1. |
- Anders, Silke, et al.
(författare)
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When seeing outweighs feeling : a role for prefrontal cortex in passive control of negative affect in blindsight
- 2009
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Ingår i: Brain. - Oxford : Oxford University Press. - 0006-8950 .- 1460-2156. ; 132:11, s. 3021-3031
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Tidskriftsartikel (refereegranskat)abstract
- Affective neuroscience has been strongly influenced by the viewthat a ‘feeling’ is the perception of somatic changesand has consequently often neglected the neural mechanisms thatunderlie the integration of somatic and other information inaffective experience. Here, we investigate affective processingby means of functional magnetic resonance imaging in nine corticallyblind patients. In these patients, unilateral postgeniculatelesions prevent primary cortical visual processing in part ofthe visual field which, as a result, becomes subjectively blind.Residual subcortical processing of visual information, however,is assumed to occur in the entire visual field. As we have reportedearlier, these patients show significant startle reflex potentiationwhen a threat-related visual stimulus is shown in their blindvisual field. Critically, this was associated with an increaseof brain activity in somatosensory-related areas, and an increasein experienced negative affect. Here, we investigated the patients’response when the visual stimulus was shown in the sighted visualfield, that is, when it was visible and cortically processed.Despite the fact that startle reflex potentiation was similarin the blind and sighted visual field, patients reported significantlyless negative affect during stimulation of the sighted visualfield. In other words, when the visual stimulus was visibleand received full cortical processing, the patients’ phenomenalexperience of affect did not closely reflect somatic changes.This decoupling of phenomenal affective experience and somaticchanges was associated with an increase of activity in the leftventrolateral prefrontal cortex and a decrease of affect-relatedsomatosensory activity. Moreover, patients who showed strongerleft ventrolateral prefrontal cortex activity tended to showa stronger decrease of affect-related somatosensory activity.Our findings show that similar affective somatic changes canbe associated with different phenomenal experiences of affect,depending on the depth of cortical processing. They are in linewith a model in which the left ventrolateral prefrontal cortexis a relay station that integrates information about subcorticallytriggered somatic responses and information resulting from in-depthcortical stimulus processing. Tentatively, we suggest that theobserved decoupling of somatic responses and experienced affect,and the reduction of negative phenomenal experience, can beexplained by a left ventrolateral prefrontal cortex-mediatedinhibition of affect-related somatosensory activity.
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4. |
- Buerger, Katharina, et al.
(författare)
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CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.
- 2006
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 129:Pt 11, s. 3035-41
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Tidskriftsartikel (refereegranskat)abstract
- Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.
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6. |
- Carlsson, Thomas, et al.
(författare)
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Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration.
- 2009
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 132, s. 319-335
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that serotonin neurons play an important role in the induction and maintenance of l-DOPA-induced dyskinesia in animals with lesion of the nigrostriatal dopamine system. Patients with Parkinson's disease that receive transplants of foetal ventral mesencephalic tissue, the graft cell preparation is likely to contain, in addition to dopamine neurons, serotonin neurons that will vary in number depending on the landmarks used for dissection. Here, we have studied the impact of grafted serotonin neurons-alone or mixed with dopamine neurons-on the development of l-DOPA-induced dyskinesia in rats with a partial 6-hydroxydopamine lesion of the host nigrostriatal projection. In these rats, which showed only low-level dyskinesia at the time of transplantation, serotonin grafts induced a worsening in the severity of dyskinesia that developed during continued l-DOPA treatment, while the dopamine-rich graft had the opposite, dampening effect. The detrimental effect seen in animals with serotonin neuron grafts was dramatically increased when the residual dopamine innervation in the striatum was removed by a second 6-hydroxydopamine lesion. Interestingly, rats with grafts that contained a mixture of dopamine and serotonin neurons (in approximately 2:1) showed a marked reduction in l-DOPA-induced dyskinesia over time, and the appearance of severe dyskinesia induced by the removal of the residual dopamine innervation, seen in the animals with transplants of serotonin neurons alone, was blocked. FosB expression in the striatal projection neurons, which is associated with dyskinesias, was also normalized by the dopamine-rich grafts, but not by the serotonin neuron grafts. These data indicate that as long as a sufficient portion, some 10-20%, of the dopamine innervation still remains, the increased host serotonin innervation generated by the grafted serotonin neurons will have limited effect on the development or severity of l-DOPA-induced dyskinesias. At more advanced stages of the disease, when the dopamine innervation of the putamen is reduced below this critical threshold, grafted serotonin neurons are likely to aggravate l-DOPA-induced dyskinesia in those cases where the dopamine re-innervation derived from the grafted neurons is insufficient in magnitude or do not cover the critical dyskinesia-inducing sub-regions of the grafted putamen. We conclude that it is not the absolute number of serotonin neurons in the grafts, but the relative densities of dopamine and serotonin innervations in the grafted striatum that is the critical factor in determining the long-term effect of foetal tissue graft, beneficial or detrimental, on dyskinesia in grafted Parkinson's disease patients.
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7. |
- Carta, Manolo, et al.
(författare)
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Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats.
- 2007
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 130:7, s. 1819-1833
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Tidskriftsartikel (refereegranskat)abstract
- n patients with Parkinson's disease, the therapeutic efficacy of L-DOPA medication is gradually lost over time, and abnormal involuntary movements, dyskinesias, gradually emerge as a prominent side-effect in response to previously beneficial doses of the drug. Here we show that dyskinesia induced by chronic L-DOPA treatment in rats with 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway is critically dependent on the integrity and function of the serotonergic system. Removal of the serotonin afferents, or dampening of serotonin neuron activity by 5-HT1A and 5-HT1B agonist drugs, resulted in a near-complete block of the L-DOPA-induced dyskinesias, suggesting that dysregulated dopamine release from serotonin terminals is the prime trigger of dyskinesia in the rat Parkinson's disease model. In animals with complete dopamine lesions, the spared serotonin innervation was unable to sustain the therapeutic effect of L-DOPA, suggesting that dopamine released as a 'false transmitter' from serotonin terminals is detrimental rather than beneficial. The potent synergistic effect of low doses of 5-HT1A and 5-HT1B agonists to suppress dyskinesia, without affecting the anti-parkinsonian effect of L-DOPA in presence of spared dopamine terminals, suggests an early use of these drugs to counteract the development of dyskinesia in Parkinson's disease patients.
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8. |
- Cervenka, Simon, et al.
(författare)
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Support for dopaminergic hypoactivity in restless legs syndrome : a PET study on D2-receptor binding
- 2006
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Ingår i: Brain. - Karolinska Univ Hosp Solna, Dept Clin Neurosci, Psychol Sect, Karolinska Inst, SE-17176 Stockholm, Sweden. Karolinska Univ Hosp Huddinge, Div Clin Pharmacol, Dept Lab Med, Stockholm, Sweden. Karolinska Univ Hosp Huddinge, Dept Neurol, Stockholm, Sweden. GlaxoSmithKline Inc, Translat Med & Genet, Cambridge, England. Univ Manchester, Wolfson Mol Imaging Ctr, Manchester, Lancs, England. GlaxoSmithKline Inc, Neurol Discovery Med, Harlow, Essex, England. : OXFORD UNIV PRESS. - 0006-8950 .- 1460-2156. ; 129, s. 2017-2028
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Tidskriftsartikel (refereegranskat)abstract
- Clinical observations support a central role of the dopamine system in restless legs syndrome (RLS) but previous imaging studies of striatal dopamine D2-receptors have yielded inconclusive results. Extrastriatal dopaminergic function has hitherto not been investigated. Sixteen RLS patients naive to dopaminergic drugs and sixteen matched control subjects were examined with PET. [C-11]Raclopride and [C-11]FLB 457 were used to estimate D2-receptor availability in striatum and extrastriatal regions, respectively. Examinations were performed both in the morning (starting between 10:00 and 12:00 h) and evening (starting at 18:00 h). Measures were taken to monitor and control for head movement during data acquisition. In the striatum, patients had significantly higher [C-11]raclopride binding potential (BP) values than controls. In extrastriatal regions, [C-11]FLB 457 BP was higher in patients than controls, and in the regional analysis the difference was statistically significant in subregions of thalamus and the anterior cingulate cortex. The diurnal variability in BP with [C-11]FLB 457 and [C-11]raclopride was within the previously reported test-retest reproducibility for both radioligands. The study supports involvement of the dopamine system in both striatal and extrastriatal brain regions in the pathophysiology of RLS. The brain regions where differences in D2-receptor binding were shown are implicated in the regulation of affective and motivational aspects of sensory processing, suggesting a possible pathway for sensory symptoms in RLS. Increased D2-receptor availability in RLS may correspond to higher receptor densities or lower levels of endogenous dopamine. Both interpretations are consistent with the hypothesis of hypoactive dopaminergic neurotransmission in RLS, as increased receptor levels can be owing to receptor upregulation in response to low levels of endogenous dopamine. The results do not support variations in dopamine D2-receptor availability as a correlate to the diurnal rhythm of RLS symptoms.
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10. |
- Donadio, Vincenzo, et al.
(författare)
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Arousal elicits exaggerated inhibition of sympathetic nerve activity in phobic syncope patients.
- 2007
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 130:Pt 6, s. 1653-62
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Tidskriftsartikel (refereegranskat)abstract
- Alerting stimuli causing arousal have been shown to elicit a reproducible transient inhibition of muscle sympathetic nerve activity (MSNA) in healthy subjects. The aim of the present study was to test whether this inhibitory response to arousal is exaggerated in patients with a history of vasovagal syncope. We studied 24 untreated syncope patients, 12 of whom met the DSM-IV-TR diagnostic criteria for blood/injury phobia and 18 age-matched healthy subjects. MSNA was recorded from the peroneal nerve at the fibular head. Arousal was induced by randomly presented trains of five electrical pulses delivered to a finger. The pulses were triggered on five consecutive R waves of the ECG, with a delay of 200 ms. Patients also underwent cardiological and neurological examinations, tilt test and a structured interview to investigate diagnostic criteria for specific phobia. The syncope patients had significantly lower resting MSNA (29 +/- 2 bursts/min) and diastolic blood pressure (BP, 78 +/- 2 mmHg) compared to controls (36 +/- 2 bursts/min and 84 +/- 3 mmHg; P < 0.05), whereas no significant differences were found for resting heart rate and systolic BP. The phobic patient group exhibited prolonged sympathetic inhibitions to arousal stimuli compared to controls and non-phobic patients, whereas no difference was found between tilt-positive and tilt-negative patients or between controls and non-phobic patients. The findings suggest that the degree of inhibition in response to arousal stimuli is related to a subjective factor coupled to fear of blood/injury. The exaggerated inhibition in patients with phobia to blood/injury may be a factor predisposing to syncope in those patients.
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11. |
- Ehrsson, H. Henrik, et al.
(författare)
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Upper limb amputees can be induced to experience a rubber hand as their own
- 2008
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 131:12, s. 3443-3452
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Tidskriftsartikel (refereegranskat)abstract
- We describe how upper limb amputees can be made to experience a rubber hand as part of their own body. This was accomplished by applying synchronous touches to the stump, which was out of view, and to the index finger of a rubber hand, placed in full view (26 cm medial to the stump). This elicited an illusion of sensing touch on the artificial hand, rather than on the stump and a feeling of ownership of the rubber hand developed. This effect was supported by quantitative subjective reports in the form of questionnaires, behavioural data in the form of misreaching in a pointing task when asked to localize the position of the touch, and physiological evidence obtained by skin conductance responses when threatening the hand prosthesis. Our findings outline a simple method for transferring tactile sensations from the stump to a prosthetic limb by tricking the brain, thereby making an important contribution to the field of neuroprosthetics where a major goal is to develop artificial limbs that feel like a real parts of the body.
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13. |
- Engler, Henry, et al.
(författare)
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Two-year follow-up of amyloid deposition in patients with Alzheimer's disease
- 2006
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 129:Pt 11, s. 2856-2866
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Tidskriftsartikel (refereegranskat)abstract
- Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 +/- 3.7 (mean +/- standard deviation) to 22.7 +/- 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.
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14. |
- Eslamboli, Andisheh, et al.
(författare)
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Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain.
- 2007
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 130:3, s. 799-815
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Tidskriftsartikel (refereegranskat)abstract
- Overexpression of human alpha-synuclein (alpha-syn) using recombinant adeno-associated viral (rAAV) vectors provides a novel tool to study neurodegenerative processes seen in Parkinson's disease and other synucleinopathies. We used a pseudotyped rAAV2/5 vector to express human wild-type (wt) alpha-syn, A53T mutated alpha-syn, or the green fluorescent protein (GFP) in the primate ventral midbrain. Twenty-four adult common marmosets (Callithrix jacchus) were followed with regular behavioural tests for 1 year after transduction. alpha-Syn overexpression affected motor behaviour such that all animals remained asymptomatic for at least 9 weeks, then motor bias comprising head position bias and full body rotations were seen in wt-alpha-syn expressing animals between 15 and 27 weeks; in the later phase, the animals overexpressing the A53T alpha -syn, in particular, showed a gradual worsening of motor performance, with increased motor coordination errors. Histological analysis from animals overexpressing either the wt or A53T alpha -syn showed prominent degeneration of dopaminergic fibres in the striatum. In the ventral midbrain, however, the dopaminergic neurodegeneration was more prominent in the A53T group than in the WT group suggesting differential toxicity of these two proteins in the primate brain. The surviving cell bodies and their processes in the substantia nigra were stained by antibodies to the pathological form of alpha-syn that is phosphorylated at Ser position 129. Moreover, we found, for the first time, ubiquitin containing aggregates after overexpression of alpha-syn in the primate midbrain. There was also a variable loss of oligodendroglial cells in the cerebral peduncle. These histological and behavioural data suggest that this model provides unique opportunities to study progressive neurodegeneration in the dopaminergic system and deposition of alpha-syn and ubiquitin similar to that seen in Parkinson's disease, and to test novel therapeutic targets for neuroprotective strategies.
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15. |
- Ewers, Michael, et al.
(författare)
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Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer's disease.
- 2008
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 131:Pt 5, s. 1252-8
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Tidskriftsartikel (refereegranskat)abstract
- The Apolipoprotein (ApoE) epsilon 4 allele is a major genetic risk factor of Alzheimer's disease, and may affect the production of amyloid beta (A beta(1-42)). Recently, we have shown that beta-secretase (BACE 1) activity can be reliably detected within the brain and human CSF. Here, we have examined an association between the ApoE genotype and CSF-levels of BACE 1 activity in Alzheimer's disease and mild cognitive impairment (MCI). A total of 148 subjects were included: 60 Alzheimer's disease patients, 51 MCI subjects and 37 elderly healthy controls. The CSF-levels of A beta(1-42), BACE 1 activity and BACE protein were measured in all of these subjects. The differences between ApoE-epsilon 4 carriers and ApoE-epsilon 4 non-carriers in these CSF-based measures were determined controlling for gender, age and MMSE score. The ApoE-epsilon 4 genotype was associated with increased BACE 1 activity in both Alzheimer's disease (P = 0.03) and MCI (P = 0.04) subjects. Levels of A beta(1-42) were decreased in ApoE-epsilon 4 carriers in MCI (P = 0.004) but not Alzheimer's disease subjects. This study is the first to demonstrate the association between ApoE-epsilon 4 and CSF-BACE 1 activity in MCI and Alzheimer's disease subjects. The assessment of BACE 1 in CSF may provide a sensitive measure to detect in vivo alterations in the amyloidogenic processing potentially modified by the ApoE genotype.
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16. |
- Fang, Fang, et al.
(författare)
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Suicide among patients with amyotrophic lateral sclerosis
- 2008
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Ingår i: Brain. - Oxford, United Kingdom : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 131, s. 2729-2733
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Tidskriftsartikel (refereegranskat)abstract
- Studies on the suicide risk among patients with amyotrophic lateral sclerosis (ALS) in countries without legalized euthanasia or assisted suicide are important additions to data on the wish to die of these patients. We conducted a population-based cohort study in Sweden between 1965 and 2004, which comprised of 6642 patients with incident ALS identified from the Swedish Inpatient Register. We calculated the standardized mortality ratios (SMRs) of suicide among the patients using the suicide rates of the general Swedish population as a reference. In total, 21 patients committed suicide during follow-up, compared to the predicted 3.6 suicides. Thus, we noted an almost 6-fold increased risk for suicide among ALS patients [SMR 5.8, 95% confidence interval (CI) 3.6-8.8]. Patients who committed suicide were, on average, around 7 years younger at the time of their first period of hospitalization than patients who did not commit suicide. The highest relative risk for suicide was observed within the first year after the patients first period of hospitalization (SMR 11.2, 95% CI 5.8-19.6). After that, the relative risks decreased with time after hospitalization (P-value for trend = 0.006), but remained elevated 3 years later. The relative risks of suicide among ALS patients did not show a clear trend over time in contrast to the decreasing trend of relative risks for suicide among patients with cancer during the same period. Patients with ALS are at excess risk of suicide in Sweden and the relative risk is higher during the earlier stage of the disease.
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17. |
- Horvath, Rita, et al.
(författare)
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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
- 2009
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 132:Pt 11, s. 3165-74
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Tidskriftsartikel (refereegranskat)abstract
- Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
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18. |
- Janszky, Imre, et al.
(författare)
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Increased risk and worse prognosis of myocardial infarction in patients with prior hospitalization for epilepsy : the Stockholm Heart Epidemiology Program
- 2009
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 132:Pt 10, s. 2798-2804
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Tidskriftsartikel (refereegranskat)abstract
- The association of epilepsy with risk of acute myocardial infarction (AMI) remains uncertain, and its association with myocardial infarction prognosis has not been evaluated. In this study, we performed a population-based case-control study that included 1799 cases with first AMI and 2339 controls, frequency matched by age, sex and hospital catchment area. A history of epilepsy was identified using the Swedish hospital discharge registry. Information on lifestyle and biomarkers was determined from questionnaires and standardized clinic examinations. The cohort of cases was followed for 8 years to evaluate the relationship between epilepsy and post AMI prognosis. A diagnosis of epilepsy was associated with higher risk of incident AMI, with an odds ratio (OR) of 4.92 [95% confidence interval (CI) 2.34-10.31] after adjustment for age, gender, hospital catchment area, and education. There was a graded positive relation between number of hospitalizations for epilepsy and risk of AMI. Adjustment for smoking and levels of tissue plasminogen activator (tPA)/plasminogen activator inhibitor 1 (PAI-1) complex, von Willebrand factor and homocysteine weakened, and adjustment for high-density lipoprotein (HDL) and fibrinogen strengthened, the relationship between epilepsy and AMI. The OR for epilepsy was 4.83 (95% CI 1.62-14.43) when age, gender, hospital catchment area, education and established, clinically relevant AMI risk factors, i.e. diabetes mellitus, smoking, hypertension, physical activity, obesity, high-density lipoprotein, total cholesterol and alcohol consumption were simultaneously controlled for. Epilepsy was also associated with AMI prognosis. Multivariable adjusted hazard ratios for total and cardiac mortality and for a combined outcome of cardiac death and non-fatal reinfarction, heart failure and stroke during follow up, were 1.95 (0.70-5.43), 3.49 (1.05-11.65) and 2.39 (1.16-4.90), respectively. We conclude that epilepsy might be a risk and an adverse prognostic factor for AMI. Smoking and increase in the level of homocysteine, tPA/PAI-1 complex and von Willebrand factor are candidate mechanisms linking epilepsy to increased AMI risk. Physicians should be aware of the potential cardiovascular implications of epilepsy.
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20. |
- Jonsson, Andreas P., et al.
(författare)
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Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models
- 2006
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 129:Pt 2, s. 451-644
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Tidskriftsartikel (refereegranskat)abstract
- Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.
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21. |
- Kamm, C, et al.
(författare)
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The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group
- 2005
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 128:8, s. 1855-1860
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Tidskriftsartikel (refereegranskat)abstract
- The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.
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23. |
- Koivunen, J., et al.
(författare)
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PET amyloid ligand [C-11]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease
- 2008
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 131:Pt 7, s. 1845-1853
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Tidskriftsartikel (refereegranskat)abstract
- Variant Alzheimers disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1 E9). VarAD is neuropathologically characterized by the presence of unusually large, A42 positive, non-cored cotton wool plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [C-11]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [C-11]PIB binding to the amount and type of A deposits in another group of deceased VarAD patients brains. We studied four patients with VarAD and eight healthy controls with PET using [C-11]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 6090 min. Group differences in [C-11]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [C-11]PIB uptake was compared to the immunohistochemically demonstrated deposition of A in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [C-11] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [C-11]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43 greater than the mean of the control group. The increases in the anterior (28) and posterior (27) cingulate gyrus, occipital cortex (21) and thalamus (14) were smaller. All VarAD patients showed this similar topographical pattern of increased [C-11]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [C-11]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to detect amyloid accumulation in vivo in these patients. The pattern of increased [C-11]PIB uptake is different from that described in sporadic Alzheimers disease and resembles that seen in Alzheimers disease patients with certain presenilin-1 mutations or amyloid precursor protein gene duplication showing predominantly striatal increase in [C-11]PIB uptake.
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24. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy
- 2009
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 132:8, s. 2170-2179
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Tidskriftsartikel (refereegranskat)abstract
- Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur. The disease has so far only been identified in northern Sweden. The clinical, histochemical and biochemical phenotype is very homogenous and the patients are homozygous for a deep intronic IVS5 382GC splicing affecting mutation in ISCU, which encodes the differently spliced cytosolic and mitochondrial ironsulphur cluster assembly protein IscU. Ironsulphur cluster containing proteins are essential for iron homeostasis and respiratory chain function, with IscU being among the most conserved proteins in evolution. We identified a shared homozygous segment of only 405 000 base pair with the deep intronic mutation in eight patients with a phenotype consistent with the original description of the disease. Two other patients, two brothers, had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle ironsulphur cluster deficiency, but they presented with a disease where the clinical phenotype was characterized by early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy. The brothers were compound heterozygous for the deep intronic mutation and had a c.149 GA missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate. The missense mutation was inherited from their mother who was of Finnish descent. The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon. In western blot analysis of protein extracts from fibroblasts, there was no pronounced reduction of IscU in any of the patients, but the analysis revealed that the species corresponding to mitochondrial IscU migrates slower than a species present only in whole cells. In protein extracted from isolated skeletal muscle mitochondria the western blot analysis revealed a severe deficiency of IscU in the homozygous patients and appearance of a faint new fraction that could represent a truncated protein. There was only a slight reduction of mitochondrial IscU in the compound heterozygotes, despite their severe phenotype, indicating that the IscU expressed in these patients is non-functional.
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25. |
- Kärppä, Mikko, et al.
(författare)
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Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA
- 2005
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 128:Pt 8, s. 1861-9
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Tidskriftsartikel (refereegranskat)abstract
- Myopathy is a typical clinical finding among patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), but the variability in such findings has not been properly established. We have previously determined the prevalence of patients with 3243A>G in a defined population in northern Finland and characterized a group of patients who represent a good approximation to a population-based cohort. We report here on examinations performed on patients belonging to this cohort in order to determine the frequency of myopathy and to evaluate the clinical, histological, ultrastructural and single fibre mtDNA variability in muscle involvement. Fifty patients with 3243A>G underwent a thorough structured interview and clinical examination. Muscle histology, ultrastructure and single fibre analysis were examined in a subset of patients. A clinical diagnosis of myopathy was made in 50% of cases [95% confidence interval (CI), 36-64] and abnormalities in muscle histology were found in 72% (95% CI, 55-86). Moderate limb weakness leading to functional impairment was the most common myopathic sign, but mild weakness, ptosis and external ophthalmoplegia could also be found. The presence of intramitochondrial crystals and cytochrome c oxidase (COX)-negative fibres and variation in mitochondrial size and shape were more common in the muscles of the myopathic patients. Longitudinal variations in mutation heteroplasmy were examined in single muscle fibres from two severely affected patients. Although the total variation in mutation heteroplasmy along four ragged red fibres (RRFs) was small, the mutation heteroplasmy in five 10 microm segments was clearly lower (median 68%, range 64-74%) than that in the neighbouring segments. There were also segments with deviant mutation load in histologically normal fibres in one patient. The highest incidence of myopathy was in the fifth decade of life, but, apart from age, no other clinical variables such as gender, muscle heteroplasmy, physical inactivity or diabetes were associated with an increased risk of myopathy. The clinical presentation of myopathy is highly variable in patients with 3243A>G.
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26. |
- Lenfeldt, Niklas, et al.
(författare)
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Idiopathic normal pressure hydrocephalus : increased supplementary motor activity accounts for improvement after CSF drainage.
- 2008
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 131:Pt 11, s. 2904-2912
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Tidskriftsartikel (refereegranskat)abstract
- In patients with idiopathic normal pressure hydrocephalus (INPH), the changes in brain function that take place in conjunction with improved behavioural performance after CSF drainage is still unknown. In this study, we use functional MRI (fMRI) to investigate the changes in cortical activity that accompany improved motor and cognitive performance after long-term external lumbar drainage (ELD) of CSF in patients with INPH. Eighteen INPH patients were initially included together with age- and sex-matched controls. Data from 11 INPH patients were analysed both before and after ELD. The average drain volume for these 11 patients was 400 ml/3 days. Brain activation was investigated by fMRI before and after the procedure on a 1.5T Philips scanner using protocols taxing motor performance (finger tapping and reaction time) and cognitive functioning (memory and attention). Behavioural data were compared using non-parametric tests at a significance level of 0.05, whereas fMRI data were analysed by statistical parametric mapping including conjunction analysis of areas with enhanced activity after drainage in patients and areas activated in controls (P < 0.005, uncorrected). Improved regions were defined as areas in the INPH brain that increased in activity after ELD with the requirement that the same areas were activated in control subjects. Following ELD, right-hand finger tapping improved from 104 +/- 38 to 117 +/- 25 (mean +/- SD) (P = 0.02). Left-hand finger tapping showed a tendency to improve, the number of keystrokes increasing from 91 +/- 40 to 105 +/- 20 (P = 0.12). Right-hand reaction time improved from 1630 +/- 566 ms to 1409 +/- 442 ms, whereas left-hand reaction time improved from 1760 +/- 600 ms to 1467 +/- 420 ms (both P-values = 0.01). Significant improvements in motor performance were accompanied by bilateral increased activation in the supplementary motor area. No improvement was found in cognitive functioning. The results suggest that motor function recovery in INPH patients after CSF removal is related to enhanced activity in medial parts of frontal motor areas considered crucial for motor planning; a finding consistent with INPH being a syndrome related to a reversible suppression of frontal periventricular cortico-basal ganglia-thalamo-cortical pathways.
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27. |
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28. |
- Lin, Cindy Shin-Yi, et al.
(författare)
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Axonal changes in spinal cord injured patients distal to the site of injury.
- 2007
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 130:Pt 4, s. 985-94
-
Tidskriftsartikel (refereegranskat)abstract
- It is generally assumed that the peripheral nervous system remains intact following a spinal injury. Accordingly, the electrical thresholds of motor axons in a peripheral nerve below the lesion should be similar to those in intact subjects. Yet in attempts to enter the common peroneal nerve with microelectrodes in 24 quadriplegic or paraplegic individuals it was often found that electrical stimulation over or within the nerve failed to elicit contractions in the pre-tibial flexors. To investigate whether consistent changes in axonal physiology occurred distal to the site of injury in patients with spinal cord injury (SCI), motor nerve excitability was formally tested in 15 of these patients. Threshold tracking techniques were used to measure axonal excitability parameters (stimulus-response curves, strength-duration properties, threshold electrotonus, a current-threshold relationship and the recovery cycle) of motor axons in the median and common peroneal nerves. In these patients motor axons were uniformly of high threshold and consequently, stimulus-response curves were shifted to the right. In some SCI patients, axons were completely inexcitable. Amplitudes of compound motor action potentials were reduced, consistent with axonal loss and strength-duration time constant was significantly reduced in SCI patients (SCI 0.13 +/- 0.02 ms, controls 0.43 +/- 0.02 ms, mean +/- SE, P < 0.0001). Excitability changes were more prominent the more clinically severe the injury, with progressive deterioration over time since the original injury. While compression and traction sustained during the original injury or subsequent hospital rehabilitation may contribute in part to some of these changes, it is difficult to attribute these findings solely to such processes. Changes in axonal structure and ion channel function, but perhaps more critically decentralization and consequent inactivity, are likely to underlie the complex changes observed in axonal excitability in SCI patients.
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29. |
- Lind, Johanna, et al.
(författare)
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Reduced functional brain activity response in cognitively intact apolipoprotein E ε4 carriers
- 2006
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 129:5, s. 1240-1248
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Tidskriftsartikel (refereegranskat)abstract
- The apolipoprotein E epsilon4 (APOE epsilon4) is the main known genetic risk factor for Alzheimer's disease. Genetic assessments in combination with other diagnostic tools, such as neuroimaging, have the potential to facilitate early diagnosis. In this large-scale functional MRI (fMRI) study, we have contrasted 30 APOE epsilon4 carriers (age range: 49-74 years; 19 females), of which 10 were homozygous for the epsilon4 allele, and 30 non-carriers with regard to brain activity during a semantic categorization task. Test groups were closely matched for sex, age and education. Critically, both groups were cognitively intact and thus symptom-free of Alzheimer's disease. APOE epsilon4 carriers showed reduced task-related responses in the left inferior parietal cortex, and bilaterally in the anterior cingulate region. A dose-related response was observed in the parietal area such that diminution was most pronounced in homozygous compared with heterozygous carriers. In addition, contrasts of processing novel versus familiar items revealed an abnormal response in the right hippocampus in the APOE epsilon4 group, mainly expressed as diminished sensitivity to the relative novelty of stimuli. Collectively, these findings indicate that genetic risk translates into reduced functional brain activity, in regions pertinent to Alzheimer's disease, well before alterations can be detected at the behavioural level.
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30. |
- Low, W C, et al.
(författare)
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Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
- 2007
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 130:Part 2, s. 357-367
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Tidskriftsartikel (refereegranskat)abstract
- Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.
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31. |
- Malipiero, Ursula, et al.
(författare)
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TGF beta receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis
- 2006
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 129, s. 2404-2415
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Tidskriftsartikel (refereegranskat)abstract
- In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1 beta (IL-1 beta). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGF beta) is a potent deactivator of PMN and macrophages since TGF beta suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGF beta receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGF beta receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGF beta was found to impair the expression of L (leucocyte)-selectin on PMN from control mice but not from mice lacking TGF beta receptor II. L-Selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGF beta signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearance.
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32. |
- Malmgren, Kristina, 1952, et al.
(författare)
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Seizure outcome after resective epilepsy surgery in patients with low IQ.
- 2008
-
Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 131:Pt 2, s. 535-42
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Tidskriftsartikel (refereegranskat)abstract
- Epilepsy surgery has been questioned for patients with low IQ, since a low cognitive level is taken to indicate a widespread disturbance of cerebral function with unsatisfactory prognosis following resective surgery. The prevalence of epilepsy in patients with cognitive dysfunction is, however, higher than in the general population and the epilepsy is often more severe and difficult to treat. It is therefore important to try to clarify whether IQ predicts seizure outcome after resective epilepsy surgery. The Swedish National Epilepsy Surgery Register, which includes data on all epilepsy surgery procedures in Sweden since 1990, was analysed for all resective procedures performed 1990-99. Sustained seizure freedom with or without aura at the 2-year follow-up was analysed as a function of pre-operative IQ level categorized as IQ <50, IQ 50-69 and IQ >or=70 and was also adjusted for the following variables: age at epilepsy onset, age at surgery, pre-operative seizure frequency, pre-operative neurological impairment, resection type and histopathological diagnosis. Four hundred and forty-eight patients underwent resective epilepsy surgery in Sweden from 1990 to 1999 and completed the 2-year follow-up: 72 (16%) had IQ <70, (18 with IQ <50 and 54 with IQ 50-69) and 376 IQ >or=70. There were 313 adults and 135 children or=70 group. There was a significant relation between IQ category and seizure freedom [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.27-0.62] and this held also when adjusting for clinical variables [OR 0.58 (95% CI 0.35-0.95)]. In this population-based epilepsy surgery series, IQ level was shown to be an independent predictor of seizure freedom at the 2-year follow-up. However, many of the low-IQ patients benefit from surgery, especially patients with lesions. Low IQ should not exclude patients from resective epilepsy surgery, but is an important prognostic factor to consider in the counselling process.
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33. |
- Marklund, Petter, 1968-, et al.
(författare)
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Temporal dynamics of basal ganglia under-recruitment in Parkinson's disease : transient caudate abnormalities during updating of working memory
- 2009
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 132:2, s. 336-346
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Tidskriftsartikel (refereegranskat)abstract
- Using hybrid-blocked/event-related fMRI and the 2-back taskwe aimed to decompose tonic and phasic temporal dynamics ofbasal ganglia response abnormalities in working memory associatedwith early untreated Parkinson's disease. In view of the tonic/phasicdopamine hypothesis, which posits a functional division betweenphasic D2-dependent striatal updating processes and tonic D1-dependentprefrontal context-maintenance processes, we predicted thatnewly diagnosed, drug-naïve Parkinson's disease patients,with selective striatal dopamine deprivation, would demonstratetransient rather than sustained activation changes in the basalganglia during 2-back performance. Task-related activation patternswithin discrete basal ganglia structures were directly comparedbetween patients and healthy elderly controls. The obtainedresults yielded uniquely transient underactivation foci in caudatenuclei, putamen and globus pallidus in Parkinson's disease patients,which indicates suboptimal phasic implementation of striatalD2-dependent gating mechanisms during updating. Sustained underactivationwas only seen in the anterior putamen, which may reflect initialsigns of tonic control impairment. No significant changes wereexhibited in prefrontal cortex. The present findings resonatewell with the tonic/phasic dopamine account and suggest thatbasal ganglia under-recruitment associated with executive dysfunctionin early Parkinson's disease might predominantly stem from deficienciesin phasic executive components subserved by striatum.
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34. |
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35. |
- Munoz, Ana, et al.
(författare)
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Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia.
- 2008
-
Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 131, s. 3380-3394
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Tidskriftsartikel (refereegranskat)abstract
- Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT(1A) and 5-HT(1B) agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT(1) agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.
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36. |
- Olsen, Rikke K J, et al.
(författare)
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ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.
- 2007
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 130:Pt 8, s. 2045-54
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Tidskriftsartikel (refereegranskat)abstract
- Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.
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37. |
- Piccini, P, et al.
(författare)
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Factors affecting the clinical outcome after neural transplantation in Parkinson's disease
- 2005
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 128:12, s. 2977-2986
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Tidskriftsartikel (refereegranskat)abstract
- Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson's disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and F-18-dopa and C-11-raclopride PET, factors which may influence the functional outcome after transplantation. We observed increased F-18-dopa uptake in the grafted putamen, signifying continued survival of the transplanted dopaminergic neurons, in parallel with a progressive reduction of F-18-dopa uptake in non-grafted regions for the whole patient group. The patients with the best functional outcome after transplantation exhibited no dopaminergic denervation in areas outside the grafted areas either preoperatively or at 1 or 2 years post-operatively. In contrast, patients with no or modest clinical benefit showed reduction of F-18-dopa in ventral striatum prior to or following transplantation, which may have limited graft-induced improvement. We obtained no evidence that dyskinesias were caused by abnormal dopamine (DA) release from the grafts. As has been observed for intrinsic dopaminergic neurons, there was a significant correlation between F-18-dopa uptake and methamphetamine-induced change of C-11-raclopride binding (as a measure of DA release) in the putamen containing the graft. Furthermore, we observed no correlation between C-11-raclopride binding in anterior, posterior or entire putamen under basal conditions or after methamphetamine, and dyskinesia severity scores in the contralateral side of the body. Withdrawal of immunosuppression at 29 months after transplantation caused no reduction of F-18-dopa uptake or worsening of UPDRS motor score, indicating continued survival and function of the graft. However, patients showed increased dyskinesia scores, which might have been caused either by growth of the graft or worsening of a low-grade inflammation around the graft. These findings indicate that poor outcome after transplantation is associated with progressive dopaminergic denervation in areas outside the grafts, a process which may have started already before surgery. Also, that the development of dyskinesias after transplantation is not associated with excessive DA release from the grafts. Finally, our data provide evidence that long-term immunosuppression can be withdrawn without interfering with graft survival or the motor recovery induced by transplantation.
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38. |
- Pouladi, Mahmoud A, et al.
(författare)
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Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin.
- 2009
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 132, s. 919-932
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in clinical Huntington disease, we chose to assess whether a model for Huntington disease not subject to environmental stressors, namely the YAC mouse model of Huntington disease, displays a depressive phenotype. Indeed, the YAC transgenic mice recapitulate the early depressive phenotype of Huntington disease as assessed by the Porsolt forced swim test as well as the sucrose intake test as a measure of anhedonia. The YAC model mirrors clinical Huntington disease in that there were no effects of CAG repeat length or disease duration on the depressive phenotype. The depressive phenotype was completely rescued in YAC transgenic animals expressing a variant of mutant huntingtin that is resistant to cleavage at amino acid 586 suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on this aspect of the disease. In conclusion, our study provides strong support for a primary neurobiological basis for depression in Huntington disease.
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39. |
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40. |
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41. |
- Thorsell, Annika, et al.
(författare)
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Viral vector-induced amygdala NPY overexpression reverses increased alcohol intake caused by repeated deprivations in Wistar rats
- 2007
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 130:Pt 5, s. 1330-1337
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Tidskriftsartikel (refereegranskat)abstract
- Acute administration of neuropeptide Y (NPY) modulates alcohol intake in genetic and chemical models of high intake, while leaving intake unaffected during 'normal' or baseline conditions. In non-selected, normal rat lines, alcohol consumption can be increased by prolonged exposure to alcohol, and it is unclear what effect a constitutive increase in NPY function will have on alcohol intake. The purpose of the present study was to examine the effects on alcohol intake of an inducible, constitutive overexpression of NPY, one of the most abundant neuropeptides in the central nervous system. A liquid diet was used in combination with repeated alcohol deprivation sessions to increase alcohol intake in normal Wistar rats. We then examined the effect of NPY overexpression in the amygdala on excessive alcohol intake produced by prolonged exposure to alcohol and alcohol deprivation. Repeated withdrawal increased alcohol consumption in a 24-h continuous access two-bottle choice model. Both the number of withdrawals as well as the length of the withdrawal periods affected alcohol consumption with an increased intake resulting from multiple withdrawals and the alcohol deprivation effect being enhanced by longer periods of abstinence. The increase in intake following repeated abstinence was blunted by intra-amygdala administration of a Sindbis viral vector containing NPY cDNA. Amygdala NPY overexpression also was demonstrated to be anxiolytic in the open field test. Repeated withdrawal in combination with a history of alcohol consumption significantly elevated alcohol intake, and the amygdala may mediate the transition to high-drinking states in this model.
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42. |
- Tikka, Saara, et al.
(författare)
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Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients
- 2009
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 132, s. 933-939
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by mutations in NOTCH3 gene, which encodes a large transmembrane receptor Notch3. The key pathological finding is the accumulation of granular osmiophilic material (GOM), which contains extracellular domains of Notch3, on degenerating vascular smooth muscle cells (VSMCs). GOM has been considered specifically diagnostic for CADASIL, but the reports on the sensitivity of detecting GOM in patients skin biopsy have been contradictory. To solve this contradiction, we performed a retrospective investigation of 131 Finnish, Swedish and French CADASIL patients, who had been adequately examined for both NOTCH3 mutation and presence of GOM. The patients were examined according to the diagnostic practice in each country. NOTCH3 mutations were assessed by restriction enzyme analysis of specific mutations or by sequence analysis. Presence of GOM was examined by electron microscopy (EM) in skin biopsies. Biopsies of 26 mutation-negative relatives from CADASIL families served as the controls. GOM was detected in all 131 mutation positive patients. Altogether our patients had 34 different pathogenic mutations which included three novel point mutations (p.Cys67Ser, p.Cys251Tyr and p.Tyr1069Cys) and a novel duplication (p.Glu434_Leu436dup). The detection of GOM by EM in skin biopsies was a highly reliable diagnostic method: in this cohort the congruence between NOTCH3 mutations and presence of GOM was 100. However, due to the retrospective nature of this study, exact figure for sensitivity cannot be determined, but it would require a prospective study to exclude possible selection bias. The identification of a pathogenic NOTCH3 mutation is an indisputable evidence for CADASIL, but demonstration of GOM provides a cost-effective guide for estimating how far one should proceed with the extensive search for a new or an uncommon mutations among the presently known over 170 different NOTCH3 gene defects. The diagnostic skin biopsy should include the border zone between deep dermis and upper subcutis, where small arterial vessels of correct size are located. Detection of GOM requires technically adequate biopsies and distinction of true GOM from fallacious deposits. If GOM is not found in the first vessel or biopsy, other vessels or additional biopsies should be examined.
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43. |
- Wallgren-Pettersson, Carina, et al.
(författare)
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Distal myopathy caused by homozygous missense mutations in the nebulin gene
- 2007
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 130:Pt 6, s. 1465-1476
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Tidskriftsartikel (refereegranskat)abstract
- We describe a novel, recessively inherited distal myopathy caused by homozygous missense mutations in the nebulin gene (NEB), in which other combinations of mutations are known to cause nemaline (rod) myopathy (NM). Two different missense mutations were identified in homozygous form in seven Finnish patients from four unrelated families with childhood or adult-onset foot drop. Both mutations, when combined in compound heterozygous form with more disruptive mutations in NEB, are known to cause NM. Hitherto, no patients with NM have been found to have two missense mutations in NEB. Muscle weakness predominantly affected ankle dorsiflexors, finger extensors and neck flexors, a distribution different both from the patterns of weakness seen in NM caused by NEB mutations, and those of the known recessively inherited distal myopathies. Singleton cases need to be distinguished from the Laing type of distal myopathy. Histologically, this myopathy differs from NM in that nemaline bodies were not detectable with routine light microscopy, and they were inconspicuous or absent even with electron microscopy. Rimmed vacuoles, commonly seen in other distal myopathies, were not a feature. We conclude that homozygous missense mutations in NEB cause a novel distal myopathy, predominantly involving lower leg extensor muscles, finger extensors and neck flexors.
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45. |
- Zrinzo, Ludvic, et al.
(författare)
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Stereotactic localization of the human pedunculopontine nucleus : atlas-based coordinates and validation of a magnetic resonance imaging protocol for direct localization.
- 2008
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 131:Pt 6, s. 1588-98
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Tidskriftsartikel (refereegranskat)abstract
- The pedunculopontine nucleus (PPN) is a promising new target for deep brain stimulation (DBS) in parkinsonian patients with gait disturbance and postural instability refractory to other treatment modalities. This region of the brain is unfamiliar territory to most functional neurosurgeons. This paper reviews the anatomy of the human PPN and describes novel, clinically relevant methods for the atlas-based and MRI-based localization of the nucleus. These two methods of PPN localization are evaluated and compared on stereotactic MRI data acquired from a diverse group of 12 patients undergoing implantation of deep brain electrodes at sites other than the PPN. Atlas-based coordinates of the rostral and caudal PPN poles in relation to fourth ventricular landmarks were established by amalgamating information sourced from two published human brain atlases. These landmarks were identified on acquired T1 images and atlas-derived coordinates used to plot the predicted PPN location on all 24 sides. Images acquired using a specifically modified, proton-density MRI protocol were available for each patient and were spatially fused to the T1 images. This widely available and rapid protocol provided excellent definition between gray and white matter within the region of interest. Together with an understanding of the regional anatomy, direct localization of the PPN was possible on all 24 sides. The coordinates for each directly localized nucleus were measured in relation to third and fourth ventricular landmarks. The mean (SD) of the directly localized PPN midpoints was 6.4 mm (0.5) lateral, 3.5 mm (1.0) posterior and 11.4 mm (1.2) caudal to the posterior commissure in the anterior commissure-posterior commissure plane. For the directly localized nucleus, there was similar concordance for the rostral pole of the PPN in relation to third and fourth ventricular landmarks (P>0.05). For the caudal PPN pole, fourth ventricular landmarks provided greater concordance with reference to the anteroposterior coordinate (P<0.001). There was a significant difference between localization of the PPN poles as predicted by atlas-based coordinates and direct MRI localization. This difference affected mainly the rostrocaudal coordinates; the mean lateral and anteroposterior coordinates of the directly localized PPN poles were within 0.5 mm of the atlas-based predicted values. Our findings provide simple, rapid and precise methods that are of clinical relevance to the atlas-based and direct stereotactic localization of the human PPN. Direct MRI localization may allow greater individual accuracy than that afforded by atlas-based coordinates when localizing the human PPN and may be relevant to groups evaluating the clinical role of PPN DBS.
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47. |
- Carlsson, Thomas, et al.
(författare)
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Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors.
- 2005
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156. ; 128:3, s. 559-569
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Tidskriftsartikel (refereegranskat)abstract
- Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that is effective in reducing L-DOPA-induced dyskinesias by >85%, and reverse lesion-induced motor impairments. Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer. These findings form a strong basis for replacing, or supplementing, conventional systemic L-DOPA therapy by continuous intrastriatal DOPA using in vivo gene transfer in the treatment of patients with advanced Parkinson's disease.
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