Assessing impairment of executive function and psychomotor speed in premanifest and manifest Huntington's disease gene-expansion carriers.

Executive functions (EF) and psychomotor speed (PMS) has been widely studied in Huntington's disease (HD). Most studies have focused on finding markers of disease progression by comparing group means at different disease stages. Our aim was to investigate performances on nine measures of EF and PMS in a group of premanifest and manifest HD-gene expansion carriers and to investigate which measures were most sensitive for assessment of individual patients by analyzing frequencies of impaired performances relative to healthy controls. We recruited HD gene-expansion carriers, 48 manifest and 50 premanifest and as controls 39 healthy gene-expansion negative individuals. All participants underwent neurological examination and neuropsychological testing with nine cognitive measures. The frequency of impairment was investigated using cutoff scores. In group comparisons the manifest HD gene-expansion carriers scored significantly worse than controls on all tests and in classification of individual scores the majority of scores were classified as probably impaired (10th percentile) or impaired (5th percentile) with Symbol Digit Modalities Test (SDMT) being the most frequently impaired. Group comparisons of premanifest HD gene-expansion carriers and healthy controls showed significant differences on SDMT and Alternating fluency tests. Nevertheless the frequencies of probably impaired and impaired scores on individual tests were markedly higher for Alternating and Lexical fluency tests than for SDMT. We found distinct group differences in frequency of impairment on measures of EF and PMS in manifest and premanifest HD gene-expansion carriers. Our results indicate to what degree these measures can be expected to be clinically impaired.

Neuroticism in Remitted Major Depression: Elevated with Early Onset but Not Late Onset of Depression.

BACKGROUND: The personality trait of neuroticism is strongly related to depression, but depression is etiologically heterogeneous. Late-onset depression (LOD) may be more closely related to vascular factors, and previous studies of neuroticism in LOD versus early-onset depression (EOD) have not been consistent. METHOD: We examined neuroticism, extraversion and perceived stress in 88 fully remitted depressed patients with a mean age of 60 years and with a history of hospitalization for major depressive disorder. Patients were divided into those with onset after and those with onset before 50 years of age (LOD and EOD, respectively), and the two groups were compared both with each other and with matched control groups of healthy subjects. RESULTS: EOD patients showed increased levels of neuroticism in comparison with both LOD and matched controls, who did not differ. The association between age of onset and neuroticism was confirmed in analyses based on age of depression onset as a continuous variable. CONCLUSION: Neuroticism may be an etiological factor in EOD but not or less so in LOD. This finding contributes to the growing evidence for etiological differences between early- and late-onset late-life depression.

Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.

We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

Relationship of frontal D(2/3) binding potentials to cognition: a study of antipsychotic-naive schizophrenia patients.

Studies of in vivo dopamine receptors in schizophrenia have mostly focused on D(2) receptors in striatal areas or on D(1) receptors in cortex. No previous study has examined the correlation between cortical dopamine D(2/3) receptor binding potentials and cognition in schizophrenia patients. The objective was to examine this relation in the frontal cortex in first-episode, drug-naive schizophrenia patients. Based on preclinical and pharmacological evidence, we specifically expected to find a relation between D(2/3) receptor binding potentials and set shifting. This was a cross-sectional, case-control study using single-photon emission computerized tomography with the D(2/3)-receptor ligand [(123)I]epidepride, co-registered with structural magnetic resonance imaging and correlated to cognitive measures. Participants were 24 antipsychotic-naive, first-episode schizophrenia patients and 20 healthy controls matched for gender and age. For patients, a significant linear correlation between D(2/3) BP(ND) and set shifting was found, while significant quadratic associations were observed for verbal fluency, planning and attention. For controls, the only significant association with D(2/3) BP(ND) was a quadratic partial correlation for set shifting. The main findings indicated a relation between D(2/3) receptor binding in the frontal cortex and set shifting, planning and attention, but also support a differential involvement of cortical dopamine D(2/3) receptor binding in at least some cognitive functions, perhaps particularly attention, in schizophrenia patients compared to healthy people. The results suggest that cortical D(2/3) receptor function may be more involved in some cognitive functions (i.e. attention, fluency and planning) in patients with schizophrenia than in healthy people, suggesting that information processing in schizophrenia may be characterized by lower signal:noise ratios.

Cognitive impairment in the preclinical stage of dementia in FTD-3 CHMP2B mutation carriers: a longitudinal prospective study.

OBJECTIVE AND METHODS: A longitudinal study spanning over 8 years and including 17 asymptomatic individuals with CHMP2B mutations was conducted to assess the earliest neuropsychological changes in autosomal dominant neurodegenerative disease frontotemporal dementia (FTD) linked to chromosome 3 (FTD-3). Subjects were assessed with neuropsychological tests in 2002, 2005 and 2010. RESULTS: Cross-sectional analyses showed that the mutation carriers scored lower on tests of psychomotor speed, working memory, executive functions and verbal memory than a control group consisting of not-at-risk family members and spouses. Longitudinal analyses showed a gradual decline in psychomotor speed, working memory capacity and global executive measures in the group of non-demented mutation carriers that was not found in the control group. In contrast, there were no significant group differences in domain scores on memory or visuospatial functions. On an individual level the cognitive changes over time varied considerably. CONCLUSION: Subjects with CHMP2B mutation show cognitive changes dominated by executive dysfunctions, years before they fulfil diagnostic criteria of FTD. However, there is great heterogeneity in the individual cognitive trajectories.

Cognitive effects of six months of treatment with quetiapine in antipsychotic-naïve first-episode schizophrenia.

Effects of quetiapine on cognition were assessed in a group of first-episode antipsychotic-naïve patients with schizophrenia (N=24). A comprehensive battery of neuropsychological tests was administered at baseline and after 6 months of treatment with quetiapine. In order to examine retest effects, a matched healthy control group (N=24) was also tested at baseline and after 6 months. Only few differential changes were observed between patients and healthy controls. Of 8 cognitive domains examined, only significant changes in executive function suggested possible ameliorating effects of quetiapine. Patients also improved on speed of processing; however, this was parallel to the retest effects found in healthy controls. When covaried for differences at baseline, patients showed smaller improvements in speed of processing than the retest effects found in controls, as well as a lack of retest effects on sustained attention and working memory that were found in healthy controls. The main result of the study is that there was very little evidence of efficacy of quetiapine on cognition. The study also indicated a lack of normal retest effects in patients compared to controls.

Assessment of dementia in ethnic minority patients in Europe: a European Alzheimer's Disease Consortium survey.

BACKGROUND: In most European countries the ethnic minority migrant populations are currently reaching an age where dementia becomes an increasingly important issue. There is no European consensus on good clinical practice with these patient groups, who often have special needs and expectations with regard to dementia services. METHODS: A survey was conducted in clinical dementia centers in 15 European countries. Questionnaires focusing on different points in the clinical assessment of dementia in ethnic minority patients were mailed to leading dementia experts of the European Alzheimer's Disease Consortium. RESULTS: Thirty-six centers from 15 countries responded to the survey. Ethnic minority patients were seen on a regular basis in 69% of these centers. The diagnostic evaluation was in accordance with evidence-based clinical guidelines in 84-100% of the centers, but most centers performed cognitive assessment with instruments that are only validated in Western cultures and frequently relied on family members for interpretation. Diagnostic evaluation of the patients was considered to be challenging in 64% of the centers, mainly because of communication problems and lack of adequate assessment tools. In general, there were few indicators of culturally sensitive dementia services in the centers. CONCLUSIONS: Ethnic minority patients are seen on a regular basis in European dementia clinics. Assessment of such patients is difficult for a number of reasons. Results from this study show that the most challenging issues are communication problems and assessment of cognitive function where there is a need to develop specific tests for ethnic minority patients.

Suitable reverberation times for halls for rock and pop music.

The existing body of literature regarding the acoustic design of concert halls has focused almost exclusively on classical music, although there are many more performances of popular music, including rock and pop. Objective measurements were made of the acoustics of 20 rock music venues in Denmark and a questionnaire was used in a subjective assessment of those venues with professional rock musicians and sound engineers as expert listeners. Correlations between the measurements show that clarity, including bass frequencies down to 63 Hz, is important for the general impression of the acoustics of the hall. The best-rated halls in the study have reverberation times that are approximately frequency independent from 0.6 to 1.2 s for hall volumes from 1000 to 6000 m(3). The worst rated halls in the study had significantly higher reverberation times in the 63 and 125 Hz bands. Since most audiences at rock concerts are standing, absorption coefficients were measured with a standing audience from 63 Hz to 4 kHz. These measurements showed that a standing audience absorbs about five times as much energy in mid-/high-frequency bands as in low-frequency bands.

Increase in voice level and speaker comfort in lecture rooms.

Teachers often suffer from health problems related to their voice. These problems are related to their working environment, including the acoustics of the lecture rooms. However, there is a lack of studies linking the room acoustic parameters to the voice produced by the speaker. In this pilot study, the main goals are to investigate whether objectively measurable parameters of the rooms can be related to an increase in the voice sound power produced by speakers and to the speakers' subjective judgments about the rooms. In six different rooms with different sizes, reverberation times, and other physical attributes, the sound power level produced by six speakers was measured. Objective room acoustic parameters were measured in the same rooms, including reverberation time and room gain, and questionnaires were handed out to people who had experience talking in the rooms. It is found that in different rooms significant changes in the sound power produced by the speaker can be found. It is also found that these changes mainly have to do with the size of the room and to the gain produced by the room. To describe this quality, a new room acoustic quantity called "room gain" is proposed.

Social Cognition, Executive Functions and Self-Report of Psychological Distress in Huntington's Disease.

OBJECTIVE: Huntington's disease (HD) is characterized by motor symptoms, psychiatric symptoms and cognitive impairment in, inter alia, executive functions and social cognition. The aim of this study was to investigate the relationship between subjective feeling of psychological distress using a self-report questionnaire and performances on tests of executive functions and social cognition in a large consecutive cohort of HD patients. METHOD: 50 manifest HD patients were tested in social cognition and executive functions and each answered a self-report questionnaire about current status of perceived psychological distress (the Symptom Checklist-90-Revised (SCL-90-R)). Correlation analyses of test performance and SCL-90-R scores were made as well as stepwise linear regression analyses with the SCL-90-R GSI score and test performances as dependent variables. RESULTS: We found that less psychological distress was significantly associated with worse performances on social cognitive tests (mean absolute correlation .34) and that there were no significant correlations between perceived psychological distress and performance on tests of executive functions. The correlations between perceived psychological distress and performance on social cognitive tests remained significant after controlling for age, Unified Huntington's Disease Rating Scale-99 total motor score and performance on tests of executive functions. CONCLUSIONS: Based on previous findings that insight and apathy are closely connected and may be mediated by overlapping neuroanatomical networks involving the prefrontal cortex and frontostriatal circuits, we speculate that apathy/and or impaired insight may offer an explanation for the correlation between self-report of psychological distress and performance on social cognitive tests in this study.

Do I misconstrue? Sarcasm detection, emotion recognition, and theory of mind in Huntington disease.

OBJECTIVE: Emotion recognition has been widely studied in Huntington disease (HD), but only a few studies have investigated more complex social cognition and, when so, exclusively in manifest HD. The present study sought to investigate social-cognitive functions in a large, consecutive cohort of premanifest and manifest HD gene expansion carriers using tests assessing sarcasm detection, theory of mind (ToM), and emotion recognition. METHOD: Fifty manifest, 50 premanifest HD gene expansion carriers, and 39 at risk gene expansion negative healthy controls were included. All participants were tested with sarcasm detection, ToM, and emotion recognition tasks. Between-group comparisons of test performances and correlation analyses of test performances and disease burden scores were made. RESULTS: Group comparisons showed significant differences in performances on the social-cognitive tests between manifest HD gene expansion carriers and healthy controls, but differences in performances between premanifest HD gene expansion carriers and healthy controls were not statistically significant. Correlation analysis showed that the worse test performances were associated with higher disease burden scores in all HD gene expansion carriers. CONCLUSION: Our findings support a theory of impaired social-cognitive functions in the early stages of HD. Test performances decreased with increasing disease burden in all HD gene expansion carriers, suggesting that social-cognitive tests may be useful for tracking disease progression. Simple emotion recognition tasks are just as sensitive for measuring social-cognitive deficits as more complex measures, but knowledge of the quality of social-cognitive impairments in HD can be of great importance to both patients and caregivers.

The executive interview as a screening test for executive dysfunction in patients with mild dementia.

OBJECTIVES: To validate the Executive Interview (EXIT25) as a screening instrument for executive cognitive dysfunction in patients with mild dementia. DESIGN: Validation using group comparison and correlation studies. SETTING: The Copenhagen University Hospital Memory Clinic, a multidisciplinary outpatient clinic based in a neurological setting. PARTICIPANTS: Thirty-three patients with mild dementia (MMSE score > or =20) and 30 healthy controls. MEASUREMENTS: The EXIT25, a 25-item screening instrument for executive dysfunction, was administered to all participants. Global cognitive function was measured using the MMSE. Patients were evaluated using traditional neuropsychological tests for executive dysfunction (Wisconsin Card Sorting Test, Trail Making Part B, Stroop Test, verbal fluency, design fluency, and verbal abstraction). Changes in behavior and functional impairment in activities of daily living were assessed using the Frontal Behavioral Inventory (FBI) and the Disability Assessment for Dementia Scale. RESULTS: EXIT25 scores were significantly higher in patients than in the healthy controls; MMSE scores could not account for the differences. Thirteen of the 25 items separated the two groups. EXIT25 was found to correlate significantly with the Stroop Test, the verbal fluency tests, and the FBI. CONCLUSION: The EXIT25 is able to capture executive cognitive deficits not primarily related to the general level of intellectual reduction in patients with mild dementia. In clinical practice, the EXIT25 might be a valuable supplement to the MMSE.

Reduced regional cerebral blood flow in SPG4-linked hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) linked to the spastic gait gene 4 (SPG4) is controversial, as the "pure" form traditionally has been considered confined to the long axons of the spinal cord. However, recent immunolabeling experiments have demonstrated extensive Spastin expression in the cortex and striatum. This could indicate a more widespread neuropathology from mutations in the SPG4 gene than previously assumed. The aim of this study was therefore to ascertain the extent of cerebral involvement in SPG4 linked HSP by neuropsychological examination and measurement of the regional cerebral blood flow (rCBF) as an indirect marker of regional neuronal activity. Eighteen SPG4 patients and 18 matched control subjects were studied. Resting state rCBF was measured using Positron Emission Tomography (PET) and the (15)O-labelled water bolus technique and relative group differences were explored using Statistical Parametric Mapping (SPM 99). Neuropsychological assessment was performed using established and nationally validated tests (RH Basic Battery). Compared to healthy controls, the patient group had significantly decreased rCBF in the left fronto-temporal cortex (P<0.05), and more extensive changes were observed in a separate analysis of the most disabled individuals. The neuropsychological assessment revealed only significantly impaired recognition memory for faces. In summary, the findings support cerebral pathology in SPG4-linked HSP, although the decreased rCBF in fronto-temporal cortex was not associated with severe cognitive impairment.

Effects of low-dose risperidone and low-dose zuclopenthixol on cognitive functions in first-episode drug-naive schizophrenic patients.

BACKGROUND: Studies on the effects of antipsychotics on cognitive deficits in schizophrenia mostly suggest a superior effect of atypical over typical compounds, although findings are inconsistent and effect sizes small. Several methodological issues, such as heterogeneous patient samples, incomparable drug doses, effects of prior medication, construct validity, and retest effects on neuropsychological tasks, confound most results and the comparability between studies. Consequently, the conclusion concerning effects of antipsychotics on cognition is still equivocal. OBJECTIVE: The present randomized clinical trial examined the effects on cognition of comparatively low doses of a typical antipsychotic (zuclopenthixol) and an atypical antipsychotic (risperidone) in a homogeneous group of drug-naive first-episode schizophrenic patients in a longitudinal setting. METHODS: First-episode schizophrenic patients who had never previously been exposed to antipsychotic treatment (N=25) were randomly allocated to treatment with flexible doses of zuclopenthixol or risperidone in an open-label design. Cognitive functions were examined both when patients were drug-naive, and after 13 weeks of treatment. A comprehensive neuropsychological battery was used in order to optimize construct validity, and principal components of cognitive functions were extrapolated in order to reduce type I errors. A healthy control group was tested at baseline and after 13 weeks, in order to examine retest effects. The cognitive domains studied were executive functions, selective attention, and reaction time. RESULTS: The patients showed considerable cognitive deficits when drug-naive. There were few differential effects of risperidone and zuclopenthixol on cognitive deficits, except for a differential significance, respectively, tendency towards improved reaction and movement times in the risperidone group, and a lack of such in the zuclopenthixol group. These differences were no longer significant after covarying for extrapyramidal side effects and anticholinergic medication that were more prevalent in the zuclopenthixol group and the increases after medication were comparable with retest effects in controls. CONCLUSION: The study underscores the importance of examining impact of factors, such as clinical improvement, extrapyramidal side effects, anticholinergic medication and retest effects in longitudinal efficacy studies. This study does not support efficacy of either risperidone or zuclopenthixol on cognitive functions in drug-naive schizophrenia patients after 3 months of medication, because neither could be distinguished from retest effects of the healthy control group.

[The working brain--how does it look like?]. / Den arbejdende hjerne--hvordan kan den se ud?

Numerous brain functions, such as awareness of surroundings, control of movements, thoughts, and memory have always been a kind of mystery, which has provoked human curiosity and thus inspired research in many areas. The present paper gives an overview on imaging research of the human brain's functions. The historical progress is briefly reviewed with the emphasis on major Danish contributions. The major methods of mapping brain functions and their biological basis are mentioned. These methods are positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). They are highly technological and generate enormous amounts of data. Thus, data analysis will per se be a research area in brain imaging. Finally, several examples of the authors' results on functional activation are dealt with. These examples aim to illustrate the research area and its contribution to our increased knowledge of the working brain.

Clinical utility of short social cognitive tests in early differentiation of behavioral variant frontotemporal dementia from Alzheimer's disease.

BACKGROUND: Traditional cognitive tests used in clinical practice may not be sensitive enough for the early differentiation of behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD). A growing body of literature has shown that deficits in various aspects of social cognition can be found in bvFTD. AIM: The objective of this study is to investigate whether short and easily administered tests of social cognition are useful in providing clinical information which might aid in the differentiation of bvFTD from AD in the early stages of bvFTD. METHODS: 11 patients diagnosed with bvFTD and 10 patients diagnosed with AD completed a neuropsychological assessment comprising global, executive and social cognitive tasks. RESULTS: Measures of global cognitive function showed no significant difference between the two groups, whereas even the short social cognitive measures (the Reading the Mind in the Eyes Test and the Emotion Hexagon) showed significant group differences, reflecting a poorer performance by the bvFTD group. CONCLUSION: Our results suggest that it may indeed be relevant to include short and easily administered measures of social cognition in the differential diagnosis of early bvFTD and AD.

Cognitive deficits in the remitted state of unipolar depressive disorder.

BACKGROUND: Patients with unipolar depressive disorder may present with cognitive deficits in the remitted state, and the aim of the present study was to investigate whether cognitive deficits within specific cognitive domains are present. METHOD: Via the Danish registers (Civil Person Register, Danish Psychiatric Register) we identified individuals between 40 and 80 years of age with a diagnosis of unipolar disorder at their first discharge from a psychiatric hospital, and a gender- and age-matched control group. Particular emphasis was placed on assuring that patients were in a remitted state. Cognitive function was assessed with a broad range of neuropsychological tests. RESULTS: A total of 88 patients and 50 controls were included in the study. In multiple linear regression analyses with simultaneous adjustment for age, gender, education level, premorbid IQ, and residual depressive symptoms, a diagnosis of unipolar disorder predicted lower performance on the Trail Making Test, the Symbol Digit Modalities Test, and on the Stroop test. CONCLUSION: Cognitive deficits are present in patients with unipolar disorder in the remitted state. The deficits seem to reside more within the cognitive domain of attention than within other domains, and may be characterized by impairment of processing speed and cognitive flexibility.

Lack of association between prior depressive episodes and cerebral [11C]PiB binding.

Depressive symptoms are frequent in Alzheimer's disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-ß (Aß) levels using [(11)C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group of nondemented patients with prior depressive episodes. Twenty-eight elderly patients (mean age 61 years, range 51-75, 18 women) with onset of first depressive episode more than 6 years ago but now remitted from depression and 18 healthy subjects (mean age 61 years, range 50-76, 12 women) were included. All subjects were investigated with cognitive testing, 3T magnetic resonance imaging (MRI) and [(11)C]PiB high resolution research tomography (HRRT) positron emission tomography scan. There was no between-groups difference in [(11)C]PiB binding (p = 0.5) and no associations to number of depressive episodes, cognitive performance, or antidepressant treatment. Patients with late onset of depression had increased severity of white matter lesions (p = 0.04). In this study depressive episodes were not associated with increased levels of [(11)C]PiB. Thus, our results do not support the notion that depressive episodes previously in life are a risk factor for developing AD.

Cognitive function is related to fronto-striatal serotonin transporter levels--a brain PET study in young healthy subjects.

RATIONALE: Pharmacological manipulation of serotonergic neurotransmission in healthy volunteers impacts on cognitive test performance. Specifically, markers of serotonin function are associated with attention and executive functioning, long-term memory, and general cognitive ability. The serotonin transporter (SERT) protein is a key regulator in the serotonin system. We hypothesized that higher performance on tests sensitive to serotonin would be associated with higher SERT levels in specific fronto-striatal brain regions. METHODS: Thirty-two healthy subjects (25 males, mean age 26.0 years, range 19-37) underwent positron emission tomography using the SERT ligand [(11)C]DASB. Subjects underwent the following tests: Stroop Color Word Test, Trail Making Test B, Rey's Auditory Verbal Learning Test and Complex Figure Test, logical reasoning subtest from Intelligenz-Struktur-Test 2000 R, and a Danish version of National Adult Reading Test. RESULTS: We found positive associations between performance on the Stroop Color Word Test and right-sided dorsolateral prefrontal SERT binding (R(2) = 0.12, p = 0.048). Furthermore, scores of logical reasoning (correlating with IQ) and educational level associated positively with SERT binding in the caudate, most prominent on the left side (logical reasoning: R(2) = 0.34, p = 0.0026 (left), R(2) = 0.2, p = 0.022 (right), educational level: R(2) = 0.19, p = 0.012 (left), R(2) = 0.15, p = 0.027 (right)). Scores of logical reasoning also associated with left-sided ventrolateral prefrontal cortex (R(2) = 0.24, p = 0.014). There were no significant associations between SERT binding and tests of long-term episodic memory. CONCLUSIONS: The results imply that in healthy subjects, high SERT binding in fronto-striatal regions is associated with better performance on tasks involving executive function and logical reasoning.