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  • 851.
    Wittmann, Walter
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Schimmang, Thomas
    Univ Valladolid, Inst Biol & Mol Genet, Valladolid 47003, Spain.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Progressive effects of N-myc deficiency on proliferation, neurogenesis, and morphogenesis in the olfactory epithelium2014In: Developmental Neurobiology, ISSN 1932-8451, E-ISSN 1932-846X, Vol. 74, no 6, p. 643-656Article in journal (Refereed)
    Abstract [en]

    N-myc belongs to the myc proto-oncogene family, which is involved in numerous cellular processes such as proliferation, growth, apoptosis, and differentiation. Conditional deletion of N-myc in the mouse nervous system disrupted brain development, indicating that N-myc plays an essential role during neural development. How the development of the olfactory epithelium and neurogenesis within are affected by the loss of N-myc has, however, not been determined. To address these issues, we examined an N-myc(Foxg1Cre) conditional mouse line, in which N-myc is depleted in the olfactory epithelium. First changes in N-myc mutants were detected at E11.5, with reduced proliferation and neurogenesis in a slightly smaller olfactory epithelium. The phenotype was more pronounced at E13.5, with a complete lack of Hes5-positive progenitor cells, decreased proliferation, and neurogenesis. In addition, stereological analyses revealed reduced cell size of post-mitotic neurons in the olfactory epithelium, which contributed to a smaller olfactory pit. Furthermore, we observed diminished proliferation and neurogenesis also in the vomeronasal organ, which likewise was reduced in size. In addition, the generation of gonadotropin-releasing hormone neurons was severely reduced in N-myc mutants. Thus, diminished neurogenesis and proliferation in combination with smaller neurons might explain the morphological defects in the N-myc depleted olfactory structures. Moreover, our results suggest an important role for N-myc in regulating ongoing neurogenesis, in part by maintaining the Hes5-positive progenitor pool. In summary, our results provide evidence that N-myc deficiency in the olfactory epithelium progressively diminishes proliferation and neurogenesis with negative consequences at structural and cellular levels. 

  • 852.
    Wuolikainen, Anna
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Metabolomics studies of ALS: a multivariate search for clues about a devastating disease2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS), also known as Charcot’s disease, motor neuron disease (MND) and Lou Gehrig’s disease, is a deadly, adult-onset neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, resulting in evolving paresis of the linked muscles. ALS is defined by classical features of the disease, but may present as a wide spectrum of phenotypes. About 10% of all ALS cases have been reported as familial, of which about 20% have been associated with mutations in the gene encoding for CuZn superoxide dismutase (SOD1). The remaining cases are regarded as sporadic. Research has advanced our understanding of the disease, but the cause is still unknown, no reliable diagnostic test exists, no cure has been found and the current therapies are unsatisfactory. Riluzole (Rilutek®) is the only registered drug for the treatment of ALS. The drug has shown only a modest effect in prolonging life and the mechanism of action of riluzole is not yet fully understood. ALS is diagnosed by excluding diseases with similar symptoms. At an early stage, there are numerous possible diseases that may present with similar symptoms, thereby making the diagnostic procedure cumbersome, extensive and time consuming with a significant risk of misdiagnosis. Biomarkers that can be developed into diagnostic test of ALS are therefore needed. The high number of unsuccessful attempts at finding a single diseasespecific marker, in combination with the complexity of the disease, indicates that a pattern of several markers is perhaps more likely to provide a diagnostic signature for ALS. Metabolomics, in combination with chemometrics, can be a useful tool with which to study human disease. Metabolomics can screen for small molecules in biofluids such as cerebrospinal fluid (CSF) and chemometrics can provide structure and tools in order to handle the types of data generated from metabolomics. In this thesis, ALS has been studied using a combination of metabolomics and chemometrics. Collection and storage of CSF in relation to metabolite stability have been extensively evaluated. Protocols for metabolomics on CSF samples have been proposed, used and evaluated. In addition, a new feature of data processing allowing new samples to be predicted into existing models has been tested, evaluated and used for metabolomics on blood and CSF. A panel of potential biomarkers has been generated for ALS and subtypes of ALS. An overall decrease in metabolite concentration was found for subjects with ALS compared to their matched controls. Glutamic acid was one of the metabolites found to be decreased in patients with ALS. A larger metabolic heterogeneity was detected among SALS cases compared to FALS. This was also reflected in models of SALS and FALS against their respective matched controls, where no significant difference from control was found for SALS while the FALS samples significantly differed from their matched controls. Significant deviating metabolic patterns were also found between ALS subjects carrying different mutations in the gene encoding SOD1.

  • 853. Wåhlin, A.
    et al.
    Fordell, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ekman, U.
    Lenfeldt, N.
    Malm, J.
    Rehabilitation of chronic spatial neglect strengthens functional connectivity between nodes of the dorsal attention networkManuscript (preprint) (Other academic)
  • 854.
    Wåhlin, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    In healthy elderly the volumes of several brain regions are related to pulsatility in cerebral arteries and cerebrospinal fluidManuscript (preprint) (Other academic)
  • 855.
    Wåhlin, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Intracranial pulsatility is associated with regional brain volume in elderly individuals2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 2, p. 365-372Article in journal (Refereed)
    Abstract [en]

    Excessive intracranial pulsatility is thought to damage the cerebral microcirculation, causing cognitive decline in elderly individuals. We investigated relationships between brain structure and measures related to intracranial pulsatility among healthy elderly. Thirty-seven stroke-free, non-demented individuals (62-82 years of age) were included. We assessed brain structure, invasively measured cerebrospinal fluid (CSF) pulse pressure, and magnetic resonance-quantified arterial and CSF flow pulsatility, as well as arterial pulse pressure. Using both multivariate partial least squares and ordinary regression analyses, we identified a significant pattern of negative relationships between the volume of several brain regions and measures of intracranial pulsatility. The strongest relationships concerned the temporal lobe cortex and hippocampus. These findings were also coherent with observations of positive relationships between intracranial pulsatility and ventricular volume. In conclusion, elderly subjects with high intracranial pulsatility display smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain. This calls for research investigating altered intracranial cardiac-related pulsatile stress as a potential risk factor that may cause or worsen the prognosis in subjects developing cognitive impairment and dementia.

  • 856.
    Wåhlin, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Wieben, O
    Johnson, KM
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Measuring pulsatile flow in cerebral arteries using 4D phase-contrast magnetic resonance imaging2013In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 34, no 9, p. 1740-1745Article in journal (Other academic)
    Abstract [en]

    BACKGROUND AND PURPOSE: 4D PCMRI can be used to quantify pulsatile hemodynamics in multiple cerebral arteries. The aim of this study was to compare 4D PCMRI and 2D PCMRI for assessments of pulsatile hemodynamics in major cerebral arteries. MATERIALS AND METHODS: We scanned the internal carotid artery, the anterior cerebral artery, the basilar artery, and the middle cerebral artery in 10 subjects with a single 4D and multiple 2D PCMRI acquisitions by use of a 3T system and a 32-channel head coil. We assessed the agreement regarding net flow and the volume of arterial pulsatility (V) for all vessels. RESULTS: 2D and 4D PCMRI produced highly correlated results, with r = 0.86 and r = 0.95 for V and net flow, respectively (n = 69 vessels). These values increased to r = 0.93 and r = 0.97, respectively, during investigation of a subset of measurements with <5% variation in heart rate between the 4D and 2D acquisition (n = 31 vessels). Significant differences were found for ICA and MCA net flow (P = .004 and P < .001, respectively) and MCA V (P = .006). However, these differences were attenuated and no longer significant when the subset with stable heart rate (n = 31 vessels) was analyzed. CONCLUSIONS: 4D PCMRI provides a powerful methodology to measure pulsatility of the larger cerebral arteries from a single acquisition. A large part of differences between measurements was attributed to physiologic variations. The results were consistent with 2D PCMRI.

  • 857.
    Wåhlin, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Fordell, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ekman, Urban
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Lenfeldt, Niklas
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rehabilitation in chronic spatial neglect strengthens resting-state connectivity2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, no 3, p. 254-259Article in journal (Refereed)
    Abstract [en]

    Objectives: Rehabilitation of patients with chronic visuospatial neglect is underexplored, and little is known about neural mechanisms that can be exploited to promote recovery. In this study, we present data on resting-state functional connectivity within the dorsal attention network (DAN) in chronic neglect patients as they underwent training in a virtual reality (VR) environment that improved left-side awareness.

    Methods: The study included 13 patients with visuospatial neglect persisting more than six months after a right-sided stroke. The patients underwent resting-state functional magnetic resonance imaging (fMRI). Scans were collected at baseline and after five weeks of intense training. We specifically examined resting-state functional connectivity within the DAN. In addition, using spatial concordance correlation, we compared changes in the spatial topology of the DAN with that of other networks.

    Results: We found a longitudinal increase in interhemispheric functional connectivity between the right frontal eye field and the left intraparietal sulcus following training (before: 0.33 +/- 0.17 [mean +/- SD]; after: 0.45 +/- 0.13; P = 0.004). The spatial concordance analyses indicated that training influenced the DAN connectivity more than any of the other networks.

    Conclusion: Intense VR training that improved left-sided awareness in chronic stroke patients also increased sporadic interhemispheric functional connectivity within the DAN. Specifically, a region responsible for saccadic eye movement to the left became more integrated with the left posterior parietal cortex. These results highlight a mechanism that should be exploited in the training of patients with chronic visuospatial neglect.

  • 858. Wårdell, Karin
    et al.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Richter, Johan
    Antonsson, Johan
    Eriksson, Ola
    Zsigmond, Peter
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Hariz, Marwan I
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Intracerebral microvascular measurements during deep brain stimulation implantation using laser Doppler perfusion monitoring2007In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 85, no 6, p. 279-286Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate if laser Doppler perfusion monitoring (LDPM) can be used in order to differentiate between gray and white matter and to what extent microvascular perfusion can be recorded in the deep brain structures during stereotactic neurosurgery. An optical probe constructed to fit in the Leksell Stereotactic System was used for measurements along the trajectory and in the targets (globus pallidus internus, subthalamic nucleus, zona incerta, thalamus) during the implantation of deep brain stimulation leads (n = 22). The total backscattered light intensity (TLI) reflecting the grayness of the tissue, and the microvascular perfusion were captured at 128 sites. Heartbeat-synchronized pulsations were found at all perfusion recordings. In 6 sites the perfusion was more than 6 times higher than the closest neighbor indicating a possible small vessel structure. TLI was significantly higher (p < 0.005) and the perfusion significantly lower (p < 0.005) in positions identified as white matter in the respective MRI batch. The measurements imply that LDPM has the potential to be used as an intracerebral guidance tool.

  • 859. Yang, Fei
    et al.
    Pedersen, Nancy L
    Ye, Weimin
    Liu, Zhiwei
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Trolle Lagerros, Ylva
    Bellocco, Rino
    Alfredsson, Lars
    Knutsson, Anders
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Galanti, Maria Rosaria
    Lager, Anton C J
    Araghi, Marzieh
    Lundberg, Michael
    Magnusson, Cecilia
    Wirdefeldt, Karin
    Moist smokeless tobacco (Snus) use and risk of Parkinson's disease2017In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 46, no 3, p. 872-880Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cigarette smoking is associated with a lower risk of Parkinson's disease. It is unclear what constituent of tobacco smoke may lower the risk. Use of Swedish moist smokeless tobacco (snus) can serve as a model to disentangle what constituent of tobacco smoke may lower the risk. The aim of this study was to determine whether snus use was associated with a lower risk of Parkinson's disease.

    METHODS: Individual participant data were collected from seven prospective cohort studies, including 348 601 men. We used survival analysis with multivariable Cox regression to estimate study-specific relative risk of Parkinson's disease due to snus use, and random-effects models to pool estimates in a meta-analysis. The primary analyses were restricted to never-smokers to eliminate the potential confounding effect of tobacco smoking.

    RESULTS: During a mean follow-up time of 16.1 years, 1199 incident Parkinson's disease cases were identified. Among men who never smoked, ever-snus users had about 60% lower Parkinson's disease risk compared with never-snus users [pooled hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28-0.61]. The inverse association between snus use and Parkinson's disease risk was more pronounced in current (pooled HR 0.38, 95% CI 0.23-0.63), moderate-heavy amount (pooled HR 0.41, 95% CI 0.19-0.90) and long-term snus users (pooled HR 0.44, 95% CI 0.24-0.83).

    CONCLUSIONS: Non-smoking men who used snus had a substantially lower risk of Parkinson's disease. Results also indicated an inverse dose-response relationship between snus use and Parkinson's disease risk. Our findings suggest that nicotine or other components of tobacco leaves may influence the development of Parkinson's disease.

  • 860. Zachau, A C
    et al.
    Strigård, Karin
    Division of Surgery, CLINTEC, Karolinska Institutet, Department of Surgical Gastroenterology, Karolinska University Hospital, Huddinge, Sweden.
    Baig, S
    Höjeberg, B
    Olsson, Tomas
    Distribution of plasma cells secreting antibodies against nervous tissue antigens during experimental allergic encephalomyelitis enumerated by a nitrocellulose immunospot assay.1989In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 91, no 3, p. 323-336Article in journal (Refereed)
    Abstract [en]

    The B cell response to central nervous system (CNS) myelin and myelin basic protein, as well as total numbers of IgG secreting cells, was studied in acute experimental allergic encephalomyelitis using a nitrocellulose immunospot assay. The method was able to detect single plasma cells secreting antibodies. Cells secreting antibodies against myelin antigens were detected in regional lymph node cell suspension by day 5 post-immunization (p.i.). At that time no anti-myelin antibodies were detected free in serum. Later, at day 15 p.i., specific antibody secreting cells were found in bone marrow and spleen indicating a generalization of the immune response. The B cell response became partly sequestered to the target of immune attack since an increased number of IgG secreting cells was detected among mononuclear cells recovered from the CNS. Studies of cellular secretion of antibodies rather than free levels in body fluids may be a more accurate reflection of the in vivo B cell response. These findings may be generally considered in studies of B cell mediated immunity in neuroinflammatory diseases.

  • 861.
    Zarrinkoob, Laleh
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Cerebral blood flow distribution, collateral function and pulsatility in healthy and in patients with symptomatic carotid stenosis : a magnetic resonance imaging approach2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: For the detection and treatment of early cerebral vascular disease it is of paramount importance to first understand the normal physiology of the cerebral vasculature, and subsequently, to understand how and when pathology can develop from that. This is especially important as the population above 65 years of age is increasing and aging itself is an established risk factor for the development of cerebral vascular disease. This, however, is not always an easy task, since there is a subtle balance and overlap between age-related physiological and pathophysiological changes in the arterial system. Atherosclerotic changes that lead to the development of carotid artery stenosis are responsible for about one fifth of all ischemic strokes. Today, the current state of evidence and the algorithm for carotid revascularization is mainly focused on the degree of carotid stenosis and not on its impact on cerebral hemodynamics. One reason for this is the lack of a non-invasive method, that allows for repeated investigations and provides accurate and reliable results to study cerebral hemodynamic changes. The overall aim of this thesis was to explore and develop a comprehensive approach to investigate the cerebral blood flow distribution, collateral function and pulsatility in healthy subjects and in patients with symptomatic carotid stenosis using a phase-contrast magnetic resonance imaging (PCMRI) platform. The thesis is based on four scientific papers (papers I—IV). 

    Methods: In papers I and II, 49 healthy young (mean 25 years) and 45 healthy elderly (mean 71 years) subjects were included. 2D PCMRI was used to assess cerebral blood flow rate (BFR), pulsatility index (PI) and dampening factor (DF) in 15 cerebral arteries and in the ophthalmic arteries (OA). Thirty-eight patients (mean 72 years) with symptomatic carotid stenosis were included in paper III. Nineteen of these patients (mean 71 years) underwent carotid endarterectomy (CEA) (paper IV). 4D PCMRI was used for BFR assessment in papers III and IV. BFR, its distribution and collateral routes, was measured in 17 cerebral arteries and in the OA. The BFR on ipsilateral side (with symptomatic stenosis) was compared to the contralateral side (papers III and IV). BFR laterality was defined as contralateral BFR minus ipsilateral BFR in paired arteries and, BFR was compared before and after CEA (paper IV).

    Results: On average, in healthy subjects, 72% of the total cerebral blood flow (tCBF) was distributed through the anterior circulation and 28% through the posterior circulation. The distribution was symmetrical and not affected by age, sex, or brain volume (paper I). Aging resulted in lower BFRs, increased pulsatility and reduced dampening capacity in cerebral arteries. Anatomical variations in the circle of Willis resulted in an asymmetrical distribution of blood flow (papers I and II). In patients with carotid stenosis, a lower BFR was found in the internal carotid artery (ICA) and its branches on the ipsilateral side. The anterior cerebral artery territory was bilaterally, primarily, supplied by the contralateral ICA. In addition to the supply through the ICA, the middle cerebral artery (MCA) territory on the ipsilateral side was secured by collateral supply from the OA and the posterior communicating arteries, seen as retrograde flow in those arteries. Despite these compensations, BFR in ipsilateral side MCA was lower, and this laterality was more pronounced in patients with severe carotid stenosis (≥70%). After CEA, the distribution of BFR going into the cerebral arteries was found to be symmetrically distributed. Total CBF increased postoperatively in patients with collateral recruitment preoperatively (n=9). The BFR laterality in MCA observed prior to CEA, was found only in the group of patients with collateral recruitment preoperatively (paper IV). The degree of stenosis did not differ between the groups with and without collateral recruitment. 

    Conclusions: This thesis provides a new and comprehensive approach to mapping and quantifying normal cerebral blood flow and pulsatility. By presenting the distribution of tCBF going into cerebral arteries, instead of using absolute values, the effect of age could be neutralized and the results can be applicable when describing healthy cerebral blood flow, regardless of age. 4D PCMRI made it possible to describe the altered blood flow distribution and collateral ranking in patients with carotid stenosis prior to CEA and its normalization after the procedure. Our findings highlight the importance of BFR quantification for understanding cerebral hemodynamics in patients with carotid stenosis. 4D PCMRI technique is a promising clinical tool for investigations of cerebral hemodynamics in patients with stroke.

  • 862.
    Zarrinkoob, Laleh
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Quantification and mapping of cerebral hemodynamics before and after carotid endarterectomy: a 4D PCMRI studyManuscript (preprint) (Other academic)
    Abstract [en]

    Background and purpose: A carotid stenosis can have a profound impact on the cerebral hemodynamics that cannot be inferred from the degree of stenosis by itself. We aimed to quantify and map the distribution of blood flow rate (BFR) in cerebral arteries before and after carotid endarterectomy (CEA), using four-dimensional phase-contrast magnetic resonance imaging (4D PCMRI).

    Methods: Nineteen patients (71±6 years, 2 women) with symptomatic carotid stenosis (≥50%)undergoing CEA were investigated using 4D PCMRI before and after surgery. BFR was measured in 17 cerebral arteries and in the ophthalmic arteries (OA). Collateral recruitment through the anterior and posterior communicating arteries, OA and the leptomeningeal arterial route was identified and quantified. BFR laterality was described as contralateral BFR minus ipsilateral BFR in paired arteries.

    Results: Total cerebral blood flow increased by 15% (p<0.01) after CEA. On the ipsilateral side, increased BFR was found after CEA in internal carotid artery (ICA) (246±62mL/min vs. 135±80mL/min; p<0.001), anterior cerebral artery (87±mL/min vs. 38±58mL/min; p<0.01) and middle cerebral artery (MCA) (149±43mL/min vs. 119±34mL/min; p<0.01), resulting in a postoperative BFR distribution without signs of laterality. In patients with preoperatively recruited collaterals (n=9), BFR laterality was found in MCA before, but not after, CEA (p<0.01). This laterality was not found in patients without collateral recruitment (n=10) (p=0.2). The degree of stenosis did not differ between the groups with vs. without collateral recruitment (p=0.85). 

    Conclusion: 4D PCMRI is a useful technique to quantify cerebral hemodynamic changes seen in patients with carotid stenosis before and after CEA. MCA laterality, seen in patients with collateral recruitment before CEA, pointed towards a hemodynamic disturbance in MCA territory for those patients. This study introduces a new and non-invasive way to evaluate cerebral hemodynamics due to carotid stenosis prior to and after CEA.

  • 863. Zeiler, Frederick A.
    et al.
    Ercole, Ari
    Beqiri, Erta
    Cabeleira, Manuel
    Aries, Marcel
    Zoerle, Tommaso
    Carbonara, Marco
    Stocchetti, Nino
    Smielewski, Peter
    Czosnyka, Marek
    Menon, David K.
    Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: a CENTER-TBI analysis2019In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 9, p. 1955-1964Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Impaired cerebrovascular reactivity in adult traumatic brain injury (TBI) is known to be associated with poor outcome. However, there has yet to be an analysis of the association between the comprehensively assessed intracranial hypertension therapeutic intensity level (TIL) and cerebrovascular reactivity.

    METHODS: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we derived pressure reactivity index (PRx) as the moving correlation coefficient between slow-wave in ICP and mean arterial pressure, updated every minute. Mean daily PRx, and daily % time above PRx of 0 were calculated for the first 7 days of injury and ICU stay. This data was linked with the daily TIL-Intermediate scores, including total and individual treatment sub-scores. Daily mean PRx variable values were compared for each TIL treatment score via mean, standard deviation, and the Mann U test (Bonferroni correction for multiple comparisons). General fixed effects and mixed effects models for total TIL versus PRx were created to display the relation between TIL and cerebrovascular reactivity.

    RESULTS: A total of 249 patients with 1230 ICU days of high frequency physiology matched with daily TIL, were assessed. Total TIL was unrelated to daily PRx. Most TIL sub-scores failed to display a significant relationship with the PRx variables. Mild hyperventilation (p < 0.0001), mild hypothermia (p = 0.0001), high levels of sedation for ICP control (p = 0.0001), and use vasopressors for CPP management (p < 0.0001) were found to be associated with only a modest decrease in mean daily PRx or % time with PRx above 0.

    CONCLUSIONS: Cerebrovascular reactivity remains relatively independent of intracranial hypertension therapeutic intensity, suggesting inadequacy of current TBI therapies in modulating impaired autoregulation. These findings support the need for investigation into the molecular mechanisms involved, or individualized physiologic targets (ICP, CPP, or Co2) in order to treat dysautoregulation actively.

  • 864. Zeiler, Frederick A.
    et al.
    Ercole, Ari
    Beqiri, Erta
    Cabeleira, Manuel
    Thelin, Eric P.
    Stocchetti, Nino
    Steyerberg, Ewout W.
    Maas, Andrew I. R.
    Menon, David K.
    Czosnyka, Marek
    Smielewski, Peter
    Koskinen, Lars-Owe
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Association between Cerebrovascular Reactivity Monitoring and Mortality Is Preserved When Adjusting for Baseline Admission Characteristics in Adult Traumatic Brain Injury: A CENTER-TBI Study2019In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042Article in journal (Refereed)
    Abstract [en]

    Cerebral autoregulation, as measured using the pressure reactivity index (PRx), has been related to global patient outcome in adult patients with traumatic brain injury (TBI). To date, this has been documented without accounting for standard baseline admission characteristics and intracranial pressure (ICP). We evaluated this association, adjusting for baseline admission characteristics and ICP, in a multi-center, prospective cohort. We derived PRx as the correlation between ICP and mean arterial pressure in prospectively collected multi-center data from the High-Resolution Intensive Care Unit (ICU) cohort of the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. Multi-variable logistic regression models were analyzed to assess the association between global outcome (measured as either mortality or dichotomized Glasgow Outcome Score-Extended [GOSE]) and a range of covariates (IMPACT [International Mission for Prognosis and Analysis of Clinical Trials] Core and computed tomography [CT] variables, ICP, and PRx). Performance of these models in outcome association was compared using area under the receiver operating curve (AUC) and Nagelkerke's pseudo-R2. One hundred ninety-three patients had a complete data set for analysis. The addition of percent time above threshold for PRx improved AUC and displayed statistically significant increases in Nagelkerke's pseudo-R2 over the IMPACT Core and IMPACT Core + CT models for mortality. The addition of PRx monitoring to IMPACT Core ± CT + ICP models accounted for additional variance in mortality, when compared to models with IMPACT Core ± CT + ICP alone. The addition of cerebrovascular reactivity monitoring, through PRx, provides a statistically significant increase in association with mortality at 6 months. Our data suggest that cerebrovascular reactivity monitoring may provide complementary information regarding outcomes in TBI.

  • 865. Zeiler, Frederick A.
    et al.
    Ercole, Ari
    Cabeleira, Manuel
    Beqiri, Erta
    Zoerle, Tommaso
    Carbonara, Marco
    Stocchetti, Nino
    Menon, David K.
    Lazaridis, Christos
    Smielewski, Peter
    Czosnyka, Marek
    Patient-specific ICP Epidemiologic Thresholds in Adult Traumatic Brain Injury: A CENTER-TBI Validation Study2019In: Journal of Neurosurgical Anesthesiology, ISSN 0898-4921, E-ISSN 1537-1921Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patient-specific epidemiologic intracranial pressure (ICP) thresholds in adult traumatic brain injury (TBI) have emerged, using the relationship between pressure reactivity index (PRx) and ICP, displaying stronger association with outcome over existing guideline thresholds. The goal of this study was to explore this relationship in a multi-center cohort in order to confirm the previous finding.

    METHODS: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit cohort, we derived individualized epidemiologic ICP thresholds for each patient using the relationship between PRx and ICP. Mean hourly dose of ICP was calculated for every patient for the following thresholds: 20, 22 mm Hg and the patient's individual ICP threshold. Univariate logistic regression models were created comparing mean hourly dose of ICP above thresholds to dichotomized outcome at 6 to 12 months, based on Glasgow Outcome Score-Extended (GOSE) (alive/dead-GOSE≥2/GOSE=1; favorable/unfavorable-GOSE 5 to 8/GOSE 1 to 4, respectively).

    RESULTS: Individual thresholds were identified in 65.3% of patients (n=128), in keeping with previous results (23.0±11.8 mm Hg [interquartile range: 14.9 to 29.8 mm Hg]). Mean hourly dose of ICP above individual threshold provides superior discrimination (area under the receiver operating curve [AUC]=0.678, P=0.029) over mean hourly dose above 20 mm Hg (AUC=0.509, P=0.03) or above 22 mm Hg (AUC=0.492, P=0.035) on univariate analysis for alive/dead outcome at 6 to 12 months. The AUC for mean hourly dose above individual threshold trends to higher values for favorable/unfavorable outcome, but fails to reach statistical significance (AUC=0.610, P=0.060). This was maintained when controlling for baseline admission characteristics.

    CONCLUSIONS: Mean hourly dose of ICP above individual epidemiologic ICP threshold has stronger associations with mortality compared with the dose above Brain Trauma Foundation defined thresholds of 20 or 22 mm Hg, confirming prior findings. Further studies on patient-specific epidemiologic ICP thresholds are required.

  • 866. Zeiler, Frederick A.
    et al.
    Ercole, Ari
    Cabeleira, Manuel
    Beqiri, Erta
    Zoerle, Tommaso
    Carbonara, Marco
    Stocchetti, Nino
    Menon, David K.
    Smielewski, Peter
    Czosnyka, Marek
    Compensatory-reserve-weighted intracranial pressure versus intracranial pressure for outcome association in adult traumatic brain injury: a CENTER-TBI validation study2019In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 7, p. 1275-1284Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Compensatory-reserve-weighted intracranial pressure (wICP) has recently been suggested as a supplementary measure of intracranial pressure (ICP) in adult traumatic brain injury (TBI), with a single-center study suggesting an association with mortality at 6 months. No multi-center studies exist to validate this relationship. The goal was to compare wICP to ICP for association with outcome in a multi-center TBI cohort.

    METHODS: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we derived ICP and wICP (calculated as wICP = (1 - RAP) × ICP; where RAP is the compensatory reserve index derived from the moving correlation between pulse amplitude of ICP and ICP). Various univariate logistic regression models were created comparing ICP and wICP to dichotomized outcome at 6 to 12 months, based on Glasgow Outcome Score-Extended (GOSE) (alive/dead-GOSE ≥ 2/GOSE = 1; favorable/unfavorable-GOSE 5 to 8/GOSE 1 to 4, respectively). Models were compared using area under the receiver operating curves (AUC) and p values.

    RESULTS: wICP displayed higher AUC compared to ICP on univariate regression for alive/dead outcome compared to mean ICP (AUC 0.712, 95% CI 0.615-0.810, p = 0.0002, and AUC 0.642, 95% CI 0.538-746, p < 0.0001, respectively; no significant difference on Delong's test), and for favorable/unfavorable outcome (AUC 0.627, 95% CI 0.548-0.705, p = 0.015, and AUC 0.495, 95% CI 0.413-0.577, p = 0.059; significantly different using Delong's test p = 0.002), with lower wICP values associated with improved outcomes (p < 0.05 for both). These relationships on univariate analysis held true even when comparing the wICP models with those containing both ICP and RAP integrated area under the curve over time (p < 0.05 for all via Delong's test).

    CONCLUSIONS: Compensatory-reserve-weighted ICP displays superior outcome association for both alive/dead and favorable/unfavorable dichotomized outcomes in adult TBI, through univariate analysis. Lower wICP is associated with better global outcomes. The results of this study provide multi-center validation of those seen in a previous single-center study.

  • 867. Zeiler, Frederick A
    et al.
    Ercole, Ari
    Cabeleira, Manuel
    Carbonara, Marco
    Stocchetti, Nino
    Menon, David K
    Smielewski, Peter
    Czosnyka, Marek
    Comparison of Performance of Different Optimal Cerebral Perfusion Pressure Parameters for Outcome Prediction in Adult Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study2019In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 36, no 10, p. 1505-1517Article in journal (Refereed)
    Abstract [en]

    It has been postulated previously that individualized cerebral perfusion pressure (CPP) targets can be derived from cerebrovascular reactivity indices. Differences between real CPP and target CPP (named generically optimal CPP) has been linked to global outcome in adult traumatic brain injury (TBI). Different vascular reactivity indices can be utilized in the determination. The goal of this study is to evaluate CPPopt parameters, derived from three intracranial pressure (ICP)-derived cerebrovascular reactivity indices, and determine which one is superior for 6- to 12-month outcome prediction. Using the prospectively collected data from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, the following indices of cerebrovascular reactivity were derived: pressure reactivity index (PRx; correlation between ICP and mean arterial pressure [MAP]), pulse amplitude index (PAx; correlation between pulse amplitude of ICP [AMP] and MAP), and RAC (correlation between AMP and CPP). CPPopt was derived using each index. Univariate logistic regression models were created to assess the association between CPPopt with global dichotomized outcome at 6 to 12 months, as assessed by Glasgow Outcome Score-Extended. Models were compared via area under the receiver operating curve (AUC) and Delong's Test. A total of 204 patients had available data. CPPopt derived from PRx, PAx, and RAC performed variably in their association with outcomes. PRx- and RAC-based CPPopt performed similarly, with RAC parameters trending towards highest AUC values. PAx-based CPPopt parameters failed to reach significant associations with dichotomized outcomes at 6 to 12 months. CPPopt parameters derived from PRx and RAC appear similar in their overall ability for 6- to 12-month outcome prediction in moderate/severe adult TBI.

  • 868. Zeiler, Frederick A.
    et al.
    Ercole, Ari
    Cabeleira, Manuel
    Zoerle, Tommaso
    Stocchetti, Nino
    Menon, David K.
    Smielewski, Peter
    Czosnyka, Marek
    Univariate comparison of performance of different cerebrovascular reactivity indices for outcome association in adult TBI: a CENTER-TBI study2019In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 6, p. 1217-1227Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Monitoring cerebrovascular reactivity in adult traumatic brain injury (TBI) has been linked to global patient outcome. Three intra-cranial pressure (ICP)-derived indices have been described. It is unknown which index is superior for outcome association in TBI outside previous single-center evaluations. The goal of this study is to evaluate indices for 6- to 12-month outcome association using uniform data harvested in multiple centers.

    METHODS: Using the prospectively collected data from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, the following indices of cerebrovascular reactivity were derived: PRx (correlation between ICP and mean arterial pressure (MAP)), PAx (correlation between pulse amplitude of ICP (AMP) and MAP), and RAC (correlation between AMP and cerebral perfusion pressure (CPP)). Univariate logistic regression models were created to assess the association between vascular reactivity indices with global dichotomized outcome at 6 to 12 months, as assessed by Glasgow Outcome Score-Extended (GOSE). Models were compared via area under the receiver operating curve (AUC) and Delong's test.

    RESULTS: Two separate patient groups from this cohort were assessed: the total population with available data (n = 204) and only those without decompressive craniectomy (n = 159), with identical results. PRx, PAx, and RAC perform similar in outcome association for both dichotomized outcomes, alive/dead and favorable/unfavorable, with RAC trending towards higher AUC values. There were statistically higher mean values for the index, % time above threshold, and hourly dose above threshold for each of PRx, PAx, and RAC in those patients with poor outcomes.

    CONCLUSIONS: PRx, PAx, and RAC appear similar in their associations with 6- to 12-month outcome in moderate/severe adult TBI, with RAC showing tendency to achieve stronger associations. Further work is required to determine the role for each of these cerebrovascular indices in monitoring of TBI patients.

  • 869. Zeiler, Frederick Adam
    et al.
    Aries, Marcel
    Cabeleira, Manuel
    van Essen, Thomas
    Stocchetti, Nino
    Menon, David
    Timofeev, Ivan
    Czosnyka, Marek
    Smieleweski, Peter
    Hutchinson, Peter John
    Ercole, Ari
    Statistical Cerebrovascular Reactivity Signal Properties after Secondary Decompressive Craniectomy in Traumatic Brain Injury: A CENTER-TBI Pilot Analysis2020In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042Article in journal (Refereed)
    Abstract [en]

    Decompressive craniectomy (DC) in traumatic brain injury (TBI) has been suggested to influence cerebrovascular reactivity. We aimed to determine if the statistical properties of vascular reactivity metrics and slow-wave relationships were impacted after DC, as such information would allow us to comment on whether vascular reactivity monitoring remains reliable after craniectomy. Using the CENTER-TBI high-resolution intensive care unit (ICU) cohort, we selected those secondary DC patients with high-frequency physiologic data for both: at least 24 hours before DC, and more than 48 hours post-DC. Data for all physiology measures was separated into: the 24 hours before DC, the first 48 hours post DC, and beyond 48 hours post-DC. We produced slow-wave data sheets for intra-cranial pressure (ICP) and mean arterial pressure (MAP) per patient. We also derived pressure reactivity index (PRx) as continuous cerebrovascular reactivity metrics updated every minute. The time-series behavior of PRx was modeled for each time period per patient. Finally, the relationship between ICP and MAP during these 3 time periods was assessed using time-series vector autoregressive integrative moving average (VARIMA) models, impulse response function (IRF) plots, and Granger causality testing. Ten patients were included in this study. Mean PRx and proportion of time above PRx thresholds were not affected by craniectomy. Similarly, PRx time-series structure was not affected by DC, when assessed in each individual patient. This was confirmed with Granger causality testing, and VARIMA IRF plotting for the MAP/ICP slow-wave relationship. PRx metrics and statistical time-series behavior appears not to be substantially influenced by DC. Similarly, there is little change in the relationship between slow-waves of ICP and MAP before and after DC. This may suggest that cerebrovascular reactivity monitoring in the setting of DC may still provide valuable information regarding autoregulation. Keywords: cerebrovascular reactivity, decompressive craniectomy, DC, PRx, TBI.

  • 870. Zetterberg, H.
    et al.
    Winblad, B.
    Bernick, C.
    Yaffe, K.
    Majdan, M.
    Johansson, G.
    Newcombe, V.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Sharp, D.
    Tenovuo, O.
    Blennow, K.
    Head trauma in sports - clinical characteristics, epidemiology and biomarkers2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 6, p. 624-634Article, review/survey (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is clinically divided into a spectrum of severities, with mild TBI being the least severe form and a frequent occurrence in contact sports, such as ice hockey, American football, rugby, horse riding and boxing. Mild TBI is caused by blunt nonpenetrating head trauma that causes movement of the brain and stretching and tearing of axons, with diffuse axonal injury being a central pathogenic mechanism. Mild TBI is in principle synonymous with concussion; both have similar criteria in which the most important elements are acute alteration or loss of consciousness and/or post-traumatic amnesia following head trauma and no apparent brain changes on standard neuroimaging. Symptoms in mild TBI are highly variable and there are no validated imaging or fluid biomarkers to determine whether or not a patient with a normal computerized tomography scan of the brain has neuronal damage. Mild TBI typically resolves within a few weeks but 10-15% of concussion patients develop postconcussive syndrome. Repetitive mild TBI, which is frequent in contact sports, is a risk factor for a complicated recovery process. This overview paper discusses the relationships between repetitive head impacts in contact sports, mild TBI and chronic neurological symptoms. What are these conditions, how common are they, how are they linked and can they be objectified using imaging or fluid-based biomarkers? It gives an update on the current state of research on these questions with a specific focus on clinical characteristics, epidemiology and biomarkers.

  • 871. Zhao, Charlie W.
    et al.
    Daley, Mark J.
    Pruszynski, J. Andrew
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Dept. of Computer Science, Western University, London, Ontario, Canada; Brain and Mind Institute, Western University, London, Ontario, Canada; Dept. of Physiology and Pharmacology, Western University, London, Ontario, Canada; Dept. of Psychology, Western University, London, Ontario, Canada; Robarts Research Institute, Western University, London, Ontario, Canada.
    Neural network models of the tactile system develop first-order units with spatially complex receptive fields2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0199196Article in journal (Refereed)
    Abstract [en]

    First-order tactile neurons have spatially complex receptive fields. Here we use machine-learning tools to show that such complexity arises for a wide range of training sets and network architectures. Moreover, we demonstrate that this complexity benefits network performance, especially on more difficult tasks and in the presence of noise. Our work suggests that spatially complex receptive fields are normatively good given the biological constraints of the tactile periphery.

  • 872.
    Zhu, Shaochun
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wu, Junfang
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Öhman, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wingsle, Gunnar
    Moritz, Thomas
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Trupp, Miles
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS2019In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 69, no 4, p. 643-657Article in journal (Refereed)
    Abstract [en]

    The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share some common molecular deficits including disruption of protein homeostasis leading to disease-specific protein aggregation. While insoluble protein aggregates are the defining pathological confirmation of diagnosis, patient stratification based on early molecular etiologies may identify distinct subgroups within a clinical diagnosis that would respond differently in therapeutic development programs. We are developing targeted multiple reaction monitoring (MRM) mass spectrometry methods to rigorously quantify CSF proteins from known disease genes involved in lysosomal, ubiquitin-proteasomal, and autophagy pathways. Analysis of CSF from 21 PD, 21 ALS, and 25 control patients, rigorously matched for gender, age, and age of sample, revealed significant changes in peptide levels between PD, ALS, and control. In patients with PD, levels of two peptides for chromogranin B (CHGB, secretogranin 1) were significantly reduced. In CSF of patients with ALS, levels of two peptides from ubiquitin carboxy-terminal hydrolase like protein 1 (UCHL1) and one peptide each for glycoprotein non-metastatic melanoma protein B (GPNMB) and cathepsin D (CTSD) were all increased. Analysis of patients with ALS separated into two groups based on length of survival after CSF sampling revealed that the increases in GPNMB and UCHL1 were specific for short-lived ALS patients. While analysis of additional cohorts is required to validate these candidate biomarkers, this study suggests methods for stratification of ALS patients for clinical trials and identifies targets for drug efficacy measurements during therapeutic development.

  • 873. Zhuravleva, Z. D.
    et al.
    Lebedeva, A. V.
    Volnova, A. B.
    Mukhina, I. V.
    Druzin, Michael Ya.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    The effect of glycine microinjections in the medial preoptic area of the hypothalamus on the sexual behavior of male rats2015In: Neurochemical Journal, ISSN 1819-7124, Vol. 9, no 2, p. 141-145Article in journal (Refereed)
    Abstract [en]

    The mechanisms that underlie the early loss of the male reproductive function are still unknown. Therefore, investigation of this problem is an important task. The medial preoptic nucleus takes part in the regulation of sexual behavior; however, the role of glycine transmission in this nucleus has not yet been studied. Our study focuses on these questions.

  • 874. Zrinzo, Ludvic
    et al.
    Akram, Harith
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, Unit Funct Neurosurg, London WC1N 3BG, England.
    Comment on "Appropriate MRI sequences are required to accurately determine lead location after deep brain stimulation surgery"2014In: Journal of clinical neuroscience, ISSN 0967-5868, E-ISSN 1532-2653, Vol. 21, no 12, p. 2257-2258Article in journal (Refereed)
  • 875. Zrinzo, Ludvic
    et al.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Deep brain stimulation for dystonia2014In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 120, no 6, p. 1496-1496Article in journal (Refereed)
  • 876.
    Zrinzo, Ludvic
    et al.
    UCL, UCL Inst Neurol, Unit Funct Neurosurg, Sobell Dept Motor Neurosci & Movement Disorders, London, England.
    Foltynie, Thomas
    UCL, UCL Inst Neurol, Unit Funct Neurosurg, Sobell Dept Motor Neurosci & Movement Disorders, London, England.
    Limousin, Patricia
    UCL, UCL Inst Neurol, Unit Funct Neurosurg, Sobell Dept Motor Neurosci & Movement Disorders, London, England.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Image-verified deep brain stimulation reduces risk and cost with no apparent impact on efficacy2012In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 27, no 12, p. 1585-1586Article in journal (Refereed)
  • 877. Zrinzo, Ludvic
    et al.
    Foltynie, Thomas
    Limousin, Patricia
    Hariz, Marwan I.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Deep brain stimulation and hemorrhage RESPONSE2012In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 116, no 4, p. 930-932Article in journal (Refereed)
  • 878. Zrinzo, Ludvic
    et al.
    Foltynie, Thomas
    Limousin, Patricia
    Hariz, Marwan I.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review Clinical article2012In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 116, no 1, p. 84-94Article, review/survey (Refereed)
    Abstract [en]

    Object. Hemorrhagic complications carry by far the highest risk of devastating neurological outcome in functional neurosurgery. Literature published over the past 10 years suggests that hemorrhage, although relatively rare, remains a significant problem. Estimating the true incidence of and risk factors for hemorrhage in functional neurosurgery is a challenging issue. Methods. The authors analyzed the hemorrhage rate in a consecutive series of 214 patients undergoing image-guided deep brain stimulation (DBS) lead placement without microelectrode recording (MER) and with routine postoperative MR imaging lead verification. They also conducted a systematic review of the literature on stereotactic ablative surgery and DBS over a 10-year period to determine the incidence and risk factors for hemorrhage as a complication of functional neurosurgery. Results. The total incidence of hemorrhage in our series of image-guided DBS was 0.9%: asymptomatic in 0.5%, symptomatic in 0.5%, and causing permanent deficit in 0.0% of patients. Weighted means calculated from the literature review suggest that the overall incidence of hemorrhage in functional neurosurgery is 5.0%, with asymptomatic hemorrhage occurring in 1.9% of patients, symptomatic hemorrhage in 2.1% and hemorrhage resulting in permanent deficit or death in 1.1%. Hypertension and age were the most important patient-related factors associated with an increased risk of hemorrhage. Risk factors related to surgical technique included use of MER, number of MER penetrations, as well as sulcal or ventricular involvement by the trajectory. The incidence of hemorrhage in studies adopting an image-guided and image-verified approach without MER was significantly lower than that reported with other operative techniques (p < 0.001 for total number of hemorrhages, p < 0.001 for asymptomatic hemorrhage, p < 0.004 for symptomatic hemorrhage, and p = 0.001 for hemorrhage leading to permanent deficit; Fisher exact test). Conclusions. Age and a history of hypertension are associated with an increased risk of hemorrhage in functional neurosurgery. Surgical factors that increase the risk of hemorrhage include the use of MER and sulcal or ventricular incursion. The meticulous use of neuroimaging-both in planning the trajectory and for target verification-can avoid all of these surgery-related risk factors and appears to carry a significantly lower risk of hemorrhage and associated permanent deficit. (DOI: 10.3171/2011.8.JNS101407)

  • 879. Zrinzo, Ludvic
    et al.
    Foltynie, Thomas
    Limousin, Patricia
    Hariz, Marwan I.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Response to: Editorial - Functional neurosurgery and hemorrhage2012In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 116, no 1, p. 83-83Article in journal (Refereed)
  • 880. Zrinzo, Ludvic
    et al.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Conclusions should be supported by the data presented2013In: British Journal of Neurosurgery, ISSN 0268-8697, E-ISSN 1360-046X, Vol. 27, no 4, p. 545-546Article in journal (Refereed)
  • 881. Zrinzo, Ludvic
    et al.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Errors of Image Coregistration may Necessitate Intraoperative Refinement in Functional Neurosurgery2013In: J NEUROL SURG PART A, ISSN 2193-6315, Vol. 74, no 5, p. 335-336Article in journal (Refereed)
  • 882. Zrinzo, Ludvic
    et al.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. UCL Institute of Neurology, University College London, London, United Kingdom.
    Hyam, Jonathan A.
    Foltynie, Thomas
    Limousin, Patricia
    A paradigm shift toward MRI-guided and MRI-verified DBS surgery2016In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 124, no 4, p. 1135-1137Article in journal (Refereed)
  • 883. Zrinzo, Ludvic
    et al.
    Zrinzo, Laurence V.
    Massey, Luke A.
    Thornton, John
    Parkes, Harold G.
    White, Mark
    Yousry, Tarek A.
    Strand, Catherine
    Revesz, Tamas
    Limousin, Patricia
    Hariz, Marwan I.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holton, Janice L.
    Targeting of the pedunculopontine nucleus by an MRI-guided approach: a cadaver study2011In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 118, no 10, p. 1487-1495Article in journal (Refereed)
    Abstract [en]

    Laboratory evidence suggests that the pedunculopontine nucleus (PPN) plays a central role in the initiation and maintenance of gait. Translational research has led to reports on deep brain stimulation (DBS) of the rostral brainstem in parkinsonian patients. However, initial clinical results appear to be rather variable. Possible factors include patient selection and the wide variability in anatomical location of implanted electrodes. Clinical studies on PPN DBS efficacy would, therefore, benefit from an accurate and reproducible method of stereotactic localization of the nucleus. The present study evaluates the anatomical accuracy of a specific protocol for MRI-guided stereotactic targeting of the PPN in a human cadaver. Imaging at 1.5 and 9.4 T confirmed electrode location in the intended region as defined anatomically by the surrounding fiber tracts. The spatial relations of each electrode track to the nucleus were explored by subsequent histological examination. This confirmed that the neuropil surrounding each electrode track contained scattered large neurons morphologically consistent with those of the subnucleus dissipatus and compactus of the PPN. The results support the accuracy of the described specific MR imaging protocol.

  • 884.
    Árnadóttir, Guðrún
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Occupational Therapy. 1Occupational Therapy Unit, Grensás, Landspítali University Hospital, Reykjavík; 2Division of Occupational Therapy, Faculty of Health, University of Akureyri, Akureyri, Iceland.
    Löfgren, Britta
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Occupational Therapy.
    Fisher, Anne G
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Occupational Therapy.
    Difference in impact of neurobehavioural dysfunction on Activities of Daily Living performance between right and left hemispheric stroke2010In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 42, no 10, p. 903-907Article in journal (Refereed)
    Abstract [en]

    Objective: To explore whether persons with right- and left-sided cerebrovascular accidents differ significantly in mean impact of neurobehavioural impairments on ability to perform activities of daily living. Design and subjects: Retrospective study of data from 215 persons (103 right-sided, 112 left-sided cerebrovascular accident). The Activities of daily living-focused Occupation-based Neurobehavioral Evaluation was used to evaluate ability on an activities of daily living scale and the impact of neurobehavioural impairment on ability on another scale. Methods: To control for possible differences in activities of daily living ability between groups, analysis of covariance, with activities of daily living ability as a covariate, was used to test for a significant difference in impact of neurobehavioural impairments on activities of daily living ability between groups. Results: Expected moderate correlation (r=-0.57) was obtained between activities of daily living ability and neurobehavioural impact measures, and there was no difference in mean neurobehavioural impact measures between groups (F [1, 212] = 2.910,p = 0.090). Conclusion: This study is the first: to explore directly the impact of neurobehavioural impairment on activities of daily living ability. While persons with right-sided and left-sided cerebrovascular accidents may differ in type of neurobehavioural impairments, direct evaluation of the impact of such impairments on activities of daily living ability reveals no difference between groups.

  • 885.
    Ängquist, Karl-Axel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Human skeletal muscle fibre structure: effects of physical training and arterial insufficiency1978Doctoral thesis, comprehensive summary (Other academic)
  • 886.
    Ågren Wilsson, A
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Roslin, M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Koskinen, LO
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bergenheim, AT
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Malm, J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Intracerebral microdialysis and CSF hydrodynamics in idiopathic adult hydrocephalus syndrome2003In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 74, no 2, p. 217-221Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In idiopathic adult hydrocephalus syndrome (IAHS), a pathophysiological model of "chronic ischaemia" caused by an arteriosclerotic process in association with a CSF hydrodynamic disturbance has been proposed. OBJECTIVE: To investigate whether CSF hydrodynamic manipulation has an impact on biochemical markers related to ischaemia, brain tissue oxygen tension (PtiO(2)), and intracranial pressure. METHODS: A microdialysis catheter, a PtiO(2) probe, and an intracerebral pressure catheter were inserted into the periventricular white matter 0-7 mm from the right frontal horn in 10 patients with IAHS. A subcutaneous microdialysis probe was used as reference. Intracranial pressure and intracerebral PtiO(2) were recorded continuously. Samples were collected for analysis between 2 and 4 pm on day 1 (baseline) and at the same time on day 2, two to four hours after a lumbar CSF hydrodynamic manipulation. The concentrations of glucose, lactate, pyruvate, and glutamate on day 1 and 2 were compared. RESULTS: After CSF drainage, there was a significant rise in the intracerebral concentration of lactate and pyruvate. The lactate to pyruvate ratio was increased and remained unchanged after drainage. There was a trend towards a lowering of glucose and glutamate. Mean intracerebral PtiO(2) was higher on day 2 than on day 1 in six of eight patients. CONCLUSIONS: There is increased glucose metabolism after CSF drainage, as expected in a situation of postischaemic recovery. These new invasive techniques are promising tools in the future study of the pathophysiological processes in IAHS.

  • 887.
    Ågren-Wilsson, A
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Lekman, A
    Sjöberg, W
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Rosengren, L
    Blennow, K
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus2007In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 116, no 5, p. 333-339Article in journal (Refereed)
    Abstract [en]

    BACKGROUND To evaluate cerebrospinal fluid (CSF) markers for neuronal degeneration and demyelination in idiopathic normal pressure hydrocephalus (INPH), subcortical arteriosclerotic encephalopathy (SAE), and neurologically healthy subjects.

    METHODS Lumbar CSF concentrations of sulfatide, neurofilament protein light (NFL), total-tau (T-tau), hyperphosphorylated tau (P-tau), and beta-amyloid(1-42) (Abeta42) were analyzed in 62 INPH patients, 26 SAE patients, and 23 neurologically healthy controls. In INPH patients, samples before and after shunt surgery were analysed.

    RESULTS The CSF concentration of NFL was elevated in INPH and SAE compared with the controls, and levels of T-tau, P-tau, and Abeta42 were lower in INPH compared with SAE and controls. No difference was seen for sulfatide. All markers except Abeta42 were significantly elevated after shunt surgery.

    CONCLUSIONS The most striking finding was the power of the combined pattern of NFL, P-tau, and Abeta42 in distinguishing between the clinical diagnoses of INPH, SAE, and neurologically healthy elderly.

  • 888.
    Ågren-Wilsson, Aina
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Koskinen, L-O D
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brain energy metabolism and intracranial pressure in idiopathic adult hydrocephalus syndrome2005In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 76, no 8, p. 1088-1093Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The symptoms in idiopathic adult hydrocephalus syndrome (IAHS) are consistent with pathology involving the periventricular white matter, presumably reflecting ischaemia and CSF hydrodynamic disturbance. OBJECTIVE: To investigate whether a change in intracranial pressure (ICP) can affect energy metabolism in deep white matter. METHODS: A microdialysis catheter, a brain tissue oxygen tension probe, and an ICP transducer were inserted into the periventricular white matter 0-7 mm from the right frontal horn in 10 patients with IAHS. ICP and intracerebral Ptio2 were recorded continuously during lumbar CSF constant pressure infusion test. ICP was raised to pressure levels of 35 and 45 mm Hg for 10 minutes each, after which CSF drainage was undertaken. Microdialysis samples were collected every three minutes and analysed for glucose, lactate, pyruvate, and glutamate. RESULTS: When raising the ICP, a reversible drop in the extracellular concentrations of glucose, lactate, and pyruvate was found. Comparing the values during baseline to values at the highest pressure level, the fall in glucose, lactate, and pyruvate was significant (p < 0.05, Wilcoxon sign rank). There was no change in glutamate or the lactate to pyruvate ratio during ICP elevation. Ptio2 did not decrease during ICP elevation, but was significantly increased following CSF drainage. CONCLUSIONS: Raising intracranial pressure induces an immediate and reversible change in energy metabolism in periventricular white matter, without any sign of ischaemia. Theoretically, frequent ICP peaks (B waves) over a long period could eventually cause persisting axonal disturbance and subsequently the symptoms noted in IAHS.

  • 889. Åkerstedt, Torbjörn
    et al.
    Nordin, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Alfredsson, Lars
    Westerholm, Peter
    Kecklund, Göran
    Predicting changes in sleep complaints from baseline values and changes in work demands, work control, and work preoccupation - The WOLF-project2012In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 13, no 1, p. 73-80Article in journal (Refereed)
    Abstract [en]

    Study objective: Stress as a cause of disturbed sleep is often taken for granted, but the longitudinal evidence is limited. The aim of this study was to evaluate new cases of poor sleep as a function of changes in reported work demands, work control, and work preoccupation. Methods: Longitudinal study of change with measures occurring twice within a 5-year interval during a period when the prevalence of impaired sleep was increasing in Sweden. The sample of companies was taken from northern Sweden (Norrland) and included 3637 individuals from the "WOLF Norrland" longitudinal cohort, collected through company health services. Measurement and results: During the measurement period, 16% of those studied developed new cases of impaired sleep. Logistic regressions adjusted for demographics, work environment factors, and disturbed sleep at T1 period one showed a significant increase in new cases for high work demands and high work preoccupation (OR = 1.37; Ci = 1.09-1.72 and OR = 1.80; CI = 1.42-2.28, respectively). The analysis of change in the predictors showed effects of a change from low to high work demands (OR = 1.39; Ci = 1.00-1.95) on new cases of impaired sleep. Consistent high work demands (high at both points) showed a similar increase (OR = 1.49; Ci = 1.06-2.11) but no effect was seen for reduced demands. Change in work preoccupation yielded stronger effects with OR = 2.47 (1.78-2.47) for increased work preoccupation and OR = 3.79 (2.70-5.31) for consistent high work preoccupation. Also, a reduction in work preoccupation was associated with a reduction in new cases of disturbed sleep. Control at work was not related to sleep. Stratification with respect to gender mainly led to fewer significant results (particularly for women) due to larger confidence intervals. Conclusions: It was concluded that self-reported work preoccupation predicts subsequent impairment of sleep and that increased preoccupation is associated with new cases of impaired sleep. Similar, but weaker, results were obtained for work demands. (C) 2011 Elsevier B.V. All rights reserved.

  • 890.
    Åsberg, Signild
    et al.
    Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Henriksson, Karin M
    Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden; AstraZeneca R&D, Mölndal, Sweden.
    Terént, Andreas
    Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden.
    Warfarin-Associated Intracerebral Hemorrhage After Ischemic Stroke2014In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 45, no 7, p. 2118-2120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: The aim was to investigate the risk of intracerebral hemorrhage (ICH) in patients with ischemic stroke taking warfarin and whether this risk changed over time.

    METHODS: Between 2001 and 2008, the Swedish Stroke Register registered 12 790 patients with ischemic stroke discharged on warfarin. The patients was studied in two 4-year periods (inclusion 2001-2004: follow-up until 2005 and inclusion 2005-2008: follow-up until 2009) for which rates of subsequent ICH were calculated. Adjusted hazard ratios, comparing the second period with the first period, were estimated in Cox regression models.

    RESULTS: Of 6039 patients, 58 patients (1.0%) in the first period and 69 of 6751 patients (1.0%) in the second period had subsequent ICH. Annual rates of ICH ranged from 0.37% in the first period to 0.39% in the second period (adjusted hazard ratio, 1.04; 95% confidence interval, 0.73-1.48).

    CONCLUSIONS: In this nationwide study, the risk of warfarin-associated ICH among ischemic stroke patients was low and did not change during the 2000s.

  • 891. Åström, Mattias
    et al.
    Tripoliti, Elina
    Martinez-Torres, Irene
    Zrinzo, Ludvic U
    Limousin, Patricia
    Hariz, Marwan I
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Wårdell, Karin
    Patient-specific models and simulations of deep brain stimulation for postoperative follow-up2009In: World Congress on Medical Physics and Biomedical Engineering September 7 - 12, 2009 Munich, Germany: Vol. 25/9 Neuroengineering, Neural Systems, Rehabilitation and Prosthetics / [ed] Dössel, Olaf; Schlegel, Wolfgang C., Springer , 2009, p. 331-334Conference paper (Other academic)
  • 892.
    Ögren, Joachim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Serious hemorrhage and secondary prevention after stroke and TIA2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: The number of stroke survivors is growing worldwide, and these patients have an increased risk of new vascular events and death. This risk decreases with secondary treatment medications recommended in guidelines. However, the characteristics of unselected stroke patients differ from patients included in randomized controlled trials (RCTs). Thus, the efficacy of these treatments based on RCT results may not be directly transferable to the patients treated in clinical practice. A treatment may be associated with a higher risk of serious side-effects or less benefit than expected:1) Antithrombotic treatment increases the risk of a serious hemorrhage, a risk that is not well studied in an unselected population with older age and more comorbidities; 2) Treatment of modifiable risk factors after a stroke can be improved. Many patients do not reach treatment targets, which indicates a need for strategies to improve secondary prevention and increase treatment benefit.It is therefore essential to evaluate recommended treatments through studies in a real-world setting.

    Aims: The aims of this thesis were to assessincidence, temporal trends, effect on mortality, and factors associated with an increased risk of a serious hemorrhage after ischemic stroke (IS) or transient ischemic attack (TIA); andif a nurse-led, telephone-based intervention including medical titration could improve modifiable risk factors in patients after stroke or TIA.

    Methods: In paper I, all patients registered with an IS in the national stroke register Riksstroke during 1998–2009 were studied. The register was combined with the In-Patient Register and a diagnosis of intracranial haemorrhage (ICrH) within 1 year after IS was identified. In paper II, any diagnosis of serious hemorrhage was identified during follow-up up to 2015 in all patients with an IS or TIA diagnosis, 2010–2013, at Östersund hospital. The incidences of ICrH (papers I and II) and all serious hemorrhages (paper II) were calculated. Kaplan–Meier analysis was used to assess any temporal trend in paper I and if a serious hemorrhage affected survival in study II. Cox regression analysis was used in both studies I and II to assess any factor associated with hemorrhage.

    In the randomized controlled NAILED stroke trial, all patients with acute stroke or TIA treated at Östersund hospital during 2010–2013 were screened for participation. Patients whose condition permitted a telephone-based follow-up were randomized to either a control group with follow-up according to usual care or to an intervention group with a nurse-led, telephone-based follow-up including titration of medication. Blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) were assessed at 1, 12, 24, and 36 months. We assessed the effect of the intervention on mean levels of BP and LDL-C and on the proportion of patients reaching treatment targets at 12 months (Study III) and at 36 months (Study IV). Study III also assessed for interactions between group allocation and measurement levels at baseline with BP and LDL-C at the 12-month follow-up. Study IV also explored temporal trends.

    Results: The risk of an ICrH was 1.97% per year at risk, within the first year after IS,  and 0.85% excluding the first 30 days. Between 1998 and 2009, the risk of an ICrH increased during the first 30 days after an IS but decreased during days 31–365. The risk of a serious hemorrhage was 2.48% per year at risk in paper II. It was more common in elderly. The incidence rate was higher in patients discharged with AP compared with RCTs. A hemorrhage increased the risk of death in patients with good functional status but did not affect the already high mortality in patients with impaired functional status. Male sex and previous ICrH were associated with an increased risk of ICrH during the first year after IS, thrombolytic treatment, atrial fibrillation and warfarin were associated with an increased risk in the acute phase. A previous diagnosis of hypertension was associated with an increased risk of all serious hemorrhages. 

    The NAILED trial intervention group had a significantly lower mean systolic BP (SBP), diastolic BP (DBP), and LDL-C at 12 and 36 months. The mean SBP at 36 months was 128.1 mmHg (95% confidence interval (CI): 125.8–130.5) in the intervention group, 6.1 mmHg (95% CI: 3.6–8.6; p<0.001) lower than the control group. The interaction analysis at 12 months showed that the effect of the intervention was confined to patients whose values were above the respective targets at baseline and therefore had their medication adjusted. At 36 months, a significantly higher proportion of patients in the intervention group reached treatment targets for SBP, DBP, and LDL-C. The mean differences and differences in proportions reaching treatment target for BP increased during the 36 months of follow-up.

    Conclusion: A serious hemorrhage after an IS or TIA is fairly common. It is more common in elderly and patients with impaired functional status. The incidence is higher in patients discharged with AP compared with RCTs. A serious hemorrhage could affect survival in patients with good functional status. The nurse-led, telephone-based intervention including medical titration used in the NAILED stroke trial improved risk factor levels after stroke and TIA, and more patients reached treatment targets. The effect increased over time. 

  • 893.
    Ögren, Joachim
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Irewall, Anna-Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Söderström, Lars
    Mooe, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Long-term, telephone-based follow-up after stroke and TIA improves risk factors: 36-month results from the randomized controlled NAILED stroke risk factor trial2018In: BMC Neurology, ISSN 1471-2377, E-ISSN 1471-2377, Vol. 18, article id 153Article in journal (Refereed)
    Abstract [en]

    Background: Strategies are needed to improve adherence to the blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) level recommendations after stroke and transient ischemic attack (TIA). We investigated whether nurse-led, telephone-based follow-up that included medication titration was more efficient than usual care in improving BP and LDL-C levels 36 months after discharge following stroke or TIA.

    Methods: All patients admitted for stroke or TIA at Ostersund hospital that could participate in the telephone-based follow-up were considered eligible. Participants were randomized to either nurse-led, telephone-based follow-up (intervention) or usual care (control). BP and LDL-C were measured one month after discharge and yearly thereafter. Intervention group patients who did not meet the target values received additional follow-up, including lifestyle counselling and medication titration, to reach their treatment goals (BP < 140/90 mmHg, LDL-C < 2.5 mmol/L). The primary outcome was the systolic BP level 36 months after discharge.

    Results: Out of 871 randomized patients, 660 completed the 36-month follow-up. The mean systolic and diastolic BP values in the intervention group were 128.1 mmHg (95% CI 125.8-1305) and 75.3 mmHg (95% CI 73.8-76.9), respectively. This was 6.1 mmHg (95% CI 3.6-8.6, p < 0.001) and 3.4 mmHg (95% CI 1.8-5.1, p < 0.001) lower than in the control group. The mean LDL-C level was 22 mmol/L in the intervention group, which was 03 mmol/L (95% CI 0.2-0.5, p < 0.001) lower than in controls. A larger proportion of the intervention group reached the treatment goal for BP (systolic: 79.4% vs. 55.3%, p < 0.001; diastolic 90.3% vs. 77.9%, p < 0.001) as well as for LDL-C (69.3% vs. 48.9%, p < 0.001).

    Conclusions: Compared with usual care, a nurse-led telephone-based intervention that included medication titration after stroke or TIA improved BP and LDL-C levels and increased the proportion of patients that reached the treatment target 36 months after discharge.

  • 894.
    Ögren, Joachim
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Irewall, Anna-Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Söderström, Lars
    Mooe, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Serious hemorrhages after ischemic stroke or TIA - Incidence, mortality, and predictors2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195324Article in journal (Refereed)
    Abstract [en]

    Background: Data are lacking on the risk and impact of a serious hemorrhage on the prognosis after ischemic stroke (IS) or transient ischemic attack (TIA). We aimed to estimate the incidence of serious hemorrhage, analyze the impact on mortality, and identify predictors of hemorrhage after discharge from IS or TIA.

    Methods and findings: All patients admitted to Östersund Hospital for an IS or TIA in 2010–2013 were included (n = 1528, mean age: 75.1 years). Serious hemorrhages were identified until 31st December 2015. Incidence rates were calculated. The impact on mortality (stratified by functional level) was determined with Kaplan-Meier analysis. Non-parametric estimation under the assumption of competing risk was performed to assess the cumulative incidence and predictors of serious hemorrhages. The incidence rates of serious (n = 113) and intracranial hemorrhages (n = 45) after discharge from IS and TIA were 2.48% and 0.96% per year at risk, respectively. Patients with modified Rankin Scale (mRS) scores of 3–5 exhibited 58.9% mortality during follow-up and those with mRS scores of 0–2 exhibited 18.4% mortality. A serious hemorrhage did not affect mortality in patients with impaired functional status, but it increased the risk of death in patients with mRS scores of 0–2. Hypertension was associated with increased risk of serious hemorrhage.

    Conclusions: We found that, after discharge from an IS or TIA, serious hemorrhages were fairly common. Impairments in function were associated with high mortality, but serious hemorrhages only increased the risk of mortality in patients with no or slight disability. Improved hypertension treatment may decrease the risk of serious hemorrhage, but in patients with low functional status, poor survival makes secondary prevention challenging.

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