Urban Ekman

Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study

BACKGROUND Many patients with Parkinsons disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinsons disease with and without MCI. METHODS Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinsons disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umeå catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at Umeå University. Included patients fulfilled the UK Parkinsons Disease Society Brain Bank clinical diagnostic criteria for Parkinsons disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1·5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest. FINDINGS Compared with controls (n=24), patients with Parkinsons disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0·001). Within the Parkinsons disease group, patients with Parkinsons disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0·005) and the bilateral anterior cingulate cortex (p<0·001) compared with patients with Parkinsons disease without MCI (n=26). In patients with Parkinsons disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinsons disease without MCI (p=0·008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0·32, p=0·031). INTERPRETATION These altered brain responses in patients with Parkinsons disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction. FUNDING Swedish Medical Research Council, Swedish Parkinson Foundation, Swedish Parkinsons Disease Association, Umeå University, Kempe Foundation, Foundation for Clinical Neuroscience at Umeå University Hospital, Västerbotten County Council (ALF), King Gustaf Vs and Queen Victorias Freemason Foundation, Knut and Alice Wallenberg Foundation, and Swedish Brain Power.

Cognitive function in the early phase of Parkinson's disease, a five‐year follow‐up

Presence of mild cognitive impairment (MCI) as a predictor for Parkinsons disease dementia (PDD) has been discussed from a clinical perspective. Recently, a Movement Disorder Society (MDS) commissioned Task Force published guidelines for PD‐MCI. However, long‐term follow‐ups of the PD‐MCI guidelines for the prediction of PDD have been sparse.

Distinct subtypes of Alzheimer’s disease based on patterns of brain atrophy: longitudinal trajectories and clinical applications

Atrophy patterns on MRI can reliably predict three neuropathological subtypes of Alzheimer’s disease (AD): typical, limbic-predominant, or hippocampal-sparing. A method to enable their investigation in the clinical routine is still lacking. We aimed to (1) validate the combined use of visual rating scales for identification of AD subtypes; (2) characterise these subtypes at baseline and over two years; and (3) investigate how atrophy patterns and non-memory cognitive domains contribute to memory impairment. AD patients were classified as either typical AD (n = 100), limbic-predominant (n = 33), or hippocampal-sparing (n = 35) by using the Scheltens’ scale for medial temporal lobe atrophy (MTA), the Koedam’s scale for posterior atrophy (PA), and the Pasquier’s global cortical atrophy scale for frontal atrophy (GCA-F). A fourth group with no atrophy was also identified (n = 30). 230 healthy controls were also included. There was great overlap among subtypes in demographic, clinical, and cognitive variables. Memory performance was more dependent on non-memory cognitive functions in hippocampal-sparing and the no atrophy group. Hippocampal-sparing and the no atrophy group showed less aggressive disease progression. Visual rating scales can be used to identify distinct AD subtypes. Recognizing AD heterogeneity is important and visual rating scales may facilitate investigation of AD heterogeneity in clinical routine.

Longitudinal changes in task-evoked brain responses in Parkinson's disease patients with and without mild cognitive impairment

Cognitive deficits are common in Parkinsons disease. Previous cross-sectional research has demonstrated a link between cognitive impairments and fronto-striatal dopaminergic dysmodulation. However, longitudinal studies that link disease progression with altered task-evoked brain activity are lacking. Therefore, our objective was to longitudinally evaluate working-memory related brain activity changes in Parkinsons disease patients with and without mild cognitive impairment (MCI). Patients were recruited within a longitudinal cohort study of incident patients with idiopathic parkinsonism. We longitudinally (at baseline examination and at 12-months follow-up) compared 28 patients with Parkinsons disease without MCI with 11 patients with Parkinsons disease and MCI. Functional MRI blood oxygen level dependent signal was measured during a verbal two-back working-memory task. Patients with MCI under-recruited bilateral medial prefrontal cortex at both time-points (main effect of group: p < 0.001, uncorrected). Critically, a significant group-by-time interaction effect (p < 0.001, uncorrected) was found in the right fusiform gyrus, indicating that working-memory related activity decreased for patients with Parkinsons disease and MCI between baseline and follow-up, while patients without MCI were stable across time-points. The functional connectivity between right fusiform gyrus and bilateral caudate nucleus was stronger for patients without MCI relative to patients with MCI. Our findings support the view that deficits in working-memory updating are related to persistent fronto-striatal under-recruitments in patients with early phase Parkinsons disease and MCI. The longitudinal evolution of MCI in Parkinsons disease translates into additional task-evoked posterior cortical changes.

The A/T/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment

The objective of this study was to evaluate the A/T/N biomarker scheme in relation with brain atrophy patterns in individuals with mild cognitive impairment (MCI). Of the 154 participants with MCI, 74 progressed to AD within 36-months, and 80 remained stable. In addition, 101 cognitively healthy participants and 102 participants with AD were included. The A/T/N classification was assessed with cerebrospinal fluid markers. Each individual was rated as either positive (abnormal) or negative (normal) on each biomarker. Brain atrophy was assessed with visual ratings from magnetic resonance imaging. None of the individuals with MCI progressed to AD if they had a negative “A” biomarker in conjunction with minimal atrophy. In contrary, several individuals with MCI progressed to AD if they had a positive “A” biomarker in conjunction with minimal atrophy. Numerous individuals with MCI showed inconsistency in the neurodegeneration domain (“N”) regarding t-tau and atrophy. The assessment of the A/T/N classification scheme in addition with brain atrophy patterns in MCI, increases the knowledge of the clinical trajectories and the variability within the neurodegeneration domain. This emphasises that individuals with MCI display heterogeneous longitudinal patterns closely connected to their biomarker profiles, which could have important clinical implications.

Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury: Changes Linked to Altered Striato-thalamic-cortical Functioning

Objective: To investigate whether functional magnetic resonance imaging (fMRI) can be used to detect fatigue after traumatic brain injury (TBI). Setting: Neurorehabilitation clinic. Participants: Patients with TBI (n = 57) and self-experienced fatigue more than 1 year postinjury, and age- and gender-matched healthy controls (n = 27). Main Measures: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task. Results: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001). The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%. Conclusion: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.

Differentiating Patients at the Memory Clinic With Simple Reaction Time Variables: A Predictive Modeling Approach Using Support Vector Machines and Bayesian Optimization

Background: Mild Cognitive Impairment (MCI) and dementia differ in important ways yet share a future of increased prevalence. Separating these conditions from each other, and from Subjective Cognitive Impairment (SCI), is important for clinical prognoses and treatment, socio-legal interventions, and family adjustments. With costly clinical investigations and an aging population comes a need for more cost-efficient differential diagnostics. Methods: Using supervised machine learning, we investigated nine variables extracted from simple reaction time (SRT) data with respect to their single and conjoined ability to discriminate both MCI/dementia, and SCI/MCI/dementia, compared to—and together with—established psychometric tests. One-hundred-twenty elderly patients (age range = 65–95 years) were recruited when referred to full neuropsychological assessment at a specialized memory clinic in urban Sweden. A freely available SRT task served as index test and was administered and scored objectively by a computer before diagnosis of SCI (n = 17), MCI (n = 53), or dementia (n = 50). As reference standard, diagnosis was decided through the multidisciplinary memory clinic investigation. Bonferroni-Holm corrected P-values for constructed models against the null model are provided. Results: Algorithmic feature selection for the two final multivariable models was performed through recursive feature elimination with 3 × 10-fold cross-validation resampling. For both models, this procedure selected seven predictors of which five were SRT variables. When used as input for a soft-margin, radial-basis support vector machine model tuned via Bayesian optimization, the leave-one-out cross-validated accuracy of the final model for MCI/dementia classification was good (Accuracy = 0.806 [0.716, INS [0].877], P < 0.001) and the final model for SCI/MCI/dementia classification held some merit (Accuracy = 0.650 [0.558, 0.735], P < 0.001). These two models are implemented in a freely available application for research and educatory use. Conclusions: Simple reaction time variables hold some potential in conjunction with established psychometric tests for differentiating MCI/dementia, and SCI/MCI/dementia in these difficult-to-differentiate memory clinic patients. While external validation is needed, their implementation within diagnostic support systems is promising.

Increase of frontal neuronal activity in chronic neglect after training in virtual reality

A third of patients with stroke acquire spatial neglect associated with poor rehabilitation outcome. New effective rehabilitation interventions are needed. Scanning training combined with multisensory stimulation to enhance the rehabilitation effect is suggested. In accordance, we have designed a virtual‐reality based scanning training that combines visual, audio and sensori‐motor stimulation called RehAtt®. Effects were shown in behavioural tests and activity of daily living. Here, we use fMRI to evaluate the change in brain activity during Posner′s Cuing Task (attention task) after RehAtt® intervention, in patients with chronic neglect.

Fatigue after traumatic brain injury is linked to altered striato-thalamic-cortical functioning

Ten-year follow-up of patients in a double blinded randomized study on prostacyclin treatment in severe traumatic brain injuryMental fatigue is a common symptom in the chronic phase of traumatic brain injury. Despite its high prevalence, no treatmentis available for this disabling symptom, and the mechanisms underlying fa ...Accepted Abstracts from the International Brain Injury Association’s 12 World Congress on Brain Injury March 29, 2017−April 1, 2017 New Orleans, Louisiana 0001 Enhancing emotional insight after traumatic brain injury: A treatment for alexithymia Dawn Neumann, James Malec, and Flora Hammond Indiana University, Indianapolis, IN, USA; Rehabilitation Hospital of Indiana, Indianapolis, IN, USA; EmotEd, Indianapolis, IN, USA ABSTRACT Objective: Alexithymia is a common problem after traumatic brain injury (TBI), with a prevalence ranging between 30% and 61%. Characteristic features of alexithymia are poor emotional awareness, difficulty in labelling and differentiating emotions and poor interoceptive awareness. Alexithymia is often associated with emotion dysregulation, including anxiety, depression and anger. The purpose of this study was to explore the preliminary effectiveness of an intervention designed to improve emotional insight in people with TBI. Methods: Seventeen adults who had a moderate-to-severe TBI, who had a minimum of 1 year after injury and had moderate-tosevere alexithymia and completed an intervention targeting problems with alexithymia. The study was a within-subject design with three assessment times: baseline, post-test and 2-month follow-up. Primary outcome measures were the Toronto Alexithymia Scale-20 (TAS-20) for alexithymia and the Levels of Emotional Awareness Scale (LEAS), which is a performancebased assessment pertaining to emotional cognizance and labelling. Secondary outcome measures evaluated anxiety [Trait Anxiety Inventory(TAI)], depression (PHQ-9), anger [State Trait Anger Expression Inventory(STAXI)], affect [Positive and Negative Affect Scale(PANAS)] and overall emotional dysregulation [Difficulty with Emotion Regulation Scale(DERS)]. The intervention consisted of eight 60to 90-minute sessions (2 per week) for 1month. Sessions were one-on-one between a therapist research assistant and participant, in which a web-based training programme was used to deliver structured content and exercises aimed at enhancing participants’ emotional vocabulary, emotional insight and interoceptive awareness were conducted. Results: Thirteen participants completed the intervention. Repeated-measures analysis of variance revealed significant improvements on the TAS-20, LEAS, TAI, STAXI, Positive Affect and DERS, which were followed by planned comparisons. Changes on these measures were all significant between baseline and post test. Changes between baseline and 2-month follow-up continued to show significant improvements on the TAS-20, LEAS, TAI and Positive affect. Effect sizes were mostly medium to large. Post-treatment satisfaction scores showed strong satisfaction for the programme. Conclusions: These preliminary findings suggest that alexithymia can be reduced after TBI with treatment and may also coincide with better emotional regulation. More research needs to be conducted using a randomized controlled trial and a larger sample.Objective: Alexithymia is a common problem after traumatic brain injury (TBI), with a prevalence ranging between 30% and 61%. Characteristic features of alexithymia are poor emotional awareness, difficulty in labelling and differentiating emotions and poor interoceptive awareness. Alexithymia is often associated with emotion dysregulation, including anxiety, depression and anger. The purpose of this study was to explore the preliminary effectiveness of an intervention designed to improve emotional insight in people with TBI. Methods: Seventeen adults who had a moderate-to-severe TBI, who had a minimum of 1 year after injury and had moderate-tosevere alexithymia and completed an intervention targeting problems with alexithymia. The study was a within-subject design with three assessment times: baseline, post-test and 2-month follow-up. Primary outcome measures were the Toronto Alexithymia Scale-20 (TAS-20) for alexithymia and the Levels of Emotional Awareness Scale (LEAS), which is a performancebased assessment pertaining to emotional cognizance and labelling. Secondary outcome measures evaluated anxiety [Trait Anxiety Inventory(TAI)], depression (PHQ-9), anger [State Trait Anger Expression Inventory(STAXI)], affect [Positive and Negative Affect Scale(PANAS)] and overall emotional dysregulation [Difficulty with Emotion Regulation Scale(DERS)]. The intervention consisted of eight 60to 90-minute sessions (2 per week) for 1month. Sessions were one-on-one between a therapist research assistant and participant, in which a web-based training programme was used to deliver structured content and exercises aimed at enhancing participants’ emotional vocabulary, emotional insight and interoceptive awareness were conducted. Results: Thirteen participants completed the intervention. Repeated-measures analysis of variance revealed significant improvements on the TAS-20, LEAS, TAI, STAXI, Positive Affect and DERS, which were followed by planned comparisons. Changes on these measures were all significant between baseline and post test. Changes between baseline and 2-month follow-up continued to show significant improvements on the TAS-20, LEAS, TAI and Positive affect. Effect sizes were mostly medium to large. Post-treatment satisfaction scores showed strong satisfaction for the programme. Conclusions: These preliminary findings suggest that alexithymia can be reduced after TBI with treatment and may also coincide with better emotional regulation. More research needs to be conducted using a randomized controlled trial and a larger sample. 0002 The influence of alexithymia, depression and anxiety on aggression after brain injury Dawn Neumann, James Malec, and Flora Hammond Indiana University, Indianapolis, IN, USA; Rehabilitation Hospital of Indiana, Indianapolis, IN, USA; EmotEd, Indianapolis, IN, USA ABSTRACT Objective: The aims of this study were twofold: 1) To determine the differences in aggression severity and prevalence in people with traumatic brain injury (TBI) and healthy controls (HCs) and 2) examine the influence of alexithymia (blunted emotional insight), depression and anxiety on aggression. Methods: Forty-six participants with moderate-to-severe TBI with age 49 years and gender-matched HCs. Participants with TBI had a minimum of 3 months after injury. Participants completed measures of trait aggression (Buss Perry Aggression Questionnaire); depression (Patient Health Questionnaire-9); trait anxiety [State Trait Anxiety Inventory (STAI)] and alexithymia (Toronto Alexithymia Scale-20). Results: Participants with TBI had significantly higher total aggression, physical aggression, verbal aggression, anger and hostility than HCs. Compared to HCs, significantly more participants with TBI were classified as having higher than average total aggression (34.8% vs 14.3%), verbal aggression (41.3% vs 18.4%), anger (39.1% vs 20.4%) and hostility (45.7% vs 20.4%). Together alexithymia, depression and anxiety accounted for 34.2% of the adjusted aggression variance for participants with TBI and 45.7% for HCs. The largest unique contributor to these models was alexithymia for participants with TBI and depression for HCs. Conclusion: This study provides empirical data showing that aggression is more severe and prevalent in people with TBI than HCs. Moreover, our findings suggest that alexithymia is a major contributing factor to aggression after TBI. This is concerning as alexithymia is prevalent in up to 61% of people with TBI. Because people with alexithymia have poor emotional insight, they may not have the awareness needed to properly regulate escalating feelings of anger and aggression. Clinical implications for the treatment of aggression will be discussed. BRAIN INJURY 2017, VOL. 31, NOS. 6–7, 719–1017 http://dx.doi.org/10.1080/02699052.2017.1312145Objective: The aims of this study were twofold: 1) To determine the differences in aggression severity and prevalence in people with traumatic brain injury (TBI) and healthy controls (HCs) and 2) examine the influence of alexithymia (blunted emotional insight), depression and anxiety on aggression. Methods: Forty-six participants with moderate-to-severe TBI with age 49 years and gender-matched HCs. Participants with TBI had a minimum of 3 months after injury. Participants completed measures of trait aggression (Buss Perry Aggression Questionnaire); depression (Patient Health Questionnaire-9); trait anxiety [State Trait Anxiety Inventory (STAI)] and alexithymia (Toronto Alexithymia Scale-20). Results: Participants with TBI had significantly higher total aggression, physical aggression, verbal aggression, anger and hostility than HCs. Compared to HCs, significantly more participants with TBI were classified as having higher than average total aggression (34.8% vs 14.3%), verbal aggression (41.3% vs 18.4%), anger (39.1% vs 20.4%) and hostility (45.7% vs 20.4%). Together alexithymia, depression and anxiety accounted for 34.2% of the adjusted aggression variance for participants with TBI and 45.7% for HCs. The largest unique contributor to these models was alexithymia for participants with TBI and depression for HCs. Conclusion: This study provides empirical data showing that aggression is more severe and prevalent in people with TBI than HCs. Moreover, our findings suggest that alexithymia is a major contributing factor to aggression after TBI. This is concerning as alexithymia is prevalent in up to 61% of people with TBI. Because people with alexithymia have poor emotional insight, they may not have the awareness needed to properly regulate escalating feelings of anger and aggression. Clinical implications for the treatment of aggression will be discussed. BRAIN INJURY 2017, VOL. 31, NOS. 6–7, 719–1017 http://dx.doi.org/10.1080/02699052.2017.1312145