Determinants of vascular cognitive impairment : White matter lesions, brain atrophy and their neuropsychological correlates

The concept of vascular cognitive impairment (VCI) covers a wide spectrum of cognitive dysfunctions related to cerebrovascular disease. Among the pathophysiological determinants of VCI are cerebral stroke, white matter lesions and brain atrophy, which are known to be important risk factors for dementia. However, the specific mechanisms behind the brain abnormalities and cognitive decline are still poorly understood. The present study investigated the neuropsychological correlates of particular magnetic resonance imaging (MRI) findings, namely, medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), general cortical atrophy and corpus callosum (CC) atrophy in subjects with cerebrovascular disease. Furthermore, the cognitive profile of subcortical ischaemic vascular disease (SIVD) was examined. This study was conducted as part of two large multidisciplinary study projects, the Helsinki Stroke Aging Memory (SAM) Study and the multinational Leukoaraiosis and Disability (LADIS) Study. The SAM cohort consisted of 486 patients, between 55 and 85 years old, with ischaemic stroke from the Helsinki University Hospital, Helsinki, Finland. The LADIS Study included a mixed sample of subjects (n=639) with age-related WMH, between 65 and 84 years old, gathered from 11 centres around Europe. Both studies included comprehensive clinical and neuropsychological assessments and detailed brain MRI. The relationships between the MRI findings and the neuropsychological test performance were analysed by controlling for relevant confounding factors such as age, education and other coexisting brain lesions. The results revealed that in elderly patients with ischaemic stroke, moderate to severe MTA was specifically related to impairment of memory and visuospatial functions, but mild MTA had no clinical relevance. Instead, WMH were primarily associated with executive deficits and mental slowing. These deficits mediated the relationship between WMH and other, secondary cognitive deficits. Cognitive decline was best predicted by the overall degree of WMH, whereas the independent contribution of regional WMH measures was low. Executive deficits were the most prominent cognitive characteristic in SIVD. Compared to other stroke patients, the patients with SIVD also presented more severe memory deficits, which were related to MTA. The cognitive decline in SIVD occurred independently of depressive symptoms and, relative to healthy control subjects, it was substantial in severity. In stroke patients, general cortical atrophy also turned out to be a strong predictor of cognitive decline in a wide range of cognitive domains. Moreover, in elderly subjects with WMH, overall CC atrophy was related to reduction in mental speed, while anterior CC atrophy was independently associated with frontal lobe-mediated executive functions and attention. The present study provides cross-sectional evidence for the involvement of WMH, MTA, general cortical atrophy and CC atrophy in VCI. The results suggest that there are multifaceted pathophysiological mechanisms behind VCI in the elderly, including both vascular ischaemic lesions and neurodegenerative changes. The different pathological changes are highly interrelated processes and together they may produce cumulative effects on cognitive decline.

Cognitive deficits and the Paced Auditory Serial Addition Test performance among patients with multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system, characterized especially by myelin and axon damage. Cognitive impairment in MS is common but difficult to detect without a neuropsychological examination. Valid and reliable methods are needed in clinical practice and research to detect deficits, follow their natural evolution, and verify treatment effects. The Paced Auditory Serial Addition Test (PASAT) is a measure of sustained and divided attention, working memory, and information processing speed, and it is widely used in MS patients neuropsychological evaluation. Additionally, the PASAT is the sole cognitive measure in an assessment tool primarly designed for MS clinical trials, the Multiple Sclerosis Functional Composite (MSFC). The aims of the present study were to determine a) the frequency, characteristics, and evolution of cognitive impairment among relapsing-remitting MS patients, and b) the validity and reliability of the PASAT in measuring cognitive performance in MS patients. The subjects were 45 relapsing-remitting MS patients from Seinäjoki Central Hospital, Department of Neurology and 48 healthy controls. Both groups underwent comprehensive neuropsychological assessments, including the PASAT, twice in a one-year follow-up, and additionally a sample of 10 patients and controls were evaluated with the PASAT in serial assessments five times in one month. The frequency of cognitive dysfunction among relapsing-remitting MS patients in the present study was 42%. Impairments were characterized especially by slowed information processing speed and memory deficits. During the one-year follow-up, the cognitive performance was relatively stable among MS patients on a group level. However, the practice effects in cognitive tests were less pronounced among MS patients than healthy controls. At an individual level the spectrum of MS patients cognitive deficits was wide in regards to their characteristics, severity, and evolution. The PASAT was moderately accurate in detecting MS-associated cognitive impairment, and 69% of patients were correctly classified as cognitively impaired or unimpaired when comprehensive neuropsychological assessment was used as a "gold standard". Self-reported nervousness and poor arithmetical skills seemed to explain misclassifications. MS-related fatigue was objectively demonstrated as fading performance towards the end of the test. Despite the observed practice effect, the reliability of the PASAT was excellent, and it was sensitive to the cognitive decline taking place during the follow-up in a subgroup of patients. The PASAT can be recommended for use in the neuropsychological assessment of MS patients. The test is fairly sensitive, but less specific; consequently, the reasons for low scores have to be carefully identified before interpreting them as clinically significant.

Cognitive Functioning in Young Adults with Depression, Anxiety Disorders, or Burnout Symptoms : Findings from a Population-based Sample

Background. Evidence of cognitive dysfunction in depressive and anxiety disorders is growing. However, the neuropsychological profile of young adults has received only little systematic investigation, although depressive and anxiety disorders are major public health problems for this age group. Available studies have typically failed to account for psychiatric comorbidity, and samples derived from population-based settings have also seldom been investigated. Burnout-related cognitive functioning has previously been investigated in only few studies, again all using clinical samples and wide age groups. Aims. Based on the information gained by conducting a comprehensive review, studies on cognitive impairment in depressive and anxiety disorders among young adults are rare. The present study examined cognitive functioning in young adults with a history of unipolar depressive or anxiety disorders in comparison to healthy peers, and associations of current burnout symptoms with cognitive functioning, in a population-based setting. The aim was also to determine whether cognitive deficits vary as a function of different disorder characteristics, such as severity, psychiatric comorbidity, age at onset, or the treatments received. Methods. Verbal and visual short-term memory, verbal long-term memory and learning, attention, psychomotor processing speed, verbal intelligence, and executive functioning were measured in a population-based sample of 21-35 year olds. Performance was compared firstly between participants with pure non-psychotic depression (n=68) and healthy peers (n=70), secondly between pure (n=69) and comorbid depression (n=57), and thirdly between participants with anxiety disorders (n=76) and healthy peers (n=71). The diagnostic procedure was based on the SCID interview. Fourthly, the associations of current burnout symptoms, measured with the Maslach Burnout Inventory General Survey, and neuropsychological test performance were investigated among working young adults (n=225). Results. Young adults with depressive or anxiety disorders, with or without psychiatric comorbidity, were not found to have major cognitive impairments when compared to healthy peers. Only mildly compromised verbal learning was found among depressed participants. Pure and comorbid depression groups did not differ in cognitive functioning, either. Among depressed participants, those who had received treatment showed more impaired verbal memory and executive functioning, and earlier onset corresponded with more impaired executive functioning. In anxiety disorders, psychotropic medication and low psychosocial functioning were associated with deficits in executive functioning, psychomotor processing speed, and visual short-term memory. Current burnout symptoms were associated with better performance in verbal working memory and verbal intelligence. However, lower examiner-rated social and occupational functioning was associated with problems in verbal attention, memory, and learning. Conclusions. Depression, anxiety disorders, or burnout symptoms may not be associated with major cognitive deficits among young adults derived from the general population. Even psychiatric comorbidity may not aggravate cognitive functioning in depressive or anxiety disorders among these young adults. However, treatment-seeking in depression was found to be associated with cognitive deficits, suggesting that these deficits relate to increased distress. Additionally, early-onset depression, found to be associated with executive dysfunction, may represent a more severe form of the disorder. In anxiety disorders, those with low symptom-related psychosocial functioning may have cognitive impairment. An association with self-reported burnout symptoms and cognitive deficits was not detected, but individuals with low social and occupational functioning may have impaired cognition.

The scientific basis and development of a matrix metalloproteinase (MMP) -8 specific chair-side test for monitoring of periodontal health and disease from gingival crevicular fluid

Matrix metalloproteinase (MMP) -8, collagenase-2, is a key mediator of irreversible tissue destruction in chronic periodontitis and detectable in gingival crevicular fluid (GCF). MMP-8 mostly originates from neutrophil leukocytes, the first line of defence cells which exist abundantly in GCF, especially in inflammation. MMP-8 is capable of degrading almost all extra-cellular matrix and basement membrane components and is especially efficient against type I collagen. Thus the expression of MMP-8 in GCF could be valuable in monitoring the activity of periodontitis and possibly offers a diagnostic means to predict progression of periodontitis. In this study the value of MMP-8 detection from GCF in monitoring of periodontal health and disease was evaluated with special reference to its ability to differentiate periodontal health and different disease states of the periodontium and to recognise the progression of periodontitis, i.e. active sites. For chair-side detection of MMP-8 from the GCF or peri-implant sulcus fluid (PISF) samples, a dip-stick test based on immunochromatography involving two monoclonal antibodies was developed. The immunoassay for the detection of MMP-8 from GCF was found to be more suitable for monitoring of periodontitis than detection of GCF elastase concentration or activity. Periodontally healthy subjects and individuals suffering of gingivitis or of periodontitis could be differentiated by means of GCF MMP-8 levels and dipstick testing when the positive threshold value of the MMP-8 chair-side test was set at 1000 µg/l. MMP-8 dipstick test results from periodontally healthy and from subjects with gingivitis were mainly negative while periodontitis patients sites with deep pockets ( 5 mm) and which were bleeding on probing were most often test positive. Periodontitis patients GCF MMP-8 levels decreased with hygiene phase periodontal treatment (scaling and root planing, SRP) and even reduced during the three month maintenance phase. A decrease in GCF MMP-8 levels could be monitored with the MMP-8 test. Agreement between the test stick and the quantitative assay was very good (κ = 0.81) and the test provided a baseline sensitivity of 0.83 and specificity of 0.96. During the 12-month longitudinal maintenance phase, periodontitis patients progressing sites (sites with an increase in attachment loss ≥ 2 mm during the maintenance phase) had elevated GCF MMP-8 levels compared with stable sites. General mean MMP-8 concentrations in smokers (S) sites were lower than in non-smokers (NS) sites but in progressing S and NS sites concentrations were at an equal level. Sites with exceptionally and repeatedly elevated MMP-8 concentrations during the maintenance phase were clustered in smoking patients with poor response to SRP (refractory patients). These sites especially were identified by the MMP-8 test. Subgingival plaque samples from periodontitis patients deep periodontal pockets were examined by polymerase chain reaction (PCR) to find out if periodontal lesions may serve as a niche for Chlamydia pneumoniae. Findings were compared with the clinical periodontal parameters and GCF MMP-8 levels to determine the correlation with periodontal status. Traces of C. pneumoniae were identified from one periodontitis patient s pooled subgingival plaque sample by means of PCR. After periodontal treatment (SRP) the sample was negative for C. pneumoniae. Clinical parameters or biomarkers (MMP-8) of the patient with the positive C. pneumoniae finding did not differ from other study patients. In this study it was concluded that MMP-8 concentrations in GCF of sites from periodontally healthy individuals, subjects with gingivitis or with periodontitis are at different levels. The cut-off value of the developed MMP-8 test is at an optimal level to differentiate between these conditions and can possibly be utilised in identification of individuals at the risk of the transition of gingivitis to periodontitis. In periodontitis patients, repeatedly elevated GCF MMP-8 concentrations may indicate sites at risk of progression of periodontitis as well as patients with poor response to conventional periodontal treatment (SRP). This can be monitored by MMP-8 testing. Despite the lower mean GCF MMP-8 concentrations in smokers, a fraction of smokers sites expressed very high MMP-8 concentrations together with enhanced periodontal activity and could be identified with MMP-8 specific chair-side test. Deep periodontal lesions may be niches for non-periodontopathogenic micro-organisms with systemic effects like C. pneumoniae and possibly play a role in the transmission from one subject to another.

Refractive surgery for iatrogenic and congenital anisometropia and mild visual impairment

In anisometropia, the two eyes have unequal refractive power. Anisometropia is a risk factor for amblyopia. The visual deficiencies are thought to be irreversible after the first decade of life. There is, however, accumulating evidence that neural plasticity exists also in adult brains. The aim of this study was to investigate functional outcome of excimer laser refractive surgery in adult anisometropic and visually impaired patients. Additional goal was to examine changes in the primary visual cortex (V1) using multifocal functional magnetic resonance imaging (mffMRI) after laser refractive surgery. Study I comprised of 57 anisometropic patients (anisometropia of ≥3.25 diopters) and 174 isometropic myopic subjects formed the control group. A significant improvement in best-spectacle-corrected visual acuity (BSCVA) among myopic control subjects was evident 3 months postoperatively. The improvement in BSCVA was significantly slower for anisometropic patients and the improvement appeared to persist to the end of the follow-up (24 months). In study II we found that refractive surgery may be also successfully used for iathrogenic anisometropia. In Study III we evaluated mildly visually impaired adult patients after refractive surgery. There was a statistically significant improvement in BSCVA among visually impaired patients and the difference in the mean BSCVA between visually impaired patients and isometropic myopic control subjects diminished during follow-up. Study IV was a prospective follow-up trial examining the changes in the primary visual cortex after refractive surgery. Two anisometropic patients and two isometropic myopic patients were examined with a 61-region mffMRI before refractive surgery and at three, six, nine and twelve months postoperatively. In this study, a dramatic decrease in the number of active voxels in the fovea was found among anisometropic patients. The results presented in this thesis revealed that refractive surgery may be successfully used for the treatment of anisometropic adults with both congenital and iatrogenic anisometropia and for mildly visually impaired adults. The findings in conclusion strengthen our hypothesis of plastic changes in the visual cortex of adult anisometropic and mildly visually impaired patients after refractive surgery.

Therapeutic hypothermia after cardiac arrest : Studies on neurological and cardiological outcome and prediction of outcome in hypothermia-treated patients resuscitated from out-of-hospital cardiac arrest

The outcome of the successfully resuscitated patient is mainly determined by the extent of hypoxic-ischemic cerebral injury, and hypothermia has multiple mechanisms of action in mitigating such injury. The present study was undertaken from 1997 to 2001 in Helsinki as a part of the European multicenter study Hypothermia after cardiac arrest (HACA) to test the neuroprotective effect of therapeutic hypothermia in patients resuscitated from out-of-hospital ventricular fibrillation (VF) cardiac arrest (CA). The aim of this substudy was to examine the neurological and cardiological outcome of these patients, and especially to study and develop methods for prediction of outcome in the hypothermia-treated patients. A total of 275 patients were randomized to the HACA trial in Europe. In Helsinki, 70 patients were enrolled in the study according to the inclusion criteria. Those randomized to hypothermia were actively cooled externally to a core temperature 33 ± 1ºC for 24 hours with a cooling device. Serum markers of ischemic neuronal injury, NSE and S-100B, were sampled at 24, 36, and 48 hours after CA. Somatosensory and brain stem auditory evoked potentials (SEPs and BAEPs) were recorded 24 to 28 hours after CA; 24-hour ambulatory electrocardiography recordings were performed three times during the first two weeks and arrhythmias and heart rate variability (HRV) were analyzed from the tapes. The clinical outcome was assessed 3 and 6 months after CA. Neuropsychological examinations were performed on the conscious survivors 3 months after the CA. Quantitative electroencephalography (Q-EEG) and auditory P300 event-related potentials were studied at the same time-point. Therapeutic hypothermia of 33ºC for 24 hours led to an increased chance of good neurological outcome and survival after out-of-hospital VF CA. In the HACA study, 55% of hypothermia-treated patients and 39% of normothermia-treated patients reached a good neurological outcome (p=0.009) at 6 months after CA. Use of therapeutic hypothermia was not associated with any increase in clinically significant arrhythmias. The levels of serum NSE, but not the levels of S-100B, were lower in hypothermia- than in normothermia-treated patients. A decrease in NSE values between 24 and 48 hours was associated with good outcome at 6 months after CA. Decreasing levels of serum NSE but not of S-100B over time may indicate selective attenuation of delayed neuronal death by therapeutic hypothermia, and the time-course of serum NSE between 24 and 48 hours after CA may help in clinical decision-making. In SEP recordings bilaterally absent N20 responses predicted permanent coma with a specificity of 100% in both treatment arms. Recording of BAEPs provided no additional benefit in outcome prediction. Preserved 24- to 48-hour HRV may be a predictor of favorable outcome in CA patients treated with hypothermia. At 3 months after CA, no differences appeared in any cognitive functions between the two groups: 67% of patients in the hypothermia and 44% patients in the normothermia group were cognitively intact or had only very mild impairment. No significant differences emerged in any of the Q-EEG parameters between the two groups. The amplitude of P300 potential was significantly higher in the hypothermia-treated group. These results give further support to the use of therapeutic hypothermia in patients with sudden out-of-hospital CA.

Evaluation of Vestibular Function with Visual Feedback Posturography and Motorized Head Impulse Test.

Objectives: To evaluate the applicability of visual feedback posturography (VFP) for quantification of postural control, and to characterize the horizontal angular vestibulo-ocular reflex (AVOR) by use of a novel motorized head impulse test (MHIT). Methods: In VFP, subjects standing on a platform were instructed to move their center of gravity to symmetrically placed peripheral targets as fast and accurately as possible. The active postural control movements were measured in healthy subjects (n = 23), and in patients with vestibular schwannoma (VS) before surgery (n = 49), one month (n = 17), and three months (n = 36) after surgery. In MHIT we recorded head and eye position during motorized head impulses (mean velocity of 170º/s and acceleration of 1 550º/s²) in healthy subjects (n = 22), in patients with VS before surgery (n = 38) and about four months afterwards (n = 27). The gain, asymmetry and latency in MHIT were calculated. Results: The intraclass correlation coefficient for VFP parameters during repeated tests was significant (r = 0.78-0.96; p < 0.01), although two of four VFP parameters improved slightly during five test sessions in controls. At least one VFP parameter was abnormal pre- and postoperatively in almost half the patients, and these abnormal preoperative VFP results correlated significantly with abnormal postoperative results. The mean accuracy in postural control in patients was reduced pre- and postoperatively. A significant side difference with VFP was evident in 10% of patients. In the MHIT, the normal gain was close to unity, the asymmetry in gain was within 10%, and the latency was a mean ± standard deviation 3.4 ± 6.3 milliseconds. Ipsilateral gain or asymmetry in gain was preoperatively abnormal in 71% of patients, whereas it was abnormal in every patient after surgery. Preoperative gain (mean ± 95% confidence interval) was significantly lowered to 0.83 ± 0.08 on the ipsilateral side compared to 0.98 ± 0.06 on the contralateral side. The ipsilateral postoperative mean gain of 0.53 ± 0.05 was significantly different from preoperative gain. Conclusion: The VFP is a repeatable, quantitative method to assess active postural control within individual subjects. The mean postural control in patients with VS was disturbed before and after surgery, although not severely. Side difference in postural control in the VFP was rare. The horizontal AVOR results in healthy subjects and in patients with VS, measured with MHIT, were in agreement with published data achieved using other techniques with head impulse stimuli. The MHIT is a non-invasive method which allows reliable clinical assessment of the horizontal AVOR.

Specific language impairment in pre-adolescence, adolescence, and adulthood with special emphasis on health-related quality of life

This clinical study focused on effects of childhood specific language impairment (SLI) on daily functioning in late life. SLI is a neurobiological disorder with genetic predisposition and manifests as poor language production or comprehension or both in a child with age-level non-verbal intelligence and no other known cause for deficient language development. The prevalence rate of around 7% puts it among the most prevalent developmental disorders in childhood. Negative long-term effects, such as problems in learning and behavior, are frequent. In follow-up studies the focus has seldom been on self-perception of daily functioning and participation, which are considered important in the International Classification of Functioning, Disability, and Health (ICF). To investigate the self-perceived aspects of everyday functioning in individuals with childhood receptive SLI compared with age- and gender-matched control populations, the 15D, 16D, and 17D health-related quality of life (HRQoL) questionnaires were applied. These generic questionnaires include 15, 16, and 17 dimensions, respectively, and give both a single index score and a profile with values on each dimension. Information on different life domains (rehabilitation, education, employment etc.) from each age-group was collected with separate questionnaires. The study groups comprised adults, adolescents (12-16 years), and pre-adolescents (8-11 years) who had received a diagnosis of receptive SLI and had been examined, usually before school age, at the Department of Phoniatrics of Helsinki University Central Hospital, where children with language deficits caused by various etiologies are examined and treated by a multidisciplinary team. The adult respondents included 33 subjects with a mean age of 34 years. Measured with 15D, the subjects perceived their HRQoL to be nearly as good as that of their controls, but on the dimensions of speech, usual activities, mental functioning, and distress they were significantly worse off. They significantly more often lived with their parents (19%) or were pensioned (26%) than the adult Finnish population on average. Adults with self-perceived problems in finding words and in remembering instructions, manifestations of persistent language impairment, showed inferior every day functioning to the rest of the study group. Of the adolescents and pre-adolescents, 48 and 51, respectively, responded. The majority in both groups had received special education or extra educational support at school. They all had attended speech therapy at some point; at the time of the study only one adolescent, but every third pre-adolescent still received speech therapy. The 16D score of the adolescent or the 17D score of the pre-adolescents did not differ from that of their controls. The 16D profiles differed on some dimensions; subjects were significantly worse off on the dimension of mental functioning, but better off on the dimension of vitality than controls. Of the 17D dimensions, the study group was significantly worse off on speech, whereas the control group reported significantly more problems in sleeping. Of the childhood performance measures investigated, low verbal intelligence quotient (VIQ), which is often considered to reflect receptive language impairment, was in adults subjects significantly associated with some of the self-perceived problems, such as problems in usual activities and mental functioning. The 15D, 16D, and 17D questionnaires served well in measuring self-perceived HRQoL. Such standardized measures with population values are especially important in confirming with the ICF guidelines. In the future these questionnaires could perhaps be used on a more individual level in follow-up of children in clinics, and even in special schools and classes, to detect those children at greatest risk of negative long-term effects and perhaps diminished well-being regarding daily functioning and participation.

Visual Impairment in Finnish Children : Prevalence, causes and morbidity of full-term and preterm children with visual impairment born from 1972 through 1989

The prevalence and the causes of childhood visual impairment in Finland during the 1970s and the 1980s were investigated, with special attention to risk factors and further prevention of visual impairment in children. The primary data on children with visual impairment were obtained from the Finnish Register of Visual Impairment, one of the patient registers kept up by the National Research and Development Centre for Welfare and Health (Stakes). The data were supplemented from other registers in Stakes and from patient records of the children in Finnish central hospitals. Visual impairment had been registered in 556 children from a population of 1,138,326 children between ages 0-17, born from 1972 through 1989. The age-specific prevalence of registered visual impairment was 49/100,000 in total. Of them, 23/100,000 were blind children and 11/100,000 were children born prematurely. Boys were impaired more often and more severely than girls. Congenital malformations (52%), systemic diseases (48%), and multiple impairments (50%) were common. The main ophthalmic groups of visual impairment were retinal diseases (35%), ocular malformations (29%), and neuro-ophthalmological disorders (29%). Optic nerve atrophy was the most common diagnosis of visual impairment (22%), followed by congenital cataract (11%), retinopathy of prematurity (10%), and cerebral visual impairment (8%). Genetic factors (42%) were the most common etiologies of visual impairment, followed by prenatal (30%) and perinatal (21%) factors. The highest rates of blindness were seen in cerebral visual impairment (83%) and retinopathy of prematurity (82%). Retinopathy of prematurity had developed in the children born at a gestational age of 32 weeks or earlier. Significant risks for visual impairment were found in the association with preterm births, prenatal infections, birth asphyxia, neonatal respiratory difficulties, mechanical ventilation lasting over two weeks, and hyperbilirubinemia. A rise in blind and multi-impaired children was seen during the study period, associating with increases in the survival of preterm infants with extremely low birth weight. The incidence of visual impairment in children born prematurely was seven times higher than in children born at full term. A reliable profile of childhood visual impairment was obtained. The importance of highly qualified antenatal, neonatal, and ophthalmological care was clearly proved. The risks associated with pre- and perinatal disorders during pregnancy must be emphasized, e.g. the risks associated with maternal infections and the use of tobacco, alcohol, and drugs during pregnancy. Obvious needs for gene therapies and other new treatments for hereditary diseases were also proved.

Depression and Cognition in Type 2 Diabetes from a Life Course Perspective

Background: Type 2 diabetes is linked to several complications which add to both physical and mental distress. Depression is a common co-morbidity of diabetes which can occur both as a cause and a consequence of type 2 diabetes. Depression has been shown to correlate with glucose regulation and treating depression might prove beneficial for glucose regulation as well as for mental well being. Another complication which might affect diabetes management is cognitive decline. Several risk factors and complications of diabetes might modify the risk for developing cognitive impairment, which is increased 1.5 times among subjects with type 2 diabetes. Type 2 diabetes, depression and impaired cognitive performance have all been linked to low birth weight. This thesis aimed to explore the effects and interactions of birth weight, depression and cognitive ability in relation to type 2 diabetes from a life course perspective. Subjects and methods: Studies I, II and V were part of the Helsinki Birth Cohort Study. 2003 subjects participated in an extensive clinical examination at an average age of 61 years. A standard glucose tolerance test (OGTT) was performed and depressive symptoms were assessed using the Beck Depression Inventory (BDI). In addition data was obtained from child welfare clinics and national registers. A subset of the cohort (n=1247) also performed a test on cognitive performance (CogState ®) at the average age of 64. Studies III and IV were randomised clinical trials where mildly depressed diabetic subjects were treated with paroxetine or placebo and the effect on metabolic parameters and quality of life was assessed. The first trial included 14 women and lasted 10 weeks, while the second trial included 43 subjects, both men and women, and lasted 6 months. Results: Type 2 diabetes was positively associated with the occurrence of depressive symptoms. Among diabetic subjects 23.6% had depressive symptoms, compared to 16.7% of subjects with normal glucose tolerance (OR = 1.77, p<0.001). Formal mediation analysis revealed that cardiovascular disease (CVD) is likely to act as a mediator in the association. Furthermore, low birth weight was found to modify the association between type 2 diabetes, CVD and depression. The association between BDI score and having type 2 diabetes or CVD was twice as strong in the subgroup with low birth weight (≤ 2500g) compared with the group with birth weight > 2500g (p for interaction 0.058). In the six months long randomised clinical trial (study IV) paroxetine had a transient beneficial effect on glycosylated haemoglobin A1c (GHbA1c) and quality of life when compared to placebo after three months of treatment. In study V we found that subjects with known diabetes had a consistently poorer level of cognitive performance than subjects with normal glucose tolerance in most of the tested cognitive domains. This effect was further amplified among those born with a small birth weight (p for interaction 0.002). Conclusions: Type 2 diabetes is associated with a higher occurrence of depressive symptoms compared to subjects with normal glucose tolerance. This association is especially strong among subjects with CVD and those born with a low birth weight. Treating depressed diabetic subjects with paroxetine has no long term effect on glucose regulation. Physicians should be aware of depression as an important co-morbidity of type 2 diabetes. Both depression and the cognitive decline often seen among diabetic subjects are increased if the subject is born with a low birth weight. Physicians should recognise low birth weight as an additional risk factor and modifier of diabetic complications.

Test of the Clustering Hypothesis in the Helsinki Exchanges

This paper investigates the clustering pattern in the Finnish stock market. Using trading volume and time as factors capturing the clustering pattern in the market, the Keim and Madhavan (1996) and the Engle and Russell (1998) model provide the framework for the analysis. The descriptive and the parametric analysis provide evidences that an important determinant of the famous U-shape pattern in the market is the rate of information arrivals as measured by large trading volumes and durations at the market open and close. Precisely, 1) the larger the trading volume, the greater the impact on prices both in the short and the long run, thus prices will differ across quantities. 2) Large trading volume is a non-linear function of price changes in the long run. 3) Arrival times are positively autocorrelated, indicating a clustering pattern and 4) Information arrivals as approximated by durations are negatively related to trading flow.

Bootstrapping the Error Correction Model Cointegration Test

This paper is concerned with using the bootstrap to obtain improved critical values for the error correction model (ECM) cointegration test in dynamic models. In the paper we investigate the effects of dynamic specification on the size and power of the ECM cointegration test with bootstrap critical values. The results from a Monte Carlo study show that the size of the bootstrap ECM cointegration test is close to the nominal significance level. We find that overspecification of the lag length results in a loss of power. Underspecification of the lag length results in size distortion. The performance of the bootstrap ECM cointegration test deteriorates if the correct lag length is not used in the ECM. The bootstrap ECM cointegration test is therefore not robust to model misspecification.

Cognitive functioning and its heritability in bipolar I disorder

Bipolar I disorder is a severe psychiatric disorder characterized by episodic mood alterations that can be manic, depressive or mixed. Bipolar disorder seems to be highly genetic, but the etiology of this complex disorder has remained elusive. In recent years, studies have found that euthymic patients with bipolar disorder may have impairments particularly in executive functioning, verbal learning and memory. These impairments may be present also among some of the relatives of these patients, who may be vulnerable to the disorder. Using neuropsychological variables as endophenotypes, i.e. intermediate phenotypes between genes and the phenotypes, has been suggested to aid search for the etiological background of the disorder, but evidence is sparse on whether these variables fulfill the criteria for endophenotypes. The present thesis is part of the Genetic Epidemiology and Molecular Genetics of Severe Mental Disorders in Finland project. The specific aim was to investigate whether neuropsychological test variables would indicate genetic liability to the disorder and could therefore be regarded as endophenotypes. Thus, cognitive functions and their heritability were studied in bipolar I disorder patients and in their unaffected first-degree relatives from a population-based sample of families, comparing them to a population-based control group. In order to add homogeneity to the subgroups of bipolar disorder patients and their relatives, cognitive functions and their heritability were further studied in a group of families affected by bipolar I disorder only (bipolar families) and another group of families affected by both bipolar I disorder and schizophrenia or schizoaffective disorders (mixed families). Finally, the effect of processing speed on other cognitive functions was investigated. The study showed that especially executive functioning and processing speed fulfilled the endophenotype criteria. Impairments in these functions were found in bipolar patients and in their relatives irrespective of other severe psychopathology in the family. These functions were highly heritable in these families. Study also showed that generalized impairment in verbal memory may associate more with bipolar disorder than to vulnerability to other psychotic disorders, and be more related to fully developed disease; impairments in verbal learning and memory were found only in patients, and they were not found to be highly heritable. Finally, the most potential endophenotype, i.e. processing speed, seemed to contribute to a range of other cognitive dysfunctions seen in bipolar disorder patients. Processing speed, in particular, has also been shown to be a valid endophenotype in subsequent association analyses in psychiatric genetics in Finland and internationally. Information concerning cognitive impairments and their association with the psychosocial consequences of bipolar disorder is important in planning treatment. It is also important to understand and acknowledge that patients may have cognitive impairments that affect their everyday life. Psychosocial interventions and neuropsychological rehabilitation may supplement other conventional treatments for bipolar patients.