Papers by Annemette Løkkegaard
Background Parkinson's disease (PD) leads to a loss of neuromelanin positive, noradrenergic n... more Background Parkinson's disease (PD) leads to a loss of neuromelanin positive, noradrenergic neurons in the locus coeruleus (LC) which has been implicated in non-motor dysfunction. "Neuromelanin sensitive" magnetic resonance imaging (MRI) has emerged as a promising tool for mapping the structural integrity of LC in vivo. Objectives To identify spatial patterns of structural LC disintegration in PD and regions in the LC where structural disintegration is associated with specific non-motor dysfunctions. Methods 42 patients with PD and 24 age-matched healthy volunteers underwent ultra-high field MRI of the LC using a "neuromelanin sensitive" magnetization transfer weighted (MTw) sequence. The contrast-to-noise ratio of the MTw signal (CNRMTw) served as an estimate of structural integrity, slice- and voxel-wise analyses of CNRMTw were performed to map the spatial pattern of structural disintegration, complemented by Principal Component Analysis (PCA). We also test...
Brain Communications
Levodopa-induced dyskinesia gradually emerges during long-term dopamine therapy, causing major di... more Levodopa-induced dyskinesia gradually emerges during long-term dopamine therapy, causing major disability in patients with Parkinson disease. Using pharmacodynamic functional MRI, we have previously shown that the intake of levodopa triggers an excessive activation of the pre-supplementary motor area in Parkinson disease patients with peak-of-dose dyskinesia. In this pre-registered, interventional study, we tested whether the abnormal responsiveness of the pre-supplementary motor area to levodopa may constitute a ‘stimulation target’ for treating dyskinesia. A gender-balanced group of 17 Parkinson disease patients with peak-of-dose dyskinesia received 30 min of robot-assisted repetitive transcranial magnetic stimulation, after they had paused their anti-Parkinson medication. Real-repetitive transcranial magnetic stimulation at 100% or sham-repetitive transcranial magnetic stimulation at 30% of individual resting corticomotor threshold of left first dorsal interosseous muscle was app...
Journal of Parkinson's Disease
Background: Gastrointestinal dysfunction and related clinical symptoms are common in Parkinson’s ... more Background: Gastrointestinal dysfunction and related clinical symptoms are common in Parkinson’s disease (PD), but the underlying mechanisms are still poorly understood. Objective: In this study, we investigated how PD affects the postprandial vascular response in the splanchnic circulation. Methods: 23 patients with PD in the “ON-medication state” and 23 age- and sex-matched healthy control participants underwent serial phase-contrast magnetic resonance imaging (PC-MRI) to measure the postprandial blood flow response in the superior mesenteric artery (SMA). Participants ingested a standardized liquid test meal (∼400 kcal) and underwent four PC-MRI runs within the following hour. Each PC-MRI run consisted of six consecutive measurements of SMA blood flow. Results: In both groups, standardized food intake triggered an increase of blood flow in the SMA, but absolute and relative increases in blood flow were attenuated in patients compared to the control group (p < 0.001). While ba...
Dopaminergic dysfunction is central to movement disorders and mental diseases. The dopamine trans... more Dopaminergic dysfunction is central to movement disorders and mental diseases. The dopamine transporter (DAT) is essential for the regulation of extracellular dopamine but the genetic and mechanistic link between DAT function and dopamine-related pathologies remains elusive. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here we identify a novel coding DAT variant, DAT-K619N, in a patient with early-onset parkinsonism and comorbid neuropsychiatric disease and in 22 individuals from exome-sequenced samples of neuropsychiatric patients. The variant localizes to the critical C-terminal PDZ-binding motif of DAT and causes reduced uptake capacity, decreased surface expression, and accelerated turnover of DAT in vitro. In vivo, we demonstrate that expression of DAT-K619N in mice and dropsophila imposes impairments in dopamine transmission with accompanying changes in dopamine-directed behaviors. Importantly, both cellular studies and...
Acta Neuropathologica Communications
Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known ab... more Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P
Frontiers in neurology, 2017
Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain... more Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Establis...
Movement Disorders, 2016
Backgro und: Levodopa-induced dyskinesias are a common side effect of dopaminergic therapy in PD,... more Backgro und: Levodopa-induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood. Objectives: This study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting-state cortico-striatal connectivity. Methods: Twelve PD patients with peak-of-dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast-acting soluble levodopa and then underwent resting-state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa-induced modulation of cortico-striatal resting-state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity. Results: Dopaminergic modulation of resting-state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P < .0001). Modulation of resting-state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R 2 5 0.627, P 5 .004). Resting-state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity. Conclusions: The results corroborate the notion that altered dopaminergic modulation of cortico-striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD. V
Clinical Physiology and Functional Imaging, May 1, 2012
The clinical picture in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more The clinical picture in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) is characterized by bradykinesia, rigidity, resting tremor and postural instability. In advanced stages of the disease, many patients will experience reduced efficacy of medication with fluctuations in symptoms and dyskinesias. Surgical treatment with deep brain stimulation in the subthalamic nucleus (STN-DBS) is now considered the gold standard in fluctuating PD. Many patients experience a gain of weight following the surgery. The aim of this study was to identify possible mechanisms, which may contribute to body weight gain in patients with PD following bilateral STN-DBS surgery. Ten patients with PD were studied before bilateral STN-DBS surgery, and seven patients were studied again 3 and 12 months postoperatively. Clinical examination and resting metabolic rate with and without medical treatment was measured before and after STN-DBS. Furthermore, free-living energy expenditure, body composition, energy intake, peak oxygen consumption, maximal workload and leisure time physical activity were measured before and 3 and 12 months after surgery. The STN-DBS operated patients had a significant weight gain of 4·7 ± 1·6 kg (mean ± SE) 12 months postoperatively, and the weight gain was in the fat mass. The free-living energy expenditure decreased postoperatively 13 ± 4% even though the reported dietary intake was reduced. A decreased energy expenditure took place in the non-resting energy expenditure. The reported daily leisure time activity, peak oxygen consumption and maximal workload were unchanged. The STN-DBS operated patients have a significant postoperative weight gain, as a result of a decrease in free-living energy expenditure concomitant with an insufficient decrease in energy intake.
Human Brain Mapping, 2015
Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, ofte... more Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements or postures. Functional neuroimaging studies have yielded abnormal task-related sensorimotor activation in dystonia, but the results appear to be rather variable across studies. Further, study size was usually small including different types of dystonia. Here we performed an activation likelihood estimation (ALE) meta-analysis of functional neuroimaging studies in patients with primary dystonia to test for convergence of dystonia-related alterations in taskrelated activity across studies. Activation likelihood estimates were based on previously reported regional maxima of task-related increases or decreases in dystonia patients compared to healthy controls. The meta-analyses encompassed data from 179 patients with dystonia reported in 18 functional neuroimaging studies using a range of sensorimotor tasks. Patients with dystonia showed bilateral increases in task-related activation in the parietal operculum and ventral postcentral gyrus as well as right middle temporal gyrus. Decreases in task-related activation converged in left supplementary motor area and left postcentral gyrus, right superior temporal gyrus and dorsal midbrain. Apart from the midbrain cluster, all between-group differences in task-related activity were retrieved in a sub-analysis including only the 14 studies on patients with focal dystonia. For focal dystonia, an additional cluster of increased sensorimotor activation emerged in the caudal cingulate motor zone. The results show that dystonia is consistently associated with abnormal somatosensory processing in
Cerebral Cortex, 2015
To determine the extent of neocortical involvement in multiple system atrophy (MSA), we used desi... more To determine the extent of neocortical involvement in multiple system atrophy (MSA), we used design-based stereological methods to estimate the total numbers of neurons, oligodendrocytes, astrocytes, and microglia in the frontal, parietal, temporal, and occipital cortex of brains from 11 patients with MSA and 11 age-and gender-matched control subjects. The stereological data were supported by cell marker expression analyses in tissue samples from the prefrontal cortex. We found significantly fewer neurons in the frontal and parietal cortex of MSA brains compared with control brains. Significantly more astrocytes and microglia were observed in the frontal, parietal, and temporal cortex of MSA brains, whereas no change in the total number of oligodendrocytes was seen in any of the neocortical regions. There were significantly fewer neurons in the frontal cortex of MSA patients with impaired executive function than in patients with normal executive function. Our results indicate that the involvement of the neocortex in MSA is far more widespread and substantial than previously thought. In addition, our results suggest that the increasingly recognized cognitive impairment in MSA may be related to neuronal loss in the frontal cortex.
Brain : a journal of neurology, Jan 15, 2015
Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational ... more Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51-84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to as...
Annals of neurology, 2014
In Parkinson disease (PD), long-term treatment with the dopamine precursor levodopa gradually ind... more In Parkinson disease (PD), long-term treatment with the dopamine precursor levodopa gradually induces involuntary "dyskinesia" movements. The neural mechanisms underlying the emergence of levodopa-induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic resonance imaging (fMRI) to map the emergence of peak-of-dose dyskinesias in patients with PD. Thirteen PD patients with dyskinesias and 13 PD patients without dyskinesias received 200mg fast-acting oral levodopa following prolonged withdrawal from their normal dopaminergic medication. Immediately before and after levodopa intake, we performed fMRI, while patients produced a mouse click with the right or left hand or no action (No-Go) contingent on 3 arbitrary cues. The scan was continued for 45 minutes after levodopa intake or until dyskinesias emerged. During No-Go trials, PD patients who would later develop dyskinesias showed an abnormal gradual increase of activity in the presuppleme...
Ugeskrift for laeger, Jan 17, 2003
Neurobiology of Disease, 2015
Total numbers of neurons, oligodendrocytes, astrocytes, and microglia in the basal ganglia and re... more Total numbers of neurons, oligodendrocytes, astrocytes, and microglia in the basal ganglia and red nucleus were estimated in brains from 11 patients with multiple system atrophy (MSA) and 11 age- and gender-matched control subjects with unbiased stereological methods. Compared to the control subjects, the MSA patients had a substantially lower number of neurons in the substantia nigra (p=0.001), putamen (p=0.001), and globus pallidus (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), and, to a lesser extent in the caudate nucleus (p=0.03). A significantly lower number of oligodendrocytes were only observed in the putamen (p=0.04) and globus pallidus (p=0.01). In the MSA brains the total number of astrocytes was significantly higher in the putamen (p=0.04) and caudate nucleus (p=0.01). In all examined regions a higher number of microglia were found in the MSA brains with the greatest difference observed in the otherwise unaffected red nucleus (p=0.001). The results from the stereological study were supported by cell marker expression analyses showing increased markers for activated microglia. Our results suggest that microgliosis is a consistent and severe neuropathological feature of MSA, whereas no widespread and substantial loss of oligodendrocytes was observed. We have demonstrated significant neuronal loss in the substantia nigra, striatum, and globus pallidus of patients with MSA, while neurons in other basal ganglia nuclei were spared, supporting the region-specific patterns of neuropathological changes in MSA.
Motor control, 2013
We investigated lower-extremity isometric tremor Approximate Entropy (irregularity), torque stead... more We investigated lower-extremity isometric tremor Approximate Entropy (irregularity), torque steadiness and rate of force development (RFD) and their associations to muscle activation strategy during isometric knee extensions in patients with Parkinson's disease (PD). Thirteen male patients with idiopathic PD and 15 neurologically healthy matched controls performed isometric maximal contractions (extension/flexion) as well as steady submaximal and powerful isometric knee extensions. The patients with PD showed decreased isometric tremor irregularity. Torque steadiness was reduced in PD and the patients had increased muscle coactivation. A markedly lower RFD was found in PD and the decreased RFD correlated with reduced agonist muscle activation. Furthermore, patient RFD correlated with the Movement-Disorder-Society-Unified-Parkinson's-Disease-Rating-Scale 3 (motor part) scores. We concluded that both knee isometric tremor Approximate Entropy and torque steadiness clearly diffe...
Ugeskrift for laeger, Jan 21, 2005
Quantitative Methods in Neuroscience, 2004
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Papers by Annemette Løkkegaard