Merete Karlsborg

Imaging of dopamine transporters and D2 receptors in patients with Parkinson’s disease and multiple system atrophy

PurposeThe aim of this study was to ascertain whether combined presynaptic and postsynaptic dopaminergic single-photon emission computed tomography (SPECT) scanning is useful for differentiation between patients with idiopathic Parkinson’s disease (IPD), patients with multiple system atrophy of the striatonigral type (MSA) and healthy subjects.MethodsSPECT measurements of the dopamine transporter (DAT) were done with 123I-β-CIT, while for determination of the dopamine D2-like receptors (D2), 123I-epidepride was used. Clinical evaluation and SPECT scans were carried out in 14 patients with IPD, eight patients with MSA and 11 healthy age-matched control subjects.ResultsPutaminal DAT binding was reduced to 32% of control values in IPD and to 19% of control values in MSA . Significantly higher striatal asymmetry in DAT binding was found in MSA than in controls, but IPD patients had significantly higher asymmetry than MSA patients. Striatal D2 binding did not differ significantly between patients and healthy controls but the ratio between caudate DAT and D2 binding was significantly higher in patients with IPD than in those with MSA, even when disease severity was taken into account.ConclusionPatients with reduced striatal 123I-β-CIT binding and a side-to-side difference greater than 15% are likely to suffer from IPD. Patients with reduced striatal 123I-β-CIT binding and a side-to-side difference of between 5% and 15% are more likely to have MSA. 123I-epidepride SPECT measurements may add further diagnostic information, since the ratio between DAT and D2 receptor binding is significantly higher in IPD than in MSA.

A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia

OBJECTnThe authors aim was to compare the subthalamic nucleus (STN) with the globus pallidus internus (GPi) as a stimulation target for deep brain stimulation (DBS) for medically refractory dystonia.nnnMETHODSnIn a prospective double-blind crossover study, electrodes were bilaterally implanted in the STN and GPi of 12 patients with focal, multifocal, or generalized dystonia. Each patient was randomly selected to undergo initial bilateral stimulation of either the STN or the GPi for 6 months, followed by bilateral stimulation of the other nucleus for another 6 months. Preoperative and postoperative ratings were assessed by using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and video recordings. Quality of life was evaluated by using questionnaires (36-item Short Form Health Survey). Supplemental Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were assessed for patients with focal dystonia (torticollis) by examining the video recordings.nnnRESULTSnOn average for all patients, DBS improved the BFMDRS movement scores (p < 0.05) and quality of life physical scores (p < 0.01). After stimulation of the STN, the mean 6-month improvement in BFMDRS movement score was 13.8 points; after stimulation of the GPi, this improvement was 9.1 points (p = 0.08). Quality of life did not differ significantly regardless of which nucleus was stimulated. All 12 patients accepted 6 months of stimulation of the STN, but only 7 accepted 6 months of stimulation of the GPi. Among those who rejected stimulation of the GPi, 3 accepted concomitant stimulation of both the STN and GPi for 6 months, resulting in improved quality of life physical and mental scores and BFMDRS movement scores. Among the 4 patients who were rated according to TWSTRS, after 6 months of stimulation of both the STN and GPi, TWSTRS scores improved by 4.7% after stimulation of the GPi and 50.8% after stimulation of the STN (p = 0.08).nnnCONCLUSIONSnThe STN seems to be a well-accepted, safe, and promising stimulation target in the treatment of dystonia, but further studies are necessary before the optimal target can be concluded. Simultaneous stimulation of the STN and GPi should be further investigated. Clinical trial registration no.: KF 01-110/01 (Committees on Biomedical Research Ethics of the Capital Region of Denmark).

Unchanged total number of neurons in motor cortex and neocortex in amyotrophic lateral sclerosis : a stereological study

Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. The total number of neurons in the neocortex and motor cortex from eight patients suffering from amyotrophic lateral sclerosis (ALS) and nine controls was estimated. No attempt was made to estimate subpopulations of neurons such as the number of giant pyramidal cells of Betz. No difference was found in the average number of neurons in neocortex in ALS and controls, 21.7 and 22.3 x 10(9), respectively, and 1.33 and 1.29 x 10(9) in motor cortex, respectively. In the light of our stereological measurements, results obtained from in-vivo proton magnetic resonance spectroscopy (1H-MRS), suggesting neuronal loss in ALS, may instead be due to neuronal metabolic dysfunction and/or alteration in the size or the volume fraction of the neurons.

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.

Corticospinal tract degeneration and possible pathogenesis in ALS evaluated by MR diffusion tensor imaging

BACKGROUND: MR diffusion tensor imaging (DTI) appears to be a powerful method to investigate the neuronal and axonal fibre distribution in the human brain. Changes in diffusion characteristics of water molecules in the white matter can be estimated as the apparent diffusion coefficient (ADC) and the fractional anisotropy index (FA). OBJECTIVES: To characterize DTI changes at three different levels in the corticospinal tract (CST) (corona radiata, internal capsule and pons) in order to elucidate if pathogenesis of ALS is due to an anterograde or retrograde axonal degeneration. METHODS: We studied eight ALS patients with clinical signs of upper motor neuron involvement. The patients were compared with 11 healthy age‐matched controls. RESULTS: ADC was significantly increased in the CST in ALS patients at the level of the internal capsule and also increased in the pons, but without statistical significance. ADC was unchanged at the level of the corona radiata. FA was significantly reduced at the lowest level (pons), only tended to be reduced in the internal capsule, but was also unchanged in the corona radiata. CONCLUSIONS: Segmentation of the CST into three regions supports the hypothesis of a ‘dying back’ mechanism in ALS and suggests that ADC is a more sensitive measure than FA to detect pathological changes in ALS.

Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

Patients who have dementia with Lewy bodies (DLB) show both clinical and histopathologic overlap with Alzheimer disease patients and Parkinson disease patients. In this study, we correlated the core features of DLB (dementia, parkinsonism, hallucinations, and fluctuations) with striatal dopamine transporter (DAT) availability as assessed with SPECT and 123I-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl) nortropane (123I-PE2I) in patients with newly diagnosed DLB. Methods: Two hundred eighty-eight patients were consecutively included in the study as they were referred for diagnostic SPECT scanning of DAT with 123I-PE2I. Of those patients, 51 had, on the basis of clinical guideline criteria, a probable-DLB diagnosis at follow-up 16 ± 11.6 mo later. Before or on the day of the SPECT scan, DLB patients had a routine neurologic examination including Hoehn and Yahr grading and were cognitively evaluated with the Mini Mental State Examination. Results: There was no correlation between Mini Mental State Examination, Hoehn and Yahr score, fluctuations or hallucinations, and striatal DAT availability as measured with 123I-PE2I and SPECT. Conclusion: In patients with newly diagnosed DLB, symptoms are not associated with a reduction in striatal DAT despite its firm involvement in DLB pathology.

Predictive value of dopamine transporter SPECT imaging with ( 123 I)PE2I in patients with subtle parkinsonian symptoms

PurposeTo examine the diagnostic sensitivity and specificity of dopamine transporter SPECT imaging with a highly dopamine transporter selective radioligand. The study included consecutively enrolled, drug-naive patients with an average short history of parkinsonian motor symptoms, referred for diagnostic scanning.MethodsThe study group comprised 288 patients naive to antiparkinson treatment who were enrolled as they were admitted for a diagnostic SPECT scan with the radioligand [123I]-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl)nortropane (123I-PE2I). After the diagnostic scanning, patients were followed clinically with an average follow-up of 19.7 ± 12.5xa0months.ResultsA diagnosis could be clinically settled in 189 patients and among these patients, a dopamine transporter scan had a sensitivity of 88% and a specificity of 91% for discrimination between patients with and without striatal neurodegeneration. In cognitively impaired patients (Mini Mental State Examination <27) the specificity was 75% and the sensitivity 95%. A striatal anterior–posterior ratio (APR) of >2 differentiated between idiopathic Parkinson’s disease and atypical parkinsonian syndromes with a specificity of 84% and a sensitivity of 63%.ConclusionIn drug-naive patients with subtle clinical parkinsonian motor symptoms, dopamine transporter scan using 123I-PE21 has a high sensitivity and specificity in distinguishing between patients with and without striatal neurodegeneration. The specificity is lower in patients who are also cognitively impaired. Calculation of the striatal APR can assist in differentiating between idiopathic Parkinson’s disease and atypical parkinsonian syndromes.

Dopamine transporter imaging and the effects of deep brain stimulation in patients with Parkinson’s disease

PurposeSingle-photon emission computed tomography (SPECT) with [123I]FP-CIT is a marker for loss of presynaptic dopamine transporters in the striatum in Parkinson’s disease (PD). We used [123I]FP-CIT SPECT in order to evaluate binding to the dopamine transporter before and after neurosurgical treatment with bilateral stimulation in the subthalamic nucleus (STN).MethodsThirty-five patients with levodopa-responsive PD were examined with [123I]FP-CIT SPECT pre-operatively (baseline scan: mean 3xa0months before surgery), and 3 and 12xa0months after surgery.ResultsPre-operatively, all patients already had substantial signs of severe nigrostriatal neuronal loss as determined from the [123I]FP-CIT SPECT scans. One year after surgery the specific [123I]FP-CIT binding to the striatum was significantly reduced by 10.3% compared with the pre-operative baseline scan. The mean time span from the baseline scan before surgery to the follow-up scan 1xa0year after surgery was 16.2xa0months. Hence, the rate of reduction equals a mean annual reduction of 7.7%. A comparable control group of patients with PD who did not undergo surgery was also examined longitudinally. In this group the specific binding of [123I]FP-CIT was reduced by 6.7% per year.ConclusionThe specific binding of [123I]FP-CIT was reduced equally in the STN-stimulated patients and a group of non-operated PD patients with advanced disease. Our study does not support the notion that electrode implantation and STN stimulation exert a neuroprotective effect by themselves.

July 2017 ENCALS statement on edaravone

Neurologists of the ENCALS centers throughout Europe have discussed the potential of edaravone as a new therapy for amyotrophic lateral sclerosis (ALS, Motor Neuron Disease, MND) at the ENCALS meeting, 18–20 May 2017, in Ljubljana, Slovenia. n nIn May 2017, the US Food and Drug Administration (FDA) granted a license for the drug known as edaravone (licensed in Japan in 2015 as Radicut®) for the treatment of ALS in the United States (to be marketed as Radicava®). We are not aware of any official request from Mitsubishi Tanabe Pharma, the manufacturer of edaravone, to the European Medicines Agency (EMA) to register the drug for use in ALS in Europe. However, edaravone can be imported to Europe from Japan or the United States. n nThe FDA approval of edaravone is based on a single positive clinical trial. The ENCALS neurologists were of the view that the outcome of this trial requires a balanced and considered interpretation when considering how best to advise those with ALS and their families. This study showed that edaravone may slow disease progression in ALS, but the disease-modifying effect was limited to a subgroup of ALS patients with distinct clinical characteristics. For ALS patients without those characteristics there is currently no evidence for a therapeutic benefit of edaravone.