helped conceive the study, and participated in its design and coordination, assisted with interpretation of the study results and helped to draft and review the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/12/228/prepub


The evidence for associations between occupational factors and the risk of Parkinson's disease (PD) is inconsistent. We assessed the risk of PD associated with various occupational factors in Japan.We examined 249 cases within 6 years of onset of PD. Control subjects were 369 inpatients and outpatients without neurodegenerative disease. Information on occupational factors was obtained from a self-administered questionnaire. Relative risks of PD were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) based on logistic regression. Adjustments were made for gender, age, region of residence, educational level, and pack-years of smoking.P = 0.08). According to a stratified analysis by gender, the decreased risk of PD for persons in professional or technical occupations was statistically significant only for men. Adjusted ORs for a professional or technical occupation among men and women were 0.22 (95% CI: 0.06-0.67) and 0.99 (0.47-2.07), respectively, and significant interaction was observed (P = 0.048 for homogeneity of OR). In contrast, risk estimates for protective service occupations and transport or communications were increased, although the results were not statistically significant: adjusted ORs were 2.73 (95% CI: 0.56-14.86) and 1.74 (95% CI: 0.65-4.74), respectively. No statistical significance was seen in data concerning exposure to occupational agents and the risk of PD, although roughly a 2-fold increase in OR was observed for workers exposed to stone or sand.Working in a professional or technical occupation tended to be inversely related to the risk of PD: adjusted OR was 0.59 (95% CI: 0.32-1.06, The results of our study suggest that occupational factors do not play a substantial etiologic role in this population. However, among men, professional or technical occupations may decrease the risk of PD. The cause of Parkinson's disease (PD) remains unknown, although a complex interaction among genetic and environmental factors is likely to be involved in the development and progression of the disease ,2. The iResults of studies of twins suggest that genetic factors are important in early-onset PD cases, whereas environmental factors play a predominant etiologic role in late-onset PD patients ,5. AmongOccupational studies provide a useful approach to the investigation of environmental exposures as markers of exposure to agents used in the workplace , and thePatients with PD were recruited at three university hospitals and one national hospital in Fukuoka Prefecture, a metropolitan area of Kyushu Island in southern Japan, and in three university hospitals, three national hospitals and one municipal hospital in Osaka, Kyoto, and Wakayama Prefectures, which are part of the Kinki region that is in the midwestern part of the mainland. Eligible cases were patients who were within 6 years of the onset of PD and who had been diagnosed by the collaborating neurologists according to the United Kingdom Parkinson's Disease Society Brain Bank clinical diagnostic criteria (steps 1 and 2) . The neuDuring the same period, control subjects without a previous diagnosis of a neurodegenerative disease were recruited from departments other than the department of neurology in 3 of the 11 collaborating hospitals, namely, one university hospital in Fukuoka Prefecture, and one university hospital and one national hospital in the Kinki region . Control subjects were not, individually or in larger groups, matched to cases. When a potential control subject was seen as an outpatient or was hospitalized in any of these three hospitals, that individual was asked by an attending doctor or one of our research nurses to participate in our case-control study as a control subject. In the end, from a group of 528 potential control subjects, 372 elected to participate in our study, and 156 refused (response rate: 70%).One case and 3 control subjects were excluded due to missing data on the factors under investigation, so data for 249 cases and 369 control subjects were ultimately available for analysis. The ethics committees of the 11 collaborating hospitals approved our case-control study . Written informed consent was obtained from all subjects.Participants filled out a set of two self-administered questionnaires and mailed these materials to a data management center or handed them directly to research nurses. Our research technicians completed missing answers and/or corrected illogical data using telephone or direct interviews.One of the self-administered questionnaires elicited information on gender, age, educational level, smoking habits, occupational history, and exposure to specific occupational agents .The second questionnaire was a validated self-administered diet history questionnaire, however dietary data were not used in the current study.In Japan, because most workers are in traditional lifetime employment systems, relatively few experience plural occupations during their lifetime. Therefore, the employment data used in this study focused on the type of job held for the longest period of time during the subject's working life. The mean duration of the job held for the longest time in the study population was 24.8 years. Occupational exposure to agents was defined as being present if the subject reported exposure for 10 or more hours per week for more than 1 year.Jobs held for the longest period of time were coded using the Japanese Standard Occupational Classification and stratified into 11 major groups . Multiple logistic regression analysis was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for PD in relation to occupational factors. Gender, age, region of residence, educational level, and pack-years of smoking were used as confounding variables. The following factors were classified: region of residence (Fukuoka and Kinki), educational level , and pack-years of smoking . Age was used as a continuous variable. The reference category for all occupational factors was based on a comparison of those exposed to a single agent with all those who were unexposed to that agent, including potential subjects who were exposed to other etiologic factors. The crude and adjusted risk estimates were nearly identical; therefore we reported only adjusted results. All analyses were performed using the SAS software package version 9.2 .The characteristics of cases and control subjects are summarized in Table P = 0.08). On the other hand, risk estimates for protective service occupations and transport or communications were increased, although the results were not statistically significant: adjusted ORs were 2.73 (95% CI: 0.56-14.86) and 1.74 (95% CI: 0.65-4.74), respectively.Table Results for occupational exposures are shown in Table P = 0.048 for homogeneity of OR). Regarding occupations other than professional or technical occupations and exposure to any of the occupational agents, there were no measurable differences by gender. No significant interactions were observed between any of the exposures under study and smoking status with regard to the risk of PD.To examine whether gender or smoking status affected the association between occupations, or exposure to occupational agents, and the risk of PD, we conducted further analyses that were stratified by gender and smoking status. When stratifying the subjects according to gender, a decreased risk of PD in relation to professional or technical occupations was significant only among men. Adjusted ORs for professional or technical occupations among men and women were 0.22 (95% CI: 0.06-0.67) and 0.99 (0.47-2.07), respectively, and significant interaction was observed  showed a lack of association between professional, technical and managerial occupations and the risk of PD . Also noPossible biological mechanisms that might protect those in professional or technical occupations against PD are unknown. Since occupations classified as professional or technical include a wide range of work activities and potential exposures, identifying specific factors that might be protective is likely to be extremely difficult. Some common lifestyle factors among those holding such positions might be responsible for the decreased risk estimate observed. Alternatively, levels of job strain and decision latitude in relation to occupation may contribute to a decreased risk of PD . In geneOur data did not show any significant association between farming and exposure to pesticides, herbicides, and fungicides and the risk of PD. Our results are in agreement with previous epidemiological studies that showed no associations between farming or exposure to pesticides, herbicides, or rodenticides and the risk of PD -14; howeA particular strength of our study is that since all PD patients were diagnosed by a neurologist according to established criteria, there is little reason to suspect that a misdiagnosis of PD occurred. Also, the response rate among eligible cases was relatively high (84%). Although we took into consideration information on potential confounders, the effects of residual confounding could not be ruled out.Our study has, however, some important limitations. As our sample size was relatively small, we may have failed to detect associations with various occupational categories or occupational exposures due to a lack of statistical power. In the present study, occupational categories based on the Japanese Standard Occupational Classification were used and the classification is somewhat crude. Additionally, we considered only the longest job held, rather than all occupations held by individuals, and occupational information was based on self-reporting. Moreover, with regard to occupational agents, information on exposure patterns such as frequency or concentration, and exposure modifiers such as work practices, local ventilation systems, or the use of personal protective devices during work, was not available. Consequently, the possibility of inaccurate exposure data and resultant misclassification bias should be considered when interpreting our findings. Another problem with retrospective case-control studies is recall bias, as patients in a case-control study may attribute greater significance to past events and perceived environmental exposure than the control subjects. Since the recruitment of case participants was conducted at 11 collaborating hospitals, whereas control subjects were selected from one university hospital in Fukuoka Prefecture, and one university hospital and one national hospital in the Kinki region, it is possible that the control subjects did not entirely represent the population from which cases were drawn.The present study showed the lack of significant associations between occupational factors and the risk of PD. Our findings suggest that occupational factors did not play a substantial etiologic role in this population. However, since our study had several limitations, such as the small number of study subjects, the possibility of recall bias, and the possibility of inaccurate exposure data, our results are not conclusive. Further studies with larger study populations and more accurate measures of exposure are needed to more clearly identify etiologic factors.Other members of the Fukuoka Kinki Parkinson's Disease Study Group are as follows: Yasuhiko Baba and Tomonori Kobayashi ; Hideyuki Sawada, Eiji Mizuta, and Nagako Murase ; Tsuyoshi Tsutada and Hiroyuki Shimada ; Jun-ichi Kira ; Tameko Kihira and Tomoyoshi Kondo ; Hidekazu Tomimoto ; Takayuki Taniwaki ; Hiroshi Sugiyama and Sonoyo Yoshida ; Harutoshi Fujimura and Tomoko Saito ; Kyoko Saida and Junko Fujitake ; Naoki Fujii ; Masatoshi Naito and Jun Arimizu ; Takashi Nakagawa, Hirofumi Harada, and Takayuki Sueta ; Toshihiro Kikuta and George Umemoto ; Eiichi Uchio and Hironori Migita ; Kenichi Kazuki, Yoichi Ito, and Hiroyoshi Iwaki ; Kunihiko Siraki and Shinsuke Ataka ; Hideo Yamane and Rie Tochino ; Teruichi Harada ; and Yasushi Iwashita, Motoyuki Shimizu, Kenji Seki, and Keiji Ando .CI: confidence interval; OR: odds ratio; PD: Parkinson's disease.The authors declare that they have no competing interests.KT contributed to the study design, data collection, data management, statistical analysis, data interpretation, and writing of the manuscript. YM contributed to the study design, data collection, overall management, and manuscript editing. WF contributed to the study design, data collection, and data management. SS and CK contributed to the study design. YT, TY, TO, TM, NK, NS and HF contributed to the outcome definition and case recruitment. YH and MN contributed to the supervision of the design and execution of the study. Authors listed in the Appendix contributed to case or control subject recruitment. All authors contribute to the preparation of the manuscript and approved the final version submitted for publication.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/83/prepub


This study examined long-term improvement of quality of life amongst heroin users enrolled in methadone maintenance treatment (MMT).The sample contained 553 heroin-dependent individuals from 4 hospitals in northern Taiwan who enrolled in MMT for an average of 184 days. Each patient signed a consent form and was assessed prospectively 3 times semi-annually. Quality of life was measured using the WHOQOL-BREF questionnaire, 26 items of which were scored by the participants. The WHOQOL-BREF consists of four domains: physical, psychological, social, and environmental. 285 and 155 participants completed 6-month and 12-month follow-ups respectively.After controlling for demographic and clinical characteristics, there were statistically significant improvements in the psychological and environmental domains between baseline and 6 months. Significant improvements were found in psychological and social domains between baseline and 12 months.It is concluded that methadone maintenance treatment improves heroin users’ long-term quality of life in the psychological and social relationship domains. Illicit drug use is a complicated problem that not only impacts individuals’ physical and psychological health but also derogates public security and society’s productivity because of morbidity and mortality . It is eHeroin users are at high risk of morbidity and mortality. They may struggle with dependence for many years, suffering poor interpersonal relationships and poor health ,4, partiFollow-up studies have found that this risk continues for many years after diagnosis of heroin dependence , indicatAlthough opioid treatment programs are effective in reducing the amount and frequency of heroin use and its consequences as describe above, prospective research on possible improvement in quality of life from the patient’s perspective has been limited. Quality of life was defined by the WHO as “an individual’s perception of their position in life, in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns”. Quality of life has been an important indicator of efficacy in the treatment of various chronic diseases such as diabetes and hypertension, creating a transition from cure to care. In their report of a qualitative interview study, Laudet, Becker, and White  noted thFurther, MMT is not free to patients. A recent study on 2,728 MMT patients in China  indicateWe used a 12-month prospective multisite study to examine the improvement of quality of life from the patient’s perspective. The study protocol was reviewed and approved by the institutional review board (IRB) of Taipei Medical University  and by Taipei City Hospital . This was an open, nonrandomized, and observational study.Participants were recruited from four outpatient MMT clinics in northern Taiwan during the years 2008 and 2009. Each patient at admission self-reported his/her history of drug use, and underwent morphine, HIV and HCV tests. Patients paid the associated medical costs of each MMT service utilized during his/her duration of treatment, including registration, diagnosis, various tests, prescription, medication as well as health education, with the exception of those who were HIV positive. Per Taiwan’s policy, HIV-positive patients were reimbursed for all medical costs from Taiwan Department of Health. Counseling and/or psychotherapy may be offered only on demand. The inclusion criteria in this study were age above 20 years, heroin dependence, and literacy. After signing a consent form, each patient was interviewed face-to-face by a trained research assistant at three times: baseline, 6 months into the study, and 12 months into the study. Each patient was reimbursed approximately 3 US dollars for each interview.Based on definition of quality of life, we used the World Health Organization Quality of Life Assessment-Brief Version (WHOQOL-BREF), which was developed to measure overall quality of life and general health status ,27. The The WHOQOL-BREF questionnaire uses a five-point Likert scale 1–5). Four types of scale descriptors  were selected for this study. Participants responded to questions according to their experience in the previous two weeks. Reverse items  were scored reversely. Domain scores for the WHOQOL-BREF are calculated by taking the mean of all items included in each domain and multiplying by a factor of four. The original domain scores were transformed to a scale of 0–100 according to the equation in the published guidelines . A high –5. Four t-test analyses were performed on categorical and continuous variables respectively to determine if there were significant differences between the two groups. Quality of life scores, age, age at first heroin use, education, methadone dose, and duration in treatment in this study met the normality assumption. To better estimate the associations among the four domains of the quality of life between assessment waves, repeated measures analyses of variance (ANOVA) with a 0.05 significance level for longitudinal evaluations were performed to examine changes on the four domains simultaneously while controlling for age, education, gender, age at first heroin use, methadone dose and days stayed in MMT.Descriptive statistics were used to identify the characteristics of the entire sample and the two groups of patients who stayed in or dropped out of MMT during the 6-month study period. Chi-square and A total of 599 patients who enrolled in an MMT program for an average of 184 days signed the consent form and 46 did not go through the baseline assessment. Of the 553 of those who completed baseline assessment, 285 and 155 remained in the study each for 6 and 12 months.t-test analysis was found for gender, age, marital status, education, age at first heroin use, HIV, HCV, whether morphine was tested positive at baseline, methadone dose at treatment admission, employment, and number of days enrolled in the MMT before enrollment in this study.Table SD = 15.51) and the lowest mean score was in the psychological domain . Likewise, at 6 months, the highest mean score was in the physical domain  and the lowest was in the psychological domain .Table F = 3.66, p < .01, and the environmental domain, F = 2.68, p < .01. When the gained quality of life scores were divided by the total MMT cost (approximately 1179.7 US dollars) that a patient had to pay in the year of 2009 , the greatest mean increases in QoL scores were in the psychological domain: baseline to 6 months (2.84) and baseline to 12 months (3.95). In the social domain, the corresponding mean increases were 1.27 from baseline to 6 months and 3.02 from baseline to 12-months. The lowest increase (1.58) was in the physical domain from baseline to 12 months.Results from repeated measures analyses of variance of baseline, 6-month and 12-month follow-ups also showed that age, education, gender, age at first heroin use, methadone dose and days in MMT before study were also not significantly associated with changes of quality of life. Table F = 2.35, p < .01, and in the environmental domain, F = 2.00, p < .01. From baseline to 12 months, there were significant improvements in the psychological domain, F = 3.05, p < .01,and in the social domain, F = 1.95, p < .01).Table The gains in quality of life and cost per QoL point gained are also presented in Table n = 285) showed statistically significant improvement in their quality of life in the psychological and environmental domains. Similar positive effects were found in patients who stayed in the program for 12 months (n = 155), indicating that these patients showed significant improvement in their psychological health and social relationships.This study examined long-term self-reported improvement in the quality of life of heroin patients in a MMT in Taiwan. Employing a longitudinal design, we found that the MMT improved patients’ quality of life in psychological, social relations, and environmental but not physical domain, as recorded at 6 and 12 months. Specifically, patients who stayed in the program for 6 months , and that MMT has been shown to be effective in reducing patients’ drug dependence, it follows that MMT should be considered a viable way to control and prevent the adverse consequences associated with drug abuse. Further, the costs of MMT are small compared with the social costs of criminal activity, loss of productive employment, and subsequent health care utilization on the part of active drug users. To reduce these drug-related economic losses, public policy makers should consider either completely subsidizing MMT or regulating it as a treatment for compulsive drug users.This study employed a single-group prospective design which has methodological limitations in terms of causal inferences. First, we did not compare heroin users with a control group not in the MMT. The efficacy of MMT observed in this study may need to take threats of internal validity into consideration and, namely, the positive outcomes may be caused by other factors such as maturation, testing, and sample selection bias. Second, participant attrition has been shown to limit the generalizability of a study’s findings. Despite the large attrition rate in our study, no significant differences in demographics or clinical characteristics were found between individuals who completed at least 6 months of the study and those who dropped out before that. This outcome suggests that our findings are still valid. Third, the data were gathered through patient self-reports, where social desirability may be an issue. Future study may adopt alternative assessment strategies to maximize the disclosure of sensitive information; for example, ACASI – audio computer-assisted self-interview may be used to collect sensitive information. However, it is becoming increasingly important in the treatment of chronic diseases to use subjective quality of life measures as an outcome index.Another limitation of our study is that the MMT costs listed in the Table The results of the present study have important clinical implications for treating and retaining patients in MMT, particularly with respect to quality of life. Current clinical practice of MMT rarely implements the treatment and assessment of life of quality. Thus, we propose: 1) in addition to reduction in opioid drug use and HIV risk behavior, improvement in long-term quality of life can be of importance as an indicator of treatment outcome measure; 2) to carefully re-evaluate methadone maintenance dose prescribed in Taiwan. Previous study showed that higher methadone dose and longer duration of treatment were associated with better quality of life in MMT patients . Higher The authors declare that they have no competing interests.YCC draft the manuscript and analyze the data; SFS and WDT contributed to the analysis, interpretation of the data and assisted in writing of manuscript; CRL contribute to the conceptual framework and interpretation of the results. KX assisted in interpretation of results. TSHL led research implementation and contribute to the conceptual framework, data acquisition, analysis and interpretation of the data for this manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/190/prepub