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Herman, S., Niemelä, V., Emami Khoonsari, P., Sundblom, J., Burman, J., Landtblom, A.-M., . . . Kultima, K. (2019). Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects. Scientific Reports, 9, Article ID 4129.
Open this publication in new window or tab >>Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4129Article in journal (Refereed) Published
Abstract [en]

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-379886 (URN)10.1038/s41598-019-40186-5 (DOI)000460754600020 ()30858393 (PubMedID)
Funder
Åke Wiberg FoundationEU, Horizon 2020, 654241
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-10-23Bibliographically approved
Elf, K., Ronne-Engström, E., Semnic, R., Rostami-Berglund, E., Sundblom, J. & Zetterling, M. (2019). Continuous EEG monitoring after brain tumor surgery. Acta Neurochirurgica, 161(9), 1835-1843
Open this publication in new window or tab >>Continuous EEG monitoring after brain tumor surgery
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2019 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 9, p. 1835-1843Article in journal (Refereed) Published
Abstract [en]

Background

Prolonged seizures generate cerebral hypoxia and increased intracranial pressure, resulting in an increased risk of neurological deterioration, increased long-term morbidity, and shorter survival. Seizures should be recognized early and treated promptly.

The aim of the study was to investigate the occurrence of postoperative seizures in patients undergoing craniotomy for primary brain tumors and to determine if non-convulsive seizures could explain some of the postoperative neurological deterioration that may occur after surgery.

Methods

A single-center prospective study of 100 patients with suspected glioma. Participants were studied with EEG and video recording for at least 24 h after surgery.

Results

Seven patients (7%) displayed seizure activity on EEG recording within 24 h after surgery and another two patients (2%) developed late seizures. One of the patients with early seizures also developed late seizures. In five patients (5%), there were non-convulsive seizures. Four of these patients had a combination of clinically overt and non-convulsive seizures and in one patient, all seizures were non-convulsive. The non-convulsive seizures accounted for the majority of total seizure time in those patients. Non-convulsive seizures could not explain six cases of unexpected postoperative neurological deterioration. Postoperative ischemic lesions were more common in patients with early postoperative seizures.

Conclusions

Early seizures, including non-convulsive, occurred in 7% of our patients. Within this group, non-convulsive seizure activity had longer durations than clinically overt seizures, but only 1% of patients had exclusively non-convulsive seizures. Seizures were not associated with unexpected neurological deterioration.

Keywords
Brain tumor surgery, Postoperative seizures, Non-convulsive seizures, EEG monitoring
National Category
Neurosciences Neurology Surgery
Identifiers
urn:nbn:se:uu:diva-394255 (URN)10.1007/s00701-019-03982-6 (DOI)000482453900014 ()31278599 (PubMedID)
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2019-10-11Bibliographically approved
Sundblom, J., Gallinetti, S., Birgersson, U., Engqvist, H. & Kihlström, L. (2019). Gentamicin loading of calcium phosphate implants: implications for cranioplasty. Acta Neurochirurgica, 161(6), 1255-1259
Open this publication in new window or tab >>Gentamicin loading of calcium phosphate implants: implications for cranioplasty
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2019 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 6, p. 1255-1259Article in journal (Refereed) Published
Abstract [en]

BackgroundSurgical site infections (SSI) are a significant risk in cranioplasty, with reported rates of around 8-9%. The most common bacteria associated with these nosocomial infections are of the Staphylococcus species, which have the ability to form biofilm. The possibility to deliver antibiotics, such as gentamicin, locally rather than systemically could potentially lower the early postoperative SSI. Various antibiotic dosages are being applied clinically, without any true consensus on the effectiveness.MethodsDrug release from calcium phosphate (CaP), polyetheretherketone (PEEK), and titanium (Ti) samples was evaluated. Microbiological studies with Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE) including strains from clinical infection were used to establish clinically relevant concentrations.ResultsThe CaP samples were able to retain and release gentamicin overtime, whereas the Ti and PEEK samples did not show any drug uptake or release. A gentamicin loading concentration of 400g/ml was shown to be effective in in vitro microbiological studies with both SA and SE.ConclusionsOut of the three materials studied, only CaP could be loaded with gentamicin. An initial loading concentration of 400g/ml appears to establish an effective gentamicin concentration, possibly translating into a clinical benefit in cranioplasty.

Place, publisher, year, edition, pages
SPRINGER WIEN, 2019
Keywords
Gentamicin, Calcium phosphate, Titanium, PEEK, Staphylococcus, Uptake-release
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-385970 (URN)10.1007/s00701-019-03895-4 (DOI)000468224800029 ()31041594 (PubMedID)
Available from: 2019-06-18 Created: 2019-06-18 Last updated: 2019-06-18Bibliographically approved
Braisch, U., Ekwall, C., Sundblom, J. & Coleman, A. (2019). Identification of symbol digit modality test score extremes in Huntington's disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 180(3), 232-245
Open this publication in new window or tab >>Identification of symbol digit modality test score extremes in Huntington's disease
2019 (English)In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 180, no 3, p. 232-245Article in journal (Refereed) Published
Abstract [en]

Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Disease Rating Scale (UHDRS) in predicting clinical endpoints. The language-independent SDMT was used to identify patients performing very well or very poorly relative to their CAG and age cohort. We used data from REGISTRY and COHORT observational study participants (5,603 HD participants with CAG repeats above 39 with 13,868 visits) and of 1,006 healthy volunteers (with 2,241 visits), included to identify natural aging and education effects on cognitive measures. Separate Cox proportional hazards models with CAG, age at study entry, education, sex, UHDRS total motor score and cognitive (SDMT, verbal fluency, Stroop tests) scores as covariates were used to predict clinical endpoints. Quantile regression for longitudinal language-independent SDMT data was used for boundary (2.5% and 97.5% quantiles) estimation and extreme score analyses stratified by age, education, and CAG repeat length. Ten percent of HD participants had an extreme SDMT phenotype for at least one visit. In contrast, only about 3% of participants were consistent SDMT extremes at two or more visits. The thresholds for the one-visit and two-visit extremes can be used to classify existing and new individuals. The identification of these phenotype extremes can be useful in the search for disease modifiers.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
COHORT, Cox hazard model, quantile regression, REGISTRY, symbol digit modalities test
National Category
Neurology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-380420 (URN)10.1002/ajmg.b.32719 (DOI)000461018900006 ()30788902 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1002/ajmg.b.32719

Available from: 2019-04-01 Created: 2019-04-01 Last updated: 2019-04-01Bibliographically approved
Sundblom, J., Nowinski, D., Casar Borota, O. & Ryttlefors, M. (2019). Removal of giant intraosseous meningioma followed by cranioplasty using a custom-made bioceramic implant: case report. Journal of Neurosurgery, 131(3), 735-739
Open this publication in new window or tab >>Removal of giant intraosseous meningioma followed by cranioplasty using a custom-made bioceramic implant: case report
2019 (English)In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 131, no 3, p. 735-739Article in journal (Refereed) Published
Abstract [en]

Intraosseous meningioma of the chordoid type is a rare clinical entity. Radical surgical removal and subsequent cranioplasty is the treatment of choice. Here, the authors report a severe case involving more than 70% of the calvarial surface area, which was removed and repaired using a prefabricated custom-made, titanium-reinforced, bioceramic implant and bone-cutting guides. Tumor removal and good esthetic outcome were achieved, along with a 17.1% increase of intracranial volume. Bioceramic implants have shown promising initial results and may represent an important new tool in the surgeon's armamentarium.

Keywords
bioceramic implant, cranioplasty, intraosseous, meningioma, oncology
National Category
Surgery Clinical Laboratory Medicine
Research subject
Neurosurgery; Pathology
Identifiers
urn:nbn:se:uu:diva-368475 (URN)10.3171/2018.4.JNS1850 (DOI)000484026100009 ()30215553 (PubMedID)
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2020-01-08Bibliographically approved
Niemelä, V., Burman, J., Blennow, K., Zetterberg, H., Larsson, A. & Sundblom, J. (2018). Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease. PLoS ONE, 13(2), Article ID e0193492.
Open this publication in new window or tab >>Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0193492Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need further clarification.

METHODS: A clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau).

RESULTS: 52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age-adjustment.

CONCLUSION: Increased sCD27 in premanifest HD is a sign of T cell-mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-342996 (URN)10.1371/journal.pone.0193492 (DOI)000426049500119 ()29474427 (PubMedID)
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2019-10-23Bibliographically approved
Oosterloo, M., Bijlsma, E. K., van Kuijk, S. M., Minkels, F. & de Die-Smulders, C. E. (2018). Clinical and genetic characteristics of late-onset Huntington's disease.. Parkinsonism & Related Disorders, Article ID S1353-8020(18)30490-5.
Open this publication in new window or tab >>Clinical and genetic characteristics of late-onset Huntington's disease.
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2018 (English)In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, article id S1353-8020(18)30490-5Article in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive.

OBJECTIVE: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database.

METHODS: Participants with late- and common-onset (30-50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded.

RESULTS: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P < .001). Overall motor and cognitive performance (P < .001) were worse, however only disease motor progression was slower (coefficient, -0.58; SE 0.16; P < .001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P < .001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P < .001).

CONCLUSIONS: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients.

Keywords
Age of onset, Huntington's disease, Late-onset Huntington's disease
National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-375410 (URN)10.1016/j.parkreldis.2018.11.009 (DOI)30528461 (PubMedID)
Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-01-29
McNulty, P., Pilcher, R., Ramesh, R., Necuiniate, R., Hughes, A., Farewell, D., . . . Jones, L. (2018). Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study.. Journal of Huntington's disease, 7(3), 209-222
Open this publication in new window or tab >>Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study.
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2018 (English)In: Journal of Huntington's disease, ISSN 1879-6400, Vol. 7, no 3, p. 209-222Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: People with Huntington's disease (HD) have been observed to have lower rates of cancers.

OBJECTIVE: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis.

METHODS: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects.

RESULTS: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001).

CONCLUSIONS: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis.

Keywords
Huntington’s disease, cancer, neurodegeneration, trinucleotide repeat
National Category
Cancer and Oncology Nursing
Identifiers
urn:nbn:se:uu:diva-375413 (URN)10.3233/JHD-170263 (DOI)30103338 (PubMedID)
Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2020-02-28Bibliographically approved
Niemelä, V., Landtblom, A.-M., Blennow, K. & Sundblom, J. (2017). Tau or neurofilament light - Which is the more suitable biomarker for Huntington’s disease?. PLoS ONE, 12(2), Article ID e0172762.
Open this publication in new window or tab >>Tau or neurofilament light - Which is the more suitable biomarker for Huntington’s disease?
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0172762Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Previous studies have suggested cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and total tau are elevated in Huntington's disease (HD) and may be used as markers of disease stage. Biomarkers are needed due to the slow disease progression and the limitations of clinical assessment. This study aims to validate the role of NFL and tau as biomarkers in HD.

METHODS: CSF was obtained from a cohort of HD patients and premanifest HD-mutation carriers. Unified Huntington's Disease Rating Scale (UHDRS) testing was performed on all subjects at the time of sampling. NFL and tau concentrations were determined by ELISA. Spearman correlations were calculated with R version 3.2.3.

RESULTS: 11 premanifest HD and 12 manifest HD subjects were enrolled. NFL and tau levels were correlated. NFL showed strong correlations with all items included in the clinical assessment (for example the total functional capacity (TFC) (r = - 0.70 p < 0.01) and total motor score (TMS) (r = 0.83p < 0.01). Tau showed slightly weaker correlations (eg. TMS (r = 0.67 p < 0.01); TFC (r = - 0.59 p < 0.01)). NFL was significantly correlated with 5-year probability of disease onset, whereas tau was not.

CONCLUSION: This study strengthens the case for NFL as a useful biomarker of disease stage. NFL was strongly correlated to all evaluated items in the UHDRS assessment. Tau also has a potential for use as a biomarker but correlations to clinical tests are weaker in this study. We suggest that NFL and possibly tau be used in clinical drug trials as biomarkers of disease progression that are potentially influenced by future disease-modifying therapies.

Keywords
Huntingtons disease
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-317298 (URN)10.1371/journal.pone.0172762 (DOI)000395934400040 ()28241046 (PubMedID)
Projects
https://www.researchgate.net/project/Mapping-the-Huntingtons-disease-process-by-analyses-of-cerebrospinal-fluid
Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2019-10-23Bibliographically approved
Bartley, A., Jakola, A. S., Bartek, J. J., Sundblom, J., Förander, P., Marklund, N. & Tisell, M. (2017). The Swedish study of Irrigation-fluid temperature in the evacuation of Chronic subdural hematoma (SIC!): study protocol for a multicenter randomized controlled trial. Trials, 18, Article ID 471.
Open this publication in new window or tab >>The Swedish study of Irrigation-fluid temperature in the evacuation of Chronic subdural hematoma (SIC!): study protocol for a multicenter randomized controlled trial
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2017 (English)In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 18, article id 471Article in journal (Refereed) Published
Abstract [en]

Background: Chronic subdural hematoma (cSDH) is one of the most common conditions encountered in neurosurgical practice. Recurrence, observed in 5-30% of patients, is a major clinical problem. The temperature of the irrigation fluid used during evacuation of the hematoma might theoretically influence recurrence rates since irrigation fluid at body temperature (37 degrees C) may beneficially influence coagulation and cSDH solubility when compared to irrigation fluid at room temperature. Should no difference in recurrence rates be observed when comparing irrigation-fluid temperatures, there is no need for warmed fluids during surgery. Our main aim is to investigate the effect of irrigation-fluid temperature on recurrence rates and clinical outcomes after cSDH evacuation using a multicenter randomized controlled trial design.

Methods: The study will be conducted in three neurosurgical departments with population-based catchment areas using a similar surgical strategy. In total, 600 patients fulfilling the inclusion criteria will randomly be assigned to either intraoperative irrigation with fluid at body temperature or room temperature. The power calculation is based on a retrospective study performed at our department showing a recurrence rate of 5% versus 12% when comparing irrigation fluid at body temperature versus fluid at room temperature (unpublished data). The primary endpoint is recurrence rate of cSDH analyzed at 6 months post treatment. Secondary endpoints are mortality rate, complications and health-related quality of life.

Discussion: Irrigation-fluid temperature might influence recurrence rates in the evacuation of chronic subdural hematomas. We present a study protocol for a multicenter randomized controlled trial investigating our hypothesis that irrigation fluid at body temperature is superior to room temperature in reducing recurrence rates following evacuation of cSDH.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keywords
Chronic subdural hematoma, Surgical evacuation, Recurrence, Irrigation fluid, Temperature
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-338514 (URN)10.1186/s13063-017-2194-y (DOI)000412904300001 ()29021000 (PubMedID)
Funder
Region Västra Götaland
Available from: 2018-01-15 Created: 2018-01-15 Last updated: 2018-01-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5105-0508

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